Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1.CN(C)C(=O)C.[H-].[Na+].[ClH:29].[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O>[ClH:30].[ClH:29].[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1
Reactant: ClCc1ccccn1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Reaction time: 1 h

Procedure:
To a stirred mixture of 167 parts of ethyl 3-(1H-benzimidazol-2-yl-amino)-1-pyrrolidinecarboxylate and 2790 parts of N,N-dimethylacetamide were added portionwise 61.0 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 1 hour at 50° C. 127.2 Parts of 2-(chloromethyl)pyridine hydrochloride were added portionwise at 80° C. After complete addition, the whole was stirred for 2 hours at 80° C. After cooling, the reaction mixture was poured into 1000 parts of water. The product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 and 99:1 by volume) as eluents. The first and second fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane. The salt was filtered off and dried, yielding 69.5 (24%) parts of ethyl 3-[[1-(2-pyridinylmethyl)-1H-benzimidazol-2-yl]amino]-1-pyrrolidinecarboxylate dihydrochloride; mp. >140° C. (compound 23).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.Cl.[Br:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([C:22]2[CH:23]=[C:24]3[N:32]4[C:27](=[CH:28][C:29]([CH3:33])=[N:30][C:31]=24)[N:26]([CH:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])[C:25]3=[NH:41])=[C:17]([CH3:42])[CH:16]=1.C([N:46](CC)C(C)C)(C)C.N>C(Cl)(Cl)Cl.O>[Br:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([C:22]2[CH:23]=[C:24]3[N:32]4[C:27](=[CH:28][C:29]([CH3:33])=[N:30][C:31]=24)[N:26]([CH:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])[C:25]3=[N:41][C:5]([NH2:46])=[O:11])=[C:17]([CH3:42])[CH:16]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCC(CCC)n1c(=N)c2cc(-c3c(C)cc(Br)cc3C)c3nc(C)cc1n32
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCC(CCC)n1c(=NC(N)=O)c2cc(-c3c(C)cc(Br)cc3C)c3nc(C)cc1n32
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To a solution of triphosgene (1.82 g) in chloroform (9 mL) was added dropwise a solution of 4-(4-bromo-2,6-dimethyl-phenyl)-6-methyl-1-(1-propyl-butyl)-1H-1,5,7b-triaza-cyclopenta[cd]inden-2-ylideneamine hydrochloride (300 mg) synthesized by the same procedure as in example 1 and N,N-diisopropylethylamine (174 mg) in chloroform (3 mL) in an ice-cooling bath and stirred at room temperature for 1 hour. The reaction mixture was added dropwise into 25% an aqueous NH3 solution (10 mL) in an ice-cooling bath and stirred at room temperature for 2 hours. The reaction mixture was poured into H2O and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=1:1) to give a solid. The solid was washed with diisopropylether and the title compound (42 mg) was obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[NH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)=[O:13]
Reactant: O=C(Cl)CCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)CCCCCCCCCCBr)cc1

Procedure:
A solution of 20 g. of 11-bromoundecanoyl chloride in 100 ml. of methylene chloride is slowly added with stirring to a solution of 20 g. of ethyl 4-aminobenzoate in 100 ml. of methylene chloride. The mixture is filtered and the filtrate is washed with dilute hydrochloric acid and water, dried, and evaporated. Crystallization from acetonitrile affords ethyl 4-(11-bromoundecanamido)benzoate as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.C(O)C>ClCCl>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(O)C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)(C)O)cc1

Procedure:
2-hydroxy isobutyric acid (1.56 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a). The title compound (2.65 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.45.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15].[N:19]1C=CC=CC=1>>[CH3:17][O:16][C:14](=[O:15])[C:13]([NH:19][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:2]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:18]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: c1ccncc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anydrous pyridine (10 mL) was added dropwise methyl chlorooxoacetate (370 μL, 3.97 mmol) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (50 mL) was added into the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 70° C. for 5 hrs. The title compound (554 mg) was obtained as a white solid (71%) in 99.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C([O:9][CH2:10][CH2:11][N:12]1[C:16]([SH:17])=[N:15][N:14]=[N:13]1)(C)(C)C.Cl.C(OCC)(=O)C>C1(OC)C=CC=CC=1.ClCCl>[OH:9][CH2:10][CH2:11][N:12]1[C:16]([SH:17])=[N:15][N:14]=[N:13]1
Reactant: CC(C)(C)OCCn1nnnc1S
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCCn1nnnc1S
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of aluminum chloride (0.2 g) in anisole (1 ml) cooled at 0° C. is added a solution of 1-(2-t-butoxyethyl)-1H-tetrazole-5-thiol (0.202 g) in dichloromethane (2 ml), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into a mixture of 3N-hydrochloric acid (10 ml) and ethyl acetate (20 ml), shaken and the resulting organic layer is taken up. The layer is extracted with aqueous 5% sodium hydroxide. The extract is acidified with hydrochloric acid and extracted again with ethyl acetate. The extract is concentrated under reduced pressure to give 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol. mp. 135°-136° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:27].[OH-]>O1CCOCC1>[NH2:27][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(C(=O)c1cccc([N+](=O)[O-])c1)cn2C1CCCC1
Yield: 97 %

Procedure:
A solution of (4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitro-phenyl)-methanone (11.3 g, 30.5 mmol) and NH4OH (200 mL) in 1,4-Dioxane (300 mL) was heated to 50° C. in a pressure reactor. After 2 h the reaction was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated to afford the title compound as a yellow solid (10.37 g, 97%). MS: 352.1 (MH+); HPLC Rf: 5.56 min. (HPLC method 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8](=[O:17])[N:7]([CH2:18][C:19]([OH:21])=[O:20])[C:6]2=[O:22].[Cl:23][C:24]1[CH:25]=[N+:26]([O-:49])[CH:27]=[C:28]([Cl:48])[C:29]=1[CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[N+:26]([O-:49])[CH:27]=[C:28]([Cl:48])[C:29]=1[CH2:30][C@@H:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1)[O:20][C:19](=[O:21])[CH2:18][N:7]1[C:6](=[O:22])[C:5]2[C:9](=[CH:10][C:11]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:17]
Reactant: COc1cc2c(cc1NS(C)(=O)=O)C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc2c(cc1NS(C)(=O)=O)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
A mixture of 2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid (0.183 g, 0.557 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.234 g, 0.557 mmol), EDC (0.321 g, 1.672 mmol) and DMAP (0.034 g, 0.279 mmol) in DCM (20 ml) was stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with 1N HCl, 5% NaHCO3 and brine. The organic phase was dried over sodium sulfate, the solvent was removed, and the crude was purified by flash chromatography on silica gel cartridge (DCM:ethyl acetate from 1:1 to 4:1) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-methoxy-6-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a pale orange solid (0.097 g, 0.133 mmol, 24% yield). MS/ESI+ 730.13 [MH]+; [αD]=−33.40, c=0.43, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.54 (br. s., 1H), 8.44 (s, 2H), 7.77 (s, 1H), 7.55 (s, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.39 (s, 2H), 4.04 (s, 3H), 3.93 (d, 2H), 3.39 (dd, 1H), 3.23 (dd, 1H), 3.15 (s, 3H), 1.01-1.37 (m, 1H), 0.50-0.72 (m, 2H), 0.25-0.45 (m, 2H)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[C:28]([OH:31])=[N:29][N:30]=1)C1C=CC=CC=1.C(O)(=O)C.CN(C)C=O>CO.[C].[Pd]>[OH:31][C:28]1[N:27]([C:32]2[CH:33]=[CH:34][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:36][CH:37]=2)[C:26]([C:10]2[CH:11]=[C:12]([CH:23]([CH3:25])[CH3:24])[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])=[N:30][N:29]=1
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc(N3CCOCC3)cc2)c(O)cc1O
Reaction time: 1 h
Yield: 59.6 %

Procedure:
5-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-4-(4-morpholin-4-yl-phenyl)-4H-[1,2,4]triazol-3-ol (1.2 g, 2.07 mmol) was suspended in methanol (100 mL), acetic acid (50 mL) and dimethylformamide (50 mL), and mixed with palladium carbon (60 mg), and catalytic reduction was carried out under a hydrogen atmosphere at 80° C. for 1 hour and then at room temperature overnight. After completing the reaction, the catalyst was removed by filtration and the solvent was concentrated under reduced pressure. The residue was mixed with 5% aqueous sodium hydrogencarbonate to make it neutral and then extracted twice with chloroform. The organic layer thus obtained was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (dichloromethane:methanol 15:1-10:1). The obtained product was purified by suspending in ethanol to obtain the title compound (OH-a01: white crystals, 489 mg, 59%). The analytical data of this compound were the same as that of the target compound obtained in Example 2-1A.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21]CC2C=CC(OC)=CC=2)[CH:12]=[C:11]([CH:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:32]2)[C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:12]=[C:11]([CH:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:32]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(COc2ccccc2-c2cc(C3CCCN(C(=O)OCc4ccccc4)C3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccccc2O)cc(C2CCCN(C(=O)OCc3ccccc3)C2)c1C(=O)O
Reaction time: 8 h
Yield: 147.2 %

Procedure:
To a solution of tert-butyl 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-{2-[(4-methoxybenzyl)oxy]phenyl}nicotinate (0.95 g, 1.67 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (10 mL), and the stirring was continued at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was diluted with toluene, then concentrated under reduced pressure to remove excess of trifluoroacetic acid by azeotropic distillation to give 2-amino-4-{1-[(benzyloxy)carbonyl]-3-piperidinyl}-6-(2-hydroxyphenyl)nicotinic acid (1.1 g, yield; quant.).
Reaction SMILES: NC1S[C:4]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[O:8])=[CH:5]N=1.[CH2:18]([O:20]C=CC(Cl)=O)[CH3:19].ClC1C=CC=C(C)C=1N.Cl>O1CCCC1.O.N1C=CC=CC=1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[NH:9][C:7](=[O:8])/[CH:4]=[CH:5]/[O:20][CH2:18][CH3:19]
Reactant: CCOC=CC(=O)Cl
Reactant: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Agent: Cc1cccc(Cl)c1N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Temperature: 20 °C
Reaction time: 2 h

Procedure:
PCT Publication No. WO 2005/077945 provides a process for the preparation of 2-amino-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carboxamide (Formula 1c) which involves adding 3-ethoxyacryloyl chloride to a cold stirring solution of 2-chloro-6-methylaniline and pyridine in tetrahydrofuran at a temperature of 0° C. to 5° C. The mixture thus obtained was then warmed, stirred for 2 hours at 20° C., and hydrochloric acid was added at 0° C. to 10° C. The mixture was diluted with water and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene and stirred for 15 minutes at 20° C. to 22° C. then for 1 hour at 0° C. to obtain (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[S:2]([OH:5])(=[O:4])=[O:3]
Reactant: COc1cccc(OC)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)O)c(OC)c1

Procedure:
To a solution prepared by adding 57 ml of chlorosulfonic acid to 250 ml of chloroform, was added dropwise 50 g of 1,3-dimethoxybenzene at a temperature below 5° C. with stirring. After stirring at 5° C. for 30 minutes, the crystals thus-precipitated were collected by filtration and washed with 100 ml of chloroform.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1)C(O)=O.C([N:31]([CH2:34]C)CC)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)[O:37]C1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[N:31]([CH:2]([CH3:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[N:14]=2)=[CH:11][CH:12]=1)=[C:34]=[O:37]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)N=C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To 2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-propanoic acid (0.84 g, 2.2 mmol) in toluene (21.6 mL) was added triethylamine (0.33 mL, 2.4 mmol) and diphenyl phosphorazidate (0.47 mL, 2.2 mmol) and the solution was stirred at room temperature for 2 hours. The reaction was diluted with ethyl acetate and water and the layers separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was loaded onto a Celite® cartridge and purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent to afford the title compound as a white solid (0.53 g, 58%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.21-8.11 (m, 2H), 7.88-7.77 (m, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 3.94-3.80 (m, 1H), 2.87 (d, J=6.8 Hz, 2H), 1.35 (d, J=6.5 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 389 ([M+H]+).
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[F:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:36][CH:35](O)[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=3)[O:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cc(F)cc(F)c1)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1cc(F)cc(F)c1)O2

Procedure:
2-(3,5-Difluorophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 500 mg of 2-(3,5-difluorophenyl)chroman-4,6-diol. 1H NMR (300 MHz, d6-DMSO) δ: 8.82 (s, 1H), 7.20-7.14 (m, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.53 (d, 1H, J 2.9 Hz), 6.50 (dd, 1H, J 8.6, 2.9 Hz), 5.05 (dd, 1H, J 9.8, 2.2 Hz), 2.88 (ddd, 1H, J −16.7, 10.8, 5.9 Hz), 2.62 (ddd, 1H, J −16.7, 8.9, 5.0 Hz), 2.15 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[C:22](O)(=O)C>C(O)C>[CH:11]([C:7]1[CH:8]=[C:9]([CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH2:6])([CH3:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: C1CCNCC1
Agent: C=O
Solvent: CCO
Product: CC(C)c1cc(CN2CCCCC2)cc(C(C)C)c1N
Yield: 128 %

Procedure:
Following the conditions described by Miocque and Vierfond (Bull. Soc. Chim. France 1970, 1896), 2,6-diisopropylaniline (17.73 g, 0.10 mol), 37% aqueous formaldehyde (8.1 mL, 0.10 mol), piperidine (8.52 g, 0.10 mol), acetic acid (3.00 g, 0.05 mol), and ethanol (25 mL) were allowed to boil together until the temperature of the solution reached 92° C. The solution was then refluxed for 24 hours. The product was distilled under vacuum (122°-140° C. at 0.7-0.8 mm) to give the title compound (17.57 g, 64%).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].O.[CH2:14](N)[C:15]#[CH:16]>C(O)C>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH:6][CH2:16][C:15]#[CH:14])=[S:5]
Reactant: COC(C(N)=S)c1ccccn1
Reactant: C#CCN
Solvent: O
Solvent: CCO
Product: C#CCNC(=S)C(OC)c1ccccn1
Reaction time: 8 h

Procedure:
To 4.4 g. (0.026 mole) of 2-methoxy-2-(2-pyridyl)thioacetamide in 20 ml. of water at 0°C. is added 2.9 g. (0.053 mole) of propargylamine with stirring and the resulting suspension is allowed to stand overnight at 5°C. Ethanol (5 ml.) is added and the mixture is stirred for five hours, then extracted with dichloromethane. The extracts are dried and concentrated. The residue is chromatographed on a silica gel "dry-column," using 1:10 ethyl acetate/ether as the eluant. The product fraction is treated with charcoal, filtered, concentrated and the residue is recrystallized from benzene/ligroin to give 2-methoxy-N-propargyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1ccc(F)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-fluorobenzaldehyde and acetophenone, 3-(4-fluorophenyl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].CN(C(ON1N=NC2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:37]3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Nc1nc(-n2cc(C(=O)NC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The trisilyl derivative acid 20 (0.14 g, 0.2 mmol) was then dissolved in 5 mL dichloromethane. To the solution was added HBTU (0.19 g, 0.4 mmol), HOBt (0.076 g, 4 mmol), N-methylmorpholine (0.04 g, 0.4 mmol) and cat. DMAP. The mixture was allowed to stir at RT for 24 h. The mixture was then washed with 10% citric acid, saturated NaHCO3, brine and dried over MgSO4. The solvent was removed and the residue was treated with 5 mL 0.5N NH4F/MeOH. The solution was heated at reflux for 24 h. The solvent was evaporated and the residue was purified by preparative TLC to afford compound 21, MS 445.26 (M+1).
Reaction SMILES: [N:1]1([C:6]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:16]1[S:17][C:18]([Br:21])=[CH:19][N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:21][C:18]1[S:17][C:16]([N:9]2[CH2:8][CH2:7][C:6]([CH2:12][CH2:13][OH:14])([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:11][CH2:10]2)=[N:20][CH:19]=1
Reactant: Brc1cnc(Br)s1
Reactant: OCCC1(N2CCCC2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCC1(N2CCCC2)CCN(c2ncc(Br)s2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A mixture of 2-(4-pyrrolidine-1-ylpiperidine-4-yl)ethanol (4.11 g), 2,5-dibromothiazole (5.03 g), potassium carbonate (3.43 g) and dimethylformamide (75 mL) was stirred at 60° C. for 16 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and washed with magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (3.88 g). Yield: 52%.