Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:50])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:49])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:48])[NH:31][C@@H:32]4[CH2:35][C@H:34]([C:36]([N:38]5[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:47])[CH3:46])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:52])[CH3:51])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH2:44]([N:41]1[CH2:42][CH2:43][N:38]([C:36]([C@H:34]2[CH2:35][C@@H:32]([NH:31][C:30]([C@:14]34[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]3[C@@H:16]3[C@@:11]([CH3:49])([CH2:12][CH2:13]4)[C@@:10]4([CH3:50])[C@@H:19]([C@:20]5([CH3:23])[C@@H:7]([CH2:8][CH2:9]4)[C:6]([CH3:51])([CH3:52])[C@@H:5]([OH:4])[CH2:22][CH2:21]5)[CH2:18][CH2:17]3)=[O:48])[C:33]2([CH3:46])[CH3:47])=[O:37])[CH2:39][CH2:40]1)[CH3:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCN(CC)CC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-3-(4-ethylpiperazine-1-carbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 69, 550 mg) in MeOH:THF (2:1) at 0° C. temperature 2N NaOH (4 mL) was added and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles was evaporated, the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried with Na2SO4. The solvent was evaporated and the resulting crude was stirred in hexane to get crude solid. The solid crude was purified over silica-gel column chromatography to afford the title compound. Wt: 200 mg, Yield: 93.3%. 1H NMR (300 MHz, CDCl3): δ 5.86 (d, 1H, J=8.1 Hz), 4.72 (s, 1H), 4.57 (s, 1H), 4.18-4.06 (m, 1H), 3.78-3.68 (m, 1H), 3.52-3.30 (m, 3H), 3.23-3.08 (m, 2H), 2.92-2.86 (m, 1H), 2.52-2.20 (m, 3H), 2.01-1.88 (m, 2H), 1.80-1.12 (m, 33H), 0.96, 0.93, 0.87, 0.81, 0.74 (s, 18H); Mass: [M+1]+ 649 (5%), [M+Na]+ 671 (100%); IR (KBr, cm−1): 3353, 2937, 2858, 1635, 1618, 1533, 1459, 1390, 1262, 1250, 1148, 1048, 1033, 1020, 983, 883; M.R: 177° C.-188.7° C.; HPLC: 95.72%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@@H:8]([CH2:28][N:29]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6](=[O:40])[NH:7][C@@H:8]([CH2:28][NH2:29])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CN)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 77.8 %

Procedure:
[(S)-2-(tert-Butyl-diphenyl-silanyloxy)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-ethyl]-carbamic acid tert-butyl ester (1.1 g, 1.92 mmol) was treated with hydrazine hydrate (0.5 ml, 9 mmol) in EtOH (5 ml) at rt over night to give [(S)-1-aminomethyl-2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-carbamic acid tert-butyl ester (640 mg, 75%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.Cl>C1COCC1>[NH2:7][C@H:8]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)=[O:10]
Reactant: COc1ccccc1N1CCN(C(=O)[C@@H](Cc2cccnc2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C(=O)[C@H](N)Cc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of (R)-{2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-2-oxo-1-pyridin-3-ylmethyl-ethyl}-carbamic acid tert-butyl ester (7.54 g.; 17.1 mmol) from Example 1 in THF (60 mL) at 0° C. was added HCl (4M/Dioxane) (70 mL; 0.28 mol). The mixture was stirred at ambient temperature for 3 hours, and the solvent removed in vacuo. A small portion of the trihydrochloride residue was retained for analytical purposes. The remainder of the residue was dissolved in water (70 mL), washed with ether (40 mL), and the ether layer discarded. The aqueous layer was rendered basic (pH 9–10) with saturated aqueous Na2CO3, and the product extracted into dichloromethane (3×60 mL). The combined dichloromethane layers were washed with brine, dried over MgSO4, filtered, and the solvent removed in vacuo to afford the free base of the title compound as a clear oil (5.8 g., 100%). The analytical sample as the trihydrochloride salt was recrystallized from ethanol/ether to afford a white crystalline powder, m.p. >240° C.; MS (+) ESI, [M+H]+ @ m/z 341; 1H NMR, 400 MHz, DMSO-d6. Analysis for C19H24N4O2.3HCl Calculated: C, 50.73; H, 6.05; N, 12.46 Found: C, 50.89; H, 6.03; N, 12.41.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br.CN(C)C=O>O>[Br:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(OCCCBr)ccc2N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 12.6 g (0.076 mol) of 6-hydroxy-1,2,3,4-tetrahydro-2-quinolinone, 15.8 g (0.115 mol) of potassium carbonate (anhydrous and powdered), 46.5 g (0.23 mol) of 1,3-dibromopropane and 40 ml of N,N-dimethylformamide is stirred at room temperature for 20 hours. 200 ml of water and 100 ml of petroleum ether are added and, after stirring for 1 hour, the precipitate which has formed is filtered off with suction, washed with petroleum ether and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:28][C:29]([CH3:42])([CH3:41])[CH2:30][NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36](Br)[N:35]=1)=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:32](=[O:33])[NH:31][CH2:30][C:29]([CH3:41])([CH3:28])[CH3:42])[N:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)CNC(=O)c1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(=O)NCC(C)(C)C)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 6-bromo-pyridine-2-carboxylic acid (2,2-dimethyl-propyl)-amide.
Reaction SMILES: C([NH:3][C:4]1[N:8]([CH2:9][CH2:10][OH:11])[N:7]=[CH:6][CH:5]=1)=O.ClS([N:16]=[C:17]=[O:18])(=O)=O.O.[OH-].[Na+]>C(#N)C>[NH2:3][C:4]1[N:8]([CH2:9][CH2:10][O:11][C:17](=[O:18])[NH2:16])[N:7]=[CH:6][CH:5]=1
Reactant: O=CNc1ccnn1CCO
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: NC(=O)OCCn1nccc1N
Reaction time: 3 h

Procedure:
To a suspension of 5-formamido-1-(2-hydroxyethyl)pyrazole (1 g) in acetonitrile (50 ml) was added dropwise chlorosulfonyl isocyanate (0.77 ml) at -15° C.~-20° C. The mixture was stirred for 3 hours under ice-cooling. To the reaction mixture was added water (1 ml) and kept to stand overnight. The solution was adjusted to pH 7.5 with 5N-sodium hydroxide solution and then adjusted to pH 8.5 with 1N-sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with tetrahydrofuran. The extract and said organic layer were combined and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized from ethyl acetate to give 5-amino-1-(2-carbamoyloxyethyl)pyrazole (0.60 g).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>CN(C)C=O.C(OCC)(=O)C.O>[I:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[N:8]=[CH:7]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Ic1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(I)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.6 %

Procedure:
To a slurry of sodium hydride (0.67 g, 17 mmol) in N,N-dimethylformamide (43 mL) cooled to 0° C. was added 5-iodo-1H-indazole (3.1 g, 13 mmol). After stirring for 15 min, triisopropylsilyl chloride (3.4 mL, 17 mmol) was added dropwise and the solution was allowed to warm to room temperature. The solution was diluted with ethyl acetate and water and the layers were separated. The aqueous layer was extracted (2×100 mL ethyl acetate) and the combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 20:1 hexanes/ethyl acetate) gave 1.8 g (68%) of 5-iodo-1-[tris(1-methylethyl)silyl]-1H-indazole as a yellow solid. 1H NMR (400 MHz, CDCl3): 8.14 (d, 1H), 8.11 (d, 1H), 7.55 (dd, 1H), 7.35 (d, 1H), 1.77 (m, 3H), 1.10 (m, 18H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=O)[C:21]3[C:20](=[O:31])[N:19]([CH3:32])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].C([O-])(=O)C.[K+]>C(O)C.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[N:36][OH:37])[C:21]3[C:20](=[O:31])[N:19]([CH3:32])[C:18](=[O:33])[N:17]([CH3:34])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NO
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=NO)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[7-(2-Formylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (13 mg) and hydroxylamine hydrochloride (10 mg) were dissolved in ethanol (1 ml) and water (0.2 ml), and potassium acetate (ca. 10 mg) was added thereto. The reaction solution was stirred for 0.5 hour at room temperature, diluted with ethyl acetate, and washed with sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-[7-[2-(hydroxyiminomethyl)phenyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. This was dissolved in dichloromethane (0.5 ml) and triethylamine (ca. 0.05 ml) and methanesulfonyl chloride (0.05 ml) were added thereto. The reaction mixture was stirred at room temperature for 0.5 hour, and the solvent was removed. The residue was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 4.14 mg of the title compound.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:53])[N:37]([CH2:49][CH:50]2[CH2:52][CH2:51]2)[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=2)[CH:40]=1)(O)=[O:33]>>[CH:50]1([CH2:49][N:37]2[C:36](=[O:53])[C:35]([CH2:32][OH:33])=[CH:40][C:39]([C:41]3[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=3)=[N:38]2)[CH2:52][CH2:51]1
Reactant: CSc1ccc(-c2cc(C(=O)O)c(=O)n(CC3CC3)n2)cc1
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: CSc1ccc(-c2cc(CO)c(=O)n(CC3CC3)n2)cc1
Yield: 22.6 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellow crystalline powder (yield: 22.6%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])([CH3:17])[CH3:16]>>[CH:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: CC(C)c1cccc(N)c1
Product: Cc1cc(Nc2cccc(C(C)C)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-isopropylaniline (33 μl, 0.243 mmol) similar to Example 13 and isolated as a gray oil (70 mg, 95%). 1H NMR (CDCl3): 8.79-8.77 (m, 1H), 8.47-8.43 (m, 1H), 7.81-7.75 (m, 1H), 7.35-7.25 (m, 3H), 7.17-7.12 (m, 2H), 7.02 (d, J=7.5 Hz, 1H), 2.93-2.84 (m, 1H), 2.45 (s, 3H), 1.24 (d, J=6.9 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:22])=[CH:5][N:6]=1
Reactant: Nc1ncc(Sc2cccnc2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1ncc(S(=O)c2cccnc2)s1
Yield: 37.2 %

Procedure:
To a mixture of 2-amino-5-(3-pyridylthio)thiazole (3.0 g) in a mixture of dichloromethane (100 ml) and chloroform (100 ml) was added dropwise the solution of 3-chloroperbenzoic acid (3.4 g) in dichloromethane (50 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 3 hours. The reaction mixture was washed with aqueous sodium bicarbonate and the aqueous layer was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was recrystallized from ethanol to give 2-amino-5-(3-pyridylsulfinyl)thiazole (1.2 g, yield: 37.2%). mp: 178°-179° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:20])[CH:13]([NH2:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].O>ClCCl>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:19][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=1)[C:12]([O:11][CH2:9][CH3:10])=[O:20])[CH3:18]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1cccc(F)c1)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
36.1 ml of triethylamine were added to a solution of 25 g of aminomalonic acid diethyl ester hydrochloride in 200 ml of dichloromethane with cooling in an ice bath. Then a solution of 18.7 g of 3-fluoro-benzoyl chloride in 100 ml of dichloromethane was added dropwise. After stirring for 2 h at 0° C., 100 ml of water were added dropwise. The layers were separated, and the aqueous layer was extracted with 100 ml of dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered and evaporated to give 33.2 g of the crude title compound.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.F[C:37](F)(F)[C:38]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:37]([O:30][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:19]2[CH:20]=[C:21]3[C:16]([CH2:15][CH2:14][CH2:13][N:12]3[S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:4]=3)(=[O:10])=[O:11])=[CH:17][CH:18]=2)=[O:23])=[CH:33][CH:32]=1)[CH3:38]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC3)cc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC3)cc1

Procedure:
4 4-{[1-(3-Trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=503.0 (M−H), was prepared in analogy to example 57, steps 1 to 6. Step 5 was performed using 3-trifluromethyl-benzenesulfonyl chloride, yielding 4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:24]=1>N1C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][S:30]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)(=[O:31])=[O:32])[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: O=S(=O)(Cl)Nc1ccc(F)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)cc1)Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 45 °C
Reaction time: 48 h

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,5-diamine (example 43, step A+B, 200 mg, 0.727 mmol) was dissolved in 3 mL pyridine and 4-fluoro-phenylsulfamoyl chloride (298 mg, 1.42 mmol) was added. The reaction mixture was stirred at 45° C. for 2 days and quenched by addition of 50 mL water. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane, tetrahydrofurane 100:0->50:50 gradient). The title compound was obtained as a brown solid (43 mg, 13%), MS: m/e=449.1 (M+H+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C[O:14][C:15](=[O:45])[CH2:16][C:17]1[CH:22]=[C:21]([Br:23])[C:20]([O:24][C:25]2[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:34])=[CH:27][C:26]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=2)=[C:19]([Br:44])[CH:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:65][C:66](=[CH2:70])[CH2:67][CH2:68]O>C(Cl)Cl>[Br:44][C:19]1[CH:18]=[C:17]([CH2:16][C:15]([OH:14])=[O:45])[CH:22]=[C:21]([Br:23])[C:20]=1[O:24][C:25]1[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([O:34][CH2:68][CH2:67][C:66]([CH3:70])=[CH2:65])=[CH:27][C:26]=1[C:35](=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=1
Reactant: C=C(C)CCO
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(C(C)C)c(O)cc2C(=O)c2cccc(C)c2)c(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C(C)CCOc1cc(C(=O)c2cccc(C)c2)c(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Temperature: 40 °C

Procedure:
A solution of diethyl azodicarboxylate (42 mg, 0.24 mmol) in anhydrous CH2Cl2 (1 mL) was added over 15 min to an ice-cooled, stirred mixture of 3,5-dibromo-4-[4-hydroxy-5-isopropyl-2-(3-methylbenzoyl)phenoxy]phenylacetic acid methyl ester (70 mg, 0.12 mmol), PPh3 (63 mg, 0.24 mmol) and 3-methyl-3-buten-1-ol (24 μL, 0.24 mmol) in anhydrous CH2Cl2 (2 mL). The mixture was stirred at 0° C. for 12 h and 3 d at room temperature, and concentrated. The residue was dissolved in 30% NaOH/MeOH (2 mL) and heated at 40° C. for 12 h. The solution was allowed to cool, acidified with 1M HCl, concentrated and purified by HPLC to give the title compound. 1H NMR (CDCl3): δ 7.9–7.7 (m, 2H), 7.5 (s, 2H), 7.4–7.3 (m, 2H), 7.0(s, 1H), 6.3 (s, 1H), 4.8 (d, 2H), 4.1 (t, 2H), 3.6 (s, 2H), 3.3–3.2 (m, 1H), 2.5 (t, 2H), 2.4 (s, 3H), 1.8 (s, 3H), 1.1 (d, 6H). ESMS: m/z 629 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:34])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:34])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CS(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4S(C)(=O)=O)n3)cc21

Procedure:
Title compound was prepared from 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product isolated as a white solid (35 mg, 26%). MP 178-180, LCMS 506.06 (M+H). 1H-NMR (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 9.23 (s, 1H), 8.78 (s, 1H), 8.18 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.71-7.69 (m, 1H), 7.30 (s, 1H), 7.27-7.25 (m, 1H), 6.54 (d, J=8.6 Hz, 1H), 3.22 (s, 3H), 2.11-2.07 (m, 2H), 1.92-1.89 (s, 2H), 1.20 (s, 6H).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[CH:19]1([CH2:24][CH2:25]O)[CH2:23][CH2:22][CH:21]=[CH:20]1>>[CH:19]1([CH2:24][CH2:25][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH:21]=[CH:20]1
Reactant: OCCC1C=CCC1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCC2C=CCC2)cc1
Yield: 72 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (157 mg, 0.625 mmol) prepared in Example 1 (1a) and 2-cyclopenta-2-en-1-ylethanol (which is the compound disclosed in J. Org. Chem., (2000), 65, 4241-4250, 85 mg, 0.75 mmol) to give 128 mg of the title compound (white powder, yield: 72%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[NH2:16][C:17]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[NH:19][N:18]=1>C(N(CC)CC)C>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:20]2[NH:19][N:18]=[C:17]([NH:16][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
Under a stream of argon gas, 333 mg of benzenesulfonyl chloride was added dropwise to 4 ml of a tetrahydrofuran solution containing 150 mg of 3-amino-5-(4-fluorophenyl)-4-(4-pyridyl)pyrazole and 191 mg of triethylamine, followed by stirring at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by column chromatography using 20 g of silica gel [with an elution solvent comprising chloroform-methanol (100:1)]. Thus, 35 mg (15% yield) of the title compound was obtained as a pale-yellow powder.