Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH2:21][CH2:22][S:23][CH3:24])[CH:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>Cl>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:26])[CH:3]=1
Reactant: CSCCOc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: CS(=O)CCOc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2

Procedure:
The product from Example 81 was oxidized in 1.4N HCl solution with sodium metaperiodate at 0°-5° C. for 2 h to give the title compound.
Reaction SMILES: [Br:1][C:2]1C=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]C2OC.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1.[Li]CCCC.CN(C=O)C.[BH4-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O>O>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:14]=[C:13]2[C:7]=1[CH2:8][CH2:9][CH:17]2[O:16][CH3:15]
Reactant: COC1CCc2c(Br)cccc21
Reactant: C1CCOC1
Agent: O=C1CCC(=O)N1Br
Agent: [BH4-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCc2c(CBr)cccc21
Temperature: -78 °C

Procedure:
To a solution of 90.0 g (0.40 mol) of 4-bromo-1-methoxyindane in 200 ml of anhydrous THF 166 ml (0.42 mol) 2.5 M solution of nBuLi in hexanes was added dropwise by vigorous stirring at −78° C. This solution was stirred at this temperature for 1 hour, cooled to −100° C., and then 57.9 g (0.80 mol) of DMF was added dropwise to maintain temperature of the reaction mixture below −70° C. Further on, this mixture was stirred at room temperature for 3 hours, and then 15 ml of water was added. The resulting mixture was evaporated to dryness. The residue dried in vacuum was dissolved in a mixture of 600 ml of THF and 300 ml of methanol. To this solution 48.2 g (1.27 mol) of NaBH4 was added in small portions by vigorous stirring at 0° C. This mixture was stirred for 12 hours at room temperature and then evaporated to dryness. The formed alcohol was extracted from a mixture of the residue with 800 ml of water by 2×400 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. The residue was dissolved in 1 liter of THF, and 104 g (0.40 mol) of triphenylphosphine was added. This mixture was stirred for 10 minutes, and then 70.5 g (0.40 mol) of N-bromosuccinimide was added. The resulting mixture was stirred for 30 minutes at room temperature. The product was isolated by flash chromatography on silica gel 60 (40-63 μm, eluent: hexanes and then hexanes-ether=10:1, vol.). Yield 74.7 g (78%) of the title material. Anal. calc. for C11H13BrO: C, 54.79; H, 5.43. Found: C, 54.55; H, 5.54. 1H NMR (CDCl3): δ 7.43 (m, 1H, 7-H), 7.31 (m, 1H, 5-H), 7.27 (m, 1H, 6H), 4.88 (dd, J=6.3 Hz, J=4.0 Hz, 1H, CHOMe), 4.52 (m, 2H, CH2Br), 3.47 (s, 3H, OMe), 3.15 (m, 1H, 3-H), 2.93 (m, 1H, 3′-H), 2.42 (m, 1H, 2-H), 2.19 (m, 1H, 2′-H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:28])[C@H:13]([CH:25]([CH3:26])[CH3:27])[NH2:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 103.8 %

Procedure:
N-[(Phenylmethoxy)carbonyl]-L-valyl-L-proline tert-butyl ester (905 g) was dissolved in ethanol (4 liters) and 10% palladium on carbon (20 g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50 psi) for 12 hours and then the catalyst was removed by filtration through through diatomaceous earth. The filtrate was concentrated under vacuum and the residue twice re-evaporated from toluene (1 liter) to give L-Valyl-L-Proline tert-butyl ester as an oil (628 g); TLC, Rf =0.2, acetone:hexane (20:80); HS: m/z=271(M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[CH2:25]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[CH3:24])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:27])[CH3:26]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C)c21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Reaction time: 8 h

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (800 mg) and 10% Pd—C (118 mg) in EtOH (20 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a colorless solid. To a mixture of this solid and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (480 mg) in DMF (10 mL) was added 60% sodium hydride (58.9 mg) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 30%-50% AcOEt in hexane and silica gel, eluted with 15%-30% AcOEt in hexane). The crude materials were purified by HPLC (C18, eluted with H2O/MeCN containing 0.1% trifluoroacetic acid). To this obtained solution was added sat. NaHCO3 aq, the mixture was extracted with AcOEt, and the extract was dried over MgSO4 and concentrated in vacuo to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (119 mg) as colorless crystals (Form A).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>C(#N)C>[Cl:16][C:9]1[N:8]=[C:7]([NH:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: N#Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cccc(Nc2nc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
In step 1-1, sodium bicarbonate (1.68 g, 20 mmol) was added into a solution of 2,6-dichloro-3-nitropyridine (1.93 g, 10 mmol) and 3-amino benzonitrile (1.18 g, 10 mmol) in acetonitrile and the suspension was heated for 24 hours at 60° C. The mixture was filtered and washed twice with water to give 3-(6-chloro-3-nitropyridin-2-ylamino)benzonitrile (1-1) as a pale yellow solid. 1H NMR DMSO-d6 δ (ppm) 10.24 (s, 1H), 8.57 (d, 1H), 8.09 (m, 1H), 7.93 (m, 1H), 7.62 (m, 2H), 7.08 (d, 1H); m/z 357 M+1.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[O:19]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=3[S:4][CH:3]=2)=[CH:20]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)csc2C1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(-c3ccoc3)csc2C1
Temperature: 95 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (60.0 mg), 3-furanboronic acid (26.1 mg), EtOH (0.1 ml), 2N aqueous sodium carbonate solution (1 mL), tetrakis(triphenylphosphine)palladium (25 mg) and toluene (2 mL) was stirred at 95° C. for 12 hr under a nitrogen atmosphere, and the reaction mixture was poured into water. The mixture was extracted with ethyl acetate and the extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 0→33% ethyl acetate/hexane) to give the title compound (51.0 mg, 88.1%) as an oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH:40]1([C:46]2[S:50][C:49]([NH2:51])=[N:48][N:47]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>C1COCC1>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([NH:51][C:49]1[S:50][C:46]([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[N:47][N:48]=1)=[O:12])(=[O:3])=[O:4]
Reactant: Nc1nnc(C2CCCCC2)s1
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(Cl)c(C(=O)Nc2nnc(C3CCCCC3)s2)c1
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a mixture of 5-(aminosulfonyl)-2-chlorobenzoic acid (33 mg, 0.14 mmol) in THF in a vial was added PS-DCC (0.1 g, 0.155 mmol), PS-HOBt (0.12 g, 0.159 mmol) and then above crude 5-cyclohexyl-1,3,4-thiadiazol-2-amine (30 mg, 0.16 mmol). The reaction mixture in the vial was shaken for overnight. The reaction slurry was diluted with more THF, and filtrated to remove polymer bound reagents. The filtrate was concentrated, and then the residue was purified by using a Gilson preparative HPLC system with a Water Xterra (C-18) column 100 mm by 50 mm ID, eluting with 2% B to 90% B in 10 minutes, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-(aminosulfonyl)-2-chloro-N-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)benzamide (2.75 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[NH:5][C:4](=[O:16])[CH:3]=1.[Br:17]Br.N#N>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:15])[NH:5][C:4](=[O:16])[C:3]=1[Br:17]
Reactant: BrBr
Reactant: Cc1cc(=O)[nH]c(C)c1Cc1ccccc1
Agent: N#N
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(Br)c(C)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a solution of 4,6-dimethyl-5-benzyl-1H-pyridin-2-one (2.21 g, 10.4 mmol) in anhydrous acetic acid (10 mL) was added bromine (3.3 g, 1.06 mL, 20.7 mL). It was stirred at room temperature for one hour. Then the reaction vessel was blew N2 to remove bromine and evaporation removed volatiles. The residue was partitioned between CH2Cl2/sat. NaHCO3/saline (100/50/50 mL). The organic layer was dried over Na2SO4 and evaporation gave the brominated compound as a yellow solid (3.17 g, 100%). 1H NMR (CDCl3) δ 2.07 (s, 3H), 2.37 (s, 3H), 3.81 (s, 2H), 7.00-7.40 (m, 5H); MS (CI) m/z 293, 295 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13](C=O)=[C:14]2[N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[Cl:33])[CH2:6]1)(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[Cl:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4c(Cl)nc5ccccc54)=C(C=O)C[C@@H]32)C1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4c(Cl)nc5ccccc54)=CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
A solution of 3β-Acetoxy-17-(2-chlorobenzimidazol-1-yl)-16-formylandrosta-5,16-diene (22a), (0.15 g, 0.304 mmol) in dry toluene (3 mL) was refluxed in the presence of chlorotris (triphenylphosphine) rhodium (I) (0.29 g, 0.311 mmol) for 60 h. After cooling to room temperature, the catalyst was removed by filtration through a Celite pad. The filtrate was evaporated, and the residue was purified by FCC [petroleum ether/EtOAc (8:2)] to give 0.04 g (28%) of pure 22b: mp 161-165° C.; IR (Neat) 2926, 2853, 1629, 1403, 1462, 1369, 1233, 1035, 847 cm−1; 1H NMR (500 MHz, CDCl3) δ1.05 (d, 6H, 18 and 19-CH3), 2.04 (s, 3H, 3β-OCOCH3), 4.62 (m, 1H, 3α-H), 5.44 (m, 1H, 6-H), 6.06 (s, 1H, 16-H), 7.33 (m, 1H, aromatic-H), 7.52 (m, 1H, aromatic-H), and 7.68 (m, 2H, aromatic-H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[C:19]([C:21]1[C:22]([CH3:30])=[C:23]([C:27](O)=[O:28])[NH:24][C:25]=1[CH3:26])#[N:20]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:27]([C:23]3[NH:24][C:25]([CH3:26])=[C:21]([C:19]#[N:20])[C:22]=3[CH3:30])=[O:28])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: Cc1[nH]c(C(=O)O)c(C)c1C#N
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c(C)c1C#N

Procedure:
Title compound was synthesized by an analogous method to Example 18 by coupling 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) with 4-cyano-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (commercially available).
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH3:13][O:14][C:15](=[O:37])[C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([OH:25])[CH:19]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:37])[C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[NH:24][C:1](=[O:2])[O:25][C:20]=2[CH:19]=1
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(O)c1)NC(=O)OCc1ccccc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
A methylene chloride (15 mL) solution of carbonyl diimidazole (498 mg, 3.07 mmol) was added at 0° C. to a solution of (R)-3-(4-amino-3-hydroxy-phenyl)-2-benzyloxycarbonylamino-propionic acid methyl ester (1.17 g, 3.07 mmol), diisopropylethylamine (1.60 mL, 9.21 mmol), and methylene chloride (85 mL). The mixture was stirred at 0° C. for 4 h. The solvents were removed in vacuo and the residue was purified by silica gel chromatography using ethyl acetate/hexanes as eluent to afford the title compound as a white solid (51%). 1H-NMR (CDCl3, 500 MHz) δ 9.07 (s, 1H), 7.37-7.29 (m, 5H), 6.96 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 5.36 (d, J=8.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.07 (d, J=12.5 Hz, 1H), 4.65 (dd, J=13.5, 5.5 Hz, 1H), 3.74 (s, 3H), 3.17 (dd, J=14.0, 5.5 Hz, 1H), 3.07 (dd, J=14.0, 6.0 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 171.9, 155.7, 155.5, 144.1, 136.2, 130.8, 128.6, 128.42, 128.38, 128.2, 125.1, 111.1, 109.8, 67.2, 55.1, 52.6, 38.3. Mass spec.: 371.18 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C@H:3]1[C:8](OC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:9][CH2:8][C@H:3]1[N:2]([CH3:1])[C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@H]1CO
Temperature: -78 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A stirred solution of 0.68 g (4.33 mmole) (S)-Methyl 1-methyl-5-oxopyrrolidine-2-carboxylate in 15 ml dry tetrahydrofuran was cooled to −78° C. and under argon atmosphere, 2.2 ml (2.2 mmole) of 1M lithium aluminum hydride solution in tetrahydrofuran was added drop by drop during 20 minutes, stirred at −78° C. for 1 hour and removing the cooling bath left to warm up to 0° C. at stirring. While ice cooling, 0.22 ml 10% of sodium hydroxide aqueous solution was added, stirred for 10 minutes, then 0.22 ml of water was added and the reaction mixture stirred for 1.5 hours allowing it to warm to room temperature. The precipitate was filtered and washed with 5×2 ml of ethyl acetate. The combined filtrates were dried over magnesium sulfate and evaporated at 35° C. in good vacuum, giving 0.52 g (93%) product which was pure enough for the next step.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[OH:16])=[O:5])C.[CH3:17][C:18]([NH2:22])([C:20]#[CH:21])[CH3:19]>CCO>[CH3:17][C:18]([NH:22][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[OH:16])=[O:5])([CH3:19])[C:20]#[CH:21]
Reactant: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Reactant: C#CC(C)(C)N
Solvent: CCO
Product: C#CC(C)(C)NC(=O)c1c(O)c2sccc2[nH]c1=O

Procedure:
3.1 g (13 mmol) of 6-ethoxycarbonyl-7-hydroxy-thieno[3,2-b]pyridin-5(4H)-one and 1.3 g (1.2 eq.) of 1,1-dimethylpropargylamine in 80 ml of EtOH were stirred for 8 hours at 150° C. in an autoclave. The solvent was removed under reduced pressure and the solid residue was stirred with diethyl ether. The solid was filtered off and purified chromatographically (silica gel, methylene chloride/methanol=8/1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Cl)cc1

Procedure:
The solution of 4-chlorobenzoic acid (5 g, 31.94 mmol) in thionyl chloride (150 ml) was stirred for 5 h at 80° C. and then concentrated under vacuum to give 4-chlorobenzoyl chloride as a brown oil (4.5 g, crude).
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=O.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[Na+]>O.CC(C)=O>[CH3:20][S:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:21]=[CH:22][C:3]([CH:1]=[C:27]3[S:23][C:24](=[O:29])[NH:25][C:26]3=[O:28])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=C1CSC(=O)N1
Reactant: CS(=O)(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
1.6 g (5 mmole) N-{4-[2-(4-formylphenoxy)ethyl]phenyl}methanesulfonamide, 0.73 g (6.25 mmole) 2,4-thiazolidinedione and 1.025 g (12.5 mmole) sodium acetate were mixed and heated to 140° C. on an oil bath under vacuum (it melted at 130° C.). It was kept at 140° C. for 20 minutes and thereafter taken off the heat. When the temperature was low enough water:acetone (2:1) was added to dissolve the reaction product. Acetone was evaporated in vacuo, acetic acid was added and the obtained crystals were filtered off and recrystallized in dichloromethane to give 0.83 g (yield 40%) of 5-(4-[2-(4-methanesulfonylamino-phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([N:31]5[CH2:36][CH2:35][S:34][CH2:33][CH2:32]5)=[O:2])=[CH:9][CH:8]=4)[CH:14]=3)=[C:19]([C:20]([F:21])([F:23])[F:22])[O:18][N:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Reactant: C1CSCCN1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1)N1CCSCC1
Yield: 67 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) was converted, using thiomorpholine instead of cyclopropanemethylamine, to the title compound (55 mg, 67%) which was obtained as a light yellow solid. MS: m/e=485.1 [M+H]+.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:38]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:38].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Reactant: Fc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Yield: 55 %

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-fluorobenzyloxy]azetidine (161) (7.5 mmol) using the procedure described for compound (9). Crystallisation from DIPE-MeOH afforded the product as a white solid (1.49 g, 55%).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=2[S:5][CH:6]=1.[C:12](C(O[Na])=O)([F:15])([F:14])[F:13].CN1CCCC1=O>[Cu]I.O>[CH3:11][C:7]1[C:4]2[S:5][CH:6]=[C:2]([C:12]([F:15])([F:14])[F:13])[C:3]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2c(Br)csc12
Reactant: O=C(O[Na])C(F)(F)F
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc2c(C(F)(F)F)csc12
Reaction time: 1 h

Procedure:
A mixture of 2 g of 3-bromo-7-methylbenzo[b]thiophene, 4.8 g of CF3COONa, 3 g CuI and 20 ml of 1-methylpyrrolidone are vigorously stirred and heated at 160°. After a short while evolution of gas commences. Stirring is continued for one hour at 160° and a further hour at 180°. After cooling the reaction mixture is poured into water, extracted with ether/hexane (1/1) and the organic phase washed, dried and concentrated under vacuum. The raw product is chromatographed over silica gel (eluant: n-hexane) and the title compound obtained as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:3]1[CH:4]=[CH:5][C:6]([N+:22]([O-])=O)=[C:7]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[CH:8]=1>CCOC(C)=O.[Pd]>[NH2:22][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[C:25]([NH:27][CH:28]([CH3:29])[CH3:30])=[O:26])=[CH:8][C:7]=1[NH:9][C:10](=[O:21])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH3:20])=[CH:16][CH:17]=1
Reactant: CCOc1ccc(CC(=O)Nc2cc(N(C)C(=O)NC(C)C)ccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(CC(=O)Nc2cc(N(C)C(=O)NC(C)C)ccc2N)cc1
Reaction time: 4 h
Yield: 96.1 %

Procedure:
A mixture of N-[5-[methyl[[isopropylamino]carbonyl]amino]-2-nitrophenyl]4-ethoxy-benzeneacetamide (190 mg, 0.46 mmol) and 10% Pd/C in EtOAc (5.0 mL) was hydrogenated for 4 hours at 30 psi. The contents were filtered through Celite, and the Celite was washed with EtOAc (2×10.0 mL). The solvent was removed in vacuo to provide the title compound (170 mg, 99%), which was used without further purification. 1HNMR (400 MHz, CDCl3): δ 0.98 (d, J=6.5 Hz, 6H), 1.38 (t, J=7.1 Hz, 3H), 3.09 (s, 3H), 3.69 (s, 2H), 3.86 (spt, J=6.7 Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 4.11–4.13 (m, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.82 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 6.96 (d, J=2.3 Hz, 1H), 7.24 (d, J=8.6 Hz, 2H), 7.58 (s, 1H). MS (ESI) (M+H)+=385. 50C: N-[2-(4-ethoxybenzyl)-1-[(2S)-2-pyrrolidinylmethyl]-1H-benzimidazol-5-yl]-N′-N-(1-isopropyl)urea
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2([OH:23])[CH2:19][CH:20]3[N:15]([CH3:14])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[CH:3][CH:4]=1
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Product: CN1C2CCC1CC(O)(c1ccc(F)cc1)C2

Procedure:
The title compound was prepared from 4-bromofluorobenzene (26.3 g, 0.15 mol), n-butyllithium in hexanes (60 mL, 2.5 M; 0.15 mol) and 8-methyl-8-azabicyclo-[3.2.1]octan-3-one (10 g, 71.7 mmol). Yield 9.9 g (59%), m.p. 168.5-170° C.