Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=[O:3].[N:6]1([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][NH:24][C:25](=[O:34])[CH2:26][S:27][CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.ClC1C=C(C=CC=1)C(OO)=O>ClCCCl>[N:6]1([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][NH:24][C:25](=[O:34])[CH2:26][S:27]([CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:3])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CS(=O)(=O)O
Reactant: CC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: CC(=O)OCCS(=O)CC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: -10 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
77 μl of methanesulfonic acid was added to a solution of 0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-acetoxyethylthio)acetamide (prepared as described in Example 2) in 5.5 ml of 1,2-dichloroethane, and the resulting mixture was cooled to -10° C. 0.28 g of 3-chloroperoxybenzoic acid (purity: 80%) was then added, and the reaction mixture was stirred, whilst keeping the temperature in the range from -10° C. to -5° C., for 2 hours. At the end of this time, it was washed with a 10% w/v aqueous solution of sodium hydrogensulfite, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.38 g (yield 73%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([C:8]3[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccnc1-c1cccc(Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccnc1-c1cccc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.21 g (0.30 mmol) of (Ph3P)2PdCl2 is added under argan to a solution of 2.5 g (10.05 mmol) of methyl 6′-chloro-2,2′-bipyridine-3-carboxylate (1) in 70 ml of dioxane and the mixture is stirred for 30 min at room temperature. Thereafter, 1.98 g (12.08 mmol) of para-chlorophenylboronic acid, 4.17 g (30.17 mmol) of K2CO3 and 7 ml of H2O are added in succession to the mixture, and the mixture is stirred for 6 hours under reflux and subsequently left to stand overnight at RT. For work-up, the reaction mixture is poured into 100 ml of H2O and extracted repeatedly with CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated. The residue is purified by column chromatography over silica gel using heptane/ethyl acetate (7:3) as the mobile phase. This gives 2.7 g (82.7%) of product as a solid. M.p.: 120.5° C.; 1H NMR (CDCl3) δ 8.75 (dd, 1H), 8.17 (dd, 1H), 8.00 (m, 2H, C6H4Cl), 7.95 (dd, 1H), 7.92 (dd, 1H), 7.28 (dd, 1H), 7.45 (m, 2H, C6H4Cl), 7.40 (dd, 1H), 3.60 (s, 3H, COOMe).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C(=O)(O)[O-].[Na+].[CH2:29]([OH:32])[CH2:30][CH3:31]>S(=O)(=O)(O)O>[CH2:29]([O:32][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH2:30][CH3:31]
Reactant: CCCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
2α,3α-Epoxy-5α-pregnan-20-one (360 mg) was dissolved in 80 mL of propanol and cooled to °C. and added to a cold 1.0 mL propanol solution containing 5-drops of concentrated sulfuric acid. This reaction mixture was stirred for 30 minutes at this temperature and an additional 30 minutes at room temperature, poured into a 20% sodium bicarbonate solution and washed several times with chloroform. The combined organic phase was dried over potassium carbonate and concentrated. Purification of the crude product on a silica gel column eluting with hexane/ethyl acetate (70:30) gave the titled compound (206 mg, 50% yield) as white crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:55])([CH3:54])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[CH:9]=1.C1C(=O)N([Br:63])C(=O)C1>CC#N>[CH3:55][Si:2]([CH3:1])([CH3:54])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[C:9]=1[Br:63]
Reactant: COCCOC(=O)C1(OCCOC)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COCCOC(=O)C1(OCCOC)CCC(c2nc3c(-c4cnn(-c5ccccc5)c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate (2.28 g, 2.87 mmol) in CH3CN (50 mL) was added NBS (511 mg, 2.87 mmol) and stirred at rt for 30 min. Both TLC and LCMS showed complete conversion. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-30%, EtOAc/Hexanes, Rf=0.65 in 50% EtOAc) to afford 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate as a yellow oil (2.50 g). HPLC-MS TR=1.99 min (UV 254 nm, 3 min method); mass calculated for formula C40H61BrN6O7Si2 872.3, observed LCMS m/z 873.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:30])([C@@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br.CO.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:31])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH3:13])([CH3:30])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrBr
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc([C@@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 3-methyl-3-[(R)-1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (diastereomer 1, 0.283 g, 0.683 mmol) in AcOH (1 mL) was added a solution of bromine (0.070 mL, 1.366 mmol) in AcOH (1 mL) drop-wise and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was quenched by the addition of saturated aqueous NaS2O3 solution and aqueous NaHCO3 solution to pH 7-8. MeOH (5 mL), TEA (0.146 g, 1.439 mmol) and di-tert-butyl dicarbonate (0.188 g, 0.864 mmol) were added in sequence to the above mixture and the reaction mixture was stirred at ambient temperature for 1.5 h. The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic phase was washed with saturated brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by prep-TLC (eluting with 50% EtOAc in petroleum ether) to give 3-[(R)-1-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.128 g, 36%) as a solid. LC/MS (Table 1, Method 25) Rt=0.913 min.; MS m/z: 437 [M+H−56]+ and 439 [M+H−56]+. 1H NMR (CDCl3, 400 MHz): δ 8.26 (brs, 1H), 7.25 (s, 1H), 6.70 (s, 1H), 4.75-4.70 (m, 1H), 4.60 (d, J=12.8 Hz, 2H), 3.98-3.91 (m, 2H), 3.55 (m, 2H), 3.44 (d, J=8.4 Hz, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.46 (s, 9H), 1.32-1.27 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.O[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][C:31]([F:34])([F:33])[F:32])[CH:29]=1)[C:25]#[N:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:25]([C:24]1[CH:23]=[C:22]([CH:29]=[C:28]([O:30][C:31]([F:32])([F:34])[F:33])[CH:27]=1)[CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1)#[N:26]
Reactant: N#Cc1cc(CO)cc(OC(F)(F)F)c1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3cc(C#N)cc(OC(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (100 mg, 0.386 mmol) and 3-(hydroxymethyl)-5-(trifluoromethoxy)benzonitrile (84 mg, 0.386 mmol) were dissolved in THF (3.0 mL) and cooled to 0° C. Triphenylphosphine (202 mg, 0.771 mmol) and diisopropylazodicarboxylate (DIAD) (0.15 mL, 0.771 mmol) were added. The mixture was warmed to room temperature and stirred for 1 h. Additional DIAD (0.15 mL, 0.771 mmol) and triphenylphosphine (202 mg, 0.771 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 50.8 mg of impure ethyl 2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. The material was dissolved in dioxane (1.3 mL) and 1.0 M aqueous LiOH (0.33 mL, 0.33 mmol) was added. The reaction was monitored by HPLC until judged complete and then acidified to pH 2 with 1.0 M HCL. The aqueous mixture was extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography followed by HPLC to give the title compound (1.1 mg). LCMS m/z=431.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 2.11-2.20 (m, 1H), 2.50 (dd, J=15.8, 8.0 Hz, 1H), 2.66-2.84 (m, 4H), 3.51-3.60 (m, 1H), 5.18 (s, 2H), 6.78 (dd, J=8.8, 2.5 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.64 (s, 1H), 7.73 (s, 1H), 7.84 (s, 1H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][C:15](O)=[O:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH:43]1([NH2:50])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C)C=O>[CH:43]1([NH:50][C:15](=[O:16])[CH2:14][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:12][C:13]=3[CH:1]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: O=C(O)Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: NC1CCCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2c(c1)Cc1ccccc1-2)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
In dimethylformamide (50 ml) was dissolved 2-fluoreneacetic acid (2.24 g) followed by addition of 1-hydroxybenztriazole (2.0 g) and, then, dicyclohexylcarbodiimide (3.1 g) with constant stirring and ice-cooling. The mixture was further ,stirred at room temperature for 15 minutes. Cycloheptylamine (1.7 g) was then added under ice-cooling and the mixture was stirred at room temperature for 8 hrs. The resulting solid was filtered off and the filtrate was distilled under reduced pressure. The residue was extracted with 50 ml of chloroform and the extract was washed with 1N aqueous sodium hydroxide solution, 1N hydrochloric acid and water in the order mentioned and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 2.1 g of N-cycloheptyl-2-fluoreneacetamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([Na])=[N:23]1.O>C(O)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]([CH3:13])([CH3:12])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:9])[CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:16][CH:17]=1
Reactant: [Na]c1nc[nH]n1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Solvent: O
Solvent: CCCO
Product: CC(C)(Oc1ccc(Cl)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 48 h
Yield: 18.4 %

Procedure:
A solution of 30 g (0.093 mol) of 2-(4-chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane in 40 ml of n-propanol is added dropwise to a solution of 7.6 g (0.107 mol) of 1,2,4-triazolyl-sodium in 60 ml of n-propanol, at room temperature. The reaction mixture is stirred at the reflux temperature for a further 48 hours and is cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography. 6.7 g (18.4% of theory) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-ol are obtained. This is stirred with 20 ml of saturated hydrogen chloride/ether solution, at room temperature. The precipitate which separates out is filtered off under suction, rinsed with a small amount of ether and dried in vacuo at 40° C. 6.5 g (89% of theory, relative to base employed) of 3-(4-chlorophenoxy)-2-(4-chlorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-butan-2-ol hydrochloride of melting point 135° C. are obtained.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.O(C(C)C)C(C)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[S:30])[CH:23]=1>>[F:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([N:2]([CH3:1])[CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:8]2)=[S:30])[CH:25]=[CH:26][CH:27]=1
Reactant: Fc1cccc(N=C=S)c1
Reactant: CCOC(=O)N1CCC(NC)CC1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)N1CCC(N(C)C(=S)Nc2cccc(F)c2)CC1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred solution of 91 parts of ethyl 4-(methylamino)-1-piperidinecarboxylate in 420 parts of 2,2'-oxybispropane were added dropwise 75 parts of 1-fluoro-3-isothiocyanatobenzene. Upon completion, stirring was continued for 1 hour. The precipitated product was filtered off and dried, yielding 150 parts (90%) of ethyl 4-[[(3-fluorophenyl)aminothioxomethyl]methylamino]-1-piperidinecarboxylate; mp. 175.2° C. (17).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[I:13][CH2:14][C:15](=O)[CH3:16].B(F)(F)F.CCOCC>C1C=CC=CC=1>[I:13][CH2:14][C:15]1([CH3:16])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: CC(=O)CI
Reactant: OCCC1=CCc2ccccc21
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(CI)OCCC2=C1Cc1ccccc12

Procedure:
To a solution of indene-3-ethanol (15 g) in 150 ml of benzene, iodoacetone (12 g) is added. The mixture is heated at reflux with 5 ml of boron trifluoride-etherate and hydrated alkali-aluminum silicate (Molecular Sieves No. 4). After a total of 2 hours the reaction is cooled, filtered and washed with 5% sodium bicarbonate, water and dried over sodium sulfate. Evaporation under reduced pressure affords an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluate gives the title compound, identical to the compound of the same name described in Example 463.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:2][NH2:3])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=C(O)c1ccc(OCc2ccc(Cl)cc2)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
2.75 mol of hydrazine hydrate was added to a solution of 0.275 mol of ethyl ester of 4-(4-chloro benzyloxy) benzoic acid (X) in 300 ml ethanol. The reaction medium was reflux-heated for 48 hours. After cooling, the expected product was separated by filtration and recrystallised from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH:11]=O)[CH:3]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C@H:40]([NH2:42])[CH3:41])=[CH:36][CH:35]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]2[CH2:9][CH2:10][CH2:11][N:42]2[C@H:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[CH3:41])[CH:3]=1
Reactant: COc1ccc([C@@H](C)N)cc1
Reactant: O=CCCC(=O)c1cc(Br)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc([C@H](C)N2CCC[C@H]2c2cc(Br)ccn2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 4-(4-bromo-pyridin-2-yl)-4-oxo-butyraldehyde (3) (720 mg, 2.97 mmol) in CH2Cl2 at −70° C. is added acetic acid (8.93 mg, 0.15 mmol), NaBH(OAc)3 (1.58 g, 7.44 mmol) and (R)-(+)-1-(4-methoxyphenyl)ethylamine (540 mg, 3.6 mmol). The reaction mixture is stirred at −70° C. for 1 hour, then warmed up to room temperature by removing the ice bath and letting it stir for another 2 hours. The reaction mixture is quenched by adding water (25 mL) is washed with 4×20 mL of water. The combined organic layers is concentrated and purified by flash column chromatography (hexane 70%, EtOAc 30%) to yield 4-bromo-2-{(1S,2S)-1-[1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (4) (386 mg, 36% yield) as a yellow solid: MS ES+363.10.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCCN
Reactant: BrCc1ccccc1
Product: CCCCCCNCc1ccccc1
Yield: 88.1 %

Procedure:
A! 200 ml (1.49 moles) of hexylamine cooled to 5° C. were added with benzyl bromide (42.3 ml, 0.35 mole), and the resultant mixture was stirred for 1 hour at room temperature. The hexylamine in excess was then distilled off under vacuum, and the residue dissolved in 300 ml of ethyl ether and washed with 200 ml of 0.5N sodium hydroxide. The ether phase was anhydrified over sodium sulfate and evaporated to dryness thus yielding 75.5 g of a crude which, by distillation under vacuum, gave 59 g (yield: 89%) of N-benzyl-N-hexylamine (b.p.--90°-95° C./0.6 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[C@@H:16]1[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.Cl[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:33]=[CH:32][N:31]=1>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:33]=[CH:32][N:31]=3)[CH:15]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[C@@H:16]1[O:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cn[nH]c3)cc2F)C1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cnn(-c4cc(C(F)(F)F)ncn4)c3)cc2F)C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Under N2, (S)-tert-butyl 2-(2-fluoro-4-(1H-pyrazole-4-carboxamido)phenyl)morpholine-4-carboxylate (60 mg, 154 μmol, Eq: 1.00), 4-chloro-6-(trifluoromethyl)-pyrimidine (CAS 37552-81-1) (28 mg, 154 μmol, Eq: 1.00) and were combined in DMSO (2 ml). The orange solution was stirred at 120° C. over 1 hour. Control with TLC: the reaction was finished. At RT, the RM was partitioned between water and EtOAc; extracted; the organic layer was washed with water and brine; dried over MgSO4; filtered; concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 15% to 60% EtOAc in heptane). Yellow solid (41 mg). MS: 535.7 ([M−H]−)
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C:7](=[CH:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([O:19][C:12]1[CH:13]=[CH:14][C:15]2[C@@H:16]3[C:7]([C@H:6]4[C@@:2]([CH2:18][CH2:17]3)([CH3:1])[CH:3]=[CH:4][CH2:5]4)=[CH:8][CH2:9][C:10]=2[CH:11]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@]12C=CC[C@H]1C1=CCc3cc(O)ccc3[C@H]1CC2
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CC=C1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Yield: 35.1 %

Procedure:
A solution of estra-1,3,5(10),7,16-pentaen-3-ol (5, 192.1 mg, 0.7612 mmol) in anh. pyridine (2.6 mL, 32 mmol) and acetic anhydride (0.36 mL, 3.8 mmol) was stirred 6 h, after which 30 mL of ethyl acetate were added. The mixture was washed with three 10 mL portions of 1N hydrochloric acid+10 mL of saturated sodium bicarbonate+10 mL of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Example 15. The residue was washed with 10 mL of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC (5% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) and recrystallization from aqueous ethanol gave fine white needles (78.6 mg, 0.267 mmol, 35%), m.p. 77-80° C. TLC (4% ethyl acetate/hexanes on silica gel) showed 2 spots at Rf 0.21 and 0.24. (NA-1994A-286A)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])cc1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
To a solution of 2-methyl-4-nitrophenol (10.2 g, 67 mmol) in acetonitrile (250 mL) was added potassium carbonate (27.6 g, 200 mmol) and methyl iodide (4.1 mL, 66 mmol). The mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the solid was removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was dissolved in dichloromethane (250 mL). The solution was washed with 2N NaOH (aq.) (200 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to yield 1-methoxy-2-methyl-4-nitrobenzene (9.5 g, 57 mmol, 85%).