Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Pb:1]=[O:2].[NH:3]1[C:10](=[O:11])[NH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5]>O>[C:4]1([O-:5])[N:6]=[C:7]([O-:8])[N:9]=[C:10]([O-:11])[N:3]=1.[C:4]1([O-:5])[N:6]=[C:7]([O-:8])[N:9]=[C:10]([O-:11])[N:3]=1.[OH2:2].[OH2:5].[OH2:5].[Pb+2:1].[Pb+2:1].[Pb+2:1]
Reactant: O=[Pb]
Reactant: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Solvent: O
Product: [O-]c1nc([O-])nc([O-])n1
Product: [Pb+2]
Reaction time: 1 h

Procedure:
A paddle mixer with built-in blade mill was used to mix 50 kg deionized water, 80 kg lead oxide (PbO) and 31.1 kg cyanuric acid. The mixture was heated to between 140° and 150° C., with the consequent rise in pressure to between 5 and 6 bar. The reaction was complete after one hour. The lead cyanurate formed was then dried in the same apparatus at 40 mbar to a residual moisture of less than 1%. 108.1 kg neutral lead cyanurate Pb3 (C3N3O3)2.2H2O was obtained.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@@H](C)C(O)=O)C=CC=CC=1.[C:23]([N:26]1[N:30]=[C:29]([NH2:31])[S:28][C:27]1([CH2:38][CH2:39][NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:25])[CH3:24].N1C=CC=CC=1>S(Cl)(Cl)=O>[C:23]([N:26]1[C:27]([CH2:38][CH2:39][NH:40][S:41]([CH3:44])(=[O:42])=[O:43])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:28][C:29]([NH:31][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])=[N:30]1)(=[O:25])[CH3:24]
Reactant: C[C@@H](C(=O)Cl)c1ccccc1
Reactant: CC(=O)N1N=C(N)SC1(CCNS(C)(=O)=O)c1ccccc1
Agent: C[C@@H](C(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N1N=C(NC(=O)C(C)c2ccccc2)SC1(CCNS(C)(=O)=O)c1ccccc1
Yield: 12 %

Procedure:
Next, (R)-(−)-2-phenylpropionyl chloride prepared from (R)-(−)-2-phenylpropionic acid (4.65 g, 3.10 mmol) and thionyl chloride (30 mL), and N-[2-(3-acetyl-5-amino-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methane-sulfonamide obtained above were treated in pyridine (5.0 mL, 61.8 mmol) in the same manner as that in Step 1 of Example 20, and the resultant was purified by silica gel column chromatography (chloroform/n-hexane/ethyl acetate/methanol=20/3/2/1) to give one diastereomer of N-[4-acetyl-5-(2-methanesulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2-phenylpropanamide (0.75 g, 12%) as a fraction eluted first, and another diastereomer of N-[4-acetyl-5-(2-methane-sulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2-phenylpropanamide (0.82 g, 13%) as a fraction eluted later.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=12.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH3:15])[C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:24]=[CH:25][C:18]=23)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H]1CCCN(Cc2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ncc2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ncnc2c1cnn2COCC[Si](C)(C)C)[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of (S)-1-benzyl-N-methylpiperidin-3-amine (500 mg, 2.4 mmol) and 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (697 mg, 2.4 mmol) in DMF (10 mL), DIEA (1.26 g, 9.7 mmol) was added and the reaction mixture was stirred at 60° C. overnight. After reaction was completed as indicated by TLC, the reaction mixture was diluted with EtOAc (40 mL) and was washed with water (3×20 mL). The EtOAc layer was then dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (550 mg, 49%). 1H NMR (400 MHz, CD3OD): δ 8.26 (s, 1H), 8.15 (bs, 1H), 7.32 (m, 3H), 7.22 (m, 2H), 5.67 (s, 2H), 3.61 (t, J=9.2 Hz, 2H), 3.57 (m, 2H), 3.31 (s, 3H), 2.95 (m, 2H), 2.24 (m, 1H), 2.03 (m, 2H), 1.80 (m, 4H), 0.86 (m, 2H), 0.07 (s, 9H). LC-MS: m/z [M+1]=453.
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1)=O.[C:20]1([C:25]([NH:27][NH2:28])=[O:26])[S:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:1][NH:28][NH:27][C:25](=[O:26])[C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)=[O:16]
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=O
Reactant: NNC(=O)c1cccs1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CNNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R,5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (47 mg) in ethanol (1 ml) was added thenohydrazide (27 mg) and the mixture was stirred at room temperature for 1 hour, and then added sodium cyanoborohydride (20 mg) and acetic acid (0.25 ml) and the mixture was stirred for 1 hour. Aqueous sodium bicarbonate was added and extracted with chloroform and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give (2R,4R,5S) -5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-(N'-thenoylhydrazino)methyl-1,3-dioxane as a residue and the residue was dissolved in methanol (2 ml) and added 1N aqueous sodium hydroxide (0.4 ml) and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was neutralized with 1N hydrochloric acid and extracted with chloroform. The organic layers were combined and dried over sodium sulfate. The solvent was evaporated in vacuo and the crude product was purified with preparative TLC (ethyl acetate as an eluent) to give (2R,4R,5S)-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-4-(N'-thenoylhydrazino)methyl-1,3-dioxane (55 mg).
Reaction SMILES: C(C1C=C(N[CH:11]([C:15]2[CH:20]=[CH:19][C:18](OC)=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])C=CC=1)(=O)N.[NH2:25][C:26]1[CH:27]=[C:28]([C:32]([F:35])=[CH:33][CH:34]=1)[C:29]([NH2:31])=[O:30].COC1C=C(B(O)O)C=CC=1[F:44].O.C(O)(=O)C=O>>[C:29]([C:28]1[CH:27]=[C:26]([NH:25][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:44])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])[CH:34]=[CH:33][C:32]=1[F:35])(=[O:30])[NH2:31]
Reactant: NC(=O)c1cc(N)ccc1F
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: COc1cc(B(O)O)ccc1F
Agent: O=CC(=O)O
Solvent: O
Product: COc1cc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)ccc1F
Yield: 43 %

Procedure:
39A was prepared in a procedure similar to that of 1A using 3-amino-6-fluorobenzamide, 7C and glyoxylic acid monohydrate. Yield: 43%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.85 (s, 3H) 5.05 (s, 1H) 6.75-6.82 (m, 1H) 6.92-6.97 (m, 1H) 7.03-7.08 (m, 3H) 7.24-7.29 (m, 1H), LCMS: 337 (M+1).
Reaction SMILES: [Cl-].[CH2:2]([O:6][P:7]([CH2:10][CH2:11][CH2:12][CH3:13])(=[O:9])[OH:8])[CH2:3][CH2:4][CH3:5].[N+:14]([C:17]1C=C([O-])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15].[Na+].[C:25]1(C)C=CC=C[CH:26]=1>>[CH2:4]([C:3]1[C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=[CH:20][C:2]=1[O:6][P:7]([CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[OH:9])[CH2:5][CH2:25][CH3:26]
Reactant: Cc1ccccc1
Reactant: CCCCOP(=O)(O)CCCC
Reactant: O=[N+]([O-])c1cccc([O-])c1
Agent: [Cl-]
Agent: [Na+]
Product: CCCCc1c(OP(=O)(O)CCCC)cccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
20 g of n-butanephosphonic acid n-butyl ester chloride are added dropwise to a suspension of 14.3 g of sodium 3-nitrophenolate in 170 ml of toluene at 20° C. After 4 hours, the mixture is filtered, the filtrate is evaporated and the residue is distilled in vacuo at 0.1 mm Hg. 16 g of n-butanephosphonic acid n-butyl-(3-nitro-phenyl) ester are obtained. After reduction with hydrogen and palladium on charcoal, in isopropanol, at 1 atmosphere pressure, 13.8 g of n-butanephosphonic acid n-butyl-(3-aminophenyl) ester are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:10][CH2:11][C:12]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[CH:13][C:14](OCCC)=[O:15])[CH2:5][C:6]([F:9])([F:8])[CH3:7]>C(#N)C.ClCCl>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([N:10]1[CH2:11][C:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:13][C:14]1=[O:15])[CH2:5][C:6]([F:9])([F:8])[CH3:7]
Reactant: CCCOC(=O)C=C(CN[C@@H](CC(C)(F)F)C(=O)OC)Oc1ccccc1Cl
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 140 °C
Yield: 44.1 %

Procedure:
A solution of (S)-2-[2-(2-chloro-phenoxy)-3-propoxycarbonyl-allylamino]-4,4-difluoro-pentanoic acid methyl ester (255 mg, 0.63 mmol) in acetonitrile (2 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 140° C. for 3.5 h. The mixture was diluted with dichloromethane and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-pentanoic acid methyl ester (100 mg, 32% over two steps) as a colorless gum: HR-ES-MS m/z calculated for C16H16NO4ClF2 [M+Na]+ 382.0628, observed 382.0629.
Reaction SMILES: [CH2:1](N1C2C(=CC=CC=2)C(=O)C1=O)[CH2:2][CH3:3].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][C:20](=[O:26])[C:19]2=[O:27].BrCCC>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[N:21]([CH2:1][CH2:2][CH3:3])[C:20](=[O:26])[C:19]2=[O:27]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2c(Cl)cc(Cl)cc2C1=O
Solvent: CCCBr
Product: CCCN1C(=O)C(=O)c2cc(Cl)cc(Cl)c21

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione using 5,7-dichloroisatin (purchased from Fisher Scientific) and 1-bromopropane (purchased from Fisher Scientific). 1H NMR δ 7.53 (d, 1H), 7.51 (d, 1H), 4.05 (t, 2H), 1.78 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[NH2:17])[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[N:17]1[C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2][C:1]1=[O:12])[CH3:14]
Reactant: CCc1cccc(CC)c1N
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: ClC(Cl)Cl
Product: CCc1cccc(CC)c1N1C(=O)Cc2ccccc2C1=O
Temperature: 180 °C

Procedure:
162 mg (1.0 mmol) of homophthalic anhydride and 149 mg (1.0 mmol) of 2,6-diethylaniline were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 2 hours. After cooled, the reactant was dissolved in chloroform, purified by silica gel column chromatography (eluent;
Reaction SMILES: N#N.COC1C=CC(C([NH:24][C:25]2[NH:26][C:27](=[O:59])[C:28]3[N:29]=[CH:30][N:31]([CH2:34][O:35][CH:36]([CH2:48][O:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:37][O:38][C:39](=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:32]=3[N:33]=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)(=O)C.O>[C:39]([O:38][CH2:37][CH:36]([O:35][CH2:34][N:31]1[CH:30]=[N:29][C:28]2[C:27](=[O:59])[NH:26][C:25]([NH2:24])=[N:33][C:32]1=2)[CH2:48][O:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])(=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OCn1cnc2c(=O)[nH]c(NC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)nc21
Agent: N#N
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OCn1cnc2c(=O)[nH]c(N)nc21
Yield: 63.2 %

Procedure:
A solution of 0.969 g of N2 -(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine in 40 ml of glacial acetic acid plus 10 ml of water was stirred at 75° C. for 3 hours. The solution was then concentrated and the residue chromatographed over silica gel eluting with 1:15 methanol:methylene chloride to give a white solid. The product was recrystallized from methanol to afford 0.385 g of 9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine, m.p. 165°-166° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[C:11]([O:14][C:15](=O)[CH3:16])(=O)[CH3:12].C(OCC)(OCC)(OCC)C>C(OCC)(=O)C.O>[CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([C:5](=[C:11]([O:14][CH2:15][CH3:16])[CH3:12])[C:6]#[N:7])=[O:8])[CH3:2]
Reactant: CCC(CC)C(=O)CC#N
Reactant: CC(=O)OC(C)=O
Agent: CCOC(C)(OCC)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(C)=C(C#N)C(=O)C(CC)CC

Procedure:
A mixture of 4-ethyl-3-oxo-hexanenitrile (1.013 g, 7.28 mmol), acetic anhydride (1.5 ml) and triethyl orthoacetate (1.240 g, 7.64 mmol) was heated to reflux overnight. The reaction mixture was taken up in ethyl acetate and water. The brine and the ethyl acetate layer were separated. The organic layer was dried and concentrated to give 1.262 g of dry oil which was used directly for the next reaction. 1H NMR (CDCl3): 0.8-1.0(m,6H), 1.44(t,3H), 1.4-1.8(m,4H), 2.61(s,3H), 3.03(m,1H), 4.28(q, 2H)ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]2[C:44]([F:45])=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][C:36]=2[F:46])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]2[C:44]([F:45])=[CH:43][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=2[F:46])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2CC[C@H](c3ccccc3F)[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(C(=O)O)cc2F)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.7 %

Procedure:
143 mg of methyl 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]-3,5-difluorobenzoate was dissolved in 4.0 mL of THF-2.0 mL of methanol and added with 2.0 mL of a 1 M aqueous sodium hydroxide solution at room temperature. After stirring at room temperature for 3 days, it was neutralized by addition of 2.1 mL of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 138 mg of 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]-3,5-difluorobenzoic acid. ESI+: 619
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N+:8]([O-:29])([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)N(C2CCCC2)C2CCCC2)cn1
Solvent: ClCCl
Product: Cc1ccc(C(=O)[N+]([O-])(C2CCCC2)C2CCCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a solution of the product of Example A (0.5 g, 1.84 mmol) in methylene chloride (15 mL), m-chloroperbenzoic acid (485 mg. 85%, 2.38 mmol) was added. After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The colorless liquid obtained was then chromatographed (silica gel, methylene chloride/methanol 94/6) to give the title compound (460 mg, 87%). 1H NMR (CDCl3) 1.4-2.2(m, 16H), 2.53 (s, 3H), 3.6-3.85 (m,2H), 7.16(dd, J=3, 8 Hz, 1H), 7.25 (d,J=8 Hz, 1H), and 8.24 ppm (d, J=3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]([CH2:21][C:22]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=2[C:24]#[N:25])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: N#Cc1ccc(F)cc1CBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1c(=O)cc(Cl)n(Cc2cc(F)ccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Alternatively, 33 was made as follows. To a solution of 6-chloro-3-methyluracil (750 g) and N,N-diisopropylethylamine (998 mL) in NMP (3 L) was added (at <30° C. over 25 min) a solution of 32 (2963 g crude material containing 1300 g of 32 in 3 L of toluene). The mixture was then heated at 60° C. for 2 hours or until completion (as determined, for example, by HPLC). Heating was then stopped and the mixture was allowed to cool overnight. Purified water (3.8 L) was added, and the resultant slurry was stirred at ambient temperature for 1 hour and at <5° C. for one hour. The mixture was then filtered under vacuum and the wet cake was washed with IPA (2×2.25 L). The material was then dried in a vacuum oven at 40±5° C. for 16 or more hours to afford 33 as a tan solid (>85% yield; purity was >99% (AUC)).
Reaction SMILES: CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19].[F:33][C:34]([F:44])([F:43])[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Br>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([C:34]([F:33])([F:43])[F:44])[CH:36]=3)[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: CC(=O)c1sc(N2CCN(Cc3cccc(C(F)(F)F)c3)C2=O)nc1C
Yield: 50 %

Procedure:
Following the procedure as describe in Preparation 16, making variations as required to replace ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one to react with 3-(trifluoromethyl)benzyl bromide, the title compound was obtained as a yellow solid in 50% yield: mp 149-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.70-7.58 (m, 4H), 4.55 (s, 2H), 4.04 (t, J=6.0 Hz, 2H), 3.51 (t, J=6.0 Hz, 2H), 2.51 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ190.9, 160.4, 155.6, 155.1, 138.5, 132.5, 130.4, 129.9 (q, 3JC-F=38 Hz), 126.6, 125.9, 125.1-124.8 (m), 122.9, 47.1, 42.6, 42.4, 30.5, 18.8; MS (ES+) m/z 384.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=O)O[C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[CH:4][CH:3]=1.ClC(=C)[C:20]#[N:21].[N+]([CH3:26])([O-])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:26][C:12]=2[C:20]#[N:21])=[CH:4][CH:3]=1
Reactant: C=C(Cl)C#N
Reactant: O=C1OC(C(F)(F)F)=NC1c1ccc(Cl)cc1
Reactant: C[N+](=O)[O-]
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: -5 °C
Reaction time: 18 h

Procedure:
4-(p-chlorophenyl)-2-(trifluoromethyl)-2-oxazolin-5-one (2.5 g; 0.01 mol) is dissolved in nitromethane (50 mL). In a single portion, 2-chloroacrylonitrile (8.0 mL; 0.10 mol) is added to the solution, and the resulting solution is stirred 18 hours at reflux under a nitrogen atmosphere. Cooling the red/brown solution to -5° C. in an ice-acetone bath causes the formation of a precipitate which-is collected by filtration and washed with a small portion of cold nitromethane. The resulting tan solid is recrystallized from hot ethylene dichloride yielding the product as white crystals (1.8 g; 56% theory), mp 238°-241° C. (dec.).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.C([Li])CCC.O=C1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1.CCCCCC>[C:4]1([CH:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3([CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[O:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(c1ccccc1)c1ccccc1Br
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(C2OC3(CCOCC3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 11.1 g. of 2-bromobenzhydryl methyl ether in 23 ml. of tetrahydrofuran and 7 ml. of hexane is cooled to -50°C. and 22 ml. of butyllithium is introduced while maintaining the temperature below -50°C. The solution is stirred for 2 hours at -60° to -70°C. To the suspension is then added a solution of 5 g. of 4-oxo-tetrahydropyran in 5 ml. of tetrahydrofuran over a span of a few minutes. The mixture is stirred at -60°C. for 3 hours and at ambient temperature overnight. Ice-water is added, the organic layer is separated, the aqueous layer is extracted with methylene chloride and the combined organic solutions are dried over sodium sulfate. The solvent is removed under reduced pressure and subjected to column chromatography over alumina. Elution with benzene removes benzhydryl methyl ether, and the column is then eluted with diethyl ether. The solid obtained is heated at reflux in 60 ml. of glacial acetic acid, and then the solvent is removed under reduced pressure to leave a crystalline solid. This solid is recrystallized from hexane to give 1,2',3,3',5',6'-hexahydro-3-phenylspiro[isobenzofuran-1,4'-pyran] as colorless crystals, m.p. 132° - 134°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC(Cl)=O)C.[NH:31]1[CH:36]=CCCC1.C[N:38](CC1C2C(=NC=CC=2)NC=1)C>ClCCl.C1(C)C=CC=CC=1>[C:16]([O:15][CH2:14][C:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[C:7]3[N:38]=[CH:3][CH:4]=[CH:5][C:6]=3[NH:31][CH:36]=2)[CH2:13][CH:12]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCC1=CCN(Cc2ccccc2)CC1)c1ccccc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: C1=CNCCC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(OCC1=CCN(Cc2c[nH]c3cccnc23)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
A solution of benzoic acid 1-benzyl-1,2,3,6-tetrahydropyridin-4-ylmethyl ester (1.35 g, 4.4 mmol) in anhydrous dichloromethane (50 ml) was cooled to 0° C. and treated with a solution of 1-chloroethyl-chloroformate (0.62 ml, 5.7 mmol) in anhydrous dichloromethane (10 ml). After stirring at 0° C. for 1.5 hours, the solvent was evaporated and the residue redissolved in methanol (50 ml). This solution was stirred at reflux for two hours. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The organic phase was separated, dried (MgSO4) and evaporated in vacuo to afford the crude product (520 mg, 58% over two steps) as a colourless oil. A solution of the crude tetrahydropyridine (520 mg, 2.5 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (520 mg, 2.5 mmol) in toluene (20 ml) was stirred at reflux for 9 hours. The solvent was evaporated and the residue chromatographed with 5% methanol in dichloromethane as eluant to afford the title compound (480 mg, 55%) as a colourless solid, m.p. 126° C.; (Found: C, 72.42; H, 6.08; N, 12.15. C21H21N3O2 requires C, 72.60; H, 6.09; N, 12.10%); δH (CDCl3) 2.20-2.30 (2H, m, tetrahydropyridinyl CH2), 2.68 (2H, t, J 5.7 Hz, tetrahydropyridinyl CH2), 3.05-3.10 (2H, m, tetrahydropyridinyl CH2), 3.80 (2H, s, NCH2Ar), 5.86-5.94 (1H, m, tetrahydropyridinyl 5-H), 4.74 (2H, s, CH2O), 7.07 (1H, dd, J 7.8, 4.7 Hz, 5-H), 7.20-7.30 (1H, m, ArH), 7.38-7.45 (2H, m, ArH), 7.50-7.60 (1H, m, ArH), 8.00-8.10 (3H, m, ArH), 8.30 (1H, dd, J 4.7, 1.5 Hz, 6-H), and 9.33 (1H, s, NH); m/z (CI+, NH3) 348 (M+1)+.