Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([CH:5]1[C:14](=[O:15])[CH:13]2[CH2:16][CH:7]3[CH2:8][CH:9]([O:17][C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)=[O:19])[CH2:10][CH:11]([CH2:12]2)[N:6]13)=O.[Li+].[Cl-].CCOC(C)=O.CO>CN(C)C=O>[O:15]=[C:14]1[CH:13]2[CH2:16][CH:7]3[CH2:8][CH:9]([O:17][C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)=[O:19])[CH2:10][CH:11]([CH2:12]2)[N:6]3[CH2:5]1
Reactant: COC(=O)C1C(=O)C2CC3CC(OC(=O)c4c[nH]c5ccccc45)CC(C2)N31
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(OC1CC2CC3CC(C1)N2CC3=O)c1c[nH]c2ccccc12
Temperature: 140 °C
Yield: 83 %

Procedure:
A mixture of 3.1 gr (8.1 mmol) of 5-(1H-Indole-3-carbonyloxy)-10-oxo-8-aza-tricyclo[5.3.1.03,8]undecane-9-carboxylic acid methyl ester and LiCl (0.69 gr, 16.23 mmol) in dimethylformamide (90 mL) is heated to 140° C. Once 4 hours have elapsed, and after checking by thin-layer chromatography (AcOEt/MeOH 9:1) that the reaction has been completed, the mixture is left to cool. Volatile substances are evaporated at low pressure and the residue is dissolved in dichloromethane (150 mL). This is washed with a saturated aqueous solution of NaCl (70 mL), and the organic phase is dried over magnesium sulphate and evaporated, to provide crude 1H-Indole-3-carboxylic acid 10-oxo-8-aza-tricyclo[5.3.1.03,8]undec-5-yl ester as a solid (2.18 gr, 83%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[N:20]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[N:19]=[CH:18][N:17]=4)[S:13][C:10]=3[C:11]=2[N:12]=1.C([O-])(=O)C.[K+].[CH3:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1>C(#N)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>[CH3:34][C:35]1[C:40]([C:2]2[CH:3]=[CH:4][C:5]3[O:6][CH2:7][CH2:8][C:9]4[CH:15]=[C:14]([C:16]5[N:20]([C:21]6[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=6[F:28])[N:19]=[CH:18][N:17]=5)[S:13][C:10]=4[C:11]=3[N:12]=2)=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: Cc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ncccc1-c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Yield: 70 %

Procedure:
5-(2-(Chloro)-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-1-(2,4-difluorophenyl)-1H-1,2,4-triazole (50 mg, 0.1 mmol) was dissolved in 1 ml acetonitrile and 1 ml water, with potassium acetate (39.9 mg, 0.406 mmol). The solution was degassed by bubbling with nitrogen for 5 min. 2-Methylpyridin-3-ylboronic acid (21.4 mg, 0.156 mmol) was added, then tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol). The reaction was microwaved at 300 watts, 140° C. for 20 minutes, cooled to room temperature, and extracted with ethyl acetate. The combined organics were concentrated and purified by reverse phase HPLC to give 474 (70% yield). MS: (ESI+)=474.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][N:15]1[C:14]2[C:19]([N:20]=[C:12]([S:11][C:4]3[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:13]=2)=[C:18]([NH2:21])[N:17]=[CH:16]1
Reactant: Clc1ccccc1CCBr
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncn(CCc4ccccc4Cl)c-3n2)c1

Procedure:
The title compounds were prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-2-chloro-benzene by a procedure similar to examples 1 and 2. The isomers were separated by preparative HPLC. 9-[2-(2-Chloro-phenyl)-ethyl]-8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine: Yield 18%, 1H NMR (DMSO-d6) δ 8.23 (s, 1H), 7.82 (bs, 2H), 7.36 (dd, J=8.0, 1.2 Hz, 1H), 7.24-7.15 (m, 2H), 7.03-6.99 (m, 2H), 6.85 (dd, J=9.2, 3.2 Hz, 1H), 6.47 (d, J=2.8 Hz, 1H), 4.46 (t, J=7.2 Hz, 2H), 3.73 (s, 3H), 3.61 (s, 3H), 3.16 (t, J=7.2 Hz, 2H); LC-MS [M+H]+ 442.1. 3-[2-(2-Chloro-phenyl)-ethyl]-8-(2,5-dimethoxy-phenylsulfanyl)-3H-purin-6-ylamine: Yield, 11%, 1H NMR (DMSO-d6) δ 8.34 (s, 1H), 8.16 (bs, 1H), 7.41 (m, 1H), 7.29-7.11 (m, 6H), 4.56 (t, J=6.8 Hz, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 3.30 (t, J=6.8 Hz, 2H), LC-MS [M+H]+ 442.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[N:6][CH:7]=1.CN1[C:30]([CH2:31][O:32]C2C=CC(C(O)=O)=CN=2)=[C:29]([C:42]2[CH:47]=CC=CN=2)[N:28]=N1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH:29]3[CH2:30][CH2:31][O:32][CH2:47][CH2:42]3)=[O:22])=[CH:18][N:17]=2)=[N:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 78 %

Procedure:
As described for example 26b, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (82 mg, 0.25 mmol), instead of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid, was converted to the title compound (80 mg, 78%) which was obtained as a white solid. MS: m/e=413.4 [M+H]+.
Reaction SMILES: C1(C)C(C=O)=CC=CC=1.[CH3:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].CN.[BH4-].[Na+].Br[CH2:25][C:26]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)=[O:27]>>[CH3:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[CH2:25][CH:26]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)[OH:27]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CNCc1ccccc1C
Agent: CN
Agent: Cc1ccccc1C=O
Agent: [BH4-]
Product: Cc1ccccc1CN(C)CC(O)c1ccc2ccccc2c1

Procedure:
o-Tolualdehyde was converted to methyl-(2-methyl-benzyl)-amine via reductive amination using aqueous methyl amine and NaBH4. Methyl-(2-methyl-benzyl)-amine was then alkylated with 2-bromo-2′-acetonaphthone followed by reduction by NaBH4 to give 2-[methyl-(2-methyl-benzyl)-amino]-1-naphthalen-2-yl-ethanol as a clear, light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.78-7.87 (m, 4H), 7.40-7.51 (m, 3H), 7.14-7.30 (m, 4H), 4.89 (dd, J=10.1, 3.9 Hz, 1H), 3.71 (d, J=12.9 Hz, 1H), 3.54 (d, J=12.9 Hz, 1H), 2.70 (dd, J=12.3, 10.3 Hz, 1H), 2.62 (dd, J=12.4, 3.9 Hz, 1H), 2.41 (s, 3H), 2.35 (s, 3H); Cl MS m/z 306 [C21H23NO+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH3:19].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:16]([C:5]1([CH2:14][CH2:2][CH2:3][CH3:4])[C:4]2[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=2)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: CCCCC1(CCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Yield: 192.6 %

Procedure:
2,7-Dibromofluorene (32.4 g, 0.1 mole), n-butyl bromide (75 g, 0.55 mole), tetra-n-butylammonium chloride (1.5 g) and 50 percent aqueous NaOH solution were stirred vigorously at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and extracted with ether. The ether extracts were washed with water and dried over anhydrous magnesium sulfate. Removal of solvent gave a yellow solid which was recrystallized from 400 mL of ethanol to provide 9,9-di-n-butyl-2,7-dibromofluorene as colorless crystals (42 g, 96 percent yield), melting point 120.5° C. to 121.5° C. HPLC analysis showed that the product had a purity of 99.5 percent and the proton and carbon-13 NMR were consistent with the title structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][CH2:12]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])[CH3:15].[O-]CC.[Na+].[Na]>C(O)C>[CH2:27]([O:26][C:24](=[O:25])[C:18]([NH:17][C:14](=[O:16])[CH3:15])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][C:11]#[C:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:28]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCC#CCCl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC#CCNC(=O)OC(C)(C)C)(NC(C)=O)C(=O)OCC
Yield: 49.4 %

Procedure:
Ex-8d) 12.1 g 1-t-Butyloxycarbonylamino-4-chloro-2-butyne is refluxed for 16 h with a mixture of 8 g diethyl acetamidomalonate and sodiumethoxide prepared from 900 mg of sodium in 100 mL of absolute ethanol. Ethanol is then removed under vacuum and the residual mass is partitioned between water and ethylacetate/ether (1:1). The organic layer is treated with 0.5N NaOH and 0.5N HCl and washed with water. It is then dried over Na2SO4, filtered and concentrated. The product is crystallized from ethylacetate/petroleum ether to give ˜7 g of Ethyl-2-acetylamino-6-t-butyloxycarbonylamino-2-ethoxycarbonyl-4-hexynoate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[CH:8]=[C:9]([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1.O>C(#N)C.CN(C)C=O>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:10]=[CH:11][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: Clc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)c1

Procedure:
27.2 g (0.4 mol) imidazole and 62.8 g (0.2 mol) of (m-chlorophenyl)-(diphenyl)-methyl chloride are heated to 80°C for 4 hours in 150 ml of dry acetonitrile and 50 ml dimethyl formamide. The solvent is then drawn off and the residue is digested with water to remove the imidazole hydrochloride. The residue is taken up in methylene chloride, dried over sodium sulfate, and the viscous oil remaining behind after the distilling off of the solvent is recrystallized from cyclohexane. 52 g (75% of the theory) of 1-[(m-chlorophenyl)-(bisphenyl)-methyl]-imidazole of m.p. 101°C are obtained.
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)=[N:6][CH:5]=1)[C:2]#[N:3].[CH3:18]O>O=P(Cl)(Cl)Cl>[CH3:18][O:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7]2[S:8][C:4]([S:1][C:2]#[N:3])=[CH:5][N:6]=2)=[N:15][CH:14]=1
Reactant: CO
Reactant: N#CSc1cnc(Nc2ccc(CO)cn2)s1
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1ccc(Nc2ncc(SC#N)s2)nc1
Temperature: 85 °C

Procedure:
(6-(5-Thiocyanatothiazol-2-ylamino)pyridin-3-yl)methanol (0.094 g, 0.356 mmol) was dissolved in POCl3 (3 mL) and the reaction was heated at 85° C. for 3 hours. POCl3 was then evaporated and the resulting oil was washed with water to give a gummy solid. Methanol (10 mL) was added to the solid and the resulting suspension was stirred at 23° C. for over a month. Methanol was evaporated to almost dryness and water was added to precipitate the oil. The resulting solid was filtered and dried under vacuum to give the crude title material (0.109 g, quant.) which was used as such in the next reaction. HPLC ret. time (Condition A): 1.603 min. LC/MS (M+H)+: 279.
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[N:9]=[C:8](F)[C:7]=1[F:16])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>C(O)CC>[C:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[N:9]=[C:8]([NH:18][NH2:19])[C:7]=1[F:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(F)nc(F)c(F)c1OC(C)(C)C
Reactant: NN
Solvent: CCCO
Solvent: O
Product: COc1c(F)nc(NN)c(F)c1OC(C)(C)C
Yield: 88.5 %

Procedure:
A mixture of 4-tert-butoxy-2,3,6-trifluoro-5-methoxypyridine (1.5 g. 6.4 mmol) and hydrazine monohydrate (1.7 mL, 34 mmol [Qun Li et al. J. Med. Chem. 1996, 39(16), 3070-3088]) in n-propanol (10 mL) was heated to reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in dichlromethane, washed with water and concentrated to afford crude (4-tert-butoxy-3,6-difluoro-5-methoxypyridin-2-yl)hydrazine (1.4 g, 90%). 1.2 g of the material was redissolved in methanol (12 mL) and 20% aqueous sodium hydroxide (2.5 mL). Oxygen was passed through the solution with vigorous stirring for 20 hours. The deep blue solution was diluted with water (12 mL) and extracted with hexane (2×30 mL). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexane (1:16) to afford the title compound (0.9 g). 1H NMR (400 MHz, CDCl3) δ 7.74 (m, 1H), 3.93 (m, 3H), 1.41 (s, 9H). MSCI: m/z=218 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]>[Pt]=O.C(O)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([N:16]3[CH:12]=[CH:10][CH:9]=[CH:15]3)[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: O=[Pt]
Solvent: CCO
Product: CCNC(=O)Nc1nc2ccc(-n3cccc3)cc2s1
Temperature: 25 °C

Procedure:
Charged about 500 mg N-ethyl-N′-(6-nitro-1,3-benzothiazol-2-yl)urea into about 75 ml ethanol. Added about 20 mg platinum oxide then evacuated and released to hydrogen three times. The system was then put under hydrogen pressure (about 20–40 psi) for about 5–20 hours. The reaction was stopped and the entire mass was filtered through diatomaceous earth and washed with methanol. The solvent was removed in vacuo and the crude N-(6-amino-1,3-benzothiazol-2-yl)-N′-ethylurea was used for the next step without further purification. Charged about 0.44 g N-(6-amino-1,3-benzothiazol-2-yl)-N′-ethylurea into about 15 ml acetic acid then added about 0.23 ml 2,5-dimethoxytetrahydrofuran. Refluxed for about 1 hour then cooled to room temperature. The solvent was removed in vacuo and the product was purified by preparative HPLC. 1H NMR 1.1 (t, 3H), 3.2 (m, 2H), 6.26 (m, 2H), 6.71 (m, 1H), 7.35 (m, 2H), 7.55 (m, 1H), 7.7 (m, 1H), 8.1 (m, 1H), 10.69 (br s, 1H); LC/MS 3.1 min, 285 (M−1).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=3[C:14](=[O:22])[N:13]([CH3:23])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>C(O)(=O)C>[Cl:21][C:20]1[C:15]2[C:14](=[O:22])[N:13]([CH3:23])[CH2:12][C:11]3[N:10]([CH:9]=[N:8][C:7]=3[C:5]3[O:6][C:2]([CH2:3][N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[CH:1][N:4]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)o1
Temperature: 25 °C
Reaction time: 67 h
Yield: 28 %

Procedure:
A solution of 3.28 g of (0.010 mol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 60 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 67 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark solid residue was dissolved in 100 ml of THF, treated with 13.7 ml (0.10 mol) of dipropylamine and stirred at room temperature for 3 hrs. The brown-orange suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the beige-brownish product was chromatographed twice: firstly over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent, then over silica gel with dichloromethane/methanol 98:2 as the eluent. There were obtained 1.2 g (28%) of 7-chloro-3-(5-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as a yellow viscous oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:23][C:24]=1[CH2:25][CH2:26][CH2:27]O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:27][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][CH:30]=4)=[N:21][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol (example 8 c]) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield (6-{3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless gum.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[CH3:23].[SH:24][C:25]1[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[N:26]=1.[OH-].[Na+]>C(O)C.O>[CH3:23][C:7]1[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:24][C:25]1[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[N:26]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(SCCCSc2nc3ccccc3[nH]2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 83 %

Procedure:
2-{[[4-(3-Chloropropylthio)-3-methyl-2-pyridinyl]methyl]thio}-1 H-benzimidazole (1 mmol) is stirred at 60° C. for 20 h with 2-mercapto-1 H-benzimidazole (1.05 mmol) and 1N sodium hydroxide solution (3 ml) in 10 ml of ethanol and subsequently diluted with a further 10 ml of water. The mixture is allowed to cool, and the precipitated solid is filtered off, washed with ethanol/water 1/1 and dried in vacuo at 50° C. The title compound is obtained as a gray powder; m.p. 85°-87° C.; yield: 83% of theory.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.C[C:14]1[C:27]2[C:18](=[C:19]3C(=[CH:25][CH:26]=2)C=[CH:22][CH:21]=[N:20]3)[N:17]=[CH:16][CH:15]=1.CI>CCCCCC.O1CCCC1.C(Cl)(Cl)Cl.O>[CH2:3]([C:2]1[C:1]2[C:19](=[C:18]3[C:27](=[CH:26][CH:25]=2)[CH:14]=[CH:15][CH:16]=[N:17]3)[N:20]=[CH:21][CH:22]=1)[CH3:4]
Reactant: [Li]CCCC
Reactant: Cc1ccnc2c1ccc1cccnc12
Solvent: CI
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1ccnc2c1ccc1cccnc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a Schlenk tube reactor equipped with a magnetic stirrer and in an inert atmosphere (argon) 2520 μl 1.6 M (4.0 mmol) n-butyllithium solution in n-hexane was added dropwise with the aid of a syringe to a solution of 600 μl diisopropylamine (HDA) in 2800 μl anhydrous tetrahydrofuran (THF) at 0° C. The resulting mixture was stirred for 15 minutes at 0° C. To this mixture a solution of 749.0 mg (3.86 mmol) 4-methyl-1,10-phenanthroline, dissolved in 18 ml anhydrous THF, was added in 5 minutes. The reactor contents were stirred at 0° C. for 1 hour, whereupon 570 mg (4.0 mmol) methyl iodide was added with the aid of a syringe. The mixture was stirred at 0° C. for 45 minutes, after which the external cooling was stopped and reactor contents were allowed to warm to room temperature (18-20° C.) and stirred at that temperature for 18 hours. Subsequently 1 ml water was added to the reactor and the mixture was stirred for about 5 minutes and transferred into a separatory funnel with the aid of 15 ml water and 100 ml chloroform. After equilibration the organic phase was removed, and the aqueous phase was extracted with 50 ml chloroform. The combined chloroform phases were washed consecutively with 10 ml water and 15 ml brine, and dried over anhydrous magnesium sulfate. The chloroform was removed at 60° C. under reduced pressure (approx. 250 mbar) using a rotary evaporator. The crude product was purified by column chromatography using basic alumina; column diameter and height: 1.7×1.8 cm. After elution with 300 ml of diethyl ether the product was eluted with 200 ml chloroform. The appropriate fraction (yellow band) was collected and the solvent was removed at 60° C. under reduced pressure (approx. 250 mbar) using a rotary evaporator. The residue was sublimed at 120-180° C. under reduced pressure (0.5 mbar). The pale yellow solid was stored in a dessicator under reduced pressure (1 mbar) over phosphorus pentoxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH:16]=[CH:15][CH2:14][O:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH:16]=[CH:15][CH2:14][O:13]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CC=CCO2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(N2CC=CCO2)c(Cl)c1

Procedure:
Prepared analogously to Example 2d from methyl 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoate and sodium hydroxide in a solvent mixture of water and ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2([OH:27])[C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N2CCOCC2)cc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1ccc(N2CCOCC2)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 77.3 %

Procedure:
With 2.00 g of the compound obtained in Step 191-1 and 953 mg of 5-chloroisatin as starting materials, 1.52 g of the title compound (pale yellow amorphous) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH:15]([F:17])[F:16])[CH2:13][CH2:12][O:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.Cl[C:20]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.C(OCC)(=O)C.CCCCCCC>ClCCl>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:20]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:14][C:10]2[O:11][CH2:12][CH2:13][C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:18])([CH:15]([F:16])[F:17])[N:9]=2)=[CH:34][CH:33]=1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)CCO1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1ccc(C(NC2=N[C@@](c3cc(Br)ccc3F)(C(F)F)CCO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a solution of (S)-4-(5-bromo-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate E6.1) (372 mg, 1.15 mmol) in dichloromethane (10 ml) was added at 0° C. 4,4′-(chloro(phenyl)methylene)bis(methoxybenzene) (585 mg, 1.73 mmol). The reaction mixture was stirred at 23° C. for 16 hours. Extraction with water, then drying of the organic layer over Na2SO4, filtration, evaporation. Chromatography on 20 g silica gel with ethyl acetate/heptane 0-50% gave the (S)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-4-(5-bromo-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (725 mg, 1.1 mmol, 95.6% yield) as a white foam. MS (ISP): m/z=625.2 [M+H]+ and 627.3 [M+2+H]+.