Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[C:2]([N:1]=[C:15]=[S:16])[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(Cl)ccc1N1CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: S=C=Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
Reaction of 4-(2-amino-4-chlorophenyl)morpholine (8.5 g) with thiophosgene (4.6 ml) in dioxan (25 ml) and water (100 ml) for 30 minutes at 0° C. and for 3 hours at room temperature gave 5-chloro-2-morpholinophenyl isothiocyanate as a pale yellow solid (m.p. 86°-87° C.).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]3)=[N:19]2)=[CH:14][CH:13]=1.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42])([O-:34])=[O:33]>ClCCl>[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][S:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N+:32]([O-:34])=[O:33])(=[O:42])=[O:43])[CH2:29][CH2:30]3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc(SCCN3CCC(NS(=O)(=O)c4ccccc4[N+](=O)[O-])CC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (318 μL, 1.82 mmol, 2.5 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (237 mg, 0.73 mmol, 1.0 eq) in dichloromethane (4 mL), followed by 2-nitro-benzenesulfonyl chloride (183 mg, 0.80 mmol, 1.1 eq). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate 100%) to afford N-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-2-nitro-benzenesulfonamide as a yellow waxy solid (307 mg, 82% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.C([Li])CCC.[C:13](=[O:15])=[O:14].Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COc1ccsc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccsc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methoxythiophene (4.81 g, 42.1 mmol) in ether (20 mL) at -78° C., butyllithium (17 mL, 47.6 mmol) was added. The reaction mixture was stirred at -78° C. for 1 hour, then it was warmed to 0° C. for 3 hours. After to recooling -78° C. the reaction mixture was poured into a beaker filled with crushed dry ice (14.5 g) and allowed to stand until the excess dry ice had completely sublimed. Then the reaction mixture was poured into a mixture of ice (10 g) to which conc. HCl (24 mL) had been added. The product was purified by precipitation from ether and filtering (6.42 g, 96%). EI-MS m/z 159 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(#N)C.CN(C)C1C=CN=CC=1>[S:29]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]
Reactant: OCCC#Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(OCCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81975.1 %

Procedure:
To a solution of 1-{3-[4-(4-hydroxybut-1-yn-1-yl)phenoxy]propyl}piperidine (393 mg) in acetonitrile (10 mL) are added successively triethylamine (0.446 mL), 4-dimethylaminopyridine (18 mg) and tosyl chloride (617 mg). The mixture is stirred overnight at room temperature, concentrated under reduced pressure and purified by chromatography over silica gel to give 495 g of 1-{3-[4-(4-tosyloxybut-1-yn-1-yl)phenoxy]propyl}piperidine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1.Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[C:12]([S:13]([C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[N:27][NH:11]2
Reactant: O=N[O-]
Reactant: Nc1cccc(OCCCl)c1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cccc(OCCCl)c12
Temperature: 3 °C

Procedure:
A mixture of 3-(2-chloro-ethoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.78 g, 2.1 mmoles) in THF (5 mL), and 4M HCl (10 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.15 g, 2.2 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.74 g, 1.93 mmoles).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([Cl:14])([Cl:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([Cl:14])([Cl:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(Cl)(Cl)CN(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a solution of 0.60 g (0.0018 mole) of 2-chloro-9-cyclopentyl-7,7-dichloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-298) in 12 mL of dimethylformamide was added 0.88 g (0.0027 mole) of cesium carbonate, followed by 0.34 mL (0.0054 mole) of iodomethane. After stirring four hours, the mixture was filtered and then concentrated under reduced pressure. Ice water was added to the residue and the resulting solid was collected by filtration, washed with water and dried under vacuum to give 0.47 g of 2-chloro-9-cyclopentyl-7,7-dichloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-298) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=1.COC1C=CC(O)=C([N+]([O-])=O)C=1.[C:37](Cl)(=[O:42])[CH2:38][C:39](Cl)=[O:40].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:13][CH:12]=3)[C:37](=[O:42])[CH2:38][C:39](=[O:40])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: COc1ccc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Agent: COc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NC(=O)CC(=O)N2c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
tert-Butyl 4-(2-amino-4-methoxyphenylamino)phenylcarbamate (500 mg, 1.52 mmol) synthesized in the same manner as that of Example 1 by using 4-methoxy-2-nitrophenol as the starting material was dissolved in anhydrous tetrahydrofuran (30 mL), and the solution was added dropwise with malonyl chloride (0.178 mL, 1.82 mmol) on an ice bath. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was added with saturated aqueous sodium hydrogencarbonate, the aqueous layer was extracted with chloroform, the organic layer was dried over sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to give the title compound (230 mg, yield 38%).
Reaction SMILES: CS(O[C@H:6]([C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([Cl:35])=[CH:28][C:27]=1[F:36])[CH2:7][CH2:8][C@H:9](OS(C)(=O)=O)[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([Cl:19])=[CH:12][C:11]=1[F:20])(=O)=O.[F:37][C:38]1[CH:39]=[C:40]([CH:42]=[C:43]([F:51])[C:44]=1[N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[NH2:41].CCN(C(C)C)C(C)C>CC#N>[Cl:19][C:13]1[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]([C@H:9]2[CH2:8][CH2:7][C@H:6]([C:26]3[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([Cl:35])=[CH:28][C:27]=3[F:36])[N:41]2[C:40]2[CH:39]=[C:38]([F:37])[C:44]([N:45]3[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]3)=[C:43]([F:51])[CH:42]=2)=[C:11]([F:20])[CH:12]=1
Reactant: Nc1cc(F)c(N2CCCCC2)c(F)c1
Reactant: CS(=O)(=O)O[C@@H](CC[C@H](OS(C)(=O)=O)c1cc([N+](=O)[O-])c(Cl)cc1F)c1cc([N+](=O)[O-])c(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3cc([N+](=O)[O-])c(Cl)cc3F)N2c2cc(F)c(N3CCCCC3)c(F)c2)c(F)cc1Cl
Temperature: 75 °C

Procedure:
To a solution of (1S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diyl dimethanesulfonate (500 mg, 0.843 mmol) in CH3CN (4.5 ml) was added 3,5-difluoro-4-(piperidin-1-yl)aniline (358 mg, 1.685 mmol) and Hunig's base (0.736 mL, 4.21 mmol). The suspension was heated at 75° C. for 24 hours. Solvent was removed by rotary evaporation and the residue was dissolved in EtOAc, washed with 1 N HCl, H2O, brine, dried (MgSO4), filtered and concentrated. The crude product was chromatographed on an ISCO 24 g silica gel cartridge eluting with 20-70% CH2Cl2/hexane to provide the title compound with some of the corresponding cis-pyrrolidine isomer.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Br:31])[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11].Cl[CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:29]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([Br:31])[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(Br)cc3c(=O)[nH]2)c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2nc3ccc(Br)cc3c(=O)n2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
DIEA (1.23 mL, 7.08 mmol) was added to 1-(6-bromo-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.980 g, 2.70 mmol) in THF (13.5 mL), followed by (2-chloromethoxy-ethyl)-trimethyl-silane (0.500 mL, 3.27 mmol). The reaction mixture was stirred at room temperature for 18 h, and concentrated. The residue was purified by FCC (0-20% EtOAc/hexanes) to yield the titled compound (1.27 g, 95% yield). MS (ESI/Cl): mass calcd. for C20H25BrN4O4Si, 492.1; m/z found, 435.1 [M−58+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH2:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31]>ClCCl>[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:20][C@@H:17]1[C@@H:15]2[C@@H:14]([CH2:13][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)(=[O:41])=[O:40])([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3aR,4S,6aS)-2-(4-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (300 mg, 0.897 mmol) from Step A of Example 256 and triethylamine (0.313 mL, 2.243 mmol) were combined in dichloromethane (20 mL). 2-Nitrobenzene-1-sulfonyl chloride (258 mg, 1.166 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water, and the organic layer was separated and concentrated. The resulted crude material was triturated with 50% diethyl ether/hexane, collected by filtration, washed with water then hexane to yield a solid. The crude solid was purified using a 12 g silica gel cartridge with a gradient of 10-100% ethyl acetate/hexane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.69 (s, 1H), 8.31 (dd, J=6.0, 3.3, 1H), 8.12 (d, J=8.2, 2H), 7.92 (dd, J=8.6, 2.1, 3H), 7.67 (dd, J=5.9, 3.3, 2H), 4.94 (s, 2H), 3.84 (dd, J=15.0, 6.2, 1H), 3.58 (dd, J=10.0, 2.4, 1H), 3.17 (dd, J=9.7, 2.7, 1H), 2.94 (dd, J=10.0, 7.7, 1H), 2.87 (dd, J=9.6, 7.7, 1H), 2.71 (td, J=9.3, 2.4, 1H), 2.60-2.50 (m, 1H), 1.94-1.80 (m, 2H), 1.71-1.58 (m, 1H), 1.23 (tt, J=10.5, 6.5, 1H); MS (ESI+) m/z 518 (M+H)+.
Reaction SMILES: [OH:1]O.O.[N:4]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]3[C:21]([S:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)=[C:20]([C:31]([OH:33])=[O:32])[S:19][C:18]=3[CH:34]=2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.Cl>C(O)(=O)C>[N:4]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]3[C:21]([S:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)=[O:1])=[C:20]([C:31]([OH:33])=[O:32])[S:19][C:18]=3[CH:34]=2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1
Reactant: OO
Reactant: COc1cccc(Sc2c(C(=O)O)sc3cc(Cn4cnc5cnccc54)ccc23)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(S(=O)c2c(C(=O)O)sc3cc(Cn4cnc5cnccc54)ccc23)c1
Temperature: 100 °C

Procedure:
Hydrogen peroxide in water (0.07 ml of 30% w/v, 0.58 mmol) was added to a mixture of 6-(1H-Imidazo[4,5-c]pyridin-1-ylmethyl)-3-[(3-methoxyphenyl)sulfanyl]benzo[b]thiophene-2-carboxylic acid (Example 23--218 mg, 0.49 mmol) in acetic acid (2 ml), and 2M hydrochloric acid (2 ml). The solution was heated to 100° C. for 1 hour. The solution was cooled and the solvents were evaporated under reduced pressure. The residue was dissolved in a hot mixture of aqueous sodium hydroxide (5 ml of 1M) and methanol (5 ml). After acidifying the solution with acetic acid, and cooling, the precipitate was collected by filtration to give the title compound as a colourless solid (95 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([N+]([O-])=O)=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:14].[BrH:15]>>[Br:15][C:7]1[C:6]2[N:2]([CH3:1])[C:3](=[O:14])[NH:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: Br
Reactant: Cn1c(=O)[nH]c2ccnc([N+](=O)[O-])c21
Product: Cn1c(=O)[nH]c2ccnc(Br)c21
Temperature: 135 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 20.0 g (103 mmol) 3-methyl-4-nitro-1H-imidazo[4,5-c]pyridin-2(3H)-one in 168 mL 48% hydrobromic acid was heated for 6 h at 135° C. An additional 33 mL of 48% hydrobromic acid was added and the reaction was stirred at 135° C. overnight. The reaction was cooled to room temperature and quenched into 1675 mL ice water. The resulting slurry was adjusted to pH 9 by the addition of 125 mL saturated aqueous ammonium hydroxide. The precipitate was filtered and washed with 200 mL water and dried in a vacuum oven at 50° C. overnight to give 17.58 g (75%) of the title product as a light yellow solids.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][SH:18]>CCO>[NH2:15][CH2:16][CH2:17][S:18][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([S:18][CH2:17][CH2:16][NH2:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nc2)cn1
Reactant: NCCS
Solvent: CCO
Product: NCCSc1ccc(-c2ccc(SCCN)nc2)cn1

Procedure:
The title compound was prepared as described by Constable et al.13 The same reaction was repeated using 6,6′-dichloro-3,3′-bipyridine (0.154 g, 0.684 mmol) in EtOH (150 mL) under reflux for 24 h to give a yellow oil. The crude product showed the presence of cysteamine (1H n.m.r.) and washing with water gave a clean product (1.3 g, 75%). Mass spectrum (ESI): m/z 153.9 [½ (M+2H)2+]; 307.2 (M+H)+. 1H n.m.r. (300 MHz, CDCl3): δ 1.5 (bs, 4H); 3.02 (t, J 6.4 Hz, 4H); 3.32 (t, J 6.4 Hz, 4H); 7.26 (dd, J 8.4, 0.6 Hz, 2H); 7.63 (dd, J 8.4, 2.4 Hz, 2H); 8.60 (d, J 2.4 Hz, 2H). 13C n.m.r. (75 MHz, CDCl3): δ 34.4; 42.1; 122.8; 129.4; 134.3; 147.7; 156.1. Spectra were consistent with literature data13.
Reaction SMILES: [CH:1]1([C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])CCCCC1.N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1.[Cl:35]CC(Cl)=O>>[Cl:35][CH2:1][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Reactant: O=C(Cl)CCl
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)CCl
Yield: 23 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 500 mg, 2.52 mmol) and 2-chloroacetyl chloride (221 μL, 2.77 mmol) were converted to the title compound (160 mg, 23%). 1H NMR (DMSO-d6) δ 8.13 (d, J=8.1 Hz, 1H), 7.68-7.66 (m, 2H), 7.24 (s, 2H), 4.58 (s, 2H), 4.20 (t, J=8.5 Hz, 2H), 3.24 (t, J=8.5 Hz, 2H); MS(ESI+) m/z 275.0 (M+H)+.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])[CH3:13].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[O:14][CH2:12][CH3:13])[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: CCOc1ccccc1C(=O)O
Agent: N
Product: CCOc1ccccc1C(=O)NC1C2CC3CC1CN(C3)C2

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 2-ethoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.53 (t, J=7 Hz, 3H), 1.94 (s, 1H), 2.02 (d, 2H), 2.11 (d, 1H), 2.20 (d, J=14 Hz, 2H), 2.32 (s, 2H), 3.48 (s, 2H), 3.59 (s, 4H), 4.28 (q, J=7 Hz, 2H), 4.47 (s, 1H), 7.06-7.10 (m, 1H), 7.17 (d, J=8 Hz, 1H), 7.48-7.53 (m, 1H), 7.96 (dd, J=8, 2 Hz, 1H); MS (APCI/NH3) m/z 301 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([OH:5])=[O:4].[N+](=[CH2:19])=[N-].C(Cl)(Cl)Cl>CCOCC>[CH3:19][O:4][C:3](=[O:5])[C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
2(R),6(R),10-trimethylundecanoic acid (270 mg., [α]D25 -8.64°) was dissolved in ether and treated with an excess of etheral solution of diazomethane at 23° C. for 2.0 hour. The crude product was subjected to evaporative distillation at 98°-101°/0.15 mm Hg to give 247 mg. of 2(R), 6(R),10-trimethylundecanoic acid methyl ester as a colorless oil, [α]D25 -11.30° (c1.1065, CHCl3).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]([OH:23])=O)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.CO[CH:39]1[CH2:44][CH2:43][NH:42][CH2:41]C1>CN(C=O)C.CO>[N:42]1([C:21]([C:16]2[CH:15]=[CH:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)[CH:12]=3)[N:17]=2)=[O:23])[CH2:41][CH:39]=[CH:44][CH2:43]1
Reactant: CC(C)N1CCC(Oc2ccc3nc(C(=O)O)ccc3c2)CC1
Reactant: COC1CCNCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc3nc(C(=O)N4CC=CC4)ccc3c2)CC1
Yield: 14 %

Procedure:
6-(1-Isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid 1:1 hydrochloride (30 mg, 0.086 mmol, see intermediate 2) was dissolved in DMF (0.300 ml). 1,1′-Carbonyl-diimidazole (17 mg, 0.10 mmol) was added and the mixture was stirred for half an hour. 4-Methoxy-piperidine was added (6 mg, 0.014 mmol) and the mixture was stirred overnight. The mixture was diluted with 0.4 ml methanol and subjected to preparative HPLC purification on reversed phase material eluting with a gradient of acetonitrile/water/triethylamine. The product fractions were evaporated to dryness to yield 4.7 mg (14%) of the title compound as light brown solid. MS (m/e): 412.4 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 120 °C
Yield: 64.2 %

Procedure:
A mixture of 4-fluoro-benzoic acid ethyl ester (1.68 g, 10 mmoles), piperidin-4-ol (1.12 g, 11 mmoles) and anhydrous potassium carbonate (138 g, 10 mmoles) in DMSO (10 ml) was heated at 120° C. for 6 hours. After cooling, the mixture was poured into water and ice (500 ml) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated. The residue was purified by flash chromatography on silica gel using hexane/EtOAc (10/30) as eluent to give the title compound as a white solid (1.6 g, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].C(N(CC)CC)C.[F:37][C:38]([F:44])([F:43])[S:39](Cl)(=[O:41])=[O:40]>ClCCl>[F:37][C:38]([F:44])([F:43])[S:39]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Yield: 62.1 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (300 mg, 0.765 mmol) was dissolved in dichloromethane (12 mL), and the solution was treated with triethylamine (0.533 mL, 3.83 mmol) and trifluoromethanesulfonyl chloride (0.138 mL, 1.30 mmol) under ice-cooling, followed by purification by flash column chromatography (chloroform/methanol=100/0 to 98/2) to obtain 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (249 mg, yield 62%).