Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([S:19]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)(=[O:21])=[O:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:31])([CH3:30])[C:6]=2[CH:32]=1.[C:33]([SiH2]OC(C)(C)[C@@H]1OC(C)(C)O[C@@H]1CO)(C)([CH3:35])[CH3:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1.O.C(OCC)(=O)C>[CH:33]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([S:19]([CH2:22][CH2:23][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)(=[O:21])=[O:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:30])([CH3:31])[C:6]=2[CH:32]=1)([CH3:35])[CH3:34]
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](CO)O1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(S(=O)(=O)CCc3ccccc3)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc2c(c1)C(C)(C)c1[nH]c3cc(S(=O)(=O)CCc4ccccc4)ccc3c1C2=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8-Hydroxy-6,6-dimethyl-3-(2-phenyl-ethanesulfonyl)-5,6-dihydro-benzo[b]carbazol-11-one (30 mg, 0.0673 mmol), [(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]methanol (22.3 mg, 0.0808 mmol), and PPh3 (23 mg, 0.0875 mmol) were dissolved in THF (0.5 ml), added with DIAD (0.0169 ml, 0.0808 mmol), and the mixture was stirred at 50° C. overnight. After cooling, the reaction solution was filtered and concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane). The resulting residues were dissolved in THF (0.4 ml) and water (0.13 ml), added with camphor sulfonic acid (28.1 mg, 0.121 mmol), and then subjected to microwave irradiation at 80° C. for 15 min under nitrogen atmosphere. Ethyl acetate was added to the resultant. The organic layer was washed with saturated aqueous solution of sodium hydrocarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by thin layer chromatography (MeOH/DCM) to obtain Compound GT20-2 (10.5 mg) and Compound GT20-3 (2.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1
Reactant: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperazine-1-carboxylate (0.0748 g, 0.194 mmol) obtained in Example B46, Step 4 in ethanol (5 mL) was added with 5% palladium/carbon (wetted with 50% water, 0.0700 g), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)propyl]piperazine-1-carboxylate (0.0642 g, 85%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=O)([O-:3])=[O:2].C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].Cl>N1C=CC=CC=1.O>[OH:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[CH:16][C:17]([OH:19])=[O:18])=[CH:7][C:6]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)O)cc([N+](=O)[O-])c1O

Procedure:
A solution of 1.0 g of 5-nitrovanillin and 4.0 g of malonic acid in 10 ml of pyridine was heated for 50 h at 80° C. The reaction mixture was diluted with water, acidified with hydrochloric acid, filtered, washed with water and dried. Yield 0.44 g (36%). The 1H-NMR spectrum was in accordance with the structure alleged.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][C@@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][C@@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][N:7]1[C:30](=[O:31])[CH2:29][NH:28][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H](CP(=O)(OCC)OCC)CCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H](CP(=O)(OCC)OCC)CCN1C(=O)CNC(=O)OC(C)(C)C

Procedure:
A solution of 1.0 g of cis 4-diethylphosphonomethyl-2-piperidinecarboxylic acid ethyl ester is reacted with 552 mg of N-t-butoxycarbonylglycine in the presence of N,N'-dicyclohexyl-carbodiimide in 10 ml of methylene chloride of room temperature for 16 hours to yield cis 1-[alpha-(t-butoxycarbonylamino)acetyl]-4-diethylphosphonomethyl-2-piperidinecarboxylic acid ethyl ester as an oil. Treatment with trimethylsilyl iodide yields cis 1-(alpha-aminoacetyl)-4-phosphonomethyl-2-piperidinecarboxylic acid ethyl ester, m.p. 150°-155° dec.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([NH:9][C:10]1([C:13](OCC)=[O:14])[CH2:12][CH2:11]1)=[O:8])([O-:3])=[O:2].[Li+].[BH4-]>O1CCCC1>[OH:14][CH2:13][C:10]1([NH:9][C:7](=[O:8])[C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc([N+](=O)[O-])c2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC1(CO)CC1)c1cccc([N+](=O)[O-])c1
Temperature: 45 °C

Procedure:
To the suspension of ethyl 1-(3-nitrobenzamido)cyclopropanecarboxylate (0.400 g, 1.438 mmol) in tetrahydrofuran 10 ml, LiBH4 (0.063 g, 2.88 mmol) was added and heated the content at 45° C. for 15 hr. Reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×10 ml). Organic layer was dried over sodium sulfate and concentrated under vacuum which was further purified by column chromatography eluting ethyl acetate (0-70%) in hexane (0.05 g, 14%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25](Cl)(=[O:27])=[O:26])[CH:24]=1>C1COCC1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)(=[O:27])=[O:26])[CH:24]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1S(=O)(=O)N1CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A stirred solution of 1,4-dioxa-8-azaspiro[4,5]decane (10.73 g, 75 mmol) and Et3N (8 mL, 57 mmol) in THF (150 mL) was cooled in an ice-water bath. To this mixture was slowly added 5-fluoro-2-methylbenzenesulfonyl chloride (10.5 g, 50.33 mmol) and stirred for 1 h and then cold bath was removed. After 15 h at room temperature, the reaction mixture was diluted with ether (200 mL), washed with 1N aq. HCl (2×50 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated to give product as an off-white solid 15.9 g, 100%). 1H NMR (500 MHz, CDCl3) δ: 7.61 (1H, dd, J=8.6, 2.8 Hz), 7.28-7.26 (1H, m), 7.15 (1H, td, J=8.1, 2.8 Hz), 3.94 (4H, s), 3.35-3.32 (4H, m), 2.57 (3H, s), 1.78-1.76 (4H, m). HRMS (M+H) calcd for C14H19FNO4S: 316.1019; found: 316.1013.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:4].ON1C2C=CC=CC=2N=N1.[NH2:26][CH2:27][C@H:28]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:40]([O:39][C:37]([NH:36][C@@H:28]([CH2:27][NH:26][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:15][CH:14]=1)[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:38])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC(=O)COc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
420 mg (0.002 mol) of 4-(methoxycarbonylmethyloxy)benzoic acid, 270 mg (0.002 mol) of 1-hydroxybenzotriazole and 588 mg (0.002 mol) of tert-butyl (2S)-3-amino-2-benzyloxycarbonylaminopropionate were dissolved in 5 ml of dimethylformamide. The solution was cooled to 0° C. and treated with 453 mg (0.0022 mol) of N,N′-dicyclohexylcarbodiimide and then stirred at 0° C. for 10 min and at room temperature for 2 h. For working-up, the urea was filtered off and the filtrate was concentrated to dryness. The pure compound was obtained by chromatography of the crude product on silica gel (dichloromethane/acetonitrile 20/1). Yield: 820 mg.
Reaction SMILES: CN1C2[C:5](=[CH:6]C(S(C3C=CC=CC=3)(=O)=O)=CC=2)[C:4](CCN)=[CH:3]1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:30][CH:31]=2)[C:26]([CH2:42][CH2:43][NH:44]C)=[C:25]1[CH3:46].CN1C2C(=CC(S(C3C=CC=CC=3)(=O)=O)=CC=2)C(CCN)=C1C.FC1C=C(S(C2C=C3C(=CC=2)N(C)C(C)=C3CCN)(=O)=O)C=C(F)C=1.FC1C=C(S(C2C=C3C(=CC=2)N(C)C(C)=C3CCNC)(=O)=O)C=C(F)C=1.CC1NC2C(C=1CCN)=CC(S(C1C3C(=CC=CC=3)C=CC=1)(=O)=O)=CC=2.[11CH4].[13NH3].[15OH2].[18FH]>>[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([S:33]([C:36]3[C:41]4[C:40](=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:30][CH:31]=2)[C:26]([CH2:42][CH2:43][NH2:44])=[C:25]1[CH3:46]
Reactant: CNCCc1c(C)n(C)c2ccc(S(=O)(=O)c3ccccc3)cc12
Reactant: Cn1cc(CCN)c2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: CNCCc1c(C)n(C)c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12
Agent: Cc1[nH]c2ccc(S(=O)(=O)c3cccc4ccccc34)cc2c1CCN
Agent: Cc1c(CCN)c2cc(S(=O)(=O)c3cc(F)cc(F)c3)ccc2n1C
Product: Cc1c(CCN)c2cc(S(=O)(=O)c3cccc4ccccc34)ccc2n1C

Procedure:
The compounds of formula I also can include isotopic labels. For example the compounds 2-[1-methyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine; 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]-N-methylethanamine; 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine; 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}ethanamine; 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}-N-methylethanamine; 2-[2-methyl-5-(1-naphthylsulfonyl)-1H-indol-3-yl]ethanamine; and pharmaceutically acceptable salts thereof may contain an isotopic label such as at least one atom selected from Carbon-11, Nitrogen-13, Oxygen-15, and Fluorine-18. Isotopically labeled compounds may be used in positron emission tomography.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24]>O>[CH:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:9]
Reactant: COC(=O)CCl
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccccc1C=O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
2. Approximately 509 g of the starting compound, salicylaldehyde (1) was introduced into a 4-liter Eriemeyer flask with powdered potassium carbonate (569 g), dimethylformamide (1,000 ml), and methyl chloroacetate (478 g) and mechanically stirred at 65° C. for about 24 hours. The stirring was stopped and the reaction mixture cooled to 25° C. The mixture was poured into cold water (0° C.) while stirring vigorously. An oil separated that suddenly solidified. Stirring was continued for 30 minutes and the solid isolated by filtration. The product was washed with water (2×1,000 ml) and pressed dry. The product can also be dried in vacuo at 25° C. A small sample (approx. 2 g) was purified by distillation. The boiling range of the pure product is 124°-128° C. at 2 mm Hg and has a melting temperature range of about 50.2°-50.6° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=2)O1>>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:17]2[C:4]3[C:3]4[CH:2]=[C:11]([O:12][CH3:13])[CH:10]=[CH:9][C:8]=4[NH:7][C:6](=[O:14])[C:5]=3[S:15][CH:16]=2)=[CH:27][CH:28]=1)(=[O:34])[CH3:33]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3scc(-c4ccc(C(C)=O)cc4)c3c2c1
Yield: 46.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.0 g, 3.2 mmol) was reacted with 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (1.2 g, 4.8 mmol) to afford the desired product (520 mg, 46%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 8.16 (d, J=8.1 Hz, 2H), 7.61-7.54 (m, 2H), 7.45-7.39 (m, 3H), 6.05 (d, J=5.4 Hz, 1H), 3.75 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [Li]CCCC.CCCCCC.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[CH:20][S:21][C:14]=12.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22](=[O:25])[CH2:23][CH3:24])[S:21][C:14]=12
Reactant: CCC(=O)Cl
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=O)c1cc2nccc(Cl)c2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2.5 M nBuLi in hexane (0.619 ml, 1.55 mmole) was added to a solution of 7-chlorothieno[3,2-b]pyridine (0.250 g, 1.47 mmole) in THF (5 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, and then propanoyl chloride (0.162 ml, 1.76 mmole) was added. The reaction mixture stirred at −78° C. and slowly warmed to 0° C. and quenched with H2O (10 ml), extracted with EtOAc (2×10 ml). The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 10-70% EtOAc in hexane to a off-white solid (0.084 g, 25%). 1H NMR (300 MHz, CDCl3) δ8.66 (1H, d, J=4.9 Hz), 8.12 (1H, s), 7.38 (1H, d, J=4.9 Hz), 3.09 (2H, q, J=7.3 Hz), 1.29 (3H, t, J=7.3 Hz,); ESIMS (MH+): 225.95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:31]=[CH:30][NH:29][N:28]=1.O=P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[N:29]1[NH:28][C:27]([NH:26][C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=3)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[CH:31][CH:30]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=C(Nc1ccn[nH]1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A 0° C. mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (41 mg, 0.1 mmol, 1 equiv) and 3-aminopyrazole (21 mg, 2.5 equiv) in 0.5 mL of pyridine was treated with 11 μL (1.1 equiv) of POCl3 for 5 minutes. After addition of 1 mL of water, the mixture was subjected to preparative reverse phase HPLC to give 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2H-pyrazol-3-yl)-amide. 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 10.37 (s, 1H), 8.24 (m, 2H), 8.18 (s, 1H), 8.00 (dd, 1H), 7.63 (d, 1H), 7.60 (d, 1H), 6.80 (d, 1H); MS (ES) (M+H)+ expected 480.0, found 480.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([CH2:16][OH:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:15]=2[CH:16]=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncccc2CO)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(Nc2ncccc2C=O)cn1
Temperature: 50 °C
Reaction time: 48 h
Yield: 101.3 %

Procedure:
6.48 g (28 mmol) of (2-(6-methoxy-3-pyridinyl)amino-3-pyridinyl)methanol was dissolved in chloroform (200 mL), and 7.3 g (84 mmol) of manganese dioxide was added thereto. The resulting mixture was stirred for 48 hours at 50° C. The reaction mixture was filtered, and the filtrate was concentrated. Thus, 6.5 g of the title compound was obtained as an orange-colored solid (yield: quantitative).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.Cl.[N:15]([O-])=O.[Na+]>>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=2)[NH:1][N:15]=1
Reactant: O=N[O-]
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: Cl
Agent: [Na+]
Product: COc1cc2[nH]nc(N)c2cc1OC
Yield: 147.5 %

Procedure:
To a solution of 6-aminoveratronitrile (39 g, 0.2 mole) and conc. hydrochloric acid (329 ml) was added a solution of sodium nitrite (17 g, 0.25 mole in minimum amt. of water). The temperature was held below 0° during the addition. Keeping the temperature between 0° to 20° the resulting solution was added dropwise to stannous chloride (33.3 g, 1.76 mole) and conc. hydrochloric acid (153 ml). The precipitate was filtered and air dried overnight. The filter cake was placed in water (1100 ml), refluxed for 20-30 min and then filtered. The filtrate was cooled and then treated with sodium hydroxide (10% - 290 ml) to precipitate a tan solid. This solid was air dried at 60° to yield 57 g of 3-amino-5,6-dimethoxyindazole.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:33][CH:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 27.5 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-aminotetrahydropyran (available from Aldrich Chemical Company, Inc.; 63 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(tetrahydro-pyran-4-ylcarbamoyl)-biphenyl-2-carboxylic acid (32 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.08 (br s, 1H), 8.39 (s, 1H), 8.25-8.33 (m, 3H), 8.17 (dd, J=8.0, 1.8 Hz, 1H), 8.02 (dd, J=8.3, 2.0 Hz, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H), 3.91-4.03 (m, 1H), 3.83 (d, J=9.8 Hz, 2H), 3.30-3.38 (m, 2H), 1.68-1.76 (m, 2H), 1.54 (qd, J=11.9, 4.3 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1cccc(CBr)c1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
3′-Methylacetophenone (5.00 g; 37.3 mmol), N-bromosuccinimide (6.63 g; 37.3 mmol), and benzoyl peroxide (100 mg) were added to carbon tetrachloride (70 ml), and the mixture was refluxed for 1 hour. The mixture was left to cool to room temperature, and crystals that precipitated were removed by filtration. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 3.08 g of the target compound (yield: 38.8%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:20])[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]=1[CH2:11][CH3:12])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]2[C:10]([CH2:11][CH3:12])=[C:6]([CH2:4][OH:3])[N:7]([CH3:20])[N:8]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(CC)c(-c2ccc(Cl)cc2)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1c(-c2ccc(Cl)cc2)nn(C)c1CO

Procedure:
In analogy to the procedure described for example 1 a], 5-(4-chloro-phenyl)-4-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [5-(4-chloro-phenyl)-4-ethyl-2-methyl-2H-pyrazol-3-yl]-methanol as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6](I)=[CH:7][CH:8]=2)[N:3]=1.[SH:14][C:15]1[CH:16]=[C:17]([C:21]2([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([S:14][C:15]3[CH:16]=[C:17]([C:21]4([C:27]#[N:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=[CH:19][CH:20]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1cc(Cl)c2ccc(I)cc2n1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(Cl)nc4c3)c2)CCOCC1
Temperature: 60 °C

Procedure:
2,4-Dichloro-7-iodo-quinoline (3.4 g, 10.5 mmol), 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (5q, 2.3 g, 10.5 mmol), iPr2NEt (3.67 mL, 21.0 mmol), Pd2dba3 (240 mg, 0.26 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (303 mg, 0.52 mmol) were dissolved in 1,4-dioxane (50 mL) and degassed with N2 for 10 minutes. The reaction was heated at 60° C. for 1 hour, and then cooled to room temperature and diluted with EtOAc and saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 5r.