Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][N:35]=1)[C:31]#[N:32].Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[C:31]([C:30]1[CH:33]=[CH:34][N:35]=[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)[CH:29]=1)#[N:32]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: N#Cc1ccnc(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cc(C#N)ccn1

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloroisonicotinonitrile as starting materials and by operations similar to those of Example 303-3 and Example 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].CN(C)C=O.[H-].[Na+].[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]3[S:32][C:33]([C:35](Cl)=[O:36])=[CH:34][C:30]=3[CH2:29][CH2:28][O:27][C:26]=2[CH:38]=1>>[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[C:31]3[S:32][C:33]([C:35]([N:12]([C:11]4[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=4[Cl:1])[CH3:13])=[O:36])=[CH:34][C:30]=3[CH2:29][CH2:28][O:27][C:26]=2[CH:38]=1
Reactant: O=C(Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CNc1ccc(C(=O)OC)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution containing methyl 3-chloro-4-(methylamino)benzoate (0.184 g, 0.922 mmol) in N,N-dimethylformamide (11.0 mL, 142 mmol) was added sodium hydride (0.0369 g, 0.922 mmol). The mixture was stirred at room temperature 30 min then 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.288 g, 0.838 mmol) was added. The reaction mixture was stirred for 16 hr. The reaction mixture was quenched with sat. NH4Cl, extracted with DCM (2×). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography EtOAc/Hex (0-100%) to give methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (yield 65%). MS: (ESI+) 508.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Cl)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH:36]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1ccc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give pale yellow amorphous of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][F:21])=[CH:14][CH:13]=1>>[F:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2[C:7]3=[N:8][O:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1
Reactant: FCCOc1ccc(Br)cc1
Reactant: Clc1cccc2nonc12
Product: FCCOc1ccc(-c2cccc3nonc23)cc1

Procedure:
Starting from 4-chloro-benzo[1,2,5]oxadiazole and 1-bromo-4-(2-fluoro-ethoxy)-benzene. Yellow crystals. MS(ES+): 259 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[S:9][C:5]=2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=1.Cl.Cl.[N:31]1([C:37]2[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Cl-].[Na+]>N1C=CC=CC=1>[CH3:13][C:12]([NH:11][C:10]([C:8]1[S:9][C:5]2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=[C:2]([NH:1][C:41](=[O:42])[C:40]3[CH:39]=[CH:38][C:37]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:45][CH:44]=3)[C:6]=2[N:7]=1)=[O:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:20]
Reactant: O=C(Cl)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.3 %

Procedure:
0.40 g (0.998 mmol) of tert-butyl 3-amino-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 10 ml of pyridine is placed in a 50 ml round-bottomed flask under argon. 0.25 g (0.996 mmol) of 4-(4-morpholinyl)benzoyl chloride dihydrochloride (prepared according to WO 95/04729) is then gradually added and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 50 ml of dichloromethane and 50 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=30 g; eluent: 99/1 dichloromethane/methanol). 0.19 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-(4-morpholin-4-ylbenzoylamino)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.61 (s, 9H); 1.70 (s, 6H); 3.29 (masked m, 4H); 3.75 (m, 4H); 7.03 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.40 (d, J=7.5 Hz, 2H); 7.97 (d, J=8.5 Hz, 2H); 8.69 (s, 1H); 11.1 (broad m, 1H). LC-MS-DAD-ELSD: 591(+)=(M+H)(+); 535(+)=591(+)-tBu+H.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>ClCCl>[S:21]([O:1][CH2:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1)([CH3:24])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1COc2ccccc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the compound 2-hydroxyethyl-1,4-benzodioxan (11.96 g) in dichloromethane (450 ml) was added triethylamine (0.12 mol, 10 ml). Mesylchloride (9.2 g) was then added dropwise and the reaction mixture was stirred for one hour at room temperature. After completion of the reaction, the solution was washed with water, brine, and concentrated to an oil, which was purified by chromatography on silica gel to yield 2-mesyloxyethyl-1,4-benzodioxan, 17.08 g.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].Cl.O1CCOCC1.[O:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1>ClCCl>[O:17]1[CH2:22][CH2:21][CH:20]([O:23][C:2]([NH:1][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])[CH2:19][CH2:18]1
Reactant: OC1CCOCC1
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.600 ml (4.80 mmol) of ethyl isocyanatoacetate was dissolved in dichloromethane. 0.06 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution, and they were stirred at room temperature for 5 minutes. 0.503 ml (5.28 mmol) of tetrahydro-4H-4-pyranol was added to the reaction mixture, and they were stirred at room temperature overnight. After concentrating the reaction mixture under reduced pressure, the residue was purified by the silica gel chromatography (hexane:ethyl acetate=9:1 to 1:4), the title compound was obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH:24]([CH2:25][C:26]([OH:28])=[O:27])[O:23][C:22]4[CH:21]=[C:20]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:19]=[CH:18][C:17]=4[C:12]=3[CH2:13][O:14][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]O.CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][O:27][C:26](=[O:28])[CH2:25][CH:24]1[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:38])[CH3:37])=[CH:16][C:15]=3[O:14][CH2:13][C:12]=2[C:17]2[CH:18]=[CH:19][C:20]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:21][C:22]=2[O:23]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(CC(=O)O)C1=C2COc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: CN(C)CCO
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)CCOC(=O)CC1Oc2cc(O[Si](C)(C)C(C)(C)C)ccc2C2=C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC2
Reaction time: 13 h

Procedure:
A mixture of [2,8-Bis-(tert-butyl-dimethyl-silyloxy)-5,11-dihydro-chromeno[4,3-c]chromen-5-yl]-acetic acid, the compound prepared as in Example 95 above, (56 mg, 0.1 mmol), 2-dimethylamino-ethanol (30 μL, 27 mg, 3.0 eq.), DIC (14 mg, 18 μL) and DMAP (12 mg) in DCM (2 mL) was stirred for 13 hours. The reaction mixture was then concentrated to yield [2,8-Bis-(tert-butyl-dimethyl-silyloxy)-5,11-dihydro-chromeno[4,3-c]chromen-5-yl]-acetic acid 2-dimethylamino-ethyl ester as a crude foam.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([O:21]C)=[O:20])[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][CH:10]([CH3:23])[C:9]1=[O:24])=[O:4].O1CCC[CH2:26]1.C(O)C>[OH-].[Na+]>[CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([OH:21])=[O:20])[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][C:10]([CH3:23])([CH3:26])[C:9]1=[O:24])=[O:4]
Reactant: COC(=O)NCCN1C(=O)C(C)Sc2cc(C)c(C(=O)OC)cc21
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)NCCN1C(=O)C(C)(C)Sc2cc(C)c(C(=O)O)cc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Methyl 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (210 mg) was dissolved in 1M aqueous sodium hydroxide solution/tetrahydrofuran/ethanol=(2:1:1), and the mixture was stirred at 80° C. for one hour. The reaction solution was concentrated under reduced pressure to remove ethanol. To the concentrated residue was added 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 4-{2-[(methoxycarbonyl)amino]-ethyl}-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid (200 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]=1[CH3:10].[CH3:11][O-:12].[Na+].CS(C)=O>O>[CH3:11][O:12][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: C[O-]
Reactant: Cc1cnc(C)c(C)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(C)cnc(C)c1C
Reaction time: 8 h

Procedure:
60 g (0.39 mol) 4-chloro-2,3,5-trimethylpyridine and 21.7 g (0.40 mol) sodium methoxide and 180 ml dry dimethylsulfoxide was heated with stirring to 55°-60° C. for 8 hrs. The reaction mixture was diluted with 600 ml water and extracted with 3x100 ml toluene and the organic layer washed with 2x50 ml water. The organic phase was added to 200 ml water and pH adjusted to 4.1 with stirring. This process was repeated twice with 200 ml and 100 ml of water. The organic layer contained almost pure starting material. The combined water phase was made alkaline and extracted with 2×150 ml methylene chloride. Evaporation of solvent gave 40.7 g of almost pure 4-methoxy-2,3,5-trimethylpyridine. NMR: 2×3H, 2,2: 3H, 2,45(s); 3H, 3,75(s); 1H, 8,2(s). (CDCl3)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N:7]1([C:16](=[O:31])[CH2:17][C:18]2[NH:23][C:22](=[O:24])[CH:21]=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:19]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.C[N:33](C)C=O>O>[NH2:33][N:23]1[C:22](=[O:24])[CH:21]=[C:20]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:19]=[C:18]1[CH2:17][C:16]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:31]
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ccccc21
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Nn1c(CC(=O)N2CCc3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
957 mg of cesium carbonate and 685 mg of o-diphenylphosphinylhydroxylamine are successively added to a suspension of 500 mg of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one (which can be obtained according to the previous step) in 5 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature for 2 hours and then diluted with 10 ml of water and extracted with dichloromethane (3×25 ml). The organic phases are combined and then dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05). The fractions of interest containing the product are combined and then evaporated under reduced pressure, and 154 mg of 3-amino-2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale yellow solid, the characteristics of which are the following:
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:40])/[C:17](/[CH3:39])=[CH:18]/[CH:19]=[C:20](\[CH3:38])/[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pt](=O)=O>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])[CH:20]([CH3:38])[CH2:19][CH2:18][CH:17]([CH3:39])[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:40])([OH:30])=[O:29]
Reactant: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1COCCO1
Product: CC(CCC(C)C(=O)N1CCC[C@@H]1C(=O)O)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 99.6 %

Procedure:
A solution of 593 mg (1.09 mmol) (2E,4E)-(R)-1-[6-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl- 6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylic acid benzyl ester in 15 ml dioxane was stirred with 25 mg (0.11 mmol) platinum (IV) oxide under 1 atm of hydrogen for 72 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo and azeotroped three times with chloroform on a rotary evaporator to remove last traces of dioxane, then triturated in ether to afford 400 mg (100%) of the title compound as a white foam. MS m/e (%): 369 (M+H+, 100).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][C:25]1([CH3:31])[O:29][C:28](=[O:30])[NH:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:27]4[CH2:26][C:25]([CH3:31])([CH3:24])[O:29][C:28]4=[O:30])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CC(C)(C)OC4=O)cn3)CC2)c(C)c1
Yield: 52.7 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (113 mg) described in Preparation Example 232 and 5,5-dimethyloxazolidin-2-one (52 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (65 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][CH:11]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH2:14][CH2:13][NH:12]1>>[CH3:9][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([N:12]2[CH2:13][CH2:14][C:15]3[CH:19]=[CH:18][S:17][C:16]=3[CH:11]2[CH3:10])[CH:5]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CC1NCCc2ccsc21
Product: Cc1cc(N2CCc3ccsc3C2C)nc(Cl)n1
Yield: 41.4 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 2,4-dichloro-6-methylpyrimidine(3.1 g, 19 mmol) and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2.9 g, 19 mmol) in Preparation 1 were used as starting materials, 2.2 g of the titled compound was obtained as white crystal. (Yield: 41%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10]2[NH:16][CH:17]=[N:15][C:11]=2[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Nc1cccc(OCc2ccccc2)c1N
Solvent: ClCCl
Product: c1ccc(COc2cccc3nc[nH]c23)cc1

Procedure:
A mixture of 3-benzyloxy-1,2-diaminobenzene 1.6 g (0.0073 mol) and formic acid (2.6 g, 0.057 mol) was heated to reflux for 1.5 h. The resulting mixture was then cooled, dissolved in methylene chloride, washed with 10% sodium carbonate solution, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was recrystallized from acetonitrile to give the title compound in 0.75 g (46%) yield, m.p. 165°-167° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:16])COC)=[CH:8][CH:7]=2)[CH2:3]1.[OH2:17].[OH-].[Li+].Cl>O.CO.C1COCC1>[OH:1][CH:2]1[CH2:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:16])=[O:17])=[CH:10][CH:11]=2)[CH2:5]1
Reactant: O
Reactant: COCC(=O)c1ccc(N2CC(O)C2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CC(O)C2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of 1-[4-(3-hydroxyazetidin-1-yl)phenyl]-2-methoxyethanone (1.33 g, 6.00 mmol) and lithium hydroxide monohydrate (504 mg, 12.0 mmol) in water (4 mL), methanol (3 mL) and THF (6 mL) was stirred at 40° C. overnight. The mixture was neutralized with 3 N HCl aqueous solution (˜4 mL) to pH about 7, extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (1.10 g, 94.9%) which was directly used in the next step without further purification. LCMS cacld. for C10H12NO3 (M+1)+: m/z=194.1. Found: 194.1.
Reaction SMILES: [F-:1].[K+].[F:3][C:4]([F:12])([C:8]([F:11])([F:10])[F:9])[C:5](F)=[O:6]>C(#N)C>[F:1][C:4]([F:12])([F:3])[C:5]([C:8]([F:11])([F:10])[F:9])([OH:6])[C:4]([F:12])([F:3])[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(F)C(F)(F)C(F)(F)F
Reactant: [F-]
Agent: [K+]
Solvent: CC#N
Product: OC(C(F)(F)F)(C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: -196 °C

Procedure:
By operating as in the above examples, 0.26 g of KF (4.5 mmol) was charged to the reactor, and then 4.0 ml of anhydrous acetonitrile was injected through the pierceable cap; the whole was then cooled down to -196° C. with the residual air being evacuated; then, 2.0 mmol of pentafluoropropionyl fluoride
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](=[O:12])[NH:4][C:3]=1[CH3:13].[CH3:14]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+].[Ag+]>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][CH3:14])=[N:4][C:3]=1[CH3:13]
Reactant: CI
Reactant: Cc1[nH]c(=O)c2c(c1Br)CCCC2
Agent: [Ag+]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1nc(C)c(Br)c2c1CCCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
8.9 g (36.8 mmol) of 4-bromo-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one are dissolved in 200 ml of chloroform and, after addition of 13.7 g (49.6 mmol) of silver(I) carbonate and 16.2 ml (36.5 g, 257 mmol) of methyl iodide, stirred at 50° C. for 3 h. After a further 24 h at RT, the suspension is filtered through Celite, concentrated and chromatographed on silica gel using n-heptane with addition of 2% ethyl acetate. A colorless oil (7.8 g, 83% yield) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O:14][C:15](=[O:25])[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:17]([CH2:16][C:15]([OH:25])=[O:14])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Product: O=C(O)CN(Cc1ccccc1)c1cc(Br)ccc1[N+](=O)[O-]
Yield: 54.8 %

Procedure:
In a manner as described above, 4-bromo-2-fluoro-1-nitro-benzene (11 g, 50 mmol), and N-benzyl-glycine ethyl ester (10 g, 50 mmol) were reacted to give crude [(5-bromo-nitro-phenyl)-benzyl-amino]-acetic acid (10 g, 55%). This product was reacted with iron powder to obtain crude 4-benzyl-6-bromo-3,4-dihydroquinoxalin-2(1H)-one (5 g, 58%). A sample was recrystallized from ethyl acetate/hexane: m.p.174-176° C. 1H-NMR (DMSO-d,) δ 3.75 (s, 2H), 4.43 (s, 2H), 6.71 (d, J=1.9 Hz, 1H), 6.81 (m, 2H), 7.32 (m, 5H), 10.57 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][C:60]([F:64])([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[O:24][CH2:61][C:60]([F:64])([F:63])[F:59])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: FC(F)(F)COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (150 mg, 0.355 mmol), 1,1′-(azodicarbonyl)dipiperdine (179 mg, 0.709 mmol) in tetrahydrofuran (7.5 mL) was added tri(n-butyl)phosphine (0.177 mL, 0.709 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.259 mL, 3.55 mmol) was added to the reaction mixture. The mixture was stirred at 65° C. for 15 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (102.9 mg, 0.204 mmol, 57%) as colorless crystals.