Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:19]2=[N:20][C:21]3[C:22](=[C:23]([C:29](OC)=[O:30])[CH:24]=[CH:25][C:26]=3[O:27][CH3:28])[N:18]2[CH2:17][CH2:16][CH2:15]1.O1[CH2:37][CH2:36][CH2:35]C1>>[CH:1]1([C:29]([CH:35]2[CH2:36][CH2:37]2)([C:23]2[C:22]3[N:18]4[CH2:17][CH2:16][CH2:15][N:14]([C:8]5[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=5[Cl:6])[C:19]4=[N:20][C:21]=3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=2)[OH:30])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: COC(=O)c1ccc(OC)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C1CCOC1
Product: COc1ccc(C(O)(C2CC2)C2CC2)c2c1nc1n2CCCN1c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 0.640 mL, 0.640 mmol) was added to a stirred suspension of methyl 1-(2,4-dichlorophenyl)-9-methoxy-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (52.0 mg, 0.128 mmol) in tetrahydrofuran (0.64 mL), and the mixture was stirred at 60° C. for 30 min. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (47.4 mg, 0.103 mmol, 80%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=[CH2:2].C1(C)C=CC=CC=1.C(=O)([O-])O.[NH4+].[CH3:22][O:23][SiH:24]([O:27][CH3:28])[O:25][CH3:26]>>[CH3:22][O:23][Si:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:2][CH2:1][CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2.[CH:1]([CH:3]1[CH2:8][C:7]2([Si:24]([O:27][CH3:28])([O:25][CH3:26])[O:23][CH3:22])[CH2:9][CH:4]1[CH2:5][CH2:6]2)=[CH2:2]
Reactant: C=CC1CC2C=CC1C2
Reactant: CO[SiH](OC)OC
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=CC1CC2([Si](OC)(OC)OC)CCC1C2
Product: CO[Si](CCC1CC2C=CC1C2)(OC)OC
Reaction time: 1 h

Procedure:
A flask equipped with a thermometer, condenser, stirrer and dropping funnel was charged with 120 g (1.0 mole) of 5-vinyl-2-norbornene, an amount (1×10−4 mole of platinum atoms per mole of 5-vinyl-2-norbornene) of toluene solution of platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex, and 0.4 g (0.005 mole) of ammonium hydrogencarbonate. To the flask at an internal temperature of 55-65° C., 124 g (1.0 mole) of trimethoxysilane was added dropwise over 4 hours. The contents were stirred for one hour at the temperature. On analysis by gas chromatography, the percentage conversion of 5-vinyl-2-norbornene was 98%. The ratio in area % of 5-(2-trimethoxysilylethyl)-2-norbornene:5-vinylnorbornyltrimethoxysilane:bissilyl adduct formed by addition to both endocyclic olefin and vinyl was 95.3:0.1:4.6. The reaction solution was distilled, collecting 218 g of 5-(2-trimethoxysilylethyl)-2-norbornene at a boiling point of 102-103° C./0.4 kPa (yield 90%, purity 99.9%).
Reaction SMILES: [C:1]1([O:11][CH:12]([Cl:17])[CH:13]([OH:16])[CH2:14][CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][NH:19]1>C(O)(C)C>[ClH:17].[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][N:19]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCC(O)C(Cl)Oc1cccc2ccccc12
Solvent: CC(C)O
Product: Cl
Product: OC(CCN1CCc2ccccc2C1)COc1cccc2ccccc12

Procedure:
A mixture of 12.5 g. (0.05 mole) of 1-(1-naphthyloxy)-2-hydroxybutyl chloride, 9.97 g. (0.075 mole) of 1,2,3,4-tetrahydroisoquinoline and 300 ml. of isopropanol was refluxed for 15 hr. On standing at room temperature a crystalline precipitate formed. The mixture was filtered and the filtrate concentrated to dryness under reduced pressure. The semi-solid residue which crystallized was recrystallized from acetone. The 12.2 g. of crystalline solid material melted at 169°-171° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH:11]1([CH:14]([N:18]2[CH:22]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=[N:19]2)[CH2:15][C:16]#[N:17])[CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.O>CCOC(C)=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>[Cl:1][C:2]1[N:7]=[C:6]([C:21]2[CH:20]=[N:19][N:18]([CH:14]([CH:11]3[CH2:13][CH2:12]3)[CH2:15][C:16]#[N:17])[CH:22]=2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Reactant: COc1cnc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CC2)c1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
A mixture of 2,4-dichloro-5-methoxypyrimidine (from Aldrich Chemicals, 1.47 g, 0.00821 mol), 3-cyclopropyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (from example 177 step 1, 2.34 g, 0.00815 mol), tetrakis(triphenylphosphine)palladium(0) (0.6 g, 0.0005 mol), and potassium phosphate (5.2 g, 0.025 mol) in 1,4-dioxane (20 mL, 0.3 mol) and water (2 mL, 0.1 mol) was heated at 100° C. overnight. After cooling to room temperature, the mixture was dilute with AcOEt, washed with water, brine, dried over MgSO4, concentrated. The residue was purified on silica gel, eluting with 0 to 60%, to give the desired product (580 mg, 23.43%). LCMS (M+H) 304.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:19]=[CH:18][C:17]2[CH:20]=[C:21]([C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)[NH:22][C:16]=2[CH:15]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH:29]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:19]=[CH:18][C:17]2[CH:20]=[C:21]([C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)[N:22]([S:34]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:36])=[O:35])[C:16]=2[CH:15]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CN(C)C(=O)c1ccc(Nc2cc3[nH]c(-c4cnn(C)c4)cc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)C1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C)c2)n3S(=O)(=O)C2CCCC2)c(Cl)c1
Temperature: 60 °C
Yield: 18.1 %

Procedure:
3-Chloro-N,N-dimethyl-4-(2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-ylamino)benzamide (Example 127, 25 mg, 0.063 mmol) was dissolved in dry DMF. The solution was degassed and a solution of sodium bis(trimethylsilyl)amide (0.1 ml of a 1M solution in THF, 1 mmol) was added. After 20 minutes reaction, cyclopentyl sulfonyl chloride (17 mg, 0.1 mmol) was added and the reaction heated to 60° C. for 3 hours. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude product was purified by silica gel column chromatography eluting with 5% methanol in ethyl acetate to afford the title compound as white foam (6 mg, 18%). 1H-NMR (500 MHz, d6-DMSO): δ 1.5 (m, 2H), 1.6 (m, 2H), 1.75 (m, 4H), 2.97 (s, 6H), 3.11 (m, 1H), 3.89 (s, 3H), 6.77 (s, 1H), 7.33 (dd, J=2 Hz, 8.6 Hz, 1H), 7.48 (d, J=2 Hz, 1H), 7.68 (s, 1H), 7.76 (s, 1H), 8.01 (s, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.51 (s, 1H), 8.7 (s, 1H). ESI-HRMS Found 527.1621, calculated for C25H27ClN6O3S (M+H+): 527.1627. MPS1 IC50 (uM): 0.092
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][C:8](=[O:15])[CH2:7][CH2:6]2.[CH:16](I)([CH3:18])[CH3:17].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:7][CH2:6]2
Reactant: CC(C)I
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(C(C)C)C(=O)CC2
Reaction time: 0.5 h

Procedure:
22.0 g of 3,4-dihydro-6,7-dimethoxy-2(1H)-naphthalenone were dissolved in 300 ml of dimethylformamide and treated with 13 g of potassium tert.-butylate. The solution was stirred at 18° for 30 minutes. After the addition of 19.7 g of isopropyl iodide the mixture was stirred for a further 30 minutes, whereby the temperature was held below 30°, and then poured into water. The product was extracted with ether, the extract was washed with water, dried over magnesium sulfate and evaporated. The oil which remained behind was purified by column chromatography (silica gel, hexane/ethyl acetate 6:1). There was obtained 3,4-dihydro-6,7-dimethoxy-1-isopropyl-2(1H)-naphthalenone, m.p. 77°-79°.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[N:6]([O-])=O.[Na+].[N+:10]([C:13]1[CH:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[NH2:19])([O-:12])=[O:11].C(OCC)C>C(O)(=O)C>[S:1]([O-:5])([OH:4])(=[O:3])=[O:2].[C:20]1([C:15]2[CH:16]=[CH:17][C:18]([N+:19]#[N:6])=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(O)O
Reactant: O=N[O-]
Reactant: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: N#[N+]c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Product: O=S(=O)([O-])O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To 70 mL of sulfuric acid at 100° C. is added portionwise sodium nitrite (7 g, 0.1 mol). The reaction mixture is warmed to 20° C. to dissolve all the sodium nitrite and then cooled to 15° C. To the reaction mixture is added over 30 minutes a suspension of 3-nitro-4-amino-1,1′-biphenyl (7.33 g, 0.034 mol), prepared in (B) above, in 60 mL of acetic acid. The reaction mixture is stirred for one hour at 100° C. and then to the reaction mixture is added 500 mL of diethyl ether. An exotherm occurs. The mixture is stirred for one hour. The solid formed is removed by filtration behind a safety shield and washed with diethyl ether to give 16.2 g of the title compound as a yellow solid. The solidis dried for 1.5 hours at 20° C. under vacuum and stored in a freezer in a polyethylene container until later use. Analysis: IR (nujol) v 1650 (N═N), 2250 (N2+) cm−1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[H-].[Na+].[CH2:13](I)[CH3:14].O>CN(C)C=O.CC(OC)(C)C>[CH2:13]([N:8]1[CH:9]=[CH:10][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1)[CH3:14].[CH2:13]([N:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:9]=[N:8]1)[CH3:14]
Reactant: c1csc(-c2cc[nH]n2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc(-c2cccs2)n1
Product: CCn1nccc1-c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 1 %
Yield: 44 %

Procedure:
3-(2-thienyl)-1H-pyrazole (31.6 mmol) was dissolved in 150 mL N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (37.9 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, ethyl iodide (47.4 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 2.50 g 1-ethyl-3-(2-thienyl)-1H-pyrazole (44% yield) and 50 mg of 1-ethyl-5-(2-thienyl)-1H-pyrazole (1% yield).
Reaction SMILES: [C:1]([O:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:23]([NH:31][C:32](=[O:48])[CH2:33][CH:34]2[C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[O:41][C:40]3[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:22]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+:50]>>[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH:9]([Na:50])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:22][C:23]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=2[O:41][C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH3:28])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1ccc(C(CCCCCc2ccccc2)OC(=O)CCC(=O)O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(C([Na])CCCCCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: O=C(O)CCC(=O)O

Procedure:
4 ml of a methanolic solution containing 165 mg (0.255 mmol) of 1-{4-t-butyl-3-[2-(9H-xanthen-9-yl)acetamido]phenyl}-6-phenylhexyl hydrogen succinate (prepared as described in Example 54) were cooled in an ice bath, and then 2.42 ml (0.242 mmol) of a 0.1N aqueous solution of sodium hydroxide was added dropwise. The reaction solution was condensed by evaporation under reduced pressure, whilst keeping its temperature below 15° C. 20 ml of toluene were added to the residue, and then sufficient ethanol was added until the solution became homogenous. The solvent was then was removed by distillation under reduced pressure. In order to remove any remaining water, toluene was added to the residue and the mixture was distilled again. This procedure was repeated several times, and gave 170 mg (a quantitative yield) of the title compound as a foam-like substance.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][C@H:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C=O)C>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][C@H:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:17]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:37][CH:36]=[CH2:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 0.33 h
Yield: 82 %

Procedure:
(S)-2-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-1-phenyl-1-(N-t-butoxycarbonylamino)ethane (1.1g, Example 2b) was dissolved in 20ml anhydrous DMF and sodium hydride (0.085g) was added. The reaction mixture was stirred for 20 min and allyl bromide (0.300g) added and stirred for a further 16h. The reaction was quenched by the addition of water (30ml) and poured into 100ml ethyl acetate. The organic layer was washed with water (3×20ml), brine and dried (MgSO4). The solvent was removed in vacuo and the residue chromatographed on silica eluting with 10% Ethyl acetate/hexane to give (S)-2-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1-phenyl-1-(N-t-butoxycarbonyl-N-allylamino)ethane as a colourless oil 0.980g. m/z=504 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].Cl[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[O:12][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1O
Reactant: Clc1ncccc1-c1ccncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dissolved 2,6-dimethyl-3-nitrophenol (1.96 g, 11.7 mmol) and 4-(2-chloropyridin-3-yl)pyrimidine (1.50 g, 7.83 mmol) in dimethylsulfoxide (15.0 ml) and added cesium carbonate (5.10 g, 15.7 mmol). Reaction mixture was heated to 1200C in a sealed tube for 8 hours. Reaction mixture was then allowed to cool to room temperature and then poured into 250 mL of rapidly stirring water in an Erlenmeyer flask. After 10 minutes, the opaque brown aqueous solution was cooled to 0° C. and allowed to stand for 10 minutes, then filtered. The precipitate was collected as the title compound. MS m/z=323 (M+H)+. Calc'd for C17H16N4O3: 324.34.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:14]2)=[CH:9][CH:8]=1>FC(F)(F)C(O)=O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:14]2)=[CH:9][C:8]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
2.24 ml of fuming nitric acid were added dropwise with stirring to 14.3 g of the product of Step C in 50 ml of trifluoroacetic acid at 0° C. The temperature was allowed to return to ambient and the mixture was stirred for 1 hour. After pouring the mixture on ice, extracting with methylene chloride, washing with water, drying, evaporating to dryness under reduced pressure, and purifying by chromatography over silica (eluent benzene--ethyl acetate 9-1), 12.3 g of 3-(4-methoxy-3-nitrophenyl)-1-(trifluoroacetyl)-piperidine were obtained which after crystallization from isopropyl ether melted at 96° C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.Cl.[CH2:15]([C:19]1([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18].C([BH3-])#N.[Na+].CO.C(Cl)(Cl)Cl>CO.C(O)(=O)C>[CH2:15]([C:19]1([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][N:22]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CCCCC1(N(C)C)CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCC1(N(C)C)CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 113 %

Procedure:
A solution of 4.73 g (1 equiv.) of tert-butyl methyl(2-oxoethyl)carbamate in 20 ml of methanol was added at room temperature to a solution of 7 g (1 equiv.) of 4-butyl-N,N-dimethylpiperidine-4-amine bis hydrochloride in 50 ml of methanol, and the resulting reaction mixture was stirred for 50 minutes at room temperature. 3.43 g (2 equiv.) of sodium cyanoborohydride were added in portions to this reaction mixture, and stirring was then carried out for 12 hours at room temperature. The progress of the reaction was monitored by thin-layer chromatography (20% MeOH/CHCl3). When the reaction was complete, the reaction mixture was cooled to 0° C. and adjusted to a pH of ˜5 with acetic acid. 2 g of tert-butyl formylmethyl-methylcarbamate and 1.7 g of sodium cyanoborohydride were then added, and the reaction mixture was stirred for a further 60 minutes at room temperature. Finally, the methanol was distilled off, 100 ml of saturated NaHCO3 solution were added, the resulting mixture was extracted with ethyl acetate (2×200 ml), and the combined organic phases were dried over Na2SO4. After removal of the solvent under reduced pressure, 10.5 g of crude product were obtained in the form of a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][OH:17])[CH2:10][CH:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:27][C:28](Cl)=[O:29].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:27][C:28]3=[O:29])[CH2:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(Br)cnc1C1=CCC(NCCO)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cnc1C1=CCC(N2CCOCC2=O)CC1

Procedure:
To a solution of 2-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-yl]aminoethanol (860 mg) and triethylamine (0.424 ml) in dichloromethane (10 ml) was added chloroacetic acid chloride (0.242 ml) under ice-cooling with stirring. The mixture was stirred at the same temperature for 1 hour, then water was added thereto, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was dissolved in isopropyl alcohol (10 ml), and hydroxide potassium (129 mg) was added thereto at room temperature with stirring. The mixture was stirred at the same temperature for 8 hours, and then to the reaction solution was added water, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (855 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:7](=O)[C:6]=2[CH:20]=1.C1(C)C(S([CH2:30][N+:31]#[C-])(=O)=O)=CC=CC=1.[O-]CC.[Na+].[Na]>O1CCCC1.C(O)C>[C:30]([CH:7]1[C:6]2[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8]1)#[N:31]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: O=C1CC(CCc2ccccc2)Oc2ccc(F)cc21
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC1CC(CCc2ccccc2)Oc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one (8.9 gm) was dissolved in anhydrous tetrahydrofuran, and toluenesulfonylmethylisocyanide (12.9 gm) added, followed by freshly prepared sodium ethoxide in ethanol (prepared from sodium (1.5 gm) in ethanol (60 mL) and the mixture stirred at room temperature overnight. The mixture was then concentrated in vacuo, and the residue partitioned between ethyl acetate and H2O, and the organic layer washed with H2O, brine, dried, filtered and evaporated. The residue was purified by column chromatography (2:1 hexanes/diethyl ether) to yield 4-cyano-2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran (2.7 gm, ir: 2250 cm-1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].[CH3:9][O:10][CH2:11][CH2:12][Br:13]>>[BrH:13].[CH3:9][O:10][CH2:11][CH2:12][N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]1=[NH:8]
Reactant: Cc1nc(N)sc1C
Reactant: COCCBr
Product: Br
Product: COCCn1c(C)c(C)sc1=N
Temperature: 85 °C
Yield: 53.5 %

Procedure:
A mixture of 4,5-dimethylthiazol-2-ylamine (9.0 g, 70 mmol) and 2-bromoethyl methyl ether (7.9 mL, 84 mmol) were heated at 85° C. for 12 hours. The mixture was cooled to ambient temperature and then triturated with isopropanol. The solid was collected by filtration and dried under vacuum to provide 10 g (56%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ ppm 2.17 (s, 3H), 2.19 (s, 3H), 3.25 (s, 3H) 3.56 (t, J=5.1 Hz, 2H) 4.16 (t, J=5.1 Hz, 2H) 9.41 (s, 1H); MS (DCI/NH3) m/z 129 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Reactant: NCc1ccc(F)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.