Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>N.CO>[F:42][C:30]([F:29])([F:41])[C:31]1[CH:32]=[C:33]([S:37]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:38])=[O:39])[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13.6 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.05 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 3-(Trifluoromethyl)benzenesulfonyl chloride (24 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH /1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (2.7 mg) as an off-white solid. MS m/z 397 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]3[NH:27][CH2:26][CH2:25][S:24]3)[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([N:31]=[C:32]=[S:33])(=[O:30])[CH3:29]>CC(C)=O>[C:28]([NH:31][C:32]([N:27]1[CH2:26][CH2:25][S:24][CH:23]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12]1)=[S:33])(=[O:30])[CH3:29]
Reactant: Fc1cccc(C2=CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Reactant: CC(=O)N=C=S
Solvent: CC(C)=O
Product: CC(=O)NC(=S)N1CCSC1c1ccccc1OCCN1CC=C(c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
A mixture of 2.69 g of 2-{2-[2-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)ethyloxy]phenyl}thiazolidine, 0.78 g of acetyl isothiocyanate and 20 ml of acetone is stirred at room temperature for 2 hours. The reaction mixture is treated in the same manner as described in Example 73. 2.2 g of N-acetyl-2-{2-[2-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide are obtained. Yield: 65%.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([OH:25])=[O:24].[CH2:27]([C:34]1[O:38][CH:37]=[C:36]([CH2:39]O)[CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([O:25][CH2:39][C:36]1[CH:35]=[C:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:38][CH:37]=1)=[O:24]
Reactant: C=C=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1coc(Cc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C=C[C@@H]1[C@@H](C(=O)OCc2coc(Cc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
1.22 g of dicyclohexylcarbodiimide and a few crystals of 4-dimethylamino-pyridine were added at 0° C. to a solution of 900 mg of (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)cyclopropane-carboxylic acid in 20 ml of methylene chloride and the mixture was stirred at 0° C. for 15 minutes. A solution of 1.23 g of 5-benzyl-3-furyl-methanol in 7 ml of methylene chloride was added to the mixture which was stirred at 20° C. for 24 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 3-7 petroleum ether (b.p.=35° to 70° C.)-benzene mixture and then a 7-3 petroleum ether (b.p.=35° to 70° C.)-benzene mixture yielded 825 mg of 5-benzyl-3-furyl-methyl (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-24° (c= 0.6% in chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][CH:3]=1.[O-:16][C:17]#[N:18].[K+]>Cl.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:14][CH:15]=1)[C:17]([NH2:18])=[O:16]
Reactant: N#C[O-]
Reactant: Nc1ccc(OCCn2ccnc2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)Nc1ccc(OCCn2ccnc2)cc1
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
1-[2-(4-Aminophenoxy)ethyl]imidazole (0.6 g) was dissolved in 1N hydrochloric acid (3.0 ml) and a solution of potassium cyanate (0.3 g) in 1 ml of water was added. The mixture was allowed to stand at room temperature for 15 minutes and the resulting solid was filtered off, washed with water and crystallised from water to give 1-[2-(4-ureidophenoxy)ethyl]imidazole (0.6 g), m.p. 199°-201° C. Found: C, 58.20; H, 5.70; N, 23.06. C12H14N4O2 requires: C, 58.52; H, 5.73; N, 22.75%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15]([F:37])[N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1>>[F:37][C:15]1[N:16]([C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:17]=[C:13]([CH2:12][CH2:11][NH:10][C:7]([C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[O:9])[N:14]=1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: Cc1cc(C(=O)O)no1
Product: Cc1cc(C(=O)NCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)n2)no1

Procedure:
5-Methylisoxazole-3-carboxylic acid and 4-(2-aminoethyl)-2-fluoro-1-triphenylmethylimidazole were reacted by the mixed anhydride procedure described for the starting material of Example 24, to give 2-fluoro-4-[2-(5-methylisoxazole-3-carboxamido)ethyl]-1-triphenylmethylimidazole. It had the following n.m.r. spectrum in d6DMSO: 2.5 (s, 3H); 2.7 (t, 2H); 3.7 (q, 2H); 6.3 (s, 1H); 6.4 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: [Na+:1].[C:2](/[C:6](=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH2:7][S:8]([O-:11])(=[O:10])=[O:9])([O:4][CH3:5])=[O:3].[H][H]>[Ni].CO.O>[Na+:1].[C:2]([CH:6]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][S:8]([O-:11])(=[O:10])=[O:9])([O:4][CH3:5])=[O:3]
Reactant: [H][H]
Reactant: COC(=O)/C(=C/c1ccccc1)CS(=O)(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)[O-]
Reaction time: 24 h
Yield: 88 %

Procedure:
To the 8 L of 1:1 methanol/water mixture containing the resultant compound from Example 1C was added 60 g of W-24 raney nickel. The resulting suspension was pressurized under 50 psi of hydrogen and was allowed to shake on a Parr shaker for 24 h, at which time an additional 20 g of raney nickel catalyst was added. After 6 h under 50 psi of hydrogen, the catalyst was removed by filtration and the solution was concentrated to dryness. To the dry white solid was added ethyl acetate (6 L) and heptane (4 L) and the solution was vigorously stirred with a mechanical stirrer overnight. The white suspension was removed by filtration yielding 530 g (88%) of the desired product as an amorphous powder that was contaminated with approximately one equivalent of NaBr. The compound was used without any additional purification: IR (KBr) 1740, 1215, 1050 cm-1. 1H NMR (DMSO D-6) δ 2.48-2.54 (m, 1H), 2.74-2.87 (m, 2H), 2.91-3.04 (m, 2H), 3.48 (s, 3H), 7.12-7.32 (m, 5H); 13C NMR (75 MHz, D2O/DMSO D-6) δ 38.18, 44.80, 52.67, 52.82, 127.42, 129.13, 129.34, 138.14, 176.84.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:2]=1.[CH3:16]I>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH3:16])[CH:2]=1
Reactant: N#Cc1ccc(Cc2cccnc2)cc1
Reactant: CI
Product: CC(c1ccc(C#N)cc1)c1cccnc1

Procedure:
Using methodology described e.g. in example 34, 4-(3-pyridylmethyl)-benzonitrile is reacted with methyl iodide to obtain 4-[1-(3-pyridyl)-ethyl]-benzonitrile.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:38])(=[O:37])[NH2:36])=[CH:25][CH:24]=2)[C:8](=[O:21])[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:10]=1.[C:39](O)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:39]([NH:36][S:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:7]2[C:6]([CH2:5][CH:3]3[CH2:4][CH:2]3[CH3:1])=[N:10][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:18])([F:20])[F:19])[C:8]2=[O:21])=[CH:28][CH:27]=1)(=[O:38])=[O:37])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC1CC1Cc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1
Product: CC1CC1Cc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from 2,4-dihydro-5-[(2-methylcyclopropyl)methyl]-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step G) and benzoic acid according to the procedure of Example 43. The crude material was purified by flash chromatography over silica gel (gradient elution using 0.5-5.0% MeOH/CH2Cl2) to give a 64% of the desired material as a white solid, homogeneous by TLC (5% MeOH/CH2Cl2); mass spectrum (FAB) m/e 647 (M+1)+ ; mp 123°-125° C.
Reaction SMILES: [O:1]1[C:6]2[CH2:5][O:4][CH2:3][C:2]1=2.[C:7]1([C@H:13]([NH2:15])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Al](C)C>>[C:7]1([CH:13]([NH:15][CH:6]2[CH2:5][O:4][CH2:3][CH:2]2[OH:1])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1OCC2=C1O2
Reactant: C[C@@H](N)c1ccccc1
Agent: C[Al](C)C
Product: CC(NC1COCC1O)c1ccccc1

Procedure:
According to the procedure of Overman, et al. (J. Org. Chem. 1985, 50, 4154), 3,4-epoxy-2,5-dihydrofuran was treated with (R)-1-phenylethylamine and trimethylaluminum to give a 1:1 mixture of diastereomers. The mixture was purified by silica gel chromatography to provide the desired compound.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.ClC1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][C:11]1[O:12][C:13]([C:15]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[CH:14][C:10]=1[CH2:9][OH:8]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1oc(-c2ccc(C(F)(F)F)cn2)cc1CO
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 2-chloro-5-trifluoromethylpyridine (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, purified by silica gel chromatography (10% ethyl acetate/hexane to 100% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.1 g, 62%) as a yellow crystal.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[C:13](=O)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+]>>[Cl:3][C:13]1[C:14]2[C:9](=[CH:8][C:7]([NH2:6])=[C:16]([Cl:17])[CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: Nc1cc2cc[nH]c(=O)c2cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2ccnc(Cl)c2cc1Cl
Temperature: 100 °C
Yield: 54.8 %

Procedure:
To 20.0 mL (215 mmol) of phosphorous oxychloride, cooled to 0 C, was added 5.00 g (25.7 mmol) of 6-amino-7-chloro-2H-isoquinolin-1-one in portions. The mixture was heated to 100° C. for 3 h then cooled to room temperature and poured over ice. After all of the ice had melted the pH of the mixture was adjusted to slightly alkaline by the slow addition of a 10% aqueous NaOH solution. A yellow solid precipitated from solution and was collected by filtration, washed with water and dried over anhydrous Na2SO4 to provide 3.0 g (55%) of 1,7-dichloro-isoquinolin-6-ylamine. MS calc. for C9H7Cl2N2 [M+H]+: 214.08. Found: 213.23 and 215.23.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH2:11][OH:12].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:15]=1.[H-].[Na+]>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:12][CH2:11][C@H:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[O:1]2)[N:17]=[C:16]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:15]=1
Reactant: OC[C@H]1COC2(CCCCC2)O1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(CSc2nc(Cl)cc(OC[C@H]3COC4(CCCCC4)O3)n2)c1F

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using (2S)-1,4-dioxaspiro[4.5]decane-2-methanol (0.46 g) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (ii) (0.75 g) in THF (8 mL) and 60% sodium hydride (39 mg) to give the subtitle compound as a pale yellow solid. Yield: 0.70 g.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27].[F:29][C:30]([F:44])([F:43])[C:31]([F:42])([F:41])[C:32]([F:40])([F:39])[C:33]([F:38])([F:37])[CH:34](I)[CH3:35]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:35][CH2:34][C:33]([F:38])([F:37])[C:32]([F:40])([F:39])[C:31]([F:42])([F:41])[C:30]([F:44])([F:43])[F:29]
Reactant: CC(I)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Solvent: CN1CCCC1=O
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C

Procedure:
276 mg of 11β-fluoro-3-hydroxy-7α-(5-(methyl-amino)-pentyl)-estra-1,3,5(10)-trien-17-one is dissolved in 3 ml of N-methylpyrrolidone, mixed with 0.6 ml of 1,1,1,2,2,3,3,4,4-nonafluor-5-iodo-hexane and heated for 1.5 hours at a bath temperature of 80° C. For working-up, the reaction mixture is cooled to room temperature, stirred into saturated common salt solution, extracted with ethyl acetate, the organic phases are washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Preparative column chromatography on silica gel with a methylene chloride-methanol gradient provides 176 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(3,3,4,4,5,5,6,6,6-nonafluoro-hexyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[N:39]1[CH:44]=[CH:43][N:42]=[CH:41][C:40]=1[C:45](O)=[O:46]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][N:39]=2)=[O:46])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(O)c1cnccn1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)c1cnccn1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure E using pyrazine-2-carboxylic acid. The final product was obtained in 64% yield.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[CH2:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])[CH3:13]
Reactant: COP(OC)OC
Reactant: CCOC(=O)Cl
Product: CCOC(=O)P(=O)(OC)OC

Procedure:
From 10,0 ml (85 mmole) of trimethylphosphite and 10.0 ml (105 mmole) of ethyl chloroformate (100° C., 1,5 hours). Yield 12,5 g (80%). Bp15 122° C.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH3:15])([CH3:14])[S:4]1)[OH:2].[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([O:2][N:1]=[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH3:15])([CH3:14])[S:4]1)=[O:19]
Reactant: CC1(C)SC(=NO)N=C1c1ccccc1
Reactant: CN=C=O
Product: CNC(=O)ON=C1N=C(c2ccccc2)C(C)(C)S1

Procedure:
2-oxo-4-phenyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-phenyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 135°-137° C. The 2-oxo-4-phenyl-5,5-dimethyl-3-thiazoline-oxime starting material (m.p. 147°-149° C.) was prepared from 2-methyl-1-phenyl-2-thiocyanato-1-propanone (b.p. [0.02 mm] 98°-100° C.).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[C:26]4=[N:27][C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:29]([N+:32]([O-])=O)[C:30](=[O:31])[N:25]4[CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:32][C:29]1[C:30](=[O:31])[N:25]2[CH2:24][CH2:23][CH2:22][N:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][CH:12]([CH3:13])[CH2:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][NH2:1])[CH:6]=4)[N:20]=3)[C:26]2=[N:27][C:28]=1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: [H][H]
Reactant: CC(Cc1cccc(CN=[N+]=[N-])c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)c([N+](=O)[O-])c3=O)n1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(CN)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)c(N)c3=O)n1
Reaction time: 2 h

Procedure:
To a solution of 9-{2-[2-(3-azidomethyl-phenyl) -1-methyl-ethylamino]-pyrimidin-4-yl}-3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (61 mg, 0.11 mmol) in 1 mL methanol was safely added 10 mg palladium on carbon (10%) and stirred over an atmosphere of hydrogen delivered by a balloon. After 2 h, the reaction was filtered through a bed of Celite and solvent removed under reduced pressure. Product was purified on silica. M+1=483 1H NMR (CDCl3) d (3H, 1.19 ppm), m (2H, 2.20 ppm), dd (1H, 2.76 ppm), dd (1H, 2.96 ppm), s (2H, 3.84 ppm), m (6H, 4.08 ppm), q (1H, 4.30 ppm), d (1H, 4.95 ppm), m (4H, 7.13 ppm), t (1H, 7.28 ppm), t (1H, 7.36 ppm), t (2H, 7.45 ppm), d (2H, 7.80 ppm), d (1H), 8.03 ppm).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].[CH3:22][S:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C1COCC1>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([S:23][CH3:22])=[CH:25][CH:26]=2)[N:20]=1
Reactant: CSc1ccc(N)cc1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A 1 M THF solution of LiHMDS (6.06 mL, 6.06 mmol) was added dropwise to a mixture of 2,6-dichloronicotinamide (331 mg, 1.733 mmol) and 4-(methylthio)aniline (289 mg, 2.079 mmol) in THF (20 mL) at 0° C. The resulting brown solution was stirred at 0° C. for 5 min, at room temperature for 30 min, quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3×25 mL). The combined extracts were washed with brine (5 mL), dried (MgSO4), and concentrated. Silica gel chromatography, eluting with 30-70% EtOAc in hexanes, gave the desired product as tan solid (376 mg, 74% yield). LCMS: (M+H)+=293.9. 1H NMR (400 MHz, chloroform-d) δ ppm 10.74 (1H, s), 7.54-7.73 (3H, m), 7.20-7.36 (2H, m), 6.68 (1H, d, J=8.03 Hz), 5.84 (2H, br. s.), 2.48 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][N:24]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: [Li+]
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and racemic pyrrolidin-3-yl-carbamic acid tert butyl ester by a method analogous to Example 1B. MS: 382/384 (MH+); HPLC Rf: 5.21 min.; HPLC purity 99%.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:28])[C:4]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13](C)[C:14](=O)OC(C)(C)C)[CH2:6][CH2:5]1.CO.C(Cl)(Cl)[Cl:32]>C(Cl)(Cl)Cl>[ClH:32].[CH3:28][N:3]([CH3:2])[C:4]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][NH:13][CH3:14])[CH2:6][CH2:5]1
Reactant: CN(CCCN1CCC(c2ccccc2)(N(C)C)CC1)C(=O)OC(C)(C)C
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CO
Product: CNCCCN1CCC(c2ccccc2)(N(C)C)CC1

Procedure:
HCl gas was passed through a solution of 9 g (1 eq) tert-butyl 3-(4-(dimethylamino)-4-phenylpiperidin-1-yl)propyl(methyl)carbamate in 100 ml chloroform at 0° C. for 1 h. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure and after trituration with diethyl ether 10 g (100%) of product were obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:10][S:11]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)(=[O:13])=[O:12]
Reactant: N#Cc1ccc(N)cn1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C#N)nc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 77 %

Procedure:
5-Amino-2-cyanopyridine (5 g) was dissolved in pyridine (30 ml). The solution was cooled to 0° C. and to the solution was added dropwise methanesulfonyl chloride (3.6 ml), followed by stirring at room temperature for 17 hours. The resulting mixture was concentrated under reduced pressure, extracted with water and dichloromethane, and then dried. The obtained residue was purified by column-chromatography (hexane/ethyl acetate=2/1) to yield an orange colored solid (6.4 g, 77%).