Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O)(=[O:19])=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH3:15])[C:23](=[O:25])[C:22]1[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:20]([S:17]([CH3:16])(=[O:18])=[O:19])[CH:21]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1Cl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1Cl
Yield: 26 %

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine (prepared according to DE10008042) and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Another purification step using preparative HPLC (Gemini NX column) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2) gave the desired compound as a colorless foam (26%). MS (ESI): m/z=469.060 [M+H]+.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[C:7]([N:10]1[CH2:15][CH2:14][C:13]([C:41]#[N:42])([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)([CH3:9])[CH3:8])C.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.CO>[C:41]([C:13]1([C:16]2[N:17]=[CH:18][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:20][CH:21]=2)[CH2:12][CH2:11][N:10]([C:7]([CH3:8])([CH3:9])[CH2:6][OH:5])[CH2:15][CH2:14]1)#[N:42]
Reactant: CCOC(=O)C(C)(C)N1CCC(C#N)(c2ccc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cn2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(C(C)(C)CO)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.8 %

Procedure:
2-Bromo-2-methylpropanoic acid ethyl ester (193 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (455 mg) described in Reference Example 169 and potassium carbonate (276 mg) in N,N-dimethylformamide (3.3 ml) and stirred at 50° C. for 12 hours. Then, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) and potassium carbonate (276 mg) were added and stirred at 50° C. for 5 hours and at 80° C. for 3 hours. Further, 2-bromo-2-methylpropanoic acid ethyl ester (100 μl) was added and stirred at 80° C. for 3 hours. Water was added to the reaction solution, the precipitated solid was purified with silica gel chromatography (chloroform/methanol) to give 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) as a white solid. MS (ESI) m/z: 570 (M+H)+. (2) Lithium borohydride (25 mg) was added to a solution of 2-{4-cyano-4-[5-({5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbonyl}amino)pyridin-2-yl]piperidin-1-yl}-2-methylpropanoic acid ethyl ester (320 mg) in tetrahydrofuran (3.7 ml) and stirred at room temperature for 1.5 hours. Then, lithium borohydride (25 mg) was added and stirred at 80° C. for 2 hours. To the reaction solution, were added methanol (1.5 ml) and sodium borohydride (85 mg), and stirred at room temperature for an hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (35 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH2:21]([N:7]1[C:6]2[CH:11]=[C:2]([Cl:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2o1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: O=c1oc2cc([N+](=O)[O-])c(Cl)cc2n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 105.6 %

Procedure:
In a 250-ml flask, place 8.6 g (0.04 m) of 5-chloro-6-nitro-benzoxazol-2-one (2b, 1.3 g of tetrabutylammonium bromide, 11.1 g (0.08 m) of potassium carbonate powder, and 80 ml of acetone. Stir the mixture at 50° C. for 30 min. Add 7.4 g (0.04 m×1.08) of benzyl bromide. Stir the reaction mixture under reflux for 15 min. Distill off acetone, add 100 ml of water and 100 ml of toluene, stir for a few min. Separate toluene solution, wash with 100 ml of water, and concentrate under a reduced pressure to dryness to give 12.9 g (100%) of 3-N-benzyl-5-chloro-6-nitro-benzoxazol-2-one (4b; X=Cl) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13]>>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(Cl)c(Cl)nc1Cl
Product: NC(=O)c1cc(Cl)c(Cl)nc1Cl

Procedure:
A solution of 2,5,6-trichloronicotinonitrile (30 g, 144.92 mmol, 1.00 equiv) in sulfuric acid (98%, 162 mL, 1.00 equiv) was stirred for 1 h at 60° C. in an oil bath. The reaction mixture was cooled and then quenched by the addition of water/ice. The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in 26 g of 2,5,6-trichloronicotinamide as a white solid. LC-MS (ES, m/z): 225 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.38 (1H, s), 8.12 (1H, s), 7.95 (1H, s).
Reaction SMILES: CC1C=CC(S(O[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([CH3:29])=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]=3[OH:22])[CH:13]=2)(=O)=O)=CC=1.[B-].[Na+]>C(Cl)(Cl)Cl.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:29][C:16]1[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:18]([OH:22])[C:19]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:21][CH:20]=2
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(O)c(-c4ccccc4)c(C)cc3c2)cc1
Agent: Cl[Ni]Cl
Agent: [B-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc2ccccc2c(O)c1-c1ccccc1
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
To a cold (5° C.) solution of 5-hydroxy-7-methyl-6-phenyl-2-naphthalenyl 4-methylbenzenesulfonate (239) (0.250 g, 0.62 mmol) in CHCl3 (5 mL) and MeOH (5 mL) was added nickel chloride hexahydrate (0.238 g, 1.24 mmol). To the above mixture sodium borohydrate (0.471 g, 12.4 mmol) was added portion-wise. The resulting black mixture was stirred at that temperature for 15 min. Reaction mixture was filtered through a pad of celite (washings were done with CHCl3). The filtrate was concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography to afford 0.064 g (44%) of the title compound (86) as an oil. 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.59-7.55 (m, 2H), 7.52-7.46 (m, 3H), 7.40-7.36 (m, 3H), 5.28 (s, 1H), 2.22 (s, 3H). LCMS (ESI) m/z (M+H)+.
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:14]4[C:18]([C:19](=[O:20])[C:7]([C:8]=23)=[CH:6][N:5]=1)=[CH:17][CH:16]=[C:15]4[N+:21]([O-:23])=[O:22])C.O.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][NH2:30])[CH3:26]>>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][NH:30][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:14]4[C:18]([C:19](=[O:20])[C:7]([C:8]=23)=[CH:6][N:5]=1)=[CH:17][CH:16]=[C:15]4[N+:21]([O-:23])=[O:22])[CH3:26]
Reactant: CCN(CC)CCN
Reactant: CCOc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Solvent: O
Product: CCN(CC)CCNc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Reaction time: 0.08 h

Procedure:
A solution of 4-ethoxy-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (4.45 g) in N,N-diethylethylenediamine (67 cc) is stirred at a temperature of about 20° C. After stirring for 5 minutes, crystals are formed. The mixture is stirred for a further 40 minutes and the dark red suspension thus obtained is then poured into iced water (335 cc). After filtering off the crystals, they are washed with water (3 × 10 cc) and then dried under reduced pressure (1 mm Hg) at 50° C. Crude 4-(2-diethylaminoethylamino)-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (4.20 g) is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[N:8][C:4]=3[CH:3]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Product: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1

Procedure:
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH3:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:15][C:7]1[N:8]([CH3:14])[C:9](=[O:13])[C:10]2[C:5]([C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2c(=O)n(C)c(C)c(-c3ccccc3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(=O)n(C)c(CBr)c(-c3ccccc3)c2c1

Procedure:
To a solution of 12 (3.08 g, 11.0 mmol) in carbon tetrachloride under Argon was added N-bromosuccinimide (1.96 g, 11.0 mmol). The contents of the reaction flask were heated to reflux. After 3 h an additional portion of N-bromosuccinimide (0.50 g, 2.81 mmol) was added to the reaction flask. After 7 h the solvent was removed in vacuo and sat. sodium bicarbonate was added. Extracted with methylene chloride (4×) and dried the combined organic portions with magnesium sulfate (anh.). Removal of the solvent in vacuo followed by trituration with ether gave 13 as a light solid (3.47 g, 9.70 mmol, 88.2%)
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.Cl.Cl.Cl.[NH2:14][CH2:15][C:16]1[N:21]=[C:20]([C:22]2[N:23]=[C:24]([N:27]=[C:28]([NH2:30])[NH2:29])[S:25][CH:26]=2)[CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O.O>[NH2:29][C:28](=[N:27][C:24]1[S:25][CH:26]=[C:22]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:15][NH:14][CH:1]=[O:3])[N:21]=2)[N:23]=1)[NH2:30]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: O=CO
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: NC(N)=Nc1nc(-c2cccc(CNC=O)n2)cs1
Reaction time: 0.5 h

Procedure:
A mixture of formic acid (0.47 ml) and acetic anhydride (0.87.ml]was stirred at 40°-50° C. for 30 minutes. To a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (3.0 g) and triethylamine (3.5 ml) in N,N-dimethylformamide (45 ml) was added the above mixture under ice-cooling and the mixture was stirred at ambient temperature for 5 hours. The reaction mixture was added to water and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was Purified by column chromatography on alumina, eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from an aqueous methanol to give 2-(diaminomethyleneamino)-4-(6-formylaminomethylpyridin-2-yl)thiazole (0.62 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH3:36])[N:31]1[CH2:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1>>[CH3:36][CH:32]1[CH2:33][CH2:34][CH2:35][CH:30]([CH3:29])[N:31]1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:43][CH:44]=1
Reactant: CC1CCCC(C)N1Cc1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2C(C)CCCC2C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-aniline Rf value: 0.6 (silica gel, methylene chloride/ethanol=5:1) C32H35N3O3
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J10) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) according to the general procedure M. Obtained as a yellow foam (228 mg).
Reaction SMILES: [OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: C[C@H](Oc1ccc(-c2ccc(CC(=O)O)cc2)cc1)[C@H](O)CCc1cccnc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Cc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
(1S,2R)-[4′-(2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy)-biphenyl-4-yl]-acetic acid (Example 55, 0.07 g), isopropylamine (0.012 g), 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) were dissolved in dimethylformamide (2 ml) and stirred for 16 hours at room temperature. The dimethylformamide was removed by vacuum distillation, the residue dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.061 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:21]([N:23]1[CH2:28][CH2:27][C:26](=[C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:33]=[CH:32][C:31]3[CH:40]=[CH:41][CH:42]=[CH:43][C:30]2=3)[CH2:25][CH2:24]1)=[O:22])[CH2:10][C:11](OCC1C=CC=CC=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:39]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=3[C:29](=[C:26]3[CH2:25][CH2:24][N:23]([C:21]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11][OH:12])=[O:22])[CH2:28][CH2:27]3)[C:35]=2[CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
797 mg (1.38 mmol) of benzyl (S)-3-[(tert-butoxycarbonyl)amino]-4-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-4-oxobutanoate was dissolved in 15 ml of tetrahydrofuran. 1.45 ml of 2 M lithium borohydride/tetrahydrofuran solution was added to the obtained solution in argon atmosphere at 0° C., and they were stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture under cooling with ice. After extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=3:1 to 1:1) to obtain the title compound.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH:6]=[CH:5][S:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:36])[CH2:30][CH2:29]1
Reactant: O=C(O)CC1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (150 mg, 0.33 mmol) and tetrahydropyran-4-yl-acetic acid (50 mg, 0.35 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). Off-white crystals (108 mg, 69%), MS (ISP) m/z=471.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=[O:4].[CH2:23]=O>C(O)(=O)C>[F:22][C:2]([F:21])([F:1])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:11][C:12]2[N:17]3[C:18](=[CH:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH2:23]1)=[O:4]
Reactant: C=O
Reactant: O=C(NCCCCNCc1cccc2nccn12)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(NCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 3860 mg (12.28 mmol) of 5-[N-(4-trifluoroacetamidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 15 ml of acetic acid was added 13.8 ml (184.21 mmol) of a 37% aqueous solution of formalin. The mixture was heated for 30 minutes at 100° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of purified water. To this solution was added 2N sodium hydroxide to adjust the pH to 8, and extracted with 150 ml of dichloromethane. The organic layer was washed with 200 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 2890 mg of the desired compound (72.0%, a white solid).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[Na].Cl>C(O)(C)C>[OH:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[CH:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@@H:15]([OH:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: C[C@H](O)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
To a stirred solution of 3α-acetoxy-5α-pregn-16-en 20-one (970 mg, 358.5 g/m, 2.7 mmol) in 130 mL of dry isopropanol was added sodium metal (8.0 g, 23 g/m, 348 mmol) slowly in small portions over 1 hr. After refluxing for 1 hour an additional amount of sodium (3.5 g) was added and reflux continued for 1 hour. The reaction mixture was acidified with 10% HCl and extracted with chloroform. The organic phase was dried over magnesium sulfate and concentrated to give the crude product. Recrystallization from acetone with cooling in the freezer gave 80 mg of a mixture (93:7) of 20α and 20β respectively. Additional recrystallization from methanol resulted in the pure title product.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:18]=[C:17]([CH2:19][CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[NH2:5][S:6]([C:9]1[CH:18]=[C:17]([CH2:19][CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:7])=[O:8]
Reactant: COC(=O)NCCc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NCCc1ccc(C(=O)OC)c(S(N)(=O)=O)c1

Procedure:
A solution of 1.4 g (3.8 mmol) of methyl 2-tert-butylaminosulfonyl-4-[2-(methoxycarbonylamino]ethyl]benzoate in 20 ml of trifluoroacetic acid was stirred for 8 hours at room temperature. The batch was evaporated completely, re-evaporated with toluene, and the residue obtained was crystallized with ethyl acetate/diisopropyl ether. This gave 0.54 g (45%) of methyl 2-aminosulfonyl-4-[2-(methoxycarbonylamino)-ethyl]benzoate of m.p.: 146-149° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32][C:33](OCC)=[O:34])=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:45][NH:46][CH3:47]>>[CH:1]1([CH2:7][C@H:8]([NH:18][C:19](=[O:20])[C@@H:21]([NH:28][C:29](=[O:30])[C@@H:31]([CH2:32][C:33](=[O:34])[N:46]([CH3:47])[CH3:45])[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)OCC)Cc1ccccc1)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)N(C)C)Cc1ccccc1)C(C)C
Yield: 20 %

Procedure:
80 mg (0.13 mmol) of ethyl (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate were taken up in 2 ml of a 5.6 molar alcoholic dimethylamine solution and heated to reflux for 3 hours. The solution was then evaporated and the residue was chromatographed on silica gel with a 20:1 mixture of methylene chloride and methanol to obtain 33 mg (20%) of (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[(R)-α-[(dimethylcarbamoyl) methyl]hydrocinnamamido]imidazole-4-propionamide as an amorphous powder. MS: 608 (M+H)+.