Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OCCCC)=[O:16])[CH2:11][CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CO>[OH:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:2]([C:4]2[S:5][CH:6]=[CH:7][N:8]=2)([OH:1])[CH3:3])[CH2:10][CH2:11]1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2nccs2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)(c1nccs1)[C@H]1CC[C@H](CO)CC1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
Butyl trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate (150 mg, 0.482 mmol) was placed in a vial under an atmosphere of nitrogen and THF (2 mL) was added. Lithium aluminum hydride (3.5 M in THF, 0.270 mL, 0.945 mmol) was added. After 20 min of stirring at 23° C. the reaction was diluted carefully with methanol (5 mL) via dropwise addition. The resulting white suspension was filtered through CELITE, and the filtrate was concentrated to afford 1-[trans-4-(hydroxymethyl)cyclohexyl]-1-(1,3-thiazol-2-yl)ethanol, which was used in subsequent synthetic transformations without purification. MS ESI calc'd. for C12H19NO2S [M+H]+ 242. found 242.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:36])(=[O:35])[NH2:34])=[CH:23][CH:22]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:35])(=[O:36])[NH:34][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[Cl:37])=[CH:23][CH:22]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-2-(3-nitrophenyl)-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step C) and 2-chlorobenzoic acid (2.5 equivalents), CDI (2.5 equiv), and DBU (2.5 equiv) according to the procedure of Example 51 to give a 95% yield of the desired material as a cream-colored solid after flash chromatography, mp 92°-95° C., homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 645 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])(=[O:17])=[O:16])=[O:13])[N:4]=1.ClCCl.[C:33](OC(=O)C)(=[O:35])C>C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[C:22]([NH:24][CH:33]=[O:35])[CH:21]=[CH:20][C:19]=2[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2C(=O)N(C)C)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=CO
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(NC=O)ccc2C(=O)N(C)C)n1

Procedure:
A solution of 1.9 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-5-amino-2-dimethylaminocarbonylbenzenesulfonamide and 10 ml of dichloromethane is added dropwise to the mixed anhydride, prepared in situ from 0.5 ml of formic acid and 1.0 ml of acetic anhydride in accordance with standard methods. After the end of reaction, the reaction mixture is concentrated and the residue is washed with water and ethyl acetate, to give 1.8 g of desired product; purity>92% (HPLC).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])#[C:2][CH2:3][CH2:4][CH3:5].[CH:16]1([O:21][C:22]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[C:28]3[CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][C:37]=2[O:45][CH3:46])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:16]1([O:21][C:22]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[C:28]3[CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40]([NH:15][S:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:1]#[C:2][CH2:3][CH2:4][CH3:5])(=[O:13])=[O:14])=[O:41])=[CH:38][C:37]=2[O:45][CH3:46])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCCC#Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC#Cc1ccccc1S(=O)(=O)NC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 20 h
Yield: 74 %

Procedure:
1.07 g of 2-(pent-1-yn-1-yl)-benzenesulfonamide and 0.94 g of 3-[N-dimethylaminopropyl]-N-ethylcarbodiimide hydrochloride as well as 0.6 g of 4-dimethylaminopyridine are added to a solution of 2.0 g of 4-[5-(cyclopentyloxycarbonylamino)-1-methyl-indol-3-yl-methyl]-3-methoxy-benzoic acid in 50 ml of methylene chloride. The reaction mixture is stirred for 20 hours under argon and then diluted with 50 ml of methylene chloride. The methylene chloride phase is washed in a separating funnel twice with 1N hydrochloric acid and once with water. The methylene chloride phase is dried over magnesium sulfate and concentrated by evaporation at 20 torr and 40°. The residue is chromatographed on 80 g of silica gel (Merck Si60, 40-63 μm), ethyl acetate being used as eluant. The fractions containing the product are concentrated by evaporation at 20 torr and 40° to yield 2.2 g of the title compound in the form of a white amorphous solid. 1H-NMR (400 MHz, DMSO-d6): 8.76 (s, b, 1H); 8.00 (d, 1H); 7.56 (m, 2H); 7.44 (m, 4H); 7.21 (d, 1H); 7.16 (d, d, 1H); 7.08 (d, 1H); 6.91 (s, 1H); 5.07 (m, 1H); 3.94 (s, 2H); 3.88 (s, 3H); 3.66 (s, 3H); 2.33 (t, 2H); 1.90-1.53 (m, 8H); 1.47 (m, 2H); 0.89 (t, 3H).
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)=O)[CH:40]=[CH:39][N:38]=1.[NH2:65][C:66]([CH:68]1[CH2:73][CH2:72][N:71]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:70][CH2:69]1)=[S:67]>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:67][C:66]([CH:68]3[CH2:73][CH2:72][N:71]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:70][CH2:69]3)=[N:65][C:44]=2[C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][S:53]([C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[C:47]=2[F:64])[CH:40]=[CH:39][N:38]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 60 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (4.80 g, 10.86 mmol) and 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperidinecarboxylate (3.19 g, 13.04 mmol) the title compound of Step A was obtained (4.31 g, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 8.57 (d, J=5.3 Hz, 1H), 7.36-7.68 (m, 5H), 7.32 (t, J=7.8 Hz, 1H), 6.90 (d, J=5.3 Hz, 1H), 4.01 (d, J=11.4 Hz, 2H), 3.20-3.34 (m, 1H), 2.92 (d, J=12.6 Hz, 2H), 2.07 (d, J=11.3 Hz, 2H), 1.52-1.70 (m, 2H), 1.40 (s, 9H). m/z (ES+): 667 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.[NH2:15]/[C:16](/[CH3:22])=[CH:17]\[C:18]([O:20][CH3:21])=[O:19].[C:23]([O:29][CH3:30])(=[O:28])[CH2:24][C:25]([CH3:27])=O>CO>[CH3:22][C:16]1[NH:15][C:25]([CH3:27])=[C:24]([C:23]([O:29][CH3:30])=[O:28])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[CH2:4][CH:3]([O:13][CH3:14])[O:2][CH3:1])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(Cc1ccccc1C=O)OC
Reactant: COC(=O)/C=C(/C)N
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1CC(OC)OC
Yield: 41.7 %

Procedure:
To a solution of 2.5 grams (0.013 mole) of 2-(2,2-dimethoxyethyl)benzaldehyde in 25 milliliters of dry methanol was added 1.48 grams (0.013 mole) of methyl 3-aminocrotonate and 1.49 grams (0.013 mole) of methyl acetoacetate and the resulting mixture was heated at reflux temperature for 3 days. At the end of this time, the solvent was removed on the rotary evaporator and the residue purified by flash chromatography on silica gel (250-400 mesh) using 2 percent methanol in chloroform as eluant to obtain 2.11 grams (42 percent yield) dimethyl 2,6-dimethyl-4-[2-(2,2-dimethoxyethyl)phenyl]-1,4-dihydropyridine-3,5-dicarboxylate intermediate (Rf 0.3) as a white solid, m.p. 113°-114° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14].[CH3:20][CH:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]1=O>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:22]1[CH2:23][CH2:24][CH2:25][C:26](=[O:27])[C:21]=1[CH3:20]
Reactant: COc1ccc(N)cc1OC1Cc2ccccc2C1
Reactant: CC1C(=O)CCCC1=O
Product: COc1ccc(NC2=C(C)C(=O)CCC2)cc1OC1Cc2ccccc2C1
Yield: 94.2 %

Procedure:
According to the same procedure as in Example 1(3), using 3-(2-indanyloxy)-4-methoxyaniline produced in Example 9(2) instead of 3-cyclopentyloxy-4-methoxyaniline, and using 2-methyl-1,3-cyclohexanedione instead of the 1,3-cyclopentanedione, the title compound (yield 94.2%) was obtained as a light brown solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].[H-].[Na+].[CH3:17]I.O>C1COCC1>[CH3:17][O:4][CH2:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)([CH3:1])[CH3:5]
Reactant: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(C)(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-methyl-2-(4-nitro-phenyl)-propan-1-ol (prepared by the method described in WO02/66470) (200 mg, 1 mmol) in THF (15 mL) was added NaH (43 mg, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 20 min, MeI (0.22 mL, 1.5 mmol) was added and the mixture was stirred for 2 h at 0° C. then overnight at RT. H2O was added and the mixture was extracted with EtOAc. The organic phase was dried, filtered and evaporated to give 1-(2-methoxy-1,1-dimethyl-ethyl)-4-nitro-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[C:11]([CH3:21])([CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH2:22].[NH2:23]O.Cl.CCN(CC)CC>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)/[C:12](=[N:23]\[OH:22])/[C:11]([CH3:21])([CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O
Reactant: CC1(C)C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC1(C)C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2/C1=N\O
Yield: 84 %

Procedure:
To a solution of (S)-4-(3,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (56) (0.8 g, 2.51 mmol) in CH2Cl2 (20 mL) and MeOH (15 mL)-H2O (5 mL) was added NH2OH.HCl (0.35 g, 5.04 mmol) and Et3N (1.01 g, 10.1 mmol). The resultant mixture was heated at reflux for 5 h before being concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:7 to 1:5) to give (S,Z)-4-(3,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydronaphthalen-1 (2H)-one oxime (60) (0.72 g, 84%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([C:32](Cl)=[O:33])[NH:26]2.C(N(C(C)C)CC)(C)C>ClCCl.O>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([C:32]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]3[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:4]=1[F:20])=[O:33])[NH:26]2
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(Cl)c1cc2c(Cl)cc(Cl)cc2[nH]1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4c(Cl)cc(Cl)cc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.16 mmol) in dichloromethane (1.5 mL) was added 4,6-dichloro-1H-indole-2-carbonyl chloride (0.060 g, 0.24 mmol) and diisopropylethylamine (0.031 g, 0.24 mmol). The resulting suspension was stirred at RT for 45 min. The reaction mixture was diluted with dichloromethane and water. A solid precipitated which was filtered and dried under vacuum to give the title compound (0.069 g, 82%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (br. s., 1H), 9.20 (br. s., 1H), 7.77-7.78 (m, 1H), 7.41-7.52 (m, 3H), 7.33-7.41 (m, 2H), 7.23-7.32 (m, 1H), 7.19-7.20 (m, 1H), 4.54 (s, 2H). ES-LCMS: m/z 522 (M−H).
Reaction SMILES: [Cl:1]CCCl.Cl[C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(OC([N:33]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][C:41]=2[CH3:47])[CH2:35][CH2:34]1)=O)(C)(C)C>C(O)(C)(C)C>[ClH:1].[CH3:20][O:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:21][CH2:22][CH2:23][O:24][CH3:25])[N:9]=[CH:8][N:7]=[C:6]2[NH:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][CH:36]2[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]2)=[C:41]([CH3:47])[CH:42]=1
Reactant: Cc1cc(N)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCCCl
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Solvent: CC(C)(C)O
Product: COCCOc1cc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2cc1OCCOC
Product: Cl
Temperature: 90 °C
Yield: 99 %

Procedure:
To a solution of 1,2-dichloroethane (20 mL) and tert-butylalcohol was added 4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline and 4-(4-amino-2-methyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. The reaction was heated at 90° C. for 1 hour. The reaction was cooled to room temperature then hydrogen chloride gas was bubbled in for 10 minutes. Ethyl acetate (30 mL) was added then cooled to 0° C. for 30 minutes. The solids were filtered and rinsed with ethyl acetate. Light yellow solids were further dried in a vacuum oven yielding the mono hydrochloride salt (1.91 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 11.42(s, 1H), 9.15(bs, 1H), 9.05(bs, 1H), 8.72(s, 1H), 8.40(s, 1H), 7.41(d, J=17.03 Hz, 2H), 7.40(d, J=2.49 Hz, 1H), 7.08(d, J=8.30 Hz, 1H), 4.67(m, 1H), 4.34(t, J=9.14, 4.98 Hz, 2H), 4.27(t, J=8.72, 4.56 Hz, 2H), 3.74(t, J=5.81, 3.32, 4H), 3.16(m, 2H), 3.07(m, 2H), 2.18(s, 3H), 2.10(m, 2H), LRMS (M+): 483.3, (M−): 481.3).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][S:18][CH2:19][CH2:20][N:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:22]([CH3:24])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:34]O>C(O)(=O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][S:18]([CH2:19][CH2:20][N:21]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:22]([CH3:24])=[O:23])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: CC(=O)N(CCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1)c1cccs1
Solvent: CC(=O)O
Product: CC(=O)N(CCS(=O)CC(=O)NCCCOc1cccc(CN2CCCCC2)c1)c1cccs1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
There was dissolved 1.0 g (0.002 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-[2-(2-thienylacetamino)ethylthio]acetamide in 30 ml of acetic acid and added 0.24 ml (0.0022 mol) of 30 % aqueous solution of hydrogen peroxide under cooling with ice, and the mixture was stirred for 12 hours at room temperature. The solvent was removed under reduced pressure, and then 15 the residue was purified by silica gel column chromatography (chloroform:ethanol=5:1) to give 0.72 g of the titled compound as crystals.
Reaction SMILES: [Cl-].[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[CH3:16][N:17]([CH3:28])[CH2:18][C:19]([CH3:27])([CH3:26])[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>ClC(Cl)Cl.O>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:23]1[CH2:24][CH2:25][CH:20]([C:19]([CH3:27])([CH3:26])[CH2:18][N:17]([CH3:16])[CH3:28])[CH2:21][CH2:22]1)=[O:15]
Reactant: CN(C)CC(C)(C)C1CCNCC1
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CC(C)(C)C1CCN(C(=O)CCCCCCCCCCBr)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
17.5 g (6.2×10-2 mole) of the chloride of 11-bromoundecanoic acid diluted in 100 ml of trichloromethane was added dropwise to a solution of N,N,β,β-tetramethyl-4-piperidineethanamine in 120 ml of trichloromethane and 19.2 ml (14.7×10-2 mole) of N,N-diethylethanamine, cooled to 0° C. The reaction mixture was stirred for 3 hours at 0° C. then for 20 hours at room temperature. The reaction mixture was poured into water and allowed to settle. The organic phase was recovered and dried over magnesium sulphate and the solvents were evaporated off under reduced pressure. 12 g (yield: 57%) of the desired product was obtained as an oil.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[N:9][N:10]([C@H:11]([CH2:16][O:17][CH3:18])[CH2:12][CH2:13][O:14][CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:19])[N:3]=1.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([Br:30])[CH:29]=1)[NH:26][CH2:25][CH2:24]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([Br:30])[CH:29]=1)[N:26]([C:2]1[C:7]3[N:8]=[N:9][N:10]([C@H:11]([CH2:16][O:17][CH3:18])[CH2:12][CH2:13][O:14][CH3:15])[C:6]=3[CH:5]=[C:4]([CH3:19])[N:3]=1)[CH2:25][CH2:24]2
Reactant: Brc1cc(Br)c2c(c1)CCN2
Reactant: COCC[C@@H](COC)n1nnc2c(Cl)nc(C)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC[C@@H](COC)n1nnc2c(N3CCc4cc(Br)cc(Br)c43)nc(C)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
(S)-4-chloro-1-(1-methoxymethyl-3-methoxypropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine (0.72 g, 2.54 mmol) and 5,7-dibromoindoline (0.72 g, 2.60 mmol) were dissolved in anhydrous THF (6 mL) and cooled in an ice bath. To that a 1 M solution of NaHMDS in THF (3.0 mL, 3.0 mmol) was added and the reaction was stirred for 20 min, allowed to warm to 25° C. and stirred for 3 h. Then water (30 mL) was added and the mixture was extracted twice with EtOAc (80 and 40 mL). The combined organic extracts was washed with brine (30 mL) dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel using 40% EtOAc/hexanes as eluent to give the product (1.14 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]2)=[C:4]([F:21])[CH:3]=1.[H][H]>[Pt]=O.CO>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:21])=[C:5]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]2)[CH:6]=1
Reactant: [H][H]
Reactant: O=c1n(CCCF)nnn1-c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: O=[Pt]
Solvent: CO
Product: Nc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Yield: 246.6 %

Procedure:
To a 500 ml Parr hydrogenation bottle was added 0.2 gram of platinum oxide, 200 ml of methanol, then 14.0 grams (0.014 mole) of 1-(4-chloro-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The bottle was placed in a Parr hydrogenator and the reaction mixture hydrogenated until the theoretical amount of hydrogen was taken up. The bottle was removed from the hydrogenator and the reaction mixture filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and subjected to column chromatography on silica gel. The appropriate fractions were combined and concentrated under reduced pressure to yield 10.0 grams of 1-(5-amino-4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 84°-86° C. The reaction was repeated several times.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(C(C)C)CC)(C)C.Cl[C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.O>O1CCCC1>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCNc2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 2-[3-(3-aminopropyl)phenoxy]-2-methylpropionate (167 mg, 0.57 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, diisopropylethylamine (73.6 mg, 0.57 mmol) and then 2-chlorobenzoxazole (96.2 mg, 0.63 mmol) were added dropwise thereto, and the mixture was stirred for four hours at room temperature. Water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=3/1), whereby the target compound was obtained (173 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[N:38]=[C:37]([NH2:39])[CH:36]=[CH:35][CH:34]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:39][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:40])([F:31])[F:41])[N:38]=3)=[O:16])[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1cccc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.192 g, 0.578 mmol; Example 58D) in dichloromethane (3 mL) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane) (0.578 mL, 1.157 mmol). The reaction was stirred for 30 minutes than concentrated to give an oil. After drying under high vacuum for 20 minutes, the residue was dissolved in dichloromethane (1 mL) and 6-(trifluoromethyl)pyridin-2-amine (0.075 g, 0.463 mmol) and 4-methylmorpholine (0.102 mL, 0.925 mmol) were added. After stirring for 20 minutes, the reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=40 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.36 (s, 1H), 8.32 (d, J=8.5, 1H), 7.86 (t, J=8.0, 1H), 7.43 (d, J=7.3, 1H), 7.36-7.29 (m, 4H), 7.06-6.96 (m, 4H), 4.22 (s, 2H), 3.54 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (ESI+) m/z 476.1 (M+H)+.