Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a cooled (0° C), stirred solution of 990 mg (2.30 mmol) 3-[3-(5-bromo-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, 842 μL of N,N-diisopropylethylamine and 500 μL of anhydrous dimethyl sulfoxide in 6.0 mL of anhydrous dichloromethane was added 732 mg (4.60 mmol) of sulfur trioxide pyridine complex. The mixture was warmed to ambient temperature over 30 min and stirred for 2 h. An additional 368 mg (2.30 mmol) of sulfur trioxide pyridine complex was added and, after 17 h, the mixture was poured into 15 mL of dichloromethane and washed with 5% (w/v) aqueous citric acid (2×25 mL). Each wash was extracted with 5 mL of dichloromethane and the combined extracts were washed with 1M pH 7 buffer (25 mL), brine (25 mL) and dried over Na2SO4 to give after concentration a white semisolid. This material was chromatographed on 35 g of silica gel with dichloromethane followed by 3% ethyl acetate-dichloromethane to afford 685 mg (69%) of the title compound as a colorless syrup: 1H-NMR (300 MHz; CDCl3) δ 9.84 (t, 1 H, J=1.4 Hz), 7.94 (d, 1 H, J=2.5 Hz), 7.70 (dd, 1 H, J=8.9, 2.5 Hz), 6.98 (d, 1 H, J=8.9 Hz), 6.61 (br s, 1 H), 6.55 (br s, 1 H), 6.45 (t, 1 H, J=2.2 Hz), 4.21 (t, 2 H, J=6.1 Hz), 4.01 (s, 3 H), 2.88 (td, 2 H, J=6.1, 1.4 Hz) and 2.27 (s, 3 H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C17H1779BrO6S: 451.0 (M+Na). Found: 451.4.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:19][C:17]1[CH:18]=[C:11]([O:10][C:5]2[C:4]([F:20])=[C:3]([CH2:2][NH:1][C:27]([C:26]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:21])=[O:28])[CH:8]=[CH:7][C:6]=2[Cl:9])[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
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: C1CCOC1
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 74.4 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.193 g, 0.542 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.150 g, 0.542 mmol) and DIPEA (0.189 mL, 1.084 mmol) were combined in THF (2 mL) and treated with HATU (0.227 g, 0.596 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. overnight. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from EtOH, cooled in an ice bath and filtered to give N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (0.195 g, 0.403 mmol, 74.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 8.26 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.46-7.60 (m, 3H), 7.37 (t, J=7.69 Hz, 1H), 4.53 (d, J=2.47 Hz, 2H). LC-MS (ES−) m/z 481.04, 483.07 [M−1]. LC-MS (ES+) m/z 482.94, 484.92 [M+H].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=3)[S:28][C:19]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:31][CH:30]=3)[S:28][C:19]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCCCC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
Piperidine (50 mg, 0.59 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.44 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (500 mg, 2.4 mmol) is added. After stirring at 0° C. for 1.5 hours, a few drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of water and then partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to 5% methanol in ethyl acetate to provide 41 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(piperidin-1-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 218–220° C.; 1H NMR (DMSO-d6) δ 1.38 (m, 2H), 1.50 (m, 4H), 2.33 (m, 4H), 3.46 (m, 2H), 3.85 (s, 3H), 7.38 (s, 1H), 7.40 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.72 (s, 1H); MS 521.3 (M−H)−.
Reaction SMILES: C[O:2]C1C=C(NC(=O)C)C([N+]([O-])=O)=CC=1C(OC)=O.[CH3:20][O:21][C:22]1[CH:30]=[C:29]([NH2:31])[C:28]([N+:32]([O-])=O)=[CH:27][C:23]=1[C:24]([O-:26])=[O:25].[Na+].[NH2:36][NH2:37]>>[OH2:2].[NH2:36][NH2:37].[CH3:20][O:21][C:22]1[CH:30]=[C:29]([NH2:31])[C:28]([NH2:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)[O-]
Agent: NN
Agent: [Na+]
Product: COc1cc(N)c(N)cc1C(=O)O
Product: O

Procedure:
In general, reaction of methyl 2-methoxy-4-acetylamino-5-nitrobenzoate with the base is preferably immediately followed by the in-situ reaction of the intermediate sodium-2-methoxy- 4-amino-5-nitrobenzoate (intermediate I) with hydrazine or its equivalent, preferably as hydrazine hydrate, to form 2-methoxy-4,5-diaminobenzoic acid (intermediate II). That product is preferably recovered and purified prior to further use.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=CC3NC4CCN(CCN(CC)CC)C(=O)C=4C=3C)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:31].C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[F:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:39](=[O:41])[CH3:40])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CC(=O)Cl
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 0 °C
Yield: 100.1 %

Procedure:
A stirred solution of 6-amino-5-fluoro-1,3-dihydro-indol-2-one (1.0 g, 6 mmol) obtained from Example 7 in 30 ml of tetrahydrofuran was added with triethylamine (1.3 ml, 9 mmol). The solution was cooled down to 0° C. in an ice-water bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated to reflux for 1.5 hours and cooled until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide (1.25 g, 99%) as a white solid.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(OC)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-methoxybenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (24%); 1H NMR (d6-DMSO) δ 12.04 (br s, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.38–7.07 (m, 15H), 6.84 (d, J=8.0 Hz, 2H), 6.39 (d, J=15.7 Hz, 1H), 3.80 (s, 3H), 2.35 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 525 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[C-:14]#[N:15].[K+].C1(C)C=CC=CC=1>O=O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:14]#[N:15])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: [C-]#N
Agent: O=O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 45 °C
Reaction time: 0.3 h
Yield: 81.8 %

Procedure:
A stirred mixture of 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (20.0 g, 0.082 mol), potassium cyanide (10.4 g, 0.159 mol) and oxygen-free ethanol (60 mL) was heated at 45° C. A slurry of chloronaphthalenylbis(triphenylphosphine)nickel (i.e. the product of Example 1, a mixture of 1- and 2-isomers) (4.01 g, 5.36 mmol) in oxygen-free ethanol (60 mL) was added in four portions to the reaction mixture. Each addition was completed in about 18 minutes, and after the first addition subsequent additions were begun approximately 50, 75, and 105 minutes after the previous addition was complete. Oxygen-free ethanol (15 mL) was added to the reaction mixture after the second addition to facilitate stirring. After the fourth addition was complete, the reaction mixture was stirred for 5.7 h at 45° C., and then more chloro-naphthalenylbis(triphenylphosphine)nickel (0.5 g, 0.67 mmol) in oxygen-free ethanol (10 mL) was added over 10 minutes. After stirring overnight at 45° C., toluene (100 mL) was added, and the solvent was evaporated under reduced pressure. More toluene (150 mL) was added, and the solvent was again evaporated under reduced pressure. The resulting solid was slurried in toluene (120 mL), filtered, and washed with toluene (100 mL) and water (2×70 mL). The solid was dried overnight in a vacuum-oven at 50° C. to give the title compound as a white solid (12.68 g, 81.8% yield). A portion of the product was recrystallized from acetonitrile to give an analytical sample melting at 204.0-204.5° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[CH2:14]([O:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:15]>C(OCC)C>[CH2:14]([O:16][C:17]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[C:18]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:15]
Reactant: CCCCCCC#COCC
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCC1=C(OCC)C(C)(C)C1=O
Reaction time: 96 h
Yield: 61 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et at, [J. Org. Chem, 38, 1451-1455, (1973)]; triethylamine (22 ml) was added dropwise at room temperature to a well-stirred solution of isobutyryl chloride (7.3 ml, 69 mmol) and 1-ethoxy-1-octyne [prepared according to the method of Kocienski, P. et al Tetrahedron Left. 1833, 30, (1989)] (6.5 g, 63 mmol) in diethylether (100 ml). The reaction was warmed to 35° and stirred for 96 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80: EtOAc 20) to give the title compound as a brown oil (8.6 g, 38 mmol, 61%). δH (CDC3, 300K) 4.34 (2H, d, J 7.1 Hz), 2.05 (2H, dd, J 5.6 Hz, 7.3 Hz), 1.44 (3H, t, J 7.1 Hz), 1.27-1.12 (8H, m), 1.23 (6H, s), 0.89 (3H, t, J 2.7 Hz). m/z (ES+, 70V) 225.0 (MH+).
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[C:20]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:24]=3[N:25]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)C.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:34]([C:15]1[C:20]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][C:24]=3[N:25]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)(=[O:38])=[O:36])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ncccc1-c1nc2cc(C(F)(F)F)ccc2s1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ncccc1-c1nc2cc(C(F)(F)F)ccc2s1
Reaction time: 0.5 h

Procedure:
265 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.38 g of 2-(2-ethylsulfanylpyridin-3-yl)-5-(trifluoromethyl)benzothiazole and 4 ml of chloroform under ice cooling, then the mixture was stirred for 30 minutes under ice cooling. 265 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to the reaction mixture under ice cooling, then the mixture was stirred at room temperature for 1 hour. An aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.35 g of 2-(2-ethylsulfonylpyridin-3-yl)-5-(trifluoromethyl)benzothiazole (hereinafter, referred to as Compound of Present Invention 46).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(#N)CC>O>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC#N
Product: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A mixture of 4-(benzyloxy)-2-chloro-5-nitropyrimidine (670 mg), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (530 mg), potassium phosphate (642 mg) and propionitrile (10 mL) was stirred at 50° C. for 1 hr, and then at 100° C. for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (170 mg).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2C)=CSC=1[C:36](OC)=[O:37].[CH:40](OCC)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[CH3:36][O:37][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:40])[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2C)c1N
Solvent: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4ccccc4C)csc3c2=O)cc1
Yield: 60 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(o -tolyl)thiophene-2-carboxylate (100 mg, 0.4 mmol), triethyl orthoformate (0.88 ml), p-anisidine (92.6 mg, 0.75 mmol), and acetic acid (0.13 ml) were used to give 83.2 mg (0.24 mmol, 60% yield) of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([CH3:21])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][C:32]([Br:35])=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Br:35][C:32]1[N:33]=[CH:34][C:29]([NH:28][C:8](=[O:10])[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([CH3:21])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:30][CH:31]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionic acid (310 mg, 1.0 mmol) in methylene chloride (5 mL) was treated with oxalyl chloride (0.175 mL, 2.0 mmol) and N,N-dimethylformamide (1 drop). The solution was stirred at 25° C. for 45 min. The reaction mixture was concentrated in vacuo, and the residue was suspended in toluene. The toluene was further concentrated in vacuo. The resulting residue was dried in vacuo. The waxy material was dissolved in methylene chloride (5 mL), cooled to 0° C., and then treated with a solution of 2-amino-5-bromopyrazine (1.74 g, 1.0 mmol) and pyridine (0.121 mL, 1.5 mmol) in methylene chloride (5 mL). The mixture was stirred at 0° C. for 20 min and then stirred at 25° C. for 3 h. The solution was extracted with methylene chloride and water. The organic layer was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium chloride solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/2 ethyl acetate/hexanes) afforded the N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide (391 mg, 84%) as a fluffy solid.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[C:15]([O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C)c1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of m-cresol (Aldrich) (80 g, 0.74 mol) in dry CH2Cl2 (300 mL) was added pyridine (71 mL, 0.89 mol) and at 0° C. was added dropwise acetyl chloride (58 mL, 0.81 mol). The reaction mixture was stirred for 1 h and then diluted with more CH2Cl2. The organic phase was washed successively with HCl 1N (3×), brine, dried over MgSO4 and evaporated. The residue was distilled under vacuum to give 108 g (97%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH2:14][CH3:15].Cl>O1CCCC1.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:16][CH2:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCNC(=O)CCc1ccc(O)cc1

Procedure:
3-(4-Hydroxyphenyl)propionic acid (12.0 g, 72.0 mmol) was dissolved in tetrahydrofuran (20 mL). n-Propylamine (5.1 g, 86.4 mmol) was added dropwise at room temperature. Subsequently, under ice-cooling, solution (20 mL) of WSCI-hydrochloric acid salt (16.5 g, 86.4 mmol) in methylene chloride was slowly added thereto, and the resultant mixture was stirred overnight. Diluted hydrochloric acid was added dropwise under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (9.7 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC=CC=1.[Si]([CH:21]=[N+:22]=[N-:23])(C)(C)C.C(O)(C(F)(F)F)=O>O1CCCC1>[NH:23]1[CH:2]([C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:3][CH:21]=[N:22]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CC=NN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
1,1-Dimethylethyl 2-propenoate (10.25 ml, 70 mmol) was added to a round-bottom flask equipped with a stirring bar and charged with toluene (100 ml) and tetrahydrofuran (THF) (100 ml) under nitrogen, and then TMS-diazomethane (42.0 ml, 84 mmol) was added. After 4 h, the reaction solvents and excess TMS-diazomethane were removed in vacuo. The residue was dissolved in dichloromethane (150 mL). TFA (6.26 ml, 84 mmol) was added at 0° C. and the resulting mixture was stirred at room temperature overnight. After this time, the reaction was quenched with sat. Na2CO3 and extracted with dichloromethane. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product as yellow oil, which was purified by silica gel chromatography (Combiflash, 120 g column, hexane/ethyl acetate 0-30% 60 min) to yield the desired product 1,1-dimethylethyl 4,5-dihydro-1H-pyrazole-5-carboxylate (9.7 g, 81% yield) as yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:24](O)=[O:25])[C:14]4=[O:31])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][N:15]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=3[CH3:30])[C:24]([NH:32][C:33]3[CH:37]=[CH:36][O:35][N:34]=3)=[O:25])[C:14]4=[O:31])[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(CC4CC4)CC3)cc2c1=O
Reactant: Nc1ccon1
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(N3CCN(CC4CC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid was reacted with 3-aminoisoxazole to give 3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 0.02 (m, 2H), 0.37 (m, 2H), 0.77 (m, 1H), 2.08 (s, 3H), 2.13 (m, 2H), 2.51 (m, 4H), 3.19 (m, 4H), 6.95 (s, 1H), 7.38 (s, 1H), 7.52 (m, 3H), 7.96 (m, 2H), 8.03 (s, 1H), 8.76 (s, 1H), 11.36 (s, 1H); Mass Spectrum: M+H+ 485.