Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)c2cccnc2c1OCc1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-bromo-8-hydroxy-[1,6]-naphthyridine-7-carboxylate (7.73 g, 27.4 mmol), 4-methoxybenzyl chloride (5.15 g, 32.9 mmol), and Cs2CO3 (10.7 g, 32.9 mmol) in DMF (150 mL) was stirred in an oil bath at 50° C. overnight. Additional quantity of 4-methoxybenzyl chloride (0.6 g), and Cs2CO3 (1 g) was added, and the mixture heated at the same temperature for 8 hour. The resulting mixture was filtered and concentrated under vacuum. The residue was partitioned between dichloromethane and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in boiling ethyl acetate (150 mL), hexane was added until solution turn cloudy. The resultant slurry was stirred at room temperature overnight. The solid precipitated was collected by filtration to provide methyl 5-bromo-8-[(4-methoxybenzyl)oxy]-[1,6]-naphthyridine-7-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:34])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[S:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH3:34])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[S:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1Cn1c(SCC(=O)OC(C)(C)C)nc(=O)c2sc(N3CCOCC3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)cccc1Cn1c(SCC(=O)O)nc(=O)c2sc(N3CCOCC3)nc21
Reaction time: 5 h

Procedure:
To a solution of 1,1-dimethylethyl {[4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]thio}acetate (182 mg, 0.348 mmol) in Dichloromethane (DCM) (2 mL) in a 20 mL Scintillation vial stirred at rt was added TFA (2 mL, 26.0 mmol). After sitting at rt for 5 hr LC/MS analysis indicated complete conversion to the acid. The DCM/TFA was removed in vacuo and the resulting residue was taken up in DCM. Attempts to extract the desired product into 1 N NaOH solution led to emulsions, so the pH was adjusted to 2 and the DCM layer was concentrated and to the residue was added water and the resultant solid was isolated by filtration and then purified by reverse phase prep HPLC on 30 mm prep column eluting with a gradient 25% to 55% AcCN over 12 minutes. LC/MS (ES) m/z=467 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 7.35 (d, 1H), 7.09 (t, 1H), 6.61 (d, 1H), 5.56 (s, 2H), 4.01 (s, 2H), 3.83 (m, 4H), 3.59 (m, 4H), 2.49 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[N:3]=[CH:4][N:5]=1
Reactant: c1cn[nH]c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(-n2cccn2)ncn1
Yield: 66.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), 1H-pyrazole (2.72 g, 40.0 mmol), and cesium carbonate (13.03 g, 40.0 mmol) was stirred in DMF (25 mL) at room temperature for 18 h. The reaction was diluted into 100 mL water and extracted with EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 240 g silica gel cartridge with 0 to 20% ethyl acetate in hexane to yield 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (4.80 g, 66% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (1H, d, J=0.76 Hz), 8.55 (1H, d, J=2.77 Hz), 7.96 (1H, d, J=1.01 Hz), 7.80 (1H, d, J=1.01 Hz), 6.51 (1H, dd, J=2.64, 1.64 Hz).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: O=C1Nc2ccccc2CCN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccccc2CCN1C1CCNCC1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
3-(1-Benzyl-piperidin-4-yl)1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one (100 mg, 0.3 mmol) in methanol (5 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 50 mg (68%) of the desired material. LC/MS: tR=1.07 min, 246.26 (MH)+.
Reaction SMILES: [Br:1][C:2]([F:11])([F:10])[CH2:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1.[CH2:12]=[O:13]>C[Si](Cl)(C)C>[Br:1][C:2]([F:10])([F:11])[CH2:3][CH:4]1[CH2:8][N:7]([CH2:12][OH:13])[C:6](=[O:9])[CH2:5]1
Reactant: C=O
Reactant: O=C1CC(CC(F)(F)Br)CN1
Agent: C[Si](C)(C)Cl
Product: O=C1CC(CC(F)(F)Br)CN1CO
Yield: 93 %

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of 4-(2-bromo-2,2-difluoro-ethyl)-pyrrolidin-2-one a6 (0.46 g, 2 mmol), paraformaldehyde (0.12 g) and TMSCl (10 ml) is heated at 60° C. for 1 h. The reaction mixture is evaporated to give the crude 4-(2-bromo-2,2-difluoro-ethyl)-1-hydroxymethyl-pyrrolidin-2-one a7 (0.48 g, 92%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.I[CH2:26][CH2:27][CH3:28].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][CH3:28])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CCCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.031 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 1-iodopropane (0.33 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-propyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C16H20ClN3, 289.13; found, m/z 290.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.35 (m, 4H), 4.03 (t, J=7.2 Hz, 2H), 3.37-3.35 (m, 2H), 3.27-3.24 (m, 2H), 3.15-3.13 (m, 2H), 2.95-2.93 (m, 2H), 1.76-1.69 (m, 2H), 0.84 (t, J=7.4 Hz, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[N:11]=[CH:12][C:13]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:14]=3[N:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>CN(C)C=O>[CH2:23]([CH:22]([N:16]1[C:14]2[N:15]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:11]=[CH:12][C:13]=2[CH:19]=[CH:18][C:17]1=[O:20])[CH2:25][CH3:26])[CH3:24]
Reactant: O=c1ccc2cnc(Nc3ccccc3)nc2[nH]1
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1c(=O)ccc2cnc(Nc3ccccc3)nc21
Temperature: 60 °C
Yield: 22.4 %

Procedure:
To a suspension of NaH (33 mg of a 60% suspension of NaH in mineral oil) in 7 mL of dimethylformamide was added 2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (154 mg, 0.65 mmol). The reaction mixture was heated to 60° C. resulting in a clear solution. The solution was cooled slightly, and 3-bromopentane (125 μL, 1.01 mmol) was added. The reaction was heated at 60° C. for 30 minutes, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with 1:1 ethyl acetate:hexane to provide 45 mg (23%) of 8-(1-ethylpropyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one , mp 116-118° C.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH:12]=O)=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:14][NH2:15].[BH4-].[Na+].O>CO>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][NH:15][CH3:14])=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1cccc2c1OCCCO2
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2c1OCCCO2
Reaction time: 3 h
Yield: 86 %

Procedure:
3,4-Dihydro-2H-benzo[b][1,4]dioxepine-6-carbaldehyde (269 mg, 1.51 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.60 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 hours. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (58.3 mg, 1.54 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (20 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×40 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylmethyl)-methyl-amine (251 mg, 86%) as a brown oil: 1H NMR (400 MHz, DMSO-d6) δ 6.96 (dd, J=8.0, 4.0 Hz, 1H), 6.88-6.82 (m, 2H), 4.10-4.05 (m, 4H), 3.60 (s, 2H), 2.25 (s, 3H), 2.10-2.06 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[C:12]([OH:15])[CH:11]=[CH:10]2)(=[O:3])[CH3:2].S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[C:12]([O:15][CH3:20])[CH:11]=[CH:10]2)(=[O:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)Nc1cccc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2cccc(NC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 8-Acetamido-2-naphthol (21 g, 0.104 mol), dimethyl sulfate (15.1 g, 0.12 mol) and potassium carbonate (41 g, 0.3 mol) in acetone (200 mL) was stirred at room temperature for 48 h. Solids were removed by filtration and washed with methanol, and the filtrate evaporated. The residue was washed in 1:1 hexane:toluene, collected by filtration and dried (24.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:22][C:17]=2[N:16]=[N:15]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[NH:13][C:11]4[N:10]([N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)[N:12]=4)[C:25](=[O:26])[CH:24]=3)=[CH:22][C:17]=2[N:16]=[N:15]1
Reactant: Nc1nc(-c2cccc(Cl)c2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=c1cc(-c2ccc3[nH]nnc3c2)[nH]c2nc(-c3cccc(Cl)c3)nn12
Temperature: 130 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
To a solution of 3-(3-chlorophenyl)-1H-1,2,4-triazol-5-amine (120 mg, 0.62 mmol) in n-BuOH (1 mL) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (214 mg, 0.92 mmol) and TsOH (5.3 mg, 0.03 mmol), and the resulting mixture was stirred for 5 h at 130° C. The solids were collected by filtration, washed with MeOH (3×1 mL) to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(3-chlorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (73 mg, 33%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[OH:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[O:28][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: O=C(c1ccccc1)N1CCC(OCc2ccc3ccccc3c2Br)C(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OC1CN(C(=O)c2ccccc2)CCC1OCc1ccc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of the alcohol 67 (1 mmole) in THF is cooled to 0° C. Methanesulfonyl chloride (1 mmole) and triethylamine (1 mmole) are added and the solution is stirred at 0° C. for 6 hr. Standard work-up and flash chromatography affords 68.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1.Cl.Cl.[CH3:25][N:26]([CH3:34])[C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([N:26]([CH3:34])[CH3:25])[CH:28]=2)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: CCCc1ccc(C(=O)Nc2cc(C(=O)Cl)ccc2Cl)cc1
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Product: CCCc1ccc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2Cl)cc1

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-3-(4-propylbenzamido)benzoyl chloride was reacted with 3-dimethylamino aniline dihydrochloride to give the title compound; NMR Spectrum: DMSOd6) 0.9 (t, 3H), 1.18 (t, 2H), 1.69 (m, 2H), 2.99 (s, 6H), 7.0 (d, 1H), 7.2-7.5 (m, 4H) 7.64-7.8 (m, 3H), 7.84 (d, 1H), 8.0 (m, 2H), 8.19 (s, 1H); Mass Spectrum: M+H+ 436 and 438.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O.CCCCCC.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:30]=1)[C@@H:10]([O:23][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H](C[C@@H](Cc1ccccc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
Analogously to Example 1j), 1.04 g (2.00 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(phenylmethyl)-hexanoic acid in 7 ml of DMF are silylated with 1.39 g (9.0 mmol) of tert-butyldimethylchlorosilane and 1.12 g (16.4 mmol) of imidazole. Hydrolysis of the silyl ester function with 1.6 g of potassium carbonate in 46 ml of methanol/THF/water 3:1:1 and column chromatography (SiO2, hexane/ethyl acetate 4:1→2:1→1:2) of the crude product yields the title compound: TLC Rf (A)=0.69.
Reaction SMILES: [CH2:1]([N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1)[CH2:2][CH3:3].[H-].[Na+].[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22]>O>[CH2:1]([N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:22][CH2:21][CH2:20][CH2:19][OH:23])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCN=C(N)Nc1ccnc(S(C)=O)n1
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCN=C(N)Nc1ccnc(OCCCO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
4-(2-Propylguanidino)-2-methylsulphinylpyrimidine (200 mg.) was added to a solution of sodium hydride (72 mg.) in 1,3-propanediol (2 ml.) and the mixture stirred at ambient temperature for 1 hour. The mixture was diluted with water and extracted with EtOAc (3×10 ml.). The extract was dried (MgSO4) and evaporated to give a gum which crystallised on standing. Recrystallisation from EtOAc gave 4-(2-propylguanidino)-2-(3-hydroxypropoxy)pyrimidine, m.p. 183°-184° (yield 25%).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]=2[CH3:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:27])C(=O)C1>>[Br:27][C:11]1[CH:10]=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[C:7]([CH3:19])[C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CCc1ccc(C2CCCC2)c(C)c1
Product: CCOC(=O)CCc1cc(C)c(C2CCCC2)c(Br)c1
Yield: 95.7 %

Procedure:
According to the procedure described in the synthesis method of Compound No. A-1, Intermediate 15 (437 mg) and NBS (320 mg) were reacted and treated to obtain the title compound (Compound No. A-24, 545 mg).
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]2[CH2:36][CH:35](O)[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(C2CC(O)c3cc(O)ccc3O2)c1
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: COc1cccc(C2CCc3cc(O)ccc3O2)c1

Procedure:
2-(3-Methoxyphenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 2-(3-methoxyphenyl)chroman-4,6-diol. 1H NMR (300 MHz, d6-DMSO) δ: 8.75 (s, 1H), 7.28 (t, 1H, J 15.7, 7.9 Hz), 6.96-6.99 (m, 2H), 6.87 (dd, 1H, J 7.9, 2.5 Hz), 6.63 (d, 1H, J 8.3 Hz), 6.52 (d, 1H, J 2.9 Hz), 6.48 (s, 1H), 4.95 (dd, 1H, J 9.8, 2.2 Hz), 3.75 (s, 3H), 2.82-2.89 (m, 1H), 2.57-2.66 (m, 1H), 2.06-2.13 (m, 1H), 1.89-1.97 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1ccccc1OCc1cccc(F)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OCc3cccc(F)c3)n2)c1

Procedure:
Example 26 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and {2-[(3-fluorobenzyl)oxy]phenyl}boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH2:8]C1)=O.C(N(CC)CC)C.[CH:25]([OH:27])=O>CN(C=O)C.C(O[Pd]OC(=O)C)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:3]2[C:2]=1[C:25](=[O:27])[N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:4]12
Reactant: O=CO
Reactant: O=C1C=CN(C(=O)c2cccc(Cl)c2Br)CC1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCN2C(=O)c3c(Cl)cccc3C2C1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
A mixture of 1-(2-bromo-chlorobenzoyl)-2,3-dihydro-4-pyridinone (Preparation 3) (300 mg, 0.954 mmol), triethylamine (0.39 mmol, 0.54 ml), formic acid (0.05 ml, 1.3 mmol) and di(triphenylphosphine) diacetoxypalladium (47 mg, 0.063 mmol) in DMF (3 ml) was heated to 80° C. for 2 h. The cooled solution was filtered through celite, diluted with water, extracted twice with ethyl acetate, the extracts dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (70 mg). MS (+CI) m/z 235/237 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([O:10][CH:11]([O:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][NH2:15])[CH3:9]>C(Cl)Cl>[CH2:17]([O:16][CH:11]([O:10][CH2:8][CH3:9])[CH2:12][CH2:13][CH2:14][NH:15][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH3:18]
Reactant: CCOC(CCCN)OCC
Reactant: O=C1C=CC(=O)O1
Solvent: ClCCl
Product: CCOC(CCCNC(=O)/C=C\C(=O)O)OCC

Procedure:
Maleic anhydride (85 g) in 1300 mL of CH2Cl2 was cooled to 15° C. and treated with 155 g of 4-aminobutyraldehyde diethyl acetal (AmBDA). (Other preparations used the reverse mode of addition with similar results.) Fifteen min after the addition was complete no further AmBDA was detected by glpc. The solvent was removed under reduced pressure (maintained at 0.2 torr for 2 h to assure completion) to give 230 g of slightly orange colored thick oil. On standing for several months at 0° C., this material solidified to an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21](=[O:26])[N:20]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:44])C=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21](=[O:26])[N:20]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH:19]=[CH:18]3)=[O:44])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2ccc3cc(SC4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cc3c2=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(Cn2ccc3cc(S(=O)C4CCN(C(=O)OC(C)(C)C)CC4)c(Cl)cc3c2=O)cc1

Procedure:
206 mg 4-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester (285) in 6 ml of dichloromethane were treated with 83 mg m-Chloroperbenzoic acid over 2 h. The mixture was diluted with dichloromethane and washed with sodium hydrogen carbonate solution and brine. After drying over sodium sulfate all volatiles were evaporated and the crude product purified by chromatography 2:1 (ethyl acetate/Heptane) to obtain 4-[7-Chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-6-sulfinyl]-piperidine-1-carboxylic acid tert-butyl ester as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:7])[CH2:5][OH:6].CO[C:19](OC)([CH3:21])[CH3:20].B(F)(F)F.O(CC)CC>CC(C)=O>[CH3:1][O:2][C:3]([C:4]1([CH3:7])[CH2:5][O:6][C:19]([CH3:21])([CH3:20])[N:8]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:16]
Reactant: COC(C)(C)OC
Reactant: COC(=O)C(C)(CO)NC(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)C1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirring solution of 3 (9.342 g, 40 mmol) in acetone (115 mL) in a flame dried round bottom flask under an inert atmosphere was added 2,2-dimethoxypropane (66 mL). To this solution was added BF3-OEt2 (0.30 mL, cat) and stirring was continued at rt for 2 h. The reaction mixture was then concentrated in vacuo to an orange oil which was purified by flash chromatography to provide 4 (9.392 g, 85%) as a white solid. Rf=0.55 (1:3 EtOAc/hexanes). Compound was observed as an uneven mixture of rotomers.