Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([C:27](O)=[O:28])[CH:24]=[N:25][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:27](=[O:28])[C:23]3[CH:22]=[C:21]([CH3:20])[CH:26]=[N:25][CH:24]=3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1cncc(C(=O)O)c1
Product: Cc1cncc(C(=O)Nc2cnc(OC3CCC3)c(-c3ccc(Cl)cc3)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and 5-methyl-3-pyridinecarboxylic acid (CAN 40473-04-9) as starting materials; MS (EI) 394.1 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1>ClC(Cl)Cl>[ClH:3].[Cl:3][CH2:6][CH2:7][S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1ccnc1SCCO
Solvent: ClC(Cl)Cl
Product: Cl
Product: Cn1ccnc1SCCCl
Temperature: 5 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Thionyl chloride (1.41 ml, 19 mmol) was slowly added to a solution of 2-(2-hydroxyethylthio)-1-methylimidazole (1.81 g, 11 mmol) in trichloromethane (20 ml) at 5° C. The mixture was stirred for 1 hour at 5° C. and then for 3 hours at ambient temperature. The volatiles were removed by evaporation and the residue azeotroped with toluene to give 2-(2-chloroethylthio)-1-methylimidazole hydrochloride (1.5 g, 77%).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O>[Pt].C(O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12
Agent: [Pt]
Solvent: CCO
Product: CC(C)CNc1c(N)c2nnnn2c2ccccc12
Yield: 39 %

Procedure:
N-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine (1.0 g, 3.5 mmole, Example 15), ethanol (100 mL) and Pt/C were placed in a Paar apparatus. The mixture was hydrogenated at 50 psi (3.44×105Pa). The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The residue was recrystallized from ethyl acetate to provide 0.35 g of N5 -(2-methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine as off white needles, m.p. 148-150° C. Analysis: Calculated for C13H16N6 : % C, 60.92; % H, 6.29; % N, 32.79; Found: % C, 60.94; % H, 6.25; % N, 32.93.
Reaction SMILES: C(O)=O.[S:4](Cl)([N:7]=C=O)(=[O:6])=[O:5].[CH3:11][N:12]([CH3:35])[C:13]([C:15]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:17]([OH:33])[C:16]=1[OH:34])=[O:14]>CN1C(=O)CCC1>[CH3:35][N:12]([CH3:11])[C:13]([C:15]1[N:19]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:17]([OH:33])[C:16]=1[O:34][S:4](=[O:5])(=[O:6])[NH2:7])=[O:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Solvent: O=CO
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(O)c(OS(N)(=O)=O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
Formic acid (165 μL, 4.31 mmol) was added dropwise to neat sulfurisocyanatidic chloride (374 μL, 4.31 mmol) at 0° C. with stirring. The reaction mixture allowed to warm to RT and stirred for 2 h, after which a solution of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (0.5 g, 1.44 mmol) in NMP (3 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and allowed to warm to RT and stirred for a further 2 h. The reaction mixture was partitioned with brine (30 mL) and EtOAc (25 mL), the aqueous layer was extracted with EtOAc (2×25 mL) the combined organics were dried (MgSO4), filtered and solvents removed in vacuo to give a yellow oil. The compound was purified by preparative HPLC (C-18 column, 21.2 mm i.d.×100 mm, 5 micron particle size, gradient 5-95% MeCN in 0.1% aqueous formic acid over 16 min) to afford ethyl 5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-4-(sulfamoyloxy)-1H-pyrrole-2-carboxylate (UL1-068) (76 mg, 12%) as a white solid: m/z 428 (M+H)+ (ES+); 426 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 1H), 7.92 (s, 2H), 7.16-7.08 (m, 2H), 6.96-6.88 (m, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 2.75 (s, 3H), 2.67 (s, 3H), 1.02 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][S:16]([C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.3 %

Procedure:
To a solution of 4.00 g (0.029 mol) of glycine ethyl ester hydrochloride in 40 mL of chloroform and 7.0 mL of pyridine was added 5.58 g (0.029 mol) of 4-fluorobenzenesulfonyl chloride and the reaction was stirred at room temperature for 15 h. The reaction mixture was then washed with water and 5% HCl solution and the organics were dried over MgSO4, filtered and concentrated in vacuo. The resulting white solid was washed with ether/hexanes (1:1) and dried in vacuo to provide 4.72 g (63%) of the sulfonamide as a white solid. Electrospray Mass Spec 261.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)nc2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)nc2)cc1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 8.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(2-(5-(3,4-dimethylphenyl)pyrimidin-2-ylcarbamoyl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)propanoate (340 mg, 0.5 mmol, 1.00 equiv) in dichloromethane (18 mL), and trifluoroacetic acid (8.9 mL). The resulting solution was stirred for ca. 5.5 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by HPLC reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 25.3 mg (8%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.35 (s, 1H), 11.26 (s, 1H), 8.72 (s, 2H), 8.25 (d, J=9 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.56˜7.741 (m, 3H), 7.37 (s, 1H), 7.28˜7.13 (m, 3H), 4.34 (s, 1H), 3.84 (s, 2H), 3.31 (m, 4H), 2.60˜2.55 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.71˜1.58 (m, 6H). MS (ES, m/z): 624 [M+H]+.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH:16]([NH:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:17])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:41]1[CH:46]=[CH:45][N:44]=[C:43]([NH:47][CH:48]2[CH2:53][C:52]([CH3:55])([CH3:54])[NH:51][C:50]([CH3:57])([CH3:56])[CH2:49]2)[N:42]=1>>[NH2:18][CH:16]([CH3:17])[CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:45]3[CH:46]=[CH:41][N:42]=[C:43]([NH:47][CH:48]4[CH2:53][C:52]([CH3:55])([CH3:54])[NH:51][C:50]([CH3:57])([CH3:56])[CH2:49]4)[N:44]=3)=[CH:7][NH:6]2)=[CH:10][CH:11]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(Cc1ccc2ccn([Si](C)(C)C(C)(C)C)c2c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(N)Cc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c2c1

Procedure:
The title compound was prepared as described in Example 215, starting from {2-[1-(tert-butyl-dimethyl-silanyl)-1H-indol-6-yl]-1-methyl-ethyl}-trityl-amine (prepared by trityl and TBDMS protection of 2-(1H-Indol-6-yl)-1-methyl-ethylamine) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ removal of the protecting groups with 2N-HCl. Yield: 406 mg (31%).
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=1>>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([O-:22])=[O:21])=[CH:16][CH:17]=1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([O-:22])=[O:21])=[CH:16][CH:17]=1.[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCCC[Sn](=O)CCCC
Product: CCCC[Sn+2]CCCC
Product: O=C([O-])CCc1ccc(O)cc1

Procedure:
Following the procedure of Example 1, dibutyltin oxide was reacted with 3.2 g (0.2 mole) 3-(4-hydroxyphenyl)propionic acid to yield 56 g of dibutyltin bis-[3-(4-hydroxyphenyl)propionate], a white crystalline material melting at 48°-50° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[CH2:10]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:12](=O)[CH2:11]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[C:10]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:12]=[C:11]3[N:8]=2)[CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: O=C1CCC(C(=O)O)C1
Product: Cc1ccc2c(c1)=C1C(=CC=C1C(=O)O)N=2

Procedure:
Utilizing the procedure of Example 1, paramethylphenylhydrazine was reacted with cyclopentanone-3-carboxylic acid to give 7-methyl-cyclopenta[b]indole carboxylic acid, m.p. 250° (decomp.).
Reaction SMILES: C=O.S(=O)(=O)(O)O.[CH:8]1[CH:17]=[C:16]2[C:18]([O:20][C:21](=[O:22])[C:14]3=[C:15]2[C:10](=[CH:11][C:12]([OH:23])=[CH:13]3)[CH:9]=1)=[O:19].[O:24]1[CH2:29]COC[CH2:25]1>>[CH:9]1[C:10]2[C:15]3[C:16]([C:18](=[O:19])[O:20][C:21](=[O:22])[C:14]=3[CH:13]=[C:12]3[C:11]=2[CH2:29][O:24][CH2:25][O:23]3)=[CH:17][CH:8]=1
Reactant: O=C1OC(=O)c2cc(O)cc3cccc1c23
Reactant: C1COCCO1
Agent: C=O
Agent: O=S(=O)(O)O
Product: O=C1OC(=O)c2cc3c(c4cccc1c24)COCO3
Temperature: 80 °C

Procedure:
Paraformaldehyde (16.0 g, 530.0 mmol) and concentrated sulfuric acid (80 mL) were added to a suspension of 3-hydroxy-1,8-naphthalic anhydride (10.24 g, 48.0 mmol) in dioxane (500 mL). The mixture was heated to 80° C. for 2 hours under stirring. After cooling, the reaction mixture was poured into ice water (1000 mL). The precipitate was filtered and dried to give 12.0 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:29]1[CH:39]=[CH:38][C:32]([CH:33]=[CH:34][C:35](Cl)=[O:36])=[CH:31][CH:30]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH2:13]([NH:12][C:29]1[CH:30]=[CH:31][C:32]([CH:33]=[CH:34][C:35]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:36])=[CH:38][CH:39]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: NCCS(=O)(=O)O
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C=CC(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)NCCS(=O)(=O)O)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 4.4 g. of p-(2,2,2-trifluoro-N-hexadecylacetamido)cinnamoyl chloride as a solution in 45 ml. of ethanol. After 24 hours, the mixture is treated with 20 ml. of 2.0 M sodium hydroxide and 25 ml. of water. After stirring for 10 min., the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compounds as white solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=4[F:41])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:41][C:32]1[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:31]=1[C:23]1[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:26]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:22]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[6-(2-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.24 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.2 g, 49%). MS (ISP) 543.1 [(M+H)+]; mp 210° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH:10]=[CH:11]/[C@@H:12]1[C@@H:19]2[C@@H:15]([O:16][CH:17]([O:20]C)[CH2:18]2)[CH2:14][C@H:13]1[OH:22])(C(C)(C)C)(C)C>Cl.C1COCC1>[OH:8][C@@H:9]([CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)/[CH:10]=[CH:11]/[C@@H:12]1[C@@H:19]2[C@@H:15]([O:16][CH:17]([OH:20])[CH2:18]2)[CH2:14][C@H:13]1[OH:22].[SiH3:1][OH:8]
Reactant: COC1C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)O[Si](C)(C)C(C)(C)C)[C@H](O)C[C@@H]2O1
Agent: Cl
Solvent: C1CCOC1
Product: OC1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Product: O[SiH3]

Procedure:
Alcohol 93 (210 mg, 0.485 mmol) was stirred with 1.5% aqueous HCl/THF (3:2) (10 ml) at r.t. for 16 h. The mixture was extracted with CH2Cl2 (5×15 ml) and the combined organic phases were dried (MgSO4), filtered, and concentrated to give the triol 94 and silanol by-product as a clear, colourless oil. This material was taken forward for the subsequent transformation without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[CH:7]([CH2:15][F:16])[CH2:6][NH:5]2.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23].BrC1C=C2C(=CC=1)N(C(=O)C)[C@@H](C)CN2C(C1OC=CC=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[CH:7]([CH2:15][F:16])[CH2:6][N:5]2[C:22]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)=[O:23]
Reactant: CC(=O)N1c2ccc(Br)cc2NCC1CF
Reactant: O=C(Cl)c1ccco1
Agent: CC(=O)N1c2ccc(Br)cc2N(C(=O)c2ccco2)C[C@@H]1C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)c2ccco2)CC1CF

Procedure:
1-(6-bromo-2-(fluoromethyl)-4-(furan-2-carbonyl)-3,4-dihydroquinoxaline-1(2H)-yl)ethan-1-one was synthesized from (1-(6-bromo-2-(fluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one and furan-2-carbonyl chloride according to the procedure outlined for (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone. MS (ESI, pos. ion) m/z 339, 341 [M−42 (acyl)]+.
Reaction SMILES: CN([CH:4]=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=O)C.[NH:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:16]([NH2:18])=[NH:17].CN1C(=O)CCC1>O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:18]=[C:16]([NH:15][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)[N:17]=2)=[CH:9][CH:10]=1
Reactant: CN(C)C=CC(=O)c1ccc(Br)cc1
Reactant: N=C(N)Nc1ccc(S(N)(=O)=O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(Br)cc3)n2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
A flask is charged with the 1-(4-bromo-phenyl)-3-dimethylamino-propenone (1.05 g, 4.10 mmol), 4-guanidino-benzenesulfonamide (1.33 g, 6.20 mmol), and NMP (30 ml). The reaction mixture is stirred at 120° C. for 20 h. The reaction mixture is cooled to room temperature, diluted with water, and filtered. The solid residue is washed with water and dried to yield 1.66 g of a white solid. MS (ESI) m/z 405.1; HRMS: calcd for C16H13BrN4O2S+H+, 405.00153; found (ESI-FTMS, [M+H]1+), 405.00158.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@@H:13]([NH:25]C(=O)OC(C)(C)C)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].Cl>CO.O1CCOCC1>[NH2:25][C@@H:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:22])[F:23])[CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reaction time: 12 h
Yield: 109.2 %

Procedure:
To a solution of 1,1-dimethylethyl ((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate (3.2 g, 7.1 mmol) in MeOH (35 mL) at RT was added 4M HCl in dioxane (18 mL). After 12 h, the solution was concentrated affording the title compound (2.7 g, quant.) as the HCl salt: LCMS (ES) m/z 349 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C:10]([CH2:39][CH:40]=O)([CH2:26][CH2:27][O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C:10]([CH2:39][CH2:40][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)([CH2:26][CH2:27][O:28][Si:29]([CH:33]([CH3:34])[CH3:35])([CH:36]([CH3:37])[CH3:38])[CH:30]([CH3:32])[CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](OCCC1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)(C(C)C)C(C)C
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCC1(CCN2CCCC2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1.02 g (1.66 mmol) of crude 2-((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde (Example 69, Step B, mixture of diastereomers), 0.55 mL (6.6 mmol) of pyrrolidine, 880 mg (4.15 mmol) of sodium triacetoxyborohydride and 285 μL (4.98 mmol) of acetic acid was suspended in a mixture of 1,2-dichloroethane (36 mL) and DMF (12 mL). After being stirred at room temperature for 20 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound (mixture of C-3 epimers) was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C=O)C>[CH2:22]([N:11]1[C:12]2[C:8](=[C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=2)[CH:9]=[CH:10]1)[CH3:23]
Reactant: COC(=O)c1cc(N2CCCC2=O)c2cc[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2c(N3CCCC3=O)cc(C(=O)OC)cc21
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a solution of methyl 4-(2-oxo-1-pyrrolidinyl)-1H-indole-6-carboxylate (B154) (500 mg, 1.94 mmol, 1 equiv) in DMF (10 ml) at room temperature was added NaH (60% dispersion in mineral oil, 84 mg, 2.1 mmol, 1.1 equiv) and the resulting mixture was stirred 15 min. Ethyl iodide (200 μl, 2.5 mmol, 1.3 equiv) was added and the resulting solution was stirred for 30 min then concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 1/4 to 1/1) gave methyl 1-ethyl-4-(2-oxo-1-pyrrolidinyl)-1H-indole-6-carboxylate (B140) (400 mg, 72%) as an off-white solid. [M+H]+=287.0, RT=2.73 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:45]=[CH:44][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH:36]4[C:40]([O:42]C)=[O:41])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH:36]4[C:40]([OH:42])=[O:41])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:44][CH:45]=1)=[O:11]
Reactant: COC(=O)C1CCCN1CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCCC5C(=O)O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylate (Example 50) (68 mg, 0.11 mmol) in a mixture of THF/MeOH (5 ml/5 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 16 hours and poured into 30 ml of water. 1M HCl was added dropwise with vigorous stirring until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylic acid as light reddish solid. Yield: 60 mg, 91%.
Reaction SMILES: [CH:1]1([S:7][C:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([S:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:9]#[N:10]
Reactant: COc1ccc(C(C#N)(CCCCCN2C(=O)c3ccccc3C2=O)SC2CCCCC2)cc1OC
Agent: NN
Solvent: O
Product: COc1ccc(C(C#N)(CCCCCN)SC2CCCCC2)cc1OC
Yield: 88.8 %

Procedure:
The procedure of Example 25 is repeated using 2.0 g of α-(cyclohexylthio)-α-(3,4-dimethoxyphenyl)-1,3-dioxo-2H-isoindole-2-heptanenitrile and 3.0 mL of hydrazine hydrate. This affords 1.32 g of the desired product as a light yellow oil. Calcd for C21H32N2SO2 0.7M H2O: C=64.81, H=8.81, N=7.20, S=8.24 Found C=65.04, H=8.49, N=6.98, S=8.20