Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([NH2:39])=[O:38])[CH:17]=2)[CH:13]=[CH:12][N:11]=1>CN(C=O)C.CCOC(C)=O>[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([NH2:39])=[O:38])[CH:17]=2)[C:13]([I:1])=[CH:12][N:11]=1
Reactant: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2ccnc(N)n2)n1COCC[Si](C)(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2nc(N)ncc2I)n1COCC[Si](C)(C)C
Temperature: 65 °C
Yield: 61.1 %

Procedure:
N-iodosuccinimide (720 mg, 3.2 mmol) was added to a solution of 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxamide (1.39 g, 3.0 mmol) in dry DMF (6 mL). The reaction mixture was heated at 65° C. for 7 h, allowed to cool to room temperature and then diluted with EtOAc (30 mL), washed with water (2×20 mL) brine, dried over sodium sulphate, and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 97/3) to afford the title compound as yellow solid (1.07 g, 60%).
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=O)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10](/[CH:15]=[N:21]/[OH:22])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NO
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C=O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(/C=N/O)ccc12
Temperature: 85 °C
Reaction time: 17.5 h
Yield: 52.5 %

Procedure:
Step 1 A mixture of 4-bromo-7-formyl-9H-carbazole-1-carboxamide (prepared according to Step 1 of Example 41-1, 200 mg, 0.631 mmol) and hydroxylamine hydrochloric acid salt (65.7 mg, 0.946 mmol) in ethanol (3 mL) was treated with 2 M aqueous sodium carbonate (0.236 mL, 0.473 mmol) and heated at 80-90° C. After 17.5 h, the mixture was cooled to rt and partitioned between EtOAc and water. The organic phase was dried and concentrated, and the residue was triturated with methanol, and the precipitate was collected by filtration, rinsed with methanol and dried to provide (E)-4-bromo-7-((hydroxyimino)methyl)-9H-carbazole-1-carboxamide as a gray-tan solid (110 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 11.87 (1H, s), 11.33 (1H, s), 8.65 (1H, d, J=8.4 Hz), 8.32 (1H, s), 8.28 (1H, br. s.), 8.09 (1H, s), 7.92 (1H, d, J=8.1 Hz), 7.64 (1H, br. s.), 7.58 (1H, d, J=8.6 Hz), 7.51 (1H, d, J=8.1 Hz). Mass spectrum m/z 332, 334 (M+H)+.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:10]=1)(=O)=O.[NH3:19].C1COCC1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[N:10]=[C:5]([NH2:19])[N:6]=[N:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2cnnc(S(C)(=O)=O)n2)c1
Reactant: N
Solvent: C1CCOC1
Product: COc1cccc(-c2cnnc(N)n2)c1
Yield: 45 %

Procedure:
5-(3-Methoxyphenyl)-1,2,4-triazin-3-amine (0.31 g, 45%) was prepared from 3-(methylsulfonyl)-5-(3-methoxyphenyl)-1,2,4-triazine (0.90 g, 3.39 mmol) and 0.5 M ammonia in THF (50 mL, 25.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [Br-].[CH2:2]([NH:5][CH2:6][CH2:7][CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3][CH3:4].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[Na+]>CCO.O>[Br-:13].[CH2:14]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCBr
Reactant: CCCNCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCN(CCC)CCC[N+](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of propylamine (5.5 mL, 0.067 mol) in EtOH (100 mL) is added 3-bromo-N,N,N-trimethylpropan-1-aminium bromide (5.0 g, 0.0191 mol) portionwise at 0° C. over 20 minutes. The solution is warmed to room temperature and then refluxed for 4 hours. The solution is cooled to room temperature, and the solvent is removed via rotary evaporator to provide the crude di-bromo salt (5.69 g, 0.0179 mol). The salt is dissolved in MeOH (200 mL) and NaOH is added portionwise (0.717 g, 0.0179 mol) in MeOH (50 mL) over 30 minutes at room temperature. The solution is stirred an additional 2 hours at room temperature after addition is complete and then the solvent is removed via rotary evaporator. The residue is stirred with CH3CN (150 mL) for 30 minutes and the solids filtered off. The filtrate is concentrated via rotary evaporation and the residue is pumped on 24 h under vacuum to provide the 3-(propylamino)-N,N,N-trimethylpropan-1-aminium bromide (4.07 g, 0.017 mol), which is used without further purification. The 3-(propylamino)-N,N,N-trimethylpropan-1-aminium bromide (4.07 g, 0.017 mol) is dissolved in EtOH (100 mL) and 1-bromododecane (4.55 mL, 0.019 mol) is added dropwise over 15 minutes. The reaction is refluxed 24 hours, cooled to room temperature, and solid NaOH (0.68 g, 0.017 mol) is added. The reaction is stirred 2 hours at room temperature, and then the solids are filtered off. The filtrate is concentrated to give a white solid. The solid is dissolved in water (200 mL) and extracted with EtOAc (3×150 mL). The organic layers are combined and discarded, and the aqueous layer is frozen and lyophilized under vacuum for 48 hours to provide 3-(dodecyl(propyl)amino)-N,N,N-trimethylpropan-1-aminium bromide as a white solid (5.29 g, 0.013 mol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[CH:3]=1.[I:31]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[C:3]=1[I:31]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N)cc3c2ncn3C)c(OC)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N)c(I)c3c2ncn3C)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
In a round bottom flask, tert-butyl 6-amino-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example 1D, 7.887 g, 19.08 mmol) was dissolved in MeCN (200 mL) and cooled to 0° C. N-Iodosuccinimide (4.51 g, 20.03 mmol) was dissolved in the remaining MeCN (50 mL) and added dropwise to the reaction mixture over 40 min. The reaction mixture was stirred at 0° C. for an additional 10 min and was quenched with 2 M sodium hydrogensulfite (125 mL). Stirring and temperature were maintained for 50 min. The mixture was transferred to a separatory funnel. The aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography using an Isco 120 g column eluting with 20-100% ethyl acetate/CH2Cl2 to provide tert-butyl 6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (8.436 g, 82% yield) as a pale yellow solid.
Reaction SMILES: N1(S(N[C:9](=O)[C:10]2[CH:15]=C(Cl)C(OCC34CC5CC(CC(CO)(C5)C3)C4)=CC=2F)(=O)=O)CCC1.[C@@H:33]12[CH2:39][C@@H:36]([CH2:37][CH2:38]1)[CH2:35][C@@H:34]2[O:40][C:41]1[C:53](Cl)=[CH:52][C:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[C:43]([F:55])[CH:42]=1>>[C@@H:33]12[CH2:39][C@@H:36]([CH2:37][CH2:38]1)[CH2:35][C@@H:34]2[O:40][C:41]1[C:53]([CH:15]2[CH2:10][CH2:9]2)=[CH:52][C:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[C:43]([F:55])[CH:42]=1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F

Procedure:
Following the procedure as described in Example 278 step 7 and making variations as required to replace N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamide with tert-Butyl 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-chloro-2-fluorobenzoate. Purification by silica gel column chromatography (10:1 hexanes:ethyl acetate) gave the title compound as a colorless oil (0.77 g, quant): 1H NMR (300 MHz, CDCl3) δ 7.33 (d, J=8.3 Hz, 1H), 6.45 (d, J=13.0 Hz, 1H), 4.20-4.13 (m, 1H), 2.49-2.44 (m, 1H), 2.35-2.29 (m, 1H), 2.01-1.91 (m, 1H), 1.82-1.73 (m, 1H), 1.70-1.63 (m, 1H), 1.61-1.56 (m, 1H), 1.55 (s, 9H), 1.50-1.44 (m, 1H), 1.27-1.09 (m, 4H), 0.88-0.81 (m, 2H), 0.63-0.56 (m, 2H); MS (ES+) m/z 291.2 (M-55).
Reaction SMILES: C([O:8][C:9](=[O:22])[C@H:10]([CH3:21])[NH:11][C@H:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:14][CH3:15])C1C=CC=CC=1.C.[H][H]>C(O)C>[CH2:19]([O:18][C:16]([C@@H:12]([NH:11][C@H:10]([C:9]([OH:22])=[O:8])[CH3:21])[CH2:13][CH2:14][CH3:15])=[O:17])[CH3:20]
Reactant: [H][H]
Reactant: CCC[C@H](N[C@@H](C)C(=O)OCc1ccccc1)C(=O)OCC
Solvent: CCO
Product: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Yield: 59.5 %

Procedure:
A solution of N-[1-(S)-ethoxycarbonyl-1-butyl]-(S)-alanine benzyl ester (14.5 g, as obtained in Step-I) in ethanol (150 ml) was hydrogenated in the presence of 10% palladised charcoal (0.8 g) under 40-45 psi hydrogen pressure for 1.5 to 2 hrs. The reaction mixture was concentrated under reduced pressure to give an oil. Crystallization from a mixture of acetonitrile and ethanol (1:3) gave 6.1 g the title compound
Reaction SMILES: [CH2:1]([N:13]([CH3:20])[CH2:14][CH2:15][C:16]([CH3:19])([NH2:18])[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21](ON1C(=O)CCC1=O)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[CH2:1]([N:13]([CH3:20])[CH2:14][CH2:15][C:16]([NH:18][C:21](=[O:22])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:19])[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCCCCCCCCCCCN(C)CCC(C)(C)N
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
Crude N1-dodecyl-N1,3-dimethylbutane-1,3-diamine (5.61 g, 19.7 mmol) was dissolved into THF (100 mL) and cooled in an ice bath. Solid CbzOSu (4.91 g, 1 equiv, 19.7 mmol) was added to the reaction in one portion. The reaction was left to stir at room temperature for 16 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (8.08 g). The crude oil was purified on an ISCO purification system with gradient elution from 25-100% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a pale yellow oil (5.71 g, yield: 69.2%). 1H NMR (CDCl3, 400 MHz): δ 0.89-0.92 (t, J=6, 3H), 1.21-1.36 (m, 17H), 1.39 (s, 6H), 1.56-1.66 (m, 4H), 2.21 (s, 3H), 2.30-2.34 (t, J=8, 2H), 2.46-2.49 (t, J=6, 2H), 5.06 (s, 2H), 7.28-7.41 (m, 5H). LRMS (ESI+) for C26H46N2O2 (418.4); Found: 419 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:8]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]3)=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:40][S:41](O)(=[O:43])=[O:42]>O1CCCC1>[CH3:40][S:41]([O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:8]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)[CH:13]=1)(=[O:43])=[O:42]
Reactant: Cc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Reactant: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3cc(OS(C)(=O)=O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Temperature: 60 °C

Procedure:
Place 6-(5-methylthiophen-2-yl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-ol (105.7 mg, 0.23 mmol) in a vial. Add ethyl acetate (2 mL) and methanesulfonic acid (18 μL). Warm the resulting mixture to ˜60° C. with stirring. Add tetrahydrofuran (1 mL) to the resulting burnt orange solution with some dark brown gum on the bottom of the vial. Sonicate the resulting solution for 15 minutes. Carefully decant the suspension from gum that forms on the flask. Carefully collect the resulting solids by vacuum filtration and wash the resulting cake with pentane (2×2 mL). Dry the resulting solids in a 40° C. vacuum oven overnight to obtain the title compound. MP (DSC)=161.90° C.
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]([OH:7])=[O:6].O1CCC[CH2:17]1>>[O:3]=[C:4]([C:8]([CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]([OH:7])=[O:6]
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Reactant: C1CCOC1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Yield: 11 %

Procedure:
Example 14 was repeated except that 4.0 ml (9.0 mmoles) of a 2.25N aqueous solution of potassium hydroxide was used instead of lithium hydroxide as a base, and 8 ml of tetrahydrofuran was used as a solvent. A mixture of 2-oxo-3-phenylbutanoic acid (65 %) and 2-oxo-3-methyl-3-phenylbutanoic acid (11 %) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.C(O)=[O:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH2:11][OH:10]
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Reactant: O=CO
Product: OCC(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Heat a solution of 1-[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole (57 g) [prepared as described in Example 2(c) of British patent application No. 2,099,818A, published 15 Dec. 1982] in formic acid (500 mL) at reflux overnight. Remove the solvent in vacuo at 85°. Dilute the residue with ice water (1 liter) and basify carefully with 10% K2CO3 solution. Dilute with MeOH (500 mL) and heat on steam bath (1.5hr). Remove the MeOH in vacuo and extract the remaining aqueous solution with EtOAc (2×500 mL). Wash the EtOAc layer with H2O and dry it oyer MgSO4 and evaporate it to dryness to give 49.7 g of the title compound as a solid, m.p. 130°-132° C.
Reaction SMILES: C[Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[O:11][C:10]([CH3:18])([CH3:17])[CH2:9][C:8]2=O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.ClCCl>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[O:11][C:10]([CH3:18])([CH3:17])[CH:9]=[C:8]2[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2c(cc1Br)C(C)=CC(C)(C)O2
Temperature: 10 °C

Procedure:
A solution of methylmagnesium bromide (3.0 M in THF, 1.67 mL, 5.0 mmol) was added slowly into a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 710 mg, 2.5 mmol) in 10 mL of THF at −30° C. The mixture was stirred and warmed to 10° C. for 2 h. The reaction mixture was quenched with 10% HCl and extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of NH4Cl, dried (MgSO4) and concentrated at reduced pressure to give a crude oil, which was then dissolved in 10 mL of dichloromethane and cooled to 0° C. with an ice bath. To this solution was added p-toluenesulfonic acid (100 mg). After stirring for 3 h at 0° C., the reaction mixture was quenched with water, extracted with dichloromethane, washed with brine, dried (MgSO4) and concentrated at reduced pressure to give a colorless oil. Purification by flash chromatography (silica gel, 95.5 hexane/ethyl acetate) gave the title compound as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([F:27])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:12]1[C:13]2[C:9](=[CH:8][C:7]([F:27])=[CH:6][C:5]=2[O:4][CH2:3][CH2:2][Cl:1])[C:10]([S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[N:11]1
Reactant: Clc1cccc(CBr)c1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cc(F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A mixture of 7-(2-chloro-ethoxy)-5-fluoro-3-(naphthalene-1-sulfonyl)-1H-indazole (0.9 g, 2.2 mmoles), 3-chlorobenzyl bromide (0.35 mL, 2.7 mmoles), and cesium carbonate (0.87 g, 2.7 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.85 g, 2 mmoles).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.[CH2:31](O)[CH2:32][CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH2:31][CH2:32][CH2:33][CH3:34])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCCCO
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Product: CCCCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reaction time: 16 h

Procedure:
2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid was mixed with EDCI and 1-butanol and the reaction mixture was stirred for 16 h to obtain butyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[N:32]=[C:33]=[O:34].C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:34])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccc5ccccc5c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
A heterogeneous mixture of 3-(4-aminomethyl-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 2-naphthyl isocyanate (0.26 g, 1.6 mmol), and triethylamine (4.9 g, 4.9 mmol) in 25 mL THF was stirred under nitrogen at ambient temperature for 18 hours. The solvent was removed under vacuum. The residue was triturated with 3% aqueous HCl (100 mL) for 1 hour and then filtered, and the filter was washed with additional 3% HCl. The resulting solid was dried, triturated with 30 mL refluxing acetone for 1 hour, and filtered, and the filter was washed with additional hot acetone. The resulting solid was dried and then triturated with 30 mL refluxing acetonitrile, filtered, and dried, to provide 0.45 g of the product in 63% yield: 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H), 2.38-2.45 (m, 1H), 2.57-2.65 (m, 1H), 2.86-2.93 (m, 1H), 4.41 (d, J=5.0 Hz, 2H), 4.43 (d, J=17.4 Hz, 1H), 4.57 (d, J=17.4 Hz, 1H), 5.16 (dd, J=13.2 Hz, J=5.1 Hz, 1H), 6.83 (t, J=5.8 Hz, 1H), 7.28-7.79 (m, 9H), 8.02 (d, J=1.8 Hz, 1H), 8.85 (s, 1H), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.6, 31.2, 39.8, 46.2, 51.6, 112.8, 119.6, 121.6, 123.6, 126.2, 126.8, 127.4, 128.2, 128.3, 128.8, 130.4, 131.7, 133.8, 135.6, 138.0, 139.9, 155.3, 168.1, 171.0, 172.8; Anal. calcd for C25H22N4O4.0.2H2O: C, 67.31; H, 5.06; N, 12.56. Found: C, 67.37; H, 4.90; N, 12.53.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[S:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]1.[BH3-]C#N.[Na+].CC(O)=O>CO>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:26][C:23]1[CH:24]=[CH:25][S:21][CH:22]=1
Reactant: COc1ccc(NCc2c(Cl)cncc2Cl)cc1OC
Reactant: O=Cc1ccsc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(N(Cc2ccsc2)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate B1 (200 mg, 0.64 mmoles) was dissolved in MeOH (10 mL). Molecular sieves (4A, 200 mg) were added, and then thiophen-3-carbaldehyde (0.056 mL, 0.64 mmoles) was added. The mixture was stirred at room temperature for 2 hours, then NaBH3CN (121 mg, 1.9 mmoles) was added. AcOH was added dropwise to pH=5. After 48 hours, molecular sieves were removed by filtration, and water was added (20 mL). The mixture was extracted with AcOEt (3×50 mL), and the organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The crude material was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 7/3) to yield the title compound in amount of 173 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:4][CH:3]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:26][C@@H:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(-c2ccc(F)cc2)c1
Product: Fc1ccc(-c2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
4′-Fluoro[1,1′-biphenyl]-3-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:8][O:9][C:10](=[O:14])[C:11]([Cl:13])=[CH2:12].Cl>O>[CH3:8][O:9][C:10](=[O:14])[CH:11]([Cl:13])[CH2:12][S:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CS
Reactant: C=C(Cl)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C(Cl)CSCC(=O)O
Reaction time: 24 h
Yield: 86.3 %

Procedure:
Under stirring there were added 0.063 gram (1.58 mmoles) of sodium hydroxide in 0.32 ml water to 1.00 gram (10.9 mmoles) of mercaptoacetic acid and 1.31 grams (10.9 mmoles) of 2-chloroacrylic acid methyl ester. Stirring was carried out subsequently for 24 hours at 10° C. After acidification of the reaction mixture with dilute hydrochloric acid the working up was carried out by extracting three times with diethyl ether, drying the combined ether phases with water free sodium sulfate and removal of the ether. There were obtained 2.00 grams (86% of theory) of 2-chloro-3-carboxymethylmercapto-propionic acid methyl ester as a colorless viscous oil.