Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH3:32])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:33])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)[CH2:31][CH3:32]
Reactant: CCCOc1c(-c2cccc3sc(C(C)=CC(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1c(-c2cccc3sc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[4-(2-Propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid was isolated as a white solid.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](SC)=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5].[F:16][C:17]([F:23])([F:22])[C:18]([NH:20][NH2:21])=O>C(O)C>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:21][N:20]=[C:18]([C:17]([F:23])([F:22])[F:16])[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NNC(=O)C(F)(F)F
Reactant: CCCCCNc1nc[nH]c1C(=N)SC
Solvent: CCO
Product: CCCCCNc1nc[nH]c1-c1nc(C(F)(F)F)n[nH]1

Procedure:
The mixture of methyl 4-(pentylamino)-1H-imidazole-5-carbimidothioate (0.53 g, 2.4 mmol) and trifluoroacetic acid hydrazide (0.45 g, 3.5 mmol) in ethanol (10 mL) was refluxed overnight. The reaction mixture was concentrated to yield the product as slightly green viscous oil. LCMS calculated for C11H16F3N6(M+H): 289.1. found: 289.1.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[Cl:11][CH:12](OC(Cl)Cl)Cl>ClC(Cl)CCl>[Cl:11][CH2:12][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: ClC(Cl)OC(Cl)Cl
Agent: Cl
Solvent: ClCC(Cl)Cl
Product: CCCCCCCCOCCl

Procedure:
33 g (1.1 mole) of (CH2O)n were stirred in 100 ml 1,1,2-trichloroethane with 130 g (1.0 mole) 1-octanol at 0°-5° C. HCl gas was passed for one hour. The product was analysed by MS-GC, as described in example 7 and was found to contain 2.3% bis-chloromethylether.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[CH2:11]2)=[CH:6][C:5]=1[O:17][CH3:18].[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34](O)=[O:35])[N:25]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:34](=[O:35])[CH2:33][N:26]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:32]4[C:24]([C:20]4[NH:19][CH:23]=[CH:22][N:21]=4)=[N:25]3)[C@@H:12]([CH3:16])[CH2:11]2)=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: COc1cc(N2CCN[C@@H](C)C2)ccc1Cl
Agent: Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)[C@@H](C)C2)ccc1Cl

Procedure:
The title compound was prepared following Protocol A. (S)-1-(4-Chloro-3-methoxyphenyl)-3-methylpiperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 8% MeOH in CH2Cl2) to provide 1-[(S)-4-(4-chloro-3-methoxyphenyl)-2-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H), 8.66 (dd, 0.4H), 8.57-8.55 (m, 1H), 7.29-7.19 (m, 4H), 6.44-6.39 (m, 2H), 5.42 (br. s, 2H), 4.83 (br. s, 0.3H), 4.49 (br. s, 0.3H), 4.30 (br. s, 0.3H), 3.89 (s, 1.2H), 3.88 (s, 1.8H), 3.83 (br. s, 0.3H), 3.72-3.69 (m, 1H), 3.54-3.52 (m, 1H), 3.38 (br. s, 1H), 3.19-3.15 (m, 1H), 3.00 (br. s, 1H), 2.80 (br. s, 1H), 1.50-1.43 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[CH3:7][C:8]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:7][C:8]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:9]=1[O:10][CH2:11][C:12]1[N:16]([C:3](=[S:4])[N:2]([CH3:6])[CH3:1])[CH2:15][CH2:14][N:13]=1
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(OCC2=NCCN2C(=S)N(C)C)c1C

Procedure:
A solution of dimethylthiocarbamoyl chloride (2.47 g; 0.020 mole) in chloroform (10 ml) was added dropwise during 10 minutes, to a stirred solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (4.08 g; 0.020 mole) prepared as in Example 1--and triethylamine (2.0 g; 0.20 mole) in chloroform (50 ml) cooling to keep the reaction below 5° C. The reaction temperature was then allowed to rise to room temperature and finally the reaction was refluxed for 5 hours. After cooling the reaction mixture was washed with water, dried and evaporated. The residue was recrystallised from isopropanol to yield white crystals of 2-(2,3-dimethylphenoxymethyl)-1-(N,N-dimethylthiocarbamoyl)-2-imidazoline, m.p. 124°-127° C. Analysis: Calculated C 61.84, H 7.27, N 14.42%. Found: C 62.15, H 7.64, N 14.35%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3ccccc3F)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-7-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 349(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[NH4+:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: COc1ccc(S(N)(=O)=O)cc1

Procedure:
Following the procedure described in Example 1, part B above, 94.94 g (0.45 m) of 4-methoxybenzenesulfonyl chloride from part A above was interacted with ammonium hydroxide to obtain 70.41 g of 4-methoxybenzenesulfonamide, shiny white crystals which melted at 111°-112° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:8](=[O:11])[N:9]([CH3:10])[C:5]=2[CH:4]=1.[C-:18]#[N:19].[Na+]>CS(C)=O.O>[CH:12]1([N:7]2[C:6]3[CH:16]=[CH:17][C:3]([CH2:2][C:18]#[N:19])=[CH:4][C:5]=3[N:9]([CH3:10])[C:8]2=[O:11])[CH2:15][CH2:14][CH2:13]1
Reactant: [C-]#N
Reactant: Cn1c(=O)n(C2CCC2)c2ccc(CCl)cc21
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)n(C2CCC2)c2ccc(CC#N)cc21
Temperature: 90 °C
Yield: 100.3 %

Procedure:
To a solution of 5-Chloromethyl-1-cyclobutyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (11.92 g, 47.5 mmol) in methyl sulfoxide (50 mL) was added sodium cyanide (6.6 g). The reaction was heated to 90° C. for 2 hours then was cooled, diluted with water and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-acetonitrile (11.5 g).
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH2:16]([O:23][C:24]([N:26]1[CH2:30][C@H:29]([O:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:28][C@H:27]1[CH2:42][OH:43])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:16]([O:23][C:24]([N:26]1[CH2:30][C@H:29]([O:31][S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:28][C@H:27]1[CH2:42][O:43][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO)N(C(=O)OCc3ccccc3)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
37.4 ml (269 mmol) of triethylamine, 38.76 g (257 mmol) of t-butyldimethylsilyl chloride and 2.99 g (24.5 mmol) of 4-dimethylaminopyridine were added, in turn, to a solution of 104.98 g (245 mmol) of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-(p-toluenesulfonyloxy)pyrrolidine [obtained as described in Preparative Example 12(i)′ above] in 610 ml of methylene chloride, and the resulting mixture was then stirred at room temperature overnight. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 119.34 g (yield: 94%) of (2S,4R)-1-benzyloxycarbonyl-2-(t-butyldimethylsilyloxy)methyl-4-(p-toluenesulfonyloxy)pyrrolidine as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11]N.[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:16][CH:15]=1>CC#N.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]2[C:3]=1[NH:11][C:20]([CH3:21])=[C:19]2[O:18][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:24][CH:23]=1
Reactant: NNc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(=O)COc1ccc(Cl)cc1
Solvent: CC#N
Solvent: O
Product: Cc1[nH]c2c(Br)ccc([N+](=O)[O-])c2c1Oc1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A mixture of the compound from (i) (2.4 g) and 1-(4-Chloro-phenoxy)-propan-2-one (1.65 g) in MeCN (20 ml) and water (5 ml) was stirred for 16 h. The volatiles were removed in vacuo. AcOH (50 ml) was added and the reaction heated at 75° C. for 72 h. The volatiles were evaporated under reduced pressure and the residue was purified by chromatography on silica eluting with 5% ethylacetate/iso-hexane. Yield 0.34 g
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[CH:6]=[N:7]\[OH:8])=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[OH:8]/[N:7]=[C:6](\[Cl:11])/[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C\c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of (E)- and/or (Z)-4-chloro-benzaldehyde oxime (27.0 g, 173 mmol) in DMF (173 mL) was added N-chlorosuccinimide (22.8 g, 173 mmol) portionwise over 1 h, keeping the temperature below 35° C. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (28.4 g, 86%) which was obtained as a light yellow solid. MS: m/e=189.1 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1.[CH3:17][O:18][C:19](=[O:54])[NH:20][C@H:21]([C:25]([N:27]1[CH2:31][C@@H:30]([S:32][CH3:33])[CH2:29][C@H:28]1[C:34]1[NH:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)[N:38]=1)=[O:26])[CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:42]2[CH:43]=[CH:44][C:39]([C:37]3[N:38]=[C:34]([C@@H:28]4[CH2:29][C@H:30]([S:32][CH3:33])[CH2:31][N:27]4[C:25](=[O:26])[C@@H:21]([NH:20][C:19]([O:18][CH3:17])=[O:54])[CH:22]([CH3:24])[CH3:23])[NH:35][CH:36]=3)=[CH:40][CH:41]=2)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[O:16]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)OC)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
To a mixture of 4-bromo-3-trifluoromethoxy-benzoic acid methyl ester (184 mg, 0.62 mmol), [(S)-2-methyl-1-((2S,4S)-4-methylsulfanyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (300 mg, 0.55 mmol) and potassium carbonate (344 mg, 2.49 mmol) at RT was added toluene (1.35 mL) followed by water (0.69 mL). The reaction mixture was purged with nitrogen, Pd(dppf)Cl2CH2Cl2 (27.4 mg, 0.034 mmol) was added under an atmosphere of nitrogen. The reaction vial was capped and heated at 100° C. overnight, cooled to RT and partitioned between EtOAc (10 mL) and water (2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brownish oil which was purified by silica gel chromatography (12 g silica gel, 0-100% EtOAc/Hexanes). Desired fractions were combined and concentrated to give the title intermediate as an orange oil. (m/z): [M+H]+ calcd for C30H33F3N4O6S 635.21. found 635.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:30])[C@@H:14]([OH:29])[CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][C@@H:18]([OH:28])[C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5](OC)=[O:6].O>C1COCC1>[OH:26][C@@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:20]([CH2:19][C@@H:18]([OH:28])[C@@H:17]3[C@@H:16]2[CH2:15][C@H:14]([OH:29])[C@@:13]2([CH3:30])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][OH:6])[CH2:25]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 82.9 %

Procedure:
A suspension of LiA1H4 (0.06 g, 3 mols. equiv.) in dry THF (25 ml) was stirred under nitrogen whilst standing in an ice/methanol bath. Methyl cholate (5a) (0.22 g, 0.52 mmol) in dry THF (10 ml) was then added dropwise and the resultant mixture stirred at ambient temperature overnight. Water was then introduced carefully to the mixture until all the excess LiA1H4 ad been destroyed. The resultant mixture was acidified with 2M HCl and extracted into EtOAc (3×). The combined organic extracts were washed with water (2×), dried and evaporated to give a white solid (0.17 g, 83%). Recrystallisation of 0.11 g from ethyl acetate afforded pure 3α,7α,12α,24-tetrahydroxy-5β-cholane (7a)7 (40 mg., 31%): m.p. 226°-227° and 231°-234° C. [Lit.7 226°-227° C.]; 1H nmr (90 MHz; CDCl 3 /DMSO d6) δ 0.64 (3H, s, 18-CH3), 0.85 (3H, s, 19-CH3), 3.0-3.6 (4H, m [exchanges on adding D2O], 3α-,7α-,12α- and 24- OH's), 3.0-3.6 (1H, m, 3β-H), 3.35-3.55 (2H, t[broadened], 24-CH2), 3.6-3.8 (1H, m, 7β-H), 3.8-4.0 (1H, 12β-H); IR (KBr) 3382 (OH's) cm-1.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:7][CH2:6][C@H:5]([C@:8]2([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]2)[CH2:4]1.[CH3:32][CH:33]1[C:38](=O)[CH2:37][CH2:36][O:35][CH2:34]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:32][CH:33]1[C@H:38]([NH:13][C@@H:10]2[CH2:11][CH2:12][C@:8]([C@H:5]3[CH2:6][CH2:7][O:3][CH2:4]3)([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)=[O:15])[CH2:9]2)[CH2:37][CH2:36][O:35][CH2:34]1
Reactant: N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COCC[C@H]1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Temperature: 25 °C
Yield: 11.7 %

Procedure:
To a solution of (1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (73.8 mg, 0.152 mmol), 3-methyltetrahydro-4H-pyran-4-one (52.1 mg, 0.456 mmol) and triethylamine (0.0848 mL, 0.608 mmol) in dry methylene chloride (4.1 mL) was added sodium triacetoxyborohydride (96.7 mg, 0.456 mmol). After being stirred at room temperature under N2, the reaction was quenched with aqueous NaHCO3 and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The organics were combined, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column) to provide the desired product (9.1 mg, 12%). MS calculated for C26H37F3N4O3; (M+H) 511.3; found 511.3.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: COc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccc([N+](=O)[O-])cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-methoxyphenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[N:21]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccc(F)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(F)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A mixture of (S)-2-tertbutoxycarbonylaminopropionic acid (480 mg, 2.53 mmol), 3-fluoro-N2-phenylbenzene-1,2-diamine (466 mg, 2.30 mmol), HOAt (345 mg, 2.53 mmol), 4-methylmorpholine (560 μL, 5.07 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (486 mg, 2.53 mmol) in DCM (15 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between additional DCM and an aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo and the resulting residue (1.0 g) was dissolved in AcOH (20 mL) and stirred for 18 h at 70° C. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) affording [(S)-1-(7-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as a yellow/orange oil (631 mg, 77%). LCMS: RT 3.64 min [M+H]+ 356.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:35]=[C:36]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:38][C:39]=1[CH3:40]>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][C:39]([CH3:40])=[C:34]([CH3:33])[CH:35]=2)[CH2:46][CH2:45]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: Cc1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1C
Yield: 14 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3,4-dimethyl-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (9.7 mg, 14%) as light yellow oil. MS m/e=519.4 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].[C:14]([OH:17])(=[O:16])[CH3:15]>C1COCC1>[C:14]([OH:17])(=[O:16])[CH3:15].[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: ClCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of NaH (1.11 g; 46.3 mmol) in dry THF, imidazole (3 g; 44.1 mmol) dissolved in 15 ml dry THF is added drop-wise at RT. After completion of the addition the mixture is refluxed for 1 h. After cooling to RT 1-bromo-4-chloro-butane (15.2 ml; 132 mmol) is added and the reaction is stirred for 16 h at RT. The mixture is acidified with acetic acid, filtered and evaporated. The residue is taken-up in hydrochloric acid (10%, 80 ml) and extracted with EtOAc (2×20 ml). The aqueous layer is adjusted to pH 8 with carbonate buffer and the product is extracted with Et2O. After addition of 1 eq AcOH the organic layer is dried over MgSO4 and concentrated in vacuo to give the compound (6.78 g).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[OH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([OH:20])[CH2:22]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: OC1CCCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCC(O)C3)c(F)c21
Yield: 53.7 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (0.43 g), 3-hydroxypiperidine (1.6 g), and pyridine (3 ml) was refluxed for 6 hours. The mixture was evaporated to dryness, treated with water, acidified with acetic acid, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from a mixture of DMF and ethanol to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxy-1-piperidinyl)-4-oxoquinoline-3-carboxylic acid (0.3 g), mp 232°-234° C.