Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[NH2:2].[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([C:26]([NH:28][C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])=[O:27])=[CH:21][N:20]=1.C(N(CC)CC)C>C1COCC1>[Cl:18][C:19]1[N:20]=[C:21]([NH:2][NH:1][CH2:3][CH2:4][CH:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[C:22]([C:26](=[O:27])[NH:28][C:29]2[C:30]([Cl:36])=[CH:31][CH:32]=[CH:33][C:34]=2[Cl:35])=[CH:23][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCNN)CC1
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCNNc2nc(Cl)ncc2C(=O)Nc2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A solution of 618 mg (2.5 mmol) of tert-butyl 4-(2-hydrazinylethyl)piperidine-1-carboxylate in 10 mL THF was cooled to 0° C. and treated sequentially with 763 mg (2.3 mmol) of 2,4-dichloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide and 355 μl (2.5 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 66 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (CH2Cl2:MeOH, 99.5:0.5 grading to CH2Cl2:MeOH, 98:2) to give the title compound 92. 1H-NMR (CDCl3) δ 1.08-1.23 (m, 3H), 1.45 (s, 9H), 1.58-1.66 (m, 2H), 1.72-1.79 (m, 2H), 2.61-2.75 (m, 2H), 3.87 (t, J=7.1 Hz, 2H), 3.99-4.14 (m, 4H), 7.24 (t, J=8.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.48 (s, 1H), 8.40 (s, 1H). Mass Spectrum (ESI) m/e=543.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([N:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=3)[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[C:32]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([N:15]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:41][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[O:30])=[CH:27][CH:28]=3)[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1ccc(N(Cc2cccnc2)c2ccc(C(=O)O)cc2)c2cc(C(C)=O)oc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N(Cc2cccnc2)c2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)c2cc(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
To a solution of 2-acetyl-7-methoxy-N-(4-carboxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran (416 mg, 1.0 mmol), benzenesulfonamide (200 mg, 1.2 mmol), and DMAP (150 mg, 1.2 mmol) in dichloromethane (5 mL) at room temperature was added EDCI (230 mg, 1.2 mmol) in one portion and the mixture was stirred at room temperature for 16 h. The mixture was partitioned between water (25 mL) and EtOAc (25 mL) and the pH was adjusted to 5-6 with 1.0 N HCl. The EtOAc was separated, washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with a linear gradient from 5% to 10% MeOH in EtOAc to give 2-Acetyl-7-methoxy-N-(4-phenylsulfonylaminocarbonylphenyl)-N-(3-pyridylmethyl)-4-aminobenzofuran (415 mg). 1H NMR (300 MHz) δ 8.53 (br,1H), 8.46 (br,1H), 8.06 (d,J=7.3 Hz,2H), 7.8-7.3 (m,6H), 7.21 (m,1H), 7.1-7.0 (m,2H), 6.91 (d,J=8.5 Hz,1H), 6.56 (d,J=7.3 Hz,2H), 4.99 (s,2H), 4.02 (s,3H), 2.54 (s,3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C(=O)OC(C)(C)C)c1ccc(N)cc1
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A mixture of tert-butyl 2-(4-nitrophenyl)propanoate (14.4 g, 57.3 mmol) and 10% palladium on carbon (1.44 g, 10% by weight) in ethanol (150 mL) was shaken under an atmosphere of hydrogen at 40 psi for 2 h. After this time, the reaction was filtered through diatomaceous earth, and concentrated under reduced pressure to afford tert-butyl 2-(4-aminophenyl)propanoate (12.5 g, 99%) as an orange oil: 1H NNR (300 MHz, CDCl3) δ 7.07 (d, J=9.1 Hz, 2H), 6.63 (d, J=9.1 Hz, 2H), 3.60 (s, 2H), 3.49 (q, J=7.1 Hz, 1H), 1.40 (d, 3H), 1.38 (s, 9H); ESI MS m/z 222 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:60])([C:54]([CH3:59])([CH3:58])[CH:55]([CH3:57])[CH3:56])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[O:28])[CH2:14][CH2:13][C@H:12]([CH2:29][O:30]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][O:10][C:9](=[O:50])[C:8]=2[C:7]([CH3:51])=[C:6]([O:52][CH3:53])[CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:60][Si:2]([CH3:1])([C:54]([CH3:58])([CH3:59])[CH:55]([CH3:56])[CH3:57])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[O:28])[CH2:14][CH2:13][C@H:12]([CH2:29][OH:30])[CH2:11][O:10][C:9](=[O:50])[C:8]=2[C:7]([CH3:51])=[C:6]([O:52][CH3:53])[CH:5]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)CCC(=O)N[C@H](c1nc(C)no1)CSC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](CO)CCC(=O)N[C@H](c1nc(C)no1)CSC2

Procedure:
(4R,9R)-16-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-9-trityloxymethyl-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione was treated with 4-toluenesulfonic acid monohydrate in methanol at 20° C. for 30 min to yield (4R,9R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-9-hydroxymethyl-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione as a white foam.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1.[Na].I[CH3:29]>CO.C(OCC)(=O)C>[CH3:29][O:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])[N:3]=1
Reactant: COC(=O)c1ccc(Cn2nc(O)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Reactant: CI
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2nc(OC)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Reaction time: 0.08 h
Yield: 28 %

Procedure:
Indazole (T) (1.68 g.) was added to a solution of sodium (0.108 g.) in methanol (1.0 ml.). After stirring for 5 minutes, iodomethane (0.32 ml.) was added and stirring continued for 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (130 g.), eluting with 2:98 v/v ethyl acetate:dichloromethane to give methyl 4-[3-methoxy-6-nitroindazol-1-ylmethyl]-3-methoxybenzoate (U) (0.481 g., 28%) as a yellow solid, with satisfactory NMR spectral data.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:60])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]3[CH:25]=[C:26]([C:29]4[C:30]([C:53]5[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=5)=[N:31][N:32]([C:34]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:33]=4)[CH:27]=[CH:28][C:23]3=[N:22][CH:21]=2)=[CH:16][CH:15]=1.O1CCCC1.N1C=CC=CC=1>O>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:60])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]3[CH:25]=[C:26]([C:29]4[C:30]([C:53]5[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=5)=[N:31][N:32]([C:34]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:33]=4)[CH:27]=[CH:28][C:23]3=[N:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: NCCCNC(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCCNC(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.014 mL acetic anhydride was added to a solution mixture of 50 mg N1-(3-aminopropyl)-4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}benzamide obtained in Example 43, 0.4 mL tetrahydrofuran and 0.2 mL pyridine under ice-cooling. The mixture was stirred at room temperature for 1 hour, water was added thereto, and the mixture was stirred for 30 minutes. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography (acetic acid/methanol) to give 53 mg N1-[3-(acetylamino)propyl]-4-(6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}benzamide. This product was subjected to deprotection of the trityl group in the same manner as in Example 89, to give 27 mg of the title compound (colorless crystals; recrystallization solvent, methanol/diethyl ether).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][CH:36]([CH3:41])[CH2:37][C:38](Cl)=[O:39]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:38](=[O:39])[CH2:37][CH:36]([CH3:41])[CH3:35])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CC(C)CC(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)CC(C)C

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 3-methyl-butyryl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H41N2O2Cl2 [(M+H)+] 579.2540, observed 579.2543.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:51]=[CH:50][CH:49]=[C:48]3[C:44]=2[CH:45]=[N:46][NH:47]3)O1>>[C:24]([O:23][C:22](=[O:28])[NH:21][CH2:20][C:18](=[O:19])[NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[S:10][C:5]3[C:4]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:3][C:2]([C:43]4[CH:51]=[CH:50][CH:49]=[C:48]5[C:44]=4[CH:45]=[N:46][NH:47]5)=[N:7][C:6]=3[CH:8]=2)[CH:12]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg) was reacted with Boc-glycine via General Procedure I to give tert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate. 70 mg of the crude tert-butyl (3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield tert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)methylcarbamate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40].O>ClCCl>[C:39]([O:22][C@@H:12]1[C@H:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCCCC[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of methyl 7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (26) (109.6 g, 231.8 mmol) in dichloromethane (500 ml) was cooled on ice. Pyridine (28.1 ml, 347 mmol) and acetyl chloride (24.0 ml, 349 mmol) were added drop wise to the solution, and the solution was stirred at room temperature for 1.5 hours. Water (600 ml) was added to the solution and the mixture was stirred, let to stand, separated into two layers, and the aqueous layer was extracted twice with dichloromethane (400 ml). The organic layers were combined and washed with 1N-hydrochloric acid (600 ml), saturated sodium bicarbonate water (800 ml) and saturated aqueous sodium chloride (800 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated under reduced pressure to give methyl 7-[(1R,2S,3R,5S)-5-acetoxy-2-(t-butyldimethylsilyloxymethyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (27) (119.2 g, 231.5 mmol, 99.9%), as slightly yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][N:11]2[C:15](=[O:16])/[C:14](=[CH:17]/[C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[C:35]([F:38])([F:37])[F:36])[N:22]=[CH:21]4)/[S:13][C:12]2=[O:39])=[CH:8][CH:9]=1)=[O:4].C(CN)O>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:23]2[C:24]3[C:20](=[CH:19][C:18](/[CH:17]=[C:14]4/[C:15](=[O:16])[N:11]([CH2:10][C:7]5[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=5)[C:12](=[O:39])[S:13]/4)=[CH:26][CH:25]=3)[CH:21]=[N:22]2)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:30]=1
Reactant: COC(=O)c1ccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)o1
Solvent: NCCO
Product: O=C(O)c1ccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)o1

Procedure:
5-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}furan-2-carboxylic acid was prepared from 5-{[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}furan-2-carboxylic acid methyl ester following General Procedure 0 and converted to the corresponding ethanolamine salt following General Procedure T.
Reaction SMILES: [S:1]([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)([O:4][CH:5]=[C:6]([F:8])[F:7])(=[O:3])=[O:2].[S:16]([O-:19])([OH:18])=[O:17].[Na+:20].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O.CO>[F:8][C:6]([F:7])([S:16]([O-:19])(=[O:18])=[O:17])[CH2:5][O:4][S:1]([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:3])=[O:2].[Na+:20]
Reactant: Cc1ccc(S(=O)(=O)OC=C(F)F)cc1
Reactant: O=S([O-])O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)S(=O)(=O)[O-])cc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 16 %

Procedure:
9.3 g of 2,2-difluoroethenyl tosylate, which had been synthesized by a conventional technique, was dispersed in 17 g of water and 37 g of methanol, after which 4.7 g of sodium hydrogen sulfite and 0.5 g of benzoyl peroxide were added. The reaction mixture was stirred at 80° C. for 40 hours. The reaction solution was allowed to cool, after which methanol was distilled off in vacuum. Toluene was added, followed by separatory operation to separate a water layer. A saturated sodium chloride aqueous solution was added to the water layer whereupon white crystals settled out. The crystals were collected by filtration, washed with a small volume of saturated sodium chloride aqueous solution and then dried in vacuum, obtaining the target compound, sodium 1,1-difluoro-2-tosyloxyethanesulfonate. White crystals, 2.5 g (yield 16%).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2C=O)cc1
Reaction time: 0.75 h

Procedure:
To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temperature was added triethylamine (56 mL, 402 mmol), then SO3 -pyridine complex (40.5 g, 254 mmol). After 45 minutes, the reaction was poured into 2.5 L of EtOAc, washed with water (4×1 L) and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde as a white powder which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[Na].[CH3:18][CH2:19][O:20][C:21]([CH2:23]P(OCC)(OCC)=O)=[O:22].[H-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)/[CH:8]=[CH:23]/[C:21]([O:20][CH2:19][CH3:18])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.3 g of the aldehyde prepared above in THF (1 mL) was added to a solution of sodium triethylphosphonoacetate prepared by combining triethylphosphonoacetate (0.37 g, 1.2 eq.) and NaH (0.1 g, 50% dispersion, 1.5 eq.) in THF (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour and then quenched with saturated ammonium chloride and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated to give ethyl trans-3, 5-di-t-butylcinnamate as a yellow oil used directly for the next step.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@H:14]([OH:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.CN1C=CN=C1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([O:17][C@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(O[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of (3aR,4R,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-ol (3.2 g, 11.75 mmol) from Step 3 in dichloromethane (15 mL) was added triethylamine (4.10 mL, 29.4 mmol) followed by 1-methylimidazole (0.281 mL, 3.53 mmol). The solution was cooled to 0° C. and 4-bromobenzene-1-sulfonyl chloride (4.50 g, 17.63 mmol) was added. The solution was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (12 mL) and washed with aqueous hydrogen chloride (0.1 N, 10 mL×2) and water (10 mL). The organic phase was dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography using 0-60% dichloromethane/hexane as eluent to give (3aR,4R,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-yl 4-bromobenzenesulfonate: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.99-7.90 (m, 2H), 7.77-7.67 (m, 2H), 7.51 (t, J=7.9, 1H), 6.99 (d, J=7.3, 1H), 6.45 (d, J=8.6, 1H), 5.17 (q, J=6.1, 1H), 3.69 (dd, J=11.4, 4.6, 1H), 3.57-3.47 (m, 1H), 3.37 (dd, J=11.4, 8.9, 1H), 3.23 (dd, J=10.7, 4.5, 1H), 2.90-2.78 (m, 1H), 2.67-2.54 (m, 1H), 2.02-1.88 (m, 1H), 1.80 (dq, J=8.2, 6.0, 1H), 1.70 (dtd, J=13.5, 8.6, 7.0, 1H), 1.51-1.37 (m, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].Br[C:32]1C=CC(C(C2C=C([N+]([O-])=O)C=CC=2C)=O)=C(Cl)C=1.CC1C=C(N)C=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH3:32])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Solvent: Cc1cccc(N)c1
Product: Cc1cccc(Nc2ccc(C(=O)c3cc([N+](=O)[O-])ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (2.82 mmol) and 3-methyl-phenylamine (3.10 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 5:95 to 30:70 as the eluent to afford the title compound.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]1([F:37])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([NH:35]N)[C:28]=2[O:27]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:37][C:26]1([F:25])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([N:35]3[C:17]([C:12]4[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:7]5[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:24])[F:1])=[CH:5][CH:6]=5)[N:11]=4)=[CH:18][CH:19]=[N:20]3)[C:28]=2[O:27]1
Reactant: NNc1cccc2c1OC(F)(F)O2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)F)cc2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc(OC(F)F)cc2)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 1-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-9) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=461.3 (M+H)+
Reaction SMILES: [O:1]([C@H:8]1[C@H:14]([OH:15])[C:13]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1.O>CN(C)C=O>[O:1]([C@H:8]1[C@@H:14]([OH:15])[C:13]2[CH:16]=[C:17]([O:20][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Oc1ccccc1)CCO2
Reactant: ClCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@H]1c2cc(OCc3ccc4ccccc4n3)ccc2OCC[C@H]1Oc1ccccc1
Reaction time: 0.33 h
Yield: 13.9 %

Procedure:
To a solution of 950 mg of the cis-title product of Example 29 in 25 ml of dimethylformamide was added 173 mg of 50% sodium hydride. After stirring for 20 minutes, 641 mg of 2-chloromethylquinoline was added. The reaction was stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo to afford the crude product which was purified by recrystallization from methyl acetate/hexane to afford 200 mg of title product, m.p. 130°-132° C.