Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.C[CH:14]([OH:18])[C:15]([O-:17])=[O:16].O1CCOC[CH2:20]1>>[CH3:20][O:17][C:15]([CH2:14][O:18][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1COCCO1
Reactant: CC(O)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First, 0.4 g of sodium hydride was added to a mixture of 1.59 g of 2-chloro-3-nitropyridine, 0.95 g of methylglycolate, and 10 ml of 1,4-dioxane at 10° C. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 1.5 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:18]([CH2:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:17](=[O:26])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:27])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:29][CH2:30][CH2:31][Cl:32].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:18]([CH2:19][C:20]([NH:22][CH:23]([CH3:24])[CH3:25])=[O:21])[C:17](=[O:26])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:27][CH2:29][CH2:30][CH2:31][Cl:32])[CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClCCCBr
Reactant: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(O)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(OCCCCl)cc2c1=O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A mixture of 2-[2-(3-chloro-4-fluorophenyl)-6-hydroxy-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (INTERMEDIATE IV.1) (373 mg, 0.96 mmol), 3-bromo-1-chloropropane (0.28 mL, 2.87 mmol) and K2CO3 (662 mg, 4.80 mmol) in acetonitrile (5 mL) was heated at reflux temperature for 24 h. The mixture was cooled to room temperature and then poured into ice water (40 mL). The resultant white solid was collected by filtration and washed with additional portions of cold water (3×20 mL) followed by washing with cold diethyl ether (3×10 mL) and cold hexane (2×10 mL) to remove residual 3-bromo-1-chloropropane. In this way 2-[2-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (391 mg, 0.84 mmol, 87%) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:9].C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([N:30]1[CH2:31][CH2:32][S:28][CH2:29]1)=[O:14])=[O:9]
Reactant: C1CSCN1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCN1CC(=O)N1CCC[C@H]1C(=O)N1CCSC1
Temperature: -25 °C
Reaction time: 12 h

Procedure:
N-[(2-Oxo-1-pyrrolidinyl)acetyl]-L-proline as prepared in Example 1-B) (623 mg) was suspended in a mixture of methylene chloride (3 ml) and DMF (5 ml), to which were added HOBt (530 mg) and thiazolidine (0.21 ml). The mixture was cooled to -25° C. and DCC (588 mg) was added thereto. The mixture was stirred at a temperature of -25°-0° C. for 3 hours and at room temperature for 12 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 468 mg of 3-{N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl}thiazolidine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH3:18])[C:6]=1[C:7]([O:9]C)=[O:8])[CH2:2][CH3:3].[OH-].[K+]>C(O)C>[CH2:16]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[C:6]=1[C:7]([OH:9])=[O:8])[CH2:17][CH3:18]
Reactant: CCCOc1cccc(OCCC)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1cccc(OCCC)c1C(=O)O

Procedure:
Methyl 2,6-dihydroxybenzoate was reacted with n-propyl iodide in the presence of sodiumd hydride to provide methyl 2,6-di-n-propoxybenzoate. The ester thus formed was saponified by reaction with 40% aqueous potassium hydroxide in ethanol to afford 2,6di-n-propoxybenzoic acid. A 20 g portion of the acid was then reacted with 30 g of thionyl chloride in 100 ml of benzene at reflux for five hours. Removal of the solvent by evaporation under reduced pressure and purification of the product by distillation provided 4.88 g of 2,6-di-n-propoxybenzoyl chloride. B.P. 135°-140° C. at 0.2 torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[OH-].[Na+].Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][Cl:20]>C(O)C>[ClH:20].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: ClCc1ccccn1
Reactant: COc1ccccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1SCc1ccccn1
Yield: 43 %

Procedure:
2-Methoxybenzenethiol (5 g) was added to a solution of sodium hydroxide (2.85 g) in ethanol (50 ml) and the resulting mixture was treated with 2-picolyl chloride, hydrochloride (5.7 g) in ethanol (25 ml) at 0° C. After 16 hours at ambient temperature the mixture was filtered through kieselghur and evaporated. The residue was converted into the hydrochloride in ether with ethereal HCl solution and this was recrystallised from propan-2-ol/acetone to give 2-(((2-methoxyphenyl)thio)methyl)pyridine, hydrochloride (4.0 g) mp 141°-3° C. (Found: C, 58.5; H, 5.4; N, 4.9. C13H13NOS.HCl requires C, 58.3; H, 5.3; N, 5.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].[Br:14]Br.O>Br.C(O)(=O)C>[Br:14][CH2:12][C:11]([C:4]1[CH:3]=[C:2]([F:1])[C:7]([S:8][CH3:9])=[C:6]([F:10])[CH:5]=1)=[O:13]
Reactant: CSc1c(F)cc(C(C)=O)cc1F
Reactant: BrBr
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CSc1c(F)cc(C(=O)CBr)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.4 %

Procedure:
To a solution of 1-[3,5-difluoro-4-(methylthio)-phenyl]ethanone (prepared in Step 1 of Example 1) (6.2 g, 30 mmol) in 30% HBr in acetic acid (10 mL) was added bromine (4.8 g, 30 mmol) dropwise, and the reaction mixture stirred at room temperature for 45 minutes. The mixture was treated with water and extracted with ethyl acetate (1×250 mL, 1×100 mL). The combined extracts were washed with dilute sodium chloride solution, dried with magnesium sulfate, and concentrated. To the residue was added hexanes (100 mL) and the mixture concentrated. The residue was dissolved in 30% HBr in acetic acid (10 mL) and treated with bromine (0.80 g, 5.0 mmol). After stirring at room temperature for 30 minutes, the mixture was treated with water and extracted with dichloromethane (1×200 mL, 1×100 mL). The combined extracts were washed with water, dried with magnesium sulfate and concentrated. To the residue was added hexanes (100 mL), and the mixture concentrated. Purification of the product by silica gel chromatography using 10% ethyl acetate in hexanes gave 2-bromo-1-[3,5-difluoro-4-(methylthio)-phenyl]ethanone as an orange solid (7.2 g, 86%), MP 30.5-33.2° C. 1H NMR (CDCl3/400 MHz) 7.46-7.50 (m, 2H), 4.33 (s, 2H), 2.57 (t, 3H, J=1.1). ESHRMS m/z 278.9260 (M−H+, Calcd 278.9291). Anal. Calcd for C9H7BrF2OS: C, 38.45; H, 2.52. Found: C, 38.19; H, 2.34.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH3:29])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([OH:28])=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[N:20]([CH3:29])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)cc(C(=O)N1CCN(c3ccccc3C(C)(C)C)CC1)n2C
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A mixture of 2-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-indol-5-ol obtained in Example 28 (510 mg), methyl bromoacetate (239 mg), potassium carbonate (276 mg), and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 3 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford crystals. Crystals were washed with diethyl ether and dried under reduced pressure to provide the title compound (509 mg, 84%) as crystals.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].C(N(CC)O)C.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:49])[C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([O:36][CH3:37])[C:30]=2[NH:38][C:39]([C:41]2[S:42][CH:43]=[C:44]([CH2:47]Cl)[C:45]=2[Cl:46])=[O:40])=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:49])[C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([O:36][CH3:37])[C:30]=2[NH:38][C:39]([C:41]2[S:42][CH:43]=[C:44]([CH2:47][N:1]3[C:12](=[O:13])[CH:11]4[CH:6]([N:7]=[CH:8][N:9]4[CH3:10])[N:4]([CH3:5])[C:2]3=[O:3])[C:45]=2[Cl:46])=[O:40])=[N:25][CH:26]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: CCN(O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN2C(=O)C3C(N=CN3C)N(C)C2=O)c1Cl
Temperature: 40 °C
Reaction time: 144 h

Procedure:
In a similar manner to that described in Paragraph F above, to a solution of theobromine (1.06 g, 5.9 mmol), N,N-diethylhydroxylamine (0.45 g, 5.0 mmol), N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.32 g, 0.6 mmol), and DMF (40 mL) was added K2CO3 (0.74 g, 5.3 mmol). The mixture was stirred at 40° C. for 6 days, then it was poured into water. The solid was isolated by filtration. Purification by recrystallization from CH2Cl2 and CH3OH afforded N-(5-chloropyridin-2-yl)-2-[((4-((2,3,4,5,6,7-hexahydro-3,7-dimethyl-2,6-dioxo-1H-purin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, as a white solid; NMR (DMSO-d6) 10.90 (s, 1H), 9.40 (s, 1H), 8.36 (d, 1H), 8.12 (d, 1H), 8.06 (s, 1), 7.90 (dd, 1H), 7.55 (s, 1H), 7.38 (d, 1H), 7.27 (d, 1H), 4.97 (s, 2H), 3.90 (s, 6H), 3.40 (s, 3H) ppm.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=O)[CH3:21].CCN=C=NCCCN(C)C.Cl.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CN(C=O)C.O>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:25](=[O:27])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:28])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
HOBt (3.48 g, 25.8 mmol) and DIPEA (6.94 g, 53.8 mmol) were added to a stirred solution of malonic acid monoethyl ester (2.84 g, 21.5 mmol) in DMF (10 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (4.95 g, 25.8 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (4 g, 21.5 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The product was extracted with ethyl acetate and the ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated to afford 5.2 g (84%) of 4-(2-ethoxycarbonyl-acetyl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS: 301.17 (M+1)+ 84.5%. 1H NMR: (CDCl3): δ 4.0 (q, 2H), 3.45 (m, 2H), 3.3 (m, 8H), 1.25 (s, 9H), 1.1 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=1.[H-].[Na+]>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:11]=[CH:12][C:13]([N+:25]([O-:27])=[O:26])=[C:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccc(O)cc2)ccc1[N+](=O)[O-]
Yield: 76.1 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-hydroxythiophenol (1.26 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified to give the title compound (2.86 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:49][O:50][CH3:51])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH:36]=[CH:37][O:38][S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])=[C:16]3[C:20]([O:22]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:21])=[O:9])[N:6]=1.C(O)=O.O>C(OCC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:49][O:50][CH3:51])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH:36]=[CH:37][O:38][S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=2)(=[O:40])=[O:41])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Solvent: O=CO
Solvent: CCOCC
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A mixture of 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxy-vinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.35 g), formic acid (10 cc) and water (3 cc) is stirred at 50° C. for 30 minutes. Water (8 cc) is then added and the mixture is filtered and concentrated to dryness at 30° C. under 0.05 mm Hg (0.007 kPa). The residue is taken up in ethanol (2×20 cc), each time concentrating the mixture to dryness at 20° C. under 20 mm Hg (2.7 kPa). The solid obtained is trituranted in diethyl ether (20 cc). After filtration ad drying, 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.12 g) is obtained in the form of yellow powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1.Cl.[NH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C(N(C(C)C)CC)(C)C>CN(C)C=O.[Cl-].[NH4+]>[CH3:30][CH:2]([CH3:1])[CH2:3][CH:4]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:27])=[CH:23][N:22]=1)[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-n2cc(C(F)(F)F)cn2)cc1
Reactant: COC(=O)CCN
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)cc2)nc1
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
To a solution of (+/−)-6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinic acid (50 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (67.7 mg, 0.178 mmol). The mixture was stirred for 45 minutes. Methyl 3-aminopropionate hydrochloride (24.6 mg, 0.178 mmol) and diisopropylethylamine (61.5 mg, 0.476 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated ammonium chloride. The solution was extracted three times with ethyl acetate. The combined organics were washed with water, dried over sodium sulfate, filtered and concentrated to give methyl 3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoate (50 mg, 83%) as a brown oil. MS (M+1): 504.1.
Reaction SMILES: CO[C:3]1[CH2:7][CH2:6][CH2:5][N+:4]=1[CH3:8].[CH3:9][O:10][S:11]([O-:14])(=[O:13])=[O:12].[CH3:15][NH:16][CH3:17]>C1C=CC=CC=1>[CH3:15][N:16]([CH3:17])[C:3]1[CH2:7][CH2:6][CH2:5][N+:4]=1[CH3:8].[CH3:9][O:10][S:11]([O-:14])(=[O:13])=[O:12]
Reactant: COC1=[N+](C)CCC1
Reactant: CNC
Agent: COS(=O)(=O)[O-]
Solvent: c1ccccc1
Product: CN(C)C1=[N+](C)CCC1

Procedure:
Add dropwise, with stirring, 22.5 g of 2-methoxy-1-methyl-1-pyrrolinium-methylsulfate to a solution of 6.76 g of dimethylamine in 45 ml of benzene and then boil the obtained admixture under reflux for 1 hour. Separate off the resulting heavy phase; extract it twice by shaking it out with diethyl ether and then free the extract from solvent residue in a vacuum to obtain 19.4 g (81.4% of theory) of title compound as reddish brown oil.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][CH:8]=C[C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[N:29]=[CH:30][N:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:32]=4)[CH:25]=[C:26]([CH3:27])[C:21]=3[N:20]=[C:19]2[CH2:39][CH2:40][CH3:41])=[CH:13][CH:12]=1)(C)(C)C.F[C:43](F)(F)[C:44]([OH:46])=[O:45]>C(Cl)Cl>[CH2:39]([C:19]1[N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[C:43]([C:44]([OH:46])=[O:45])=[CH:8][CH:9]=[CH:10][CH:5]=3)=[CH:12][CH:13]=2)[C:22]2[CH:23]=[C:24]([C:28]3[N:29]=[CH:30][N:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:32]=3)[CH:25]=[C:26]([CH3:27])[C:21]=2[N:20]=1)[CH2:40][CH3:41]
Reactant: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(C)(C)C)cc4)c3c2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)c1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CCOCC>[O:22]([CH2:5][CH:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: CC(C)N1CC(OCc2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)NCC(COc1ccccc1)OCc1ccccc1
Temperature: 180 °C
Yield: 85 %

Procedure:
To a mixture of 6.2 parts of 1-(iso-propyl)-3-benzyloxyazetidine and 28 parts of phenol 1.5 parts of potassium hydroxide was added, and the mixture was heated at 180° C. for 6 hours. The reaction mixture was cooled and 100 parts of ether were added thereto. The excessive phenol was extracted with 2 N-sodium hydroxide aqueous solution and removed. The remaining ether layer was washed in water and dried over anhydrous sodium sulfate. After distillation of ether, the residue was successively subjected to distillation to yield 7.6 parts of 1-phenoxy-2-benzyloxy-3-(iso-propylamino)-propane boiling at 158°-160° C. under 2 mm Hg. The yield was 85%. Results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][C:7]=1[C:8]([O:10]CC(C)C)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:1]([O:5][C:6]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:15][C:7]=1[C:8]([OH:10])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)c1cc(OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)COc1ccc(OCC(C)C)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
In 88 ml of ethanol is dissolved 17.48 g of isobutyl 2,5-diisobutoxybenzoate. After adding 33 ml of 5 mol/L sodium hydroxide solution, the mixture is stirred at ambient temperature for 30 minutes. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 12.16 g of 2,5-diisobutoxybenzoic acid is obtained as a white solid product.
Reaction SMILES: [C:1](=[N:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1)([C:8]1C=CC=CC=1)C1C=CC=CC=1.C(OC(OCC)CBr)C.Br.O>C(O)(C)C>[F:21][C:20]1[C:15]2[N:16]([CH:8]=[CH:1][N:14]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccnc1N=C(c1ccccc1)c1ccccc1
Agent: Br
Agent: CCOC(CBr)OCC
Solvent: CC(C)O
Solvent: O
Product: Fc1cccn2ccnc12
Temperature: 90 °C

Procedure:
A mixture of crude benzhydrylidene(3-fluoropyridin-2-yl)amine (49.4 g), 2-bromoacetaldehyde diethyl acetal (56 ml, 0.37 mol), 48% hydrobromic acid (20 ml) and water (20 ml) were heated to 90° C. for 20 min. On cooling, the mixture was diluted with isopropanol (450 ml), NaHCO8 (68 g) was added cautiously, and the mixture filtered. The residue was washed with further isopropanol (450 ml) and the combined organics were stirred and heated to 50° C. for 18 h. On cooling, the solution was concentrated in vacuo and azeotroped with EtOAc (2×440 ml). The remaining mixture was suspended in EtOAc (400 ml), filtered and the residue washed with further EtOAc until the filtrate ran clear (1 l). The solid orange-coloured residue was then suspended between water (100 ml) and EtOAc (220 ml) and the aqueous phase pH adjusted to 8-9 by addition of saturated aqueous NaHCO3 solution (450 ml). The phases were separated and the aqueous extracted with further EtOAc (2×220 ml). The combined organic extracts were dried over anhydrous MgSO4 and concentrated in vacuo affording crude 8-fluoroimidazo[1,2-α]pyridine. Purification was achieved by dissolving the crude material in EtOAc (1 l) and extracting with 2 N hydrochloric acid (5×50 ml). The acid washings were back-extracted with EtOAc (3×100 ml), adjusted to pH 11-12 using 4 N aqueous sodium hydroxide solution and re-extracted with EtOAc (5×100 ml). The combined organic fractions were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to afford 8-fluoroimidazo[1,2-α]pyridine (11.4 g, 76% from 2-chloro-3-fluoropyridine): δH (400 MHz, CDCl3) 6.69-6.74 (1H, m), 6.84-6.87 (1H, m), 7.65-7.66 (2H, m), 7.97 (1H, dd, J 1.0 and 6.8); m/z (ES+) 137 (100%, [MH]+).