Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12]Cl)[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:27][C:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12][N:31]3[CH2:32][CH2:33][C:28]([OH:27])([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:29][CH2:30]3)[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1N(C2CCCCC2)CC(CCl)C1(c1ccccc1)c1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1N(C2CCCCC2)CC(CN2CCC(O)(c3ccccc3)CC2)C1(c1ccccc1)c1ccccc1
Temperature: 200 °C
Reaction time: 48 h

Procedure:
To 150 ml. of ethanol in a steel bomb was added 15.0 g. (0.041 mole) of 1-cyclohexyl-4-chloromethyl-3,3-diphenyl-2-pyrrolidinone, 7.23 g. (0.041 mole) of 4-hydroxy-4-phenyl piperidine and 17.0 g. (0.12 mole) of potassium carbonate. The bomb was heated in an oven at 200° C. with stirring for 48 hours. The mixture was concentrated in vacuo, and the residue was partitioned between dilute sodium hydroxide solution and chloroform. The chloroform layer was dried, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and treated with ethereal hydrogen chloride. The solid which precipitated was the hydrochloride of starting piperidine compound. A further precipitate from the filtrate of this material contained a by-product of the reaction. The by-product was separated by filtration and the filtrate concentrated. The residue was partitioned between chloroform and sodium hydroxide solution, and the chloroform, after drying, was concentrated in vacuo. The residue was placed on a magnesium silicate column using chloroform as the eluent. The product was obtained upon subsequent washings of 1 and 2 percent methanol in chloroform. The washings were concentrated in vacuo, and the residue crystallized using an isopropyl ether-ethyl acetate mixture. The solid (1.5 g.; m.p. 179°-184° C.) after recrystallizing from ethyl acetate weighed 1.0 g. and melted at 188°-190° C.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[NH:7][C:6]2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:9][C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:11][C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=1[CH3:41]>CN(C=O)C>[F:22][CH:2]([F:1])[C:3]1[N:4]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[C:32]=2[CH3:41])[C:5]2[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[C:6]=2[N:7]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)F)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 70 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of methyl 2-(difluoromethyl)-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 68 (500 mg, 1.6 mmol), K2CO3 (442 mg, 3.2 mmol) and 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (480 mg, 1.9 mmol) in DMF (15 mL) was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was poured into water (100 mL) and filtered, the filter cake was collected and purified by silica gel chromatography eluted with petroleum ether:EtOAc=1:1 to give the desired product (710 mg, 98%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.53 (s, 3H), 3.14 (t, 4H, J=4.5 Hz), 3.73 (t, 4H, J=4.5 Hz), 3.93 (s, 3H), 5.75 (s, 2H), 6.27 (d, 1H, J=7.8 Hz), 7.22 (t, 1H, J=7.8 Hz), 7.30 (d, 1H, J=2.1 Hz), 7.36 (t, 1H, J=51.6 Hz), 7.58-7.61 (m, 2H); LC-MS: m/e=484 [M+1]+
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][Cl:26])=[O:23]>C(OCC)C>[C:22](=[O:23])([O:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[O:24][CH2:25][Cl:26]
Reactant: O=C(CCCO)OCc1ccccc1
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCCOC(=O)OCCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of benzyl 4-hydroxybutanoate (synthesized by the procedure described in Weber et al., J. Med. Chem, 1991, 34, 2692-2701, 5.0 g) in diethyl ether (100 ml), pyridine (2.3 ml) was added under a nitrogen atmosphere, and chloromethyl chloroformate (3.7 g) was added dropwise at −10 ° C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered with glass filter and then the filtrate was washed with water and a saturated sodium chloride aqueous solution successively. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure, and thus the residue was subjected to silica gel column chromatography and eluted with acetone/hexane (1:1 v/v) to obtain chloromethyl (3-benzyloxycarbonylpropyl) carbonate (7.25 g) as a colorless oily product.
Reaction SMILES: O[C:2]1([C:29]([F:32])([F:31])[F:30])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:8]2[CH2:19][NH:20][CH:21]([C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:22][N:6]3[C:7]2=[C:3]1[CH:4]=[CH:5]3.O=S(Cl)Cl>N1C=CC=CC=1>[CH:26]([NH:25][C:23]([CH:21]1[NH:20][CH2:19][C:8]2=[C:7]3[C:3](=[C:2]([C:29]([F:31])([F:32])[F:30])[C:10]([CH2:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:9]2)[CH:4]=[CH:5][N:6]3[CH2:22]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)NC(=O)C1Cn2ccc3c2C(=CC(CCc2ccccc2)C3(O)C(F)(F)F)CN1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)NC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Yield: 88.7 %

Procedure:
The 7-hydroxy-N-isopropyl-6-phenethyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (9 mg, 0.021 mmol) was further processed with SOCl2 and pyridine as described in Example 1, above to yield N-isopropyl-6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (8 mg).
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]O)[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.S(Cl)([Cl:33])=O>C(Cl)Cl.C1COCC1>[Cl:33][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[C:2]([Cl:1])[CH:3]=1)=[N:18][CH:19]=[N:20]2
Reactant: OCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: ClCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12

Procedure:
To a stirred solution of the 2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethanol (20 g) in DCM (200 ml) and THF (200 ml) was added thionyl chloride (20 ml) at ambient temperature. The solution was then heated under reflux for 2 hours. The solution was cooled and product filtered off to give 5-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine as its hydrochloride salt (25 g, 98%); NMR spectrum (DMSO-d6) 4.20-4.40 (t, 2H), 4.60-4.80 (t, 2H), 5.40 (s, 2H), 7.20-7.60 (m, 3H), 7.60-7.80 (m, 3H), 7.90-8.10 (m, 3H), 8.60-8.70 (d, 1H), 8.9 (s, 1H), 10.65-10.83 (bs, 1H); Mass spectrum MH+ 441.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]([NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:34][CH:35]([CH3:38])[CH:36]=O.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]([NH:28][C:29](=[O:33])[C:30]([C:31]#[N:32])=[CH:34][CH:35]([CH3:38])[CH3:36])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: C[C@@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Reactant: CC(C)C=O
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)C=C(C#N)C(=O)N[C@@H](C)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
A suspension of N-[(2S)-1-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]propan-2-yl]-2-cyanoacetamide (250 mg, 0.56 mmol, 1.00 equiv), 2-methylpropanal (81 mg, 1.12 mmol, 2.00 equiv) and piperidine (47 mg, 0.55 mmol, 1.00 equiv) in methanol (15 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). The purified product was re-purified on Prep-HPLC eluting with TFA (0.05%)/H2O and CH3CN. The organic phase was removed off under reduced pressure. The aqueous phase was adjusted to 10 with potassium carbonate, which was extracted with DCM. The organic layers were combined, washed with brine, dried over sodium sulfated, filtrated and concentrated. This resulted in 46.4 mg (17%) of the title compound as a white solid. LC-MS m/z: 500 (M+1). H-NMR (400 MHz, CDCl3, ppm): 8.49 (s, 1H), 8.12 (d, J=7.2 Hz, 1H), 7.60 (t, J=8.8 Hz, 1H), 7.44 (m, 3H), 7.25-7.21 (m, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.94 (dd, J=8.4, 2.4 Hz, 1H), 6.88 (dd, J=11.2, 2.4 Hz, 1H), 5.51 (brs, 2H), 4.74-4.55 (m, 3H), 3.00-2.95 (m, 1H), 1.21 (d, J=6.8, 3H), 1.15 (d, J=6.8 Hz, 6H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].FC1C=CC(CCl)=CC=1>>[F:8][C:6]1[CH:7]=[CH:2][C:3]([CH2:9][N:35]2[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=3)=[N:36]2)=[CH:4][CH:5]=1
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Agent: Fc1ccc(CCl)cc1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)cc2)c1=O
Yield: 86.6 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-fluorobenzyl chloride were reacted to yield the title compound as a slightly-yellow crystalline powder (yield: 86.6%).
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[C-:30]#[N:31].[K+]>C(Cl)(Cl)(Cl)Cl.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.O>[C:30]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.2 %

Procedure:
In 120 ml of carbon tetrachloride are dissolved 12.2 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 2.44 g of tri-n-octylmethylammonium chloride and, under stirring, a solution of 2.15 g of potassium cyanide in 30 ml of water is added. The mixture is stirred vigorously at the same temperature for 15 minutes and the organic layer is separated, while the aqueous layer is extracted with chloroform. The organic layers are combined, washed with water and treated in the same manner as (1) of Example 13 to give 7.66 g of (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=O.[C:9]([NH:12][CH2:13][CH2:14][N:15]1[C:19]([CH3:20])=[CH:18][C:17](C=O)=[C:16]1[CH3:23])(=[O:11])[CH3:10].N1CCCCC1>N1C=CC=CC=1>[C:9]([NH:12][CH2:13][CH2:14][N:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH:3]=[CH:2][C:1]([O:7][CH3:8])=[O:6])=[C:19]1[CH3:20])(=[O:11])[CH3:10]
Reactant: COC(=O)CC(=O)[O-]
Reactant: CC(=O)NCCn1c(C)cc(C=O)c1C
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC(=O)C=Cc1cc(C)n(CCNC(C)=O)c1C
Reaction time: 24 h
Yield: 56.7 %

Procedure:
6.1 g (0.05 mol) of monomethyl malonate are dissolved in 20 ml of pyridine. After addition of 10.4 g (0.05 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole-3-aldehyde (see Example 13) and 1 ml of piperidine, the mixture is heated under reflux for 15 hours. After addition of a further 27 g of monomethyl malonate, heating is continued for a further 24 hours, the mixture is concentrated, the residue is taken up in water, the mixture is extracted with methylene chloride and the methylene chloride phase is washed with dilute acid and alkali and concentrated. Column chromatography with methylene chloride:methanol=98:2 as the mobile phase gives 7.5 g of product, which can be recrystallized from ethyl acetate.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26]C=1.BrC1C=CC=C[N:32]=1.IC1C=CC=CC=1>>[ClH:1].[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:32]=1
Reactant: Brc1ccccn1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccn3)c(=O)c2)cc1

Procedure:
4-[3-(2-Oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile hydrochloride salt was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-bromopyridine for the iodobenzene in Step 3.
Reaction SMILES: [NH:1]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([O:34]CC)=O)[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][C:21](=[O:23])[NH2:22])=[O:17])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[NH2:44][NH2:45].O>CO>[NH:1]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:44][NH2:45])=[O:34])[CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:20][C:21](=[O:23])[NH2:22])=[O:17])[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 48 h
Yield: 79 %

Procedure:
2.80 Grams of Boc-Gly-Ser(Bzl)-Asn-Leu-OEt was dissolved in 30 ml of methanol. Thereto was added 2.25 ml of NH2NH2.H2O. The mixture was allowed to stand for 2 days at room temperature. The resulting precipitate was collected by filtration and washed with methanol to obtain 2.16 g (yield: 79.0%) of the above objective compound. Melting point: 221°-224° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.CN1CCOCC1.[C:25]1([CH2:31][S:32](Cl)(=[O:34])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:31]([S:32]([NH:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:34])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (960 mg, 4.0 mmol), as prepared in the preceding step, and N-methylmorpholine (840 μL, 8.0 mmol) in methylene chloride (40 mL) was added α-toluenesulfonyl chloride (765 mg, 4.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Additional methylene chloride (50 mL) was added. The resulting methylene chloride solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. The solvent was concentrated to give a solid which was washed with ethyl acetate/hexane (1:2, 60 mL) to give the title compound as a white solid (1.4 g, 89%). 1H-NMR (300 MHz, CDCl3) δ7.35 (d, J=7.5 Hz, 1H), 7.31 (m, 5H), 7.20 (s, 1H), 6.02 (d, J=7.4 Hz, 1H), 4.75 (s, 2H), 4.31 (s, 2H), 2.27 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21](OC(C)(C)C)=[O:22]>C(Cl)Cl>[N:21]([S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22]
Reactant: CC(C)(C)ON=O
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=NSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Triphenylmethyl mercaptan (0.050 g, 0.18 mmol) was dissolved in anhydrous methylene chloride and cooled to 0° C. Tert-butyl nitrite (0.186 g, 1.80 mmol) was added and the resulting mixture was stirred at 0° C. for 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The solvent and excess of tert-butyl nitrite were evaporated to give the title compound as a green solid (0.054 g, 98%). 1H NMR (CDCl3) δ: 7.13-7.18 (m, 4H), 7.25-7.39 (m, 11H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:16][CH:13]1[CH2:15][CH2:14]1)=[O:8]
Reactant: NC1CC1
Reactant: O=C(Cl)/C=C/c1cccc(Br)c1
Solvent: Cc1ccccc1
Product: O=C(/C=C/c1cccc(Br)c1)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A solution of trans 3-bromocinnamoyl chloride (12.2 g) in dry toluene (150 ml) was added dropwise (rapidly) with rapid stirring to a solution of cyclopropylamine (6.3 g) in dry toluene (150 ml). The reaction mixture was stirred at room temperature for 2 hours, then at 30°-35° C. for an additional hour; and the solvent and excess amine were removed under reduced pressure. The residue was triturated with water to remove cyclopropylamine hydrochloride. The product was filtered, washed with dilute hydrochloric acid and then with water. It was then recrystallized from ethanol:water (1:10) to give white crystalline trans 3-bromo-N-cyclopropylcinnamamide (12 g), m.p. 110°-111° C. Elemental analysis, NMR and 1R data were all consistent with the assigned structure. TLC gave one spot run on silica gel with 5:1 and with 3:1 hexane:ethanol.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[O:12][C:11]([OH:13])=[N:10][N:9]=2)[CH2:4][CH2:3]1.Cl[C:15]1[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=1>>[OH:13][C:11]1[O:12][C:8]([CH:5]2[CH2:4][CH2:3][N:2]([C:15]3[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=3)[CH2:7][CH2:6]2)=[N:9][N:10]=1
Reactant: Oc1nnc(C2CCNCC2)o1
Reactant: OB(O)c1cnc(Cl)nc1
Agent: Cl
Product: OB(O)c1cnc(N2CCC(c3nnc(O)o3)CC2)nc1

Procedure:
Prepared from 5-(piperidin-4-yl)-1,3,4-oxadiazol-2-ol hydrochloride (1.30 g, 6.32 mmol) and (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) in accordance with General Method C to give the title compound as an off-white semi-solid. HPLC-MS: m/z (M−H)+ 290.2, RT 0.17 minutes.
Reaction SMILES: P(Cl)(Cl)Cl.[P:5]([OH:8])([OH:7])[OH:6].[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[NH:14][CH:15]=O>O>[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[NH:14][CH:15]([P:5]([OH:8])(=[O:6])[OH:7])[P:5]([OH:8])(=[O:7])[OH:6]
Reactant: OP(O)O
Reactant: O=CNc1nccs1
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(Nc1nccs1)P(=O)(O)O
Reaction time: 1 h
Yield: 29.9 %

Procedure:
7 g of phosphorus trichloride are mixed with 4.0 g of phosphorous acid and the mixture is heated, while stirring, at 60° for 1 hour. 6.12 g of N-(thiazol-2-yl)formamide are added thereto and the mixture is heated for a further 6 hours at approximately 60°. The mixture is then stirred with 30 ml of water, filtered with suction, subsequently washed with aqueous methanol and dried under reduced pressure. 2.0 g of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 275° (decomposition) are obtained.
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[O:21][C:22]2[CH:29]=[CH:28][C:25](C=O)=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([OH:36])(=[O:35])[CH2:31][C:32](O)=O.Cl>N1C=CC=CC=1.N1CCCCC1>[C:1]1([C:7]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[O:21][C:22]2[CH:23]=[CH:24][C:25](/[CH:32]=[CH:31]/[C:30]([OH:36])=[O:35])=[CH:28][CH:29]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(Oc2c(-c3ccccc3)c(C(F)(F)F)cc3ccccc23)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C(F)(F)F)cc3ccccc23)cc1
Temperature: 85 °C
Yield: 79.6 %

Procedure:
4-{[2-Phenyl-3-(trifluoromethyl)-1-naphthalenyl]oxy}benzaldehyde (183) (92 mg, 0.24 mmol) was dissolved in pyridine (3 mL). To this solution was added malonic acid (74 mg, 0.70 mmol) and 1 drop of piperidine. The reaction mixture was heated at 85° C. overnight, cooled and poured into 5 N HCl (20 mL). The mixture was extracted with EtOAc. The combined organic extract was washed with 5 N HCl, water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown viscous oil, which upon trituration with 1% MeOH in hexanes, yielded 83 mg (81%) of the title compound (184) as a white solid. mp 210-211° C. 1H NMR (400 MHz, CH3OH-d4): δ 6.28 (d, J=15.9 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 7.10-7.30 (m, 5H), 7.37 (d, J=8.7 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.60-7.72 (m, 2H), 7.89 (d, J=8.1 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.36 (s, 1H). LCMS (APCI): m/z 435 (M+H)+, m/z 433 (M−H)−. Anal. Calc for C26H17F3O3.⅙H2O: C, 71.39; H, 3.99. Found: C, 71.50; H, 3.94.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[O:19][CH2:20][O:21][CH3:22].CN(C)CCN(C)C.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[C:10]([O:19][CH2:20][O:21][CH3:22])=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:13][C:14]=1[CH3:1]
Reactant: [Li]CCCC
Reactant: COCOc1c(C(OC)OC)cccc1C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COCOc1c(C(F)(F)F)ccc(C)c1C(OC)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
A n-butyllithium-1.59M n-hexane solution (40.0 ml, 64.4 mmol) was added dropwise to a solution of 1-(dimethoxymethyl)-2-(methoxymethoxy)-3-(trifluoromethyl)benzene (12.0 g, 42.9 mmol) obtained in Example (6-4) and N,N,N′,N′-tetramethylethylenediamine (9.70 ml, 64.4 mmol) in tetrahydrofuran (100 ml) at −40° C. over 5 minutes. The reaction mixture was stirred at 0° C. for 15 minutes. After the reaction mixture was cooled to −40° C., methyl iodide (5.3 ml, 85.85 mmol) was added thereto and the mixture was further stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1) to give 2-(dimethoxymethyl)-3-(methoxymethoxy)-1-methyl-4-(trifluoromethyl)benzene as an oil (7.19 g, yield: 57%).