Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:12])([CH3:11])[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1)([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:22][C:23]([O:26][C:27]([N:29]1C(C2C=CC(C#N)=CC=2)O1)=[O:28])([CH3:25])[CH3:24]>ClCCl>[C:23]([O:26][C:27](=[O:28])[NH:29][N:9]1[CH2:10][CH:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:12])[CH3:11])[CH2:8]1)([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NN1CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-azetidine (300 mg, 1.6 mmol) was combined with dichloromethane (16 mL) to give a brown solution. N,N-Diisopropylethylamine (455 mg, 615 μl, 3.52 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (355 mg, 1.44 mmol) in dichloromethane (10 mL) was added during 25 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 12 g, ethyl acetate/n-heptane 1/1) to give the title compound (320 mg, 67%) as white waxy solid; GC-MS (EI) 302.0 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH:11](O)=O>C=O.O>[CH3:11][N:7]1[CH2:8][CH2:9][CH:4]([C:3]([O:2][CH3:1])=[O:10])[CH2:5][CH2:6]1
Reactant: O=CO
Reactant: COC(=O)C1CCNCC1
Agent: C=O
Solvent: O
Product: COC(=O)C1CCN(C)CC1

Procedure:
Dissolve isonipecotic acid methyl ester in formaldehyde (19.4 mL of a 37.5% solution in water, 262 mmol) and treat with formic acid (10.2 mL of a 90% solution, 240 mmol). Heat on a steam bath for 2 hours and evaporate the solvent in vacuo. Dissolve the residue in ethyl ether, dry (MgSO4), filter and evaporate the filtrate in vacuo. Purify by distillation under an argon atmosphere to give 1-methyl-4-piperidinecarboxylic acid, methyl ester as a clear colorless oil (bp 195°-205° C., 760 mm).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([CH3:32])[CH:21]([C:23]1OC2C=CC=CC=2N=1)[OH:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[K+].[Br-]>CCOC(C)=O>[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([CH3:32])[CH:21]([C:23]1[O:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2)[OH:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ncccc1O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ncccc2o1
Yield: 12 %

Procedure:
This material was prepared as a 1:1 mixture of isomers in 12% yield from the above cyanohydrin (978 mg, 4.18 mmol) and 2-amino-3-hydroxypyridine (505 mg, 4.60 mmol) using the procedure described above for compound 16. An analytical sample was obtained by recrystallization from EtOAc in hexanes (one isomer). mp: 159-161° C.; IR (KBr) υ 1719, 1699 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J=4.8, 1.2 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 7.44 (dd, J=8.1, 5.1 Hz, 1H), 7.39-7.08 (m, 6H), 6.33 (d, J=6.0 Hz, 1H), 5.00-4.82 (m, 2H), 4.74 (m, 1H), 4.10-4.00 (m, 1H), 1.21 (d, J=6.7 Hz, 3H); 13C-NMR (100.6 MHz, DMSO-d6) δ 169.34, 155.32, 154.73, 146.08, 142.32, 136.99, 128.21, 127.59, 127.37, 120.57, 119.04, 69.99, 64.99, 49.91, 16.31; FAB MS m/z: 328 (MH+); HRMS calcd for C17Hl8N304 (MH+) 328.1297, found: 328.1286; Anal (C17H17N3O4) C, H, N.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([CH3:22])=[CH:17][C:16]=2[NH2:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:24]([O-])([O-])OC>C(O)=O>[F:21][C:19]1[C:18]([CH3:22])=[CH:17][C:16]2[N:23]=[CH:24][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]=2[CH:20]=1
Reactant: Cc1cc(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Reactant: COC([O-])[O-]
Solvent: O=CO
Product: Cc1cc2ncn(C3CCNCC3)c2cc1F
Temperature: 60 °C
Yield: 99 %

Procedure:
To a solution of 4-(2-amino-5-fluoro-4-methyl-phenylamino)piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.309 mmol) in formic acid (3 mL) was added methyl orthoformate (0.5 mL). After heating for 3 hours at 60° C., the volatiles was removed under reduced pressure to afford crude product 6-fluoro-5-methyl-1-piperidin-4-yl-1H-benzoimidazole (180 mg, 99%) as a brown solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@H:15]3[CH2:17][O:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([C:27]1([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([C:27]1([OH:33])[CH2:32][CH2:31][N:30]([CH2:17][C@@H:15]([OH:16])[CH2:14][O:13][C:12]2[CH:18]=[CH:19][C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][CH:11]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: c1ccc(COc2ccc(OC[C@H]3CO3)cc2)cc1
Solvent: CCO
Product: O[C@@H](COc1ccc(OCc2ccccc2)cc1)CN1CCC(O)(Cc2ccccc2)CC1
Yield: 86.3 %

Procedure:
(R)-{[4-(Phenylmethoxy)phenoxy]methyl}-oxirane (0.55 g, 2.2 mmol) and 4-benzyl-4-hydroxy-piperidine (0.49 g, 2.4 mmol) were dissolved in ethanol (10 ml) and refluxed for 2 h. After evaporation of the solvent, the residue was chromatographed over silica gel (ethyl acetate-MeOH, 9:1) to give (R)-4-benzyl-1-[3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-piperidin-4-ol (0.85 g, 88%) as colorless oil. MS: m/e=448.5 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC.[CH3:15][C:16]1[C:20]([C:21]2[N:22]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[C:23]3[C:28]([C:29]=2[CH:30](O)[C:31]([NH2:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH3:42])[O:18][N:17]=1>>[CH3:15][C:16]1[C:20]([C:21]2[N:22]([C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)[C:23]3[C:28]([C:29]=2[CH2:30][C:31]([NH2:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH3:42])[O:18][N:17]=1
Reactant: Cc1noc(C)c1-c1c(C(O)C(N)=O)c2ccccc2n1-c1ccc(O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1-c1c(CC(N)=O)c2ccccc2n1-c1ccc(O)cc1
Reaction time: 1 h

Procedure:
1 ml TFA and 19 μl Et3SiH were added to 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-hydroxyacetamide at 0° C. and the mixture was stirred for 60 min. The solvent was evaporated without heating followed by short silica gel purification (EtOAc/heptane; 1:9 to 8:2) to provide 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)acetamide (E37). ES/MS m/z: 362.3 (M+H); 1H NMR (methanol-d3, 500 MHz): 8.98 m, 1H), 8.46-8.35 (m, 5H), 8.16 (m, 2H), 4.78 (d, 2H, J=1.9 Hz), 3.54 (s, 3H) and 3.19 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12](F)[C:9]=1[C:10]#[N:11]>>[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][CH3:6])[C:9]=1[C:10]#[N:11]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC[C@H](N)CO
Product: CC[C@H](N)COc1cccc(N)c1C#N

Procedure:
Prepared as in Example 24d from (S)-2-aminobutan-1-ol and 2-amino-6-fluorobenzonitrile as brown solid (73%). MS 206 (MH+).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1[C:46](=O)[CH3:47]>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]=[C:46]([C:37]2[CH:38]=[CH:39][C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:36]=2)[CH3:47])=[CH:29][CH:30]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: COc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: COc1ccc(CC=C(C)c2ccc3ccccc3c2)cc1
Yield: 48.3 %

Procedure:
Starting from p-methoxyphenethyltriphenylphosphonium bromide (3.15 g, 6.60 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.2 mL, 6.60 mmol, 1.0 equiv.) and 1-(naphthalen-2-yl)ethanone (1.69 g, 9.90 mmol, 1.5 equiv.), 0.92 g (48%) of the title compound as a yellow oil was obtained after purification by flash chromatography on SiO2 (hexanes/EtOAc 995:5→99:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([OH:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(=O)c3ccccc3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(O)c3ccccc3)cc21
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of 6-benzoyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.35 g, 1.0 mmol) in methanol (10 mL) was added sodium borohydride (0.114 g, 3.0 mmol) and the reaction mixture was stirred for 1 hour. Water (5 mL) was added and the reaction mixture was concentrated. Water was added and the product was extracted with EtOAc. The combined organic phase was dried (MgSO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-60% EtOAc in 40-60 petroleum ether) gave the title compound (0.26 g, 73%) as an oil. MS: [M+H]+=355.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1)OCc1ccccc1
Yield: 93.7 %

Procedure:
Treatment of (±)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.290 g, 0.877 mmol) with diisopropylethylamine (0.170 g, 1.315 mmol) followed by benzyl chloroformate (0.165 g, 0.965 mmol) generally according to the procedure described for Intermediate 12 provided 0.352 g (94%) of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 198-200° C.; Anal. calcd. for C23H19Cl2NO3: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.2; H, 4.43; N, 3.21. Chiral HPLC separation of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]carbamate (Chiralcel AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=5.174 min, Chiralcel AD, ethanol:hexane 1:1); Fraction 2 (Rt=6.229 min, Chiralcel AD, ethanol:hexane 1:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cccc(O)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cccc(O)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3'-hydroxyacetophenone (2.06 g, 15.1 mmol), trimethylsilyl triflate (7.0 mL, 36.2 mmol), triethylamine (8.52 mL, 61.1 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 201°-204° C.; 1H NMR (250 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.41 (m, 1H), 6.82 (s, 1H), 6.93 (m, 2H), 7.09 (m, 2H), 7.30 (m, 4H), 9.91 (br, 1H).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.Cl.N1C=CC=CC=1.[CH2:18]([C:22]1[O:26][N:25]=[C:24]([CH2:27][NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][C:30]=2[NH2:39])[CH:23]=1)[CH2:19][CH2:20][CH3:21]>C(#N)C>[CH2:18]([C:22]1[O:26][N:25]=[C:24]([CH2:27][N:28]2[C:29]3[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[N:32]=[CH:31][C:30]=3[N:39]=[CH:1]2)[CH:23]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: CCCCc1cc(CNc2c(N)cnc3ccccc23)no1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCc1cc(Cn2cnc3cnc4ccccc4c32)no1
Yield: 86.5 %

Procedure:
Triethyl orthoformate (0.80 mL, 4.80 mmol) and pyridine hydrochloride (0.092 g, 0.80 mmol) were sequentially added to a solution of N4-[(5-butylisoxazol-3-yl)methyl]quinoline-3,4-diamine (1.19 g, 4.00 mmol) in acetonitrile (100 mL), and the solution was heated gently at reflux overnight. An analysis by HPLC indicated the presence of starting material, and additional triethyl orthoformate and pyridine hydrochloride were added. The solution was heated at reflux for an additional 24 hours. The solvents were removed under reduced pressure, and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was separated and extracted with dichloromethane, and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with 3% to 8% methanol in dichloromethane) to provide 1.06 g of 1-[(5-butylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32]C)=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:36])[CH2:8][C:9]([CH3:35])([CH3:34])[O:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].CO>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([OH:32])=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:19][CH2:20]2)=[C:11]2[C:6]([C:7](=[O:36])[CH2:8][C:9]([CH3:34])([CH3:35])[O:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(=O)O)cc43)CC1)OC(C)(C)CC2=O
Temperature: 40 °C
Reaction time: 20.5 h

Procedure:
4.0 g of the above crude product of methyl 1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxylate was dissolved in 40.0 mL of tetrahydrofuran and added with 16 mL of 1 N aqueous sodium hydroxide. 20 mL of methanol was added to remove the separation of layers of the reaction mixture, and the reaction mixture was stirred at 40° C. for about 20.5 hours. When the reaction mixture was cooled with an ice-water bath and the pH was adjusted to 7 with 15 mL of 1 N hydrochloric acid, crystals precipitated. 10 mL of water was further added to this slurry, and crystals were obtained by filtration and the crystals were washed with 24 mL of a mixture of 2-propanol and water (1:5). The crystals were dried in vacuo and 3.34 g of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>CCOC(C)=O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1cccc(Br)c1F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(Br)c1F
Yield: 92 %

Procedure:
To a stirred solution of 3-bromo-2-fluorobenzoic acid 1 (25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2SO4 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[S:19])SC)([OH:4])(=[O:3])=[O:2].[N-:20]=[N+:21]=[N-:22].[Na+]>>[S:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:16]([SH:19])=[N:22][N:21]=[N:20]1)([OH:4])(=[O:3])=[O:2]
Reactant: CSC(=S)NCCCCCCCCCCS(=O)(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: O=S(=O)(O)CCCCCCCCCCn1nnnc1S

Procedure:
Methyl 10-sulfodecyldithiocarbamate (31.4 g., 0.096 mol.) is reacted with 6.5 g. (0.1 mol.) of sodium azide as described above to give 1-(10-sulfodecyl)tetrazole-5-thiol.
Reaction SMILES: [OH-].[Na+].Cl[CH:4]([NH:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17]C(=O)C)[C:5]([Cl:8])([Cl:7])[Cl:6].CC(C)=O.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:26]1([S:32][CH:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[C:5]([Cl:6])([Cl:7])[Cl:8])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)NC(Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(Sc1ccccc1)C(Cl)(Cl)Cl)c1ccccc1O
Reaction time: 1 h
Yield: 80 %

Procedure:
10.3 g of a 20% acqueous NaOH solution was added dropwise to the mixture of 16.6 g of N-(1,2,2,2-tetrachloroethyl)-2-acetoxybenzamide, 70 ml of acetone and 5.3 g of phenyl mercaptan under stirring at 10°-15° C. The reaction was effected at room temperature for one hour. Water was added thereto, the dichloromethane layer was separated, and the solution was dried and concentrated. 100 ml of ethanol and 1.5 ml of 35% hydrochloric acid were added to the residue and the reaction was effected under reflux for two hours. The solvent was distilled off to obtain 14.5 g of N-(1-phenylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide as white crystals.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31](Cl)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCCCN1CCOCC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OCCCN2CCOCC2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
To a stirred solution of 3-morpholin-4-yl-propan-1-ol (1.0 mmol, 0.145 g) in THF (3 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (1.3 mmol, 0.052 g) and continued stirring for 15 min. The reaction mixture was allowed to come to room temperature. To the mixture was added 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.74 mmol, 0.26 g). After completion of addition, the reaction mixture was warmed to 70° C. for 3 h. The reaction was concentrated onto SiO2 and purified via flash chromatography using 20-50% ethyl acetate in hexanes to give 4-{3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-propyl}-morpholine (0.26 g, 75%). The free amine may be dissolved in DCM and 2 N HCl in diethyl ether followed by evaporation of the solvents to provide the title compound. LCMS: m/z 463 [M+1]. 1H NMR (400 MHz, CDCl3): δ 7.32-7.49 (5H, m), 7.21-7.26 (2H, m), 7.03-7.09 (2H, m), 6.74 (1H, s), 5.12 (2H, s), 4.58 (2H, t), 3.67-3.76 (4H, m), 2.83-2.91 (2H, m), 2.41-2.56 (6H, m), 1.98-2.08 (2H, m), 1.56-1.68 (2H, m), 1.21-1.33 (2H, m), 0.83 (3H, t).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.Cl>CN(C)C=O>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[N:6][N:5]=1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: Sc1nnc(S)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CSc2nnc(S)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
To a mixture of 1.2 g of 2,5-dimercapto-1,3,4-thiadiazole, 1.1 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was added 0.5 g of ethyl p-(bromomethyl)benzoate followed by stirring at room temperature for 3 hours. The reaction mixture was made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography followed by eluting with a solvent mixture of toluene-ethyl acetate (9:1). The thus obtained crystals were recrystallized from toluene-n-hexane to give 230 mg of ethyl p-[(5-mercapto-1,3,4-thiadiazol-2-yl)thiomethyl]benzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[CH:31]2)=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH:34]=[CH:33][CH:32]=[CH:31]5)=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: BrCc1ccc(-n2cccc2)cc1
Product: Cc1nc(-c2ccn(Cc3ccc(-n4cccc4)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-(4-bromomethyl-phenyl)-1H-pyrrole as described in Example 49 and isolated as a white solid (0.08 g, 52% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.54-8.57 (m, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.26-7.43 (m, 6H), 7.07 (d, J=8 Hz, 2H), 6.86 (s, 1H), 6.35 (d, J=4 Hz, 2H), 6.18-6.25 (m, 1H), 5.36 (s, 2H), J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=455.2; Rt=1.38 min; HRMS (M+H)+=455.17.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([F:33])[C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([F:33])[C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)c(B(O)O)c1F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: Cc1ccc(Cl)c(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1F
Yield: 2.4 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-6-fluoro-5-methylphenylboronic acid (available from Combi-Blocks Inc.; 94 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-6′-fluoro-5′-methyl-biphenyl-2-carboxylic acid (3 mg, 2%). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.48-8.56 (m, 1H), 8.26-8.37 (m, 2H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.27-7.39 (m, 2H), 2.54 (s, 8H).