Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([C@@H:5]1[C@:13]2([CH3:14])[C@H:8]([C@@H:9]([OH:15])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:4].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+].ClN1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[OH:15][C@@H:9]1[C@H:8]2[C@@:13]([CH3:14])([C@@H:5]([C@H:3]([CH3:4])[CH:2]=[O:1])[CH2:6][CH2:7]2)[CH2:12][CH2:11][CH2:10]1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 15 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
Under a nitrogen atmosphere, a solution of (1R,3aR,4S,7aR)-octahydro-1-{(S)-1-hydroxypropane-2-yl}-7a-methyl-1H-indene-4-ol (Compound 14: 2.05 g, 9.659 mmol) synthesized according to the method described in J. Org. Chem. 1986, 51, 1264-1269, 4-acetamide-2,2,6,6-tetramethyl-1-piperidinyloxy free radical (155 mg, 0.7244 mmol) and tetra-n-butylammonium chloride (134 mg, 0.4830 mmol) in methylene chloride (90 ml) was cooled in an ice bath, and 0.5 M sodium hydrogen carbonate (45 ml) and 0.05 M potassium carbonate (45 ml) were added thereto. N-chlorosuccinimide (3.87 g, 28.98 mmol) was added thereto over 10 minutes. The reaction solution was stirred in the ice bath for 1.5 hours, at 10° C. to 18° C. for 4.5 hours, at 5° C. for 11.5 hours, and then at 10° C. to 15° C. for 4.25 hours. After adding saturated aqueous sodium thiosulfate solution (15 ml), the resulting mixture was stirred at 15° C. for 20 minutes. The resulting mixture was extracted 3 times with methylene chloride. The combined organic layer was dried over sodium sulfate, and evaporated under reduced pressure. The crude product (2.90 g) was purified by flash column chromatography to obtain (S)-2-{(3R,3aR,7S,7aR)-octahydro-7-hydroxy-3a-methyl-1H-indene-3-yl}propanal (1.87 g).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:44][N:45]([CH2:47][C:48]1[C:56]2[C:51](=[N:52][CH:53]=[C:54](/[CH:57]=[CH:58]/[C:59](O)=[O:60])[CH:55]=2)[NH:50][CH:49]=1)[CH3:46]>CN(C)C=O>[CH3:44][N:45]([CH2:47][C:48]1[C:56]2[C:51](=[N:52][CH:53]=[C:54](/[CH:57]=[CH:58]/[C:59]([N:11]3[CH2:12][CH:9]([O:8][CH2:7][C:3]4[S:2][CH:6]=[CH:5][CH:4]=4)[CH2:10]3)=[O:60])[CH:55]=2)[NH:50][CH:49]=1)[CH3:46]
Reactant: CN(C)Cc1c[nH]c2ncc(/C=C/C(=O)O)cc12
Reactant: c1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1c[nH]c2ncc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cc12
Reaction time: 8 h

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (61 mg, 0.30 mmol), EDCI (71.5 mg, 0.37 mmol), HOBt (52 mg, 0.37 mmol) and diisopropylethylamine (110 μL, 0.62 mmol) were successively added to a solution of (E)-3-(3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylic acid hydrochloride (70 mg, 0.25 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated, basified with an aqueous solution of sodium hydroxyde (2N) until pH 12 and finally extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (1:0:0.1 to 9:1:0.1) as eluent. The title product was obtained as a yellow solid (10 mg, 10%).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][C:27]1([CH3:36])[O:32][CH2:31][CH2:30][NH:29][C@@H:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:30][CH2:31][O:32][C:27]([CH3:26])([CH3:36])[C@H:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC1(C)OCCN[C@@H]1C(=O)O
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CN2CCOC(C)(C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 55 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (6.8 g, 15.3 mmol) was reacted with (S)-2,2-dimethylmorpholine-3-carboxylic acid (2.44 g, 15.3 mmol) according to the procedure as described in Example 46, Step F to give the title compound as a yellow solid (4.4 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:8]=2)[NH:3]1.[OH-].[Na+:20].[O:21]1CCOCC1>O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][C:9]=1[CH2:10][C:2]([O-:21])=[O:1].[Na+:20]
Reactant: C1COCCO1
Reactant: O=C1Cc2cc(Oc3ccccc3Cl)ccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Oc2ccccc2Cl)cc1CC(=O)[O-]

Procedure:
A mixture of 2-oxo-5-(2-chlorophenoxy)indoline (3.2 g.), sodium hydroxide (2 g.), dioxane (20 ml.) and water (40 ml.) was refluxed under heating for 5 days with stirring. After cooling, the reaction mixture was filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate under warming and filtered. The filtrate was cooled in an ice bath and the precipitating crystals were collected by filtration, washed with ethyl acetate and then recrystallized from a mixture of methanol and ethyl acetate to give the captioned compound (3.2 g.). mp 105° to 115° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]1([C@@H:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:12]1([C@@H:18]([NH:20][CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](NC1CCC2(CC1)OCCO2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (10 g, 64.03 mmol) was dissolved in dry dichloroethane (300 mL) under an atmosphere of nitrogen. (1S)-1-phenylethylamine (8.96 mL, 70.43 mmol) was added neat at room temperature followed by sodium triacetoxyborohydride (20.36 g, 96.04 mmol) neat in small portions. The reaction was stirred at room temperature overnight. The reaction was quenched by the addition of distilled water (200 mL). The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate. The filtrate was concentrated under reduced pressure. A yellow oil was obtained of satisfactory purity based on (11.2 g, 67% yield). M+1: 262.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH2:16][C@@H:17]([OH:19])[CH3:18])C1C=CC=CC=1>CO.[Pd]>[OH:19][C@@H:17]([CH3:18])[CH2:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cc1ccc(OCc2ccccc2)c(C[C@H](C)O)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(O)c(C[C@H](C)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The mixture of (S)-1-(2-(benzyloxy)-5-methylphenyl)-propan-2-ol (3b) (0.50 g, 1.9 mmol) and Pd/C (100 mg, 20%) in MeOH (10 mL) was introduced H2 at ambient temperature. It was stirred at ambient temperature for 18 h. The mixture was filtered through Celite and concentrated to give the title compound (3c).
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23]N[CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CC[O:30]CC1>>[N:19]1([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:20][CH2:21][O:30][CH2:23][CH2:24]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: C1COCCN1
Product: O=c1c2c[nH]c3ccc(N4CCOCC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using morpholine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.01 (4H, brm), 3.78 (4H, brm), 7.12 (1H, dt, J=7.56, 7.33 Hz), 7.23 (1H, d, J=9.28 Hz), 7.45 (2H, dd, J=8.54, 7.32 Hz), 7.88 (1H, d, J=9.53 Hz), 8.21 (2H, dd, J=8.55, 1.22 Hz), 8.57 (1H, s). m/z 348.4 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:3]([OH:5])=O.C(OC#C)C.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][C:28]#[N:29])=[CH:25][CH:24]=1.Cl>C(OCC)(=O)C>[F:16][C:2]([F:1])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:3]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][C:28]#[N:29])=[CH:25][CH:24]=1)=[O:5]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N#CCc1ccc(N)cc1
Agent: C#COCC
Agent: Cl
Solvent: CCOC(C)=O
Product: N#CCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
Perfluorovaleric acid (10 g), ethoxyacetylene (12.3 g) and ethyl acetate (175 mL) were stirred overnight at room temperature under a nitrogen atmosphere. 4-Aminobenzylcyanide (5.57 g) was added and the resulting mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was cooled in ice and 10% aqueous HCl solution was added until a precipitate formed. The solid was collected and washed with water and hexane, sequentially, and dried in vacuo to yield 7.4 g (53%) of 2,2,3,3,4,4,5,5,5-nonafluoro-N-[4-(cyanomethyl)phenyl]pentanamide as a tan solid, m.p. 126°-128° C.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][NH:8][C:7](=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].CCCCCC.CCOC(C)=O.O=P(Cl)(Cl)[Cl:32]>>[CH2:1]([C:5]1[CH:6]=[C:7]([Cl:32])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(=O)[nH]nc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCc1cc(Cl)nnc1-c1ccccc1
Temperature: 85 °C

Procedure:
5-butyl-6-phenyl-2H-pyridazin-3-one (3.6 g, 15.8 mmol)) is dissolved in POCl3 (40 mL) and the solution is heated at 85° C. for 3 hours. The excess POCl3 is evaporated in vacuo and the residue is partitioned between saturated aqueous NaHCO3 solution (50 mL) and EtOAc (50 mL). The organic layer is washed with water (35 mL), brine (35 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides a yellow oil. Flash column chromatograph (silica gel, 4:1 hexane, EtOAc) provides a light yellow oil. LC-MS (M+1) 247. 1H NMR (δ, CDCl3) 7.47 (s, 5H), 7.42 (s, 1H), 2.62 (t, J=7.2 Hz, 2H), 1.43-1.53 (m, 2H), 1.18-1.31 (m, 2H), 0.81 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([OH:18])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[OH:18][CH:12]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=[C:2]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:11]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)cc(C(O)c2nccs2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2nccs2)c1
Temperature: 95 °C

Procedure:
To a mixture of methyl 3-bromo-5-(hydroxy(thiazol-2-yl)methyl)benzoate (320 mg, 0.98 mmol), p-tolylboronic acid (0.16 g, 1.2 mmol), potassium carbonate (0.20 g, 1.5 mmol), 1,4-dioxane (5 mL), and water (0.5 mL, 0.03 mol) under argon was added tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol). The reaction mixture was heated at 95° C. for 8 h. After cooling, the mixture was treated with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([NH:16][CH:17]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].Br[CH2:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>C(Cl)Cl>[O:13]=[C:12]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:36][C:37](=[O:38])[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:3]=2)[CH2:9][CH:10]([C:14]([NH:16][CH:17]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH2:11]1
Reactant: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(N)c2)C1)c1cccnc1
Reactant: O=C(CBr)Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(NCC(=O)Nc3ccccc3)c2)C1)c1cccnc1
Temperature: 25 °C

Procedure:
To a suspension of ethyl 3-{(1-(3-aminophenyl)-5-oxopyrrolidin-3-yl)carbonylamino}-3-(3-pyridyl)propanoate (100 mg, 0.25 mmol, 1.1 eq), NaHCO3 (20 mg, 0.23 mmol, 1.0 eq), and CH2Cl2 (4 mL), was added 2-bromo-N-phenyl acetamide (50 mg, 0.23 mmol, 1.0 eq) in 2 mL CH2Cl2 dropwise. The reaction mixture was heated up to reflux for 5 hours, then cooled to room temperature.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[H-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C>O1CCCC1.C(OCC)(=O)C.O>[Br:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][CH:6]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1nc(Br)cnc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 80 mL of tetrahydrofuran was dissolved 4.0 g of 3-amino-6-bromo-2-pyrazinecarbonitrile synthesized according to the procedure mentioned in U.S. Pat. No. 3,341,540. While cooling the solution with ice, 1.2 g of 60% sodium hydride and 2.8 mL of benzoyl chloride were successively added, and further 0.8 g of 60% sodium hydride was added. The mixture thus obtained was stirred at an ice-cooled temperature for one hour and thereafter at room temperature for 30 minutes. Then, 0.4 g of 60% sodium hydride was added additionally, and the mixture thus formed was stirred at room temperature for 30 minutes. After cooling the reaction mixture with ice, the mixture was poured into a liquid mixture consisting of 50 mL of ethyl acetate and 100 mL of water, and pH was adjusted to 5 with 6 mol/L hydrochloric acid. The deposited matter was collected by filtration, and the residue thus obtained was dissolved in a mixture of 50 mL of ethyl acetate and 100 mL of tetrahydrofuran, treated with active charcoal, and filtered, after which the solvent was removed under reduced pressure. The residue thus obtained was washed with diisopropyl ether to obtain 1.7 g of N-(5-bromo-3-cyano-2-pyrazinyl)-benzamide as a light yellow-colored solid product. Furthermore, organic layer was separated from the filtrate obtained above, and organic layer was washed successively with water and saturated aqueous solution of sodium chloride, treated with active charcoal and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was washed with diisopropyl ether to obtain 2.9 g of N-(5-bromo-3-cyano-2-pyrazinyl)-benzamide as a yellow-colored solid product.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([O:20]C)=[O:19])[C:10](=[O:26])[CH:9]=2)=[C:4]([CH2:29][NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:3]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([OH:20])=[O:19])[C:10](=[O:26])[CH:9]=2)=[C:4]([CH2:29][NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:3]=1
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)OC)ccc2C)c(=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To methyl 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate (from Step 3) (0.17 g, 0.36 mmol) was added 1.5 N NaOH solution in 1:1 MeOH:water (0.39 mL, 0.59 mmol). The reaction mixture was stirred at 60° C. for 2.5 h. The solution was cooled (0° C.), neutralized by the slow addition of 5% citric acid, and organic products extracted in DCM. A white solid suspended in the organic layer was filtered, washed with DCM and water, dried in vacuo, and found to be the desired product (0.090 g, 55%). 1H NMR (CD3OD/400 MHz) δ8.03 (m, 1H), 7.75 (s, 1H), 7.52 (d, 1H, J=8.0 Hz), 7.47 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 3.65 (s, 3H), 2.12 (s, 3H), 1.90 (s, 3H). ESHRMS m/z 455.1632 (M+H calculated for C24H24FN2O6 requires 455.1613).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[C:16]([CH2:18][C:19](OCC)=O)#[N:17]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:19]([CH2:18][C:16]#[N:17])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC#N
Reactant: Nc1cnc(Br)cc1Nc1ccccc1
Product: N#CCc1nc2cnc(Br)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
The product from Step 4 (2.1 g, 7.95 mmol) and ethyl cyanoacetate (3.6 g, 31 mmol) were heated together at 195° C. in a sealed tube for 54 minutes. After cooling to room temperature, the product crystallized and the crystals were collected and washed with ethanol to give the title compound (0.87 g, 35%). MS (ES+) m/e 313/315 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[C:5]#[N:6].S(Cl)([Cl:19])=O.O>N1C=CC=CC=1>[Cl:19][CH2:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[C:5]#[N:6]
Reactant: O=S(Cl)Cl
Reactant: N#CC(CCO)c1ccccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: N#CC(CCCl)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4-Hydroxy-2-(2-trifluoromethylphenyl) butyronitrile (2.6 g) was dissolved in pyridine (10 mL). Thionyl chloride (2.1 mL) was carefully added and the mixture was heated with stirring at 60° C. for four hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.3 g). The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[C:10]([C:13](OC)=[O:14])[CH:11]=[N:12][C:3]1=2.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1.O.C(OCC)(=O)C>[OH:14][CH2:13][C:10]1[CH:11]=[N:12][C:3]2[N:2]([CH3:1])[CH2:7][C:6](=[O:8])[NH:5][C:4]=2[CH:9]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)CN2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CC(=O)Nc2cc(CO)cnc21
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Methyl 4-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (500 mg, 2.25 mmol) was taken up in tetrahydrofuran (25 mL) in an inert environment. To the stirred suspension at room temperature was added NaH (60% dispersion in mineral oil, 136 mg, 3.40 mmol) and stirred 30 min. The reaction was then cooled to −45° C. and lithium aluminum hydride (2M in THF, 3.3 mL, 6.6 mmol) was added. The reaction was stirred at a temperature between −20 and −10° C. for 1 h. The reaction was then cooled back to −60° C. and MeOH (1 mL) followed by water (1 mL) was added. The reaction was allowed to stir at ambient temperature for 2 h and then poured into ethyl acetate (300 mL) and water (200 mL). The biphasic mixture was stirred vigorously and then filtered through a medium frit. The layers were separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (100 mL), dried with sodium sulfate and concentrated to yield the title compound (415 mg, 95%) as a white solid. [M+H] calc'd for C9H11N3O2, 194. found, 194.
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)Cl>[CH:1]1([NH:7][C:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=4)[CH:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-Amino-benzyl)-piperidine-4-carboxylic acid cyclohexylamide BB-1 (80 mg, 0.25 mmol) in DCM (3 mL) is treated with DIPEA (33 mg, 43 μl, 0.25 mmol) under argon and cooled to 0° C. A solution of 4-chlorobenzoylchloride (49 mg, 0.28 mmol) in DCM (1 mL) is added and the resulting solution is stirred at 0° C. for 2 h. The mixture is diluted with DCM (25 mL) and washed twice with aq. sat. NaHCO3 (25 mL). The solvent is evaporated and the title compound is obtained by prep. LC-MS F as a colorless powder: LC-MS A: tR=0.81 min; [M+H]+=454.4. 1H-NMR (DMSO-d6): δ 1-1.3 (m, 6H), 1.5-1.7 (m, 9H), 1.8-2.1 (m, 3H), 2.8-2.9 (m, 2H), 3.4-3.5 (m, 3H), 7.03 (d, J=8, 1H), 7.29 (t, J=8, 1H), 7.5-7.7 (m, 5H), 7.98 (d, J=8, 1H), 10.2 (s, 1H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[C:7]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:8]=2[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.S(=O)(=O)(O)O>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:7]2[C:6]3[N:12]([CH:3]=[CH:4][N:5]=3)[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[NH:9][C:8]=2[CH:17]=1
Reactant: COc1ccc2c(c1)Nc1ccccc1N=C2NCC(OC)OC
Agent: O=S(=O)(O)O
Product: COc1ccc2c(c1)Nc1ccccc1-n1ccnc1-2

Procedure:
In the manner given in Example 5, 3-methoxy[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethylacetal is treated with concentrated sulfuric acid to give 11-methoxy-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine.