Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:12][C@@:13]1([C:32](NC(C)(C)C)=[O:33])[CH2:17][C@@H:16]([CH2:18][NH2:19])[CH2:15][C@@H:14]1[CH2:20][CH2:21][CH2:22][B:23]1[O:27]C(C)(C)C(C)(C)[O:24]1)(=O)C.[BH4-].[Na+].C[OH:42]>C(O)(=O)C.O>[NH2:12][C@@:13]1([C:32]([OH:33])=[O:42])[CH2:17][C@@H:16]([CH2:18][NH:19][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][C@@H:14]1[CH2:20][CH2:21][CH2:22][B:23]([OH:24])[OH:27]
Reactant: CO
Reactant: O=Cc1ccccc1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)C[C@@H](CN)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N[C@@]1(C(=O)O)C[C@@H](CNCc2ccccc2)C[C@@H]1CCCB(O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirring solution of benzaldehyde (43 mg, 0.40 mmol) in methanol (3.5 mL) was added (1S,2S,4S)-1-acetamido-4-(aminomethyl)-N-(tert-butyl)-2-(3-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)propyl)cyclopentanecarboxamide (148 mg, 0.35 mmol) and glacial acetic acid (one drop). The reaction mixture was stirred at 50° C. for 1 h, then cooled using an ice bath prior to adding sodium borohydride (17 mg, 0.45 mmol). After stirring for an additional hour (1 h) at 3° C., the reaction was allowed to warm to room temperature, and stirred for another 20 minutes. Following quenching of the reaction with water (1 mL)., the crude product mixture was treated with a 2:1:1 mixture of concentrated HCl:glacial acetic acid:water (8 mL) in a pressure bottle, stirred for 2 h at 60° C., and then capped and stirred for an additional 18 h at 130° C. The reaction mixture was then cooled to room temperature prior to uncapping of the pressure bottle. The crude mixture was diluted with water (20 mL), extracted with methylene chloride (20 mL) and concentrated in vacuo. The residue obtained was treated with water (20 mL) and concentrated three times to remove excess HCl. The crude reaction mixture was then dissolved in water (40 mL) and treated with DOWEX® 550A-OH resin (3 g) which had been rinsed with methanol prior to use. After stirring for 40 min, the reaction mixture was filtered and the resin washed successively with water, methanol and methylene chloride twice. Following washing, the resin was stirred with 1N HCl (15 mL×4) and filtered. The combined filtrates were concentrated and the residue was treated with water (20 mL) followed by concentration of the aqueous mixture three times to remove excess HCl. Purification of the crude product by HPLC followed by formation of the hydrochloride salt afforded the subject compound (71.4 mg, 50%) as a hygroscopic white foam. NMR (D2O) δ 7.40 (br s, 5 H), 4.17 (br s, 2 H), 3.02 (d, J=5.5 Hz, 2 H), 2.70 (m, 1 H), 2.51 (m, 1 H), 2.15 (m, 1 H), 1.80 (m, 2 H), 1.55 (m, 1 H), 1.30-1.45 (m, 2 H), 1.20 (m, 1 H), 1.05 (m, 1 H), 0.60-0.75 (m, 2 H). MS (M+1): 335.5; MS (M−H2O+1): 317.4; MS (M−2H2O+1): 299.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@@H:11]([CH:13]=[CH2:14])[C@H:10]([O:15][Si](CC)(CC)CC)[C:9]=2[CH3:23])=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>C1COCC1>[CH3:23][C:9]1[C@@H:10]([OH:15])[C@H:11]([CH:13]=[CH2:14])[CH2:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: C=C[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of compound 31b (50 mg, 0.152 mmol) in THF (1 ml) at 0° C. was added tetrabutylammonium fluoride (0.152 ml of 1 M solution in THF, 0.152 mmol) dropwise. The reaction mixture was stirred at 0° C. for 30 min and water (1 ml) and ethyl acetate (2 ml) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×2 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica (16-50% EtOAc/hexanes) afforded pure alcohol 5b (28 mg, 83%) as a white solid: [α]22D=−26.0 (c=0.3, CHCl3); TLC Rf=0.25 (silica gel, 50% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.43 (s, 1H), 7.46 (dd, J=1.8 Hz, 7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.0-5.95 (m, 1H), 5.14 (d, J=16.8 Hz, 1H), 5.08 (d, J=10.2 Hz, 1H), 4.48 (s, 1H), 2.96-2.91 (m, 1H), 2.69-2.60 (m, 2H), 2.32 (s, 3H), 2.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.6, 149.9, 140.2, 139.4, 136.7, 135.6, 131.2, 122.3, 115.4, 86.4, 52.3, 38.5, 18.5, 13.2; HRMS calcd for C14H17NO+Na+ 238.1208; found 238.1191 [M+Na+].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1)(=[O:33])=[O:34].[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCC(=O)O
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: Cl
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc2c2cc[nH]c12
Yield: 38.9 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 46 mg (0.21 mmol) of naphthalene-2-sulfonyl chloride. After recrystallization from methanol, 36 mg (40%) of 8-(naphthalene-2-sulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a brown solid.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2nccs2)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
N-Boc-4-hydroxy-aniline (3.9 g, 0.019 mol) was combined with 2-bromothiazole (2.4 mL, 0.027 mol) in DMSO (20 mL) at room temperature. K2CO3 (3.9 g, 0.028 mol) was added and with rapid stirring, the reaction mixture was heated at about 140° C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into water (300 mL), extracted with ethyl acetate (2×) and the combined organics were dried over MgSO4. Decolorizing charcoal was added, stirred for 30 minutes and filtered through a plug of celite and silica (1:1) to obtain an amber filtrate. The solvent was removed by rotary evaporation and the residue was purified by flash column chromatography (ethyl acetate:hexanes; 5%-50% ethyl acetate gradient) to give the title compound (1.4 g, 4.8 mmol, 25%) MS (ESI APCI) m/z 293.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ 9.49 (s, 1H) 7.53 (d, J=9.0 Hz, 2H) 7.21-7.28 (m, 2H) 7.16-7.19 (m, 2H) 1.48 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=O)(=[O:3])[CH3:2].Cl>CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:6]=1[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCc1ccc(F)cc1NC(C)=O
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1cc(F)cc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in (4) above (42 gm) was dissolved into 100 ml of methanol. After the addition of 200 ml of 1N hydrochloric acid, the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated to 200 ml and, after acidifying with the addition of concentrated hydrochloric acid, extracted three times with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, and to the residue were added 100 ml of dichloromethane, then 17 gm of sodium carbonate and 12 ml of thionyl chloride. The mixture was heated under reflux for 2 hours, and then cooled to room temperature to remove insoluble substances by filtration. The filtrate was concentrated and 200 ml of 1,2-dichloromethane and 40 gm of aluminum chloride were added to the residue. The mixture was stirred for 3 hours at 70° C., then for 1 hour at 90° C. The reaction product was poured into ice-coled water and extracted with chloroform. The extract was washed with water, saturated sodium bicarbonate, and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform-ethyl acetate (7:3) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to obtain 17 gm of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)[CH3:2].[CH:8](C1NC=C(CC)C=1)=[O:9].OC1C=C(NC2C3=CC(C)=CN3N=CN=2)C=CC=1C>>[CH:8]([C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[CH2:1][CH3:2])=[O:9]
Reactant: CCc1c[nH]c(C=O)c1
Reactant: CCc1cc[nH]c1
Agent: Cc1cc2c(Nc3ccc(C)c(O)c3)ncnn2c1
Product: CCc1cc[nH]c1C=O

Procedure:
3-Ethylpyrrole was converted to a mixture of Compound A and 2-formyl-4-ethylpyrrole as described in the preparation of Compound A of Example 5. [M+H]+=124.1
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>ClCCl>[CH3:10][S:11]([O:1][CH2:2][CH2:3][C:4]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:13])=[O:12]
Reactant: OCCC1(O)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of 1-(2-hydroxyethyl)cyclopentanol (19 0 mg, 1.46 mmol) in dry dichloromethane (2 mL) was added methanesulfonyl chloride (200.3 mg, 1.75 mmol) dropwise at 0° C., followed by TEA (295 mg, 2.92 mmol). Then the mixture was stirred at room temperature 1 h. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product (50 mg, 31.1% yield), which was used without purification.
Reaction SMILES: [Cr+6].[Cr:2](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[C:13]([OH:16])(=[O:15])[CH3:14]>O>[C:13]([O-:16])(=[O:15])[CH3:14].[Cr+6:2].[C:13]([O-:16])(=[O:15])[CH3:14].[C:13]([O-:16])(=[O:15])[CH3:14].[C:13]([O-:16])(=[O:15])[CH3:14].[C:13]([O-:16])(=[O:15])[CH3:14].[C:13]([O-:16])(=[O:15])[CH3:14]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [K+]
Solvent: O
Product: CC(=O)[O-]

Procedure:
Chromium (VI) Micelle: Weighed 17 grams of potassium dichromate (K2CrO4), and added to a 4 liter beaker. Dissolved the contents of the beaker in 200 ml of distilled water and added 25 ml of glacial acetic acid to produce chromium (VI) acetate in solution. Added 100 grams of chrysotile asbestos (Union Carbide, high purity, grade 7), and diluted to 3.5 liters with distilled water. Added 400 ml of 1 N sodium hydroxide. Heated at 100° C. for 30 minutes. Allowed to cool and collected by the vacuum filtration using a Whatman #1 filter. A pale green product was obtained and allowed to air dry for 16 hours. The filter cake was dried at 330° F. for 90 minutes. The dry cake was fiberized by use of a blender at high speed for 1 minute. A sample of the product was completely dissolved for analysis by treatment with 20% by weight sodium peroxide at 850° C. Elemental analysis of the product is shown in Table I. HF insoluble matter increased to 45% compared to 8.6% for an untreated chrysotile sample as shown in Table II.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.CS(C1C=CC(N2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC2=O)=CC=1)(=O)=O.ClC(OC(C)C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([O:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(OC(=O)Cl)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1

Procedure:
Example 268 was prepared according to procedures described in Example 2 substituting tert-butyl 4-(5-chloro-1-(4-cyano-3-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate in Step A and substituting isopropyl chloroformate for 1,1,1-trifluoropropan-2-yl chloroformate in Step C except that the crude product was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2). 1H NMR (400 MHz, CDCl3) δ ppm 7.67-7.87 (m, 1H), 7.30-7.49 (m, 3H), 6.00 (s, 1H), 4.86-5.11 (m, 1H), 4.53-4.70 (m, 1H), 3.44-3.76 (m, 4H), 1.79-2.15 (m, 4H), 1.26 (s, 6H). MS (ESI) 434 (M+H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]2[CH:24]=[CH:23][N:22]3[N:25]=[CH:26][CH:27]=[C:21]3[N:20]=2)[CH:8]=1.[OH-:28].[Na+].Cl.[CH2:31](Cl)Cl>CN(C=O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]2[CH:24]=[CH:23][N:22]3[N:25]=[CH:26][C:27]([CH:31]=[O:28])=[C:21]3[N:20]=2)[CH:8]=1
Reactant: Oc1ccc(F)cc1[C@H]1CCCN1c1ccn2nccc2n1
Reactant: [OH-]
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)nc12
Yield: 80 %

Procedure:
After POCl3 (221 μL, 2.41 mmol) was added drop-wise to a DMF (4 mL) solution of (R)-4-fluoro-2-(1-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenol (600 mg, 2.01 mmol) at ambient temperature, the reaction was stirred for 5 minutes before NaOH (804 mg, 10.1 mmol) was introduced. The reaction was stirred for another 10 minutes before HCl (4 N dioxane, 3 mL) was added, followed by DCM (50 mL). After filtering through Celite®, the reaction was concentrated and purified by reverse-phase column chromatography, eluting with 0-70% acetonitrile/H2O to provide (R)-5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (524 mg, 80% yield) as beige solid. MS (apci) m/z=327.2 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[N:23]1([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([S:39]([C:30]4[CH:31]=[CH:32][C:33]5[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:29]=4)(=[O:41])=[O:40])[CH2:13][CH2:12]3)=[O:28])=[CH:22][CH:21]=2)[CH:27]=[N:26][N:25]=[N:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(-n3cnnn3)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O
Product: O=C(COc1ccc(-n2cnnn2)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
In a two neck round bottom flask 2-(4-(1H-tetrazol-1-yl)phenoxy)-1-(piperazine-1-yl)ethanone hydrochloride (compound 3, 0.882 mmoles, 0.286 g, 1 eq) and 2-naphthalene sulfonylchloride (0.882 mmoles, 0.2 g, 1 eq) were charged in DCM (20 mL). TEA (2.646 moles, 0.267 g, 3 eq) was added drop wise to the reaction mixture over a period of 10 min at 0° C. The resulting mixture was stirred for 3 h at room temperature and monitored by TLC. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (Silica gel 60-120, 3:7, Ethyl acetate/Hexane) to obtain the title compound (0.300 g, 71.09%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[Si:25]([O:32][CH2:33][CH2:34][CH:35]=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[BH3-]C#N.[Na+]>C(Cl)Cl.CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:35][CH2:34][CH2:33][O:32][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cccc(NCCCO[Si](C)(C)C(C)(C)C)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3.3 %

Procedure:
A mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (0.2 g, 6 mmol) and 3-(tert-butyldimethylsilyloxy)propionaldehyde (0.25 g, 13 mmol) in CH2Cl2 (10 mL) and MeOH (5 mL) was stirred at room temperature for 15 min and then NaCNBH3 (57 mg, 1.5 eq) was added. The reaction mixture was stirred at RT overnight and then concentrated under vacuo. The residue was purified by preparatory TLC to give 98 mg 3-(1-methylindol-3-yl)-4-[3-(3-tert-butyldimethylsilyloxypropylamino)phenyl]-1H-pyrrole-2,5-dione (32%) MS (LSIMS): (M+H)+ 490, MP: 58-65° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].[N+]([C:15]1[CH:16]=[C:17]([CH3:22])[N+:18]([O-:21])=[CH:19][CH:20]=1)([O-])=O>CN1CCCC1=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[CH:16]=2)=[CH:4][C:3]=1[F:9]
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: Oc1ccc(Br)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Br)c(F)c2)cc[n+]1[O-]
Temperature: 180 °C
Yield: 38.6 %

Procedure:
To a room temperature solution of 4-bromo-3-fluorophenol (6 g, 31.41 mmol) in N-methylpyrrolidone (20 ml) was added sodium hydride (1.34 g, 56 mmol, 60% in mineral oil) portionwise. After stirring for 10 minutes 4-nitro-2-picoline N-oxide (5.6 g, 36.12 mmol) was added. The reaction mixture was heated at 180° C. for 60 minutes under microwave irradiation. After cooling to room temperature the mixture was diluted with EtOAc (250 ml) and washed with water (250 ml). The solution was then extracted with additional EtOAc (2×150 ml) The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 13 (3.61 g, 39%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5](N)=[N:6][CH:7]=1.N(OCCC(C)C)=O.C[Si](C)(C)[Br:26].C(=O)(O)[O-].[Na+]>BrCBr.CCCCCCC>[Br:26][C:5]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: C[Si](C)(C)Br
Reactant: Nc1ncc(Br)nc1-c1ccc(Cl)cc1
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Solvent: CCCCCCC
Product: Clc1ccc(-c2nc(Br)cnc2Br)cc1
Temperature: 25 °C
Yield: 103.8 %

Procedure:
To a suspension of 12.00 g (0.033 mol) 5-bromo-3-(4-chloro-phenyl)-pyrazin-2-ylamine in 80 ml dibromomethane was added 5.93 g isoamyl nitrite. To the resulting mixture was added dropwise during ca 45 min a solution of 7.75 g trimethylbromosilane in 20 ml dibromomethane with stirring at ambient temperature. The mixture was stirred at room temperature for 2 h. To the resulting dark solution was added 100 ml of a 10% aqueous sodium bicarbonate. The phases were separated and the organic phase washed with brine. To the organic phase was added silica gel (ca. 100 g) and the solvent was removed under aspirator vacuum. The product was purified by chromatography with dichloromethane:heptane=1:3 to yield 11.93 g (79% yield) 2,5-dibromo-3-(4-chloro-phenyl)-pyrazine as white crystals melting at 123-125° C. and as a byproduct 0.300 g 5-bromo-3-(4-chloro-phenyl)-2-(3-methyl-butoxy)-pyrazine as a yellow oil. MS (ISP) (M+H+)=357.0 and 355.0.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3].[C:12]([NH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)(=[O:14])[CH3:13].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH:3]=[CH:20][C:19]1[CH:22]=[CH:23][C:16]([N:15]([C:24](=[O:26])[CH3:25])[C:12](=[O:14])[CH3:13])=[CH:17][CH:18]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C(C)=O)c1ccc(C=Cc2ccc3ccccc3n2)cc1
Temperature: 130 °C
Reaction time: 48 h

Procedure:
A mixture of quinaldine (10 ml) and 4-acetamidobenzaldehyde (12 g) in acetic anhydride (60 ml) was stirred at 130° C. for 2 days, then cooled to room temperature, evaporated to dryness and chromatographed on column of flash silica gel (800 g) using as solvent a mixture of hexane-ethyl acetate (1:1) to provide the title product as a yellow solid: m.p. 148-150° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[OH-].[K+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[CH:28]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1)=[CH2:29]>C(O)C>[CH:28]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)=[CH2:29]
Reactant: OCc1ccc(O)cc1
Reactant: C=Cc1ccc(CCl)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1ccc(COc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A mixture of 4-hydroxybenzyl alcohol (56.7 g, 0.459 molar), 85% potassium hydroxide (32.4 g, 0.459 molar) and 2,6-di-tert-butyl-p-cresol (1 g) in ethanol (600 ml) was stirred at room temperature for 30 minutes. To this mixture was added 4-vinylbenzylchloride (70.5 g, 0.459 molar) very rapidly and it was then heated to 80° C. for 6 hours and stirred at ambient temperature overnight. The mixture was cooled, filtered and the solvent reduced to 300 ml by placing on a rotary evaporator. The solution was then placed in the freezer overnight. The next day the product was filtered to give a white solid. This material was recrystallized from methanol/dichloromethane (2/1) to give a white solid: m.p. of 110°-111.5° C. Yield of 77%. Analysis calculated for C16H16O2 : C, 79.97, H, 6.71. Found: C, 79.31, H, 6.69. 1H NMR (CDCl3) δ 2.55 (broad s, 1H, OH), 4.5 (s, 2H, CH2OH), 5.08 (s, 2H, ArCH2OAr), 5.25+5.75 (AB quartet, 2H, CH2 =), 6.8 (m, 1H, CH=), 6.8-7.6 (m, 8H, ArH's).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11](N)[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].[C:30]([N:33]1C2C(=CC(C3C=CC(S(C)(=O)=O)=CC=3)=C(Br)C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>[Cu]Br>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11]([C:30]#[N:33])[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)N1c2cc(Br)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: [Cu]Br
Product: CC(=O)N1c2cc(C#N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
Isopropyl (S)-4-acetyl-6-cyano-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-6-bromo-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 238), substituting copper (I) cyanide for copper (I) bromide. MS (ESI, pos. ion) m/z 408 [M+H]+.