Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCSCCCC(F)(F)C(F)(F)F)[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=2)[C:3]1=[O:41].CS(OCCCCC[CH2:53][CH2:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][CH2:60][C:61]([F:67])([F:66])[C:62]([F:65])([F:64])[F:63])(=O)=O>>[CH3:1][C:2]1([CH3:42])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:53][CH2:54][CH2:55][CH2:56][S:57][CH2:58][CH2:59][CH2:60][C:61]([F:67])([F:66])[C:62]([F:63])([F:65])[F:64])[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]([C:37]([F:39])([F:40])[F:38])[CH:29]=2)[C:3]1=[O:41]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Yield: 43 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 1, 10-[(4,4,5,5,5-pentafluoropentypthio]undecyl methanesulphonate (prepared according to an experimental protocol similar to that described in WO 2005077968) replacing 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate. The expected compound is obtained in the form of a pale yellow oil with a yield of 43% (328 mg).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1.[CH2:29]=[O:30].C([NH:35][CH2:36][CH2:37][CH2:38][CH3:39])CCC.C[O-].[Na+].Cl>>[CH2:11]([C:12]1[CH:13]=[C:14]([C:16]([CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:17])[CH3:18])[CH:15]=[C:10]([N:8]2[N:35]=[C:36]3[CH:37]=[CH:38][C:39]([C:2]([F:1])([F:28])[F:27])=[CH:5][C:6]3=[N:7]2)[C:29]=1[OH:30])[C:12]1[CH:13]=[C:14]([C:16]([CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:17])[CH3:18])[CH:15]=[C:10]([N:8]2[N:7]=[C:6]3[CH:25]=[CH:26][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][C:5]3=[N:9]2)[C:11]=1[OH:24]
Reactant: CCCCNCCCC
Reactant: C=O
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)CC(C)(C)c1cc(Cc2cc(C(C)(C)CC(C)(C)C)cc(-n3nc4ccc(C(F)(F)F)cc4n3)c2O)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
The compound prepared in Example 31 (7.0 g, 0.018 mol), paraformaldehyde (0.29 g, 0.0093 mol) and di-n-butylamine (2.43 g, 0.0186 mol) are charged to a reaction and which is then sealed. The temperature is increased to 160° C. and held there for four hours. The reaction mass is cooled to 110° C. at which time sodium methoxide (0.16 g, 0.0028 mol) is added. The reaction mixture is then heated to 205° C. and held there for three hours.The reaction mass is then cooled to 110° C. and 100 mL of xylenes are added. The reaction mass is neutralized with 10% aqueous hydrochloric acid and the organic phase is twice washed with water. Xylene is then distilled off and replaced with heptane. After cooling the heptane solution, yellow crystals separate out and are isolated by filtration. After drying to constant weight, the title compound (5 g) is obtained as a solid melting at 178° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:29])[CH:3]=1.[S:30]1(=[O:36])(=[O:35])[CH2:34][CH2:33][CH2:32][NH:31]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:31]5[CH2:32][CH2:33][CH2:34][S:30]5(=[O:36])=[O:35])=[CH:3][C:4]=4[F:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Reactant: O=S1(=O)CCCN1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 51.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 123 and isothiazolidine 1,1-dioxide (96 mg) and by the reaction and treatment in the same manner as in Example 4, the title compound (209 mg) was obtained.
Reaction SMILES: [K+].C(OC([NH:9][C:10]([CH3:19])(/[CH:14]=[CH:15]\[CH2:16][C:17]#[N:18])[C:11]([O-:13])=[O:12])=O)(C)(C)C.[ClH:20]>O>[ClH:20].[NH2:9][C:10]([CH3:19])(/[CH:14]=[CH:15]\[CH2:16][C:17]#[N:18])[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)NC(C)(/C=C\CC#N)C(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(N)(/C=C\CC#N)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The (3Z)-2-[(tert-butoxycarbonyl)amino]-5-cyano-2-methylpent-3-enoic acid potassium salt product of Example 1j is taken up in DI water (80 mL) containing HCl. The reaction mixture is stirred at 50° C. for 2 h. and concentrated on a rotary evaporator to give the crude product. It is purified using a Gilson chromatographic system to provide the desired title product.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:30][CH:29]=[CH:28][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li]CCCC.CN(C)[CH:38]=[O:39]>C1COCC1>[N:1]1([C:7]2[C:8]3[S:30][C:29]([CH:38]=[O:39])=[CH:28][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:27])([CH3:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[CH:14]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(C)(C)[SiH2]Oc1cccc(-c2nc(N3CCOCC3)c3sccc3n2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(C)(C)[SiH2]Oc1cccc(-c2nc(N3CCOCC3)c3sc(C=O)cc3n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine (2.26 g, 5.29 mmol) in dry THF (40 mL) cooled to −78° C. was added nBuLi (2.5 M solution in hexanes, 2.75 mL, 1.3 eq.). After stirring for 20 minutes, dry N,N-dimethylformamide (617 μL, 1.5 eq.) was added, and the reaction mixture was stirred for 20 minutes at −78° C. and then warmed slowly to room temperature. After a further 30 minutes at room temperature the reaction mixture was quenched with ice/brine and then extracted exhaustively with chloroform. The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to yield compound 8 as a yellow solid (2.38 g, 99%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].CS(O[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O>CN(C=O)C>[N:1]1([CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of the pyrazole (200 mg, 3.0 mmol) in DMF (20.0 ml) under nitrogen atmosphere was added sodium hydride (120 mg, 3.3 mmol) and the solution stirred for 5 min. After bubbling ceased, the title compound from Step A (400 mg, 3.0 mmol) in 5.0 mL of DMF was added to the solution. The mixture was placed in a microwave reaction vessel and nitrogen was blown into it before closing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[N:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]3=[N:24][C:23]=2[C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36]C)=O)[CH:19]=[CH:18][N:17]=1.[F:41][C:42]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:43]=1[NH2:44].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:41][C:42]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:43]=1[NH:44][C:34](=[O:36])[C:33]1[CH:38]=[CH:39][CH:40]=[C:31]([C:23]2[N:24]=[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]3[C:22]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[CH:8][C:3]=3[O:2][CH3:1])[N:21]=2)[CH:32]=1
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCOCC4)cc3OC)n2)c1
Reactant: Nc1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N2CCOCC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 75 %

Procedure:
To a solution of methyl 3-[3-(2-{[2-(methyloxy)-4-(4-morpholinyl)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoate (65 mg, 0.12 mmol) in 2 mL THF was added 2,6-difluoroaniline (0.065 mL, 0.60 mmol) and a 1M solution of NaHMDS in THF (0.72 mL, 0.72 mmol). When LC/MS showed the reaction to be complete it was concentrated onto silica gel and purified by flash column chromatography to give 57 mg (75%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.38 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.60-7.52 (m, 2H), 7.47-7.40 (m, 2H), 7.35-7.30 (m, 1H), 7.11-7.07 (m, 1H), 6.98-6.94 (m, 1H), 6.67 (s, 1H), 6.48-6.43 (m, 2H), 3.78 (s, 3H), 3.73-3.72 (m, 4H), 3.10-3.09 (m, 4H). MS (ESI) m/z=634 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:13])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li+].[CH3:15][CH:16]([N-]C(C)C)C.O1CC1.O>C1COCC1>[Br:13][C:4]1[S:3][C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]=1[CH2:15][CH3:16]
Reactant: CC(C)[N-]C(C)C
Reactant: Brc1cc(-c2ccccc2)c(Br)s1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CO1
Solvent: O
Product: CCc1c(Br)sc(Br)c1-c1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-dibromo-3-phenylthiophene (2.54 g, 8.0 mmol) in dry THF (30 mL) at −65° C. was added LDA (8.8 mmol) dropwise. After stirring for 30 min at −65° C., oxirane (20.0 mmol) was added and the reaction was stirred for 2 h. The reaction mixture was then warmed to room temperature and water was added. The resulting mixture was extracted with EtOAc (3×100 mL), washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH2:21].C(N(CC)CC)C>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH:21][C:12]1[CH:13]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[C:10]([Cl:15])[N:11]=1
Reactant: COC(=O)CN
Reactant: Clc1cc(Cc2ccccc2)nc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CNc1cc(Cc2ccccc2)nc(Cl)n1
Temperature: 70 °C
Yield: 15.6 %

Procedure:
1.87 g (7.8 mmole) of 4-benzyl-2,6-dichloro-pyrimidine was dissolved in 15 mls of DMF. To this solution was added 1.08 g of glycine methyl ester HCl. Next 3.0 mls of triethyl amine was added dropwise and the reaction stirred was then heated to 70° C. for 3 hours. The reaction was diluted with 10 mls of H2O and extracted with two portions of EtOAc. The combined organic layers were washed with two portions of saturated NaCl solution, dried over MgSO4, filter and evaporated under reduced pressure to yield a crude oil. This material was chromatographed on silica gel with 10% Ethyl Acetate-90% Heptane as the eluent. (6-Benzyl-2-chloro-pyrimidin-4-ylamino)-acetic acid methyl ester (0.354 g, 20%) was isolated a clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:33])C=1.C(O)C.O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:33])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
2-[[3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (monohydrate) (20 g) was dissolved in chloroform (200 ml), to which was added slowly dropwise below 5° C. a solution of m-chloroperbenzoic acid (13.5 g) in chloroform (200 ml), and stirred at the same temperature for about 10 minutes. After completion of the reaction, the reaction mixture was washed with a solution of sodium hydrogencarbonate, and dried over magnesium sulfate, and chloroform was evaporated off under reduced pressure. To the residue was added ethanol (100 ml) for crystallization, which was ice-cooled; the resulting crystals were collected by filtration and washed with ice-cooled ethanol. The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 90 ml), heated (65°-70° C.) and stirred so that the crystals were dissolved, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystallization and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2), and dried in vacuo, to give white needles of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (14.9 g, yield: 74.9%).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CON(C)[C:8](=[O:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O1CCCC1>[C:10]1([CH2:9][C:8](=[O:16])[CH:1]=[CH2:2])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 73 %

Procedure:
A 1M solution of vinylmagnesium bromide in THF (80 mL, 80 mmol) was added dropwise to a stirred solution of N-methoxy-N-methylphenylacetamide (12.8 g, 71.5 mmol) in distilled tetrahydrofuran (THF) (200 mL), cooled to 0°-5° C. in an ice-water bath. The solution was stirred at 0°-5° C. for 2 h and was then poured into cold 1N HCl solution (150 mL). The THF layer was separated and the aqueous (aq.) layer was extracted with EtOAc (100 mL). Organic extracts were combined, dried (MgSO4), filtered and concentrated. The crude oil was chromatographed on a silica gel column and eluted with 5-20% ethylacetate (EtOAc) in hexanes to obtain title 4-phenyl-but-1-ene-3-one (7.62 g, 73%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]2)=[C:4]([F:20])[CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:17])[F:18])[C:12]([CH3:19])=[N:11]2)=[C:4]([F:20])[CH:3]=1
Reactant: COc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 10 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A stirred mixture of 4.6 g (0.015 mole) of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 200 mL of methylene chloride was cooled to 10° C. and a solution of 11.2 g (0.045) mole of boron tribromide in 45 mL of methylene chloride was added. Upon complete addition the reaction mixture was stirred for four hours as it warmed to ambient temperature. After this time 100 mL of water was added, and stirring was continued for an additional 18 hours. The organic layer was separated, dried with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield 4.4 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one; mp 147°-152° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:13]([OH:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].N>CN1CCN(C)C1=O>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][OH:21])=[CH:16][CH:17]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: OC(Br)Cc1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: OCCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Temperature: 180 °C
Reaction time: 36 h
Yield: 50.6 %

Procedure:
A mixture of 4-phenylimidazole (4.32 g, 30 mmol), Bromophenethyl alcohol (10.5 ml, 75 mmol), CuBr (10.4 g, 72 mmol) and Na2CO3 (3.8 g, 36 mmol) in 1,3-dimethyl-2-imidazolidinone (100 mL) was stirred at 180° C. for 36 h. After cooling, to the mixture was added 25% NH3 aq. (50 mL). After 30 min, insoluble materials were removed by Celite filtration and washed with dichloromethane. The aqueous layer was extracted with dichloromethane. The organic phase was dried (MgSO4) and concentrated under reduced pressure. To the residue was added diisopropylether (100 mL) and the flask was cooled to 0° C. Filtration of the diisopropylether gave 4.01 g of the title compound as colorless solid (51%): MS (ESI) m/z 265 [M+H]+, 1H-NMR (CDCl3) δ 2.94 (2H, t, J=6.4 Hz), 3.93 (2H, br), 7.26-7.30 (2H, m), 7.35-7.44 (5H, m), 7.55 (1H, d, J=1.2 Hz), 7.82-7.86 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:14](O)[CH:15]=[CH2:16]>>[CH2:16]([O:8][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=1)[CH:15]=[CH2:14]
Reactant: C=CCO
Reactant: O=C(O)COc1ccc(Cl)c(Cl)c1
Product: C=CCOC(=O)COc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.4 %

Procedure:
To a solution of commercially available (3,4-dichloro-phenoxy)-acetic acid (2.65 g, 12.0 mmol) in allyl alcohol (12.0 cm3, 180 mmol) at ambient temperature under an atmosphere of dry nitrogen was added 4 drops concentrated sulfuric as a catalyst. The solution was stirred at ambient temperature for 20 hours and the volatile fractions removed in vacuo. The residue was dissolved in ethyl ether (50 cm3), washed with water (25 cm3), washed with saturated sodium bicarbonate (25 cm3), washed with brine (25 cm3), dried over magnesium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to afford the title compound as a colorless viscous oil (3.02 g, 96.8%) with positive ion ESI (M+H)+261.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 27.7 %

Procedure:
3-cyanophenol (2.38 g, 20 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.88 g, 22 mmol). The addition of sulfuric acid (20 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(910 mg, 28%). 1H NMR (CD3COCD3): δ 8.30 (d, 1H), 7.67 (s, 1H), 7.49 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]([OH:13])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C.CCCCCCC>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:10]([OH:13])[CH2:11][O:12][S:22]([CH3:21])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)COS(C)(=O)=O
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To a solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol 65.42 g(Net.63.38 g)dissolved in ethyl acetate 320 ml were added isopropyleter 320 ml, and then methane sulfonylchloride 28.3 g under ice-cooling, and triethylamine 25.0 g, successively, and the solution was stirred for 1 hr. N-heptane was added to the reaction solution and the solution was stirred for further 1 hr to deposit crystals, which were filtered and dried in vacuum to obtain the crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methane sulfonyloxybutane 89.3 g (Net.55.7 g). The crude crystals. A ratio of main components in the crude crystals, which contain triethylamine hydrochloride, is the diol derivative compound: the 2-sulfonate derivative: the 1-sulfonate derivtive(the object product): the 1,2-disulfonate compound=1.3:0.1:95.4:3.2. A part of the crude crystal was dissolved in ethyl acetate, washed with water, and purified by recrystallization from ethyl acetate and isopropyl ether. The purified recrystals were used for anlysyses.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]N(C)C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[C:4]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:46]=[C:44]([NH:43][C:33]2[CH:34]=[CH:35][C:36]([N:37]3[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]3)=[C:31]([O:30][CH3:29])[CH:32]=2)[N:45]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(F)cc1Cl
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1-c1ccc(F)cc1Cl

Procedure:
The title compound was prepared from crude ethyl 2-(2-chloro-4-fluoro-benzoyl)-3-dimethylamino-acrylate (50 mg, 0.17 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (51 mg, 0.14 mmol) using in analogous manner the procedure described in example 28b). Obtained as a yellow solid (14 mg, 21%).
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[Cl:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][Cl:22])[CH:25]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.8 %

Procedure:
Triethylamine (1.93 mL; 13.78 mmol) was added at 0° C. to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.3 g; 5.51 mmol) and 3-(chloromethyl)benzoyl chloride (1.13 g; 5.79 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to furnish 1.45 g (76%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide as a white solid.
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.NC1SC=CN=1.C[O:32][C:33]1[CH:34]=[C:35]([C:39]2[C:40]3[CH2:53][CH2:52][N:51]([C:54]4[S:55][CH:56]=[CH:57][N:58]=4)[C:41]=3[N:42]=[C:43]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[N:44]=2)[CH:36]=[CH:37][CH:38]=1>>[N:45]1([C:43]2[N:44]=[C:39]([C:35]3[CH:34]=[C:33]([OH:32])[CH:38]=[CH:37][CH:36]=3)[C:40]3[CH2:53][CH2:52][N:51]([C:54]4[S:55][CH:56]=[CH:57][N:58]=4)[C:41]=3[N:42]=2)[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2nccs2)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: Nc1nccs1
Product: Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2nccs2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 2-aminothiazole, 4-(3-methoxy-phenyl)-7-(thiazol-2-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.