Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=O.C(Cl)(=O)OCC>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]1[O:16][C:8](=[O:17])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)CCCCl
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1oc(CCCCl)nc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Triethylamine (7.60 ml) was added to a suspension of anthranilic acid (3.52 g) in methylene chloride (35 ml) and then the mixture was cooled with ice. The mixture, with 4-chlorobutyryl chloride (3.62 g) dropwise added thereto, was stirred for 3 hours at room temperature and then cooled with ice. The reaction mixture, with triethylamine (4.00 ml) and ethyl chlorocarbonate (2.70 ml) dropwise added thereto, was stirred for 1 hour at 0° C. and further for 3 hours at room temperature. The reaction mixture, with chloroform added thereto, was washed with water and saturated brine successively. The organic layer was dried over sodium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 125 g, chloroform-hexane), thereby yielding 4.00 g of the aimed compound as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](C#N)=[CH:4][N:3]=1.[CH:11]([OH:13])=O.[H][H]>[Ni].O>[NH2:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([NH2:8])[C:7]=1[CH:11]=[O:13]
Reactant: [H][H]
Reactant: N#Cc1cnc(N)cc1N
Reactant: O=CO
Agent: [Ni]
Solvent: O
Product: Nc1ccnc(N)c1C=O

Procedure:
A suspension of 13.4 g of 2,4-diamino-5-cyanopyridine from Example 14, 2 g of Raney nickel catalyst, 40 mL of 97-100% formic acid, and 80 mL of water were shaken in a Parr apparatus under an atmosphere of nitrogen until the requisite amount of hydrogen was consumed. The solvents were removed under reduced pressure and the residue treated with 17 mL of concentrate HCl. The resulting pink solid was slurried in a small amount of water, filtered, washed with isopropyl alcohol, followed by diethylether, and dried. Crystallization from ethanol afforded 6.5 g of the title compound 2,4-diaminonicotinaldehyde.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:34])=[C:15]([CH3:33])[C:16]=1[C:17]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28]C)=[C:21]([CH:30]([CH3:32])[CH3:31])[CH:20]=1)=[O:18].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:34])=[C:15]([CH3:33])[C:16]=1[C:17]([C:19]1[CH:20]=[C:21]([CH:30]([CH3:31])[CH3:32])[C:22]([OH:28])=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=1)=[O:18]
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc4ccccc4c3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Yield: 53.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (1.04 g, 2.29 mmol) and 1M boron tribromide/CH2Cl2 (4.81 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 0.542 g (54%) of the title compound. 1H NMR (DMSO-d6) δ 1.12 (d, 12 H), 1.82 (s, 3 H), 2.18 (s, 3 H), 3.31 (septet, 2 H), 4.02 (s, 2 H), 7.22 (dd, 1 H), 7.43-7.50 (m, 4 H), 7.55 (s, 1 H), 7.76-7.86 (m, 3 H), 9.12 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1O)[CH:5]=O.[ClH:14].[NH2:15]O.CC1C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Cl:14][C:9]1[C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]([C:5]#[N:15])=[CH:3][C:2]=1[OH:1]
Reactant: Cl
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: N#Cc1cc(O)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (5 g, 27.3 mmol), hydroxylamine hydrochloride (2.467 g, 35.5 mmol), tosic acid (0.779 g, 4.10 mmol) and magnesium sulfate (26.3 g, 218 mmol) in toluene (25 ml) was heated at reflux for 6 hours. The reaction mixture was cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The layers were separated and aqueous layer was extracted with ethyl acetate two more times. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to a small volume and a brown precipitate formed. the precipitate was collected by filtration and after drying under vacuum to give 4.1 g of 4-chloro-3-hydroxy-5-nitrobenzonitrile.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:41]([Si:45]([CH3:48])([CH3:47])Cl)([CH3:44])([CH3:43])[CH3:42].N1C=CN=C1>C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:32]=1)[C@@H:10]([O:25][Si:45]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:48])[CH3:47])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g (4.54 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxy-phenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid in 42 ml of DMP are silylated, under a protective gas, with 3.15 g (20.9 mmol) of tert-butyldimethylchlorosilane and 2.53 g (37.3 mmol) of imidazole at RT for 20 h. The reaction mixture is diluted with ethyl acetate, and this mixture is washed with sat. NaHCO3 solution, water and saline. The aqueous phases are extracted 2× with ethyl acetate, and the organic phases are dried with Na2SO4 and evaporated. The residue is dissolved in 50 ml of methanol and 13 ml of THF, and this solution is treated with 3.8 g of potassium carbonate and 13 ml of water, and stirred at RT for 1 h. Subsequently, the reaction mixture is partially evaporated and the residue is diluted with ice-cold 10% citric acid solution; this mixture is then extracted 3× with ethyl acetate. The organic phases are washed with 2 portions of water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 2:1) results in the pure title compound: TLC Rf (C)=0.13; tRet (II)=21.7 min. 7d) 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.O>CS(C)=O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][N:10]1[C:9]2[C:8](=[O:20])[N:7]([CH3:21])[C:6](=[O:22])[N:5]([CH3:23])[C:4]=2[N:3]=[C:2]1[N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1c(=O)c2c(nc(Br)n2Cc2c(F)cccc2Cl)n(C)c1=O
Reactant: C1CCNC1
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)c2c(nc(N3CCCC3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
A solution of 8-bromo-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (50 mg, 0.12 mmol) in 300 μL DMSO was treated with pyrrolidine (55 μL, 0.55 mmol) and heated at 130° C. for 15 h. The reaction was cooled to 25° C. and treated with 1 mL H2O. After centrifugation for 1 h the liquid was decanted, and the process was repeated. The reaction was treated with 1 mL toluene and concentrated under reduced pressure. The residue was treated with 2 mL CH2Cl2 followed by isocyanate scavenger resin (500 mg, 0.58 mmol, 1.16 mmol/g). The reaction was filtered after agitating for 30 min, and the filtrate was concentrated under reduced pressure to give 48 mg (>99% yield) of the title compound: 1H NMR (CDCl3, 300 MHz) 7.27-7.18 (m, 2H), 7.02-6.91 (m, 1H), 5.73 (s, 2H), 3.59-3.48 (m, 7H), 3.35 (s, 3H), 1.98-1.87 (m, 4H); MS (ESP+) m/e 392 (MH+); TLC (EtOAc:hexanes/1:1) Rf=0.24.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[H][H].C(N(CC)CC)C>O1CCCC1>[O:12]=[S:9]1(=[O:11])[C:8]([CH3:13])=[CH:7][C:6]2[CH:14]=[CH:2][CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[C:5]=2[O:10]1
Reactant: [H][H]
Reactant: CC1=Cc2cc(Br)cc(S(N)(=O)=O)c2OS1(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Temperature: 0 °C
Yield: 75.1 %

Procedure:
120 g of 6-bromo-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide are dissolved in 2.4 liters of tetrahydrofuran and the solution is hydrogenated with hydrogen for 40 minutes, in the presence of 41.3 g of triethylamine and 12.0 g of 5% on carbon catalyst, under normal pressure and in the temperature range from 20° to 25° C. The mixture is filtered, the filtrate is concentrated, and the residue is taken up in 1300 ml of hot 90% aqueous ethanol. The insoluble constituents are separated and the solution is cooled to 0° C. The precipitate is separated and dried, affording 70 g of 2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide of m.p. 204°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2([C:13]([CH3:16])([CH3:15])[CH3:14])C[O:11]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([OH:11])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C1(C=Cc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Solvent: CCO
Product: CC(C)(C)C(O)(C=Cc1ccc(Cl)cc1)n1cncn1
Yield: 80.9 %

Procedure:
A solution of 17.75 g (0.075 mol) of 2-(4-chlorophenyl-ethenyl)-2-tert.-butyl-oxirane and 6.9 g (0.1 mol) of 1,2,4-triazole in 30 ml of ethanol was heated in a bomb tube at 150° C. for 20 hours. The reaction mixture was thereafter concentrated, and the crystalline residue was stirred with ether. The solid material was then filtered off under suction and was recrystallized from acetonitrile. 17.7 g (77% of theory) of 1-(4-chloro-phenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl)-1-penten-3-ol of melting point 139°-141° C. were obtained.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])[CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[Pd]>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:13]=4)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl (E)-3-(1-cyclohexyl-4-oxo-4,5-dihydroimidazo-[1,5-a]quinoxalin-8-yl)acrylate as synthesized in Example 154, 2.0 g was dissolved in 100 mL of acetic acid, and to the solution 10% Pd/C 200 mg was added in nitrogen atmosphere. After substituting the atmosphere with hydrogen, the reaction liquid was stirred at 25° C. for 2 days. The reaction liquid was filtered through Celite and from the filtrate the solvent was distilled off to provide 1.48 g of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1.[H][H].[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:21][C:20]=1[C:30]1C=C(S(OCC)(=O)=O)C=C[C:31]=1C.[OH-].[Na+]>CCCCCC.CN(C)C=O.C(OCC)(=O)C>[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:21][C:20]=1[CH2:30][CH2:31][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: [H][H]
Reactant: CCOS(=O)(=O)c1ccc(C)c(-c2nc(-c3ccccc3)oc2C)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.4 %

Procedure:
Sodium hydride (60% in oil, 2.11 g, 88.1 mmol) was washed twice with n-hexane (10 ml) under a nitrogen atmosphere, suspended in N,N-dimethylformamide (50 ml) and ice-cooled. To this solution was added methyl 3-(p-hydroxyphenyl)propionate (15.9 g, 88.1 mol) over 15 min. After 10 min when hydrogen bubbling finished, a solution of ethyl 2-(5-methyl-2-phenyl-4-oxazolyl)-p-toluenesulfonate (20.0 g, 56.0 mmol) in N,N-dimethylformamide (50 ml) was added. The mixture was stirred at room temperature for 5 hr, and ethyl aceate (500 ml) and 1N aqueous sodium hydroxide solution (200 ml) were added for partition. The obtained organic layer was washed with 1N hydrochloric acid (100 ml), saturated aqueous sodium hydrogencarbonate solution (100 ml) and saturated brine (100 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=85:15) to give the title compound (14.0 g, yield 68%) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)CCC>[Br:12][C:8]1[C:7](=[O:13])[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cn1cccc(Br)c1=O
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNC(=O)Cn1cccc(Br)c1=O
Yield: 62 %

Procedure:
As described for example 112a, (3-bromo-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at reflux for 16 h. The precipitate was filtered and triturated with hot methanol to afford the title compound as an off-white solid (yield: 62%). MS: m/e=244.2/246.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncccn4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncccn4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.77 g) was dissolved in methylene chloride (23.1 ml), and a solution of m-chloroperbenzoic acid (0.31 g) in methylene chloride (15.4 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 261) (485 mg).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C=O)C.C(O)(C(F)(F)F)=O.[Mn]>[CH3:11][S:8]([NH:7][CH2:6][C:5]1[CH:12]=[CH:13][C:2]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CCOC(=O)C(C)Cl
Reactant: CS(=O)(=O)NCc1ccc(Br)cc1
Agent: [Mn]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To a stirred solution of N-(4-bromobenzyl)methanesulfonamide (675 mg, 2.555 mmol) in DMF were added ethyl 2-chloropropionate (0.42 mL), manganese (280 mg) and (2,2′-bipyridine)nickel(II)-dibromide (NiBr2bipy) (67 mg, 0.17885 mmol). TFA (1-2 drops) was added. The reaction mixture was stirred for 36 h at 60° C. After cooling down to room temperature, the mixture was hydrolyzed by 1N HCl and extracted with diethyl ether. The organic layer was dried (MgSO4) and filtered. The solvent was removed in vacuo. The crude product was purified by CC. Ethyl 2-(4-(methylsulfonamidomethyl)phenyl)propanoate (325 mg) was obtained.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:16])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:17][CH:18]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[CH3:7][C:8]([NH:16][C:19](=[O:20])[CH:18]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])[Br:17])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CCC(C)(C)C(Br)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(C)(C)C(Br)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), α,α-dimethylbenzylamine (9 g) and triethylamine (7.4 g), and α-bromo-tert-amylacetyl chloride (15.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 15.8 g of N-(α,α-dimethylbenzyl)-α-bromo-tert-amylacetamide. M.P., 136°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.S(=O)(=O)(O)[OH:12].[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:4](=[O:12])[C:3]1[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]=1[Cl:1])[CH3:17]
Reactant: CCO
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(O)cc1Cl
Yield: 38 %

Procedure:
A solution of 2-chloro-4-hydroxy-benzonitrile (5.0 g, 32.6 mmol) in ethanol (125 ml) was treated with conc. sulphuric acid (25 ml) and the mixture heated at reflux for 3 days. Conc. sulphuric acid (25 ml) was added and the mixture was heated at reflux for another 2 days. The volatiles were removed in vacuo, and the aqueous residue was basified with saturated NaHCO3 and extracted 4 times with diethyl ether. The combined organic extracts were dried and concentrated in vacuo to yield the title compound (2.5 g, 38%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][CH:11]([S:14][C@@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[CH:17]([C:18](=O)[CH2:19][C@@H:20]4[C@@H:29]3[CH2:28][CH2:27][C@@:25]3([CH3:26])[C@H:21]4[CH2:22][CH2:23][C:24]3=[O:34])[CH2:16]2)[CH2:10]1.Cl.[NH2:37][OH:38]>>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][CH:11]([S:14][C@@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[CH:17](/[C:18](=[N:37]/[OH:38])/[CH2:19][C@@H:20]4[C@@H:29]3[CH2:28][CH2:27][C@@:25]3([CH3:26])[C@H:21]4[CH2:22][CH2:23][C:24]3=[O:34])[CH2:16]2)[CH2:10]1
Reactant: NO
Reactant: C[C@]12CC[C@@H](SC3CCNC3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: C[C@]12CC[C@@H](SC3CCNC3)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
The title compound was prepared following the procedure described in Example 1 and starting from 3α-[3-(RS)-pyrrolidinylthio]androstane-6,17-dione fumarate (I-dc, Example 81, 115 mg) and hydroxylamine hydrochloride (20 mg). The crude product was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3 9/1/0.1). To the concentrated fractions the stoichiometric amount of fumaric acid in MeOH was added. After addition of EtOAc, the precipitate was filtered to give the title compound I-dd as a white solid in 65% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.72 (1H, bs), 6.42 (1H, m), 4.69 (1H, m), 3.57 (1H, m), 3.30-3.10 (6H, m), 2.40-0.95 (20H, m), 0.76 (3H, s), 0.63 (3H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)(=[O:10])=[O:9].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Cl:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:24]1[N:29]=[C:28]([NH:2][C:3]2[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=2)[CH2:6][NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)(=[O:9])=[O:10])[C:27]([Cl:31])=[CH:26][N:25]=1
Reactant: Nc1cccc(CNS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of N-(3-aminobenzyl)-3-nitrobenzenesulfonamide hydrochloride (0.400 g, 1.16 mmol) and 2,4,5-trichloropyrimidine (0.12 mL, 1.06 mmol) in DMF (2.8 mL) was added potassium carbonate (0.51 g, 3.7 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated (sat'd) NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give 660 mg of crude residue, which was purified by Combi-Flash column chromatography (12 g column, 0 to 30% EtOAc in hexane) to give the desired product (135 mg, 28%). LCMS for C17H13Cl2N5O4S (M+H)+: m/z=453.9, 455.9, 457.9. 1H NMR (400 MHz, CD3OD): δ 8.85 (s, 1H), 8.48 (t, J=2.0 Hz, 1H), 8.29 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.21 (s, 1H), 8.08 (ddd, J=8.0, 1.6, 0.8 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.41 (m, 2H), 7.17 (t, J=8.0 Hz, 1H), 4.21 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:11]=[CH:12][C:3]=12
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C=O)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 2.78 mmol) in THF (9 mL) was added NaH (136 mg, 3.42 mmol) at 0° C. After 10 minutes, SEMCl (0.59 mL. 3.33 mmol) was added slowly to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 20% Ethyl acetate/Hexane) as a solvent to afford title compound (810 mg, 94% yield). 1H NMR (600 MHz, CDCl3) δ 10.62 (s, 1H), 8.90 (s, 1H), 7.52 (d, J=3.6 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 5.76 (s, 2H), 3.60 (t, J=8.4 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H).