Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:14](=[O:20])[C:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[NH:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:49](=[CH:50][CH:51]=1)[CH2:48][C@:30]1([C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[N:32](COCC[Si](C)(C)C)[C:31]1=[O:47])[CH2:29]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([NH:25][C:26]3[CH:27]=[C:28]4[C:49](=[CH:50][CH:51]=3)[CH2:48][C@:30]3([C:38]5[C:33](=[N:34][CH:35]=[CH:36][CH:37]=5)[NH:32][C:31]3=[O:47])[CH2:29]4)=[O:19])[C:14](=[O:20])[C:13]([CH2:21][CH3:22])([CH2:23][CH3:24])[NH:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(N)cc3C2)c2cccnc21
Reactant: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetic acid hydrochloride (43 mg, 0.119 mmol, described in Intermediate 29), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (30 mg, 0.119 mmol, described in Intermediate 9), HOBT (27 mg, 0.179 mmol), and EDC (34 mg, 0.179 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=560 (M+1). HRMS: m/z=560.2469; calculated m/z=560.2468 for C31H32F2N5O3.
Reaction SMILES: C([O:3][C:4](=[O:32])[C@H:5]([CH3:31])[CH2:6][C@H:7]([NH:22][C:23]([C:25]1[O:29][N:28]=[C:27]([OH:30])[CH:26]=1)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:22][C:23]([C:25]3[O:29][N:28]=[C:27]([OH:30])[CH:26]=3)=[O:24])[CH2:6][C@@H:5]([CH3:31])[C:4]([OH:32])=[O:3])=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, to a solution of (2R,4S)-5-(3′-chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester (73 mg, 0.16 mmol) in ethanol (4 mL) is added 1N NaOH (2 mL) and the resulting mixture is stirred at room temperature for 2 hours. The mixture is acidified with 1N HCl and the solvent is removed under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to give (2R,4S)-5-(3′-chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid; HPLC Retention time 1.05 minutes (condition C): MS 429.1 (M+1); 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, 3 H) 1.58 (ddd, J=13.89, 9.98, 4.42 Hz, 1 H) 1.87 (ddd, J=13.71, 9.66, 3.92 Hz, 1 H) 2.41 (ddd, J=9.54, 7.14, 4.55 Hz, 1 H) 2.82 (dd, J=6.69, 3.41 Hz, 2 H) 4.10-4.24 (m, 1 H) 6.50 (s, 1 H) 7.28 (d, J=8.34 Hz, 2 H) 7.36-7.42 (m, 1 H) 7.47 (t, J=7.83 Hz, 1 H) 7.58-7.65 (m, 3 H) 7.70 (t, J=1.89 Hz, 1 H) 8.66 (d, J=8.59 Hz, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([CH3:29])[CH:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:29])[C:21]([S:25]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][OH:8])(=[O:26])=[O:27])=[C:22]([CH3:24])[CH:23]=1
Reactant: OCC1CCCCN1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 63 %

Procedure:
Piperidin-2-yl-methanol (60.77 mmol, 1 eq) was dissolved in methylene chloride (150 ml) and triethylamine (151.92 mmol, 2.5 eq) at 0° C. and a solution of 4-methoxy-2,6-dimethyl-benzenesulfonyl chloride (60.77 mmol, 1 eq) in methylene chloride (50 ml) was added dropwise at 0° C. The reaction solution was stirred at room temperature for 14 h. The reaction solution was then diluted with methylene chloride (200 ml) and the organic phase was washed with saturated sodium chloride solution (2×50 ml), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (5-20% ethyl acetate in hexane). Yield: 63%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:10])[CH2:4][CH2:3][CH:2]=[CH2:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCOCC
Product: C=CCCC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 156.1 %

Procedure:
To a suspension of 14.6 g (80 mmol) of CdCl2 in 200 mL of ether cooled to 0° C. was added 115 mL of 1.3 M solution of 3-butene-1-magnesium bromide dropwise. The mixture was refluxed for 1 h and ether was then removed by distillation. Benzene (500 mL) was introduced, followed by a solution of 17.5 g (100 mmol) 4-fluorophenylacetyl chloride. After refluxing for 1 h, the reaction mixture was quenched with 200 mL of saturated aqueous NH4Cl, 50 mL of 1 N HCl, and extracted with 200 mL of 1:1 hexane/EtOAC. The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluted with 4:1 hexane/EtOAc to give 15 g of the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.39 mmol), N-methylpiperazine (117 mg, 1.17 mmol) and acetic acid (117 mg, 1.95 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Then the mixture was cooled to 0° C. and sodium triacetoxyborohydride (124 mg, 0.58 mmol) was added. After the addition, the mixture was stirred at room temperature for 5 h. Dichloromethane was removed under reduced pressure. The crude product was purified by prep-HPLC to give the title compound (48 mg, yield 22%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.02 (s, 3H), 3.60-3.81 (m, 8H), 4.36-4.38 (d, J=7.6 Hz, 1H), 4.47 (s, 2H), 4.80-4.82 (d, J=7.6 Hz, 1H), 6.93-6.97 (m, 2H), 7.12-7.15 (m, 2H), 7.22-7.24 (m, 1H), 7.43-7.45 (m, 2H), 7.52-7.57 (m, 3H), 7.64-7.68 (m, 1H). LC-MS (ESI) m/z: 470 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=2[CH3:12])[N:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+]>O.CO>[CH3:12][C:10]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]([CH3:16])=[C:6]2[C:11]=1[C:2]([O:18][CH3:17])=[CH:3][CH:4]=[N:5]2
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(Cl)ccnc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccnc2c(C)cc([N+](=O)[O-])c(C)c12
Reaction time: 21 h

Procedure:
In a flask is placed 4-chloro-5,8-dimethyl-6-nitroquinoline (1.52 g, 5.4 mmol) with sodium methoxide (2.27 g, 4.2 mmol) and methanol (25 mL). The mixture is refluxed under argon with stirring for 21 hours, diluted with water (100 mL) and methanol (50 mL) and extracted with dichloromethane (2×200 mL). The organic layer is dried over potassium carbonate, filtered and evaporated. The product is purified by flash chromatography (7/3 hexanes/ethyl acetate), yielding 5,8-dimethyl-4-methoxy-6-nitroquinoline.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[S:18][C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:11]=3[CH:10]=[N:9]2)[C:3]=1[CH:22]=[O:23].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[S:18][C:17]5[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:11]=4[CH:10]=[N:9]3)[C:3]=2[CH:22]=[O:23])=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 70 °C
Yield: 53 %

Procedure:
A round bottom flask was charged with 124a, 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101 l (271 mg, 0.58 mmol), PdCl2(dppf) (50 mg, 0.06 mmol), K3PO4.3H2O (323 mg, 1.16 mmol), THF (15 mL), and H2O (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 70° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 124b as a yellow solid (200 mg, 53%). LCMS: [M+H]+ 651
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[C:12]1[N:13]([CH3:31])[C:14](=[O:30])[CH:15]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:17]=1[C:18]([O-:20])=O.[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CCN(C(C)C)C(C)C>C1COCC1>[F:29][C:23]1[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:16]1[C:17]([C:18]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:20])=[CH:12][N:13]([CH3:31])[C:14](=[O:30])[CH:15]=1
Reactant: NCCCO
Reactant: Cn1c(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 95 %

Procedure:
2,3,4,5,6-Pentafluorophenyl-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with 3-aminopropanol in THF in the presence of DIEA as for example 4, step B. The reaction solvent was removed under reduced pressure and the resulting oil purified by chromatography on silica gel (50% acetone/CH2Cl2) to give 4-(2-fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (95%), m.p. (Et2O) 81-86° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.11 (s, 1H), 8.40 (br s, 1H), 8.24 (s, 1H), 7.74 (d, J=9.7 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 5.59 (s, 1H), 4.48 (t, J=5.1 Hz, 1H), 3.48 (q, J=5.7 Hz, 2H), 3.37 (s, 3H), 3.30-3.24 (m, 2H), 1.67 (pentet, J=6.7 Hz, 2H). Anal. Calcd for C16H17FIN3O3.0.5H2O: C, 42.3; H, 4.0; N, 9.3. Found: C, 42.2; H, 3.8; N, 9.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:31]=[N:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1cnc2ccccc2c1
Product: CCN(Cc1cnc2ccccc2c1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-quinolin-3-ylmethyl-amine
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]1>>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]3)=[CH:4][CH:5]=2)[C:12](=[O:24])[CH:13]=1
Reactant: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CBr)cc1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccco4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(Furan-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 6.1c from 50 mg (0.13 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(furan-2-ylmethoxy)-1H-pyridin-2-one (example 6.1b) and 73 mg (0.52 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=O.[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12]>>[CH2:9]([NH:13][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)c1ccco1
Reactant: CCCCN
Product: CCCCNCc1ccco1

Procedure:
The desired amine was prepared using the method described in Example 1171A starting with 2-furoic acid and butylamine.
Reaction SMILES: [CH3:1][C:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:29])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:3][CH2:4][C:5]1[C:10]([OH:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[OH:13].C(O[C:34](=[O:36])[CH3:35])(=O)C>N1C=CC=CC=1>[CH3:1][C:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:29])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:3][CH2:4][C:5]1[C:6]([O:13][C:10](=[O:11])[CH3:9])=[CH:7][C:8]([O:12][C:8](=[O:12])[CH3:7])=[CH:9][C:10]=1[O:11][C:34](=[O:36])[CH3:35]
Reactant: CC(=CCc1c(O)cc(O)cc1O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(OC(C)=O)c(CC=C(C)CCCC(C)CCCC(C)CCCC(C)C)c(OC(C)=O)c1
Reaction time: 4 h
Yield: 59 %

Procedure:
2-(3,7,11,15-Tetramethyl-2-hexadecenyl)-1,3,5-benzenetriol (1.00 g;2.47 mmole) was dissolved in 10 ml of pyridine and 833 mg (8.16 mmole) of acetic anhydride was added thereto with ice-cooling, followed by bringing it back to room temperature, stirring for 4 hours, removing the solvent by distillation and subjecting the resulting residue to silica gel column chromatography to thereby recover 0.77 g of the title compound from the fractions eluted with hexane-ethyl acetate (5:1). Yield=59%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH:14]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:15][NH:16][C:17]2[N:25]=[C:24]([C:26](=[O:46])[NH:27][CH2:28][CH2:29][NH:30][C:31]([NH:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)[CH2:36][CH2:35]3)=[O:32])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[C@@H:47]2[CH2:51][C@H:50]([NH:52][C:53]([CH2:55][O:56]C(=O)C)=[O:54])[C@@H:49]([OH:60])[C@H:48]2[OH:61])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:37]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:38][CH2:39][CH:34]([NH:33][C:31](=[O:32])[NH:30][CH2:29][CH2:28][NH:27][C:26]([C:24]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[C@@H:47]3[CH2:51][C@H:50]([NH:52][C:53](=[O:54])[CH2:55][OH:56])[C@@H:49]([OH:60])[C@H:48]3[OH:61])=[C:17]([NH:16][CH2:15][CH:14]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:25]=2)=[O:46])[CH2:35][CH2:36]1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of acetic acid [(1S,2R,3S,4R)-4-(6-(2,2-diphenyl-ethylamino)-2-{2-[3-(3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)-ureido]-ethylcarbamoyl}-purin-9-yl)-2,3-dihydroxy-cyclopentylcarbamoyl]-methyl ester trifluoroacetate (0.015 g, 16 μmol) in methanol (1 ml) is treated with potassium carbonate (0.01 g, 10 μmol) and the reaction mixture is allowed to stir at room temperature for 1 hour. The solvent is removed in vacuo and purification of the crude by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water −0.1% TFA) yields the title product. (MH+ 778.6)
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:36])=[CH:38][CH:39]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, light yellow solid (98 mg, 80%), MS (ISP) m/z=489.4 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-tert-butyl-benzoic acid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.[N+](=[CH2:27])=[N-]>CO.CCOCC>[OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH3:27])=[O:23])[CH2:3]1
Reactant: C=[N+]=[N-]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 0.17 h

Procedure:
A solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (350 mg.) in methanol (20 ml.) and ether (10 ml.) was treated with a dry ethereal solution of diazomethane. After 10 minutes, any unreacted diazomethane was destroyed by the addition of a drop of glacial acetic acid and the mixture was evaporated to small bulk. This was taken up in ether and washed with dilute sodium hydrogen carbonate solution, with water, dried and evaporated to a foam. The product was crystallised from acetone and petrol to give title compound (28/ mg.) as off white needles; m.p. 162 163°; [α]D + 77°.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:24][CH2:25][C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)(c2ccccc2)C1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,3-diphenylpyrrolidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 68% overall yield. FDMS m/e=412 (M+ of free base). mp 193°-194°. α[D]589 =-9.11 (c=0.33, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@@H:18](O)[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:28])CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[C@H:18]([F:28])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@@H](F)[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile prepared according to example 1 (30 mg, 0.0983 mmol) in DCM (2 mL) at 0° C. was added DAST (0.02 mL, 0.1475 mmol) and the reaction mixture was stirred at same temperature for 2 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with DCM, water and extracted. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by preparative TLC method (40% EtOAc in hexane) provided the title compound.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[O:15]1[CH2:19][C:18](=[O:20])[CH2:17][C:16]21[CH2:25][CH2:24][C@H:23]1[C@H:26]3[C@H:36]([CH2:37][CH2:38][C@:21]21[CH3:22])[C@:34]1([CH3:35])[C:29](=[CH:30][C:31](=[O:39])[CH:32]=[CH:33]1)[CH2:28][CH2:27]3.N.[Li]>O1CCOCC1.O1CCCC1>[O:15]1[CH2:19][C:18](=[O:20])[CH2:17][C:16]21[CH2:25][CH2:24][C@H:23]1[C@H:26]3[C@H:36]([CH2:37][CH2:38][C@:21]21[CH3:22])[C@:34]1([CH3:35])[C:29](=[CH:30][C:31](=[O:39])[CH2:32][CH2:33]1)[CH2:28][CH2:27]3
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21CC(=O)CO1
Agent: N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21CC(=O)CO1

Procedure:
The compounds of this invention defined by the introductory formula when R therein represents methyl can be prepared as follows: 21-(Hydroxymethyl)-5α,17α-pregn-20-ene-3β,17-diol, upon prolonged contact with p-toluenesulfonyl chloride in pyridine, affords spiro[5α-androstane-17,2' (5'H)-furan]-3β-ol, from which, upon consecutive contact in cold tetrahydrofuran under nitrogen with borane and sodium peroxide (formed in situ), 4',5'-dihydrospiro[5α-androstane-17,2'(3'H)-furan] -3β,4'-diol is obtained. The hydroxyls therein are oxidized to oxos with Jones' reagent (prepared by dissolving 10 parts of chromium trioxide in 20 parts of water and consecutively adding to the resultant solution 15 parts of concentrated sulfuric acid and 20 parts of water) in acetone. The 4',5'-dihydrospiro[5α-androstane-17,2'(3'H)-furan]-3,4'-dione thus obtained, upon heating in dioxane under nitrogen with dichlorodicyanobenzoquinone, affords a mixture of 4',5'-dihydrospiro[5α-androst-1-ene-17,2'(3'H)-furan]-3,4'-dione and 4',5'-dihydrospiro[androsta-1,4-diene-17,2'(3'H)-furan]-3,4'-dione, separable by chromatography. The Δ1,4 product, consecutively contacted in tetrahydrofuran with liquid ammonia and lithium, affords 4',5'-dihydrospiro[androst-4-ene-17,2'(3'H)-furan]-3,4'-dione.