Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:9]=[CH:8][N:7]=1)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(C)C=CC=CC=1>O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:4]([NH:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:9]=[CH:8][N:7]=2)=[O:20])[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)Nc1cc(-c2ccccc2OC)ncn1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cc(NC(=O)NC2CCCN(C(=O)OC(C)(C)C)C2)ncn1
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
A mixture of [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-carbamic acid ethyl ester (XL) (0.32 g, 1.1 mmol), 3-amino-piperidine-1-carboxylic acid tert-butyl ester (XLI) (0.23 g, 1.1 mmol) and toluene (4 ml) was subjected to microwave conditions at 120° C. and 100 psi pressure for 10 min. The reaction was monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.40 g of 3-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (XLII).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[Br:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][N:65]([C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:20][CH:19]=2)[CH2:64][CH2:63]1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Br)CC1)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a stirred solution of (4-phenylamino-benzoylamino)-acetic acid (0.074 g, 0.00027 mol) in DMF (5 mL) was added DIPEA (0.088 g, 0.0006827 mol), HOBt (0.036 g, 0.00027 mol) and EDCI.HCl (0.065 g, 0.00034 mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.066 g, 0.00023 mol) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 0.036 g (31%) of N-{2-[4-(2-bromo-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LCMS: 507.13 (M+1)+, 96.75%, 1H NMR (DMSO-d6): δ 8.6 (s, 1H), 8.2 (t, 1H), 7.8 (d, 2H), 7.4 (dd, 1H), 7.3 (t, 2H), 7.2 (m, 3H), 7.1 (d, 2H), 6.9 (t, 1H), 6.8 (d, 1H), 6.6 (t, 1H), 4.6 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.6 (s, 1H), 3.2 (m, 3H), 2.8 (m, 2H), 2.0 (m, 3H).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>ClCCl>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 5.0 g of 1,2,3,4-tetrahydro-5H-1-benzazepine and 5.91 ml of triethylamine in 50 ml of dichloromethane, chilled in an ice bath, is added, dropwise, 6.32 g of 4-nitrobenzoyl chloride in 75 ml of dichloromethane. The mixture is stirred at 0° C. for 1.5 hr and then at room temperature for 18 hours. The mixture is washed with H2 O, 1M HCl, 1M NaOH and dried (Na2SO4). The solvent is removed and the residue re-crystallized from ethanol with the aid of activated carbon to give 7.75 g of light yellow crystals, m.p. 148.5°-150.5° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH:19]=1)[C:16](O)=[O:17].C(N(CC)CC)C.F[B-](F)(F)F.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C>CN(C)C=O.C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15]([CH:19]=1)[C:16]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:17]
Reactant: NCCc1ccccc1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
3.0 g phenethylamine, 5.0 g 5-chloro-2-methoxy-benzoic acid, and 2.72 ml triethylamine were dissolved in 100 ml dimethylformamide. 8.80 g O-((Ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate were added portionwise. The reaction mixture is stirred at room temperature for three hours. 300 ml ethyl acetate were added and the mixture was washed three times with portions of 50 ml saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4 and then the solvent was removed in vacuo to obtain 6.5 g 5-Chloro-2-methoxy-N-phenethyl-benzamide.
Reaction SMILES: Cl.CN(C)S([N:7]1[CH:11]=[C:10]([CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[N:9]=[C:8]1[CH:18]([NH:43][C:44](=[O:46])[CH3:45])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][C:28]3[CH:32]=[N:33][N:34](COCC[Si](C)(C)C)[C:27]2=3)=[CH:22][CH:21]=1)(=O)=O>CO>[CH3:16][C:13]([CH3:17])([CH2:14][CH3:15])[CH2:12][C:10]1[N:9]=[C:8]([CH:18]([NH:43][C:44](=[O:46])[CH3:45])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][C:28]4[CH:32]=[N:33][NH:34][C:27]3=4)=[CH:24][CH:25]=2)[NH:7][CH:11]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(N3CCCc4cnn(COCC[Si](C)(C)C)c43)cc2)NC(C)=O)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(N3CCCc4cn[nH]c43)cc2)NC(C)=O)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added to an ambient temperature solution of N-{1-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-2-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]ethyl}acetamide (30 mg, 0.04 mmol) in methanol (3 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded the title compound. (M+H) found: 435.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC[O-].[Na+].[CH:17](=O)[C:18]1C(=CC=C[CH:24]=1)O.C([O-])([O-])=O.[K+].[K+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(O)C.C(Cl)(Cl)Cl>[NH2:1][C@:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH2:24][CH:18]=[CH2:17])[C:10]([OH:12])=[O:11]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=Cc1ccccc1O
Agent: CC[O-]
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=CC[C@](N)(Cc1ccccc1)C(=O)O
Reaction time: 2.5 h
Yield: 69.2 %

Procedure:
Following the procedure of Block (J. Chem. Soc. (C), 329, (1971)), L-Phenylalanine (16.5 g, 100 mmol) was added to a solution of NaOEt (100 mmol) in absolute ethanol (1L). Salicylaldehyde (12.2 g, 100 mmol) was added and the yellow-green solution was concentrated in vacuo and dried under hi-vac for three h at 50° C. The residue was dissolved in 400 ml of EtOH-free CHCl3 and K2CO3 (138 g, 1 mol) was added. Mechanical stirring was started and a solution of triphosgene (11 g, 37mmol) in 100 ml CHCl3 was added dropwise such that the reaction temperature remained at or below 30° C. Stirring was continued for 2-3 h at which time the reaction was filtered and the salts were washed with several portions of solvent. The organic solution was washed with H2O, dried (MgSO4), and concentrated in vacuo. Recrystallization from ethyl acetate-hexane mixtures provided the title compound as a colorless solid (14.2 g, 48%). mp=158°-159° C.; [α]D =+150.25° (c=1, CH2Cl2); MS(DCI): 296(M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:13]([O-])=O)[CH:9]=2)[N:4]=1)#[N:2]>CCOC(C)=O.CO.[H][H].[Pd]>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:13])[CH:9]=2)[N:4]=1)#[N:2]
Reactant: [H][H]
Reactant: N#Cc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cc(N)ccc2n1
Yield: 76.3 %

Procedure:
Compound 45B (212 mg, 1.1 mmol) was dissolved in 30 mL of a 1:2 mixture of EtOAc and MeOH and hydrogenated at 1 atmosphere of hydrogen in the presence of 10% Pd/C (42 mg, 20 wt. %) for 1 h. The reaction was filtered, concentrated and purified by silica gel flash chromatography eluting with 2-3% MeOH—CH2Cl2 to give the title compound (142 mg, 79%) as a light yellow solid. LC/MS m/z 170 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.C(N(CC)CC)C.[NH2:28][CH2:29][CH2:30][OH:31]>C(Cl)(Cl)Cl>[OH:31][CH2:30][CH2:29][NH:28][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCO)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
The crude product (130 mg, 0.39 mmol) from the preparation of 2-(5-amino-3-methyl-1H-pyrazol-4-yl)benzothiazole-6-sulfonyl chloride was suspended in chloroform. Triethylamine (0.1 mL) and 2-aminoethanol (26 mg, 0.43 mmol) were then added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the product was purified using preparative TLC eluting with EtOAc:hexanes:MeOH=6/4/0.3 to yield 22 mg (16%) of the product as a cream coloured powder. MS (m/z, ES+): 354 (M+1, 100%); 1H NMR (400 MHz, ppm, DMSO-d6): δ 12.25-11.75 (br s, 1H, exchangeable), 8.47 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.59 (br s, 1H, SO2NH, exchangeable), 7-5.5 (br s, 2H, exchangeable), 4.66 (t, J=5.6 Hz, 1H, OH, exchangeable), 3.34 (m, J=6.2 Hz, 2H), 2.80 (br s, 2H), 2.41 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12]Br)[C:5]([O:7][CH3:8])=[O:6].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(CBr)c(Br)c1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Methyl 3-bromo-4-bromomethylbenzoate (0.61 g; 2.0 mmol) (Part A) was dissolved in THF (10 mL) and pyrrolidine (0.66 mL; 7.9 mmol) was added at room temperature. The mixture was stirred overnight at room temperature, then poured into 80 mL of saturated aqueous aqueous sodium bicarbonate. Extraction was carried out with EtOAc (3×35 mL). The combined organics were washed with brine and dried by passage through sodium sulfate. The product was isolated as a colorless oil (0.46 g; 80% yield) by flash chromatography on silica gel eluting with EtOAc.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:15]2[C:14](=[CH:19][CH:18]=[C:17]([O:20][CH3:21])[CH:16]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2ccc(OC)cc2c1=O
Yield: 36.5 %

Procedure:
Ethyl 2-butyryl-3-(4-methoxyphenylamino)acrylate (78 g) was added dropwise to boiling diphenyl ether (600 ml) and heating continued under reflux for 45 minutes. When cool, the mixture was diluted with petrol and the precipitate was filtered off, washed with petrol and dried to give 3-butyryl-6-methoxy-4(1H)-quinolone (24 g, 49%) as a light tan solid, m.p. 252°-254°.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH:11][C:27]([C:25]3[C:24]([C:30]([F:33])([F:32])[F:31])=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CC(C)(C)c2cccc(NC(=O)c3cn(C)nc3C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
Into a solution composed of 0.15 g of (R)-1,1,3-trimethyl-4-aminoindane (optical purity: 99% ee), 0.13 g of triethylamine, 5 mg of 4-dimethylaminopyridine and 1 mL of THF, a solution of 0.18 g of 1-methyl-3-trifluoromethylpyrazole-4-carbonyl chloride in THF was dropped under ice cool. The mixture was stirred at room temperature for 15 minutes, then, to the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline sequentially, then, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.18 g of (R)-(−)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-trifluoromethylpyrazole-4-carboxamide (hereinafter, referred to as present carboxamide compound (1)) (optical purity: 99% ee).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13](O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.[CH:20]1[CH:25]=[N:24][C:23]2[N:26](O)N=[N:28][C:22]=2[CH:21]=1.C1(N)C=CC=CC=1N>CN(C=O)C.C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[NH:28][C:22]3[C:23]([N:26]=2)=[N:24][CH:25]=[CH:20][CH:21]=3)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: On1nnc2cccnc21
Reactant: CCOC(=O)C1CCC(CC(=O)O)CC1
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CCOC(=O)C1CCC(Cc2nc3ncccc3[nH]2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Compound AAA was prepared by the following procedure. To a solution of 4-carboxymethyl-cyclohexanecarboxylic acid ethyl ester (10.5 g, 49.0 mmol), EDC (9.4 g, 49.0 mmol) and HOAt (6.7 g, 49.0 mmol) in 80 mL anhydrous DMF was added phenylenediamine (5.3 g, 49.0 mmol) and the reaction mixture stirred for 1 h. The resulting reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc and the organic portion washed 3× with water. The organic layer was dried with MgSO4 and concentrated to yield a yellow oil. The crude material was dissolved in toluene/TFA (1:1 300 mL), heated to 90° C., and stirred overnight. The reaction mixture was then concentrated and purified by column chromatography on silica using EtOAc followed by 90:10:1 CH2Cl2/MeOH/NH4OH to give 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid ethyl ester as a colorless oil. Data for cis/trans mixture: mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 287].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:26](O)(=[O:32])[CH2:27][CH2:28][C:29]([NH2:31])=[O:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:26](=[O:32])[CH2:27][CH2:28][C:29](=[O:30])[NH2:31])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: NC(=O)CCC(=O)O
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)CCC(N)=O)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-1-(3-carbamoyl-propionyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using succinamic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a colorless oil. MS m/e: 465.1 [M]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11]C=O)[CH2:4][CH2:3]1.[ClH:14]>C(O)C>[ClH:14].[O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH2:11])[CH2:4][CH2:3]1
Reactant: O=CNC1CCC(=O)c2sccc21
Agent: Cl
Solvent: CCO
Product: NC1CCC(=O)c2sccc21

Procedure:
A mixture of (+)-N-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)formamide (52.65 grams) in 525 ml. of 95% ethanol and 525 ml. of 2 N HCl is heated at reflux for two hours. The mixture is cooled, filtered through glass wool and the filtrate is evaporated to dryness. The dark solid is dissolved in 180 ml. of water and the insoluble material is collected by filtration. The filter cake is washed with 70 ml. of water and the combined solution containing the title compound is used in the next operation. A 3 ml. solution is evaporated to dryness and the residue is dissolved in 95% ethanol. The ethanol solution is decolorized with activated carbon and filtered. The filtrate is evaporated to dryness to afford 0.5 grams of the title compound, m.p. 212°-214° C. (dec.), [α]D26 =+13.56° (c, 0.59 in methanol).
Reaction SMILES: [Na].[C:2]([CH2:4]P(=O)(OCC)OCC)#[N:3].[CH3:13][O:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:17]1.C(O)(=O)C>C(O)C>[CH3:13][O:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:29][CH2:30][C:31](=[CH:4][C:2]#[N:3])[CH2:32][CH2:33]3)=[CH:24][CH:23]=2)[CH2:17]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COC[C@H]1CN(c2ccc(C3CCC(=O)CC3)cc2)C(=O)O1
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: COC[C@H]1CN(c2ccc(C3CCC(=CC#N)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
0.66 g of sodium were dissolved in 70 ml of ethanol under argon. Thereafter, 5.08 g (=4.51 ml) of diethyl cyanomethylphosphonate dissolved in 20 ml of ethanol were added at 20°. The mixture was stirred at room temperature for 30 minutes and then 2.9 g of (R)-5-methoxymethyl-3-[4-(4-oxo-cyclohexyl)-phenyl]-oxazolidin-2-one were added. Thereafter, the reaction mixture was stirred at reflux for a further 1 hour, cooled to room temperature, adjusted to pH 6 with about 1 ml of glacial acetic acid and evaporated in a vacuum. The residue was dissolved in dichloromethane and washed three times with water, subsequently dried and evaporated. The excess phosphoric ester, which was still present in the residue, was distilled off at a bath temperature of ~100° and 0.03 mm vacuum (bP0.03 34°). The residue remaining (3.2 g) was chromatographed over 250 g of silica gel using medium pressure. Elution was carried out with dichloromethane, dichloromethane/ethyl acetate 20:1. The fractions which were pure according to thin-layer chromatography were combined and concentrated in a vacuum. 2.6 g of mixture of (R)- and (S)-[4-[4-[(R)-5-methoxymethyl-2-oxo-oxazolidin-3-yl]-phenyl]-cyclohexylidene]-acetonitrile (~1:2 E/Z or Z/E) were obtained as a slightly turbid oil. This was used directly for the reduction.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:6][N:7]([C:9]2([CH2:25][C:26]#[N:27])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:24])([CH3:23])[C:19](OC)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)(=[O:3])[NH2:2].[Li+].[BH4-]>C1COCC1.CCOC(C)=O.[Cl-].[NH4+]>[C:1]([C:4]1[C:5]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)=[N:6][N:7]([C:9]2([CH2:25][C:26]#[N:27])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:24])([CH3:23])[CH2:19][OH:20])=[O:16])[CH2:13][CH2:14]2)[CH:8]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)C(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CO)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-methoxy-2-methyl-1-oxopropan-2-yl 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (70 mg, 0.14 mmol) in THF (1.9 mL) at ambient temperature was added LiBH4 (25 mg, 1.2 mmol). The mixture was allowed to stir at ambient temperature for 3 hours. The mixture was then diluted with EtOAc and saturated aqueous ammonium chloride. The organic layer was separated, washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/EtOAc) to afford the title compound, Example 29.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20]CCO)[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:34])(C(C)(C)C)(C)C.[C:36]([O:39][C:40](=O)[CH3:41])(=[O:38])[CH3:37]>N1C=CC=CC=1>[CH3:35][C:10]1([CH3:34])[C@@H:9]([OH:8])[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:11]1[CH2:12][CH2:13][C:14]1[C:15]3[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=12)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:41][CH2:40][O:39][C:36](=[O:38])[CH3:37])[CH2:17][CH:16]=3
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Solvent: c1ccncc1
Product: CC(=O)OCCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-ol (150 mg) is acetylated in a mixture of 2 ml of pyridine and 1 ml of acetic anhydride. The tert-butyldimethylsilyl protecting group is split of by treatment with tetra-butylammonium fluoride hydrate according to the procedure outlined in example 2. After column chromatography and crystallisation from acetone/water, the title compound (36 mg) is obtained. 1H-NMR (CDCl3, 300 MHz): δ=5.35 (1H, s); 4.05 (2H, m); 3.23 (1H, m); 2.04 (3H, s). MS: Calculated: 428.7. Found 428.3.