Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][C:13]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>C(O)(C)C>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:26][CH2:25][CH2:24][NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([NH2:12])[N:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCNc1nc(N)nc2ccccc12
Solvent: CC(C)O
Product: Nc1nc(NCCNCC(O)COc2ccccc2)c2ccccc2n1

Procedure:
3.32 g. Phenyl glycidyl ether and 9.0 g. 2-amino-4-(2-aminoethylamino)-quinazoline are stirred for 24 hours at 50° C. in 100 ml. isopropyl alcohol. The reaction mixture is then evaporated and the residue purified chromatographically in the manner described in Example 38. There are obtained 2.0 g. (26% of theory) of the desired product in the form of a colorless oil.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=O)[CH2:2][CH2:3][CH3:4].[NH3:17]>>[NH2:17][C:1]([CH2:2][CH2:3][CH3:4])=[CH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: CCCC(=O)CC(=O)OCc1ccccc1
Reactant: N
Product: CCCC(N)=CC(=O)OCc1ccccc1

Procedure:
A mixture of benzyl butyrylacetate (22.0 g, 0.10 mol) and 10 g of 4 Å molecular sieves was treated with ammonia gas which was bubbled through the mixture for 38 hrs at 50° C. After filtration, benzyl 3-amino-2-hexenoate was obtained as a yellowish oil (21 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:24]([N:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=[CH:31][C:30]([CH:40]=O)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)=[CH:31][C:30]([CH2:40][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)=[N:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Product: Cc1ccc(-c2cc(CNCCN3CCN(C(c4ccccc4)c4ccc(Cl)cc4)CC3)nn2C(C)(C)C)cc1
Yield: 41 %

Procedure:
Compound 99 was prepared using the same method as that of Example 1 except for using 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][CH2:40][CH2:41][C:42](O)=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:42](=[O:43])[CH2:41][CH2:40][NH:39][C:37]([O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Product: O=C(CCNC(=O)OCc1ccccc1)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Yield: 100.2 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-β-alanylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (590 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-benzyloxycarbonyl-β-alanine (450 mg) according to a similar manner to that of Example 5, mp. 136°-141° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:6]=1.S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[CH3:16][O:9][C:8](=[O:10])[CH:7]([NH2:11])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: N[C@H](C(=O)O)c1ccccc1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)C(N)c1ccccc1
Product: Cl
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a stirred solution of (S)-phenylglycine (50 g, 0.3 mol) in MeOH (500 mL) at 0° C. was added thionyl chloride (42.84 g, 0.36 mol) dropwise. After stirring for 2 h, the solvent was concentrated, and the precipitated solid was washed with diethyl ether to afford product 8 (65 g, 97.6%). 1H NMR (400 MHz, D2O) δ 3.70 (s, 3 H), 5.17 (s, 1 H), 7.35-7.41 (m, 5 H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3]C.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.C[C:16]1([CH3:24])[O:23][C:21](=[O:22])[CH2:20][C:18](=O)O1>C(#N)C.N1CCC[C@H]1C(O)=O>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:18]([CH2:1][CH2:2][CH3:3])[CH2:20][C:21]([O:23][CH2:16][CH3:24])=[O:22])=[CH:7]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCC=O
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC#N
Product: CCCC(CC(=O)OCC)c1c[nH]c2ccccc12
Reaction time: 8 h
Yield: 78.6 %

Procedure:
10.7 g (148 mmol) of butanal was added gradually to 300 ml of a solution of 11.6 g of indole (98.6 mmol) and 14.2 g of Meldrum's acid (98.6 mmol) in acetonitrile at room temperature. 500 mg of proline was added to the reaction mixture which was then stirred overnight. The solvent was removed by evaporation under reduced pressure. The residue was dissolved in 200 ml of pyridine, and 15 ml of ethanol and 2.5 g of copper powder were added to the resulting solution. The reaction mixture was then refluxed for 4 hours and the copper powder was filtered off after this time. The solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 15% v/v solution of ethyl acetate in hexane) to yield 20.1 g (78%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([Br:7])[N:6]=1.F[P-](F)(F)(F)(F)F.[N:18]1(OC(N(C)C)=[N+](C)C)[C:22]2C=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.N1CCCCC1.C(Cl)Cl.C(N(CC)CC)C>>[Br:1][C:2]1[S:3][C:4]([C:8]([N:18]2[CH2:24][CH2:25][CH2:26][CH2:21][CH2:22]2)=[O:10])=[C:5]([Br:7])[N:6]=1
Reactant: O=C(O)c1sc(Br)nc1Br
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C(c1sc(Br)nc1Br)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a stirred solution of 2,4-dibromo-5-thiazole carboxylic acid (48, 400 mg, 1 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (790 mg, 2.1 mmol) and piperidine (180 uL, 1.8 mmol) in methylene chloride (5.0 mL, 78 mmol) was added triethylamine (580 μL, 4.2 mmol) at room temperature. The resulting turbid mixture was allowed to stir at rt overnight and quenched with water. The product was extracted using dichloromethane and washed with water, citric acid solution, water and brine. Removal of solvent gave the intermediate (49) (2,4-Dibromo-thiazol-5-yl)-piperidin-1-yl-methanone (300 mg, 30%) which was used as such for the next step.
Reaction SMILES: COCCCC[N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH3:15])=[O:13].[Br:16]N1C(=O)CCC1=O>ClCCl>[Br:16][C:11]1[NH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCCn1cccc1C(=O)OC
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)[nH]1
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Methyl 1-(4-methoxybutyl)-1H-pyrrole-2-carboxylate (4.5 g) was dissolved in dichloromethane (30 ml), N-bromosuccinimide (4.0 g) was added and the mixture was stirred for 1 hr. The reaction mixture was washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object product (2.2 g).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[N+:16]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH3:13])([CH3:14])[C:11](=[O:12])[N:2]([CH3:1])[C:3]2=[O:15])=[CH:8][CH:7]=1)([O-:18])=[O:17]
Reactant: CN1C(=O)c2ccccc2C(C)(C)C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN1C(=O)c2cc([N+](=O)[O-])ccc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
2,4,4-Trimethyl-4H-isoquinoline-1,3-dione (5 g, 24.6 mmol) [prepared according to H. Takechi et al., Synthesis. 1992, 778] was dissolved in concentrated sulfuric acid (50 ml) at 0° C. Fuming nitric acid (2.5 ml) was added dropwise over 5 min and the reaction warmed to 25° C. After stirring for 30 min at 25° C. the reaction mixture was poured into ice water (100 ml) and the organics extracted into dichloromethane (3×50 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound (5.31 g, 86%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(#N)C.C(OCC)(=O)C>[CH3:23][S:24]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH:5]=1)(=[O:26])=[O:25]
Reactant: O=C1NCCN1c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc(N2CCNC2=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Alternatively, 1-[3-(2-hydroxyethyl)phenyl]-2-imidazolidinone was suspended in acetonitrile (5 vol) at room temperature and under nitrogen. Triethylamine (1 vol) was added dropwise over 15 minutes. The mixture was cooled to 0° C. and methanesulfonyl chloride (0.73 vol) was added over 30 minutes. The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate (10 vol). The mixture was washed with a saturated solution of ammonium chloride (2×3 vol), followed by water-brine 1:1 (2×3 vol). The organic phase was concentrated to 5 vol, ethyl acetate (5 vol) was added and the solution was evaporated to dryness, yielding the title compound as a cream-coloured solid (yield: 90% th).
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][CH:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: COC(=O)C(N)CC=Cc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)C(CC=Cc1ccccc1)N=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-5-phenyl-4-pentenoate, prepared as described by D. Ferroud, J. P. Gene:, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-5-phenyl-4-pentenoate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].I[CH:28]([O:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH3:29].O.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:28]([O:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH3:29])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)OC(=O)OC(C)I
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(=O)OC(C)C)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (4.0 g) in dimethylsulfoxide (40 ml) was added isopropyl 1-iodoethoxyformate (5.1 g). The mixture was stirred for 30 minutes at ambient temperature and poured into a mixture of cold water and ethyl acetate. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of benzene and ethyl acetate (3:2) as an eluent. The eluates containing an object compound were collected and evaporated to dryness to give 1-isopropoxycarbonyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (1.5 g), mp 120° to 125° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.[H-].[Na+].CN(C)C=O.[CH2:35](I)[CH3:36]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=2)[CH2:35][CH3:36])[N:3]=1
Reactant: CCI
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2cc3ccc(Cl)cc3c(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(CC)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)amino]phenoxy}propionate (0.36 g), sodium hydride (0.05 g, 60%) and dimethylformamide (10 ml) was stirred at room temperature for 15 minutes. Ethyl iodide (0.17 g) was added and stirring was continued for a further 15 minutes. The mixture was then poured into ethyl acetate and washed with water, dried (MgSO4) and evaporated. Purification by column chromatography over silica gel gave ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-ethylamino]phenoxy}propionate as a yellow oil (0.40 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl.CN(C)C=O>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[C:8]([F:11])[CH:7]=2)=[O:6])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(F)cnc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
2-Chloro-5-fluoro nicotinic acid (5.00 g, 28.48 mmol) (see Preparation 41), was dissolved in dichloromethane (200 ml) and N,N-dimethylformamide (1 drop) was added, followed by addition of oxalyl chloride (7.45 ml, 85.44 mmol). The reaction mixture was held at room temperature for 18 hours, after which the solvent was removed in vacuo. The residue was th en suspended in dichloromethane (150 ml) and triethylamine (11.91 ml, 85.44 mmol) added followed by addition of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (6.85 g, 34.18 mmol). The reaction mixture was then stirred under an atmosphere of nitrogen at room temperature for 64 hours before being washed sequentially with water (2-fold 100 ml), a saturated aqueous solution of sodium chloride (100 ml) and a 10% solution of citric acid in water (50 ml). The organic phase was separated, dried over anhydrous magnesium sulphate and the solvent was removed in vacuo giving 4-[(2-chloro-5-fluoro-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (8.7 g) as an off-white solid.
Reaction SMILES: [H-].[Na+].CC[OH:5].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=O)[CH:7]=1.[CH2:14]([O:16][C:17](=[O:22])[CH2:18]N(C)C)[CH3:15].COC(=O)CN(C)C>CCCCCC.CCOCC>[CH2:14]([O:16][C:17](=[O:22])[C:18]([OH:5])=[CH:12][C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)[CH3:15]
Reactant: O=Cc1cccnc1
Reactant: CCO
Reactant: CCOC(=O)CN(C)C
Agent: COC(=O)CN(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)C(O)=Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A dry 1 L round bottomed flask was charged with anhydrous Et2O (500 mL) and cooled to 0° C. (ice-water bath). After having been rinsed with hexane, NaH (60% w/w suspension in mineral oil, 16 g, 400 mmol, 2 eq, weight before rinsing) was added followed by absolute EtOH (23.2 mL, 400 moles, 2 eq). After 10 minutes, a mixture of 3-pyridine carboxaldehyde (18.8 mL, 200 mmol, 1 eq) and N,N-dimethyl glycine ethyl ester (84.8 mL, 3 eq) (N,N-dimethyl glycine methyl ester also performs satisfactorily in this preparation) was added during 1 minute. This mixture was as stirred overnight at room temperature, heated at 30° C. for 1 h, and then transferred to a 2 L separation funnel. The mixture was diluted with EtOAc (500 mL) and H20 (500 mL) and the organic phase was transferred to a beaker and stirred with 1N HCl (500 mL) at room temperature for 10 minutes. The mixture was checked to confirm a pH=1 and then the phases were separated. The aqueous layer was retained and slowly neutralized by the addition of solid NaHCO3. This solution was extracted with EtOAc (3×300 mL), the combined extracts dried (Na2SO4), filtered and concentrated to a yellow solid. Crystallization from EtOAc-Hexanes (4:1) provided 20.0 g (52% yield) of pale yellow 8. RP-HPLC Method 2-100% B.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]2[O:14][CH2:13][CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:9]([CH:10]2[O:11][CH2:12][CH2:13][O:14]2)=[CH:8][CH:7]=[C:6]([Cl:15])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(Cl)ccc(C2OCCO2)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(Cl)ccc(C2OCCO2)c1Cl
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a suspension of 2,6-dichloro-3-(1,3-dioxolan-2-yl)-benzaldehyde (3.9 g) in methanol (19.5 ml) was added sodium borohydride (299 mg) under nitrogen atmosphere, and the mixture was stirred for 1 hour under ice-cooling. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give 2,6-dichloro-3-(1,3-dioxolan-2-yl)-1-hydroxymethylbenzene (3.69 g) as colorless crystals.
Reaction SMILES: OC1CON(C([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:23])[CH3:22])[C:12]=3[S:11][C:10]=2CC2C3C(=NC=CC=3)NC=2)=O)C1.[CH3:34][NH:35][C:36]1[NH:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1.[C:45]([O:48][CH2:49]C)(=[O:47])[CH3:46]>>[CH3:19][N:15]1[C:16](=[O:18])[C:17]2[C:46]([C:45]([O:48][CH3:49])=[O:47])=[C:10]([CH2:9][N:40]3[C:39]4[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=4[N:37]=[C:36]3[NH:35][CH3:34])[S:11][C:12]=2[N:13]([CH:21]([CH3:22])[CH3:23])[C:14]1=[O:20]
Reactant: CNc1nc2ccccc2[nH]1
Reactant: CCOC(C)=O
Reactant: CC(C)n1c(=O)n(C)c(=O)c2c(C(=O)N3CC(O)CO3)c(Cc3c[nH]c4ncccc34)sc21
Product: CNc1nc2ccccc2n1Cc1sc2c(c1C(=O)OC)c(=O)n(C)c(=O)n2C(C)C

Procedure:
Prepared using the procedure described in example 13 vii) part a) from the product of example 8 part c) and 2-methylaminobenzimidazole to give the sub-title compound after trituration with ethyl acetate followed by filtration. MS(ESI) 442 [M+H]+. δ 1HDMSO 1.40-1.42 (6H,d), 2.94-2.96 (3H,d), 3.16 (3H,s), 3.85 (3H,s), 4.3 (1H, bs), 5.39 (2H,s), 6.84-6.99 (3H,m), 7.11-7.14 (1H, d), 7.20-7.22 (1H, d)
Reaction SMILES: Cl.N=[C:3]([O:7][CH2:8][CH3:9])[CH:4]([CH3:6])[CH3:5].[CH2:10]([OH:12])[CH3:11].[CH3:13][CH2:14][O:15]CC>>[CH2:8]([O:7][C:3]([O:15][CH2:14][CH3:13])([O:12][CH2:10][CH3:11])[CH:4]([CH3:6])[CH3:5])[CH3:9]
Reactant: CCOCC
Reactant: CCO
Reactant: CCOC(=N)C(C)C
Agent: Cl
Product: CCOC(OCC)(OCC)C(C)C
Reaction time: 72 h
Yield: 42 %

Procedure:
To a suspension of 1-imino-1-ethoxyisobutane hydrochloride (610.0 g) in ether (12.5 L) was added ethanol (1940.0 g, 10 mol). The mixture was stirred at 35°-37° C. under N2 for 72 hours. The reaction mixture was filtered, the filtrate was washed with a 10% sodium carbonate solution, followed by a saturated sodium carbonate solution and the organic layer was dried over K2CO3. The organic layer was concentrated in vacuo and the residue was dissolved in ether, filtered and the filtrate was washed successively with a 10% NaOH solution and water. The organic layer was dried over K2CO3, the solvent was removed in vacuo and the residue was diluted with hexane, cooled in an ice-bath and filtered. The filtrate was concentrated in vacuo and the residue was distilled at 70°-72° C. (27 mmHg) to afford 320 g (42%) of 1,1,1-triethoxyisobutane.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[ClH:17].Cl.[CH:19]([CH:32]1[NH:37][CH2:36][CH2:35][N:34]([CH2:38][C:39]2[CH:44]=[C:43]([N:45]3[C:49]([C:50]([F:53])([F:52])[F:51])=[N:48][N:47]=[N:46]3)[CH:42]=[CH:41][C:40]=2[O:54][CH3:55])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.CO>[ClH:17].[ClH:17].[CH:19]([CH:32]1[CH2:33][N:34]([CH2:38][C:39]2[CH:44]=[C:43]([N:45]3[C:49]([C:50]([F:53])([F:52])[F:51])=[N:48][N:47]=[N:46]3)[CH:42]=[CH:41][C:40]=2[O:54][CH3:55])[CH2:35][CH2:36][N:37]1[CH3:1])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCNC(C(c2ccccc2)c2ccccc2)C1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1CCN(C)C(C(c2ccccc2)c2ccccc2)C1
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (146 mg) was added portionwise to a mixture of 37% aqueous formaldehyde (30 mg) and 3-benzhydryl-1-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]piperazine dihydrochloride in a mixture of dichloromethane (4 ml) and methanol (2 drops) at 0° C. and the whole was stirred at 5° C.˜room temperature overnight. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (60:1). The fractions containing the objective compound were collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give 2-benzhydryl-4-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-1-methylpiperazine dihydrochloride (32.9 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].CCCCCC>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCC(=O)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: O=C1C=C(c2cccc(F)c2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 42568.4 %

Procedure:
1-(3-Fluorophenyl)-1,4-pentandione (23 g, 0.12 mmol) was dissolved in water (550 ml) containing 11 g of sodium hydroxide and the solution was stirred at 100° C. for 3 hours. After cooling to 0° C. the resultant brown crystals were collected by filtration and washed with water. The title compound (9 g, 45% yield) was obtained by recrystallization from hexane as a yellow solid.