Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].[F:15][C:16]([F:30])([F:29])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=O>CCO>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:13]([C:5]3[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([F:2])[CH:4]=3)[N:14]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=2)=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1F
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1F
Temperature: 25 °C
Yield: 86.5 %

Procedure:
[3-fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride (0.354 g, 1.47 mmol) was added to a solution of 4,4,4-Trifluoro-1-(4-bromophenyl)butane-1,3-dione (0.395 g. 1.34 mmol) in EtOH (20 mL). The mixture was heated at reflux temperature for 17 hours and cooled down to room temperature. The reaction mixture was concentrated in vacuo, and the residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from ethyl acetate/hexane to give the subtitle compound (0.537 g, 86.6% yield).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:30][CH2:29][CH:28]([C:31]([O:33]C)=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4].CO>O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC(C(=O)O)C3)ccc2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
NaOH (2 mL, 2 M, 4.0 mmol) was added to a solution of methyl 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}pyrrolidine-3-carboxylate (570 mg, 1.22 mmol) in a 1:1 mixture of MeOH:H2O (30 mL) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (100 mL). The solvent was concentrated to 100 mL. The resulting solution was neutralized with HCl solution, the product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 480 mg (87%); MS (ESI) (M+H)+=450.1.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[NH:18]1[CH:22]=[N:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[N:4]=[C:3]([CH2:2][N:18]3[CH:22]=[N:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:19]3)[CH:8]=[N:7][C:6]=2[O:9][CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ncc(CBr)nc1-c1cccc(Cl)c1
Reactant: COC(=O)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ncn(Cc2cnc(OC)c(-c3cccc(Cl)c3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine (Intermediate 3, 200.00 mg, 0.64 mmol), in acetone (3.19 mL), was added methyl 1H-1,2,4-triazole-3-carboxylate (121.60 mg, 0.96 mmol) and potassium carbonate (264.44 mg, 1.91 mmol). The reaction was stirred at room temperature for 2 h. The LC/MS showed two peaks with [M+H] values consistent with the two major regioproducts. The mixture was diluted with DCM (5 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification (FCC, SiO2, 20-100% EtOAc/hexanes) afforded the title compound (100 mg; 44%). 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.26 (s, 1H), 8.01 (td, J=1.1, 2.1 Hz, 1H), 7.99-7.90 (m, 1H), 7.45-7.36 (m, 2H), 5.64 (s, 2H), 4.07 (s, 3H), 3.92 (s, 3H). [M+H]=360.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[N:5][CH:4]=1
Reactant: ClCc1ccccc1
Reactant: COc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
A mixture of 9.0 g of 5-methoxy-2-(4-hydroxyphenyl)pyrimidine, 8.45 g of benzyl chloride, 270 ml of dimethylformamide (DMF), and 12.3 g of potassium carbonate was stirred at 80° C. for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and distilled to remove ethyl acetate to obtain 8.42 g (percent yield: 64.2%) of 5-methoxy-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][CH2:33][N:27]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2nc(N3CCCNCC3)ccc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-quinoline
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[C:4]([C:10]([CH3:12])=[O:11])[CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:11])[CH3:12])[CH:5]=[C:6]([CH3:9])[C:7]=1[O:8][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)c1cc(C)c(O)c(C)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(C)cc(C(C)O)cc1C

Procedure:
In the process for the production of 3,5-dimethyl-4-acetoxystyrene monomer, one may begin with commercially available 2,6-dimethyl phenol and esterify it with acetic anhydride to produce 2,6-dimethyl phenyl acetate. Then, via a Friedel-Crafts catalysis or Fries rearrangement this is converted to 3,5-dimethyl-4-hydroxy acetophenone. The 3,5-dimethyl-4-hydroxy acetophenone is then esterified with acetic anhydride. The latter is then hydrogenated to form 1-(3,5-dimethyl-4-acetoxyphenyl)ethanol. This is then dehydrated with an acid to form 3,5-dimethyl-4-acetoxystyrene monomer, copolymerized with unsubstituted 4-acetoxystyrene, and hydrolyzed to produce poly (3,5,-dimethyl-4-hydroxystyrene-co-4-hydroxystyrene).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:21][C:22]([OH:24])=O)[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][NH:32][CH2:33][CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][N:32]([CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)[C:22](=[O:24])[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: OCCNCc1ccccn1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)C)cn2)cc1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]3[O:26][CH2:25]3)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:30])[NH2:29]>C1COCC1>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]([OH:26])[CH2:25][NH:29][N:28]([CH3:30])[CH3:27])=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc(Nc2ccc(OCC3CO3)cc2)nc1Nc1ccccc1
Reactant: CN(C)N
Solvent: C1CCOC1
Product: CN(C)NCC(O)COc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 73.1 %

Procedure:
4-Anilino-5-bromo-2-[4-(2,3-epoxypropoxy)anilino]pyrimidine (Method 3, 100 mg, 0.24 mmol) was dissolved in THF (1 ml). N,N-Dimethylhydrazine (148 mg, 2.42 mmol) was added and the mixture was heated at 100° C. for 1 hour. Volatile material was removed by evaporation and the residue was triturated with diethyl ether (2 ml) to give the product as a yellow solid (83 mg, 74%). MS (MH+): 473, 475; HPLC (RT): 3.37.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](C(O)=O)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)=O>>[CH3:1][C:2]1[S:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1sc(C(=O)O)cc1-c1ccccc1
Agent: O=C=O
Product: Cc1sccc1-c1ccccc1

Procedure:
The 5-methyl-4-phenyl-2-thiophenecarboxylic acid (54 g, 0.25 mol) prepared as described above was heated to 220–230° C. until the evolution of carbon dioxide ceased. The product was collected and distilled, b.p. 117° C./10 torr. Yield 30 g (70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][C@H:8]([C:12]1[O:13][CH:14]=[C:15]([C:17](O)=[O:18])[N:16]=1)[CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:33][NH:34][CH3:35].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:33][N:34]([CH3:35])[C:17]([C:15]1[N:16]=[C:12]([C@H:8]([CH2:9][CH:10]=[CH2:11])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[O:13][CH:14]=1)=[O:18]
Reactant: CNC
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)c1nc(C(=O)O)co1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C=CC[C@H](CC(=O)OC(C)(C)C)c1nc(C(=O)N(C)C)co1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.8 %

Procedure:
A solution of 2-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-3-butenyl]-1,3-oxazole-4-carboxylic acid (Preparation 116) (10.77 g, 38.3 mmol) in dichloromethane (250 ml), at 0° C., was treated with 1-hydroxybenzotriazole hydrate (5.75 g, 42.6 mmol), dimethylamine hydrochloride (3.45 g, 42.3 mmol) and N,N-diisopropylethylamine (13 ml, 75.13 mmol) and lastly 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.10 g, 42.3 mmol), allowed to warm to room temperature and stirred for 20 hours under a nitrogen atmosphere. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, aqueous citric acid (10%), water and brine, dried over anhydrous sodium sulphate and filtered. The solvent was removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 7:3 (pentane:ethyl acetate) gradually changing to 1:1 (pentane:ethyl acetate) to afford the title compound as a colourless oil (9.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4](Cl)=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:7]=1F.NC(N)=[S:22].N1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[Cl:12][C:8]1[C:7]2[S:22][C:4]([C:3]3[C:2]([Cl:1])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:19])=[N:5][C:6]=2[CH:11]=[CH:10][N:9]=1
Reactant: NC(N)=S
Reactant: Fc1c(N=C(Cl)c2c(Cl)cccc2Cl)ccnc1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Clc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
A mixture of 2,6-dichloro-N-(2-chloro-3-fluoropyridin-4-yl)benzimidoyl chloride (400 mg, 1.15 mmol), thiourea (305 mg, 4.0 mmol) and pyridine (325 μL, 4.0 mmol) in anhydrous isopropanol (6 mL) was heated under reflux under nitrogen for 3.5 hours. Triethylamine (1 mL) was added and heating was continued for a further 2 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The resultant residue was partitioned between DCM (15 mL) and water (15 mL). The aqueous phase was extracted with DCM (2×10 mL), the combined organic extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% EtOAc in pentane) to give the title compound as a beige solid (270 mg, 74% yield). 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.52-7.48 (m, 2H), 7.45 (dd, J=9.6, 6.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:32])[CH2:19][CH2:18][C:17]([CH2:30][NH2:31])([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:31][CH2:30][C:17]1([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][CH2:19][C:14]([F:13])([F:32])[CH2:15][CH2:16]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: COc1cccc(C(=O)O)c1Cl
Product: COc1cccc(C(=O)NCC2(c3cnc(C(F)(F)F)nc3)CCC(F)(F)CC2)c1Cl

Procedure:
From 2-chloro-3-methoxybenzoic acid and [4,4-Difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine. LCMS (MH+): m/z=464.1, tR (minutes, Method F)=3.02
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].Cl.[Cl-].[Na+]>O1CCCC1>[F:18][C:19]([F:26])([F:25])[C:20]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1)=[O:21]
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
n-Butyllithium (2.5 M in hexane, 46 ml) was initially charged at −90° C. in tetrahydrofuran (250 ml). At −95° C., 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (25 g, 103 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 40 min, then cooled to −100° C., and ethyl trifluoroacetate (16.1 g, 113 mmol) was added dropwise, in the course of which the temperature was kept between −90° C. and −80° C. The reaction mixture was gradually warmed up to −20° C. and then cooled to −80° C. 10% hydrochloric acid and saturated sodium chloride solution were added dropwise. The reaction mixture was thawed within 16 h and then extracted with diethyl ether. The organic phase was washed with water and saturated sodium chloride solution and dried over sodium sulphate, and the solvent was removed under reduced pressure. The residue was taken up in toluene and distilled first at standard pressure, then under reduced pressure. 22.5 g (86% of theory) of 2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone were obtained.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C1C(=O)N(Cl)C(=O)C1.[Cl:20][C:21]1[C:29]([F:30])=[C:28]2[C:24]([CH:25]=[C:26]([CH:38]3[CH2:40][CH2:39]3)[N:27]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH3:37])[CH:35]=2)=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[C:29]([F:30])=[C:28]2[C:24]([C:25]([S:1][C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=3)=[C:26]([CH:38]3[CH2:40][CH2:39]3)[N:27]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH3:37])[CH:35]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(S)n1
Reactant: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)OC)n3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a stirred solution of methyl 6-mercaptopicolinate 6 (3.15 g, crude) in CH2Cl2 (50 mL) under inert atmosphere was added NCS (2.49 g, 18.63 mmol) at RT and stirred for 1 h. To this, indole 5 (5.6 g, 18.47 mmol) in CH2Cl2 (50 mL) was added at RT and stirred for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted CH2Cl2 (100 mL) washed with water (3×100 mL). The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel column chromatography; 10% EtOAc/hexanes) to afford 9 (2.8 g, 32%) as a pale brown solid. 1H NMR (500 MHz, DMSO-d6): δ 7.79 (d, J=7.5 Hz, 1H), 7.66 (d, J=10.5 Hz, 2H), 7.51 (t, J=7.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.10-7.07 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.28 (q, 2H), 4.00 (s, 3H), 1.75-1.69 (m, 1H), 1.58 (t, J=7.0 Hz, 3H), 1.09-1.08 (m, 2H), 0.87-0.84 (m, 2H); LC-MS: 98.4%; m/z 471.4 (M+H+);(column; X-select CSH C-18, (50×3.0 mm, 3.5 μm); RT 4.25 min. 5.0 mM NH4OAc (Aq): ACN; 0.8 mL/min); HPLC: 98.1%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.02 min. ACN: 0.025% TFA (aq); 0.5 mL/min).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1.C(N(C(C)C)[CH:28]([CH3:30])[CH3:29])C.C(Br)C=C>CN(C)C=O>[CH2:30]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1)[CH:28]=[CH2:29]
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCNCc1noc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 6 %

Procedure:
5.17 g (15 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 45 ml of N,N-dimethylformamide, 6.5 ml (37.5 mmol) of N-ethyldiisopropylamine and 3.63 g (30 mmol) of allyl bromide were stirred at room temperature for 1 hour. The reaction solution was evaporated and the residue was chromatographed on 250 g of silica gel while eluting with ethyl acetate. The uniform fractions having the smaller Rf value were evaporated. There was obtained 0.344 g (6%) of 3-(3-allylaminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]-[1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 171°-174°.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[C:28]([O:36][CH3:37])=[C:29]([OH:35])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1>CN(C)C=O.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>[OH:35][C:29]1[C:30]([O:33][CH3:34])=[C:31]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)[CH:32]=[CH:27][C:28]=1[O:36][CH3:37]
Reactant: COc1ccc(Br)c(OC)c1O
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
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: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Temperature: 85 °C
Yield: 40.7 %

Procedure:
A stirring solution of 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-isobenzofuran-1-one (2.23 g, 8.58 mmol) in dimethylformamide (30 mL) was purged with argon for 1 h, to this cesium carbonate (8.37 g, 25.74 mmol), Pd(PPh3)4 (495 mg, 0.429 mmol) and 3-bromo-2,6-dimethoxy-phenol (2.0 g, 8.58 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded the title compound as a solid (1 g, 40.7%).
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:10])[CH3:9]>CCOCC>[C:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: [O-]c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCOCC
Product: CC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A vigorously stirred suspension of thallous phenoxide (5 g., 0.017 m.) in anhydrous ether (15 ml.) is treated dropwise with freshly distilled acetyl chloride (1.33 g., 0.017 m.) in anhydrous ether (3 ml.) over 5 mins. at such a rate that the exothermic reaction is controlled. The mixture is then stirred for 1 hour at room temperature, the precipitated thallous chloride removed by filtration through Celite and the solvent evaporated under vacuum. The residual colorless oil is distilled to give phenyl acetate, 2.27 g., 98%, b.p. 110°/58 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:12])[NH:6][C:5]2=[O:13].[CH3:14][O-].[Na+].IC>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12][CH3:14])[NH:6][C:5]2=[O:13]
Reactant: O=c1[nH]c(=S)[nH]c2ccc(Br)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CI
Product: CSc1nc2ccc(Br)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
To a solution of compound 4a (8.43 g, 32.8 mmol) in 130 mL of DMF was added a solution sodium methoxide (0.50 M, 32.8 mmol) in methanol (65.6 mL) and the mixture was stirred at room temperature for 15 minutes. Iodomethane (2.04 mL, 32.8 mmol) was added and the reaction mixture was stirred at room temperature for 22 hours. The solvents were evaporated under reduced pressure and the remaining solid was dissolved in 500 mL of EtOAc and washed with 400 mL of a saturated solution of aqueous NaHCO3. The organic layer was dried over MgSO4, concentrated under reduced pressure and precipitated from 50 mL of ethyl alcohol, to give 5a as a white solid (8.03 g, 90%). mp: 230° C.,
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[CH3:40]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([C:39](=[O:41])[CH3:40])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(=O)N1CCN(C(=O)N2C(c3ccc(C(C)(C)C)cc3OC(C)C)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H55N4O3Cl2 [(M+H)+] 663.2863, observed 663.2857.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([CH:20]=[O:21])[N:10](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].CO.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([CH:20]=[O:21])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1cc2nc(Cl)ccc2[nH]1
Reaction time: 0.67 h

Procedure:
A solution of 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde (0.42 g, 1.3 mmol, prepared in Step 1) in THF (10 mL) was added to a mixture of 2.8 M NaOH (12 mL, 34 mmol) and MeOH (10 mL) at 0° C. After 40 minutes, the reaction was allowed to come to room temperature and stir for 30 minutes. Saturated NH4Cl was added and was extracted twice with DCM. The extracts were washed with water and then with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a white solid (0.19 g, 80%).