Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC=CC=1)C1C=CC=CC=1.[C:14]1([C:19]2[CH:20]=[C:21]([CH:40]=[CH:41][C:42]=2[O:43][C:44]([F:47])([F:46])[F:45])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C@@H:30]([C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][CH:15]=1>CO.[Pd]>[CH:14]1([C:19]2[CH:20]=[C:21]([CH:40]=[CH:41][C:42]=2[O:43][C:44]([F:46])([F:47])[F:45])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C@@H:30]([C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C[C@@H](c1ccc(OCc2ccc(OC(F)(F)F)c(C3=CCCC3)c2)cc1)c1ccon1
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CO
Product: O=C(O)C[C@@H](c1ccc(OCc2ccc(OC(F)(F)F)c(C3CCCC3)c2)cc1)c1ccon1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of Pd/C (20.0 mg, 10%) with Ph2S (1.0%) in MeOH (5.0 mL), was added 20 (25.0 mg, 0.164 mmol) in MeOH (1.0 mL). The reaction mixture was purged with hydrogen three times. The mixture was then stirred under hydrogen at room temperature overnight. The catalyst was filtered off, and the solvent was evaporated to give the title compound 23. 1H NMR (CD3CN) δ 1.55-2.02 (m, 8H), 2.93 (dd, J=7.3, 16.4 Hz, 1H), 3.16 (dd, J=7.3, 16.4 Hz, 1H), 3.33 (m, 1H), 4.53 (m, 1H), 5.05 (s, 2H), 6.24 (d, J=1.7 Hz, 1H), 6.94 (d, J=6.6 Hz, 2H), 7.22-7.26 (m, 4H), 7.49 (d, J=5.0 Hz, 1H), 8.45 (d, J=1.7 Hz, 1H). MS ESI (pos.) m/e: 476 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]([NH2:12])=[N:10][N:11]=1.[C:13]1([CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCCC)CCCC)CCC>O>[C:13]1([C:19]2[C:20]([OH:21])=[N:12][C:9]3[N:10]([N:11]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[N:8]=3)[C:25]=2[OH:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nnc(-c2ccccn2)[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2nc(-c3ccccn3)nn2c(O)c1-c1ccccc1
Temperature: 180 °C
Yield: 50 %

Procedure:
20 g (124.1 mmol) 5-Pyridine-2-yl-4H-[1,2,4]triazole-3-ylamine and 52.8 g (223.4 mmol) diethyl phenylmalonate are heated in 48.8 mL (204.8 mmol) tributylamine at 180° C. over night. After addition of additional 27 mL diethyl phenylmalonate the reaction mixture is heated for another night at 180° C. The reaction mixture is diluted with water and 2N NAOH and extracted three times with methyl-tert.butylether. The organic extracts are discarded after TLC check. The aqueous phase is acidified with 2M HCl until a pH of 1. The formed precipitate is collected by filtration, washed with plenty of water and dried. 18.96 g (45%) of the desired product are obtained which are used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Li]CCCC.[CH3:17][O:18]C=O>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH:17]=[O:18]
Reactant: COC=O
Reactant: FC(F)(F)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-3-trifluoromethylbenzene (1.0 g, 5.54 mmol) in THF (15 mL) cooled to −78° C., under N2 protection was added dropwise n-BuLi (3.81 mL of a 1.6 M solution in hexane, 6.1 mmol). After an hour, formic acid methyl ester (664.8 mg, 11.08 mmol) was added slowly to the solution. After the addition, the solution was warmed to ambient temperature slowly and stirred for 30 min. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (15:1) as eluent to give 2-chloro-6-trifluoromethylbenzaldehyde as a colorless oil.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:44]=[CH:43][C:20]3[CH2:21][C@@H:22]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:23](=[O:37])[N:24]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:25][C:19]=3[CH:18]=2)=O)=CC=1)([O-])=O>CO.[Pd]>[NH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:44]=[CH:43][C:20]2[CH2:21][C@@H:22]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:23](=[O:37])[N:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[CH2:25][C:19]=2[CH:18]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OCCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)C[C@@H]1Cc2ccc(OCCCN)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Reaction time: 4.5 h
Yield: 102 %

Procedure:
To methyl (S)-8-[3-(4-nitrobenzyloxycarbonylamino)-1-propyloxy]-3-oxo-2-[4-(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.12 g, 0.19 mmol) in MeOH (2 mL) was added 10% Pd/C (20 mg). The reaction vessel was flushed with hydrogen and then fitted with a hydrogen-filled balloon. After 4.5 h, the hydrogen was vented and the catalyst was removed by filtration through celite®. Removal of solvent gave the title compound (0.09 g) as a pale yellow residue. This material was used without further purification. MS (ES) m/e 465.3 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4]1([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][C:5]1=[O:14])[CH3:2].[H-].[Na+].[CH3:18]I>>[CH2:1]([S:3][C:4]1([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:14])[CH3:2]
Reactant: CI
Reactant: CCSC1(C)C(=O)Nc2ccc(F)cc21
Agent: [H-]
Agent: [Na+]
Product: CCSC1(C)C(=O)N(C)c2ccc(F)cc21

Procedure:
11.3 g (0.05 mole) of 3-(ethylthio)-5-fluoro-3-methyl-1,3-dihydro-2(2H)-indolone are methylated as described under 2.2, starting with 2.6 g (0.055 mole) of 50% strength NaH and 3.7 ml of methyl iodide.
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].I[CH:15]([CH2:17][CH3:18])[CH3:16].C(N1C=C(I)C(C2SC=CC=2)=N1)(CC)C>CN(C)C=O.CC(OC)(C)C.O>[CH:15]([N:4]1[C:3]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[C:2]([I:1])[CH:6]=[N:5]1)([CH2:17][CH3:18])[CH3:16]
Reactant: Ic1c[nH]nc1-c1cccs1
Reactant: CCC(C)I
Agent: CCC(C)n1cc(I)c(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)n1ncc(I)c1-c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4-iodo-3-(2-thienyl)-1H-pyrazole (7.1 mmol) in 57 mL dry N,N-dimethylformamide under argon atmosphere at 0° C. was added sodium hydride (8.5 mmol, 60% dispersion in mineral oil) in portions. The reaction mixture was stirred at 0° C. for 15 min, then 2-iodobutane (10.6 mmol) was added dropwise. After 14 h at room temperature, water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 2.7 g of a mixture of 1-sec-butyl-4-iodo-3-(2-thienyl)-1H-pyrazole and 1-sec-butyl-4-iodo-5-(2-thienyl)-1H-pyrazole (80:20; 88% yield). The mixture was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100 and cyclohexane:toluene 100:0 to 0:100) to afford 1.16 g 1-sec-butyl-4-iodo-3-(2-thienyl)-1H-pyrazole (48% yield) and 71 mg of 1-sec-butyl-4-iodo-5-(2-thienyl)-1H-pyrazole (3% yield).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:15]=O)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1>C(O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:15]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 42.7 %

Procedure:
To a solution of 12.5 g (107 mmol) of 2,4-thiazolidinedione and 25.0 g (107 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 300 ml of ethanol, 1.05 ml (10.7 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 15.23 g of the desired compound (42.8% yield, pale yellow crystals).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([CH:30]=O)[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=12.[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37].[BH4-].[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([CH2:30][NH:37][CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([Cl:32])[CH:34]=2)[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=12
Reactant: NCc1cccc(Cl)c1
Reactant: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(C=O)cc12
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(CNCc3cccc(Cl)c3)cc12
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbaldehyde (30 mg, 0.07 mmol) prepared in Step 1 of Example 864 and 3-chlorobenzylamine (9.75 μl, 0.08 mmol) in methanol (3 ml) was refluxed for 3 hours. Titanium(IV) isopropoxide (40 μl) and sodium borohydride (5.49 mg, 0.15 mmol) were added at room temperature to the reaction mixture, which was then stirred overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 21.7 mg of the titled compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Br:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Br:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=4[O:41][CH3:42])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Br)ccc43)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Br)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester (0.19 g, 0.28 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid as a white powder (Yield, 0.15 g, 81%).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH4-].[Na+]>[OH-].[Na+]>[CH2:8]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a stirred solution of D-serine (14.7 g, 140.0 mmol) in aqueous 2M NaOH (70 mL) was added benzaldehyde (14.6 g, 14.0 mL, 138.0 mmol). The reaction mixture was then stirred at r.t. for 1 h before cooling to 5° C. NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of between 6 and 10° C. was maintained. After addition, the reaction mixture was allowed to stir at 5° C. for 30 minutes and then at r.t. for 1 h. The reaction mixture was cooled to 5° C. and a further portion of NaBH4 (1.5 g, 40.0 mmol) was added portionwise such that an internal temperature of <10° C. was maintained. The ice bath was removed on completion of addition and the reaction mixture stirred at r.t. for 16 h. The reaction mixture was then extracted with Et2O (3×100 mL) and the aqueous phase acidified to pH 5 with conc. HCl. The resultant white precipitate was filtered and washed with water. The product was dried in vacuo to give the title compound (24.0 g, 88%) as a white solid. δH (DMSO-d6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (1H, t, J 5.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].BrCC1C=CC=C(F)C=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Fc1cccc(CBr)c1
Product: N#Cc1cccc(COc2cccc(N)c2)c1

Procedure:
3-Nitro-phenol was reacted with 3-bromomethyl-benzonitrile according to the procedure from Example 199A substituting 3-bromomethyl-benzonitrile for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:3][C@H:4]([C:6]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[C:30]=1[C:31]#[N:32]
Reactant: C[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 56.3 %

Procedure:
To a solution of 2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile dihydrochloride (110 mg, 0.29 mmol) in IPA (3 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (45 mg, 0.29 mmol) and DIPEA (148 μL, 0.87 mmol) and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 330 as a white solid (65 mg, 56%). 1H NMR 400 MHz δ (d6-DMSO): 8.08 (1H, dd, J=8.9, 4.9 Hz), 7.78 (1H, s), 7.70 (1H, d, J=7.2 Hz), 7.62-7.56 (1H, m), 7.55-7.43 (4H, m), 7.33 (1H, dd, J=10.4, 9.0 Hz), 7.15 (2H, br s), 5.28 (1H, quin, J=6.9 Hz), 1.48 (3H, d, J=6.9 Hz), LCMS (Method K): RT=3.73 min, [M+H]+=399
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Cl:11][C:9]1[CH:8]=[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=1)[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: CC1Cc2c(Cl)cc(Cl)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1=Cc2cc(Cl)cc(Cl)c2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 29.3 g (0.136 mol) of 4,6-dichloro-2-methylindan-1-one in 370 ml of a mixture of THF-methanol (2:1, vol.), 11.8 g (0.312 mol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 1000 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 700 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic fractions were evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 60 mm, l 150 mm). Yield 24.6 g (91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([O:14][CH3:15])=[CH:10][C:11]=1[O:12][CH3:13])[O:5]COC.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:22][C:23](=[O:24])[NH:1][C:2]2[CH:3]=[C:4]([OH:5])[C:9]([O:14][CH3:15])=[CH:10][C:11]=2[O:12][CH3:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCOc1cc(N)c(OC)cc1OC
Reactant: O=C=Nc1ccccc1
Product: COc1cc(OC)c(NC(=O)Nc2ccccc2)cc1O

Procedure:
(3-Amino-4,6-dimethoxyphenoxy)methoxymethane and phenyl isocyanate were treated in the same manner as described in Example 1 to give 3-(3-phenylureido)-4,6-dimethoxyphenol (melting point: 162°-164° C.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:32]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:40][C:38]1[CH:37]=[CH:36][C:35]([CH2:41][C:42]([O:44][CH3:45])=[O:43])=[C:34]([C:32]#[C:33][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)[CH:39]=1
Reactant: C#Cc1cc(F)ccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(F)cc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.252 g, 0.552 mmol), methyl 2-(2-ethynyl-4-fluorophenyl)acetate (A50) (0.106 g, 0.552 mmol), PPh3 (0.007 g, 0.03 mmol), CuI (0.005 g, 0.03 mmol) and PdCl2(PPh3)2 (0.019 g, 0.028 mmol) in DMF (3 mL) and Et3N (1.0 mL) was heated under microwave irradiation for 20 minutes at 120° C. The resulting mixture was diluted with EtOAc (100 mL) then washed with water (100 mL), brine (25 mL) and dried over MgSO4. The volatiles were evaporated in vacuo and the residue was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compound A51 as a yellow solid (0.158 g, 47%); 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J=1.0 Hz, 1H), 7.75 (s, 1H), 7.62-7.55 (m, 2H), 7.38-7.27 (m, 2H), 7.25-7.19 (m, 2H), 7.14 (td, J=8.3, 2.7 Hz, 1H), 4.36-4.20 (m, 2H), 3.92 (s, 2H), 3.72 (s, 3H), 2.82 (t, J=12.8 Hz, 2H), 2.66 (td, J=8.5, 4.2 Hz, 1H), 1.89-1.78 (m, 2H), 1.70-1.54 (m, 2H), 1.51 (s, 9H). LCMS-A: rt 1.852 min; m/z 613 [M+H]+.
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].O>CCOCC.O1CCCC1>[O:10]1[C:9]2[CH:13]=[CH:14][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[CH:7][C:8]=2[O:12][CH2:11]1
Reactant: [Li]C
Reactant: CC(=O)c1ccc2c(c1)OCO2
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
About 600 ml of a 1.5 M solution of methyllithium in ether was added to 500 ml of tetrahydrofuran to obtain a mixture. A suspension of 93.45 g of 5-acetyl-1,3-benzodioxole in 900 ml of tetrahydrofuran was added to the mixture, while keeping it at -20° C. by cooling and the obtained mixture was stirred as such for one hour. Water was added to the reaction mixture and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous magnesium sulfate. The resulting mixture was filtered and the filtrate was concentrated to obtain 97 g of the title compound as an oil.
Reaction SMILES: N1C2=C3N=CN=C3C=CC2=CC=C(C(O)=O)N=1.[CH:18]1[N:22]2[C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[CH:25]=[N:26][CH2:27][C:21]2=[CH:20][N:19]=1>>[CH:18]1[N:22]2[C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[CH2:25][N:26]=[CH:27][C:21]2=[CH:20][N:19]=1
Reactant: C1=NCc2cncn2-c2ccccc21
Agent: O=C(O)c1ccc2ccc3ncnc3c2nn1
Product: C1=NCc2ccccc2-n2cncc21

Procedure:
The process described in U.S. Pat. No. 4,280,957 comprises decarboxylating the corresponding imidazo-benzodiazepine-carboxylic acid at 100°-350° C., optionally in the presence of a solvent and a catalyst. This process has the disadvantage that in addition to the desired 4H-imidazo[1,5-a][1,4]-benzodiazepine derivative of formula I there is obtained a considerable amount of the corresponding isomeric 6H-imidazo[1,5-a][1,4]-benzodiazepine derivative, which requires an expensive re-isomerization.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH2:19][S:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClC1C=CC=C(C(OO)=[O:39])C=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH2:19][S:20]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)=[O:39])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)c1ccc(SCc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COC(=O)c1ccc(S(=O)Cc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
In a manner analogous to that of Example 2(b), 2.96 g (7 mmol) of methyl 4-[3-(1-adamantyl)-4-methoxyphenylmethylthio]benzoate were reacted with 1.42 g (7 mmol) of meta-chloroperbenzoic acid and 2.33 g (76%) of the expected methyl ester, having a melting point of 151°-2° C., were recovered.