Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[Cl:11].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[NH2:21][C:17]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([Cl:11])[CH:4]=2)[C:15](=[O:14])[CH:16]=1
Reactant: NNCc1ccc(Br)c(Cl)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Br)c(Cl)c2)[nH]1
Reaction time: 2 h

Procedure:
48.8 g of 4-bromo-3-chlorobenzylhydrazine are added dropwise under nitrogen to a solution of 33.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of toluenesulphonic acid in 150 ml of ethanol. After stirring for a further two hours, the mixture was left to stand and the compound identified above began to crystallise out after four hours. It was filtered off and twice recrystallised from ethanol. Melting point: 145°-146°, 23 g (37%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:3][CH2:2]1)=[O:22]
Reactant: O=C1Cc2ccccc2N1C1CCNCC1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
1-(4-Piperidyl)indol-2-one (53 mg, 0.245 mmole), 2,4-dimethoxybenzoyl chloride (54 mg, 0.27 mmole), and 38 mL (0.27 mmole) triethylamine were mixed in 4 ml of chloroform at 0° C. The reaction mixture was stirred at 0° C. for 5 minutes and then at 23° C. for 15 minutes during which time the pH was adjusted to 7.5 with triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative thick layer chromatography (CHCl3 --CH3OH--NH4OH; 95:5:0.5) to yield 42 mg of the title compound: m.p. 88°-93° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)[CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: O=C(c1ccc2c(c1)OCCO2)c1c[nH]c2ccccc2c1=O
Product: O=C(c1ccc2c(c1)OCCO2)c1cn(Cc2cccc(C(F)(F)F)c2)c2ccccc2c1=O
Yield: 15.2 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-1H-quinolin-4-one 70.7 mg (0.296 mmol) and 71.1 mg (0.296 mmol) of 1-Bromomethyl-3-trifluoromethyl-benzene, to give 21 mg of desired compound. LCMS (M+H)+: 466.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:22]=2)[CH2:17][C@@H:16]1[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:14])[C:9]([OH:12])([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]([C:9]([OH:12])([CH3:10])[CH3:11])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[CH:22]=2)[CH2:17][C@@H:16]1[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:14]
Reactant: COc1ccc(N2CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CCN(C(=O)[C@H](N)C(C)(C)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of {(R)-1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carbonyl]-2-hydroxy-2-methyl-propyl}-carbamic acid tert-butyl ester intermediate in CH2Cl2 (1 mL) at 0-5° C. was treated with trifluoroacetic acid and stirred at room temperature for 8 hr. After this time the reaction mixture was evaporated and the residue partitioned between EtOAc (5 ml) and a saturated aqueous solution of NaHCO3 (5 mL). The organic extract was further washed with brine then dried over MgSO4, filtered, and evaporated to afford the title compound as an oil (69 mg, 83%). LC/MS (Method B) 2.97 min, [M+1]+ 482.
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15]C(C)(C)C)=O)[N:8]1C(OC(C)(C)C)=O)=[O:6].FC(F)(F)C(O)=O.[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH2:48][O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)C(O)=O)=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl.C(#N)C>[Cl:28][C:2]([Cl:1])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:15])[C@@H:44]([NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH2:48][O:49][Si:50]([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[NH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl) ester (prepared according to the procedure described in Angew. Chem. Int. Ed. English 1999, 38, 2443.), (5.0 g, 10.8 mmol) in anhydrous dichloromethane (33 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (33 mL, 432 mmol). The solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo and the residue co-evaporated from toluene (3×). The resulting brown viscous oil was dissolved in anhydrous acetonitrile (5 mL) and added to a solution of (S)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionic acid (2.39 g, 5.4 mmol, prepared as in PCT Int. Appl. 2006, WO 2006004880 A2), N,N-diisopropylethylamine (3.76 mL, 21.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.05 g, 5.4 mmol) in anhydrous acetonitrile (25 mL) that had been previously stirred at 0° C. for 20 minutes. The reaction was warmed to room temperature and stirred for 16 h before being concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to give the title compound (1.8 g, 49%) as a clear viscous oil. 1H NMR (300 MHz, CDCl3) δ 1.08 (s, 9H), 1.46 (s, 9H), 1.53-1.67 (m, 1H), 1.80-2.01 (m, 2H), 2.82-2.96 (m, 1H), 3.19-3.32 (m, 1H), 3.62 (d, J=10.9 Hz, 1H), 3.80-3.97 (m, 3H), 4.23-4.34 (m, 1H), 4.61 (d, J=12.0 Hz, 1H), 4.90 (d, J=12.0 Hz, 1H), 5.18-5.27 (m, 1H), 5.51-5.63 (m, 1H), 7.35-7.49 (m, 6H), 7.58-7.70 (m, 4H). LCMS (m/z) 686.2 [M+H], Tr=4.32 min.
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-:52])[C:14]([CH2:17][O:18][NH:19][C:20]([CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[N:24]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]3[NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:23]2[C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2[Cl:51])=[O:21])=[CH:15][CH:16]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>C(O)C.C(Cl)(Cl)Cl>[Cl:51][C:45]1[CH:46]=[C:47]([Cl:50])[CH:48]=[CH:49][C:44]=1[CH:23]1[CH:22]([C:20]([NH:19][O:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][OH:9])=[CH:12][N+:13]=2[O-:52])=[O:21])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]1[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[NH:39][S:40]([CH3:43])(=[O:41])=[O:42]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccc(COC(=O)c3ccccc3)c[n+]2[O-])C1c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccc(CO)c[n+]2[O-])C1c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
A solution of 153 mg of (6-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1-oxidopyridin-3-yl)methyl benzoate in 3 ml of ethanol was cooled to 0° C., and 32 mg of sodium hydroxide was added thereto, followed by stirring at 0° C. for 2 hours. The solution was neutralized with 1 M hydrochloric acid, and a saturated aqueous sodium hydrogen carbonate solution and chloroform were added for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 24 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1-oxidopyridin-2-yl]methoxy}-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][OH:15].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCO
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: OCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-aminoethanol according to general procedure 1 providing the intermediate (78 mg, 32%) as a white solid: Rf=0.41 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.73 (d, J=9.7 Hz, 1H), 3.80 (t, J=5.7 Hz, 2H), 3.52 (t, J=5.7 Hz, 2H); ES-MS: (M+H)=257, 259 m/z.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=1)=O)C.[BH4-].[Na+]>C(O)C>[OH:3][CH2:4][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccn2)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(-c2ccccn2)no1
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(5-ethoxycarbonyl-isoxazol-3-yl)-pyridine (6.5 gm), in ethanol (80 ml) was added sodium borohydride (2 gm) in lots at 30° C. It was stirred at 30° C. over a period of 1.5 h. The reaction was monitored by TLC. Upon consumption of ethyl ester, aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate. Combined organic layers was washed with water and concentrated under vacuum to provide title compound in 7.7 gm quantity. It was purified by silica gel column chromatography to afford tile compound in 4.5 g (85%) quantity as a off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.[F:17][CH:18]([F:22])[C:19](O)=[O:20].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:17][CH:18]([F:22])[C:19]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1)=[O:20]
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1)C(F)F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A suspension of (5S)-5-Aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 5.0 g, 14.88 mmol) in methylene chloride (CH2Cl2, 50 mL) was treated with difluoroacetic acid (2.14 g, 1.41 mL, 22.32 mmol, 1.5 equiv) and N,N-diisopropylethylamine (DIEA or Hunig's base, 3.85 g, 5.18 mL, 29.76 mmol, 2.0 equiv), and the resulting reaction mixture was cooled down to 0-5° C. before being treated with EDCl (4.30 g, 22.32 mmol, 1.5 equiv) at 0-5° C. The reaction mixture was subsequently stirred at 0-5° C. for 1 h before being gradually warmed up to room temperature for 12 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (50 mL) and CH2Cl2 (50 mL). The two layers were then separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed H2O (50 mL) and the saturated aqueous NaCl solution (50 mL), dried over MgSO4, and concentrated in vacuo to afford the crude (5 S) 2,2-difluoro-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1026, 5.64 g, 6.16 g theoretical, 91.6%) as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For 1026: 1H NMR (300 MHz, DMSO-d6) δ 3.54 (t, 2H, J=5.5 Hz), 3.77 (dd, 1H, J=6.3, 9.2 Hz), 4.15 (t, 1H, J=9.2 Hz), 4.77-4.86 (m, 1H), 6.25 (t, 1H, J=53.52 Hz, —CHCF2), 7.18 (dd, 1H, J=2.4, 8.7 Hz), 7.55 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (t, 1H, J=8.5 Hz), 9.19 (t, 1H, J=5.5 Hz, —CONH); C12H10F3IN2O3, LCMS (EI) m/e 415 (M++H), 456 (M++H+CH3CN).
Reaction SMILES: [C:1]([CH:3]1[C:6]2=[C:7](OC)[CH:8]=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1>ClC1C=CC=CC=1Cl>[C:1]([CH:3]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4][CH2:20][CH:19]1[C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)#[N:2]
Reactant: C=Cc1ccc(OC)cc1
Reactant: COc1cccc2c1C(C#N)C2
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C2CCc3ccccc3C2C#N)cc1
Reaction time: 12 h

Procedure:
A solution of 1-cyano-4-methoxybenzocyclobutene (7.5 g.; described in the Journal of the American Chemical Society, 1976, 98, 8185) and p-methoxystyrene (11.1 g.) in o-dichlorobenzene (40 ml.) was heated under reflux for 30 minutes under an atmosphere of argon and then evaporated to dryness, and the residue was purified by chromatography on a silica gel column using a 20:1 v/v mixture of toluene and ethyl acetate as eluant. A mixture of a solution of the residue (12.0 g.) in toluene (200 ml.), a solution of sodium hydroxide (20 g.) in water (200 ml.) and 40% w/v aqueous tetrabutylammonium hydroxide solution (1 ml.) was stirred vigorously under an atmosphere of argon at laboratory temperature for 12 hours and the layers were then separated. The aqueous layer was extracted twice with diethyl ether (100 ml. each time) and the combined organic solutions were washed with water, dried and evaporated to dryness. There was thus obtained as residue (1RS,2SR)-1-cyano-1,2,3,4-tetrahydro-2-p-methoxyphenylnaphthalene, m.p. 126°-131° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.Br[CH:21]([OH:23])[CH3:22].[Li]CCCC>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[CH2:22][CH2:21][OH:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Reactant: CC(O)Br
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1CCO
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 19.1 %

Procedure:
Solution A was prepared by combining pyridin-4-yl-carbamic acid tert-butyl ester (388 mg, 2 mmol) in THF (5 mL) and cooling to −78° C. t-BuLi (2.8 mL, 1.7M solution in pentane) was added dropwise. Once the addition was complete, the solution was stirred at −78° C. for 15 minutes, then warmed to −15° C. and stirred for 90 minutes. In a separate flask, solution B was prepared by combining bromoethanol (0.21 mL, 3 mmol) in THF (5 mL) and cooling to −78° C. n-BuLi (1.44 mL, 2.5M solution in hexanes) was added dropwise. Once the addition was complete, the solution was stirred at −78° C. for 10 minutes. Solution A was recooled to −78° C., and solution B was added to solution A via cannula. Stirred with warming to room temperature for 2 hours. The reaction was recooled, and quenched with water. Partitioned between CH2Cl2 and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 100% ethyl acetate to provide 91 mg (19%) of [3-(2-hydroxy-ethyl)-pyridin-4-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([O:14]C3C(F)=C(F)C(F)=C(F)C=3F)(=O)=[O:12])[CH:9]=2)[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:3]1.[CH3:42][C:43]1[S:47][C:46]([NH2:48])=[N:45][C:44]=1[C:49]([F:52])([F:51])[F:50].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([NH:48][C:46]3[S:47][C:43]([CH3:42])=[C:44]([C:49]([F:52])([F:50])[F:51])[N:45]=3)(=[O:12])=[O:14])[CH:9]=2)[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:28][C:27]=2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:3]1
Reactant: Cc1sc(N)nc1C(F)(F)F
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(NS(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C)c3c2)nc1C(F)(F)F
Reaction time: 1 h
Yield: 27 %

Procedure:
A flask was charged with perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)-phenyl)-1H-indole-6-sulfonate (INTERMEDIATE E) (44.48 mg, 0.074 mmol), 5-methyl-4-(trifluoromethyl)thiazol-2-amine (17.51 mg, 0.096 mmol) and THF (0.5 mL). The flask was cooled in an ice bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (185 μl, 0.185 mmol) was added dropwise to give an orange solution. The mixture was stirred for 1 h, then an additional portion of the base solution (0.08 mL) was added. After 20 min, the cooling bath was removed. The mixture was stirred for an additional 20 min, then an additional portion of 5-methyl-4-(trifluoromethyl)thiazol-2-amine (10 mg) was added. The mixture was stirred for 20 min, then was quenched with AcOH (0.1 mL) and concentrated from MeOH/DCM. The crude product was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(5-methyl-4-(trifluoromethyl)thiazol-2-yl)-1H-indole-6-sulfonamide (12.27 mg, 0.020 mmol, 27.7% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=8.01 (d, J=1.5 Hz, 1 H), 7.94-7.82 (m, 2 H), 7.77 (d, J=0.9 Hz, 1 H), 7.61 (d, J=8.5 Hz, 1 H), 7.50 (dd, J=1.7, 8.5 Hz, 1 H), 7.37 (d, J=1.9 Hz, 1 H), 7.24 (s, 1 H), 6.34 (d, J=1.9 Hz, 1 H), 3.82 (s, 3 H), 3.24 (s, 3 H), 2.40-2.35 (m, 3 H). m/z (ESI) 600.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=O.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>>[CH2:12]([NH:15][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:9]([OH:10])=[C:8]([Cl:11])[CH:7]=1)[CH:13]=[CH2:14]
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Reactant: C=CCN
Product: C=CCNCc1cc(Cl)c(O)c(Cl)c1

Procedure:
Prepared from 3,5-dichloro-4-hydroxybenzaldehyde and allylamine using the method of preparation 90 to give the title compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[C:8]([CH2:16][C:17](=O)[CH3:18])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)Cl.O>C(O)(=O)C>[CH3:18][C:17]1[CH:16]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]2[N:4]=[C:5]([SH:7])[N:6]=[C:2]2[N:1]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Nc1n[nH]c(S)n1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccccc2)n2nc(S)nc2n1

Procedure:
A mixture of 10.0 9 (86 mmol) 3-amino-5-mercapto-1,2,4-triazole and 14.0 g (86.5 mmol) of benzoylacetone in 100 ml of glacial acetic acid was heated at reflux 4 hours. Methylene chloride (500 ml) and excess water were added. The organic layer was separated and washed with water, brine, dried over magnesium sulfate and evaporated in vacuo to give a residue to which n-butyl chloride was added. Filtering gave 4.9 g of crude 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidin-2-thiol which was used directly in the next step.
Reaction SMILES: [NH:1]([C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16](Br)=[CH:15][C:14]=2[Cl:21])[N:11]=[C:10]([C:22]#[N:23])[C:9]=1[S:24][C:25]([F:28])([F:27])[F:26])C1C=CC=CC=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+].COCCOCCOC>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O>[Cl:21][C:14]1[CH:15]=[C:16]([C:34]2[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=2)[CH:17]=[C:18]([Cl:19])[C:13]=1[N:12]1[C:8]([NH2:1])=[C:9]([S:24][C:25]([F:28])([F:26])[F:27])[C:10]([C:22]#[N:23])=[N:11]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1nn(-c2c(Cl)cc(Br)cc2Cl)c(Nc2ccccc2)c1SC(F)(F)F
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOCCOC
Product: N#Cc1nn(-c2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)c(N)c1SC(F)(F)F
Temperature: 20 °C
Yield: 66.4 %

Procedure:
A mixture of 6 g of 5-amiino-3-cyano-1-(2,6-dichloro-4-bromophenyl)-4-trifluoromethylthiopyrazole (prepared according to procedures reported in U.S. Pat. No. 5,232,940), 4-trifluoromethylphenylboronic acid (5.3 g), K2CO3 (5.8 g), tris-(dibenzylidene acetone) dipalladium (0.6 g) and diglyme was heated at 130° C. for 25 hours. After cooling to 20° C., the mixture was poured into water and extracted with diethyl ether. The ether solutions were combined, dried, filtered and the filtrate concentrated and purified by chromatography. The desired product as a solid (3.9 g, mp 181-184° C.) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[N:15]1([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([CH:32]=O)=[CH:26]3)[CH2:19][CH2:18][CH2:17][CH2:16]1.N1CCCCC1>C(O)C>[O:1]=[C:2]1[C:10](=[CH:32][C:27]2[NH:28][C:29]3[C:25]([CH:26]=2)=[CH:24][C:23]([O:22][CH2:21][CH2:20][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:31][CH:30]=3)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=2)[NH:3]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCCC4)ccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 79.9 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide (28 mg, 0.13 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (34 mg, 0.13 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 90° C. for 2 hours. The reaction was cooled at 0° C. for overnight. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 47 mg (80%) of the title compound as an orange solid.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.S(O)(O)(=O)=O.[CH:13]([NH:16][NH2:17])([CH3:15])[CH3:14]>O.Cl>[CH:13]([N:16]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]([OH:7])=[N:17]1)([CH3:15])[CH3:14]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)NN
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)n1nc(O)ccc1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
The following example illustrates the preparation of the novel compounds: ##STR6## 58.8 g (0.6 mol) of maleic anhydride were added to a solution of 73.8 g (0.6 mol) of isopropylhydrazine sulphate in 180 ml of water and 10 ml of concentrated hydrochloric acid at 60° C. The mixture was then boiled for 3 hours under reflux after which it was cooled to 0° C. After half an hour, the product which had precipitated was filtered off. 59 g (64% of theory) of 1-isopropyl-1,6-dihydro-3-hydroxy-6-oxo-pyridazine were thus obtained in the form of colorless crystals of melting point 148° C.