Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([CH:21]=O)[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:17]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(OCC)=O)C>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH:20]=[C:19](/[CH:21]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:17]2)=[CH:30][CH:31]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Sodium hydride (60%, oily, 1.10 g) was added to a solution of 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (9.66 g) and ethyl diethylphosphonoacetate (5.46 ml) in N,N-dimethylformamide (150 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. Ice water was poured into the reaction mixture, and the resulting crystals were collected by filtration. After drying, recrystallization from ethyl acetate-hexane gave ethyl (E)-3-[1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl]propenoate (10.60 g, yield: 93%). Melting point: 113–114° C.
Reaction SMILES: CO.[Na].[C:4]([O:12]C)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15].Cl>C1(C)C(C)=CC=CC=1>[C:17]1([C:14](=[O:16])[CH2:15][C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: CO
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
Methanol (0.26 ml, 6.4 mmol) and sodium (0.14 g, 6.1 mmol) were combined in xylene (60 ml) and stirred for 20 min at room temperature. Methyl benzoate (49, 2.47 ml, 19.7 mmol) and acetophenone (0.58 ml, 5.0 mmol) were added and the mixture stirred for 6 hr at 140° C. The mixture was cooled to room temperature and hydrochloric acid (10 ml, 6 N) was added and stirred for 15 min. The resulting mixture was extracted into ethyl acetate, washed twice with water, twice with saturated sodium bicarbonate and twice with water. The ethyl acetate was dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was chromatographed on silica gel with ethyl acetate/hexane to give a solid. The solid was recrystallized from methanol to give 0.71 g (63%) of a pink-orange solid: mp 70-71° C. [expected mp 77-78° C.]; 1H NMR: δ 6.85 (s, 1H), 7.51 (m, 6H), 7.98 (d, 4H, J=6.8 Hz); 13C NMR: δ 93.1, 127.1, 128.6, 132.4, 135.5, 185.6.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]#[CH:9])=[C:6]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]([C:25]2[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][C:26]=2[Cl:36])[N:4]=1)#[N:2].[Br:37]N1C(=O)CCC1=O.CCOCC.O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([C:3]1[C:7]([C:8]#[C:9][Br:37])=[C:6]([N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:5]([C:25]2[C:26]([Cl:36])=[CH:27][C:28]([C:32]([F:34])([F:35])[F:33])=[CH:29][C:30]=2[Cl:31])[N:4]=1)#[N:2]
Reactant: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1c(C#CBr)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyano-5-di-(t-butoxycarbonyl)amino-1-(2,6-dichloro-4-trifluoromethylphenyl)4-ethynylpyrazole (100 mg, the compound of Example B4) in acetone (10 ml) was added silver nitrate (5 mg) and N-bromosuccinimide (80 mg). The mixture was stirred at room temperature for one hour and then poured into ether (100 ml) and water (100 ml). The organic layer was separated, dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica gel eluted with dichloromethane to provide the title compound as a pale yellow solid m.p. 130-1° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>O1CCOCC1.CCOCC>[ClH:29].[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[N:20]=3)[NH:16][N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cccc(C(F)(F)F)n3)n2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: FC(F)(F)c1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Temperature: 25 °C

Procedure:
A mixture of 4-[5-(6-trifluoromethyl-pyridine-2-yl)-1H-[1,2,4]triazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (3.26 g) and 4M HCl in dioxane (47 mL) was stirred at rt until the reaction was complete. The reaction was diluted with Et2O and stirred for 30 minutes. The solid was filtered, taken up in ACN and stirred for 15 minutes. The solid was filtered, dissolved in warm MeOH, cooled to 0° C. and triturated with Et2O. The resulting solid was filtered and dried to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:33]>ClCCl>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH2:26][O:27][C:28]3=[O:33])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(OCC)c1ccc(C=Nc2cccc3c2COC3=O)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 84.5 %

Procedure:
To a stirred mixture of 4-(diethoxymethyl)benzaldehyde (3.75 g, 18 mmol) and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (300 mL) was added 4-aminoisobenzofuran-1(3 H)-one (2.24 g, 15 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give 4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (4.3 g, yield 84%) as a light yellow solid. LC-MS (ESI) m/z: 340 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>ClCCl>[N:13]1([C:7]([C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([Cl:11])=[N:4][CH:5]=2)=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: C1CNC1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
Commercially available 5,6-dichloronicotinic acid (200 mg, 1.04 mmol) was dissolved in dichloromethane (5.0 mL), and azetidine hydrochloride (125 mg, 1.34 mmol), HATU (440 mg, 1.16 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.58 mmol) were added, followed by stirring at room temperature for 5 hours under nitrogen atmosphere. 0.5N hydrochloric acid (30 mL) was added, and extraction was carried out with dichloromethane (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (162 mg, yield 67%) as a colorless liquid.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]1[C:8]([CH3:10])([CH3:9])[C:7]([F:12])([F:11])[CH2:6][N:5]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Li+].[OH-]>CO.O>[F:12][C:7]1([F:11])[CH2:6][N:5]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C@H:4]([C:3]([OH:20])=[O:2])[C:8]1([CH3:10])[CH3:9]
Reactant: COC(=O)[C@H]1N(C(=O)OC(C)(C)C)CC(F)(F)C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(F)(F)C(C)(C)[C@H]1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of methyl ester F4 (4.7 g, 16 mmol) in methanol (100 mL) was added a solution of LiOH (6.8 g, 160 mmol) in water (50 mL) and the solution was heated at 50° C. for 14 h. The methanol was removed in vacuo and the remaining solution was diluted with water (200 mL). The aqueous solution was extracted with ether (2×200 mL), acidified with 1N HCl (200 mL) and extracted again with ether (2×200 mL). The combined organics were washed with brine (1×200 mL), dried with magnesium sulfate and concentrated in vacuo. The while solid was dried overnight at 40° C. under vacuum. Isolated yield: 4.3 g (95%). 1H NMR (400 MHz, DMSO-d6): □ 12.95 (bs, 1H), 3.93 (s, 1H), 3.84–3.74 (m, 2H), 1.38 (s)+1.33 (s) (9H), 1.19 (s, 3H), 1.01 (s, 3H); 19F NMR (376 MHz, DMSO-d6): □ −111.4 (dt, J=227, 13 Hz)+−112.4 (dt, J=227, 13 Hz) (1F), −113.5 (dt, J=227, 14 Hz) +−113.9 (dt, J=227, 15 Hz) (1F); MS-APCI (m/z+): 180.1, (m/z−): 278.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:28].[CH2:30]1[CH2:40]CN2C(=NCCC2)C[CH2:31]1.[Br-].O>C(O)C.C(OCC)(=O)C>[CH2:40]([O:28][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH:30]=[CH2:31]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC)co2)ccc1OC(F)F
Reaction time: 2 h

Procedure:
A 0.15 g quantity of the compound obtained in Example 229 and 0.17 ml of DBU were dissolved in 4 ml of ethanol, 0.14 g of ally bromide was then added to the obtained solution, and heating and refluxing were conducted for 2 hours. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from aqueous 80% ethanol, thereby yielding 90 mg of white powdery 3-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: CO[C:3](=[O:34])[C:4]1[C:5](=[CH:10][C:11]([N:24]([CH2:31][CH:32]=[CH2:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([N:14]([CH2:21][CH:22]=[CH2:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=[O:7].[NH3:35]>CO>[CH2:31]([N:24]([C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[CH:13][C:12]=1[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:21][CH:22]=[CH2:23])[C:3]([NH2:35])=[O:34])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:32]=[CH2:33]
Reactant: N
Reactant: C=CCN(c1ccccc1)c1cc(C(=O)OC)c(C(=O)OC)cc1N(CC=C)c1ccccc1
Solvent: CO
Product: C=CCN(c1ccccc1)c1cc(C(N)=O)c(C(=O)O)cc1N(CC=C)c1ccccc1
Temperature: 120 °C

Procedure:
In an autoclave, 457 mg (1 mmol) of 4,5-bis(N-allylanilino)phthalic acid dimethyl ester are dissolved in 5 ml of methanol, and 15 ml of ammonia areused for the purpose of amide formation. The autoclave is closed and then heated at 120° C. for 24 hours, then cooled and opened, and the ammonia is driven off with nitrogen. The residue is rinsed out with ethyl acetate and filtered, and the filtrate is chromatographed on silica gel with hexane/ethyl acetate 3:1. The product fractions are concentrated by evaporation and crystallized from hexane/ethyl acetate, yielding the titlecompound in the form of yellow crystals, FAB-MS: 410 [M+ +H], m.p. 122°-127° C. As by product of the reaction, 4,5-Bis-(N-allyl-N-phenylamino)phthalic acid monoamide was isolated and recrystallized from hexane/ethyl acetate to yield yellow crystalIs, FAB-MS: 428 [M+ +H], m.p. 114°-116° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([NH2:28])=O)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1.N1C=CC=CC=1>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[S:49])[NH2:28])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=S)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 21.7 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenamide (2.50 g), Lawesson's reagent (2.26 g) and pyridine (15 mL) was heated under reflux for 30 min. After concentration of the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenethioamide as yellow crystals (0.56 g, yield 22%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-diethyl ether gave yellow prism crystals. melting point: 129-131° C.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=O)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[CH:9][C:10]#[N:11])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2cc(OC)cc(OC)c2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (2.15 ml, 13.66 mmol) in anhydrous THF (10 ml) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 13.66 ml, 13.66 mmol) slowly. The mixture was stirred in rt for 40 min. To the mixture, a solution of (3,5-dimethoxyphenyl)-(4-methoxyphenyl)methanone (5193-23-B, 1.86 g, 6.83 mmol) in anhydrous THF (20 ml) was added. The mixture was refluxed overnight. The solution was poured into ice water (20 ml) and the two phases were separated. The THF phase was evaporated and combined with the aqueous phase, which were then extracted with CH2Cl2 (2×40 ml), washed with water (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (20% EtOAc in hexane) to give 3-(3,5-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile as a yellow oil which was solidified slowly (1.97 g, 98%): mp, 79-81° C.; 1HNMR (DMSO-d6) δ 7.35-7.31 (m, 2H, Ar), 7.07-6.96 (m, 2H, Ar), 6.65-6.62 (m, 1H, Ar), 6.46-6.44 (m, 2H, Ar), 6.23 (s, 0.43H, double bond H of one isomer), 6.20 (s, 0.58H, double bond H of the other isomer), 3.82-3.68 (multiple singlets, 9H, OCH3); 13C NMR (CDCl3) δ 162.8, 162.6, 161.7, 161.3, 160.9, 160.8, 141.7, 139.2, 131.5, 131.0, 130.1, 129.3, 118.4, 118.2, 114.2, 114.0, 107.8, 107.2, 102.2, 102.1, 93.8, 93.0, 55.6, 55.5, 55.5; Anal. Calcd. for C18H17NO3+0.05H2O: C, 72.92; H, 5.89; N, 4.65. Found: C, 72.90; H, 5.52; N, 4.67.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:4][C:5]([C:22](F)([F:24])[F:23])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([CH2:14][CH2:15][CH3:16])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:24][CH:22]([F:23])[C:5]1[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH2:14][CH2:15][CH3:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:27])([F:1])[F:26])[N:4]=1
Reactant: CCCC1C(C(=O)OCC)=C(C(F)(F)F)NC(C(F)(F)F)=C1C(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(C(=O)OCC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: 0 °C
Yield: 64.7 %

Procedure:
A mixture of 20.0 g (0.05 mole) of diethyl 2,6-bis(trifluoromethyl)-1,4-dihydro-4-n-propyl-3,5-pyridinedicarboxylate, 7.62 g (0.05 mole) of DBU, and 200 ml of THF is held at reflux for 9 hours, cooled and poured into 500 ml of ice water. The mixture is extracted with ether (2×200 ml). The ether extract is washed with diluted hydrochloric acid, dried (MgSO4), and concentrated to give 12.4 g (64.5%) of the desired product, nD25 1.4436.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH3:22])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][N:21]([CH3:22])[C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: CNCCc1ccc(Br)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCc1ccc(Br)cc1)C(=O)OCc1ccccc1
Yield: 64.8 %

Procedure:
Benzyl chloroformate (0.97 mL, 6.7 mmol) was added dropwise to a solution of 23B (1.1 g, 5.1 mmol)in CH2Cl2 (26 mL) and triethylamine (1 mL, 7.5 mmol). The reaction mixture washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (0% to 50% EtOAc in hexanes) afforded 28C (1.15 g, 65%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.70-2.94 (m, 5 H) 3.47 (m, 2 H) 5.08 (m, 2 H) 6.90-7.12 (m, 2 H) 7.26-7.44 (m, 7 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:24]=[N+:25]=[N-:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OCCCc1cc(Cl)cc(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCCCc1cc(Cl)cc(Cl)c1
Yield: 97.8 %

Procedure:
3-(3,5-Dichlorophenyl)propanol (0.052 mol), tosyl chloride (0.104 mol) and sodium azide (0.104 mol) were reacted substantially as described in Example 7E to obtain 11.7 g (98%) of an oily product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH2:36][CH3:37])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The reaction was carried out under argon. Allyl (rac)-4-[4-cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1300 mg, 2.44 mmol) and morpholine (1.5 eq., 318 mg, 3.66 mmol) were initially charged in dry THF (65 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 141 mg, 0.122 mmol) was added, and the reaction mixture was stirred at RT for 16 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (100 ml). The organic phase was washed with 0.1 N hydrochloric acid (2×40 ml) and with saturated sodium chloride solution (3×30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. Methanol (10 ml) was added to the residue. The precipitated product was filtered off with suction and washed with methanol (2×5 ml). The title compound was isolated as a solid (1120 mg, 93% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18]C)=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.NC1N=C(C2C=C(Br)C=C[C:28]=2[OH:34])C=C(Cl)N=1>COCCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][O:34][CH3:28])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Solvent: COCCO
Product: COCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 42 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and 2-methoxy-ethanol provided 4-[5-bromo-2-(2-methoxy-ethoxy)-phenyl)-6-chloro-pyrimidin-2-ylamine (42% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]=2[CH:4]([OH:22])[CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:22][CH:4]1[CH2:3][CH:2]([CH3:1])[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]1=2)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(O)C1
Solvent: c1ccncc1
Product: CC(=O)OC1CC(C)Cc2nnc(-c3cccc(C(F)(F)F)c3)cc21
Yield: 82.2 %

Procedure:
To a pyridine solution (1 mL) of 7-methyl-3-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydrocinnolin-5-ol (61.6 mg, 0.2 mmol) obtained in Example 6 was added acetic anhydride (0.027 mL, 0.24 mmol) under ice cooling and subjected to reaction at room temperature for 2 hours. The reaction solution was concentrated as it is under reduced pressure, followed by purification of thus obtained residue using silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain an objective compound (57.6 mg, 82.3%).