Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.O.[NH2:11][NH2:12]>CCO>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH:11][NH2:12])=[N:6][CH:7]=1
Reactant: Cc1cc(Cl)ncc1Br
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(NN)ncc1Br
Temperature: 120 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Combined 5-bromo-2-chloro-4-methylpyridine (15.0 g, 72.46 mmol) and EtOH (60 mL) and added hydrazine hydrate (85%, 45 mL) and stirred at 120° C. overnight. The reaction mixture was concentrated to give a residue which was extracted with EtOAc (50 mL×2) and water (50 mL×2). Then combined organic layers were extracted with brine, dried over Na2SO4 to and concentrated to give a residue which was purified by flash chromatography (petroleum ether: EtOAc=10:1 to 1:5) to give the title compound (7.8 g, 53%).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:14]1[CH2:19][C@@H:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][CH2:16][C@@H:15]1[CH3:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH2:20]([C@H:18]1[CH2:19][N:14]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:15]([CH3:27])[CH2:16][N:17]1[C:29]([O:31][CH3:32])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H]1CN[C@H](Cc2ccccc2)CN1Cc1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Pyridine (0.57 ml, 7.0 mmol) was added to a stirring solution of (2S,5R)-1,5-dibenzyl-2-methylpiperazine (0.40 g, 1.2 mmol) and methyl chloroformate (0.20 ml, 2.5 mmol) in CH2Cl2 (14 ml). After stirring at ambient temperature for 2 h, the reaction was evaporated in vacuo and the residue purified by flash chromatography (SiO2, 3% MeOH in CH2Cl2) to afford pure product (0.28 g, 68% yield over the two steps). MS (ESI) 339 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH2:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)([CH3:19])[CH3:20])[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(C)(C)CC=Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2.0 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methyl-1-pentene, 0.2 g of 5% Pd-C and 40 ml of ethyl acetate was put in a 200 ml autoclave and pressed up to 10 kg/cm2G with hydrogen gas, and stirred at 80° C. for three hours. After cooling, the reaction mixture was filtered and the solvent was evaporated, and the residue was purified by column chromatography on silica gel to 1.7 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methylpentane.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][SiH:5]1[CH2:10][CH2:9][CH:8](Br)[CH2:7][CH2:6]1.Cl[SiH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.Cl[SiH]1CCC(C2C=CC(OC(F)(F)F)=CC=2)CC1>>[F:1][CH2:2][CH2:3][CH2:4][Si@H:5]1[CH2:10][CH2:9][C@H:8]([Si@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH3:27])=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1
Reactant: CCCc1ccc(C2CC[SiH](Cl)CC2)cc1
Reactant: FCCC[SiH]1CCC(Br)CC1
Agent: FC(F)(F)Oc1ccc(C2CC[SiH](Cl)CC2)cc1
Product: CCCc1ccc([C@H]2CC[Si@H]([C@H]3CC[Si@H](CCCF)CC3)CC2)cc1

Procedure:
The above compound was obtained in the same manner as Example 23, using 4-(3-fluoropropyl)-4-silacyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-n-propylbenzene instead of 4-(4,4-difluorobutyl)-4-silacyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-trifluoromethoxybenzene, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][C:32]#[CH:33])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][C:32]#[CH:33])[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: C#CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)Cl
Product: C#CCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)=O
Yield: 53 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(prop-2-yn-1-ylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 53% yield; NMR spectrum (DMSO-d6) 2.03 (s, 3H), 3.27 (s, 1H), 3.93-4.04 (m, 2H), 4.24-4.32 (m, 2H), 4.43 (t, 1H), 4.56-4.63 (m, 1H), 5.31 (s, 2H), 7.13 (d, 1H), 7.25 (d, 1H), 7.34 (d, 1H), 7.35-7.41 (m, 1H), 7.52-7.63 (m, 2H), 7.70-7.79 (m, 1H), 7.86-7.93 (m, 2H), 8.44 (s, 1H), 8.61 (d, 1H), 9.69 (s, 1H); Mass spectrum MH+ 502.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:3]1.Cl.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][N:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:11][CH:12]=2)[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:3]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cn1nc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 65 °C
Yield: 79.4 %

Procedure:
A mixture of 4-(2-methyl-5-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)phenol (80 mg, 0.32 mmol), 2-(chloromethyl)quinoline hydrochloride (71 mg, 0.33 mg), and cesium carbonate (414 mg, 1.27 mmol) in dimethylformamide was heated at 65° C. for 20 h, filtered, the filtrate concentrated and chromatographed on silica eluted with ethyl acetate-hexanes providing material containing starting phenol. This was dissolved in ethyl acetate, washed with aqueous NaOH, dried and concentrated giving a colorless solid (100 mg, 80%). 1H NMR (CDCl3, 400 mHz) δ 8.56 (d, 2H, J=6.2 Hz), 8.24 (d,1H, J=8.3 Hz), 8.12 (d, 1H, J=8.3 Hz), 7.85 (d, 1H, J=8.3 Hz), 7.75 (ddd, 1H, J=8.5, 7, 1.6 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.65 (d, 2H, J=6.2 Hz), 7.57 (m, 1H), 7.41 (m, 2H), 7.08 (m, 2H), 5.45 (s, 2H), 4.27 (s, 3H). MS (AP+) m/e 394 (MH+).
Reaction SMILES: [Cl-].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]C1C=CC=CC=1.[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH:43][CH2:44][CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:38][C:37]=1[O:53][CH3:54])=O>C1COCC1>[CH3:54][O:53][C:37]1[CH:38]=[C:39]([CH2:42][NH:43][CH2:44][CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[CH:40]=[CH:41][C:36]=1[CH:34]=[CH:7][C:3]1[S:2][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(CNCCOC(=O)C(C)(C)C)ccc1C=O
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(CNCCOC(=O)C(C)(C)C)ccc1C=Cc1cccs1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Thiophene-2-ylmethyl triphenylphosphonium chloride (4.4 g, 16.3 mmol) was added to THF (50 ml), and PhLi (8.6 g of 19% solution in hexane, 19.6 mmol) was added dropwise thereto in an ice bath. After 20 minutes, 2,2-dimethylpropionic acid 2-[(4-formyl-3-methoxyphenyl)methylamino]ethyl ester (4.0 g, 13.6 mmol) dissolved in THF (15 ml) was added dropwise. The mixture was reacted for 2 hours. The reaction mixture was added to 300 ml of ice water, and the oily matter was subjected to 3 times of extraction with dichloromethane (50 ml). Washing with a saturated saline solution, drying over Na2SO4, and concentration were performed. The residue was purified by silica gel chromatography to give a yellow oily matter (yield: 4.0 g (79.3%)).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11](I)([F:16])[C:12]([F:15])([F:14])[F:13].CCCCCC>C(Cl)Cl>[C:2]1([C:1]([C:11]([F:16])([F:10])[C:12]([F:15])([F:14])[F:13])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: FC(F)(F)C(F)(F)I
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(c1ccccc1)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 37.1 %

Procedure:
Firstly, the starting material was prepared as follows: under protective gas, 35 g (0.25 mol) of benzoyl chloride in 150 ml of CH2Cl2 were initially introduced at about -20° C. into a round-bottomed flask. 67 g (0.27 mol) of pentafluoroethyl iodide were firstly condensed in and 66.7 g (0.27 mol) of phosphorous acid trisdiethylamide were then metered in. The reaction mixture was subsequently stirred at 0° C. for a further 5 hours. After addition of the same volume of hexane to the reaction mixture, 2 phases formed. After phase separation, the lower phase was carefully extracted using hexane; the combined hexane phases were concentrated and distilled under reduced pressure. 20.8 g (58% yield) of pentafluoroethyl phenyl ketone of b.p. 76°-77° C./40 mbar were obtained.
Reaction SMILES: O=O.[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH:16]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C1C=CC=CC=1>[C:3]1(=[O:16])[C:15]2[C:7]([C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=[CH:4]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: O=O
Solvent: N#Cc1ccccc1
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
In an oxygen atmosphere, a mixture of 10 millimoles of fluorene, 1 millimole of N-hydroxyphthalimide, 0.05 millimole of acetylacetonatomanganese Mn(AA)3 and 25 milliliters of benzonitrile was stirred at a temperature of 100° C. for six hours. Products in the reaction mixture were analyzed with gas chromatography, and fluorene was transformed into fluorenone (yield 28%) with a transformation rate of 32 percent.
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].O.[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:18]([NH:7][CH:8]([C:13](=[O:16])[CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CCC(=O)C(N)C(=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)C(NC(=O)C=Cc1ccccc1)C(=O)OC

Procedure:
Sodium hydrogen carbonate (10.0 g) was added to a mixture of methyl 2-amino-3-oxovalerate hydrochloride (9.1 g), ethyl acetate (50 ml) and water (40 ml) with ice-cooling and stirring followed by dropwise addition of a solution of cinnamoyl chloride (8.3 g) in ethyl acetate (10 ml). The whole mixture was stirred under ice-cooling for 2 hours and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and isopropyl ether was added to the residue to give methyl 2-cinnamoylamino-3-oxovalerate as crystals; yield 8.8 g (63.8%). Recrystallization from ethanol gave colorless needles melting at 119°-120° C.
Reaction SMILES: [C:1]([O:20][CH2:21][C:22]([CH2:51][O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]/[CH:61]=[CH:62]\[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[NH:23][CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[C:79]1(=[O:85])[O:84][C:82](=[O:83])[CH2:81][CH2:80]1>C1COCC1>[C:1]([O:20][CH2:21][C:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH2:51][O:52][C:53](=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]/[CH:61]=[CH:62]\[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[N:23]([CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])[C:79](=[O:85])[CH2:80][CH2:81][C:82]([OH:84])=[O:83])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)(COC(=O)CCCCCCC/C=C\CCCCCCCC)NCCS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)(COC(=O)CCCCCCC/C=C\CCCCCCCC)N(CCS(=O)(=O)O)C(=O)CCC(=O)O
Reaction time: 18 h

Procedure:
To 566 mg (0.553 mmol) of 2-[tris(oleoyloxymethyl) methylamino]-1-ethanesulfonic acid in 10 mL THF was added 410 mg (4.06 mmol) of triethylamine. After 5 min 96 mg (0.960 mmol) of succinic anhydride was added. The yellow solution was stirred for 18 h under reflux. The solvent was removed under reduced pressure. The residual oil was purified by chromatography on silica gel, eluted with an ethyl acetate/methanol gradient (25:75 vol/vol to 0:100 vol/vol). N-[tris(oleoyloxymethyl)methyl]-N-(2-sulfoethyl) succinic acid monoamide was isolated as a yellow heavy viscous oil with a yield of 240 mg (38%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[N:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:15][C:16]3[C:17](=[CH:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=3)[N:24]3[CH:25]=[CH:26][CH:27]=[C:28]23)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(-n2cccc2)c(N)c1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)NC1(CCN(C(C)=O)CC1)c1cccn1-2

Procedure:
7.06 g (0.05 mole) of 1-acetyl-4-piperidone and 5 ml. of glacial acetic acid are added to a solution of 9.41 g (0.05 mole) of 1-(2-amino-4-methoxy-phenyl)pyrrole [Example 19(b)] in 150 ml. of absolute ethanol. The solution is refluxed for 12 hours. The volume of the solvent is reduced to about one fifth and the solution is cooled. A solid precipitates and is filtered, dried, and recrystallized from ethanol to give 1'-acetyl-4,5-dihydro-7-methoxyspiro[pyrrolo(1,2-a) quinoxaline-4,4'-piperidine], m.p. 211°-213° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][C:16]3=[CH:18][N:19]=[C:20]([CH3:21])[N:15]3[C:14]2=[O:22])[CH2:9][CH2:8]1)=[O:6].C1CCN2C(=NCCC2)CC1.[C:40]1([N:46]=[C:47]=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[CH3:21][C:20]1[N:15]2[C:14](=[O:22])[N:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:5](=[O:6])[CH:4]([NH:3][C:47]([NH:46][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:48])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:8][CH2:9]3)[CH2:17][C:16]2=[CH:18][N:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)Nc3ccccc3)c3ccccc3)CC1)C2
Yield: 60.1 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.21 g) obtained in Example 115a) and DBU (0.15 g) were dissolved in acetonitrile (10 ml). Phenyl isocyanate (66 mg) was added thereto, and mixed at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) and solidified with ethyl acetate and diethyl ether to obtain the title compound (0.14 g, 59%) as colorless powder.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].CO[C:15](=O)[NH:16][C:17]1[CH:18]=[N:19][C:20]([N:31]2[CH2:36][CH2:35][S:34][CH2:33][CH2:32]2)=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:15][NH:16][C:17]1[CH:18]=[N:19][C:20]([N:31]2[CH2:32][CH2:33][S:34][CH2:35][CH2:36]2)=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30]
Reactant: COC(=O)Nc1cnc(N2CCSCC2)cc1-c1ccc(F)cc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CNc1cnc(N2CCSCC2)cc1-c1ccc(F)cc1C
Temperature: 25 °C

Procedure:
Methyl-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-amine can be produced by diluting Red-Al in toluene and adding this solution dropwise to a solution of [4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-carbamic acid methyl ester in toluene. The yellow solution obtained is stirred at room temperature, cooled to about 0° C., and poured slowly onto a mixture of 4 N aqueous sodium hydroxide and ice (very exothermic). After stirring, the phases are separated, the aqueous phase extracted with tert-butyl-methyl-ether, and the organic phases washed with brine. The combined organic extracts are dried and concentrated under reduced pressure to yield methyl-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-amine as a brown oil which can be used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][CH2:37][O:38][CH3:39]>CS(C)=O>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:36][CH2:37][O:38][CH3:39])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[N:8]=1)=[O:5]
Reactant: COCCBr
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCOc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Reaction time: 6 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide ((for a preparation see Example 36)101 mg, 0.254 mmol) in DMSO (1 ml) was added cesium carbonate (166 mg, 0.508 mmol) and then 1-bromo-2-(methyloxy)ethane (0.035 ml, 0.372 mmol, Aldrich) under nitrogen at ambient temperature. The solution was stirred for 6 h. The mixture was filtered using a hydrophobic frit and the filtrate diluted with methanol (1 ml). The filtrate was purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a pale yellow gum (35 mg); LCMS: (System 4) MH+=456, tRET=2.84 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[N:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[N:40][CH:39]=[N:38][CH:37]=2)[CH:31]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isobutylamino-phenyl)-carbamic acid tert-butyl ester (Example J16) (235 mg, 0.75 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white foam (260 mg, 64%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH:14][C:15](OC)=[O:16])[C:11]([F:13])=[CH:12][C:7]=2[S:6][C:5]1=[O:19])([CH3:3])[CH3:2].[H-].[Na+].[NH2:22]/[C:23](/[C:30]([F:33])([F:32])[F:31])=[CH:24]\[C:25]([O:27]CC)=O.O>CN(C)C=O>[CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([N:14]3[C:25](=[O:27])[CH:24]=[C:23]([C:30]([F:31])([F:32])[F:33])[NH:22][C:15]3=[O:16])[C:11]([F:13])=[CH:12][C:7]=2[S:6][C:5]1=[O:19])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COC(=O)Nc1cc2c(cc1F)sc(=O)n2C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Yield: 41.8 %

Procedure:
To a solution of 3-isopropyl-6-fluoro-5-methoxycarbonylamino -2(3H)-benzothiazolone (2.8 g) in N,N-dimethylformamide (10 g), sodium hydride (0.4 g) and ethyl 3-amino-4,4,4-trifluorocrotonate (0.9 g) were added, and the resultant mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography to give 1-[3-isopropyl-6-fluoro-2(3H) -benzothiazolon -5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine -2,6-dione (0.8 g).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1.[C:11]([O:14][CH2:15][C:16](=O)[CH2:17][C:18](OCC)=[O:19])(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:15][C:16]1[NH:1][C:2]2[N:6]([N:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[N:3]=2)[C:18](=[O:19])[CH:17]=1)(=[O:13])[CH3:12]
Reactant: CCOC(=O)CC(=O)COC(C)=O
Reactant: COC(=O)c1nnc(N)[nH]1
Product: COC(=O)c1nc2[nH]c(COC(C)=O)cc(=O)n2n1
Reaction time: 0.67 h
Yield: 82.6 %

Procedure:
A mixture of 71 mg (0.5 mmol) of methyl 5-amino-4H-s-triazole-3-carboxylate and 188 mg of ethyl 4-acetoxy-3-oxo-butyrate is held at about 160° C. for 40 minutes. After cooling the product is crystallized and recrystallized from methanol. There are obtained 110 mg of methyl 5-(acetoxymethyl)-4,7-dihydro-7-oxo-s-triazolo[1,5-a]pyrimidine-2-carboxylate as beige crystals of melting point 223° C. (dec.).