Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])(=O)[CH:2]([CH3:4])C.[C:12]1([CH3:19])[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[C:7]([O:6][C:1]1[CH2:2][CH2:4][CH2:19][CH2:12][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:18][CH2:16][CH2:17][C@@H:12]([CH3:19])[CH:13]=1)(=[O:11])[CH:8]([CH3:9])[CH3:10]
Reactant: Cc1ccccc1C
Reactant: CC(C)C(=O)OC(=O)C(C)C
Product: CC(C)C(=O)OC1=C[C@H](C)CCCCCCCCCCCC1
Yield: 81 %

Procedure:
A crude product was prepared under the same condition as that in Example 6 except that isobutanoic anhydride was used instead of n-butanoic anhydride and xylene was used in an amount of 14 g, and was purified and isolated by silica gel column chromatography to give 2.5 g (8.14 mmol) of the title compound (R)-3-methyl-1-cyclopentadecenyl isobutyrate (yield: 81%). Gas chromatographic analysis thereof gave E/Z=1.4/98.6.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[CH2:7][CH:8]([NH:12][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:33]=2[C:34]([NH:36][CH2:37][C:38]#[CH:39])=[O:35])[C:28]([Cl:45])=[CH:27][N:26]=1>>[Cl:45][C:28]1[C:29]([NH:31][C:32]2[C:33]([C:34](=[O:35])[NH:36][CH2:37][C:38]#[CH:39])=[CH:40][CH:41]=[CH:42][C:43]=2[F:44])=[N:30][C:25]([NH:1][C:2]2[CH:23]=[CH:22][C:5]3[C:6]([CH3:20])([CH3:21])[CH2:7][CH:8]([NH:12][C:13]([N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[O:14])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:26][CH:27]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CC(NC(=O)N2CCCC2)C(=O)Nc2cc(N)ccc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)N2CCCC2)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from Pyrrolidine-1-carboxylic acid (8-amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-amide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (47 mg, 35%), HPLC purity 96%, LCMS 550 (M-propargyl amide), 1H-NMR (DMSO-d6, 400 MHz) δ 9.48 (s, 1H), 9.39 (s, 1H), 9.16 (s, 1H), 8.92 (t, 1H), 8.18 (s, 1H), 7.58-7.48 (m, 2H), 7.40-7.32 (m, 1H), 7.23-7.20 (d, 1H), 7.08-7.02 (m, 2H), 5.95 (m, 1H), 4.18-4.12 (m, 1H), 3.99 (d, 2H), 3.56 (m, 1H), 3.20 (m, 4H), 2.15-2.10 (m, 1H), 2.00-1.92 (m, 1H), 1.79 (m, 4H), 1.32 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [CH:1](N)=O.[NH2:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=2)[N:8]=[CH:7][C:6]=1[C:18]([NH2:20])=[O:19]>O>[CH3:16][C:14]1[CH:15]=[C:10]([N:9]2[C:5]3[N:4]=[CH:1][NH:20][C:18](=[O:19])[C:6]=3[CH:7]=[N:8]2)[CH:11]=[C:12]([CH3:17])[CH:13]=1
Reactant: NC=O
Reactant: Cc1cc(C)cc(-n2ncc(C(N)=O)c2N)c1
Solvent: O
Product: Cc1cc(C)cc(-n2ncc3c(=O)[nH]cnc32)c1
Temperature: 190 °C
Yield: 69.21 %

Procedure:
Charged 300.0 g of formamide into a 2.0 L 4 necked round bottom flask connected to a mechanical stirrer, thermo meter socket, and condenser under nitrogen atmosphere. 90.0 g (0.39 mol) of 5-Amino-1-(3,5-dimethyl-phenyl)-1H-pyrazole-4-carboxylic acid amide (Compound No. 77) was charged. Reaction mass temperature was raised to reflux (185-195° C.). Maintained the mass temperature at reflux for 60-90 min. Reaction mass temperature was cooled to 140-150° C. 900.0 ml of water was added slowly at maintaining the mass temperature 80-150° C. Maintained the mass temperature at 80-90° C. for 45-60 min. Reaction mass temperature was cooled to 25-30° C. Maintained the mass temperature at 25-30° C. for 90-120 min. Solid was filtered and solid was washed with 150.0 ml of water. 500.0 ml of DM Water and wet crude compound were charged into a 2.0 L 4 necked round bottom flask connected to a mechanical stirrer, thermo meter socket, and condenser. Mass temperature was raised to reflux. Maintained the mass temperature at reflux for 75-90 min and mass temperature was cooled to 25-30° C. Maintained the mass temperature at 25-30° C. for 90-120 min. Solid was filtered and solid was washed with 100.0 ml of water. Compound was dried under vacuum at 60-65° C. Dry weight of the compound: 65.0 g (yield 69.21%)
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.ON1C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.O.C(Cl)CCl>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:13]([C:14]([N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:15])[C:12]([C:18]([F:19])([F:20])[F:21])=[CH:11][C:10]=2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(F)(F)F)c(C(=O)O)cc1OCc1ccccc1
Reactant: C1CCNCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-4-{[(phenylmethyl)oxy]carbonyl}-2-(trifluoromethyl)benzoic acid (may be prepared as described in Description 55; 142 mg, 0.14 mmol) in N,N-dimethylformamide (4 ml) was added diisopropylethylamine (120 ul), piperidine (0.05 ml, 0.52 mmol), 1-hydroxy-7-azabenzotriazole (60 mg), and EDC (120 mg). The solution was stirred for 18 hours. Water (10 ml) and ethyl acetate (10 ml) were added and the organic layer was separated, washed with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 1:1 ethyl acetate/cyclohexane) to yield the title compound as a gum. 170 mg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1)#[CH:2].[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:22])[C:17](Br)=[N:18][C:19]=1[CH3:20])=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:22])[C:17]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)=[N:18][C:19]=1[CH3:20])=[O:14])[CH3:11]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1cccc(C)c1
Product: CCOC(=O)c1c(C)nc(C#Cc2cccc(C)c2)n1C

Procedure:
The title compound, MS: m/e=283.6 (M+H+), was prepared in accordance with the general method of example 1b from 1-ethynyl-3-methyl-benzene and 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CC(O)=O>[CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=3)[CH2:25][CH2:26]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(CC=O)ccc1C#N
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methyl-4-(2-oxoethyl)benzonitrile (130 mg, 0.8 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (190 mg, 0.8 mmol) in 25 mL of dry methanol were added 2 drop of HOAc and then stirred at room temperature for 1 hr. Then NaBH(OAc)3 (380 mg, 1.8 mmol) was added an the then the mixture was stirred overnight. Concentrated and the residue was purified via prep-TLC to give 2-Methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.15 (d, J=8.6 Hz, 2H), 7.36˜7.53 (m, 3H), 7.12 (t, J=9.4 Hz, 2H), 2.65˜2.97 (m, 16H), 2.52 (s, 3H). MS m/e: 379 (M+1)+. (0.19 μM)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].O>CN(C)C=O>[CH3:16][C:10]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CCOC(=O)C(C)(C)Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (25 g) in N,N-dimethylformamide (100 mL) was added ethyl 2-bromo-2-methylpropanoate (39 mL), and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was 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 (50 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4](Br)[CH:3]=1.[CH3:19][S-:20].[Na+].C[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:20][CH3:19])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COc1ccc(COc2cc(Br)cc(Br)c2)cc1
Reactant: C[S-]
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Br)cc(SC)c2)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
1,3-Dibromo-5-(4-methoxy-benzyloxy)-benzene (4.0 g) was dissolved in DMF (60 mL), followed by addition of sodium thiomethoxide (829 mg). The resulting mixture was stirred at 75° C. for 5 h. Over the period of 4 hours additional amount of sodium methoxide (total 754 mg) was added in two equal portions. When the starting material was completely consumed the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (2.1 g, 60% yield). HRMS calcd for C15H15O2BrS [M+H]+ 339.0049, observed 339.0047.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:14]([OH:23])[C@@H:15]([CH:20]2[CH2:22][CH2:21]2)[CH2:16][N:17]=[N+]=[N-])(=O)=O)=CC=1.CCN(C(C)C)C(C)C>CO.[Pd]>[CH:20]1([C@H:15]2[CH2:16][NH:17][CH2:12][C@@H:13]([NH:24][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C@@H:14]2[OH:23])[CH2:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)[C@H](CN=[N+]=[N-])C2CC2)cc1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C2CC2)[C@H]1O
Reaction time: 3 h

Procedure:
A mixture of (2R,3R,4S)-5-azido-2-[(tert-butoxycarbonyl)amino]-4-cyclopropyl-3-hydroxypentyl 4-methylbenzenesulfonate (0.506 g, 1.11 mmol), DIPEA (0.31 mL, 1.8 mmol), and 10% palladium (dry basis) on activated carbon (wet, Degussa type E101 NE/W) (0.1 g) in MeOH (5 mL) was stirred under an atmosphere of hydrogen introduced via a balloon. After 3 h, the crude reaction mixture was filtered through a pad of diatomaceous earth and the solids were washed thoroughly with MeOH. The volatile organic solvents were removed under reduced pressure and the residue was dried under high vacuum to afford the sub-title compound as a solid. The crude product was used directly in the subsequent displacement reaction without further purification. LCMS (ESI) m/z calc. for C13H25N2O3 257.2 [M+H]+. found 257.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:23])[CH2:21][SH:22].CCN(CC)CC.O>CS(C)=O>[CH3:18][O:19][C:20]([C:21]1[S:22][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=[CH:15][C:12]=2[CH:13]=1)=[O:23]
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(OCc2ccccc2)cc1F
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2ccc(OCc3ccccc3)cc2s1
Temperature: 80 °C
Yield: 95.8 %

Procedure:
To a solution of 4-benzyloxy-2-fluoro-benzaldehyde (1.3 g, 5.6 mmol) in DMSO (55 mL) was added mercapto-acetic acid methyl ester (1.2 mL, 11.3 mmol) and Et3N (2.4 mL, 1.7 g, 16.8 mmol) and the reaction mixture was heated (80° C., 12 h). The reaction mixture was cooled (rt), treated with H2O (100 mL) and filtered. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-30%) to provide the title compound as yellow solid (1.6 g, 96%). MS (ESI): mass calcd. for C17H14O3S, 298.1; m/z found, 299.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.98 (s, 1H), 7.75 (d, J=8.8, 1H), 7.53-7.30 (m, 6H), 7.10 (dd, J=8.8, 2.3, 1H), 5.14 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2/[C:9](=[N:19]\[NH2:20])/[NH:8][C:7]1=[O:21])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:22]([O-])([O-])OCC>>[CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:16])([F:18])[F:17])[NH:11][C:10]=2[C:9]2=[N:19][N:20]=[CH:22][N:8]2[C:7]1=[O:21])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1c(=O)[nH]/c(=N/N)c2[nH]c(C(F)(F)F)nc21
Reactant: CCOC([O-])[O-]
Product: CCCCCn1c(=O)n2cnnc2c2[nH]c(C(F)(F)F)nc21
Temperature: 100 °C

Procedure:
(6E)-3-Pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-6-hydrazone (0.15 g, 0.20 mmol) was mixed with ethyl orthoformate (2 mL, 10 mmol). The mixture was heated at 100° C. for 30 min, concentrated under reduced pressure and purified by preparative HPLC to yield the desired product. LCMS calculated for C12H14F3N6O (M+H): 315.1. found: 315.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]2[C@@H:18]1[CH2:20][C@@H:19]1[F:21])(=[O:3])[CH3:2].[C:26]([O:30][C:31]([NH:33][C:34]1([C@H:37]2[CH2:41][NH:40][CH2:39][C@H:38]2[F:42])[CH2:36][CH2:35]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CN1CCCCC1>CS(C)=O>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:40]2[CH2:41][C@H:37]([C:34]3([NH:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32])[CH2:35][CH2:36]3)[C@H:38]([F:42])[CH2:39]2)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]2[C@@H:18]1[CH2:20][C@@H:19]1[F:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2F)CC1
Solvent: CN1CCCCC1
Solvent: CS(C)=O
Product: CC(=O)Nc1c(F)c(N2C[C@@H](F)[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(C)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 80 °C

Procedure:
A mixture consisting of 5-acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (2.60 g, 7.34 mmol), (3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine (2.69 g, 11.0 mmol), 1-methylpiperidine (1.34 ml, 11.1 mmol) and dimethyl sulfoxide (13 ml) was heated at an outer temperature of 80° C. for 7 hours under a condition of 2.94×108 Pa (converted from 3,000 kgf/cm2). When analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed ratio of the compound of interest 5-acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was 72%. Also residual ratio of the material was 11%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1.[NH2:34][C:35]1[CH:39]=[CH:38][O:37][N:36]=1>N1C=CC=CC=1>[O:37]1[CH:38]=[CH:39][C:35]([NH:34][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)=[N:36]1
Reactant: Nc1ccon1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O

Procedure:
Phosphorus oxychloride (0.11 ml) was added to a mixture of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.30 g), 3-aminoisoxazole (0.12 ml) and pyridine (5 ml) and the resultant suspension was heated to 120° C. for 5 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The mixture was evaporated. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate), evaporated and the residue purified by column chromatography on a silica column using initially methylene chloride and then a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.14 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.24 (s, 3H), 2.49 (m, 4H), 3.29 (m, 4H), 7.06 (d, 1H), 7.50 (d, 1H), 7.63 (m, 3H), 8.09 (m, 2H), 8.13 (s, 1H), 8.85 (d, 1H), 11.46 (s, 1H); Mass Spectrum: M+H+ 445.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][C:7]=1[C:17]([F:20])([F:19])[F:18])=[O:5])C.[OH-].[Na+]>CO.O>[N:16]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:17]([F:19])([F:20])[F:18])[N:8]=1
Reactant: CCOC(=O)c1sc(-c2ncccn2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1sc(-c2ncccn2)nc1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-pyrimidin-2-yl-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (1.6 g) and sodium hydroxide (1.2 g) in MeOH (10 mL) and water (3 mL) is heated at 50° C. with stirring for 30 min, cooled and evaporated. The residue is acidified with citric acid solution and extracted with EtOAc six times. The combined extracts are washed once with brine, dried over Na2SO4 and concentrated to give the title compound as a solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27]>CN(C)C1C=CN=CC=1>[C:26]([N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(=O)N1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reaction time: 3 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (1 g, 2.4 mmol) in 24 mL of CH2Cl, was added 4-dimethylamino pyridine (0.88 g, 7.2 mmol) and acetyl chloride (0.21 g, 2.6 mmol). The solution was stirred for 3 h and the solvent was removed under reduced pressure. The residue was treated with saturated NH2OH (20 mL) and the suspension was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (1×50 mL), dried over MgSO4, filtered and concentrated to leave a solid. The solid was triturated with ether and was filtered to leave the title compound: MS (M+H): 381 (base peak).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.I[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH3:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:18][C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[C:5]1=[O:10]
Reactant: O=C1NCCc2sccc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2sccc2C1=O
Yield: 56.4 %

Procedure:
Using analogous reaction conditions as described in example 1, 6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-7d: 100 mg, 0.6527 mmol) was reacted with 3-iodo-4-methyl-pyridine (171.5 mg, 0.7832 mmol), 1,4-dioxane (20 mL), copper iodide (9.7 mg, 0.0652 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (27.8 mg, 0.1958 mmol) and potassium phosphate (346.3 mg, 1.6318 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 90 mg of the product (56.2% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][OH:6].Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.[OH-].[Na+]>CC(N(C)C)=O>[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][O:6][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCC(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a stirred suspension of sodium hydride (4.9 g, 120 mmol, 60% in oil) in DMA (100 mL) is added dropwise 2,2,3,3,3-pentafluoropropan-1-ol (8.1 mL, 82 mmol) at 0° C. After stirring for 10 minutes, a solution of methyl 6-chloronicotinate (7.0 g, 41 mmol) in DMA (120 mL) is added dropwise at 0° C., and the mixture is stirred for 30 minutes at rt. Then, the mixture is stirred at 90° C. for 2 hours. After cooled to rt, 2M aqueous sodium hydroxide is added (pH is around 6). The mixture is extracted with n-hexane/EtOAc (1:2, 200 mL). The organic layer is washed with water, brine, and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure to give 8.4 g of the title compound as crude product (include 2,2,3,3,3-pentafluoropropyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate as a byproduct). The residue is used for the next reaction (Step-2) without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1.[CH2:15]([O:17][C:18](=[O:24])[C:19](OCC)=[O:20])[CH3:16].CC[O-].[Na+]>CCO>[CH2:15]([O:17][C:18](=[O:24])[C:19](=[O:20])[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1)[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
Sodium hydride (0.4163 g, 17.35 mmol) was added slowly to a NaCl ice bath containing EtOH (5.3 mL, 2.5 M) stirring under N2. 66 (2.4253 g, 13.28 mmol) and diethyloxalate (1.803 g, 13.28 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After 10 minutes, the reaction solidified and an additional 10 mL EtOH was added. After stirring for 5 h, the reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 1:1 Hexanes: CH2Cl2): Only pure fractions were combined and concentrated to obtain 67 (1.7561 g, 46.8%): 1H (CDCl3, 400 MHz): δ 14.27 (1H, broad s), 7.22 (2H, d, J=8.3 Hz), 7.10 (2H, d, J=8.3 Hz), 6.32 (1H, s), 4.31 (2H, q, J=7.2 Hz), 2.92 (2H, t, J=7.8 Hz), 2.78 (2H, t, J=7.8 Hz), 1.34 (3H, t, J=7.2 Hz) ppm. 13C (CDCl3, 100 MHz): δ 201.59, 166.07, 161.79, 138.51, 132.00, 128.53, 128.54, 101.72, 62.38, 42.08, 29.60, 13.88 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 13.88; CH2 carbons: 62.38, 42.08, 29.60; CH carbons: 129.53, 128.54, 101.72ppm. HPLC: 11.103 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH2:19][OH:20])([C:14]([O:16]CC)=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH2:19][OH:20])([C:14]([OH:16])=[O:15])[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C1(CO)CC(c2cc(Cl)cc(Cl)c2)=NO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(CO)CC(c2cc(Cl)cc(Cl)c2)=NO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.80 g (8.80 mmol) of ethyl 3-(3,5-dichlorophenyl)-5-(hydroxymethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate were dissolved in 100 ml of methanol, and a solution of mg (11.4 mmol) of NaOH in 20 ml of water was added. After 18 h of stirring at RT, the solvents were removed under reduced pressure, water and methylene chloride were added and the organic phase was separated off. On acidification of the aqueous phase, the product separated off as a white precipitate, which was filtered off and dried.