Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[CH:3]=1.[Li]C(C)(C)C.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[C@@H:25]1[N:29]2[CH:30]=[N:31][CH:32]=[C:28]2[C:27](=[O:33])[CH2:26]1)[C:20]#[N:21]>C1COCC1>[CH:8]1([C:4]2[CH:3]=[C:2]([C@:27]3([OH:33])[C:28]4[N:29]([CH:30]=[N:31][CH:32]=4)[C@@H:25]([C:24]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=4[F:16])[CH2:26]3)[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:9]1
Reactant: Brc1cccc(C2CC2)c1
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2C[C@](O)(c3cccc(C4CC4)c3)c3cncn32)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a solution of 1-bromo-3-cyclopropyl-benzene (0.018 ml, 0.124 mmol) in THF (0.2 ml) cooled to −78° C. was added a solution of 1.6 M t-BuLi (0.155 ml, 0.249 mmol). The crude was stirred at −78° C. for 2 hrs. To this solution was add a solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (20 mg, 0.083 mmol) in THF (0.2 ml). The crude was stirred at −78° C. for 1 hr, then at 0° C. for 1 hr and room temperature for 1 hr. This reaction was quenched with water and extract the aq. with CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified via preparation plate using 10% (2M NH3 in MeOH)/CH2Cl2. The entitled product (4 mg) was isolated as the major diastereomer. MS 360.1 (M+H); LCMS condition B, retention time 1.16 min. 1H NMR (400 MHz, CDCl3) δ ppm 0.52-0.65 (m, 2H), 0.85-0.95 (m, 2H), 1.74-1.91 (m, 1H), 2.57 (br. s., 1H), 2.92 (d, 1H), 3.30 (dd, 1H), 5.73 (d, 1H), 6.91 (s, 1H), 6.96 (ddd, 1H), 7.12 (t, 1H), 7.16-7.28 (m, 3H), 7.29-7.41 (m, 2H), 7.42-7.53 (m, 1H).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH3:13])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:13][C:12]1[N:11]=[CH:10][N:9]2[C:8]=1[CH:7]=[N:6][NH:5][C:4]2=[O:3]
Reactant: CCOC(=O)NN=Cc1nc[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ncn2c(=O)[nH]ncc12

Procedure:
A mixture of 10.26 gm. of 3-(5-methyl-4-imidazolylmethylene)carbazic acid ethyl ester and 100 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 276°-282° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][C:14]1=[O:19])[CH:11]=[CH2:12]>>[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:8]2[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=2[Cl:1])[C:14]1=[O:19])[CH:11]=[CH2:12]
Reactant: Nc1ccc(I)c(Cl)c1
Reactant: C=CCC1CCCNC1=O
Product: C=CCC1CCCN(c2ccc(N)cc2Cl)C1=O

Procedure:
Analogously to the process described under example 93A, 6.00 g (23.7 mmol) of 3-chloro-4-iodoaniline and 4.11 g (29.6 mmol) of the compound from example 96A are used to obtain 1.57 g (25% of theory) of the title compound. The purification is effected by suction filtration using silica gel with 2:1→1:2 cyclohexane/ethyl acetate as the eluent.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][NH:13][C:12]2=[O:19].[H-].[Na+].Br[CH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1>CN(C)C=O>[CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([CH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1)[C:12]2=[O:19]
Reactant: Cc1cc(CBr)no1
Reactant: CN1C[C@@H]2C[C@H]1CN2c1ccc2nc[nH]c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cnc3ccc(N4C[C@@H]5C[C@H]4CN5C)cc3c2=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 6-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazolin-4(3H)-one (Example 10A) (150 mg, 0.583 mmol) in dimethylformamide was cooled to 0° C. added and sodium hydride (21 mg, 0.875 mmol) was added, after 5 minutes 3-bromomethyl-5-methylisoxazole (75 mg, 0.426 mmol) was added and the reaction stirred at room temp for 1 h. The reaction was quenched with ammonium chloride and the dimethylformamide evaporated off. The residue was dissolved in 10% methanol in dichloromethane and dried over sodium sulphate before evaporation to dryness. The product was purified by silica chromatography, elueting with 10% methanol in dichloromethane to afford 6-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-((5-methylisoxazol-3-yl)methyl)quinazolin-4(3H)-one (0.10 g, 0.284 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].N12CCN(CC1)CC2>C(OC)(C)(C)C>[C:14](=[O:15])([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: O=C(Cl)Oc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: COC(C)(C)C
Product: CN1C(C)(C)CC(OC(=O)Oc2ccccc2)CC1(C)C
Reaction time: 2 h

Procedure:
Into a 500 ml 3-neck flask was added 17.1 grams (0.1 mole) 1,2,2,6,6-pentamethyl-4-piperidinol and 300 mls of methyl t-butyl ether (MtBE). The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 15.6 grams (0.1 mole) phenyl chloroformate. The phenyl chloroformate was slowly added to the 1,2,2,6,6-pentamethyl-4-piperidinol solution without any appreciable exotherm. Then 11.2 grams (0.1 mole) of 1,4-diazabicyclo(2.2.2)octane (DABCO) was added at room temperature. The temperature rose to 50° C. and a precipitate formed. The reaction was stirred for 2 hours, an additional 2 grams of DABCO and 1.25 grams of phenyl chloroformate was added, the reaction heated to reflux and refluxed 2 hours. The reaction mixture was cooled, transferred to a separatory funnel and washed with water to remove DABCO, DABCO hydrochloride and a small amount of 1,2,2,6,6-pentamethyl-4-piperidinol. The product was then extracted out of the MtBE layer with 100 mls of 5% HCl diluted with water to 400 mls. The MtBE layer which contained diphenyl carbonate was discarded. The acid layer was made basic with 100 ml of 10% NaOH. The product was extracted out of the aqueous layer with 200 ml MtBE. The MtBE extract was washed with 100 ml 5% NaHCO3, dried over anhydrous MgSO4, filtered and the MtBE stripped off on a rotating evaporator under reduced pressure. The residue was a white solid weighing 20.4 grams (70.1% crude yield) which had a melting point of 63°-67° C. Liquid chromatography indicated the product was essentially one component. The infrared spectrum contained a strong carbonyl peak at 1755 cm-1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1)=[O:3].[Se](=O)=[O:13]>>[F:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[O:13])[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1cc(F)cc(F)c1
Product: O=CC(=O)c1cc(F)cc(F)c1
Yield: 85.6 %

Procedure:
(3,5-Difluorophenyl)(oxo)acetaldehyde (28 g, 84%) was prepared from 3,5-difluoro acetophenone (30.0 g, 192.3 mmol) and selenium dioxide (23.55 g, 214.0 mmol) according to the typical procedure used for Preparation 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](=[O:34])[NH:19][C:20]3([C:29]([O:31]CC)=[O:30])[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](=[O:34])[NH:19][C:20]3([C:29]([OH:31])=[O:30])[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CN(C(=O)OC(C)(C)C)CC3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.5 %

Procedure:
The product (217) (2.46 g, 5.3 mmol) and KOH (2.5 g, 45 mmol) is dissolved in EtOH (20 mL) and water (1 mL) under a water bath. The water bath is removed when the KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (50 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (218) as white solid (1.4 g, 61%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([C:12]([NH2:15])([CH3:14])[CH3:13])(I)[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1>>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[S:10][C:9]([C:12]([NH2:15])([CH3:14])[CH3:13])=[CH:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)(N)C1(I)Cc2nc(Cl)nc(N3CCOCC3)c2S1
Product: CC(C)(N)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine-6-yl)propan-2-amine (30 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 11.5 mg of 310. MS (Q1) 395.0 (M)+
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.CN(C)[CH2:19][CH2:20]CN=C=NCC.C(O)C>C(OCC)C.CN(C)C1C=CN=CC=1>[CH2:19]([O:14][C:13](=[O:15])[CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Yield: 93.3 %

Procedure:
In an oven-dried 250 mL round bottom flask under nitrogen, a mixture of (1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-azetidinyl)acetic acid (10 g, 46.5 mmol) in diethyl ether (100 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (9.80 g, 51.1 mmol), 4-(dimethylamino)pyridine (0.568 g, 4.65 mmol), and ethanol (5.97 mL, 102 mmol) at room temperature and the white mixture was stirred over the weekend. The white reaction mixture became a colorless solution with gummy material at the bottom of the flask after 1 h. The reaction mixture was diluted with ether (300 mL) and washed with 1M aq NaHSO4 solution (150 mL) and saturated aq NaHCO3 solution (150 mL). The organic phase was isolated, dried over MgSO4, and concentrated in vacuo to give the title compound (10.55 g, 93%) as a clear colorless liquid. MS(ES)+ m/e 244.4 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].[C:18]([O-:21])(=[O:20])[CH3:19].[Na+]>CN(C=O)C>[C:18]([O:21][CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])(=[O:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(COC(C)=O)c1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
50 ml of a DMF solution containing 5.0 g of methyl 3-bromomethyl-2-chloro-4-methanesulfonylbenzoate and 1.2 g of sodium acetate, was stirred for 2 hours at 100° C. After cooling, the reaction mixture was poured into ice water and extracted with chloroform. After washing the extract with water and drying it, the solvent was distilled off to obtain 4.2 g of the desired product. Melting point: 165°-168° C.
Reaction SMILES: [CH2:1]1[CH2:23][O:22][C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:17])[C:15]#[N:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:18]=[CH:19][CH:20]=[CH:21][C:4]2=3)[O:2]1.[OH2:24].[OH-].[K+]>CO>[CH2:23]1[CH2:1][O:2][C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:17])[C:15]([NH2:16])=[O:24])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:18]=[CH:19][CH:20]=[CH:21][C:4]2=3)[O:22]1
Reactant: CC(C#N)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(N)=O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Yield: 57 %

Procedure:
3.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionitrile is refluxed for 3 hours in 50 ml. of water and 10 ml. of methanol containing 0.55 gm. of potassium hydroxide. The solution is cooled and extracted with ethyl acetate. The extract is washed with aqueous sodium carbonate and water, then dried and evaporated to yield 57% of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetonitrile and a 1 hour reaction time gives a similar yield of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Product: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 45.6 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (55 mg, 0.16 mmol) obtained in Example 36 and piperidine (0.018 ml, 0.18 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (30 mg, 0.073 mmol, yield 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+].[CH3:12][O:13][CH2:14]Cl>N1C=CC=CC=1>[F:1][CH:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]1([CH2:12][O:13][CH3:14])[OH:9]
Reactant: Oc1ccc(F)cc1F
Reactant: COCCl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COCC1(O)C=CC(F)=CC1F
Yield: 71 %

Procedure:
To a reaction mixture containing 2,4-difluorophenol (25, 2 g, 15.37 mmol) in 30 mL of dry pyridine was added powdered KOH (0.854 g, 15.25 mmol) and methoxymethyl chloride (1.6 g, 19.37 mmol) and this reaction mixture was heated under reflux for 3.5 hours (FIG. 2E). The reaction was cooled and partitioned between 1 M NaOH and ethyl ether (2×30 mL). The organic solution was washed with 1 M HCl (2×20 mL), water, and then dried (MgSO4), filtered, and the solvent removed under vacuo to afford a oily residue. The crude product was purified by column chromatography (EtOAc:hexanes; 5:95) to afford the desired product as a pale yellow oil in 71% yield. 1H NMR (CDCl3) δ7.1-7.16 (m, 1 H, ArH), 6.78-6.88 (m, 2 H, ArH), 5.15 (s, 2 H, CH2), 3.52 (s, 3 H, CH3).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:16]=[C:14]([CH2:13][C:11]#[N:12])[S:15][CH:2]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: N#CCC(N)=S
Product: N#CCc1nc(-c2ccccn2)cs1
Yield: 73 %

Procedure:
This compound was synthesized from 2-bromo-1-(pyridin-2-yl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (0.37 g, yield 73%): 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=5.5 Hz, 1H), 8.15 (m, 2H), 7.84 (t, J=8.4 Hz, 1H), 7.30 (m, 1H), 4.21 (s, 2H). MS (ESI) m/z: Calculated for C10H7N3S: 201.04. found: 202.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][NH:13][C@@H:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
The mixture of ethyl {5-[(tert-butoxycarbonyl)amino]pyridin-2-yl}acetate (3.72 g, 15.6 mmol, step 4 of Example 1) and platinum oxide (300 mg) in ethanol (6 mL) and acetic acid (6 mL) was stirred under hydrogen (4 atom) at room temperature for 8 h. The mixture was filtered through a pad of Celite washing with ethanol and the filtrate was concentrated. The resulting residue was diluted with 2N aqueous sodium hydroxide solution (100 mL), and extracted with dichloromethane (100 mL×3). The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (20:1) to give 2.48 g (65%) of the title compound as a colorless oil. (trans isomer 559 mg, 15% yield)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>>[C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]2[NH:11][CH2:10][CH2:9]1)(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)nn2c1NCCC2c1ccccc1N
Product: C=CC(=O)Nc1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(OCc4ccccc4)cc3)nn21

Procedure:
The desired product was prepared from 7-(2-aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and acryloyl chloride using the procedure similar to that for compound 8. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.46-7.37 (m, 7H), 7.33-7.28 (m, 2H), 7.21 (t, J=7.6 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 6.81 (br s, 1H), 6.64 (d, J=7.6 Hz, 1H), 6.53 (dd, J=10.3, 16.8 Hz, 1H), 6.27 (d, J=1.8, 16.8 Hz, 1H), 5.59-5.57 (m, 2H), 5.12 (s, 2H), 3.30-3.26 (m, 1H), 3.04-2.92 (m, 1H), 2.35-2.27 (m, 1H) and 1.95-1.97 (m, 1H). MS (ESI) m/e [M+1]+ 493.9.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:40]=[CH:39][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[O:33]=[C:31]1[NH:30][C:29](=[O:34])[CH:28]([CH2:27][C:26]2[CH:35]=[CH:36][C:23]([O:22][CH2:21][C:19]3[N:18]([CH3:37])[C:17]4[CH:38]=[C:13]([O:12][C:11]5[CH:39]=[CH:40][C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:48]([NH:47][C:41]6[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=6)=[O:49])=[CH:9][CH:10]=5)[CH:14]=[CH:15][C:16]=4[N:20]=3)=[CH:24][CH:25]=2)[S:32]1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCNc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)Nc1ccccc1)c1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Reaction time: 48 h

Procedure:
A mixture of 5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.39 g), phenyl isocyanate (95 mg) and anhydrous tetrahydrofuran (20 ml) was allowed to stand at room temperature for 2 days. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:2 as the eluant and the product was reprecipitated from a mixture of n-hexane and diethyl ether to afford the title compound (0.30 g, Rf=0.56: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=2:1 as the eluant).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]=[C:14](Cl)[C:13]1=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[CH2:4]([O:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]=[C:14]([NH:2][NH2:3])[C:13]1=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=c1c(Cl)nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n1OCc1ccccc1
Reactant: NN
Solvent: ClCCl
Solvent: O
Product: NNc1nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Temperature: 0 °C
Yield: 90.9 %

Procedure:
Hydrazine hydrate (2.7 ml, 55 mmol) was added to a solution of 5.9 g (14 mmol) of 1-benzyloxy-3-chloro-6-(1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one in 100 ml of dichloromethane with stirring at 0° C. After 1 h the mixture was evaporated to dryness and the residue was triturated with water and dried to give 5.3 g (90%) of crude title compound.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[O:16][C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14]2)=[CH:9][CH:8]=1>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[O:16][C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-n2nc(C(C)(C)C)oc2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1nn(-c2ccc(O)cc2)c(=O)o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.5 g of boron tribromide are slowly added dropwise, at −60°, to a mixture of 70 ml of dichloromethane and 1.5 g of 1-methoxy-4-(5-oxo-2-tert-butyl-3,4-diaza-1-oxa-cyclopent-2-en-4-yl)-benzene. The reaction mixture is stirred at room temperature for 12 hours and then discharged onto ice/water. The aqueous mixture is extracted with dichloromethane, the extract is washed with water and concentrated and the residue is recrystallised from toluene/pentane, yielding 1-hydroxy-4-(5-oxo-2-tert-butyl-3,4-diaza-1-oxa-cyclopent-2-en-4-yl)-benzene, which melts at from 170° to 172°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[N:6][N:5]=[C:4]2[NH:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:3]=12.O[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[N:6][N:5]=[C:4]2[N:15]([CH2:25][C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[N:16]=[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:3]=12
Reactant: Fc1cccc(-c2nnc3[nH]nc(-c4ccccc4)c3c2Cl)c1
Reactant: O=C(CO)N1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3cccc(F)c3)nnc21)N1CCCC1

Procedure:
A mixture of 4-chloro-5-(3-fluorophenyl)-3-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-hydroxy-1-(pyrrolidin-1-yl)ethanone (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 11.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:36][CH:33]3[CH2:35][CH2:34]3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC1CC1)N1CCN(C2CCCC2)CC1
Yield: 38 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone (example 10), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (38%).