Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=3[N+:26]([O-])=O)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:29])[N:4]([CH3:30])[C:3]1=[O:31]>C(O)C>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][C:19]=3[NH2:26])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:29])[N:4]([CH3:30])[C:3]1=[O:31]
Reactant: CSc1ccc(OCCCN2CCN(c3cc(=O)n(C)c(=O)n3C)CC2)c([N+](=O)[O-])c1
Solvent: CCO
Product: CSc1ccc(OCCCN2CCN(c3cc(=O)n(C)c(=O)n3C)CC2)c(N)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
2.0 g of the Compound v obtained in Reference Example 17 was dissolved in 20 ml of ethanol, and 4.5 g of stannic chloride (II) was added dropwise. The solution was heated up to 70° C. and then stirred for 30 minutes. The precipitated insolubles were removed by filtration, and the filtrate was then diluted with 100 ml of chloroform. Next, 20 ml of a 1N aqueous sodium hydroxide solution was added to the solution, followed by stirring vigorously. The formed insolubles were removed by filtration, and the resultant chloroform layer was separated, washed with water, dried over anhydrous sodium sulfate and then concentrated. The thus obtained oily product was purified through a silica gel column chromatograph (chloroform/methanol=100/1 in volume ratio), thereby obtaining 0.62 g of 1,3-dimethyl-6-[4-(3-[2-amino-4-methylmercaptophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 114).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH2:16])[CH:8]=2)[CH2:3][CH2:2]1.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH:16][C:20]([CH:17]3[CH2:19][CH2:18]3)=[O:21])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(N2CCOCC2)n2nccc2n1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(N2CCOCC2)n2nccc2n1)C1CC1

Procedure:
7-Morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9A, 0.10 mmol) in pyridine (0.4 ml), cyclopropanecarboxylic acid (0.15 mmol) in pyridine (0.4 ml), HATU (0.17 mmol) in pyridine (0.4 ml) and DIEA (0.34 mmol) are mixed together before microwave irradiation at 150° C. for 6 minutes. The crude product was then purified by preparatory HPLC to give the titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00-1.09 (m, 2H) 1.09-1.16 (m, 2H) 1.99-2.09 (m, 1H) 3.91-3.98 (m, 4H) 4.12-4.21 (m, 4H) 6.47 (d, J=2.26 Hz, 1H) 7.27 (s, 1H) 7.51 (s, 1H) 7.98 (d, J=2.07 Hz, 1H) 13.03 (br. s., 1H); ESI-MS: m/z 288 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:11].[N:13]#[C:14]Br.C(O)C>O>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:11][C:14]([NH2:13])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: N#CBr
Reactant: COC(=O)c1cccc(N)c1O
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccc2nc(N)oc12
Yield: 76 %

Procedure:
A mixture of 913 mg (5.46 mmol) 3-amino-2-hydroxy-benzoic acid methyl ester, 894 mg (8.19 mmol) of cyanogen bromide, 14.4 mL of ethanol and 1.6 mL of water was heated under reflux for 1 h. Ethanol was evaporated under reduced pressure and 20 mL of 2 N aq. Na2CO3 was added to the residue. The precipitated solid was filtered and washed with water. The remaining product was treated with methanol and the soluble filtrate containing the product was evaporated in vacuo to provide 797 mg (4.15 mmol, 76%) of 2-amino-benzooxazole-7-carboxylic acid methyl ester. LCMS: 193 (M+1)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12](B(O)O)=[C:11]([CH3:19])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[C:24]([O:26][CH3:27])=[O:25].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:29]2[C:30]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:21][CH:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[CH:28]=2)=[C:11]([CH3:19])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1B(O)O
Reactant: COC(=O)c1ccc(OC(C)C)c(Br)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(OC(C)C)c(-c2c(C)cc(O[Si](C)(C)C(C)(C)C)cc2C)c1
Yield: 81.8 %

Procedure:
A mixture of (4-{[tert-butyl(dimethyl)silyl]oxy}-2,6-dimethylphenyl)boronic acid (500 mg, 1.83 mmol) and methyl 3-bromo-4-isopropoxybenzoate (667 mg, 2.38 mmol) was dissolved in a mixture of 2 M aqueous sodium carbonate solution (2.38 mL) and toluene (20 mL), and after argon substitution, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (118 mg, 0.29 mmol) and tris(dibenzylideneacetone)dipalladium(0) (67.0 mg, 0.07 mmol) were added. The reaction mixture was heated under reflux under an argon atmosphere for 1 day. The reaction mixture was cooled, and brine was added. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-hexane/ethyl acetate=10/1) to give the title compound (642 mg, yield 82%) as a yellow oil.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[C:25]([CH3:31])=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[C:25]([CH3:31])=[C:26]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c(N)cccc1F
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(F)c2C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3-fluoro-2-methylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.94 (s, 3H), 2.06 (s, 3H), 2.14 (s, 3H), 4.32 (bs, 2H), 6.76 (bs, 1H), 6.86-6.95 (m, 1H), 7.01-7.13 (m, 3H), 7.17 (t, J=6.4 Hz, 1H), 7.63 (t, J=8.4 Hz, 1H), 7.75 (s, 1H), 8.43 (d, J=4.2 Hz, 1H); MS (ESI) m/z 338.2 (M+1)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[C:6](=[C:17](Cl)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]([N:32]([CH3:40])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)=[O:31])[CH3:28]>>[CH3:28][N:27]([CH2:29][C:30]([N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:37][CH:38]=1)[CH3:40])=[O:31])[CH3:26]
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccc(C(F)(F)F)cc21
Product: CN(C)CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(F)(F)F)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine
Reaction SMILES: [CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([NH2:26])=O)[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]#[N:26])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4]
Reactant: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(N)=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.3 %

Procedure:
To a solution of 6-[2-(butan-2-yl)-6-chloro-5-methoxyindol-1-ylmethyl]pyridine-2-carboxamide (118 mg) in dichloromethane (1.6 mL) were successively added triethylamine (0.225 mL) and trifluoroacetic anhydride (0.112 mL) under ice-cooling. This mixture was stirred at room temperature for 22 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (98 mg). 1H-NMR (CDCl3) δ ppm: 0.86 (3H, t, J=7.4 Hz), 1.24 (3H, d, J=6.8 Hz), 1.45-1.80 (2H, m), 2.60-2.75 (1H, m), 3.93 (3H, s), 5.40 (2H, s), 6.31 (1H, s), 6.50-6.65 (1H, m), 7.11 (1H, s), 7.14 (1H, s), 7.50-7.70 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][CH2:8][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:11][C:5]=2[C:4]=1OS(C(F)(F)F)(=O)=O)#[N:2].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:28]([NH:35][C:4]1[C:5]2[CH2:11][CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7][C:6]=2[CH:18]=[CH:19][C:3]=1[C:1]#[N:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1ccc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)C(F)(F)F)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1NCc1ccccc1)CCN(C(=O)C(F)(F)F)CC2
Yield: 53.6 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-cyano-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (125 mg, 0.3 mmol) with benzylamine (0.1 mL, 0.9 mmol) using palladium(II) acetate (7 mg, 0.03 mmol), BINAP (37 mg, 0.06 mmol) and cesium carbonate (137 mg, 0.4 mmol) in toluene (3 mL). Purify by chromatography on silica gel eluting with heptane/EtOAc (4:1 to 1:1) to give 6-benzylamino-7-cyano-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (60 mg, 54%). ES (ES+) m/z: 374 (M+H)+.
Reaction SMILES: CO.Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:13][S-:14].[Na+]>O>[CH3:13][S:14][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1ncccc1[N+](=O)[O-]
Reaction time: 17 h
Yield: 63.5 %

Procedure:
A methanol (50 ml) solution of 2-chloro-3-nitropyridine (4.30 g, 27.1 mmol) was added dropwise to a methanol (30 ml) solution of sodium thiomethoxide (2.10 g, 28.5 mmol) while being cooled with ice, and the mixed solution was stirred for 17 hours. Water was then added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crystals were recrystallized from a mixture of an ethyl acetate-hexane mixture to obtain 2.93 g (yield 64%) of 2-methylthio-3-nitropyridine as a yellow needle crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[C:6]([OH:12])[CH:5]=1.[CH3:14]OS(OC)(=O)=O.[OH-].[Na+].OS(O)(=O)=O>O>[OH:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:14])[C:7]=1[OH:11])[C:3]([O:2][CH3:1])=[O:13]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(O)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47 %

Procedure:
To a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na2B4O7 (50 g) in water (1000 mL) was added Me2SO4 (120 mL) and aqueous NaOH solution (25%, 200 mL) successively at room temperature. The mixture was stirred at room temperature for 6 h before it was cooled to 0° C. The mixture was acidified to pH˜2 by adding conc. H2SO4 and then filtered. The filtrate was extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.Cl>O1CCCC1>[CH3:1][N:2]1[C:6]([B:12]([OH:17])[OH:13])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nccc1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred solution of 1-methyl-1H-pyrazole (2.49 mL, 30 mmol) in tetrahydrofuran (100 mL) was added butyllithium (2.5 M in hexane, 15.6 mL, 39 mmol) at −78° C. dropwise. After stirring for 1 hour, triisopropyl borate (27.6 mL, 120 mmol) was added and the reaction mixture was gradually warmed to room temperature for 16 hours. Hydrochloric acid (1 N aqueous solution) was added to the reaction mixture until pH 7 achieved. The mixture was extracted with dichloromethane:methanol (9:1, 5×200 mL). Combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to obtain crude residue. Purification was undertaken by flash column chromatography (ISCO™) eluting with dichloromethane:methanol (7:3, by volume) to afford the title compound as a white solid, 1258 mg, 33% yield.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:22][OH:23])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1.Cl[C:25]1[CH:26]=[C:27]2[N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:12]=1)[CH2:22][O:23][C:25]1[CH:26]=[C:27]2[NH:34][CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(C(F)(F)F)c3)c(F)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E65 using NaH (11.04 mg, 0.276 mmol), (3-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenoxy)-phenyl)methanol (56.0 mg, 0.184 mmol) and tertbutyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (50 mg, 0.18 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29]/[CH:30]=[C:31]1/[C:32]2[CH:45]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:43]=[CH:42][C:33]=2[O:34][CH2:35][C:36]2[N:41]=[CH:40][CH:39]=[CH:38][C:37]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:14]2[CH2:18][CH2:17][N:16]([CH2:28][CH2:29][CH:30]=[C:31]3[C:37]4[CH:38]=[CH:39][CH:40]=[N:41][C:36]=4[CH2:35][O:34][C:33]4[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]3=4)[CH2:15]2)[CH2:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: CCNC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCNC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-N-ethyl-acetamide (0.09 g, 0.31 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.07 g, 0.51 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.095 g, 0.25 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]1.O.NN>CO.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:18]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCN(C(C)C)CC2)c(F)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(N2CCN(C(C)C)CC2)c(F)cc1N
Temperature: 64 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To 1-[2-fluoro-5-(methyloxy)-4-nitrophenyl]-4-(1-methylethyl)piperazine (2.0 g, 6.7 mmol) in MeOH (100 mL) was added iron (III) chloride (0.3 g, 2.0 mmol) and actived carbon (2.0 g). The reaction mixture was stirred at 64° C. for 20 min before the dropwise addition of hydrazine hydrate (4.0 mL, 80.7 mmol) over 5 min. The reaction was kept stirring at 64° C. for additional 4 h. Filtration, concentration of the residue, and purification via column chromatography on SiO2 (0-10% 2 M NH3 in MeOH/DCM) afforded 5-fluoro-4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline as a dark brown solid (1.7 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) 5 ppm 0.96 (d, J=6.6 Hz, 6 H), 2.45-2.54 (m, 4 H), 2.62 (dt, J=13.0, 6.6 Hz, 1 H), 2.79-2.86 (m, 4 H), 3.69 (s, 3 H), 4.55 (s, 2 H), 6.38 (d, J=13.6 Hz, 1 H), 6.49 (d, J=8.2 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Product: COCc1cc(Nc2cccc(OC)c2)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (100 mg, 0.402 mmol) and m-anisidine (45 μl, 0.402 mmol) similar to Example 13 and isolated as a tan solid (154 mg). 1H NMR (CDCl3): 8.23 (d, J=9.0 Hz, 2H), 7.34 (s, 1H), 7.25-7.16 (m, 4H), 6.92-6.89 (m, 1H), 6.75 (s, 1H), 6.69-6.65 (m, 1H), 4.51 (s, 2H), 3.78 (s, 3H), 3.47 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[CH3:20][NH2:21]>O1CCOCC1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([CH2:2][NH:21][CH3:20])=[CH:4][CH:5]=1
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reactant: CN
Solvent: C1COCCO1
Product: CNCc1ccc(C(=O)Nc2ccccc2OC)cc1
Yield: 100 %

Procedure:
4-Chloromethyl-N-(2-methoxyphenyl)benzamide (400 mg, 1.45 mmol) was dissolved in dioxane (4 ml) and then mixed with 50% methylamine aqueous solution (4 ml) at room temperature. After 1 hour of stirring at the same temperature, dioxane was removed by evaporation, and the resulting residue was diluted with methylene chloride (10 ml). After drying on anhydrous sodium carbonate, the solvent was removed by evaporation to obtain 500 mg (100%) of the title compound in the form of colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](O)=[O:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:45]([Si:49]([CH3:60])([CH3:59])OCCN1C=CC(N)=N1)([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl>[C:45]([Si:49]([CH3:60])([CH3:59])[O:23][CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:3]=[CH:2][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:6][CH:5]=2)[CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[N:17]1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
The 3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 3, 184 mg, 0.62 mmol) was dissolved in methylene chloride (3 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (31 μL, 0.62 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (144 μL, 1.24 mmol) was added dropwise. A strong exotherm and bubbling were observed. The solution continued to stir at 0° C. for 10 min. The 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 150 mg, 0.62 mmol) was added as a solution in methylene chloride (3 mL), the ice bath was removed and the solution continued to stir at 25° C. for 25 min. The solution was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (150 mg, 44%) as a white foam: ESI-LRMS m/e calcd for C26H41N3O4SSi [M+] 519.26, found 520.36 [M+H+].
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:14]=[CH:15][CH:16]=[CH2:17]>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]=[CH:11][CH:12]=[CH2:13].[CH:15]([Li:9])([CH2:16][CH3:17])[CH3:14]
Reactant: [Li]CCCC
Agent: C=CC=C
Solvent: C=Cc1ccccc1
Product: [Li]C(C)CC

Procedure:
After a first addition of styrene, the mixture was polymerized for 15 minutes. A second addition of initiator (s.-BuLi 2) was made to initiate new polymer chains, and further styrene was added in portions to continue block build-up. The reaction time for build-up of a styrene block was 15 minutes, and that for a butadiene block was 40 minutes. The polymerization was terminated by adding 3 mL of isopropanol. 0.1% by weight of Kerobit TBK (2,6-di-tert-butyl-p-cresol), based on the solids content of the block copolymer, was added for stabilization. Table 4 gives the amounts of styrene, butadiene, and sec-butyllithium used in each of the stages, and also gives the properties of the resultant block copolymer mixtures.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ccc(C2(CN)CCC(F)(F)CC2)cn1
Product: Cc1ccc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and (4,4-difluoro-1-(6-methylpyridin-3-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=413.2, tR (minutes, Method D)=0.51