Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.[Cu](I)I>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[C:30]([N:1]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[C:2]3=[O:3])[CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1cccc(-c2ccc(OCc3ccccc3)cc2)c1
Reactant: O=C1Nc2ccccc2C1=O
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(c2cccc(-c3ccc(OCc4ccccc4)cc3)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isatin (0.12 g, 0.81 mmoles) in anhydrous DMF (30 mL) was cooled in an ice bath under nitrogen and treated with sodium hydride (21 mg, 1.1 equivalents). The reaction was stirred in ice for 0.5 hour and then warmed to room temperature. This solution was then treated with 4-(3-bromophenyl)phenol benzyl ether (Hajduk, et al., J. Am. Chem. Soc., 1997, 119, pp. 5818-5827), (0.16 g, 0.47 mmoles) followed by copper iodide (0.32 g, 1.68 mmoles). The reaction was heated in an oil-bath at 140° C. After ˜16 hours, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (˜75 mL) and filtered. The filtrate was concentrated under reduced pressure to afford a sticky, brown solid which was purified by preparative TLC on silica gel using 25% ethyl acetate in hexanes as the developing solvent. Rf (product)=0.38. Yield=47 mg (25%); MALDI-TOF MS 407.02 obs. (405.5 calc.); 1H-NMR (CDCl3) 5.12 (s, 2H), 6.95 (d, 1H, J=8 Hz), 7.06 (d, 2H, J=8.8 Hz), 7.18 (t, 1H, J=7.5 Hz), 7.33-7.47 (m, 7H), 7.53 (d, 2H, J=8.8 Hz), 7.57-7.60 (m, 2H), 7.71 (d, 1H, J=7.5 Hz).
Reaction SMILES: Cl.[SH:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[OH-].[Na+].[CH:13]1([C:19]2[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)C>C(Cl)(Cl)Cl>[CH:13]1([C:19]2[CH:26]=[CH:25][C:22]([CH2:23][S:2][C@@H:3]3[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]3)=[CH:21][CH:20]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: ClCc1ccc(C2CCCCC2)cc1
Reactant: O=C(O)[C@@H]1C[C@H](S)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H]1C[C@H](SCc2ccc(C3CCCCC3)cc2)CN1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
To (4S)-4-mercapto-L-proline hydrochloride (300 mg) is added 2 N sodium hydroxide (1.6 ml) aqueous solution, and the mixture is stirred at 0° C. A solution of 4-cyclohexylbenzyl chloride (340 mg) in a mixed solvent of ethanol (5 ml)/chloroform (1 ml) is added thereto, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and deposited crystals are filtered off. The crystals are washed with water, ethanol and diethyl ether successively to give 470 mg (91%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[NH2:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:17][C:12]2[CH:13]=[CH:14][C:15]([NH2:16])=[C:10]([F:9])[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(O)cc1F
Reactant: Clc1ccnc(Cl)c1
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Yield: 86 %

Procedure:
Using a procedure analogous to Example A2, 2,4-dichloropyridine (8.0 g, 54 mmol) and 3-fluoro-4-aminophenol (8.0 g, 62.9 mmol) were combined to provide 4-(2-chloro-pyridin-4-yloxy)-2-fluorophenylamine (11g, 86% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (d, J=5.7 Hz, 1H), 7.00 (dd, J=9.0, 2.7 Hz, 1H), 6.89-6.73 (m, 4H), 5.21 (br s, 2H); MS (ESI) m/z: 239.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+].O>ClC1C=CC=CC=1Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:9][CH3:10])=[C:6]([N:7]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:8]=1
Reactant: COc1c(N)cc(Br)cc1C(C)(C)C
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Temperature: 200 °C
Reaction time: 22 h
Yield: 116.7 %

Procedure:
5-Bromo-3-(tert-butyl)-2-methoxyaniline (311 g) and bis(2-chloroethyl)amine hydrogenchloride (251 g) were suspended in 4 L of 1,2-dichlorobenzene, and the mixture was vigorously stirred for 22 hours at an external temperature of 200° C. The mixture was cooled to room temperature, and then potassium carbonate (620 g) and water were added and extraction was performed with methylene chloride (6 L). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to yield a black oil (460 g). Purification was performed by NH-silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (161 g) as blackish purple solid (41%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1>[CH3:28][S:29]([O:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)nc2)cc1O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)nc2)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of ethyl 2-[(2-hydroxy-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)hydrazono]propanoate (21.1 g) in pyridine (220 mL) was added methanesulfonyl chloride (5.0 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, and then at room temperature for 16 h. The mixture was cooled to 0° C., and methanesulfonyl chloride (5.0 mL) was added to the mixture again. After stirring at room temperature for 2 h, water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was solidified with ethyl acetate-diethyl ether, and the resulting solid was washed with diethyl ether to give the title compound (20.0 g, 79%) as a pale yellow solid. MS 472 (MH+).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CS(C)=O>[C:12]1([NH:11][C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)=[NH:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cccnc1
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N=C(Nc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
Sodium hydride (60% in mineral oil, 11.52 g, 288 mmol) was added portion-wise over 30 min to a stirred solution of 3-pyridinecarbonitrile (30 g, 288 mmol) and aniline (26 g, 290 mmol) in dimethylsulfoxide (150 mL) at 10° C. The reaction mixture was allowed to warm to ambient temperature with stirring for 18 h. The reaction mixture was slowly and cautiously poured into water containing crushed ice. The solid that precipitated was filtered, washed with petroleum ether, dissolved in dichloromethane and dried over anhydrous Na2SO4. The volatiles were removed under reduced pressure (high vacuum) and the residue was dried to afford 36.5 g of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]([N:6](C)C)=C(C)C.[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([C:25]([OH:27])=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.C(N(CC)CC)C.Cl.CN.CN(C1C=CN=CC=1)C>[CH3:2][NH:6][C:25]([CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17]1)=[O:27]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)c2ccccc21
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)C1CN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.35 ml of 1-chloro-N,N,2-trimethylpropenylamine is added to a solution of 0.59 g of 1-(tert-butoxycarbonyl)indoline-3(R,S)carboxylic acid in methylene chloride at 0° C. After 30 min, 0.93 ml of triethylamine, 0.23 g of methylamine hydrochloride and 4-DMAP, as a catalyst, are added and the mixture is stirred at room temperature for 3 h. The reaction mixture is then chromatographed directly over 80 g of silica gel (mobile phase J). This gives the title compound: Rf (P)=0.65.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].C(=O)(O)[O-].[Na+].CC(C)=O.O.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:23]([O:30][C:31](=[O:32])[NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([C:2]2[O:1][CH:5]=[N:4][N:3]=2)[CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(-c2nnco2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1cccc(-c2nnco2)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A solution of 3-(1,3,4-oxadiazol-2-yl)aniline (1 g, 6.2 mmol) and sodium bicarbonate (1.1 g, 13 mmol) in a 2:1 mixture of acetone/water (10 mL) was cooled to 0° C. Benzylchloroformate (0.92 mL, 6.5 mmol) was added dropwise over 5 minutes. The reaction mixture was brought to room temperature and stirred for 30 minutes at which point LCMS indicated completion of the reaction. The reaction mixture was diluted with water and filtered on a glass frit to give (3-[1,3,4]Oxadiazol-2-yl-phenyl)-carbamic acid benzyl ester as a white powder (1.7 g, 93%). M+1=296.4
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:20]1([CH2:23][NH:24][C:25](=[O:42])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][NH:24][C:25]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[C:30]([C:2]3[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:31]=2)=[O:42])[CH2:22][CH2:21]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NCC4CC4)ccc3C)nc2)c1

Procedure:
6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(3-methoxybenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 3.07 min, MH+ 430. NMR: δH [2H6]-DMSO 9.30,(1H, t), 9.16,(1H, d), 8.62,(1H, t), 8.36,(1H, dd), 7.94,(1H, s), 7.85,(1H, d), 7.74,(1H, d), 7.43,(1H, d), 7.27,(1H, t), 6.94–6.92,(2H, m), 6.84,(1H, d), 4.51,(2H, d), 3.75,(3H, s), 3.14,(2H, t), 2.39,(3H, s), 1.03,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[C@H:49]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][CH:53]([N:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][C@H:49]3[C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:54][CH2:55]2)=[O:41])=[CH:28][C:29]=1[Cl:38]
Reactant: CCOC(=O)[C@@H]1CN(C)CCN1C1CCNCC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(C)CCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.40 mL (2.88 mmol) triethylamine were added to a mixture of 260 mg (0.46 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 210 mg (0.58 mmol) ethyl(S)-4-methyl-1-piperidin-4-yl-piperazine-2-carboxylate (Example A9f) and 170 mg (0.53 mmol) TBTU in 2.4 mL DMF and the reaction mixture was stirred for 18 h at RT. The reaction mixture was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Cl:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc2c(cc1Cl)C(C)CNCC2
Reaction time: 8 h
Yield: 114.4 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-chloro-1-methyl-2,3,4,5tetrahydro-1H-3-benzazepine (23 mg, 0.066 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 19 mg of a white solid. 1H NMR (400 MHz, CD3OD) d 7.12 (s, 1 H), 6.81 (s, 1 H), 6.03 (m, 1 H), 5.43 (d, J=17 Hz, 1 H), 5.24 (d, J=10 Hz, 1 H), 4.57 (d, J=5 Hz, 2 H), 3.1-2.9 (m, 5 H),
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][C:9]=1[NH:26][C:27]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][C:34]([O:38][CH3:39])=[C:33]([O:40][CH3:41])[C:32]=2[O:42][CH3:43])=[O:28])(=O)=O.[Li+].[Cl-:45].CCOC(C)=O>CN(C=O)C>[CH2:19]([O:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH2:7][CH2:6][Cl:45])=[C:9]([NH:26][C:27]([C:29]2[NH:30][C:31]3[C:36]([CH:37]=2)=[CH:35][C:34]([O:38][CH3:39])=[C:33]([O:40][CH3:41])[C:32]=3[O:42][CH3:43])=[O:28])[CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCOS(C)(=O)=O)[nH]c2c(OC)c1OC
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCCl)[nH]c2c(OC)c1OC
Reaction time: 72 h
Yield: 80.9 %

Procedure:
To a solution of 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl methanesulfonate (0.11 g, 0.17 mmol) in dry DMF (2 mL) was added LiCl (0.29 g, 6.94 mmol) at room temperature under N2 atmosphere and stirred for 3 days. The reaction mixture was diluted AcOEt (100 mL) and washed with H2O (20 mL) and saturated aqueous NaCl (10 mL), and then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica-gel column (AcOEt:Petroleum ether=1:4) to yield as a white solid 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl chloride (75 mg, 81%): mp 180-184° C.; 1H NMR (CDCl3, 500 MHz) δ 9.23 (s, 1H), 8.63 (s, 1H), 8.42 (d, 7.5, 1H), 7.84 (d, 8.5, 1H), 7.53-7.60 (m, 4H), 7.49 (t, 8.0, 1H), 7.44 (t, 7.0, 2H), 7.38 (t, 7.5, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 5.29 (s, 2H), 4.10 (s, 3H), 4.05 (t, 6.0, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.60 (t, 6.0, 2H); EIMS m/z 545 (M+); IR (neat) νmax 3271, 2932, 1722, 1634, 1592, 1537, 1503, 1464, 1409, 1370, 1306, 1258, 1237, 1111, 1076, 1050, 998, 910, 830, 761, 736, 700cm−1.
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[I:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.S(=O)(=O)(O)O>C(O)(C)C>[CH2:15]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:13])(=[O:11])=[O:12])=[CH:6][C:5]=1[I:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+:2]
Reactant: O=S(=O)(O)c1ccc(O)c(I)c1
Reactant: BrCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=S(=O)([O-])c1ccc(OCc2ccccc2)c(I)c1
Temperature: 84 °C
Reaction time: 0.21 h

Procedure:
Sodium hydroxide (pellets, 110 g, 2.75 mol, 3.00 eq) was added portionwise to the vigorously stirring aqueous solution of the 4-hydroxy-3-iodo-benzenesulfonic acid. After addition was complete, 10-15 min., isopropyl alcohol (150 mL) was added to the resulting white suspension. The dropping-funnel was charged with benzyl bromide (Aldrich; 164.9 g, 0.964 mol, 1.05 eq.) and added to the reaction mixture over a period of approx. 5 mins. and the reaction mixture was heated to 80°≦Tint≦84° C. After approx. 25 min. it was determined that the reaction was not proceeding further and therefore additional sodium hydroxide (3.67 g, 91.8 mmol, 0.1 eq.) and then benzyl bromide (15.7 g, 91.8 mmol, 0.1 eq.) were added to the reaction mixture to give a homogenous solution. After 70 min. from the original benzyl bromide addition, the heating was stopped and the reaction was allowed to cool slowly in the oil-bath with stirring. At 7.5 h, the reaction mixture appeared as a suspension of fine-reflective precipitate in brown liquid. The reaction mixture was acidified with 3:1 water-sulfuric acid from about pH 13 to between pH 7.5 and 8 (approx. 70 mL is required). The reaction mixture was then cooled gradually to about 5° C. and stirred at that temperature for ˜1 h. The waxy white plaques were collected by filtration, washed with dichloromethane and dried under high vacuum (lyophilizer, 100-200 mTorr) for ˜24 h to give sodium 4-benzyloxy-3-iodo-benzenesulfonate as a brilliant white, crystalline solid, (267.7 g, 71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1>C(OCC)C>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[CH2:24][N:16]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:15]1
Reactant: BrCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Solvent: CCOCC
Product: c1coc(Cn2cc(C3CCNCC3)c3cccnc32)c1

Procedure:
This compound was prepared following the procedure described in example 7, parts E and F, starting with 0.3 g (1 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2.12 ml of a freshly prepared 0.61 M solution of 2-bromomethylfuran in ethyl ether. After standard work-up, 0.28 g (97% of yield) of the expected product were isolated.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([CH:16]=O)=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:11]2[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:23]1[CH3:32]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ncccc1S(=O)(=O)c1ccccc1
Product: COC(=O)Cn1c(C)c(Cc2ncccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 3-benzenesulfonylpyridine-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13]([CH3:18])([N+:15]([O-])=O)[CH3:14])[CH2:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni].O>[NH2:15][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[C:8](=[O:19])[CH2:9]1)([CH3:18])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)(C1CCN(Cc2ccc(F)cc2)C(=O)C1)[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CC(C)(N)C1CCN(Cc2ccc(F)cc2)C(=O)C1

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(1-methyl-1-nitroethyl)piperidin-2-one (1.05 g, 3.57 mmol) in degassed ethanol (75 mL) was added Raney Nickel (2 g of a 50% by weight slurry in water). The reaction mixture was shaken under 55 psi of hydrogen fro 4 hours. The reaction mixture was filtered through a bed a celite, then concentrated under vacuum to give an oil that solidified on standing. The solid was triturated in ether and collected by filtration to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 4.65 (d, J=14.5 Hz, 1H), 4.44 (d, J=14.6 Hz, 1H), 3.26 (m, 2H), 2.60 (d, J=5 Hz, 1H), 2.25 (m, 1H), 1.97 (d, J=11.5 Hz, 1H), 1.75 (m, 1H), 1.44 (m, 1H), 1.11 (d, J=9 Hz, 6H) ppm. ES MS M+1=265.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:19][C:20]([CH3:24])([CH3:23])[CH:21]=O)[CH2:15][CH2:16][CH:17]=[CH2:18].C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:21][C:20]([S:19][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])([CH3:24])[CH3:23]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: C=CCCCSC(C)(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.1 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.155 g, 7/9×10-4 mol) and 0.30 g (1.74×10-3 mol, 220 M%) of 2-(4-pentenylthio)-2-methylpropanal were dissolved in 40 ml methanol. Acetic acid (0.09 ml, 1.59×10-3 mol, 200 M%) was added followed by 0.155 g (2.3×10-3 mol, 300 M%) sodium cyanoborohydride. The reaction was stirred at room temperature under nitrogen for 17 hr, then 20 ml 0.5 M HCl was added and the mixture was extracted with 2×40 ml diethyl ether. The ether layer was washed with 30 ml saturated NaCl solution and dried (Na2SO4), and the solvent was removed on the rotary evaporator. The product was purified by radial chromatography on a 2 mm silica plate eluting with 50 ml 100% hexane and 100 ml 90% hexane/ether to give 0.27 g (97% yield) of 2-(2-mercapto-2-methylpropylamino)-1-[2-(4-pentenylthio)-2-methylpropylamino]-benzene as an oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCCC1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCCCn1ccnc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCCn1ccnc1)Nc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A 2.5 g. portion of 1H-imidazole-1-propanamine was added to 20 ml. of toluene and then 7 ml. of tetrahydrofuran was added to produce solution. A solution of 3.1 g. of distilled p-chlorophenyl isocyanate in 20 ml. of toluene was added, the mixture was stirred overnight and then evaporated to a waxy solid. This solid was triturated with ether and the resulting crystals recrystallized from chilled acetone, giving 2.3 g. of the desired product as colorless crystals, mp. 123°-125° C.