Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Brc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(Br)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.6 g), triethylamine (2.8 cc) and 4-(4-bromophenyl)piperazine (4.8 g) in toluene (60 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (40 cc), 2-{3-[4-(4-bromophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd ]isothiazole 1,1-dioxide (4.3 g) is obtained, m.p. 149° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]3=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:16][CH2:15][N:14]([CH3:23])[CH2:13][C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]3=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc2c(c1)CNCCC2c1ccc2[nH]ccc2c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC(c2ccc3[nH]ccc3c2)c2ccccc2C1
Yield: 50 %

Procedure:
5-(1H-indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was subjected to reductive amination using formaldehyde and sodium triacetoxyborohydride in 1,2-dichloroethane to give 5-(1H-indol-5-yl)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a white powder in 50% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])=[O:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(CC)CC>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]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:9]2[C:8]3[C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:35]=[CH:36][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=5)=[CH:3][C:4]=4[S:14][C:13]=3[C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5ccc(S(C)(=O)=O)cc5)ccc4c23)cc1
Temperature: 150 °C

Procedure:
To a suspension of 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile (Example 12, Step 9) and [4-(methylsulfonyl)phenyl]boronic acid (1.5 equiv) in 1-PrOH/H2O (4.5/1) (0.11 M) was added Pd2(dba)3 (0.03 equiv), Ph3P (0.06 equiv) and Et2NH (1.2 equiv). The mixture was degassed and heated to 150° C. for 10 min in a microwave reactor. The mixture was diluted with H2O and filtered. The crude product was swished with hot EtOH to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:31][CH2:32]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([NH:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1)=[O:6]
Reactant: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Reactant: Nc1nnn[nH]1
Product: Cc1cc(Oc2cc(Cl)c(C(=O)Nc3nnn[nH]3)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Yield: 15 %

Procedure:
The title compound was prepared in analogy to Example 39, from 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid (Example 66) and 5-amino-1H-tetrazole (commercially available, CAS RN 4418-61-5). The compound was purified twice by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 95:5) to give 17 mg (15%) of the title compound as a white solid. MS (ESI): m/z=563.109 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH:9]=[CH:10][C:5]=2[NH:4][N:3]=1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH:9]=[C:10]([Br:19])[C:5]=2[NH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-n1ccc2[nH]nc(N)c2c1=O
Solvent: CC#N
Product: Cc1ccccc1-n1cc(Br)c2[nH]nc(N)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a mixture of 3-amino-5-(2-methylphenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step E (200 mg) and acetonitrile (6 mL) was slowly added a solution of N-bromosuccinimide (163 mg) in acetonitrile (2 mL) under ice-cooling. The reaction mixture was stirred overnight at room temperature, and the resulting solid was collected by filtration, and washed with acetonitrile. The obtained solid was purified by silica gel chromatography (methanol/dichloromethane) to give the title compound (127 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](C)[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH:11](=O)C1C=CC=CC=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[NH:10][CH:11]=[N:9]2
Reactant: O=Cc1ccccc1
Reactant: Cc1nc(N)c(N)c(Cl)n1
Product: Clc1ncnc2nc[nH]c12

Procedure:
In Step 1, 6-chloro-2-methyl-4,5-pyrimidinediamine is reacted with a benzaldehyde (3) to provide a 6-chloropurine (6), essentially as described in Scheme 1, Step 2, above. In Step 2, a 6-chloropurine (6) is reacted with a piperazine (5) to provide a piperazinyl purine (7) essentially as described in Scheme 1, Step 3, above.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16]2[C:37]([CH3:41])=[CH:38][CH:39]=[CH:40][C:15]1=2)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[C:1]([N:21]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:12]([O:11][CH:8]([CH3:10])[CH3:9])=[O:13])[C:15]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:16]1=2)(=[O:3])[CH3:2]
Reactant: Cc1cccc2c1C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C(=O)OC(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cccc(C)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (423 mg, 1.62 mmol) followed by titanium isopropoxide (645 mg, 2.27 mmol) to 6-Methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (423 mg, 1.62 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (6.7 mL) and sodium borohydride (92 mg, 2.43 mmol) and stir the mixture under nitrogen at room temperature for 45 min. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-5-(3,5-Bis-trifluoromethyl-benzylamino)-6-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (27 mg, 3%). Add acetic anhydride (0.037 mL, 0.39 mmol) dropwise to a solution of the amine (27 mg, 0.055 mmol) and pyridine (0.038 mL, 0.43 mmol) in dichloromethane (0.5 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (28 mg, 96%); MS (ES+): 531 (M+H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[N:23]=[C:22]([CH:24]=O)[CH:21]=[CH:20][CH:19]=1.CS(O)(=O)=O>>[CH:1]1([N:6]2[C:10]3=[N:11][C:24]([C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:17])[N:23]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cccc(C=O)n1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: CS(=O)(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(C)n3)nc(=O)c1-2
Yield: 53.3 %

Procedure:
1-Cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9.0 mmol), 6-methyl-2-pyridinecarboxaldehyde (2.2 g, 18.0 mmol), methanesulfonic acid (0.5 ml) and xylenes (80 ml) were combined and heated to reflux for 24 hours. The solvents were removed in vacuo, ethanol was added and the solvents were removed in vacuo. The residue was partitioned between 10% K2CO3 and chloroform, the organic layer was separated and the aqueous layer was extracted with chloroform (3×200 ml). The combined organic layers were concentrated in vacuo, redissolved in dichloromethane and combined with silica gel (40 g). The slurry was air dried for 3 hours, and placed on a silica gel column (150 g). Elution with ether and concentration of the solvent in vacuo and drying the residue at 40° C. in high vacuum for 6 hours afforded 1.55 g (53%) of 1-cyclopentyl-3-ethyl-6-(6-methyl-2-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5](Cl)=[CH:6][C:7]=1[Cl:8].[CH2:14]([O:16]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:15].[F-].[Cs+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([C:14](=[O:16])[CH3:15])=[CH:6][C:7]=1[Cl:8]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1nc(C(C)=O)cc(Cl)c1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A solution of methyl 3,4,6-trichloropyridine-2-carboxylate (2.00 g, 8.31 mmol), ethoxyvinyltributyltin (3.09 mL, 9.15 mmol) and cesium fluoride (2.78 g, 18.30 mmol) in dioxane (50 mL) was sparged with nitrogen for 15 minutes. Dichlorobis(triphenylphosphine) palladium(II) (292 mg, 0.42 mmol) was then added and the mixture heated at 100° C. for 3 hours. After cooling, the mixture was concentrated, taken up into ethyl acetate and was filtered through a silica gel plug. The solvent was removed and the crude ethoxyvinyl intermediate was then dissolved in a solution of tetrahydrofuran (50 mL) and 1N HCl acid (20 mL). After stirring the mixture at room temperature overnight, the tetrahydrofuran was removed in vacuo and the remaining aqueous phase extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), and concentrated. Purification by column chromatography (10% ethyl acetate in hexane) provided methyl 3,4-dichloro-6-acetylpyridine-2-carboxylate (0.98 g, 3.95 mmol) as a white solid; 1H NMR (CDCl3): δ 8.20 (s, 1H), 4.05 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: C([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)(=O)C.BrC[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>[O-]CC>[NH2:4][CH:5]([CH2:6][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Product: CCOC(=O)CCCCCCC(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) and absolute ethanol (30 ml)) and the mixture was refluxed for 27 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract was evaporated to give crude diethyl acetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, δ2.2(3H, singlet, --COCH3), 4.17(6H, multiplet, 3×--OCH2 --CH3). This amide was refluxed with concentrated hydrochloric acid (111 ml) for 51/2 hours, the cooled solution was washed with ether, and the aqueous layer was decolorised with activated charcoal and evaporated to dryness in vacuo. The residual colourless glass was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for 1 hour, refluxed for 11/2 hours, cooled, and poured into ice-water, adjusting the pH to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-aminononanedioate (55% yield) as a colourless oil, b.p. 114°-115°/0.02-0.03 mm.
Reaction SMILES: [C:1]1([N:7]=[C:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCCCCC>[C:1]1([N:7]=[C:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Solvent: CCCCCC
Product: C(=Nc1ccccc1)=Nc1ccccc1

Procedure:
A mixture of 3,619 g. of the copolymer prepared as described in Example 2 and a solution of 30.5 g. of phenyl isocyanate in 100 ml. of n-hexane was heated under reflux for 9.25 hours. At the end of this time the solid catalyst was removed by filtration and the filtrate was evaporated to dryness to yield diphenyl carbodiimide. An infrared spectrum of the product revealed only a trace of unreacted isocyanate. In contrast, a solution of phenyl isocyanate in n-hexane, heated under reflux for the same length of time but in the absence of catalyst, showed no significant amount of absorption corresponding to carbodiimide linkages in the infrared spectrum.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH2:21][C:22]1([CH2:28][CH2:29][OH:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>C(Cl)Cl>[O:19]([CH2:20][CH2:21][C:22]1([CH2:28][CH2:29][OH:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCC1(CCO)CCCCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.1 %

Procedure:
tert-Butylchlorodiphenylsilane (34.4 mL, 0.132 mol) was added dropwise to a solution of 2-[1-(2-hydroxyethyl)cyclohexyl]ethanol (21.7 g, 0.126 mol) in methylene chloride (280 mL) while cooling on ice. After stirring the mixture for 14 hours at room temperature, 25% aqueous ammonium chloride (300 mL) was added and extraction was performed. The organic layer was washed with saturated aqueous sodium chloride, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (500 g Merck Art. 9385, hexane:ethyl acetate=4:1) to obtain the title compound as a colorless oil (36.8 g) (2 steps, 60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O)[CH3:10].C(COC)OC.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCOc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1ccccc1-c1cc(Cl)ncn1

Procedure:
To a solution of 4,6-dichloropyrimidine (6.0 g, 0.04 mol) and 2-ethoxyphenylboronic acid (4.81 g, 0.029 mol) in mixture of dimethoxyethane (120 mL) and water (18 mL) were added NaHCO3 (6.72 g, 0.08 mol) and (PPh3)2PdCl2 (0.84 g) and the reaction mixture was allowed to reflux for 8 h, then it was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), the resulting solution was washed with water (20 mL), dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica (eluent CH2Cl2) and recrystallized from hexanes. Yield of 4-chloro-6-(2-ethoxyphenyl)-pyrimidine 4.97 g (73%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:18][CH2:17][C:16]([F:25])([F:24])[F:15])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Reactant: CS(=O)(=O)OCCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OC)c(OCCC(F)(F)F)c1

Procedure:
The mixture of 3-hydroxy-4-methoxy-benzoic acid ethyl ester (1.75 g, 8.92 mmol), methanesulfonic acid 3,3,3-trifluoro-propyl ester (2.06 g, 10.7 mmol) and anhydrous K2CO3 (2.49 g, 17.8 mmol) in acetone (20 mL) is heated with stirring at reflux temperature overnight. After cooling, the mixture is diluted with AcOEt followed by washing of the organic phase with 2N aqueous NaOH and brine. The organic layer is dried over Na2SO4 and evaporated, and the crude product is purified by silica gel chromatography (eluent: hexane/AcOEt 5:1) to give the title compound as oil. TLC, Rf (hexane/AcOEt 1:1)=0.59. MS: 293.0 [M+H]+. 1H-NMR (CDCl3): δ 1.42 (t, 3H), 2.74 (m, 2H), 3.96 (s, 3H), 4.33 (m, 2H), 4.40 (m, 2H), 6.94 (m, 1H), 7.59 (s, 1H), 7.77 (m, 1H) ppm.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:15]([OH:16])[CH:14]=1>CN(C=O)C.CCOCC>[CH:1]([O:16][C:15]1[CH:14]=[C:13]([CH:21]=[CH:20][C:17]=1[O:18][CH3:19])[CH:12]=[O:11])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C=O)cc1OC(C)C
Temperature: 80 °C

Procedure:
Isopropyl bromide (19.0 mL, 200 mmol) was added to a suspension of K2CO3 (42.0 g, 302 mmol) and isovanillin (23 g, 151.3 mmol) in DMF (100 gmL) and the stirring slurry heated to 80° C. for 13 h. The reaction mixture was then cooled to room temperature, diluted with ether (200 mL) and washed with H2O (4×200 mL), dried (MgSO4) and concentrated under reduced pressure giving the title compound as a slightly tan oil (29.3 g, 100%) which required no further purification. The spectra of this material are identical with those previously reported (H. Ishii, I.-S. Chen and T. Ishikawa J. Chem. Soc., Perkin Trans. 1, 1987, 671.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([CH2:21][CH2:22][C:23]2[S:24][C:25]([CH2:29][CH3:30])=[C:26]([CH3:28])[N:27]=2)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]=[C:42]([CH2:44]Cl)[CH:43]=1)[C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:14]=[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:12]=[C:11]([CH2:21][CH2:22][C:23]2[S:24][C:25]([CH2:29][CH3:30])=[C:26]([CH3:28])[N:27]=2)[N:10]=1)[CH2:44][C:42]1[CH:41]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[CH:35]=[C:34]([Cl:33])[CH:43]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1sc(CCc2cc(N3CCOCC3)cc(NC(=O)OC(C)(C)C)n2)nc1C
Reactant: COC(=O)c1cc(Cl)cc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1sc(CCc2cc(N3CCOCC3)cc(N(Cc3cc(Cl)cc(C(=O)OC)c3)C(=O)OC(C)(C)C)n2)nc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-tert-butoxycarbonylamino-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine (500 mg) obtained in Example 109-(1) was dissolved in dimethylformamide (12 ml), and 60% sodium hydride (58 mg) was added under cooling with ice, followed by stirring at room temperature for one hour. The reaction solution was cooled with ice, and a solution of methyl 3-chloro-5-chloromethylbenzoate (438 mg) in dimethylformamide (5 ml), was added thereto, followed by stirring at room temperature for 13 hours. The reaction solution was diluted with ethyl acetate, washed with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the above identified compound (628 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[NH:10][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:8])(=[O:19])[CH3:18]
Reactant: CC(=O)c1cccc(N)c1
Reactant: Cc1cc(C(=O)Cl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cccc(NC(=O)c2cc(C)on2)c1

Procedure:
A solution of 5-methyl-3-isoxazolecarbonyl chloride (14.5 g) in acetone (30 ml) was added to a solution of m-aminoacetophenone (13.8 g) in acetone (280 ml) in the presence of anhydrous potassium carbonate (21.0 g). The mixture was stirred for 1/2hour, and then diluted with water. The precipitated product was filtered, washed with water and dried. Yield = 20.5 g (83%), m.p. 188°-190°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[C:15]1([NH:14][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=S)c1cnc(C)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
A mixture of 4 g (17.2 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate and 5 g (54 mmol) of aniline in 40 ml of dioxan was stirred at room temperature for 24 hours. The mixture was then evaporated and 100 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed with 50 ml of aqueous hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The resulting solid was purified by crystallisation from aqueous ethanol to give 3.5 g (64%) of ethyl 4-phenylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.