Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[O:14]C=[N:12][C:11]=3C(OC)=O)[CH:8]=[CH:9][C:2]1=2.[ClH:19]>CO.O1CCCC1>[ClH:19].[NH2:12][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:2]2[O:1][CH:5]=[CH:4][C:3]=2[CH:6]=1)=[O:14]
Reactant: COC(=O)c1ncoc1-c1ccc2occc2c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCC(=O)c1ccc2occc2c1
Reaction time: 8 h

Procedure:
To a solution of the crude product of methyl 5-(5-benzo[b]furyl)oxazol-4-carboxylate (1.14 g) in methanol (20 ml) and tetrahydrofuran (5 ml) was added conc. hydrochloric acid (8 ml), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with methanol-diethyl ether-acetone to obtain 5-(aminoacetyl)benzo[b]furan hydrochloride (600 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=O)=[CH:4][N:3]=1.[NH2:11][NH2:12]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[NH:11][N:12]=[CH:9][C:5]2=[CH:4][N:3]=1
Reactant: O=Cc1cnc(Cl)nc1Cl
Reactant: NN
Solvent: C1CCOC1
Product: Clc1ncc2cn[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 2,4-dichloropyrimidine-5-carbaldehyde (7.75 g, 43.8 mmol, Preparation #1) in THF (100 mL) was added to a 500 mL round-bottomed flask charged with anhydrous hydrazine (3.0 mL, 96 mmol) in THF (250 mL). The reaction mixture was allowed to stir at ambient temperature for about 1 h after which the reaction mixture was concentrated under reduced pressure. The crude product was suspended in DCM (100 mL) and filtered through a silica gel pad. The silica gel pad was washed with additional DCM (2×20 mL) and the combined organic layers were concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 30% EtOAc in heptane to provide 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.3 g, 34%) as a white solid. LC/MS (Table 2, Method a) Rt=1.29 min; MS m/z: 155 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:63][CH:64]([CH3:68])[C:65](O)=[O:66]>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[C:21]([F:38])=[C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:13][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:65](=[O:66])[CH:64]([CH3:68])[CH3:63])[N:8]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:29]
Reactant: CC(C)C(=O)O
Reactant: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 55 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
To suspension of N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.1 g, 0.178 mmol) in dichloromethane (1.778 ml) was added HATU (0.084 g, 0.222 mmol) and 2-methylpropanoic acid (0.047 g, 0.533 mmol). The reaction mixture was stirred and heated at 55° C. After 16 h, the reaction mixture was quenched with water, extracted with DCM (2×), dried over MgSO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with DCM with 10% MeOH in DCM (5% to 40%) and collected fractions to obtain the title compound as a solid (48 mg, 42% yield). MS (ESI): 633 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:6]1=2>[Pd].CCO>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCOc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN1CCOc2ccc(N)cc21
Reaction time: 3 h

Procedure:
To an oven dried, argon purged 100 mL round bottom flask fitted with a magnetic stirbar was added N,N-dimethyl-2-(6-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanamine (0.10 g, 0.398 mmol) and EtOH (10 mL). At this time, stirring of the reaction began. 10% Pd—C (0.042 g, 0.040 mmol) was added, the flask was evacuated, and the mixture was subjected to hydrogenation under standard conditions (atmospheric H2 pressure using a balloon). After 3 hours, the mixture was filtered through a pad of Celite and washed with ethanol. The pale peach colored solution, which darkened upon exposure to air, was concentrated to approximately 10 mL to yield the title compound. This compound was utilized immediately in the next step. ESI-MS (m/z, %): 222 (MH+, 100).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
The compound obtained in Example 5 (820 mg, 2.6 mmol) was dissolved in dichloromethane (50 ml). Methanesulfonyl chloride (0.24 ml, 3.1 mmol) and triethylamine (0.81 ml, 3.1 mmol) were added, which was then stirred for 30 min at 0° C. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound (600 mg, Yield 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[Cl:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([NH2:26])[CH:20]=[CH:21][CH:22]=2)[N:17]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:26][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[N:17]=[C:16]([Cl:15])[CH:25]=[CH:24]3)(=[O:10])=[O:9])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: Nc1cccc2ccc(Cl)nc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Yield: 22.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-chloro-2-nitrobenzene-1-sulfonyl chloride (Intermediate 454) (0.86 g, 3.37 mmol), 2-chloro-quinolin-8-ylamine (Intermediate 26) (0.5 g, 2.80 mmol), DMAP (cat), pyridine (0.68 ml, 8.42 mmol) and DCM (10 ml) gave the title compound (0.25 g, 23%) after purification by column chromatography DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26](O)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Reactant: Nc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)Nc2ccccc2)s1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylic acid (80.mg), aniline (0.019 ml), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (113 mg) and N,N-diisopropylethylamine (0.076 ml) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 21 hours and at 55 ° C. for 3 hours. The reaction mixture was poured into 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with ethyl ether to give tert-butyl 4-{2-[2-(acetylamino)-5-(anilinocarbonyl)-1,3-thiazol-4-yl]ethyl}phenylcarbamate (57.2 mg) as a colorless solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.CN(C)[CH:22]=[O:23]>C1COCC1>[F:13][C:14]1[N:15]=[CH:16][CH:17]=[CH:18][C:19]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cccnc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 45.9 %

Procedure:
A solution of n-butyllithium (77 mL, 2.5 M in hexane, 0.19 mol) was added to a solution of N,N-diisopropylamine (27 mL, 0.19 mol) in dry THF (400 mL) under an atmosphere of nitrogen at −78° C. After the addition, the mixture was warmed to 0° C. for 15 minutes and then cooled again to −78° C. 2-Fluoropyridine (15.0 mL, 0.174 mol) was added dropwise to the mixture and stirred at −78° C. After 45 minutes, a pale yellow precipitate formed. N,N-Dimethylformamide (27 mL, 0.35 mol) was added slowly via syringe maintaining temperature below −55° C. After ten minutes, the cooling bath was removed and the mixture slowly warmed to room temperature. The reaction was quenched with NH4Cl/H2O and then 4 M HCl to adjust the pH ˜7. NaHCO3/H2O was then added to adjust the pH 9-10, and then extracted three times with Et2O. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to a yellow oil. The residue was purified by chromatography on silica gel, eluting with 25% EtOAc/hexane to provide 2-fluoronicotinaldehyde as a pale yellow oil (10.0 g, 45%). 1H NMR (CDCl3) δ 10.33 (s, 1H), 8.49 (m, 1H), 8.32 (m, 1H), 7.40 (m, 1H). LC/MS: 126 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH2:17]([N:19]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH2:20][CH3:21])[CH3:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([C:26]2[CH:30]=[CH:31][C:23]([CH2:22][N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[CH:24][CH:25]=2)[OH:28])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: CCN(CC)Cc1ccc(C(=O)O)cc1
Product: CCN(CC)Cc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccc(C(C)=O)cc32)cc1

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-diethylaminomethyl-benzoic acid
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:38][C:39](Cl)=[O:40]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[O:12][CH2:38][C:39]1=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(F)c(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)C(=O)COC1c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of (1RS,2SR)-3-(benzylamino)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-(3-chloro-4-fluorophenyl)propan-1-ol (14.1 g) and triethylamine (4.95 mL) in THF (100 mL) was added chloroacetyl chloride (2.59 ml) under ice-cooling, and the mixture was stirred at 0° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained mixture was diluted with THF (300 ml), 1 N aqueous sodium hydroxide solution (63 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (6.72 g).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([F:14])=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].C1COCC1.Cl>CO>[F:3][C:4]1[C:13]([F:14])=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OC)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
Sodium hydroxide (2N, 50 mL) was added into a mixture of methyl 2,3-difluoro-4-methoxybenzoate (10.0 g, 49.5 mmol), THF (100 mL) and MeOH (100 mL). The mixture was stirred at room temperature for 6 h, and acidified with HCl (2N). The precipitated solid was filtered off, washed with water and dried to give a white solid (8.9 g, 96% yield, m.p. 194–196° C.); MS m/e 187 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Agent: Cl
Product: Cc1ccc(Cn2cc(C#Cc3cccc(Cl)c3)nc2C)cn1

Procedure:
The title compound, MS: m/e=322.5 (M+H30), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 5-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][N:8]=1)(=O)=O.[CH3:21][Sn:22](Cl)([CH3:24])[CH3:23]>>[C:13]1([C:10]2[CH:11]=[CH:12][C:7]([Sn:22]([CH3:24])([CH3:23])[CH3:21])=[N:8][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2)cn1)C(F)(F)F
Reactant: C[Sn](C)(C)Cl
Product: C[Sn](C)(C)c1ccc(-c2ccccc2)cn1

Procedure:
5-phenylpyridin-2-yl trifluoromethanesulfonate (1.5 mmol) was used in Procedure J with trimethyltin chloride to yield 5-phenyl-2-(trimethylstannyl)pyridine. The crude material (˜1.25 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (1 mmol). Purified by silica gel chromatography (1% acetone/methylene chloride) to yield N-(4-chloro-3-(5-phenylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a tan solid: TLC Rf=0.15 (1% acetone/methylene chloride); MS (Q1) 467 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([NH:29]C(=O)OC(C)(C)C)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([NH2:29])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Yield: 99.7 %

Procedure:
A solution of tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}carbamate (2.65 g, 4.3 mmol) was stirred in dichloromethane (32 mL) and trifluoroacetic acid (8 mL) for 1.5 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with 3.8 M NaOH. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4 to yield 2.21 g (99%) of pure 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.87 (d, J=13.56 Hz, 2 H) 2.15-2.39 (m, 2 H) 3.82-4.11 (m, 2 H) 5.10 (br. s., 2 H) 7.11-7.62 (m, 13 H) 8.40 (s, 1 H), [M+H]+ 515.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:50]3[CH2:49][CH2:48][N:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:52][CH2:51]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C37H47N4O5SCl2 [(M+H)+] 729.2639, observed 729.2634.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH2:13][CH2:14][OH:15])[CH:12]=1>C1COCC1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH2:13][CH2:14][O:15][C:1]([Cl:4])=[O:2])[CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc([N+](=O)[O-])c(CCO)c1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CCOC(=O)Cl)c1
Yield: 96 %

Procedure:
Phosgene was introduced in a solution of 2-(5-methoxy-2-nitrophenyl)ethanol (3.0 g, 15 mmol) in THF (40 ml, dist. over CaH2) at room temperature under stirring. After 2.5 h the excess phosgene and the solvent were removed by distillation in a high vacuum. 2-(5-methoxy-2-nitrophenyl)ethoxycarbonyl chloride (3.72 g, 96%) was obtained as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[Br:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27](=O)[CH2:28]Br>>[Br:23][C:24]1[CH:25]=[C:26]([C:27]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:28]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3cccc(Br)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 34 %

Procedure:
4-[4-(3-Bromo-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (106 mg, 34%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-bromophenacyl bromide (available from Aldrich Chemical Company, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.43 (s, 1H), 8.08-8.29 (m, 4H), 7.41-7.82 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:26][C:27]([F:37])([F:36])[C:28]([NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH:31]([NH:30][C:28](=[O:29])[C:27]([F:37])([F:36])[F:26])[CH2:32]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: O=C(NC1CCNC1)C(F)(F)F
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(NC(=O)C(F)(F)F)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 3-(2,2,2-trifluoroacetylamino)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.34 minutes; C23H20Cl2F3N5O3 (542.34); mass spectrum: (M−H)−=541/543/545 (chlorine isotope).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (195 mg, 0.85 mmol) in THF (5 mL) was added sodium hydride (60% dispersion in oil, 41 mg, 1.02 mmol, 1.2 equiv.). After stirring at room temperature for 2 h, 4-fluorobenzyl bromide (127 μL, 1.02 mmol, 1.2 equiv.) was added. The reaction mixture was allowed to stand overnight. After quenching with H2O, the phases were separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4. After the solvent was removed, the residue was purified by CC (SiO2, hexane/EtOAc 4:1) to afford 1-(tert-butoxycarbonyl)-4-[2-(4-fluorobenzyloxy)ethyl]piperidine (257 mg, 90%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, 2H, J=8.0 Hz, J=5.2 Hz), 7.01 (t, 2H, J=8.4 Hz), 4.61 (s, 2H), 4.05 (d, 2H, J=12.8 Hz), 3.48 (t, 2H, J=6.0 Hz), 2.66 (t, 2H, J=12.4 Hz), 1.55 (m, 5H), 1.44 (s, 9H), 1.10 (m, 2H).