Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C(N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCS(=O)(=O)C2)C=NC=1C#N.[OH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[NH2:34][C@H:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][C@H:36]1[NH:43][C:44]1[CH:45]=[C:46]([NH:53][C:54]2[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[C:56]([CH3:62])[N:55]=2)[C:47]([C:50]([NH2:52])=[O:51])=[N:48][CH:49]=1>>[OH:29][C:28]([C:30]([F:33])([F:32])[F:31])=[O:27].[NH2:34][C@@H:35]1[CH2:40][CH2:39][S:38](=[O:41])(=[O:42])[CH2:37][C@@H:36]1[NH:43][C:44]1[CH:45]=[C:46]([NH:53][C:54]2[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[C:56]([CH3:62])[N:55]=2)[C:47]([C:50]([NH2:52])=[O:51])=[N:48][CH:49]=1
Reactant: COc1cc(C)nc(Nc2cc(N[C@@H]3CS(=O)(=O)CC[C@@H]3N)cnc2C(N)=O)c1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCS(=O)(=O)C[C@@H]1Nc1cnc(C#N)c(Br)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)nc(Nc2cc(N[C@H]3CS(=O)(=O)CC[C@H]3N)cnc2C(N)=O)c1

Procedure:
rel-5-{[(3R,4R)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl]amino}-[(4-methoxy-6-methylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt (Enantiomer 2) was prepared from tert-butyl rel-{(3R,4R)-3-[(5-bromo-6-cyanopyridin-3-yl)amino]-1,1-dioxidotetrahydro-2H-thiopyran-4-yl}carbamate (Enantiomer 2, from Step 2 of Example 20) using chemistry analogous to that described for the synthesis of rel-5-{[(3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl]amino}-3-[(4-methoxy-6-methylpyridin-2-yl)amino]pyridine-2-carboxamide (Example 20, Enantiomer 1). MS ESI calc'd. for C18H25N6O4S [M+H]+ 421. found 421. 1H NMR (500 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.26-8.14 (m, 3H), 8.01 (s, 1H), 7.72 (s, 1H), 7.55-7.45 (br s, 1H), 6.74-6.20 (br s, 2H), 6.65 (s, 1H), 4.26 (s, 1H), 3.86-3.76 (m, 4H), 3.55-3.42 (m, 2H), 3.38-3.26 (m, 2H), 2.46-2.34 (m, 4), 2.30-2.21 (m, 1H).
Reaction SMILES: [C:1](=[O:48])([O:17][C:18]1[C:19]([CH3:47])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C:23]([CH3:46])([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:22][CH2:21]2)[O:2][CH2:3][C:4]1([CH3:16])[O:15][CH:5]1[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:49]1CCCC1.Cl(O)(=O)(=O)=O>O>[C:1](=[O:48])([O:17][C:18]1[C:19]([CH3:47])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C:23]([CH3:46])([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:42])[CH3:43])[CH2:22][CH2:21]2)[O:2][CH2:3][C:4]([OH:49])([CH3:16])[CH:5]([OH:15])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCC1(C)OC1COCc1ccccc1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: C1CCOC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC(C)(O)C(O)COCc1ccccc1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2

Procedure:
8.6 g (0.013 mol) of 4-benzyloxy-2,3-epoxy-2-methylbutyl 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanyl carbonate, 150 ml of tetrahydrofuran and 30 ml of water were mixed together. To the obtained mixture was slowly added dropwise a solution of 7 ml of 60% perchloric acid in 20 ml of water under ice-cooling and stirring. After the completion of the addition, the mixture was further stirred at the same temperature for 4 hours and then poured into water. After confirming that no peroxide remained therein with potassium iodide starch paper, the mixture was extracted with ether. The extract was washed with water and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, benzene:ethyl acetate=8:2). Thus 4.8 g of the title compound was obtained as a pale yellow, viscous liquid.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:22]([N:24]2[CH2:41][CH2:40][CH2:39][C@H:25]2[C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[O:27])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])=[CH:10][CH:9]=1)=[O:7])([OH:3])=O.Cl.[CH3:43][NH:44][CH3:45]>>[CH3:43][N:44]([CH3:45])[C:1]([CH2:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:22]([N:24]2[CH2:41][CH2:40][CH2:39][C@H:25]2[C:26]([NH:28][CH:29]([CH:36]([CH3:37])[CH3:38])[C:30](=[O:35])[C:31]([F:34])([F:32])[F:33])=[O:27])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])=[CH:12][CH:13]=1)=[O:7])=[O:3]
Reactant: CNC
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)Nc1ccc(C(=O)NCC(=O)O)cc1)C(C)C)C(=O)C(F)(F)F
Agent: Cl
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)Nc1ccc(C(=O)NCC(=O)N(C)C)cc1)C(C)C)C(=O)C(F)(F)F
Yield: 35.8 %

Procedure:
3(RS)-[[4-(Dimethylaminocarbonylmethylaminocarbonyl)phenylaminocarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-2-oxo-4-methylpentane (0.03 g) was prepared from 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylaminocarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-2-oxo-4-methylpentane (0.08 g) and dimethylamine hydrochloride (0.012 g) by a similar method to that of Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH:26]=[C:25]([C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[N:24]=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:18]3[CH:26]=[C:25]([C:27]4[O:28][C:29]([CH3:32])=[N:30][N:31]=4)[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nnc(-c2cc3c(Cl)ncnc3cn2)o1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: Cc1nnc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1

Procedure:
The title compound was prepared according to Procedure A from 4-benzyloxyaniline and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.33 (1H,s), 9.49 (1H,s), 9.39 (1H,s), 8.93 (1H,s), 7.80 (2H,d), 7.53 (2H,dd), 7.45 (3H,m), 7.20 (2H,d), 5.25 (2H,s), 2.75 (3H,s); m/z (M+1+) 411.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][C:21]1[O:25][C:24]([CH2:26][NH2:27])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[O:25][C:24]([CH2:26][NH:27][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:23][CH:22]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: Cc1ccc(CN)o1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccc(C)o3)s2)c(C)[nH]c1=O
Yield: 93 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (5-methylfuran-2-yl)methylamine as described in Step 5, Example 24 to give the title compound as a solid (93% yield). LC/MS: RT 2.90 min; m/e 393 (M+H); 1H NMR (δ, ppm): 11.75 (1H, br s), 8.32 (1H, br s), 7.48 (1H, d), 729 (1H, s); 7.10 (1H, d); 6.07 (1H, d), 5.92 (1H, d), 4.05 (2H, s), 2.41 (2H, q), 2.30 (3H, s), 2.15 (3H, s), 1.10 (3H, t).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:45])[CH:6]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][N:20]([C:22]([C:24]3[O:25][C:26]4[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=4[C:28]=3[CH2:29][CH2:30][CH2:31][CH3:32])=[O:23])[CH3:21])[CH:15]=2)[C:10]=1[Br:37].O.Cl>CO>[CH2:38]([CH:6]([CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][N:20]([C:22]([C:24]3[O:25][C:26]4[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=4[C:28]=3[CH2:29][CH2:30][CH2:31][CH3:32])=[O:23])[CH3:21])[CH:15]=2)[C:10]=1[Br:37])[C:5]([OH:45])=[O:4])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC(Cc4ccccc4)C(=O)OC)ccc3c2)oc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC(Cc4ccccc4)C(=O)O)ccc3c2)oc2ccccc12
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of 1 N NaOH (2.5 mL, 2.5 mmol) and 2-benzyl-3-(1-bromo-6-{[(3-butyl-benzofuran-2-carbonyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)-propionic acid methyl ester (769 mg, 1.22 mmol), prepared in the previous step, in 30 mL of methanol plus 2 mL of water was stirred under nitrogen at room temperature for 6 h. By TLC starting material remained. An additional 2.5 mL (2.5 mmol) of 1 N NaOH was added and the stirring continued at room temperature overnight. 1 N HCl (5.1 mL, 5.1 mmol) was added and the reaction concentrated under reduced pressure to remove the methanol. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (318 mg, 42%) as a white solid, mp 64-68° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH:20]([CH3:22])[CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23]([NH2:25])[CH3:24]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:25][CH2:23][CH3:24])[N:15]=[C:14]([NH:19][CH:20]([CH3:22])[CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)Nc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NC(C)C)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 42.9 %

Procedure:
0.1 g (0.000293 mol) of 4-amino-N-(6-chloro-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol, treated with 1.93 ml (0.0293 mol) of ethylamine and stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 min. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.044 g (43%) of 4-amino-N-(6-ethylamino-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 266-267° C.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[N:4]=1.[CH2:11]([OH:13])[CH3:12]>>[NH2:10][C:5]1[N:4]=[C:3]([O:13][CH2:11][CH3:12])[CH:8]=[C:7]([NH2:9])[N:6]=1
Reactant: CCO
Reactant: Nc1cc(Cl)nc(N)n1
Agent: [Na]
Product: CCOc1cc(N)nc(N)n1
Temperature: 160 °C
Yield: 72 %

Procedure:
To a solution of sodium (1.05 g) in ethanol (50 ml) was added 4-chloro-2,6-diaminopyrimidine (6 g, 41.4 mmoles). The resulting solution was heated in a reactor for 6 hours at 160° C. The reaction mixture was cooled down and the precipitated sodium chloride was filtered off. The filtrate was concentrated and precipitated from ethanol (two times), affording the pure title compound as a white solid (4.53 g, 72% yield). The spectral data are identical to those described e.g. by W. Pfleiderer et al. in Chem. Ber. (1961) 94, 12.
Reaction SMILES: [F:1][C:2]([F:23])([C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](OC)=[O:4].[NH3:24].[NH4+]>O1CCCC1>[F:1][C:2]([F:23])([C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([NH2:24])=[O:4]
Reactant: N
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 45 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A 3-1, four-necked, round-bottomed flask equipped with stirrer, thermometer, reflux condenser with bubble counter and inlet gas-tube, is charged with 658 g (1.74 mol) of methyl perfluoroheptanoate and 1.5 l tetrahydrofurane. A stream of ammonia is passed from a pressure tank into the stirring solution. The ammonia feed rate is such that a negligible amount of gas is observed exiting the reactor as observed in the bubble counter. Temperature of the mixture increases to 40-50° C. Ammonium supply is continued until the temperature begins to decrease and an increasing volume of gas is observed exiting the reactor in the bubble counter. After ending the ammonia supply, the mixture is left to stand for 12 hr. Solvent is removed under reduced pressure, yielding 626 g p perfluoroheptanoic acid amide (99%), mp 127-128° C.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH3:20])([CH3:19])[S:17](=[O:18])[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1OC1C.ClN1C(=O)C2=CC=CC=C2C1=O>C1(C)C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:19])[CH2:20][S:17](=[O:18])[C@H:13]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Agent: CC1CO1
Agent: O=C1c2ccccc2C(=O)N1Cl
Solvent: Cc1ccccc1
Product: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 61 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
To a thirty gallon stainless steel still were added 76 liters of toluene. The toluene was dried by distillative removal of about 19 liters of material. An additional 14 liters of toluene were removed leaving about 43 liters in the still. The toluene, under nitrogen, then was cooled to about 70° C., and 1.75 kg. of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide were added. Heat was added, and, when the temperature of the mixture reached about 85° C., 1,400 ml. of propylene oxide were added. Heating was continued, the mixture reaching 102° C. at reflux. A total of 700 grams of N-chlorophthalimide then was added in 87.5 gram portions at approximately 7 minute intervals. Prior to completion of the addition of the N-chlorophthalimide, 350 ml. of propylene oxide were added. Another 175 ml. of propylene oxide were added appproximately 1 hour after completion of N-chlorophthalimide addition. The mixture was refluxed at 100°-102° C. for 2.5 hours following the first addition of N-chlorophthalimide. The mixture, having a volume of 52.5 liters, then was cooled to about 61° C., and concentration of the mixture was begun, the volume of the material upon completion being about 38 liters. The mixture then was filtered into a 30 gallon glass-lined still containing a mixture of 875 ml. of stannic chloride and 13 liters of toluene pre-cooled to -2° C. The temperature rose to +14 C. and was cooled to0°-5° C. The mixture then was stirred overnight. The resulting red precipitate was filtered, and the solid was dissolved in a mixture of 8.75 liters of acetone and 17.5 liters of ethyl acetate. The solution was washed with 17.5 liters of water and then with 17.5 liters of brine. It was separated, concentrated to 15.5 liters, cooled to 0°-5° C., and stirred overnight. The resulting mixture then was filtered, and the collected solid was washed with 1.75 liters of ethyl acetate and dried at 45°-50° C. to obtain 389.6 grams (23.7%) of the title compound.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOCC)C.P(Cl)(Cl)(Cl)=O.[CH3:18][C@:19]12[CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH2:26][C:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][C:29](=[O:37])[CH:28]=4)[C@@H:23]1[CH2:22][CH2:21][C:20]2=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]=[C:26]1[C:27]2[C@:32]([CH3:33])([CH2:31][CH2:30][C:29](=[O:37])[CH:28]=2)[C@@H:34]2[C@H:24]([C@H:23]3[C@@:19]([CH2:36][CH2:35]2)([CH3:18])[C:20](=[O:38])[CH2:21][CH2:22]3)[CH2:25]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCOCC
Solvent: ClC(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), anhydrous chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and androst-4-ene-3,17-dione (0.78 g, 2.7 mmol) was stirred at reflux for about 7 hours, i.e. until the starting material had disappeared. The suspension was allowed to cool and under vigorous stirring a saturated sodium carbonate solution was added dropwise until the pH of the aqueous layer became alkaline. The organic layer was separated, neutralized with water washings, and dried with sodium sulfate. After concentration under reduced pressure the oily residue was purified by chromatography on silica gel using hexane/ethylacetate as eluant. Thus almost pure 6-methylenandrost-4-ene-3,17-dione was obtained in 60% yield (0.843 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCC1CC(c2ccc(Br)cc2)=NO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
[3-(4-Bromo-phenyl)-4,5-dihydro-isoxazol-5-yl]-methanol (84.3 g, 328 mmol) was added to anhydrous dichloromethane (500 ml) followed by addition of triethylamine (64.1 ml, 459.2 mmol). The solution was allowed to cool to 0° C. followed by dropwise addition of methane sulfonyl chloride (30.65 ml, 396 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (200 ml) was added. After further extraction with dichloromethane (2×200 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (110 g).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6](=[O:8])[N:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C>[C:11]([NH:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]([CH3:9])[C:4](=[O:10])[N:3]=1)(=[O:13])[CH3:12]
Reactant: CC1C(=O)N=C(N)NC1=O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC1=NC(=O)C(C)C(=O)N1

Procedure:
80 parts of 2-amino-4,6-dioxo-5-methyl-pyrimidine are treated for 8 hours under reflux in a mixture comprising 500 parts by volume of acetic acid and 108 parts by volume of acetic anhydride. 87 parts of the desired product are obtained by filtration, washing with ether and drying in vacuo.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:13][N:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:13][N:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCN1CCC2(c3cccc(OC)c3)CCCC2C1
Agent: Br
Solvent: CC(=O)O
Product: CCCCCN1CCC2(c3cccc(O)c3)CCCC2C1

Procedure:
Following the procedure set forth in Example 40, 4a-(3-methoxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine was reacted with aqueous hydrobromic acid in glacial acetic acid to afford 4a-(3-hydroxyphenyl)-2-n-pentyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine, which was then converted to the corresponding hydrogen bromide salt. M.P. 171°-173° C.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:47]([O:48]CC2C=CC=CC=2)[C@H:46]([O:56][C@@H:57]2[O:86][C@H:85]([CH2:87][O:88]CC3C=CC=CC=3)[C@@H:76]([O:77]CC3C=CC=CC=3)[C@H:67]([O:68]CC3C=CC=CC=3)[C@H:58]2[O:59]CC2C=CC=CC=2)[C@@H:45]([CH2:96][O:97]CC2C=CC=CC=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17]CC2C=CC=CC=2)[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@@H:13]1[CH2:35][O:36]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.Cl.CO>CO.[OH-].[Pd+2].[OH-].[C]>[C@@H:57]1([O:56][C@@H:46]2[C@@H:45]([CH2:96][OH:97])[O:44][C@H:10]([O:11][C@H:12]3[C@H:16]([OH:17])[CH2:15][NH:14][C@@H:13]3[CH2:35][OH:36])[C@H:9]([OH:8])[C@H:47]2[OH:48])[O:86][C@H:85]([CH2:87][OH:88])[C@@H:76]([OH:77])[C@H:67]([OH:68])[C@H:58]1[OH:59]
Reactant: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](O[C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC[C@H]1NC[C@@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.5 %

Procedure:
The compound (611 mg, 0.55 mmol) synthesized in Example 3 (3c) was dissolved in methanol (8 mL) and ethyl acetate (2 mL) and hydrochloric acid-methanol solution (2 mL) and 20% palladium hydroxide-carbon (400 mg) were added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere for 4 hours. After the celite filtration, the solvent was distilled off under reduced pressure and methanol (2 mL) and 28% ammonia water (300 μL) were added thereto, followed by stirring of the mixture at room temperature for 10 minutes. After the solvent was distilled off under reduced pressure, the residue was purified by ion exchange resin (Dowex 50w×8) column (water −1.4% ammonia water). Further, it was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound (54 mg, 42%) as colorless amorphous matter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:17]4=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]4[C@H:15]4[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]34)[CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: Clc1ccc(Br)cc1Cl
Product: Clc1ccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)cc1Cl

Procedure:
Using 3,4-dichloro-1-bromobenzene and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 39 as a powder. 1H NMR (CDCl3, 300 MHz) δ 1.82-1.87 (m, 2H), 2.48-2.55 (m, 1H), 2.57-2.64 (m, 1H), 2.81-3.13 (m, 6H), 3.18-3.25 (m, 1H), 3.42-3.47 (m, 1H), 3.57-3.64 (m, 1H), 3.72 (s, 2H), 5.55 (s, 1H), 6.61-6.68 (m, 2H), 6.74 (s, 1H), 6.89 (d, 1H, J=3 Hz), 7.19 (d, 1H, J=9 Hz). LRMS (ES)+: 406 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:16]=2)=[CH:9][C:8]=1[CH3:35])C.[OH-].[Na+].Cl>C(O)C>[CH:32]1([CH2:31][O:30][C:17]2[CH:16]=[C:15]([CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=2)[CH2:14][S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH3:35])[CH:9]=2)[CH2:34][CH2:33]1
Reactant: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (173 mg; 0.34 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 107 mg; 66%. HPLC-MS: m/z: 482.0 (M+H)+; Rt: 1.62 min.