Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCc1ccccc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
Under an argon atmosphere, 225 g of 2-nitro-9,10-dihydrophenanthrene, 227 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone, and 2.4 L of 1,4-dioxane were added, and then the mixture was stirred for 24 hours under heating ref lux. After having been cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography, and was then washed with methanol. Thus, 134 g of a white crystal were obtained (in 60% yield).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[Li]CCCC.[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20](S(CC)(=O)=O)[CH:19]=[C:18]2[O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>O1CCCC1>[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:19]=[C:18]2[O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1
Reactant: NCC(F)(F)F
Reactant: CCS(=O)(=O)c1cc(OCc2ccc(OC)cc2)c2cccc(Cl)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(NCC(F)(F)F)nc3c(Cl)cccc23)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
In a pre-dried 3-necked round bottom flask was dissolved 2,2,2-trifluoro-ethylamine (91 mg, 0.92 mmol, 1.2 equiv) in dry tetrahydrofuran (0.5 mL), under a nitrogen atmosphere. The flask was cooled down to −78° C. and 2.5M n-BuLi in hexanes (428 μL, 1.07 mmol, 1.4 equiv) was added via syringe. The mixture was stirred for 5 minutes then gradually warmed to 0° C. At this point, 8-chloro-2-ethanesulfonyl-4-(4-methoxy-benzyloxy)-quinoline (300 mg, 0.766 mmol, 1 equiv) in a solution of THF was slowly added. The mixture was stirred for 17 h at room temperature then quenched with brine and extracted into dichloromethane. The organic layer was dried over MgSO4 and concentrated down in vacuo to afford [8-chloro-4-(4-methoxy-benzyloxy)-quinolin-2-yl]-(2,2,2-trifluoro-ethyl)-amine (203 mg, 67% yield). LCMS found 397.11 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28]Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:31][N:32]1[CH:40]=[C:35]2[CH2:36][NH:37][CH2:38][CH2:39][C:34]2=[N:33]1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:37]5[CH2:38][CH2:39][C:34]6=[N:33][N:32]([CH3:31])[CH:40]=[C:35]6[CH2:36]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cn1cc2c(n1)CCNC2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4nn(C)cc4C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine following a procedure analogous to that described for Intermediate 42. LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Product: N#Cc1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 67 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.34 mmol), using 4-fluorobenzonitrile instead of 4-fluoroacetophenone, was converted to the title compound (90 mg, 67%) which was obtained as a white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH2:11]([S:14][C:15]1([C:18]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=O)[CH2:17][CH2:16]1)[CH2:12][CH3:13].[OH-].[K+].OO>C(O)(C)(C)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:21]=[CH:20][C:18]1([C:15]2([S:14][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17]2)[CH2:10][O:9]1
Reactant: COS(=O)(=O)OC
Reactant: CCCSC1(C(=O)C=Cc2ccc(Cl)cc2Cl)CC1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CSC
Product: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Reaction time: 14 h
Yield: 89.2 %

Procedure:
30 ml (0.41 mol) of dimethyl sulphide and 43.5 g (0.35 mol) of dimethyl sulphate are added to 60 ml of tert.-butanol and allowed to stand at room temperature for 14 hours. A solution of 40 g (0.13 mol) of 2,4-dichlorophenyl-ethenyl 1-propylmercaptocyclopropyl ketone in 120 ml of tert.-butanol is initially added dropwise to the reaction mixture with stirring and then 39.1 g of potassium hydroxide powder is introduced, the temperature of the reaction mixture being held at 20° to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is stripped off under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed using water and concentrated by stripping off the solvent under reduced pressure after drying over sodium sulphate. In this manner, 38.2 g (91% of theory) of 2-(2,4-dichlorophenylethenyl)-2-(1-propylmercaptocyclopropyl)-oxirane are obtained in the form of an oily product, which is further reacted without additional purification. ##STR77##
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.B1([C:31]2[CH:36]=[N:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:33][CH:32]=2)OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:31]3[CH:32]=[N:33][C:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[N:35][CH:36]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CC1(C)OB(c2cnc(N3CCOCC3)nc2)OC1(C)C
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cnc(N5CCOCC5)nc4)cc32)c1Cl
Yield: 27 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 2-(4-morpholino)pyrimidine-5-boronic acid pinacol ester as in General Procedure 4A to give the title compound as an off-white solid (27% yield). M.p. 250-251° C., LCMS: m/z=459.17 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.29-3.35 (m, 2H), 3.52-3.56 (m, 2H), 3.78-3.84 (m, 8H), 4.51 (s, 2H), 4.86 (bs, 1H), 6.96 (s, 1H), 7.00-7.08 (m, 1H), 7.10-7.17 (m, 1H), 7.59 (d, J=1.8 Hz, 1H), 8.46 (s, 1H).
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]O)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BrH:21]>>[F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][Br:21])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Br
Reactant: OCc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Product: FC(F)(c1ccccc1)C(F)(F)c1ccccc1CBr

Procedure:
A suspension of 3.3 g. (0.0116 mole) of 2-(α,α,β,β-tetrafluorophenethyl)benzyl alcohol in 15 ml. of 48% hydrobromic acid is stirred and heated on the steam bath for 3 hours. The product crystallizes from the cooled mixture and is collected and dissolved in benzene. Evaporation of the washed and dried benzene extract under reduced pressure and sublimation of the residual solid at 60°C. and 0.05 mm. yields white crystals, m.p. 70°-77°C. A sample for analysis from a previous preparation was purified by column chromatography on silica, eluting the product with benzene-carbon tetrachloride (2:1). The fractions that showed one spot of rf 0.85 on a fluorescent silica, thin layer plate developed with benzene were combined and the solvent evaporated under reduced pressure. The residual solid, m.p. 78°-82°C., was sublimed at 60°C. and 0.05 mm. to yield product, m.p. 80.5°-82°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([O:17]C(C)(C)C)=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: CSc1c(C(=O)OC(C)(C)C)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Yield: 98 %

Procedure:
To a magnetically stirred solution of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylate (4.00 g, 8.53 mmol) in CH2Cl2 (60 ml) was added excess TFA (8.40 ml, 0.111 mol). The solution was reacted at room temperature for 16 hours and subsequently concentrated in vacuo. Water was added and the formed precipitate was collected by filtration and subsequently dried to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylic acid in 98% yield, mp ˜100° C. (decomposition); 1H-NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 3.60 (br s, 1H), 7.08 (br d, J˜8 Hz, 2H), 7.26 (dd, J=8 and 2 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.35 (d, J=2 Hz, 1H), 7.37 (br d, J˜8 Hz, 2H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:25]2[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([CH2:32][CH3:33])[CH:26]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)#[N:11].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:25]2[CH:30]=[C:29]([O:31][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:28]=[C:27]([CH2:32][CH3:33])[CH:26]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)#[N:11]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(O)cc(CC)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(Oc2ccccc2)c1
Reaction time: 60 h
Yield: 81.4 %

Procedure:
Copper(II) acetate (223 mg, 1.20 mmol), phenylboronic acid (164 mg, 1.32 mmol) and molecular sieve 4A were added to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-hydroxy-phenyl)-acetate (390 mg, 1.20 mmol) obtained in Example 200.1 in CH2Cl2 (12 ml). Pyridine (476 mg, 6.01 mmol) was added dropwise and the mixture was stirred for 60 h. under an atmosphere of air. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2). There were obtained 391 mg (81%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-phenoxy-phenyl)-acetate as beige crystals; MS: 401 ([M+H]+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.6 M n-Butyllithium in hexanes (9.6 mL, 15 mmol) was added to a solution of N,N-diisopropylamine (2.3 mL, 16 mmol) in THF (43 mL) at −78° C. Upon complete addition, the reaction was warmed to 0° C. for 30 minutes and then was re-cooled to −78° C. A solution of 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (3.00 g, 10.2 mmol, from Example 2, Step 1) in THF (8 mL) was added dropwise. After stirring for one hour at −78° C., ethyl chloroformate (1.4 mL, 14 mmol, Alfa Aesar) was added and the reaction was stirred at −78° C. for 2 hours, after which time it was allowed to warm to room temperature. The reaction was poured into dilute HCl and the product was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted, and the solvent removed in vacuo. Flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a yellow solid (2.15 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:14]=[C:15]2[C:21]3[CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][CH2:17][N:16]2[CH:30]=1.O1CCCC1.O.O.[OH-].[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:14]=[C:15]2[C:21]3[CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][CH2:17][N:16]2[CH:30]=1
Reactant: COC(=O)c1ccc2c(c1)-c1nc(-c3nccn3-c3ccccc3Cl)cn1CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)-c1nc(-c3nccn3-c3ccccc3Cl)cn1CCO2
Temperature: 25 °C

Procedure:
To a solution of methyl 2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate (0.100 g, 0.238 mmol) in tetrahydrofuran (5.56 mL, 68.5 mmol) and Water (5.56 mL, 308 mmol) was added Lithium hydroxide, monohydrate (0.0399 g, 0.950 mmol). The reaction mixture was stirred at rt o/n. The reaction mixture was concentrated. The reaction mixture was acidified with 1M HCl then extracted with DCM (3×). The combined organics were dried over Na2SO4, filtered and concentrated to give 2-(1-(2-chlorophenyl)-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid. MS: (ESI+)=407.2
Reaction SMILES: [F:1]/[CH:2]=[C:3]1/[C@H:4]2[C@H:13]([C@H:14]3[C@@:18]([CH2:20]/1)([CH3:19])[C:17](=[O:21])[CH2:16][CH2:15]3)[CH2:12][CH2:11][C:10]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH:9]=1.[C:22]([Mg]Br)#[C:23][CH3:24]>O>[F:1]/[CH:2]=[C:3]1/[C@H:4]2[C@H:13]([C@H:14]3[C@@:18]([CH2:20]/1)([CH3:19])[C@:17]([OH:21])([C:22]#[C:23][CH3:24])[CH2:16][CH2:15]3)[CH2:12][CH2:11][C:10]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][CH:9]=1
Reactant: C[C@]12C/C(=C\F)[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC#C[Mg]Br
Solvent: O
Product: CC#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CCCC[C@@H]4[C@H]3/C(=C/F)C[C@@]21C
Reaction time: 2 h

Procedure:
(E)-11-(Fluoromethylene)estr-4-en-17-one (XII, Example 55, 382 ml) is cooled on an ice bath. Propynyl magnesium bromide (about 0.5M, 4.24 ml is THF) is added and the mixture stirred. After 2 hr TLC shows a small amount of starting material and an additional Grignard reagent is added (0.5 ml). After another 0.5 hr ice and water are added and the product extracted with ether, washed several times with water, dried over sodium sulfate, filtered, and concentrated. The residue is chromatographed over a silica gel column using ethyl acetate/hexane (10/90) as the irrigant. Fractions 39 to 45 are pooled and concentrated to give a solid which is crystallized from methanol/water to give the title compound; NMR (CDCl3) 0.83, 1.86, 5.47, 6.53 δ; MS (m/e) 328, 313, 295 and 246; IR (mull) 3428, 1677 cm-1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11].[CH3:12][N:13]([CH3:21])[CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18].[H-].[Na+]>>[CH3:12][N:13]([CH3:21])[CH2:14][CH2:15][N:16]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11])[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(C)CCNS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1Cl)S(C)(=O)=O

Procedure:
Prepared from 2-fluoro-5-nitro-chlorobenzene, N-(2-dimethylamino-ethyl)-methanesuiphonamide and sodium hydride as base
Reaction SMILES: [CH:1]1([N:7]2[C:16](=[O:17])[C:15]3[NH:14][C:13]([N+]([O-])=O)=[N:12][C:11]=3[N:10]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:29])=O>CN(C)C=O>[CH:1]1([N:7]2[C:16](=[O:17])[C:15]3[NH:14][C:13]([Cl:29])=[N:12][C:11]=3[N:10]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(C2CCCCC2)c(=O)n1C1CCCCC1
Solvent: CN(C)C=O
Product: O=c1c2[nH]c(Cl)nc2n(C2CCCCC2)c(=O)n1C1CCCCC1

Procedure:
1,3-Di-cyclohexyl-8-chloro xanthine was prepared from 1,3-di-cyclohexyl-8-nitro xanthine (2 g, 0.006 mol) and phosphorous oxychloride (3.9 g) in dimethylformamide (6 ml), using an analogous procedure to that described in Example 17. The product was obtained as a crystalline product after recrystallisation from ethyl acetate, m.pt., 135° C.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])[CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:38]1[CH:43]=[CH:42][C:41]([C:44](=[O:49])NCCC)=[CH:40][CH:39]=1)=O)C2>>[C:44]([N:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])[CH2:6]1)(=[O:49])[C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(NCCCCC1CNC1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(NCCCCC1CN(C(=O)c2ccccc2)C1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(4-(azetidin-3-yl)butyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 7.67-7.57 (m, 2H), 7.57-7.39 (m, 3H), 7.39-7.23 (m, 4H), 6.28 (s, 1H), 4.56 (s, 4H), 4.34 (t, J=8.3 Hz, 1H), 4.11 (t, J=9.0 Hz, 1H), 4.01-3.82 (m, 1H), 3.65 (dd, J=9.8, 5.8 Hz, 1H), 3.07 (dd, J=12.7, 6.8 Hz, 2H), 2.66-2.53 (m, 1H), 1.59 (dd, J=15.3, 7.7 Hz, 2H), 1.51-1.36 (m, 2H), 1.25 (dd, J=13.5, 6.4 Hz, 2H); MS (ESI(+)) m/e 378 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:37])[NH:5][C:6](=[O:36])[N:7]([CH:35]=1)[C@@H:8]1[O:34][C@H:12]([CH2:13][O:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[OH-].[K+].[CH2:40](I)[CH3:41]>C1C=CC=CC=1.O1CCOCC1>[CH2:40]([O:11][C@@H:10]1[C@@H:12]([CH2:13][O:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:34][C@@H:8]([N:7]2[CH:35]=[C:3]([CH2:1][CH3:2])[C:4](=[O:37])[NH:5][C:6]2=[O:36])[CH2:9]1)[CH3:41]
Reactant: CCI
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 6 g of 2'-deoxy-5-ethyl-5'-O-trityluridine, 1.347 g of powdered potassium hydroxide and 1.95 ml of ethyl iodide in a mixture of 60 ml of benzene and 20 ml of dioxane was stirred and heated under reflux for 14 hours. The solvents were removed by evaporation, the residue was taken up in 6 ml of methanol and the solution was poured into 250 ml of water. The resulting mixture was extracted four times with 150 ml of chloroform each time and the combined chloroform extracts were evaporated to give 2'-deoxy-3'-O-ethyl-5-ethyl-5'-O-trityluridine which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2(O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: OC1(c2ccc(Cl)nc2)CCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc(C2=CCCC2)cn1
Temperature: 25 °C
Yield: 88 %

Procedure:
1-(6-Chloro-pyridin-3-yl)cyclopentanol (2.1 g, 10.5 mmol) was treated with acetic acid (12 mL) and sulfuric acid (4 mL) and the mixture heated to reflux for 30 min. After cooling to RT, ice and 2 N NaOH (180 mL) was add and the resulting tan precipitate collected by filtration, washed with H2O and dried giving 2-chloro-5-(cyclopent-1-enyl)pyridine (1.66 g, 88%) as a tan solid: mp 59-60° C., LC/MS (ESI) m/z 179, 1H NMR (300 MHz, CDCl3) δ 8.41 (d, 1H, J=2.4 Hz), 7.66 (dd, 1H, J=8.4, 2.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 6.27 (t, 1H, J=2.1 Hz), 2.69 (bm, 2H), 2.55 (bm, 2H), 2.05 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[CH3:26].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:28][CH2:29][N:30]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)c(C)c3)CC2)n(-c2ccccc2)n1

Procedure:
172 mg (92%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(3,4-dimethylphenyl)piperazine (79 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:29])=[O:28]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:29])=[O:28]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCl)NCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCCCO
Yield: 93.2 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N-(4-hydroxybutyl)-5-chloropentanesulfonamide (515.6 mg, 2.00 mmol) prepared in Preparation Example 23 were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(4-hydroxybutyl)-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfonamide (947.0 mg) as a pale yellow oil (yield: 93.2%).