Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:41])[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH:33]([OH:41])[CH2:34][CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: NCCC(O)CCN1CCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CCN3CCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to Example 1. MS (APCl, m/z): 498 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([C:22]4[N:26](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:25]=[N:24][N:23]=4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[C:7]([C:46]([O:48][CH2:49][C:50]2[O:55][C:53](=[O:54])[O:52][C:51]=2[CH3:56])=[O:47])=[C:6]([C:57]([OH:60])([CH3:59])[CH3:58])[N:5]=1.Br>C1COCC1>[CH3:1][CH2:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]([C:46]([O:48][CH2:49][C:50]2[O:55][C:53](=[O:54])[O:52][C:51]=2[CH3:56])=[O:47])=[C:6]([C:57]([OH:60])([CH3:59])[CH3:58])[N:5]=1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Solvent: C1CCOC1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Trityl olmesartan medoxomil (250 g, 310 mmol) (97.3% area) is dissolved in THF (1560 ml) and 48 wt-% aqueous hydrobromic acid (70.6 ml, 625 mmol) is added slowly. The mixture is stirred for at 25° C. After 1 hour the precipitate forms. The mixture is stirred for 1 additional hour at 25° C., then cooled to −5° C. and stirred for 1.5 hours at −5° C. The precipitate is filtered. 940 ml of THF is added to the precipitate and the mixture is stirred for 1 h at 25° C. and then 1 hour at −5° C. Then precipitate is filtered off and washed with cold THF (150 ml). It is then dissolved in a mixture of water (875 ml) and acetone (440 ml). To a clear solution 5% aqueous solution of NaHCO3 is added to raise pH to 5.15. The mixture is stirred for 1 hour at room temperature and 1 hour at 0° C. The precipitate is filtered, washed with water and then recrystallised from a mixture of acetonitrile (280 ml) and water (70 ml) to give 124.5 g of olmesartan medoxomil (99.68% area).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.CO[C:47]([C:49]1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.C(C1C=CC(B(O)O)=CC=1)C>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:3]=[CH:2][C:43]([CH2:47][CH3:49])=[CH:42][CH:41]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2ccc(OC)cc2-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1
Yield: 48 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-ethylphenylboronic acid (39 mg, 0.2625 mmol) to produce the title compound (48 mg, 48% yield).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])=[N:25][CH:26]=1.CN(C)C=O>O>[CH3:34][C:33]1[O:32][C:31]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[N:30][C:29]=1[CH2:28][O:27][C:24]1[N:25]=[CH:26][C:21]([CH2:20][N:11]2[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:10]2)=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
Sodium hydride (60%, oily, 270 mg) was added to a mixture of ethyl 3-phenyl-1H-pyrazole-4-carboxylate (1.20 g), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (1.75 g), and N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-carboxylate (1.56 g, yield: 57%) as a colorless oily substance from the fraction eluted with diethyl ether-hexane (2:3, volume ratio).
Reaction SMILES: II.[PH2](O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)(O)[CH3:14])=[CH:9][CH:8]=1.[OH-].[Na+]>C(O)(=O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH3:14])=[CH:9][CH:8]=1
Reactant: CC(O)(c1ccc(F)cc1)c1nccs1
Agent: II
Agent: O=[PH2]O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(c1ccc(F)cc1)c1nccs1
Temperature: 60 °C

Procedure:
A mixture of iodine (856 mg, 3.37 mmol), hypophosphorous acid (3.152 mL, 20.22 mmol) and acetic acid (40 mL) was heated to 60° C. until the reaction mixture became clear. 1-(4-fluorophenyl)-1-(thiazol-2-yl)ethanol (1.05 g, 5.07 mmol) was added to the solution and the reaction mixture was heated to 80° C. overnight. After cooling to rt, the reaction mixture was neutralized with concentrated sodium hydroxide and the crude product was extracted with chloroform, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography with 0-40% ethyl acetate in hexane to afford the title compound as an oily brown residue (351 mg, 50% yield). MS (M+H)+ 208.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>O.CO>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(C(=O)O)cc1
Yield: 65.8 %

Procedure:
2-n-Butyl-1-(4-carbomethoxybenzyl)-4-chloro-5-(methoxymethyl)imidazole (15.2 g, 43.3 mmol, 1 eq), 0.5 N KOH in methanol (130 mL, 65.0 mmol, 1.5 eq), water (10 mL) and methanol (50 mL) were mixed and refluxed for 4 hours. The solvent was removed in vacuo and the residue dissolved in water (300 mL). The pH was adjusted to 4 with conc. HCl and this aqueous mixture extracted with ethyl acetate (3×300 mL). The organic layers were combined, dried (MgSO4), the solved removed in vacuo and the crude residue recrystallized from hexane/butyl chloride to yield 9.6 g of white solid; m.p. 126.5°-127.5°. NMR (200 MHz, DMSO-d6) δ 12.95 (bs, 1H); 7.93 (d, 2H, J=9 Hz); 7.16 (d, 2H, J=9 Hz); 5.30 (s, 2H); 4.31 (s, 2H); 3.19 (s, 3H); 2.50 (t, 2H, J=7 Hz); 1.49 (t of t, 2H, J=7,7 Hz); 1.24 (t of q, 2H, J=7,7 Hz); 0.80 (t, 3H, J=7 Hz). Anal. Calcd. for C17H21ClN2O3 : C, 60.62; H, 6.29; N, 8.32. Found: C, 60.89; H, 6.10; N, 8.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1)=[O:6].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:5]([C:4]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:2]([Cl:1])[CH:3]=2)=[O:6])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NCCN1CCN(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN1CCN(C(=O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The product from step (ii) above (3.3 g) was dissolved in dichloromethane (50 ml) and trifluoroacetic acid (10 ml) added. After 16 hours at room temperature the solvent was removed to give the sub-titled product as an oil (5.9 g).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](=[N:18][C:19]#[N:20])SC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH2:21]([NH2:23])[CH3:22]>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:23][CH2:21][CH3:22])=[N:18][C:19]#[N:20])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCN
Reactant: CSC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Solvent: CCO
Product: CCNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-guanidino-4-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]thiazole (1.1 g.) in ethanol (25 ml.) was treated with 70% w/v aqueous ethylamine (5 ml.) at room temperature. The mixture was stirred overnight at room temperature and the solution evaporated to dryness. The residue was crystallized from methanol to give 2-guanidino-4-[2-(2-cyano-3-ethylguanidino)ethylthiomethyl]thiazole (0.53 g.), m.p. 181°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Br>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCN2CCC(Cc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: Br
Solvent: O
Product: Oc1ccc(CCN2CCC(Cc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of 7.7 parts of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-1H-benzimidazole and 150 parts of a hydrobromic acid solution 48% in water was stirred overnight at 80° C. The reaction mixture was evaporated and water was added to the residue. The whole was treated with ammonium hydroxide and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of hexane, trichloromethane and methanol (45:45:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.5 parts (35%) of 4-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]phenol; mp. 130.3° C. (504).
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=CC=CC=2)=[N:8][NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:6]=CC=C[CH:2]=1.CC(C)C(=O)CC#[N:31]>>[CH:1]([C:7]1[CH:20]=[C:25]([NH2:31])[N:9]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:8]=1)([CH3:2])[CH3:6]
Reactant: c1ccc(C(=NNc2ccc3ncccc3c2)c2ccccc2)cc1
Reactant: CC(C)C(=O)CC#N
Product: CC(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Yield: 36 %

Procedure:
Using a procedure analogous to Example B3, 6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and 4-methyl-3-oxo-pentanenitrile (1.5 g, 13.5 mmol) were combined to provide to 3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine. (1.1 g, 36% yield). 1H NMR (400 MHz, CDCl3) δ 8.93 (dd, J=4.4, 1.6 Hz, 1H), 8.21-8.18 (m, 2H), 8.05-8.02 (m, 2H), 7.44 (dd, J=8.4, 4.4 Hz, 1H), 5.56 (s, 1H), 3.85 (br s, 2H), 2.97 (m, 1H), 1.31 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 253.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:26].O>CN(C)C=O>[CH3:26][N:7]([CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=1)[CH3:9])[C:6](=[O:22])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(OCC(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(OCC(F)(F)F)nc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred solution of tert-butyl(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamate (221 mg, 0.69 mmol, Step-1, single enantiomer) and sodium hydride (61 mg, 1.52 mmol, 60% in oil) in N,N-dimethylformamide (7 mL) is added dropwise iodomethane (0.065 mL, 1.04 mL) at room temperature. After stirring at room temperature for 3.5 hours, the reaction mixture is slowly poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer is washed with water (30 mL) and dried over sodium sulfate. After concentration in vacuo, the residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (9:1) to give 198 mg (86% yield) of the title compound as colorless oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([OH:28])=O)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.C([N:32]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([NH2:32])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.2 %

Procedure:
To a solution of 5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrole-2-carboxylic acid (1.3 g) in N,N-dimethylformamide (15 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (980 mg) and 1-hydroxybenzotriazole ammonium salt (926 mg), and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (910 mg, yield 70%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 403 (MH+).
Reaction SMILES: C(O)[C@H]([C@@H]([C@@H]([C@@H](CO)O)O)O)O.C([O:20][C@@H:21]([C@H:28]([C@@H:37]([F:40])[CH2:38][OH:39])[O:29]CC1C=CC=CC=1)[C@@H:22]([OH:27])[C:23]([F:26])([F:25])[F:24])C1C=CC=CC=1.[H][H]>[Pd]>[F:24][C:23]([F:25])([F:26])[C@@H:22]([C@H:21]([C@H:28]([C@@H:37]([F:40])[CH2:38][OH:39])[OH:29])[OH:20])[OH:27]
Reactant: OC[C@H](F)[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H](F)[C@H](O)[C@H](O)[C@@H](O)C(F)(F)F

Procedure:
Further, the aforesaid altritol Compound (10) is a new compound. When Compound (10) is reduced with hydrogen in the presence of a palladium catalyst under mild reaction conditions, the benzyl groups can be removed from Compound (10) to produce 1,5-dideoxy-1,1,1,5-tetrafluoro-L-altritol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH:30]([C:34]([NH2:36])=[O:35])[CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:29][CH:30]2[C:34]([NH2:36])=[O:35])=[CH:8][CH:9]=1
Reactant: NC(=O)C1CN(Cc2ccccc2)CCN1
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C1CN(Cc2ccccc2)CCN1CCCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
A mixture of 74.2 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis[4-fluorobenzene], 43.8 parts of 4-(phenylmethyl)-2-piperazinecarboxamide, 38.9 parts of N,N-diethylethanamine and 1350 parts of N,N-dimethylformamide was stirred for 20 hours at 70° C. The reaction mixture was evaporated in vacuo and the residue was stirred in dichloromethane. The precipitate was filtered off. The filtrate was washed three times with 200 parts of water and once with 200 parts of a diluted ammonium hydroxide solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 58.9 parts (61.9%) of 1-[5,5-bis(4-fluorophenyl)-4-pentenyl]-4-(phenylmethyl)-2-piperazinecarboxamide as a residue (int. 33).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[O:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)[CH3:21]>>[CH3:21][O:20][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: COc1cccc(CBr)c1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cccc(OC)c2)c(=O)[nH]c1=O
Yield: 44.1 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3-methoxylbenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (175 mg, yield: 44.1%).
Reaction SMILES: [CH3:1]COCC.C[Si](C=[N+]=[N-])(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([C:42]([OH:44])=[O:43])[C:17]2[C:18]([CH:41]=1)=[N:19][N:20]([CH2:22][C:23]([C:39]#[N:40])([NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[O:27])[CH3:24])[N:21]=2>C1COCC1.CO>[Cl:13][C:14]1[CH:15]=[C:16]([C:42]([O:44][CH3:1])=[O:43])[C:17]2[C:18]([CH:41]=1)=[N:19][N:20]([CH2:22][C:23]([C:39]#[N:40])([NH:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=1)=[O:27])[CH3:24])[N:21]=2
Reactant: CCOCC
Reactant: CC(C#N)(Cn1nc2cc(Cl)cc(C(=O)O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Cl)cc2nn(CC(C)(C#N)NC(=O)c3ccc(OC(F)(F)F)cc3)nc12
Reaction time: 8 h
Yield: 40 %

Procedure:
A 2 molar ether solution of trimethylsilyldiazomethane was added to 6-chloro-2-[2-cyano-2-({[4-(trifluoromethoxy)phenyl]carbonyl}amino)-propyl]-2H-benzotriazole-4-carboxylic acid (100 mg) dissolved in a ten to 1 one mixture of THF and methanol (2 mL). After overnight at room temperature, the mixture was concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (42 mg, 40%). MS (ES): M/Z [M+H]=482. 1H NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 3.78 (s, 3H), 5.44 (d, J=13.3 Hz, 1H), 5.58 (d, J=13.3 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.8 Hz, 2H), 8.02 (d, J=1.9 Hz, 1H), 8.52 (d, J=1.9 Hz, 1H) and 8.87 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:28][C:29](=[O:35])[CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:60][Si:61]([C:64]#[CH:65])([CH3:63])[CH3:62]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:28][C:29](=[O:35])[CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:3][C:2]=2[C:65]#[C:64][Si:61]([CH3:63])([CH3:62])[CH3:60])[CH2:9][CH2:10]1)=[O:27])[CH3:24]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(C#C[Si](C)(C)C)c1
Temperature: 120 °C
Yield: 15.6 %

Procedure:
To a solution of N-{3-bromo-4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-phenyl}-2-ethyl-butyramide (66 mg, 0.12 mmol) in DMF (1.5 mL) was added CuI (1.3 mg, 0.01 mmol), triphenylphosphine (73 mg, 0.28 mmol), diethylamine (220 μL, 2.1 mmol), trimethylsilylacetylene (22 μL, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium (II) (5.0 mg, 0.01 mmol). This solution was heated in a focused microwave reactor at 120° C. for 5 min, after which the solution was concentrated and purified by reverse phase HPLC to provide N-{4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-3-trimethylsilanylethynyl-phenyl}-2-ethylbutyramide (10.5 mg, 16%). This compound (18 mg, 0.03 mmol) was dissolved in MeOH and treated with K2CO3 (9.0 mg, 0.06 mmol). After 1 h, the solids were filtered off, the filtrate concentrated, and the product purified by reverse phase HPLC to afford the title compound (10 mg, 63%). MS: 489.4.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl.[N-:13]([C:16]#[N:17])[C:14]#[N:15].[Na+]>O>[C:14]([N:13]=[C:16]([NH2:17])[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)#[N:15]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CN=C(N)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.2 %

Procedure:
3-Trifluoromethylaniline (10 g, 62.1 mmol) was dissolved in 6N HCl (10.35 mmol, 62.1 mmol) and 50 ml of water. Sodium dicyanamide (5.53 g, 62.1 mmol) was added and the mixture was stirred for 12 hours at ambient temperature. The mixture was then cooled to 0° C. and stirred for 1 hour resulting in the formation of a precipitate. Filtration provided 12.22 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]1[C:29]2[CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33][C:28]=2[O:27][CH2:26][C:25]1=[O:43]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:28]4[O:27][CH2:26][C:25](=[O:43])[N:24]([CH3:23])[C:29]=4[CH:30]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Reactant: CN1C(=O)COc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc5c(c4)N(C)C(=O)CO5)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one. LCMS (M+H)+=485.0/487.0.