Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]2[O:12][C:13]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=2)C(=O)C2=CC=CC=C12.NN.[C:28]([N:30]=[C:31]([S:34][CH3:35])SC)#[N:29]>>[C:28]([NH:30][C:31](=[N:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][N:17]([CH3:18])[CH3:19])=[CH:14][CH:15]=1)[S:34][CH3:35])#[N:29]
Reactant: CN(C)Cc1ccc(CSCCCN2C(=O)c3ccccc3C2=O)o1
Reactant: CSC(=NC#N)SC
Agent: NN
Product: CSC(=NCCCSCc1ccc(CN(C)C)o1)NC#N

Procedure:
When 1-phthalimido-3-[(5-dimethylaminomethyl-2-furyl)methylthio]propane is treated with hydrazine and the resultant substituted propylamine is reacted with dimethyl cyanodithioimidocarbonate there is produced N-cyano-N'-{3-[(5-dimethylaminomethyl-2-furyl)methylthio]propyl}-S-methylisothiourea, and when this is reacted with propargylamine according to the general procedure of Example 3 the title compound is produced.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][N:32]([S:38]([NH:41][C:42]1[S:43][C:44]([F:47])=[CH:45][N:46]=1)(=[O:40])=[O:39])[CH2:33]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[F:47][C:44]1[S:43][C:42]([NH:41][S:38]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][CH:36]=[CH:37][C:28]=3[C:19]3[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=3[C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)[CH2:33]2)(=[O:39])=[O:40])=[N:46][CH:45]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncc(F)s2)C3)CC1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.020 g, 0.028 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.078 g, 0.350 mmol), 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.150 g, 0.280 mmol), and potassium phosphate (0.237 g, 1.119 mmol) in 2 mL dioxane 1 mL water, was heated to 110° C. 2 hours. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with 1N citric acid. The organic layer was then concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 50 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave N-(5-fluorothiazol-2-yl)-5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.044 g, 0.080 mmol). [M+H]+=553.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 7.72 (d, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.03-7.14 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 6.58-6.64 (m, 1H), 5.92 (br. s., 1H), 4.53 (d, J=17.3 Hz, 1H), 4.19 (d, J=17.6 Hz, 1H), 3.71-3.84 (m, 2H), 3.13-3.46 (m, 4H), 2.86-2.99 (m, 1H), 2.75-2.86 (m, 1H), 2.53-2.60 (s, 3H), 1.94-2.19 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[O:16][CH3:17])[NH:8][C:4]=2[CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:10]=3[O:16][CH3:17])[NH:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2ccc(F)cc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(F)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-fluoro-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12]>C(O)C.C(O)(=O)C.[Pt]>[NH2:9][C:4]1[C:5]([Cl:8])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1c(Cl)ccc(Cl)c1O
Agent: [Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1c(Cl)ccc(Cl)c1O
Yield: 99.7 %

Procedure:
A yellow solution of 2,5-dichloro-6-nitrophenol (10.0 g, 48.0 mmol) in ethanol (200 mL) and acetic acid (13.8 mL) at 0° C. was catalytically reduced in the presence of 5% platinum on charcoal (0.15 g) under an atmosphere of hydrogen (25 psi) for 1 hour in a Parr hydrogenator. The resultant colorless solution was filtered and concentrated under reduced pressure (15 torr). The residue was then dried under high vacuum (0.02 torr) overnight to yield 8.52 g (100%) of 2-amino-3,6-dichlorophenol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH3:20])[N:8]=1.O.CN([CH:25]=[O:26])C>>[Cl:6][C:7]1[C:12]([CH:25]=[O:26])=[N:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH3:20])[N:8]=1
Reactant: CN(C)C=O
Reactant: COCC1CCCN1c1cncc(Cl)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COCC1CCCN1c1cnc(C=O)c(Cl)n1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
Phosphoryl chloride (1.2 mL) was added dropwise to DMF (10 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-chloro-6-[2-(methoxymethyl)pyrrolidin-1-yl]pyrazine (1.45 g) in DMF (3 mL), and the mixture was stirred at 50° C. for 16 hr. Water was added to the reaction mixture, and the mixture was stirred for 2 hr, and extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (1.04 g, 64%).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH2:9]P(OCC)(=O)OCC)[O:6][N:5]=1)([CH3:3])[CH3:2].COC([O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O)C>>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[OH:22])[O:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: CCOP(=O)(Cc1cc(C(C)C)no1)OCC
Reactant: COC(C)Oc1ccccc1C=O
Product: CC(C)c1cc(C=Cc2ccccc2O)on1

Procedure:
Using the method described in Example I, 32 g (0.12 mole) of diethyl (3-isopropyl-isoxazol-5-yl)methanephosphonate and 22 g (0.12 mole) of o-(1-methoxy-ethoxy)-benzaldehyde are reacted and the product is recrystallized from toluene. 20 g (73% of theory) of colorless crystals, of melting point 129°-133° C., are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH:8]=[CH:9]2.[Mg].O1CCCC1.[Cl-].[NH4+].[CH3:21][C:22]([CH3:24])=[O:23]>>[CH3:21][C:22]([OH:23])([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH:8]=[CH:9]2)[CH3:24]
Reactant: CC(C)=O
Reactant: ClCCCCC1CC2C=CC1C2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)CCCCC1CC2C=CC1C2
Reaction time: 1 h
Yield: 84 %

Procedure:
A Grignard reagent was prepared from 95.5 g of 1-chloro-4-(5-norbornen-2-yl)butane, 13.3 g of magnesium, and 200 ml of anhydrous tetrahydrofuran. Then, under an atmosphere of nitrogen, 35.5 g of acetone was added thereto at 40° C. over a period of 1 hour. After this mixture was stirred for 1 hour, the reaction product was hydrolyzed by the addition of an aqueous solution of ammonium chloride, followed by separation into aqueous and organic phases. Subsequently, the organic phase was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by vacuum distillation to obtain 90.5 g of 2-methyl-6-(5-norbornen-2-yl)hexan-2-ol (boiling point: 93-98° C./66 Pa; yield: 87%).
Reaction SMILES: [OH:1][CH:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH:5]1[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:6]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.N.[H][H]>C(O)C.[Ni]>[NH2:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([N:7]2[CH:6]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:5]([CH2:4][CH2:3][CH:2]([OH:1])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:8]2=[O:9])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(CN)cc2)cc1

Procedure:
7 g of 4-[3-(3-hydroxy-3-phenylpropyl)-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile are dissolved in 200 ml of ethanol and, after addition of 15 ml of concentrated ammonia, hydrogenated with 7 g of 50% aqueous Raney nickel under 50 bar of hydrogen. The crude product obtained after removal of the catalyst by filtration with suction and removal of the solvent in vacuo is purified on silica gel with dichloromethane/methanol/ammonia =200:10:1. The amine is obtained. MS (FAB, +LiCI): 423 (M+Li+) [C26H28N2O3 M=416].
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4](Br)[C:5](Br)=[C:6]([CH3:9])[C:7]=1[CH3:8].[C:13](#[N:18])/[CH:14]=[CH:15]/[C:16]#[N:17].[I-].[Na+].S([O-])(O)=O.[Na+]>CN(C)C=O>[C:16]([C:15]1[C:14]([C:13]#[N:18])=[CH:8][C:7]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=1)#[N:17]
Reactant: N#C/C=C/C#N
Reactant: Cc1c(C)c(Br)c(Br)c(Br)c1Br
Agent: O=S([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc2ccccc2cc1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 0.1 mol of tetrabromoxylene were added 0.17 mol of fumaronitrile, 0.66 mol of sodium iodide and 400 ml of anhydrous dimethylformamide, and the mixture was stirred under heating at 70° to 80° C. for 7 hours. The reaction mixture was added to 800 g of ice-water, and to the resultant precipitate was added about 15 g of sodium hydrogen sulfite and the mixture was left to stand overnight. Subsequently, the mixture was filtered and dried, followed by recrystallization from chloroform/ethanol, to give white 2,3-dicyanonaphthalene. The yield was 80%.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH:23]([F:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=1.Cl[C:32]([O:34][CH3:35])=[O:33].[Cl-].[NH4+]>O1CCCC1>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([C:23]([F:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:32]([O:34][CH3:35])=[O:33])[N:18]=1
Reactant: COC(=O)Cl
Reactant: COc1cc(OC)nc(C(F)c2ccccc2)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(F)(c1ccccc1)c1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M in hexane, 1.7 ml) was added to diisopropylamine (0.59 ml) under nitrogen in dry tetrahydrofuran (15 ml) at -78° C. This solution was stirred for 30 minutes, then a solution of the product of stage (a) above (1.0 g) in tetrahydrofuran (10 ml) was added over 20 minutes. Methyl chloroformate (0.4 g) in dry tetrahydrofuran (10 ml) was added over 15 minutes at -78° C., and the reaction mixture was allowed to warm slowly to room temperature, after which it was added to aqueous ammonium chloride solution. The mixture was extracted with ether, the extracts being washed with water, dried over magnesium sulfate, and evaporated to dryness to give 1.08 g of the desired product, identical to that of Method A above.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Sodium hydride (0.20 g, 60% dispersion in mineral oil) was added to a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.92 g) in anhydrous 1-methyl-2-pyrrolidinone (5 ml), precooled in ice. After stirring for 30 minutes under nitrogen, 2,5-dibromopyridine (1.0 g) was added. The reaction mixture was then stirred for two hours at room temperature before heating to 70° C. for four hours. The resultant dark mixture was poured onto ice (200 ml) containing 2% citric acid (20 ml), and was extracted with diethyl ether (3×15 ml). The aqueous phase was then basified to pH 13 with solid sodium hydroxide, and extracted with diethyl ether (2×15 ml). The combined organics were washed water (3×20 ml), saturated brine (20 ml) and dried over anhydrous sodium sulfate and evaporated to give the title compound as a light brown oil (0.87 g, 58%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14](OCC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:25]([NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 153.7 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-O-benzyl-L-tyrosine (Bachem, 2.00 g, 5.38 mmol) in 20 mL of DMF was cooled to 0° C. and treated with iPr NEt (1.5 mL) followed by O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)-uronium hexafluoro phosphate (2.04 g, 5.38 mmol, Novabiochem, La Jolla, Calif.). The resulting suspension was stirred for 30 minutes at 0° C. and then treated with tert-butylamine (0.48 g, 6.56 mmol). The reaction mixture was stirred for 1 hour at 0° C. and warmed to room temperature. The reaction mixture was poured into Et O and washed sequentially with saturated aqueous NaHCO3 solution, and saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated. The crude residue was purified by chromatography (silica gel, 3:1 heptane/ethyl acetate) to give (S)-[2-[(1,1-dimethylethyl)amino]-2-oxo-1-(phenylmethyl)ethyl]-carbamic acid 1,1-dimethylethyl ester (2.65 g).
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>O1CCCC1>[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: NCc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cccc(Cl)c2Cl)c(=O)c1=O
Yield: 90.8 %

Procedure:
Tetrahydrofuran (12 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5.0 mmol) and 2,3-dichlorobenzylamine (0.88 g, 5.0 mmol) were stirred together at room temperature for 64 hours. The residue remaining after removal of solvent was trituated thoroughly with diethyl ether and dried to give 1.55 g of a white solid. Recrystallization (four times) of the crude product from acetonitrile provided 0.796 g of the title compound as a white solid: mp 222°-223° C. (softens 218° C.). MS (m/z) 340/342/344 (M+). HPLC indicates a major component (96.2%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58]>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 78.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (1.0 g, 1.84 mmol), sodium hydride (60% in oil, 220 mg, 5.50 mmol), 15-crown-5 (400 mg, 1.82 mmol) and t-butyl bromoacetate (0.55 ml, 3.69 mmol) in tetrahydrofuran (20 ml) was refluxed under heating for 1 hour and 15 min. The reaction solution was diluted with ethyl acetate and filtered with CELITE. Under cooling with ice, water was added dropwise to the filtrate which was then washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent and the thus obtained residue was purified by column chromatography (hexane:ethyl acetate=20:1) to give the titled compound (946.6 mg, 78%) as a colorless oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15](O)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH:25]1([NH:31][CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([N:31]([CH3:32])[C:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[CH:8]3)=[O:16])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CNC1CCCCC1
Product: Cc1cc(Nc2cc3cc(C(=O)N(C)C4CCCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Cyclohexyl-methyl-amine to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid cyclohexyl-methyl-amide. LC-MS: m/e 422 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[N+]([O-])(O)=O.[N+:14]([O:17][CH2:18][CH:19]([NH2:21])[CH3:20])([O-:16])=[O:15]>>[N+:14]([O:17][CH2:18][CH:19]([NH:21][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH3:20])([O-:16])=[O:15]
Reactant: CC(N)CO[N+](=O)[O-]
Reactant: O=C1N[C@H](C(=O)O)CS1
Solvent: O=[N+]([O-])O
Product: CC(CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 1.5 g of (4R)-2-oxothiazolidine4-carboxylic acid and 2.3 g of 1-(nitrooxymethyl)ethylamine nitrate, to obtain 0.35 g of the title compound as colorless crystals, melting at 112°-114° C. (after recrystallization from ethanol).
Reaction SMILES: O=[C:2]([CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)[CH2:3][C:4]#[N:5].Cl.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.[OH-].[Na+]>CCO>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:4]([NH2:5])=[CH:3][C:2]([CH:6]3[CH2:10][CH2:9][O:8][CH2:7]3)=[N:22]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(NN)cc1
Reactant: N#CCC(=O)C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2nc(C3CCOC3)cc2N)cc1
Temperature: 80 °C

Procedure:
To a solution of 3-oxo-3-(tetrahydrofuran-3-yl)propanenitrile (718 mg, 4.64 mmol) in EtOH (20 mL) was added conc. hydrochloric acid (0.387 mL, 4.64 mmol) and (4-methoxyphenyl)hydrazine hydrochloride (737 mg, 4.22 mmol). The reaction mixture was heated to 80° C. for 4 hr and was then cooled to RT and adjusted to pH8 by the addition of aq NaOH (2M, <5 mL). The resulting mixture was partitioned between water (20 mL) and Et2O (25 mL) and the aq layer was separated and extracted with ether (25 mL). The combined organic extracts were dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, 0-5% MeOH in DCM, gradient elution) to afford the title compound, Intermediate A12, as a pale orange solid (503 mg, 45%); Rt 1.04 min (Method 2); m/z 260 (M+H)+, (ES+).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:44]1[C:45]([OH:55])=[CH:46][C:47]3[O:51][C:50]([CH3:53])([CH3:52])[CH2:49][C:48]=3[CH:54]=1)[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:44]1[C:45]([OH:55])=[CH:46][C:47]3[O:51][C:50]([CH3:52])([CH3:53])[CH2:49][C:48]=3[CH:54]=1)([CH2:5][OH:16])[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OC(C)(C)C3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [4-bromo-3-(6-hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (25%): MS (ES+) m/z 490.5 (M+1), 492.5 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[F:27].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[F:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:10]1[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=1[CH2:8][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CBr)c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Piperidine (commercially available from Aldrich) (0.038 g, 0.44 mmol) was added to a solution of 66.63B (0.13 g, 0.37 mmol) in DMSO (3 mL). Cs2CO3 (0.18 g, 0.55 mmol) was then added to the reaction and it was stirred at room temperature for 1 hour. EtOAc (100 mL) was added and the organic phase was washed with water and brine and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:1 EtOAc/DCM) and gave 66.64A (100 mg) in 76% yield. MS ESI (pos.) m/e: 358 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][NH:25][C:26]([NH:28][NH2:29])=[O:27]>>[CH3:24][NH:25][C:26]([NH:28]/[N:29]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])=[O:27]
Reactant: CNC(=O)NN
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: CNC(=O)N/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and N-methylhydrazine-carboxamide. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1H), 9.88 (s, 1H), 8.89 (m, 1H), 8.36 (d, 1H), 8.02 (m, 2H), 7.82 (d, 1H), 7.52 (dd, 1H), 7.45 (m, 1H), 6.17 (s, 2H), 2.74 (d, 3H), 2.31 (s, 3H). LCMS (method B): [MH]+=376, tR=2.95 min.