Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole (72 mg, 0.21 mmol) from Example 32, Step C (lower Rf isomer) in THF (3 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.160 mL, 0.26 mmol). The reaction was stirred for 1 hr and then ethyl chloroformate (0.045 mL, 42 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (2×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[Cl:27][C:28]1[C:33]([CH:34]=[O:35])=[CH:32][C:31]([C:36]#[N:37])=[CH:30][C:29]=1[NH:38][C:39]1[N:44]=[C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)[C:42]2=[N:49][CH:50]=[C:51]([C:52]#[N:53])[N:41]2[N:40]=1>C1COCC1>[Cl:27][C:28]1[C:33]([CH:34]([OH:35])[C:20]([F:22])([F:21])[F:19])=[CH:32][C:31]([C:36]#[N:37])=[CH:30][C:29]=1[NH:38][C:39]1[N:44]=[C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)[C:42]2=[N:49][CH:50]=[C:51]([C:52]#[N:53])[N:41]2[N:40]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1cc(C=O)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
TBAF (1 M in THF, 0.026 mL, 0.026 mmol) was added to a suspension of (trifluoromethyl)trimethylsilane (2 M solution in THF, 0.079 mL, 0.16 mmol) and 2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (20 mg, 0.053 mmol) in dry THF (1 mL) under nitrogen in an ice bath. The bath was removed and the reaction was left stirring at room temperature overnight. Aqueous 1 N HCl was added and the reaction was left stirring for 20 min. This was neutralized with 1.3 N potassium phosphate buffer and extracted three times with EtOAc. The organic extracts were washed with brine and dried with sodium sulfate. Radial silica gel chromatography eluting with DCM containing 0 to 15% EtOAc afforded the title compound (4.1 mg) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=O)[CH2:10][CH2:9]1.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:16])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCN(c2c(Cl)cncc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (30 mg, 0.11 mmol) in THF (2 mL), at 0° C., was added a 1M solution of borane THF complex in THF (11.1 mL, 1.1 mmol). The reaction was stirred for 1 hour before warming to r.t. and stirring for a further 18 hr. To the reaction was added 2M HCl (2 ml), the mixture diluted with water (20 ml) and extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (25 mL). The combined aqueous extracts were basified with saturated sodium hydrogen carbonate and then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give a crude colourless oil (8 mg). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 97:3 to CH2Cl2, 1 M methanolic NH3, 9:1) to furnish the title compound, LC-MS (ESI, 3.5 min) Rt 1.45 min, m/z 260 (91%, [M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(O)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)O)n2)c(C(N)=O)nn1
Temperature: 120 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
A dry 50 mL round bottom flask was charged with 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (241 mg, 783 μmol) dissolved in NMP (2.00 mL) To this solution was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (168 mg, 783 μmol) and the reaction mixture was heated in an oil bath with stirring at 120° C. for 18 h. After that, it was added more tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (168 mg, 783 μmol) in small portions during 7 hours. After last addition, the reaction was continued for 18 h. After cooling to room temperature, the solvent was distilled off under high vacuum, the residue was dissolved in dichloromethane containing few drops of methanol and then purified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to yield tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (179 mg, 47.1% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 11.54 (br. s., 1H), 8.16 (br. s., 1H), 8.04 (s, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 6.53-6.70 (m, 1H), 5.81 (d, J=3.4 Hz, 1H), 5.43 (br. s., 1H), 3.71-4.14 (m, 3H), 1.23-1.90 (m, 23H); LC-MS 486.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17](=[N:19][OH:20])[NH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[CH:25]([C:31](OC)=O)[CH2:24]2.O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:31]([CH:25]3[CH:26]4[CH2:29][CH2:30][N:23]([CH2:28][CH2:27]4)[CH2:24]3)[O:20][N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(CCCC1CCN(Cc2ccccc2)CC1)=NO
Reactant: COC(=O)C1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(CCCc3noc(C4CN5CCC4CC5)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
A mixture of 4-(1-benzylpiperidin-4-yl)butanamide oxime (1.0 g), sodium hydride (0.15 g) and molecular sieves 4A (2.0 g) in tetrahydrofuran (50 ml) was stirred at ambient temperature for 30 minutes. To the mixture was added dropwise a solution of methyl 3-quinuclidine carboxylate (0.49 g) in tetrahydrofuran (10 ml) and refluxed for 6 hours. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The extracts were successively washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on alumina eluting with chloroform to give 3-[3-(1-benzylpiperidin-4-yl)propyl]-5-(quinuclidin-3-yl)-1,2,4-oxadiazole (0.5 g) as an oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH:8]1[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]2C(=O)O1>CC1C=CC=CC=1C>[CH2:6]([O:5][C:1]([C:2]1[CH:3]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[N:8]=1)=[O:4])[CH3:7]
Reactant: O=C1ONN2CCCCC12
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2n(n1)CCCC2

Procedure:
ethyl propiolate (804 mg) was added to the o-xylene (15 mL) solution of tetrahydropyridino[1,2-c][1,2,3]oxadiazolone (1.04 g) under a nitrogen atmosphere and refluxed for 16 h. The solution was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (2/1–1/1). The titled compound was obtained as yellow oil (871 mg, 65%), and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester was obtained as yellow oil (345 mg, 26%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N+]([C:15]1[CH:20]=CC(O)=C[CH:16]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[N:8]=[CH:20][CH:15]=[CH:16]2
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: O=[N+]([O-])c1cc(F)cc2cccnc12
Temperature: 130 °C
Reaction time: 4 h
Yield: 10.8 %

Procedure:
4-Fluoro-2-nitro-phenylamine (15 g, 96 mmol) was added to a mixture of 4-nitrophenol (9.5 g, 144 mmol) and glycerol (27 ml), then concentrated sulphuric acid (8.3 ml, 154 mmol) was added dropwise. The mixture was stirred at 130° C. for 4 hours. For the workup, the reaction mixture was cooled to room temperature, then poured into ice-water. The precipitate was filtered and the aqueous phase was made basic with sodium hydroxide (15% solution). There were obtained 2.0 g (11%) of 6-fluoro-8-nitro-quinoline as a brown solid; (calculated) C9H5FN2O2 [192.2]; (found) [M+H]+=193.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][N:13]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:12]2[CH:11]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=2)[CH2:10]1)(C(C)(C)C)(C)C.[H-].[Na+].[CH2:42]=[O:43].O>CN(C=O)C>[F:39][C:34]1[CH:33]=[C:32]([C:11]2([CH2:42][OH:43])[CH2:10][CH:9]([OH:8])[CH2:14][N:13]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:12]23)[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: C=O
Reactant: COc1cc(-c2nnc3n2CC(O[Si](C)(C)C(C)(C)C)CC3c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nnc3n2CC(O)CC3(CO)c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
To a mixture of (6RS,8SR)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-(3,4-difluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (209 mg) in DMF (1.9 mL) was added sodium hydride (60%, 16.6 mg) at 0° C., and the mixture was stirred for 10 min. Paraformaldehyde (18.1 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue in THF (1.9 ml) was added TBAF (1M THF solution, 0.756 ml), and the mixture was stirred at room temperature for 15 min. Saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (154 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)=[CH:4][CH:3]=1.[CH2:34]=O.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)=[CH:6][CH:7]=1
Reactant: C=O
Reactant: C[C@H](Nc1nccc(-c2sc(C3CCNCC3)nc2-c2ccc(F)cc2)n1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](Nc1nccc(-c2sc(C3CCN(C)CC3)nc2-c2ccc(F)cc2)n1)c1ccccc1
Yield: 85 %

Procedure:
4-(4-Fluorophenyl)-2-(piperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyrimidinyl) thiazole (575 mg 1.25 mmol) is dissolved in MeOH (12 ml) and treated with an aqueous 36%-solution of formaldehyde (0.2 ml 2.5 mmol and NaBH4 (95 mg 2.5 mmol), which is added as a solid in 3 portions. After 30 min at room temperature the reaction mixture is poured on water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 95/4.5/0.5 to 90/9/1) to yield the title compound (600 mg 85%) as pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Cc1nccc2c(N)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nccc2c(NC(=O)c3ccc(-c4ccccc4)cc3)cccc12
Temperature: 38 °C
Reaction time: 72 h

Procedure:
To a solution of 1-methyl-5-aminoisoquinoline (94 (75 mg, 0.47 mmol) in DCM (4 ml) was added 4-biphenylcarboxylic acid (141 mg, 0.71 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (135 mg, 0.71 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) and the reaction stirred at 38° C. for 3 days. The mixture was diluted with DCM, washed with sat. aqueous sodium bicarbonate solution and water, dried over MgSO4 and concentrated in vacuo to give the crude product which was triturated with methanol. The resulting precipitate was collected by filtration, washed with ether and dried in vacuo giving the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.48 (d, 1H), 8.33 (d, 1H), 8.21 (br, 1H), 8.06 (m, 3H), 7.78 (d, 2H), 7.68 (m, 3H), 7.58 (d, 1H), 7.51 (t, 2H), 7.41 (t, 1H), 3.02 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:26]([Cl:29])(Cl)[Cl:27].[CH3:30][C:31]1([CH3:44])[O:43][C:35]2[C:36]([CH3:42])=[N:37][CH:38]=[C:39]([CH:40]=O)[C:34]=2[CH2:33][O:32]1>CCCCCCC>[Cl:27][C:26]([Cl:29])=[CH:40][C:39]1[CH:38]=[N:37][C:36]([CH3:42])=[C:35]2[O:43][C:31]([CH3:44])([CH3:30])[O:32][CH2:33][C:34]=12
Reactant: ClC(Cl)Cl
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Product: Cc1ncc(C=C(Cl)Cl)c2c1OC(C)(C)OC2

Procedure:
To a well stirred ice-cooled mixture of 0.1 mole of triphenylphosphine and 0.1 mole of potassium t-butoxide in 250 ml. of heptane is added over thirty minutes a mixture of 0.1 mole of chloroform in 200 ml. of haptane. The resulting mixture is concentrated in vacuo at 15°-20° to a volume of about 100 ml. and a solution of 0.1 mole of 2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine-5-carboxaldehyde in 250 ml. of heptane is added. The reaction mixture was heated at 40°-50° for 5 hours, then cooled, filtered, and concentrated in vacuo to give crude product. Chromatography on silica gel and elution with ether-petroleum ether (10-50%) gives pure 5-(2,2-dichlorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine.
Reaction SMILES: [OH:1][C@@:2]1([CH3:22])[CH:7]=[CH:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.C=O.F[C:26](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[OH:1][C@@:2]1([CH3:22])[CH:7]=[CH:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[C:10](=[CH2:26])[CH2:9]3
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=C[C@]2(C)O
Reactant: O=C([O-])C(F)(F)F
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2C=C[C@]3(C)O)[C@@]2(C)CCC(=O)C=C12
Reaction time: 3.5 h
Yield: 43.5 %

Procedure:
500 mg of 17β-hydroxy-17α-methylandrosta-4,15-diene-3-one in 8.3 ml of tetrahydrofuran is stirred at 60° C. under argon with 348 mg of paraformaldehyde and 2.2 g of N-methylanilinium trifluoroacetate. After 3.5 hours, the mixture is diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated under vacuum. After the crude product has been chromatographed on silica gel with a pentane-diethyl ether gradient, 226 mg of 17β-hydroxy-17α-methyl-6-methyleneandrosta-4,15-diene-3-one is obtained, mp 162° C. (from isopropyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH:13](O)[CH2:12]1.O=S(Cl)[Cl:32].N1C=CC=CC=1>O1CCOCC1>[Cl:32][CH:13]1[CH2:12][CH:11]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14]1=[O:28]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(OC)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cccc(OC)c1C1CC(Cl)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C

Procedure:
A solution of rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)-benzyl)pyrrolidin-2-one (200 mg; 0.48 mmol) in dioxane (1 ml) was treated at rt successively with SOCl2 (69 mg; 0.58 mmol) and pyridine (46 mg; 0.58 mmol). The resulting mixture was then heated to 80° C. for 3 h. After cooling to rt, the mixture was concentrated under reduced pressure before water and AcOEt were added. The separated organic layer was washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=50/1) afforded rac-(3R*,5S*)-3-chloro-5-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one as a pale yellow solid. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 430.20 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH2:9][CH2:10][CH3:11])[C:6](O)=[O:7].S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH2:9][CH2:10][CH3:11])[C:6]([Cl:18])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CCCC(Oc1ccccc1Br)C(=O)O
Product: CCCC(Oc1ccccc1Br)C(=O)Cl
Temperature: 80 °C
Yield: 76 %

Procedure:
23.8 g (87 mmol) of 2-(2-bromophenoxy)pentanoic acid and 90 ml of thionyl chloride are placed in a 250 ml round-bottomed flask equipped with a reflux condenser. The mixture is heated at 80° C. for 4 hours. The thionyl chloride is evaporated and the residue purified by distillation under reduced pressure (0.1 millibar). 19.3 g of 2-(2-bromophenoxy)pentanoic acid chloride are obtained (76% yield); B.p.=114° C. (0.1 mb, 10 Pa).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClCCl>[CH:1]1([CH2:7][NH:8][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: NCC1CC=CCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC1CC=CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Cyclohex-3-enylmethylamine (10 g, 90 mmol) was dissolved in 200 mL of dichloromethane and cooled in an ice bath. Triethylamine (16.8 mL, 120 mmol) was added, followed by drop-wise addition of ethyl chloroformate (10.9 g, 0.100 mol). The mixture was stirred overnight at ambient temperature, then washed with water, dilute HCl, dilute aqueous sodium hydroxide, and brine (50 mL each). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude carbamate (14 g, 85%).
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]3[C:4](=[O:14])[CH:3]=[CH:2][S:1][C:13]=3[C:12]=2[CH:11]=1
Reactant: BrBr
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Solvent: CC(=O)O
Product: O=c1ccsc2c1[nH]c1ccc(Br)cc12
Reaction time: 0.17 h

Procedure:
A solution of 8.04 g (0.04 mole) of thiopyrano[3,2-b]indol-4(5H)-one in 200 ml of acetic acid is treated dropwise with stirring at room temperature with 8.0 g (0.05 mole) of bromine. An immediate heavy precipitate formed The mixture is concentrated to dryness and the solid residue suspended in 20 ml of pyridine and stirred for 10 minutes at 95°. The reaction mixture is poured onto ice, the solid is filtered and recrystallized from dimethylformamide, mp 334°-337° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH2:47]I>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:47][C:46]2[CH:49]=[C:50]([O:54][CH3:55])[C:51]([O:52][CH3:53])=[C:44]([O:43][CH3:42])[CH:45]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1cc(CI)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1cc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc(OC)c1OC

Procedure:
In analogy with Example 44c), 1 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 2b)] in 4 ml of abs. THF is deprotonated (-75° C.) with 6.42 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and with the addition of 0.66 ml of DMPU and alkylated with 1.008 g 3,4,5-trimethoxybenzyl iodide. Chromatography on silica gel (eluent, hexane/acetone 3:1) affords the title compound. TLC Rf (hexane/acetone, 3:1)=0.22. FAB-MS M+ =485.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:7]2[O:8][C@@H:6]2[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3]1.O1CCCC1.[OH-].[NH4+:22]>C(O)C>[NH2:22][C@@H:6]1[C:5]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:15])([CH3:1])[C@H:7]1[OH:8]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Temperature: 50 °C

Procedure:
To a solution of (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (3.0 g, 15.0 mmol, compound of example 1, part A) in ethanol (30 mL) and tetrahydrofuran (30 mL) was added ammonium hydroxide (30 mL) and the reaction mixture was heated at 50° C. in a pressure bottle for 16 hours. Most of the solvent was evaporated and the residue was dissolved in 1N hydrochloric acid. It was extracted with ether and the organic extracts were discarded. The aqueous layer was made basic by the addition of 1N sodium hydroxide and extracted with chloroform. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to yield (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H- 1-benzopyran-6-carbonitrile (2.8 g), as a colorless foam. This material was used for the next reaction without further purification.