Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[N:30].[Na+].[I-]>CN(C=O)C.O>[OH:1][C:2]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:16][CH:17]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(OCc2ccccc2C#N)cc1
Temperature: 25 °C
Yield: 107.7 %

Procedure:
Into a 250 mL-3 neck flask fitted with a stirrer and thermometer, 400 mg of [2-hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine in DMF (10 mL) was added dropwise to 40 mg of NaH in DMF (30 mL) while stirring at room temperature under a nitrogen atmosphere. After stirring at this temperature for 30 minutes, 290 mg of alpha-bromo 2-cyanotoluene in DMF (10 mL) was added dropwise followed by the addition of 184 mg of NaI portion wise. The reaction was then heated at 100° C. for 2 hours. The mixture was cooled to room temperature and poured into H2O and the desired product was extracted with ethyl acetate. This organic layer was washed with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 612 mg of a brown oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1:1 to yield intermediate title compound (161 mg, 28%) as a viscous oil. Ion spray M.S. 387.9 (M*−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[NH4+].[H][H]>CN(C=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1
Reactant: [H][H]
Agent: [Ni]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
100 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline are hydrogenated in 400 ml DMF in the presence of 33.1 g Raney nickel and 18.7 g ammonium chloride at 40° C., until the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is added dropwise to 1.2 l water. The suspension is stirred for 2.5 h at 0° C., suction filtered and washed with 500 ml of water. The residue is dried overnight at 55° C. under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[H][H]>CO.[Rh]>[CH3:1][C:2]1([C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(c2ccc(O)cc2)CCCCC1
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: CC1([C@H]2CC[C@@H](O)CC2)CCCCC1

Procedure:
56.1 g (0.29 mol) of 4-(1-methylcyclohexyl)phenol (from 1-methylcyclohexene and phenol in accordance with Chem. Ber. 57 (1924) 857) in 200 ml of methanol to which 1 ml of concentrated hydrochloric acid had been added were hydrogenated at 50° C. with 150 bar of hydrogen in the presence of 5 g of rhodium (5% on charcoal). After removal of the catalyst by filtration with suction, and concentration, 56.1 g (98.5% of theory) remained of an almost pure cis alcohol as a colorless solid.
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])C)[CH3:4].[C:14](O)(=O)CCC>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH2:7][CH2:9][CH3:14])[CH3:4]
Reactant: CCCC(=O)O
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Product: CCCC(=O)OC(C)OC(=O)SC

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing isobutyric acid with n-butyric acid in Step B affords O-(1-butanoyloxyethyl) S-methyl thiocarbonate (4) as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C(O)(=O)C.Br>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2cc(O)ccc21

Procedure:
A mixture of 50 g of 6-methoxy-1-tetralone, 200 ml of acetic acid and 400 ml of hydrobromic acid (47% HBr) was heated under reflux for 24 hours. After cooling, the reaction mixture was poured into 3 liters of water, solid matter was filtered out, and the resulting filtrate was extracted three times with ethyl acetate. The extracts were washed with an aqueous solution of sodium carbonate, dried over sodium sulfate and evaporated. The resulting residue together with the filtered solid matter was recrystallized from ethyl acetate to yield 40.75 g (89.5% of the theoretical yield) of 6-hydroxy-1-tetralone in the form of reddish-brown crystals melting at 153°-155° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:20][CH3:21])=[N:15][C:16]([C:17](O)=[O:18])=[C:10]2[CH:9]1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN.C1COCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:20][CH3:21])=[N:15][C:16]([C:17](=[O:18])[NH:35][CH3:34])=[C:10]2[CH:9]1[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCc1nc(C(=O)O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc(C(=O)NC)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of 3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester (47 mg; 0.100 mmol) in anhydrous DMF (1 ml) was added successively TBTU (35 mg; 0.110 mmol), DIPEA (51 μl; 0.300 mmol), and finally 2M methylamine in THF (0.15 ml; 0.300 mmol). The resulting reaction mixture was further stirred at rt, under nitrogen, for 16 h, and was then purified by preparative HPLC to give the pure product 3-ethyl-1-methylcarbamoyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (27.8 mg; 0.057 mmol; 58%).
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[CH2:4][CH2:5][C:6]=1[O:7][CH3:8].[CH2:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH3:20])[C:13]=1B(O)O)[CH3:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:19]([C:14]1[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([CH2:10][CH3:11])[C:13]=1[C:2]1[C:3](=[O:9])[CH2:4][CH2:5][C:6]=1[O:7][CH3:8])[CH3:20]
Reactant: CCc1cc(C)cc(CC)c1B(O)O
Reactant: COC1=C(Br)C(=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: CCc1cc(C)cc(CC)c1C1=C(OC)CCC1=O
Temperature: 90 °C

Procedure:
To a stirred suspension of 2-bromo-3-methoxycyclopent-2-enone (17.5 g, 91.6 mmol), 2,6-diethyl-4-methylphenyl boronic acid (26.4 g, 137 mmol) and freshly powdered potassium phosphate (38.9 g, 183 mmol) in anhydrous, degassed toluene (450 ml) under a nitrogen atmosphere are added palladium (II)acetate (0.411 g, 1.83 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.51 g, 3.67 mmol). The reaction mixture is heated at 90° C. for 6.5 hours and then allowed to cool to room temperature overnight. The reaction is diluted with water (400 ml) and extracted with ethyl acetate (3×150 ml). The combined organic extracts are washed with brine (50 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness under reduced pressure to give a brown oil. The crude product is purified by column chromatography on silica gel to give 2-(2,6-diethyl-4-methylphenyl)-3-methoxycyclopent-2-enone.
Reaction SMILES: CCCCN(C(NC(C1C=C(OC)C(OC)=C(OC)C=1)=[O:14])=S)CCCC.[CH2:27]([O:30][N:31]([CH:44]1[CH2:49][N:48]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:47]([CH2:57][O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH:46]=[C:45]1[CH2:66][C:67]#[N:68])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29].C(=NO)C.CO>O>[CH2:27]([O:30][N:31]([CH:44]1[CH2:49][N:48]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:47]([CH2:57][O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:60])[CH3:61])[CH:46]=[C:45]1[CH2:66][C:67]([NH2:68])=[O:14])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: CCCCN(CCCC)C(=S)NC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC#N)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC=NO
Solvent: O
Solvent: CO
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 15 h

Procedure:
4 Å molecular sieves (MS-4 Å) were impregnated with the corresponding metal salt (CuCl2-2H2O) as follows: 1 mmol of the salts was dissolved in 100 ml of deionized H2O and stirred with 1 g of MS-4 Å at room temperature for 6 h. The solid was filtered, washed with deionized H2O and acetone, and dried in an oven at 150° C. for 1 h. (2S)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(cyanomethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 172, 3.60 g, 5.78 mmol), Cu(II)Cl2-4 Å catalyst (200 mg), acetaldoxime (1.762 mL, 28.90 mmol, 5.0 eq) and MeOH (40.0 mL) were stirred at 60° C. for 15 h. The solid was filtered, washed with MeOH and the filtrate was evaporated to afford crude product.
Reaction SMILES: [Br:1][C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(Cl)CCl.[C:21]([S:24][CH2:25][C@H:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[CH3:22]>N1C=CC=CC=1>[Br:1][C@H:2]1[C@H:7]([O:8][C:27](=[O:28])[C@H:26]([CH3:30])[CH2:25][S:24][C:21](=[O:23])[CH3:22])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)SC[C@@H](C)C(=O)O[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
To a mixture of 94 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzopyran, 800 ml of ethylene chloride and 32.4 ml of pyridine was added 66 g of (S)-(-)-3-acetylthio-2-methylpropionyl chloride under ice-cooling over 5 minutes and stirred for 1.5 hours under room temperature. The reaction mixture was washed with diluted hydrochloric acid once and 10% aqueous sodium chloride solution twice. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give 139.8 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-[(S)-(-)-3-acetylthio-2-methylpropionyloxy]-2H-1-benzopyran as a light yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:31].[OH-].[Na+]>>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:31]
Reactant: COC(=O)[C@H]1CC[C@H](Nc2ncc3ncnc(Nc4cc(Cl)c(N)c(Cl)c4)c3n2)CC1
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(Cl)cc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)O)CC4)nc23)cc1Cl

Procedure:
Prepared from 4-[(4-amino-3,5-dichlorophenyl)amino]-6-[(trans-4-methoxycarbonylcyclohexyl)amino]pyrimido[5,4-d]-pyrimidine by hydrolysis with sodium hydroxide solution. Melting point: 339° C.; Rf : 0.37 (silica gel; petroleum ether/ethyl acetate/methanol=10:10:3)
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.[CH3:14][C:15]([O:18][C:19]([NH:21][CH2:22][CH2:23][NH2:24])=[O:20])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH:24][CH2:23][CH2:22][NH:21][C:19]([O:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:20])=[O:7])[CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(C(=O)NCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
Mono-methyl isophthalate (10.0 g, 55.5 mmol), t-butyl n-(2-aminoethyl)carbamate (8.89 g, 55.5 mmol, 1.0 eq) and EDCI (12.2 g, 63.8 mmol, 1.15 eq) were dissolved in 270 mL DCM, followed by the addition of DIPEA (29.0 mL, 166 mmol, 3.0 eq). The reaction was allowed to stir at room temperature overnight. It was then taken up in 100 mL of DCM, washed with a 1:1 solution of 1.0 N HCl in brine, water, and a 1:1 solution of brine in saturated NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to afford the product as a light yellow solid (12.81 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18].Cl>C1(C)C=CC=CC=1>[F:15][C:16]([F:24])([F:23])[C:17]([C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([OH:10])=[C:3]([O:2][CH3:1])[CH:8]=1)([OH:18])[C:19]([F:22])([F:21])[F:20]
Reactant: COc1cccc(C)c1O
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O

Procedure:
To 2-methoxy-6-methylphenol (27.6 g=0.20 mol) in 300 ml toluene, add aluminum chloride (4.0 g=30 mmol). Bubble in hexafluoroacetone (47 g=0.28 mol) over 7 hours. Heat the reaction mixture in a steel bomb 16 hours at 120° C. Cool, and pour the contents onto 1.0 N HCl. Extract with ether. Wash the ether layer with 1.0N NaOH. Acidify the basic aqueous layer with concentrated HCl, extract with ether, dry, concentrate and distill to obtain a fraction boiling at 71°-74° C./0.1 mm. Crystallize from cold hexane to obtain, as a solid m.p. 44°-45° C., 4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-6-methylphenol.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCCc1ccccn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CCc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 59.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 2-(2-chloroethyl)pyridine (0.42 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.56 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.41 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([CH3:20])[CH2:18][C:17](=N)[NH:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:21].[K+]>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([CH3:20])[CH2:18][C:17](=[O:21])[NH:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=N)NN1
Agent: [K+]
Solvent: CC(C)O
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
26.9 g of 3-(4'-fluoro-4-biphenylyl)-3-methyl-5-imino-pyrazolidine are boiled for 10 minutes with 150 ml of 2 N aqueous potassium hydroxide solution and 150 ml of isopropanol and the mixture is worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [C:1]([N:8]([CH2:23][CH2:24][N:25]1C(=O)C2=CC=CC=C2[C:26]1=[O:35])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:11][CH:10]=1)(C(OCC)=O)=[O:2]>C(O)C>[F:21][C:17]([F:22])([CH:18]([F:20])[F:19])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:1]2=[O:2])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(=O)N(CCN1C(=O)c2ccccc2C1=O)c1ccc(OCC(F)(F)C(F)F)cc1
Solvent: CCO
Product: O=C1NCCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O
Yield: 36.5 %

Procedure:
The mixture of the obtained N-ethoxalyl-N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (3.4 g), hydradine hydrate (0.7 ml) and ethanol (80 ml) was refluxed for 9 hours. The crystals separated out were filtered off before cooling and the solvent of the filtrate was distilled off under reduced pressure. Water (150 ml) and ethyl acetate (300 ml) were added to the residue to fractionate. The ethyl acetate layer was washed with 5% aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; ethyl acetate:dichloromethane: methanol=7:7:1 v/v) to give 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-piperazinedione (0.8 g) as a colorless powder.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH:27]([C:30]1[N:34]2[CH:35]=[C:36]([O:39][C@@H:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@@H:43]([NH2:50])[CH2:42][CH2:41]3)[CH:37]=[CH:38][C:33]2=[N:32][N:31]=1)([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.O>O1CCOCC1.CN(C=O)C.C(Cl)Cl.CO>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:50][C@@H:43]2[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C@@H:40]([O:39][C:36]3[CH:37]=[CH:38][C:33]4[N:34]([C:30]([CH:27]([CH3:29])[CH3:28])=[N:31][N:32]=4)[CH:35]=3)[CH2:41][CH2:42]2)=[O:24])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[N:9]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(C#N)cc2)n1
Reactant: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C#N)cc4)c4ccccc43)cn12

Procedure:
A solution of Intermediate 14b (61.6 mg, 0.148 mmol), Intermediate 5c (43.4 mg, 0.135 mmol), and DIPEA (0.029 mL, 0.169 mmol) in dioxane-DMF (3:1, 2.0 mL) was stirred at 60° C. for 18 h. Water (3 mL) was added, then the mixture extracted with DCM-MeOH (9:1, 2×3 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave an orange oil. FCC, using 2-8% MeOH in DCM, gave the title compound as a white solid after freeze-drying (35.0 mg, 44%). LCMS (Method 5): Rt 4.46 min, m/z 589 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.37 (3H, d, J 7.1), 1.39 (3H, d, J 7.1), 1.75 (1H, m), 2.01 (1H, m), 2.09-2.22 (2H, m), 3.57 (1H, sept, J 6.9), 4.88 (1H, m), 5.58 (1H, t, J 4.5), 6.38 (1H, s), 7.06 (1H, d, J 8.2), 7.23 (1H, dd, J 9.9, 2.2), 7.27 (1H, d, J 7.3), 7.29-7.38 (2H, m), 7.42 (1H, d, J 7.5), 7.69 (1H, dd, J 9.9, 0.9), 7.75 (2H, d, J 8.9), 7.96 (2H, d, J 8.7), 8.21 (2H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:5]=1[C:6]1[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][CH:9]=[CH:10][C:11]=1[NH:12]2.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>CN(C)C=O>[CH3:3][C:4]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:5]=1[C:6]1[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][CH:9]=[CH:10][C:11]=1[N:12]2[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1cccc2[nH]c3c(C)ccc(C)c3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1c1c(C)ccc(C)c1n2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of 1.47 g of 60% sodium hydride (in a oil) in 35 ml of dry N,N-dimethylformamide was added dropwise over a 30 minutes period a solution of 7.00 g of ethyl 5,8-dimethylcarbazole-4-carboxylate obtained above in 35 ml of dry N,N-dimethylformamide, and the mixture was stirred for a further 30 minutes. To the mixture was added dropwise a solution of 6.99 g of p-toluenesulfonyl chloride in 35 ml of dry N,N-dimethyl-formamide, and the mixture was stirred further overnight. The reaction solution was poured into ice water and extracted with ethyl acetate, and the organic layer was washed, in turn, with dilute hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was chromatographed on silica gel column with hexane - ethyl acetate (9 : 1) to give 7.40 g of ethyl 5,8-dimethyl-9-p-toluenesulfonylcarbazole-4- carboxylate.
Reaction SMILES: Cl[C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:24][CH2:25][CH2:26][F:27])[N:3]=1.[NH3:28]>C1COCC1>[F:27][CH2:26][CH2:25][O:24][C:4]1[N:3]=[C:2]([NH2:28])[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]=1[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]1)=[O:7]
Reactant: N
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCCF
Solvent: C1CCOC1
Product: Nc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2-fluoro-ethoxy)-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (1.30 g, 2.98 mmol) and conc. ammonia (0.90 mL, 14.92 mmol) in THF (30 mL) in analogy with method described in example 3c.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=O)=O)=CC=1.C1C2C(=CC=CC=2)CC1O.[F:31][C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[N:37][O:38][C:34]=2[CH:33]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:31][C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:40][CH2:41][N:42]([CH:11]4[CH2:12][C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:19]4)[CH2:43][CH2:44]3)=[N:37][O:38][C:34]=2[CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OC2Cc3ccccc3C2)cc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: OC1Cc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Fc1ccc2c(C3CCN(C4Cc5ccccc5C4)CC3)noc2c1

Procedure:
0.173 mole of 2-indanyl para-toluenesulfonate (prepared from 2-indanol according to the procedure described in Example 4, stage B), 0.173 mole of 6-fluoro-3-piperid-4-yl-1,2-benzisoxazole, dissolved in 50 ml of toluene, and 0.0346 mole of triethylamine are mixed.