Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=2)=[CH:4][C:5]([CH:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1.[Br:57]Br>C(O)(=O)C>[Br:57][C:7]1[C:2]([Cl:1])=[C:3]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=2)[CH:4]=[C:5]([CH:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[O:10]2)[C:6]=1[OH:8]
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a mixture of 5-chloro-4-(4-ethylbenzyl)-2-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenol (3.0 g, 3.90 mmol) and TEA (1.63 mL) in acetic acid (20.1 mL) was added dropwise bromine (0.30 mL, 5.85 mmol) at 0° C. under nitrogen atmosphere. After stirring for 2 h at rt, the reaction mixture was quenched with saturated NH4Cl solution (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 32 (2.99 g, 3.53 mmol, 90%).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1>CO>[CH3:1][O:14][C:13](=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([Br:5])=[CH:11][CH:10]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: CO
Product: COC(=O)Cc1ccc(Br)cc1
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
Acetyl chloride (10 g) was added dropwise over 5 minutes to methanol (250 mL). After 5 minutes, (4-bromo-phenyl)-acetic acid (15 g) was added. The resulting mixture was stirred for 96 hours, concentrated and the residue azeotroped with toluene (×2) to give the subtitle compound as a yellow oil (16 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[S:1]1[CH:5]=[C:4](/[CH:6]=[C:17](/[C:16]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=2)\[C:18]#[N:19])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2csc3ccccc23)cc1OC
Yield: 92.3 %

Procedure:
Benzo[b]thiophene-3-carboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (218 mg) through Method A (production step 2), to thereby yield the target product (yield: 365 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][NH2:16])=[O:14].[C:21](=S)=[S:22].[OH-].[K+]>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]1[O:14][C:21](=[S:22])[NH:16][N:15]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NN)c1Cl
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2n[nH]c(=S)o2)c1Cl
Temperature: 0 °C
Yield: 64.9 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]-benzoic acid, hydrazide (1.172 g, 3.78 mmol) is dissolved in 20 ml of methanol, and the solution is cooled to 0° C. Carbon disulfide (520 μl, 8.82 mmol) is added, followed by potassium hydroxide (266.0 mg, 4.03 mmol). The solution is heated at reflux for seven hours and allowed to cool to room temperature overnight. The solution is concentrated in vacuo and the residue dissolved in water. The aqueous solution is acidified with 1N hydrochloric acid and the resulting solids extracted into a 1:1 mixture of ether and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is chromatographed, eluting with hexane:ethyl acetate (2:1) providing 864.0 mg (65%) of product, mp 257°-259° C.
Reaction SMILES: I[C:2]1[S:3][C:4](I)=[C:5]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8].C([Sn]([C:37]1[CH:41]=[CH:40][S:39][C:38]=1[C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)(CCCC)CCCC)CCC.Cl>CN(C=O)C.[Cu]Cl>[CH2:10]([O:9][P:7]([C:6]1[C:5]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:40]2[S:39][C:38]([C:42]3[S:43][CH:44]=[CH:45][CH:46]=3)=[CH:37][CH:41]=2)[S:3][C:2]=1[C:44]1[S:43][C:42]([C:38]2[S:39][CH:40]=[CH:41][CH:37]=2)=[CH:46][CH:45]=1)([O:12][CH2:13][CH3:14])=[O:8])[CH3:11]
Reactant: CCOP(=O)(OCC)c1c(I)sc(I)c1P(=O)(OCC)OCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1-c1cccs1
Agent: Cl[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1c(-c2ccc(-c3cccs3)s2)sc(-c2ccc(-c3cccs3)s2)c1P(=O)(OCC)OCC
Temperature: 80 °C
Reaction time: 12 h

Procedure:
In DMF, 0.0971 g (0.159 mmols) of 2,5-diiodo-3,4-bis(diethoxyphosphoryl)thiophene and 0.0346 g (0.349 mmols) of commercially available copper(I) chloride were dissolved, to which 0.1744 g (0.383 mmols) of tributylstannylbithiophene was added at room temperature. Thereafter, the reaction mixture was heated to 80° C. and stirred for 12 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 0.6 M hydrochloric acid aqueous solution was added, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substance 1. The results are shown in Table 12.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:23]([CH3:28])[C:24](=[O:27])[CH:25]=[CH2:26])=[CH:14]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:23]([CH3:28])[C:24](=[O:27])/[CH:25]=[CH:26]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:14]1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1c[nH]c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1c[nH]c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 36.7 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.64 g, 2.80 mmole), N-(1H-indol-3-ylmethyl)-N-methylacrylamide (0.60 g, 2.80 mmole), Pd(OAc)2 (0.06 g, 0.28 mmole), tri-ortho-tolylphosphine (0.17 g, 0.56 mmole) and diisopropylethylamine (0.73 mL, 4.2 mmole) in propionitrile (50 mL) was deoxygenated, then was heated to reflux under N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (250 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3). The title compound (0.37 g, 37%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 361 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[NH:28][CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1>N1C=CC=CC=1>[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=4[Cl:1])=[CH:8][CH:9]=3)=[O:12])[CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Reactant: O=C(Cl)c1ccc(NC(=O)c2cc(Cl)ccc2Cl)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1)c1cc(Cl)ccc1Cl

Procedure:
As described for Example 1, 5 mmol of 4-[(2,5-dichlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido-[5,4-d] [1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(Cl)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 37.6 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 4-Chlorobenzaldehyde (39.5 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 39.8 mg (38%) of the title compound. (300 MHz, DMSO-d6) 13.39 (s, 1H), 8.14 (d, J=9 Hz, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.63 (d, J=9 Hz, 2H), 7.24 (m, 2H), 7.24 (s, 2H), 6.41 (s, 1H), 6.37 (m, 1H), 5.18 (t, J=17 Hz, 9 Hz, 1H), 2.89 (s, 1H), 2.79 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=414 (M+H), HPLC: 2.75 min (G Method)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)Cl.[CH3:15][O:16]C(Cl)Cl>O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[CH:15]=[O:16]
Reactant: COC(Cl)Cl
Reactant: COc1ccc([N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 42 h

Procedure:
p-Nitroanisole (25 g., 0.163 mole) was dissolved in 400 ml. of methylene chloride and cooled to 10° C. Titanium tetrachloride (61.8 g., 36 ml., 0.326 mole) was added, followed by 1,1-dichloromethyl methyl ether added over 2 minutes. The mixture was warmed to room temperature and stirred for 42 hours. The reaction mixture was diluted with 1 liter of ice and water and extracted with three 500 ml. portions of methylene chloride. The organic extracts were combined, washed with two portions of water and one of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (20 g.). The oil was chromatographed on 600 g. silica gel, using 2:1 methylene chloride:hexane as eluant, collecting 15 ml. fractions, and monitoring by tlc. Clean product fractions 79-185 were combined and evaporated to yield 2-methoxy-5-nitrobenzaldehyde (3.8 g.; m.p. 87-89, literature m.p. 89°-90°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2ccnc2)c(F)c1
Yield: 88.5 %

Procedure:
A mixture of 1-(2-fluoro-4-nitrophenyl)-1H-imidazole (1.81 g, 8.74 mmol) and Pd—C (10%, 0.200 g) in MeOH (20 mL) (containing 10 drops of 6N HCl) was hydrogenated under balloon H2 overnight. The mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was dried on vacuum to give 3-fluoro-4-(1H-imidazol-1-yl)benzenamine as a solid (1.37 g). MS 178.3 (M+H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH:37]=O)([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:37][CH2:36][NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:39])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.7 %

Procedure:
To a solution of 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (0.378 g, 1.00 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (0.159 g, 1.00 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.223 g, 1.05 mmol). The mixture was stirred at room temperature for 15 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL). The extracts were dried over Na2SO4 and concentrated. Purification of the crude material by column chromatography on silica gel (98:1:1 CH2Cl2—CH3OH—NH4OH) provided 499 mg (96%) of 2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a yellow foam. 1H NMR (CDCl3) δ 1.48 (s, 9H), 1.64 (s, 9H), 1.69-1.85 (m, 2H), 1.94-1.99 (m, 1H), 2.24 (m,1H), 2.61-2.87 (m, 3H), 3.09-3.19 (m, 3H), 4.07 (dd, J=9.9 Hz, 5.7 Hz, 1H), 4.26 (d, J=16.2 Hz, 1H), 4.52 (d, J=16.2 Hz, 1H), 6.98 (dd, 1H, J=7.7 Hz, 4.7 Hz, 1H), 7.26-7.32 (m, 3H), 7.57 (brs, 1H), 7.74 (m, 1H), 7.86 (m, 1H), 8.41 (d, J=3.9 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([O:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[O:31])[CH:3]=1.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([N:53]2[CH2:58][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[CH:46][CH:45]=1>>[F:40][C:39]([F:42])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:30]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:26]=2[CH:27]=[CH:28][CH:29]=[C:20]3[O:19][C:4]2[CH:3]=[C:2]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([S:50]([N:53]4[CH2:58][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]4)(=[O:51])=[O:52])=[CH:46][CH:45]=3)[N:7]=[C:6]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[CH:9]=[CH:10][C:5]=23)=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc4c(C(=O)Nc5cccc(C(F)(F)F)c5)cccc34)cc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Nc3cc(Oc4cccc5c(C(=O)Nc6cccc(C(F)(F)F)c6)cccc45)c4ccn(COCC[Si](C)(C)C)c4n3)cc2)CC1
Yield: 70.5 %

Procedure:
tert-butyl 4-(4-(4-(5-(3-(trifluoromethyl)phenylcarbamoyl)naphthalen-1-yloxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenylsulfonyl)piperazine-1-carboxylate (42 mg, 70% yield) was prepared as described for Example 5-B starting from 5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide (40 mg, 0.065 mmol) and tert-butyl 4-(4-aminophenylsulfonyl)piperazine-1-carboxylate (22 mg, 0.065 mmol). MS m/z: 917 [M+1].
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.Cl.[C:22]1([N:28]2[C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=3[CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([CH2:6][NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]4[C:31]=3[CH:30]=[N:29][N:28]4[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([OH:5])[C:7]([F:8])([F:9])[F:10])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: Nc1cccc2c1cnn2-c1ccccc1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Agent: Cl
Product: CC(C)(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)c1cccc2c1OCC2

Procedure:
Prepared similarly to Example 7 from racemic 7-{1,1-dimethyl-2-[2-(trifluoromethyl)-2-oxiranyl]ethyl}-2,3-dihydro-1-benzofuran (which may be prepared according to WO 04/063163) and 1-phenyl-1H-indazol-4-amine hydrochloride (as the free base, Intermediate 8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:25])[CH2:9]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.CC(C)=O.C(=O)=O.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:25])[CH2:9]2)=[C:4]([C:26]([F:27])([F:28])[F:29])[CH:3]=1
Reactant: COc1cccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(O)c1
Reaction time: 3 h
Yield: 96 %

Procedure:
A stirred solution of (R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(3-methoxyphenylsulfonyl)-2-methylpiperazine (2.22 g, 5.13 mmol) in anhydrous dichloromethane (60 mL) was cooled down to −50° C. (acetone+dry ice bath). BBr3 (1M in CH2Cl2) was added dropwise via addition funnel while keeping the temperature between −50° C. and −55° C. Then the reaction mixture was stirred at −50° C. to −20° C. for 3 hours. Reaction was complete as determined by TLC. The reaction mixture was quenched with water and diluted with dichloromethane. pH was adjusted to 7 using saturated NaHCO3 (aqueous) and it was allowed to stir for 20 minutes. The layers were separated; the organic layer was dried over MgSO4 and concentrated. The reaction was repeated in 2.85 g scale. The combined crud products were purified via flash column chromatography to yield 3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenol in 96% yield (4.07 g) as a white solid. HRMS: calcd for C18H18F4N2O3S+H+, 419.10470. found (ESI-FTMS, [M+H]1+), 419.104. HPLC Method 1: room temperature, 6.318 min, 100%, HPLC Method 2: room temperature, 7.220 min, 99.48%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:15][C:14]3=[CH:16][S:17][CH:18]=[C:13]3[N:12]=2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10]([C:11]2[NH:12][C:13]3=[CH:18][S:17][CH:16]=[C:14]3[N:15]=2)=[O:27])[N:4]=1
Reactant: COc1ccnc(CSc2nc3cscc3[nH]2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cscc3[nH]2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.1 g of 2-(4-methoxy-2-pyrimidinylmethylthio)-1H-thieno[3,4-d]imidazole were dissolved in 100 ml of dichloromethane and, at -10° C., 820 mg of m-chloroperbenzoic acid were added in portions. The mixture was then stirred at room temperature for 15 minutes, extracted by shaking with sodium bicarbonate solution, and the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography resulted in 300 mg of 2-(4-methoxy-2-pyrimidinylmethylsulfinyl)1H-thieno[3,4-d]imidazole (melting point 125° C. [decomposition]).
Reaction SMILES: [N+]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[C:5]=1[N+:20]([O-:22])=[O:21])([O-])=O.[N+:23](C1C2C(=O)C3C(=CC=CC=3[N+]([O-])=O)C(=O)C=2C=CC=1)([O-:25])=[O:24]>[N+]([O-])(O)=O>[N+:20]([C:5]1[C:6]2[C:7](=[O:19])[C:8]3[C:13](=[C:12]([N+:23]([O-:25])=[O:24])[CH:11]=[CH:10][CH:9]=3)[C:14](=[O:18])[C:15]=2[CH:16]=[CH:17][CH:4]=1)([O-:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21

Procedure:
y<50: Nitric acid ratio in the mixed acid is too low, where leaching of dinitroanthraquinone isomers soluble in nitric acid, including 1,8-dinitroanthraquinone, is not sufficient thus failing to obtain 1,5-dinitroanthraquinone of a high purity.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH3:11]>C(Cl)(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][Br:1]
Reactant: BrBr
Reactant: Cc1ccc(F)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Cl)c1
Yield: 80 %

Procedure:
A solution of bromine (7.10 ml) in carbon tetrachloride (70 ml) was added slowly over a period of 3 hours to a solution of 2-chloro-4-fluorotoluene (20.0 g) in carbon tetrachloride (80 ml) maintained at the reflux temperature and irradiated by light from a tungsten lamp (200 watt). After the addition was completed the mixture was heated at the reflux temperature with irradiation until the colour had been discharged (ca.1 hour). The solvent was then removed by evaporation under reduced pressure and the residual oil distilled to yield 2-chloro-4-fluorobenzyl bromide (80% pure, 18.0 g) b.p. 110°-120° C./15 mm Hg.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][Zn+]>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1cccc(C[Zn+])c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: [Cl-]
Product: COC(=O)c1cc(Cl)cnc1Cc1cccc(OC)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 58 from methyl 2,5-dichloronicotinate and 3-methoxybenzylzinc chloride: 1H-NMR (CDCl3) δ 8.64 (1H, d, J=2.5 Hz), 8.16 (1H, d, J=2.5 Hz), 7.17 (1H, t, J=7.9 Hz), 6.83–6.70 (3H, m), 4.53 (2H, s), 3.88 (3H, s), 3.75 (3H, s).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[NH:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([OH:40])[CH2:35]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:34]3[CH2:39][CH2:38][CH2:37][C@H:36]([OH:40])[CH2:35]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: O[C@H]1CCCNC1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC[C@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 85 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and (S)-piperidin-3-ol hydrochloride to afford a white solid. UPLC-MS (Condition 3) tR=0.99 min, m/z=464.1 [M+H]+, m/z=508.1 [M+formic acid-H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.35 (m, 1H) 1.37-1.52 (m, 1H) 1.56-1.70 (m, 1H) 1.78-1.93 (m, 1H) 2.53-2.64 (m, 1H) 2.65-2.81 (m, 1H) 3.43 (d, J=12.72 Hz, 1H) 3.51-3.61 (m, 1H) 3.65 (d, J=12.23 Hz, 1H) 4.72-4.83 (m, 1H) 6.54-6.69 (m, 1H) 7.34 (d, J=8.93 Hz, 2H) 7.54-7.86 (m, 1H) 7.88 (d, J=9.05 Hz, 2H) 8.15-8.37 (m, 1H) 8.68-8.78 (m, 1H) 10.31-10.46 (m, 1H) 12.96-13.18 (m, 1H).