Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:24])=O.O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6]([Cl:24])[N:7]=1
Reactant: CC(C)n1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Temperature: -30 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (8 g) was dissolved in DMF (80 ml). The solution was cooled to −30° C. To the cooled solution was added phosphoryl chloride (12.7 g) dropwise at −30˜−40° C. After addition of phosphoryl chloride, the temperature of the reaction mixture was raised to −10˜−5° C. The mixture was stirred at −10˜−5° C. for 1 hour. To the reaction mixture was added water (400 ml). The suspension was stirred at 30-35° C. for 15 hours. The pH of the suspension was adjusted to 4.5. The suspension was cooled to 0-5° C. and stirred at the same temperature for 2 hours. The precipitate was collected by filtration and washed with water, and dried in vacuo at 40-50° C., to give 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (7.1 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:39][C:40]1[N:41]=[N:42][C:43](Cl)=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:43]5[N:42]=[N:41][C:40]([Cl:39])=[CH:45][CH:44]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(Cl)nn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A solution of the compound (1.39 mg, 2.5 mmol) obtained in Example 16-5), 3,6-dichloropyridazine (1.49 mg, 10 mmol), tetrakis(triphenylphosphine)palladium(0) (577 mg, 0.5 mmol), and potassium carbonate (691 mg, 5 mmol) in dimethoxyethane (10 mL) and water (2.5 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (647 mg, 48%) as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([OH:14])=O)[CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:27]1([C@H:37]([NH2:39])[CH3:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:27]1([C@H:37]([NH:39][C:12]([CH:4]2[CH2:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)=[O:14])[CH3:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=C1CC(C(=O)O)Cc2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)C1CC(=O)c2ccccc2C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a mixture of 4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (4.6 g, 24.19 mmol) (Tetrahedron: Asymmetry 14, 2003, 3689; Journal of Medicinal Chemistry 25, 1982, 535), in DMF (20 mL), CDI (3.92 g, 24.19 mmol) was added. The reaction mixture was stirred at room temperature (RT) for 2 h. Then (R)-1-(naphthalen-1-yl)ethanamine (5.40 g, 31.5 mmol) was added and the reaction mixture was stirred at RT overnight. After completion of reaction, ice was added to the reaction mixture, solid precipitated out was filtered on Buchner funnel, washed with DM water (50 mL) and dried to get crude compound. Compound was further purified by flash chromatography (biotage) using eluent 15% ethyl acetate:hexane to yield the title compound (8 g, 96%); m/z 344.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[C:11]2[CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](=[O:17])[CH2:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(O)(=O)C(C(C(O)=O)O)O.CCOCC.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37]>O1CCOCC1>[C:36]([NH:40][CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[C:11]2[CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](=[O:17])[CH2:16][C:10]=2[CH:9]=[CH:8][CH:7]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC1(C)CCc2c(cccc2OCC(O)CCl)CC1=O
Reactant: CC(C)(C)N
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)NCC(O)COc1cccc2c1CCC(C)(C)C(=O)C2

Procedure:
2,2 g crude 1-(3-chloro-2-hydroxypropoxy)-6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocyclohepten-6-one in 20 ml dioxane and 10 ml tert-butylamine are heated at 130° for 20 hours in an autoclave. The reaction mixture is divided between 10% (w/w) aqueous tartaric acid solution and ether. The aqueous phase is made alkaline and extracted with ether. Evaporation of the ether phase yields the title compound (M.pt of hydrogen maleate 186°-188° after crystallization from ethanol).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:16][CH3:17])=[O:9])[N:7]=1
Reactant: CCO
Reactant: Nc1nc(C(=O)O)cs1
Agent: Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1csc(N)n1

Procedure:
2-Aminothiazole-4-carboxylic acid hydrobromide (10 g) (E. C. Roberts and Y. F. Shealy, J. Med. Chem. 15 (1972)1310-1312) in ethanol (35 ml) was treated with conc. sulfuric acid and refluxed for 48 hours. The solution was evaporated to 25% of original volume and water (20 ml) added. It was made basic by addition of NaHCO3, the solid filtered, washed with water and dried under vacuum to give the title compound (5.64 g). NMR δ(CDCl3) 137 (3H,t), 4.36(2H,q), 5.39(2H, broad), 7.43(1H,s).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[OH-].[Na+].Cl>CO>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CCOC(=O)CCc1ccc(N2CCN(C(=O)c3cccc(-c4ccc(OC)c(OC)c4)n3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(CCC(=O)O)cc4)CC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a THF (5 ml) and methanol (5 ml) mixed solution of 1.01 g of ethyl 3-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl }phenyl)propanoate was added 5 ml of a 1M aqueous sodium hydroxide solution, followed by 1 hour of stirring at room temperature. To the reaction solution was added 5 ml of a 1M aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated, thus obtained crude crystals were recrystallized from ethanol to obtain 673 mg of 3-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl) propanoic acid as colorless crystals.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH:20]1([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:26]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:27])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(O)C1CCCCC1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and cyclohexanecarboxylic acid, the title compound was prepared as white powder. MS: m/e=391 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:12](=[O:21])[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=O.O.S(=O)(=O)(O)O>O1CCCC1>[OH:8][CH2:9][C:11]1[C:12](=[O:21])[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: COC(=O)c1cc2ccccc2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2cc1CO
Temperature: 25 °C
Yield: 26.8 %

Procedure:
16 Grams of lithium aluminum hydride was suspended in 200 ml of dried tetrahydrofuran, then 16 g of 3-methoxycarbonylcarbostyril was added thereto at a room temperature with stirring. The reaction mixture was further stirred for 5 hours at a room temperature. The excess lithium aluminum hydride in the reaction mixture was decomposed by adding ethyl acetated dropwise. Further, water was added to the reaction mixture and concentrated under a reduced pressure to obtain residue. To the residue was added a diluted sulfuric acid and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain 3.7 g of 3-hydroxymethylcarbostyril in the form of colorless prism-like crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:4][CH:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44].C(OCC)(=O)C>O1CCCC1>[C:43]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:21])[CH3:22])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:4][CH:3]=1)(=[O:45])[CH3:44]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc(-c2ccccc2)n(CC(=O)NC(C(C)C)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.83 g) and triethylamine (0.45 mL) in tetrahydrofuran (10 mL) at 0° C. was added acetyl chloride (0.17 mL) and the resulting solution was allowed to stir for 0.5 h. The mixture was poured into ethyl acetate and the solution was washed (1N hydrochloric acid, water), dried, and evaporated to give 2-(5-acetamido-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as a foamy solid (0.86 g); TLC: Rf =0.4, methanol:dichloromethane (5:95).
Reaction SMILES: Br[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5]Br.[CH2:8]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CCOC(C)=O>[CH2:8]([C:16]1[CH:17]=[CH:18][C:19]([N:20]2[CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]2)=[CH:21][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: OC(CBr)CCBr
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc(N2CCC(O)C2)cc1
Temperature: 120 °C
Yield: 537.2 %

Procedure:
To 10 microwave vials were added 1,4-dibromobutan-2-ol (0.375 mL, 2.75 mmol), 4-octylaniline (0.572 mL, 2.5 mmol), potassium carbonate (0.380 g, 2.75 mmol) and water (3 mL). Each vial was heated in a CEM microwave at 100 watt, 120° C., 150 psi, ramp time 5 min and hold time 20 min. After cooling to room temperature EtOAc (1 mL) was added to each vial. After thorough mixing the organic layers were removed, combined and concentrated in vacuo. The product was purified by flash chromatography on silica gel (eluting with EtOAc/Hep) to provide 1-(4-octylphenyl)pyrrolidin-3-ol (3.7 g, 13.43 mmol, 53.7% yield) as a white solid which was stored under nitrogen in a sealed flask.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[Cl-].[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH2+:26][CH2:25][CH2:24]2.C(O)(=O)C.C([BH3-])#N>ClC(Cl)C.C(N(CC)CC)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([CH2:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:25][CH2:24]2
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: Clc1ccc2c(c1)CC[NH2+]C2
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CN2CCc3cc(Cl)ccc3C2)c2ccccn2c1=O
Temperature: 120 °C

Procedure:
Ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (300 mg, 1.22 mmol) and 6-chloro-1,2,3,4-tetrahydroisoquinolinium chloride (267 mg, 1.59 mmol) were dissolved in 6.2 mL of dichloroethane, and the reaction was neutralized by adding triethylamine dropwise to reach pH 7. The reaction mixture was re-acidified by adding glacial acetic acid (420 μl, 7.34 mmol). MP-Cyanoborohydride resin (1 spatula tip, excess) was added, and the reaction was stirred and heated at 120° C. for 20 minutes in a Emrys Optimizer™ microwave. The crude reaction mixture was filtered with methanol, concentrated in vacuo and redissolved in dimethylsulfoxide, then was purified by reverse phase HPLC, eluting with 20-90% acetonitrile in water to afford ethyl 1-[(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)methyl]-4-oxo-4H-quinolizine-3-carboxylate that gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 397.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23](O)[CH:22]=[C:21]3[C:16]=2[C:17]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[C:29]4[O:34][CH2:35][O:36][C:28]=24)=[N:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(C)C=CC(S([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:33][C:32]1[C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])=[CH:24][C:15]=3[O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:20]=[CH:19][N:18]=2)=[C:28]2[O:36][CH2:35][O:34][C:29]2=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 95 °C
Yield: 42.1 %

Procedure:
A mixture of 5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxyquinazoline (0.15 g), 2,2,2-trifluoroethyl 4-toluenesulphonate (0.089 g), potassium carbonate (0.1 g) and DMF (3 ml) was stirred and heated to 95° C. for 24 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic solution was washed with 1N aqueous sodium hydroxide solution and with brine and dried over magnesium sulphate. The organic solution was filtered and a 6N solution of hydrogen chloride in diethyl ether (2 ml) was added. The mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated. The residue was dissolved in methylene chloride (3 ml) and a saturated methanolic ammonia solution (1 ml) was added. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.061 g); NMR Spectrum: (CDCl3) 1.85–2.0 (m, 2H), 2.3 (m, 2H), 2.8–2.95 (m, 2H), 3.1–3.3 (m, 2H), 4.5 (m, 2H), 4.72 (m, 1H), 6.08 (s, 2H), 6.6 (d, 1H), 6.75 (d, 1H), 6.82 (d, 1H), 7.0 (d, 1H), 8.58 (s, 1H), 9.32 (s, 1H); Mass Spectrum: M+H+ 497 and 499.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23]O)#[N:2].COCCN(CCOC)S(F)(F)[F:53].C(O)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23][F:53])#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCN(C(=O)c5ccc(C#N)cc5F)CC4CO)c3)ncnc21
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: N#CCC(CN1CCN(C(=O)c2ccc(C#N)cc2F)CC1CF)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 0 °C
Reaction time: 1.17 h

Procedure:
A solution of 4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (13 mg, 0.020 mmol; Peak 1 from Example 156, Step 5) in methylene chloride (0.87 mL, 14 mmol) was cooled to 0° C., then 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (11 μL, 0.060 mmol, Aldrich) was added, followed by ethanol (0.24 μL, 0.0040 mmol). The mixture was stirred at 0° C. for 70 min, then at RT for 20 min, and quenched by the addition of 5% sodium bicarbonate. The mixture was then extracted with EtOAc. The extract was washed with water (2×), brine, dried over sodium sulfate, decanted and concentrated. The yellow solid obtained was then dissolved and stirred for 1 h in a 1:1 mixture of TFA:DCM (1.74 mL). Solvent was removed in vacuo and the residue was stirred in a solution of methanol (0.43 mL) containing aqueous ammonium hydroxide (0.13 mL). After reaction was complete as determined by LCMS, solvent was removed in vacuo. Purification via preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) afforded two regioisomeric products, the second peak to elute was the desired piperazine product (2 mg, 19%). 1H NMR (500 MHz, CD3OD, rotamers): δ 8.66 (s, 0.45H), 8.65 (s, 0.55H), 8.62 (s, 0.45H), 8.60 (s, 0.55H), 8.37 (s, 0.45H), 8.37 (s, 0.55H), 7.68-7.58 (m, 2H), 7.55-7.48 (m, 2H), 6.94 (d, 0.45H), 6.93 (d, 0.55H), 4.90-4.43 (m, 3H), 3.81-3.60 (m, 2H), 3.33-3.05 (m, 6H), 2.90-2.50 (m, 3H); 19F NMR (400 MHz, CD3OD): −230.21 (t, 1F), −115.45 (br s, 1F); LCMS (M+H)+: 516.3.
Reaction SMILES: [F:1][C:2]1([F:16])[C:7]([F:9])([F:8])[C:6]2([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:11][C:3]1([OH:15])[CH2:4][CH2:5]2.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([F:28])[C:20]=1[F:29].[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:15][C:3]23[CH2:4][CH2:5][C:6]([CH2:12][CH2:13][CH3:14])([CH2:10][CH2:11]2)[C:7]([F:9])([F:8])[C:2]3([F:16])[F:1])=[C:20]([F:29])[C:21]=1[F:28])[CH3:27]
Reactant: CCCC12CCC(O)(CC1)C(F)(F)C2(F)F
Reactant: CCOc1ccc(CBr)c(F)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCC12CCC(OCc3ccc(OCC)c(F)c3F)(CC1)C(F)(F)C2(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2,2,3,3-Tetrafluoro-1-hydroxy-4-n-propylbicyclo[2.2.2]octane (12) (0.15 g), and 4-bromomethyl-1-ethoxy-2,3-difluorobenzene (5) (0.31 g) were added to a dimethyl formamide suspension (2.0 mL) of sodium hydride (18 mg), the mixture was stirred at room temperature for 6 hours, and then added with saturated aqueous ammonium chloride solution to thereby terminate the reaction. The organic layer was extracted three times with ethyl acetate, the organic layers were combined, and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was vaporized off under reduced pressure to thereby obtain a crude product. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9:1), to thereby obtain 1-(4′-ethoxy-2′,3′-difluorophenyl)methyloxy-2,2,3,3-tetrafluoro-4-n-propyl bicyclo[2.2.2]octane (13) (yield=0.15 g, yield ratio=58%) as a colorless clear crystal.
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.CON(C)[C:20](=[O:23])[CH2:21][CH3:22]>O1CCCC1.CCOCC>[CH3:11][C:10]1[C:3]2[CH:2]=[C:6]([C:20](=[O:23])[CH2:21][CH3:22])[S:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc2scc(Br)c12
Reactant: CCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)c1cc2c(C)cccc2s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A solution of 3-bromo-4-methylbenzo[b]thiophene (1.69 g) in tetrahydrofuran (10 ml) was added dropwise under nitrogen at −70° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 3.87 ml) in ether (30 ml), then the mixture was stirred at −70° C. for 30 minutes. A solution of N-methoxy-N-methylpropionamide (1.31 g) in tetrahydrofuran (10 ml) was added dropwise at −70° C. over 10 minutes, the mixture was stirred at −70° C. for 3 hours, then it was allowed to warm to ambient temperature and quenched by the addition of saturated aqueous ammonium chloride solution (30 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (30 ml), and dried (MgSO4). The solvents were removed in vacuao to give 1-(4-methylbenzo[b]thiophen-2-yl)propan-1-one (0.53 g) as an orange solid which was used without further purification.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=O)=[N+:2]=[N-:3].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[BH3-]C#N.[Na+]>>[N:1]([CH2:4][CH:5]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3]
Reactant: C1CCNCC1
Reactant: [N-]=[N+]=NCC(=O)c1ccc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: [N-]=[N+]=NCC(c1ccc(Cl)cc1Cl)N1CCCCC1

Procedure:
In a manner similar to Preparation 21 react 2-azido-1-(2,4-dichlorophenyl)ethanone with piperidine and NaCNBH3 to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=O)[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:17]#[N:18].[CH:21]1([NH:24][C:25]2[S:26][CH2:27][C:28](=[O:30])[N:29]=2)[CH2:23][CH2:22]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:21]1([NH:24][C:25]2[S:26]/[C:27](=[CH:15]\[C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][C:6]([C:17]#[N:18])=[C:5]4[O:4][CH2:3][C:2]([CH3:20])([CH3:19])[CH3:1])/[C:28](=[O:30])[N:29]=2)[CH2:23][CH2:22]1
Reactant: O=C1CSC(NC2CC2)=N1
Reactant: CC(C)(C)COc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)COc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 4-(2,2-dimethyl-propoxy)-6-formyl-quinoline-3-carbonitrile (example 67b), 2-cyclopropylamino-thiazol-4-one (example 37c), sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2,2-dimethyl-propoxy)-quinoline-3-carbonitrile. LC-MS m/e 407 (MH+).