Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([Li])CCC.[F:16][C:17]([F:34])([F:33])[C:18](=[O:32])[CH2:19][C:20]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])([CH3:22])[CH3:21].[NH4+].[Cl-]>C1COCC1>[CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH2:1][C:18]([OH:32])([CH2:19][C:20]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])([CH3:22])[CH3:21])[C:17]([F:16])([F:34])[F:33]
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: Cc1nc2ccccc2[nH]1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1nc2ccccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methylbenzimidazole (300 mg, 2.3 mmol) in 20 mL of anhydrous THF at −30° C., n-butyl lithium (1.6 M in pentanes, 3 mL, 4.8 mmol) was slowly added. The resulting red-colored heterogeneous mixture was stirred for 2 hours at this temperature, then a solution of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (700 mg, 2.55 mmol) (see Example 1) in anhydrous THF (1 mL) was added dropwise. The reaction temperature was allowed to slowly warm to room temperature over a period of 2 hours, at which time reaction was treated with saturated NH4Cl solution. The resulting mixture was extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford an oil which was purified by chromatography on silica gel to provide 200 mg of unchanged 2-methylbenzimidazole and 60 mg of the title compound as a white solid, m.p. 80° C.-82° C.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1Oc2c(Br)cccc2NC1=O
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cccc3c2OC(C)C(=O)N3)c(C)c1
Yield: 90.5 %

Procedure:
To a solution of 8-bromo-2-methyl-2H-1,4-benzoxazin-3(4H)-one (1.20 g, 4.96 mmol) in 1,2-dimethoxyethane (50 ml) were added 2,4-dimethylphenylboronic acid (818 mg, 5.45 mmol), tetrakis(triphenylphosphine)palladium(0) (286 mg, 0.245 mmol) and 2M sodium carbonate solution (4.96 ml, 9.92 mmol). The mixture was refluxed for 16 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 20% ethyl acetate/n-hexane to afford 1.20 g (91%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24]C(=O)C)[CH2:21][O:20]C(C)(C)[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.Cl>C(O)C>[NH2:24][C:16]([CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:28])=[CH:9][CH:10]=1)([CH2:21][OH:20])[CH2:17][OH:18]
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
N-{5-[2-(4′-Bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (2.50 g) of Reference Example 10 was dissolved in ethanol (50 mL), concentrated hydrochloric acid (25 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, and neutralized with 1M aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration to give the title compound (1.36 g) as white crystals.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 110 °C
Reaction time: 48 h
Yield: 15.4 %

Procedure:
To a mixture of 112.9 g of m-fluoronitrobenzene and 65.69 g of 4-methylimidazole in 1 liter of dimethylsulfoxide is added 58.51 g of potassium carbonate followed by heating under dry conditions at 110° C. for 39 hours. The reaction mixture is poured into 3.3 liters of water and stored in a refrigerator for 2 days. The mixture is filtered and the cake washed with copious volumes of water followed by suction drying to give 25 g of brown solid. The solid is crystallized from ethyl acetate to give 15.0 g of the desired product as a beige solid, m.p. 119°-120° C. From the combined recrystallization filtrates is obtained 800 mg of 5-methyl-1-(3-nitrophenyl)-1H-imidazole as a beige solid, m.p. 130°-132° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:49]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:51]=1)[CH2:10][N:11]([CH:46]1[CH2:48][CH2:47]1)[C:12]([C@@H:14]1[C@@H:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[Cl:38])=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:15]1)=[O:13])#[N:2].C([Sn]([N:70]=[N+:71]=[N-:72])(CCCC)CCCC)CCC>O1CCOCC1.CCOC(C)=O>[CH:46]1([N:11]([CH2:10][C:9]2[CH:8]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][C:1]3[N:70]=[N:71][NH:72][N:2]=3)[CH:51]=[C:50]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[CH:49]=2)[C:12]([C@@H:14]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:18][CH2:17][N:16]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:15]2)=[O:13])[CH2:48][CH2:47]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCC#N)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCc2nn[nH]n2)c1
Temperature: 150 °C

Procedure:
To a solution of tert-butyl (3R,4S)-3-{[[3-(3-cyanopropoxy)-5-(3-methoxy-propyl)benzyl](cyclopropyl)amino]carbonyl}-4-{4-[2-(2,6-dichloro-4-methylphen-oxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in dioxane (0.17 M) was added tri-n-butyltin azide (3 eq.). The reaction was heated to 150° C. in a sealed tube for 18 h. After cooling down to rt, the reaction was diluted with EtOAc. The organic extract was washed with saturated aqueous NH4Cl solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, first 50% EtOAc in Hex to 100% EtOAc, then 5% MeOH in DCM) to afford the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([NH2:14])[C:5]=1[NH2:15])([O-:3])=[O:2].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>>[N+:1]([C:4]1[C:5]2[NH:15][C:16](=[O:17])[NH:14][C:6]=2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1cc(C(F)(F)F)cc([N+](=O)[O-])c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=c1[nH]c2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]1

Procedure:
The reaction of 3-nitro-5-(trifluoromethyl)benzene-1,2-diamine (2.2 g, 10 mmol) with 1,1′-carbonyldiimidazole (1.78 g, 11 mmol, Aldrich) under the conditions of Example 1b afforded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 248 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[SH:17][CH2:18][CH2:19][C:20](OCC)=[O:21].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:2]([S:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)CCS
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCCCCSCCCO
Yield: 84 %

Procedure:
1-Bromopentadecane is reacted in the usual way with ethyl β-mercaptopropionate and the syrup obtained reduced with lithium aluminium hydride to give a yield of 84% of theory of 3-pentadecylthiopropanol; m.p. 36°-39° C.
Reaction SMILES: [Br-].[CH2:2]([NH+:14]=[C:15]([NH2:17])[SH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[PH:18](=[O:21])([OH:20])[OH:19]>>[PH:18](=[O:19])([O-:21])[OH:20].[CH2:2]([NH+:14]=[C:15]([NH2:17])[SH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=[PH](O)O
Agent: CCCCCCCCCCCC[NH+]=C(N)S
Agent: [Br-]
Product: O=[PH]([O-])O
Temperature: 90 °C

Procedure:
n-Dodecyl thiouronium bromide (about 0.0495 mole) and hydrogen phosphonic acid (about 0.15 mole) were mixed and heated at about 90° C. to remove HBr. Water was added and the mixture was filtered (a nitrogen stream was used to remove oxygen). Approximately 12.4 g of the desired n-dodecyl thiouronium hydrogen phosphonate was isolated, m.p. 119°-122° C. The compound was re-precipitated from ethanol and water. The IR data were consistent with HPO-3 as the counterion, i.e., strong bands near 1195 cm-1, 1145 cm-1, 1097 cm-1, 991 cm-1 and 927 cm-1. A sharp band was also observed at 2380 cm-1 which is characteristic of the P-H linkage.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])=[C:4]([N+:19]([O-])=O)[CH:3]=1>C(O)C.[Pd]>[NH2:19][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10]
Reactant: CCCCCCCNC(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCNC(=O)Nc1ccc(F)cc1N
Yield: 94 %

Procedure:
To a suspension of 1-(4-fluoro-2-nitrophenyl)-3-heptylurea (1.49 g) in ethanol (10 ml) was added a catalytic amount of 10% palladium/carbon to perform catalytic reduction at a pressure of 1-2.5 atms at room temperature for 5 hrs. The catalyst was filtered off, and the solvent was distilled off. Crystallization of the residue from hexane gave 1-(2-amino-4-fluorophenyl)-3-heptylurea (1.26 g, 95%).
Reaction SMILES: [Mg].[CH2:2]([O:4][C:5](=[O:47])/[CH:6]=[CH:7]/[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:45])[CH:25]=3)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:46])=[CH:11][CH:12]=1)C.C(OCC)(=O)C.S(=O)(=O)(O)[O-].[K+]>CO.O1CCCC1>[CH3:2][O:4][C:5](=[O:47])[CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:45])[CH:25]=3)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:46])=[CH:11][CH:12]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)o1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CCC(=O)OC)o2)c(C)c1
Reaction time: 2 h
Yield: 75.8 %

Procedure:
Magnesium (24.3 mg, 1.0 mmol) was added to a solution of (E)-3-{5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-yl}-acrylic acid ethyl ester (Example 5-(1); 64.5 mg, 0.10 mmol) in methanol (2 mL) and tetrahydrofuran (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for two hours. Ethyl acetate and a potassium bisulfate aqueous solution were added to the reaction mixture to separate the layers. Then, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=10/1) to give the title compound (48 mg, 76%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH2:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C>ClCCl>[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:2](=[O:3])[O:4][CH2:5][Cl:6])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCNC(=O)OCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of chloromethyl chloroformate (2.84 g) in dichloromethane (10 ml) was added dropwise with stirring to an ice-cold solution of 3-(N-tert-butoxycarbonylamino)-propylamine (3.49 g) and diisopropylethylamine (3.10 g) in dichloromethane (30 ml). After stirring for a further 3 hours at room temperature, the mixture was extracted with ice-cold 0.5 M hydrochloric acid followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate and evaporation in vacuo gave the title compound as colourless crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.[OH-].[Na+].Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@:14]([CH3:18])([CH2:19][O:20][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH2:13]1
Reactant: BrCCOC1CCCCO1
Reactant: C[C@]1(CO)CCCN(C[C@H]2COc3ccccc3O2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Product: C[C@]1(COCCOC2CCCCO2)CCCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}-methanol (5.12 g, 18.5 mmol), 50% NaOH (125 ml) and tetrabutylammonium bromide (0.585 g, 1.8 mmol) was stirred at RT for 15 min and then heated up to 60° C. 2-(2-Bromoethoxy)tetrahydropyran (11.3 g, 54.0 mmol) was added to the reaction mixture at 60° C. during 2 h. After the addition the reaction mixture was stirred at 60° C. for 5 h. The reaction mixture was cooled down to RT and brine and water was added. The reaction mixture was extracted three times with toluene. The toluene phases were combined and washed twice with water and once with brine, dried (Na2SO4) and evaporated to give (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-3-[2-(tetra-hydropyran-2-yloxy)ethoxymethyl]piperidine. To remove the THP group, this compound was stirred in water (100 ml) and conc. HCl (10 ml) at RT for 3 h. The reaction mixture was washed twice with toluene and pH of the water phase was adjusted to 11-12 with NaOH. The alkaline phase was extracted twice with toluene. The combined extracts were washed twice with water and once with brine and dried (Na2SO4). Toluene was evaporated and EtOAc was added to the residue. EtOAc was evaporated to give 4.74 g of the crude title compound. A mixture of the crude title compound (4.6 g, 14.3 mmol), EtOAc (50 ml) and (−)-di-p-toluoyl-L-tartaric acid (5.53 g, 14.3 mmol) was stirred at 60° C. for 1 hour. The reaction mixture was cooled to RT and stirred for a few hours. The precipitate was filtered, washed with EtOAc and dried under vacuum at 80° C. The crude product (8.9 g, 12.6 mmol) was recrystallized from IPA (90 ml) to give 7.5 g of the di-p-toluoyl-L-tartrate salt of 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-ylmethoxy}ethanol. This salt was stirred in EtOAc (50 ml) and water (50 ml). The pH of the mixture was adjusted to 9 (1 M NaOH) and stirring was continued at RT for 30 min. The phases were separated and the water phase was extracted twice with EtOAc. The organic layers were combined, dried (Na2SO4) and evaporated to give 3.4 g of the pure title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16](N)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I-:30].[K+].N([O-])=O.[Na+]>C(#N)C.O.C(OCC)(=O)C>[I:30][C:16]1[N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:14]2[N:15]=1
Reactant: [I-]
Reactant: COc1ccc(-c2cccc3nc(N)nn23)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(-c2cccc3nc(I)nn23)cc1
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a solution of 5-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine (825 mg, 3.43 mmol) and p-toluene sulphonic acid (1.77 g, 10.3 mmol) in acetonitrile (40 mL) was added a solution of potassium iodide (1.42 g, 8.55 mmol) and sodium nitrite (474 mg, 6.87 mmol) in water (2 mL) at 24° C. After 18 h, ethyl acetate was added to the reaction mixture. The resulting solution was washed with water (2×) and saturated aqueous sodium chloride solution. The organic was dried over magnesium sulfate, filtered, and concentrated. Purification using ISCO CombiFlash (2→5% methanol in dichloromethane) afforded 2-iodo-5-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (950 mg, 71%). 1H NMR (400 MHz, CDCl3), δ: 7.90 (d, 2H), 7.64 (m, 1H), 7.57 (t, 1H), 7.05 (t, 3H); ES-MS m/z 351.9.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@@H:27]2[N:31]3[C:32](=[O:45])[CH:33](P(=O)(OCC)OCC)[CH2:34][CH2:35][CH2:36][C@@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26]>O1CCCC1.C(O)C>[F:19][C:20]1[CH:21]=[C:22]([C@@H:27]2[N:31]3[C:32](=[O:45])/[C:33](=[CH:8]/[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[CH2:34][CH2:35][CH2:36][C@@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CCC[C@@H]2CC[C@H](c3ccc(F)c(F)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CCC[C@@H]3CC[C@H](c4ccc(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
Lithium hydroxide (0.0668 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.20 g) and diethyl [(3R,9aR)-3-(3,4-difluorophenyl)-5-oxooctahydropyrrolo[1,2-a]azepin-6-yl]phosphonate (0.25 g) in tetrahydrofuran (1 mL) and ethanol (4 mL), and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was added to ice-sodium bicarbonate water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.20 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28])[C:8]1[CH:13]=[C:12](Cl)[N:11]=[CH:10][N:9]=1.Cl.[C:43]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28])[C:8]1[N:9]=[CH:10][N:11]=[C:12]([NH:51][CH2:50][CH2:49][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:52])[CH:13]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ncn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(NCCC(=O)OC(C)(C)C)ncn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-(6-chloropyrimidin-4-yl)-amine (300 mg) is dissolved in toluene (5 ml), and thereto are added 3-aminopropionic acid tert-butyl ester hydrochloride (888 mg) and N-ethyldiisopropylamine (1.7 ml), and the mixture is stirred at 120° C. overnight. To the reaction solution are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (hexane:ethyl acetate=9:1→3:1) to give tert-butyl 3-(6-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-4-ylamino)-propionate (70 mg). MS (m/z): 722 [M+H]+
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]([CH3:42])[CH3:41])[C:38]([CH3:43])=[C:37]([OH:44])[C:36]3=[O:45])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]([CH3:42])[CH3:41])[C:38]([CH3:43])=[C:37]([O:44][CH3:3])[C:36]3=[O:45])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C)C(C(C)C)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-isopropyl-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (0.500 g, 1.83 mmol, 1 eq) and MeOH (10 ml); yield: 0.040 g (7.6%); MS m/z: 286.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 0.54 (d, 3H), 0.94-0.92 (q, 3H), 1.95 (t, 3H), 3.86 (s, 1H), 4.73 (s, 1H), 7.26-7.15 (m, 1H), 7.65-7.51 (m, 2H), 8.22 (d, 1H), 12.46 (d, 1H); HPLC (METHOD [A]): rt 8.32 min (96.64%)