Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccccc1N1CCNCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1ccc([N+](=O)[O-])cc1N1CCNCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
To 1-[2-(methyloxy)phenyl]piperazine (11.0 g, 50.7 mmol) was added concentrated H2SO4 (60 mL) dropwise to and stirred for 4 h at 0° C. KNO3 (7.2 g, 71.2 mmol) was then added and the mixture stirred overnight while allowing to warm to rt. Reaction was then quenched with ice and then 2N NaOH (100 mL) added and extracted three times with EtOAc. Combined organic phases were dried over MgSO4 and loaded directly onto silica gel. Purified by silica gel chromatography in 0-20% MeOH/NH4OH in EtOAc. Yield 5.7 g, 42% yield, of an orange solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.8 (m, 4H) 2.9 (m, 4H) 3.1 (m, 1H) 3.9 (s, 3H) 7.1 (d, J=9.1 Hz, 1H) 7.6 (d, J=2.7 Hz, 1H) 7.9 (dd, J=9.0, 2.7 Hz, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[C:9]2[CH2:18][C:19]([OH:21])=[O:20].[CH3:22]O>ClCCl>[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[CH:10]=[C:9]2[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: Cn1c(=O)cc(CC(=O)O)c2cc(F)ccc21
Reactant: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(=O)n(C)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
16 ml (219 mmol) of thionyl chloride are added dropwise over approximately 30 minutes to a stirred suspension of 11.37 g (49.38 mmol) of a mixture of 6-fluoro-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetic acid in 120 ml of methanol. The mixture is stirred overnight (13 hours) at room temperature and the solvent is driven off under vacuum. The residue is dissolved in 400 ml of dichloromethane, and then washed with saturated aqueous sodium bicarbonate solution and then with water. After drying over sodium sulphate, filtration and concentration of the filtrate, 9.6 g of the expected product are obtained.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=3)[C:10]2=S)=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31])#[N:2].FC1C=C(N2C(=S)N(C3C=C(C(F)(F)F)C(C#N)=NC=3)C(=O)C32CCC3)C=CC=1[OH:41].C(C1(NC2C=CC(C(NC)=O)=C(F)C=2)CCC1)#N.OO>CO.CCOC(C)=O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=3)[C:10]2=[O:41])=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31])#[N:2]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: CNC(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Agent: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Agent: OO
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1ccc(N2C(=O)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide (synthesized as described for Example 1 using 5-amino-3-(trifluoromethyl)picolinonitrile (Intermediate 1) and of 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide (Intermediate 21) as starting materials) (90 mg, 0.19 mmol) and H2O2 (30%, 0.72 mL) in MeOH (8 mL) was stirred at room temperature for 5 days. The reaction mixture was diluted with EtOAc (10 mL) and the organic layer was washed with water, brine, and dried over magnesium sulfate. The residue obtained was purified by reverse phase HPLC (acetonitrile/water:TFA) to obtain 10 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide as a white solid. 1H NMR (500 MHz, CDCl3) δ 9.28 (d, 1H), 8.54 (d, 1H), 8.23 (t, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 6.93 (m, 1H), 3.07 (d, 3H), 2.71 (m, 2H), 2.57 (m, 2H), 2.28 (m, 1H), 1.82 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14](Cl)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.[NH2:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27][CH3:28])=[O:26].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14]([NH:19][C:20]3[CH:24]=[CH:23][S:22][C:21]=3[C:25]([O:27][CH3:28])=[O:26])(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)Cl)ccc21
Reactant: COC(=O)c1sccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 50.6 %

Procedure:
Synthesized as described for 3 using 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride (500.0 mg; 1.74 mmol), methyl 3-aminothiophene-2-carboxylate (301.4 mg; 1.91 mmol), 4-dimethylaminopyridine (53.1 mg; 0.44 mmol), pyridine (1.40 mL; 17.4 mmol) and anhydrous dichloromethane (200 mL). The crude residue was purified by automated silica gel chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 25% v/v over 350 mL gradient elution) to yield the title compound as a white solid (359 mg).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].CS(C)=O.[Cl-].[NH2:25][C:26]([NH2:28])=[NH2+:27].[OH-].[Na+]>O>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:25]=[C:26]([NH2:28])[NH2:27])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(N)=[NH2+]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=C(N)N)nn12
Yield: 32.2 %

Procedure:
3.36 g 3-(5-nitro-1-methyl-2-imidazolyl)-6-chloro-s-triazolo[ 4,3-b] pyridazine were dissolved in 30 ml. dimethyl sulfoxide and mixed at 70°C., while stirring, with 3.4 g guanidinium chloride. 5 ml. water were then added thereto, followed by the dropwise addition of 2.4 ml. 1ON aqueous sodium hydroxide solution, whereafter the reaction mixture was further stirred for an hour at 70°C. After cooling and diluting with water, the precipitated crystals were filtered off with suction, washed with water and dried in a vacuum. 2.5 g of crude product were thus obtained which, after recrystallization from 25 ml. dimethyl formamide, with the addition of active charcoal, gave 1.17 g 3-(5-nitro-1-methyl-2-imidazolyl)-6-(diaminomethylene-amino)-s-triazolo [4,3-b] pyridazine in the form of a yellow material which melted, with decomposition, at 278° - 280°C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([NH2:12])=[N:10][CH:11]=1.[CH:13]1([CH2:18][N:19]([CH2:30][CH3:31])[C:20]2[C:21]([CH:28]=O)=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:13]1([CH2:18][N:19]([CH2:30][CH3:31])[C:20]2[C:21]([CH2:28][NH:12][C:9]3[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[CH:11][N:10]=3)=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CSCCOc1cnc(N)nc1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CNc1ncc(OCCSC)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.8 %

Procedure:
A solution of 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (1.03 g, 5.55 mmol) obtained in Step 1 and 3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypicolinaldehyde (1.60 g, 6.10 mmol) obtained in Step 3 in 1,2-dichloroethane (60 mL) was stirred at room temperature for 10 minutes, and then added with sodium triacetoxyborohydride (1.24 g, 5.83 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (1.60 g, 67%) as pale yellow oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[H-].[Na+].[CH2:10]([O:13][C:14]1[N:19]=[C:18](OCC=C)[N:17]=[C:16]([O:24][CH2:25][CH:26]=[CH2:27])[N:15]=1)[CH:11]=[CH2:12]>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][O:7][C:18]1[N:19]=[C:14]([O:13][CH2:10][CH:11]=[CH2:12])[N:15]=[C:16]([O:24][CH2:25][CH:26]=[CH2:27])[N:17]=1)=[N+:2]=[N-:3]
Reactant: C=CCOc1nc(OCC=C)nc(OCC=C)n1
Reactant: [N-]=[N+]=NCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1nc(OCC=C)nc(OCCCN=[N+]=[N-])n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To 3-azido-1-propanol (8.7 g, 85.7 mmol) in THF (200 mL) was added sodium hydride (5.6 g, 128.6 mmol) at −78° C. The reaction mixture was stirred at −78° C. for about 30 minutes and then allowed to equilibrate at room temperature and stirred for an additional 3 hours. The reaction mixture was recooled to −78° C. and added to a solution of 2,4,6-triallyloxy-1,3,5-triazine (21.4 g, 85.7 mmole) in THF (200 mL). The reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was evaporated to a brown residue. The residue was purified by flash column chromatography over silica gel using EtOAc/hexane as the eluent. The pure fractions were pooled together and evaporated to dryness to give 8.5 g (36%) of the title compound. TLC (Rf: 0.5; 20% EtOAc/Hexane, I2). 1H NMR (CDCl3) δ 2.1 (m, 2H, CH2), 3.5 (t, 2H, CH2), 4.5 (t, 2H, CH2), 4.9 (m, 4H, CH2), 4.3 (m, 4H, CH2), 6.0 (m, 2H, CH).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W]>[CH:1]1[CH:2]=[C:3]([CH2:4][C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[C:8]([OH:9])=[CH:5][CH:6]=1
Reactant: C=O
Reactant: Oc1ccccc1
Agent: [W]
Agent: P
Solvent: O
Product: Oc1ccc(Cc2ccccc2O)cc1
Yield: 38.4 %

Procedure:
Several methods are known in the art for the production of dihydroxydiphenylmethanes. Japanese Patent Jpn. Kokai Tokkyo Koho JP 0687775 (CA 121:57131) discloses a method for the condensation of phenol with aqueous formaldehyde using phosphotungstic acid which consists of 10:43:47 ratio of 2,2′-, 2,4′- and 4,4′-dihydroxydiphenylmethane isomers. EP 331, 172: CA 112:7160 discloses a method for reacting phenol with formaldehyde in the presence of an activated clay at 80° C. for 2 hours to give 38.8% of 4,4′-, 15.8% of 2,2′-, and 38.4% of 2,4′-dihydroxydiphenylmethane and 7.0% oligomer JP 63, 238, 632: CA 116: 75045 discloses a method for reacting phenol with formaldehyde in the presence of activated clay catalyst to give 2,2′-, 2,4′-, and 4,4′dihydroxydiphenylmethane in the ratio of 17.1: 41.4:44.5.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CS([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)(=O)=O.ClCC1C=CC(C(=O)C)=CC=1>CC#N>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)c1ccc(CS(C)(=O)=O)cc1
Agent: CC(=O)c1ccc(CCl)cc1
Solvent: CC#N
Product: CC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Boc piperazine (485 mg, 2.61 mmol) was added to a stirred solution of a mixture of 1-(4-methanesulfonylmethyl-phenyl)-ethanone, 1-(4-chloromethyl-phenyl)-ethanone (obtained in STEP A, 580 mg) and TEA (0.522 ml, 3.75 mmol) in CH3CN (5 ml). The resulting mixture was stirred at room temperature overnight and then further TEA (0.250 ml, 1.80 mmol) and N-Boc piperazine (100 mg, 0.53 mmol) were added. After 4 h the solution was partitioned between water and AcOEt, the organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 7:3 to 6:4) to give 700 mg of 4-(4-acetyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCCCC1CCCc2cccnc21
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Yield: 86.5 %

Procedure:
A mixture of 3-(5,6,7,8-tetrahydroquinol-8-yl)propylamine (4.5 g), 2-chloro-3-nitro-5-(pyrid-3-ylmethyl)pyridine hydrochloride (5 g) and triethylamine (10 ml) was refluxed in ethanol (200 ml) for 7.5 hours. The solvent was removed in vacuo, the residue was dissolved in chloroform and chromatographed on silica in chloroform and later chloroform/methanol 4:1. The fractions containing the product were concentrated to give the title compound as an oil (6.1 g).
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].O>CS(C)=O>[CH2:30]([C:6]([CH2:5][CH2:4][CH2:3][C:2]([F:21])([F:1])[C:17]([F:18])([F:19])[F:20])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:29][CH2:28][CH2:27][CH:26]=[CH2:25]
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (4.0 g, 12.5 mmol) in dimethyl sulfoxide (30 ml) was cooled to 10° C. To this solution, 60% sodium hydride (600 mg, 15 mmol) was added, and the resulting mixture was stirred for 1 hour at room temperature. 6-Bromo-1-hexene (2.5 ml, 18.75 mmol) was slowly added dropwise to the reaction mixture, followed by stirring for 3 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to give diethyl 2-(5-hexenyl)-2-(4,4,5,5,5-pentafluoropentyl)malonate (3.86 g, Yield 77%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[N:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]3[N:27]=[C:28]([NH2:30])[N:29]=[C:22]23)=[CH:17][C:16]=1[C:31]([F:34])([F:33])[F:32]>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]3[N:27]=[C:28]([NH:30][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[O:6][C:2]([CH3:1])=[N:3][N:4]=5)[CH2:8][CH2:9]4)[N:29]=[C:22]23)=[CH:17][C:16]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Nc1nc2n(n1)CCCC2c1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1nnc(N2CCC(=O)CC2)o1
Product: Cc1nnc(N2CCC(Nc3nc4n(n3)CCCC4c3ccc(F)c(C(F)(F)F)c3)CC2)o1

Procedure:
Prepared in analogy to example 1h employing 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-one (see example 25b) and 8-(4-fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 1d-g). The title compound was obtained as brown solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:2]
Reactant: COC(=O)c1cccc(CC#N)c1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CCOCC2)c1
Yield: 46.5 %

Procedure:
Using methyl 3-(cyanomethyl)benzoate (1.0 g, 5.7 mmol), sodium hydride (60% in oil, 0.69 g, 17 mmol), bis(2-bromoethyl)ether (1.8 g, 6.9 mmol) and dimethyl sulfoxide (12 mL) as starting materials and in the same manner as in Reference Example 31, the title compound (650 mg, 46%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH3:45])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH3:45])[CH:43]=[N:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.30 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.17 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 0.5 hour at −78° C. and to the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4→1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 131) (204 mg) as yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C=CC=CC=1.Cl>O1CCCC1>[C:4]1([CH:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(O)c1ccccc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Under an atmosphere of nitrogen, 1.80 ml of a 0.99 M solution of acetophenone in tetrahydrofuran was added to the solution of reagent (A), obtained in Example 1, and the mixture stirred at 30° C. for 24 hours. The reaction mixture was poured into a mixture of 15 ml of benzene and 10 ml of 2 M hydrochloric acid, extracted with benzene, and the extract was washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by distillation in vacuo (130°-135° C./25 mmHg) to give 185 mg of 1-phenylethanol, and an additional purification was carried out by a fractional gas chromatography to give 1-phenylethanol having the following optical rotation:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Fc1ccc(OCCBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Fc1ccc(OCCN2CCNCC2)c(F)c1
Yield: 73 %

Procedure:
A mixture of piperazine (8.7 g, 101.26 mmol) in butanone (70 ml), 4-(2-bromo-ethoxy)-1,3-difluoro benzene (6.0 g, 25.31 mmol), anhydrous K2CO3 (3.5 g, 25.31 mmol) and KI (4.2 g, 25.31 mmol) was refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in CH2Cl2 (200 ml) and washed with water (50 ml). Drying and removal of the solvent followed by chromatography (CH2Cl2:CH3OH:NH4OH 10:1) afforded desired product in 73% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:5][C:4]=1[CH3:27].[NH3:28]>>[CH3:27][C:4]1[N:5]=[CH:6][N:7]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH2:2][NH2:28]
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CCl
Reactant: N
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CN
Yield: 26.4 %

Procedure:
A solution of 5-(chloromethyl)-4-methyl-1-trityl-1H-imidazole (1.00 g, 2.68 mmol) in ammonia (7 N in CH3OH, 4 mL, 28 mmol) was heated to 50° C. in a sealed tube for 16 h. The reaction mixture was concentrated under reduced pressure and the crude material purified by column chromatography (silica gel, 100% CH2Cl2 to 50% CH3OH) to provide (4-methyl-1-trityl-1H-imidazol-5-yl)methanamine (250 mg, 26%). 1H NMR consistent.
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)C.[Li+].[CH2:9]1[C:22]2[CH:13]([NH:14][CH:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH2:16]3)[CH2:12][CH2:11][CH2:10]1.C(N(C1CCCCC1)C#N)(C)(C)C>O1CCCC1>[C:1]([CH:12]1[C:13]2[C:22](=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[N:14]=2)[CH2:9][CH2:10][CH2:11]1)#[N:4]
Reactant: C1=CCC2NC3CCCCC3=CC2=C1
Reactant: CC(C)[N-]C(C)C
Agent: CC(C)(C)N(C#N)C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1CCCc2cc3c(nc21)CCCC3
Reaction time: 8 h

Procedure:
A solution of lithium diisopropylamide [ex 1.55M BuLi/hexane (32.3 ml, 50 mM), diisopropylamine (3.5 ml, 25 mM), tetrahydrofuran (20 ml)] maintained at 0° C. under an argon atmosphere was treated with a solution of octahydroacridine (4.68 g, 25 mM) in the tetrahydrofuran (10 ml). After 0.5 hours a solution of N-t-butyl-N-cyclohexylcyanamide (4.6 g, 28 mM) in tetrahydrofuran (10 ml) was added and the mixture stirred overnight. The reaction was quenched with water, extracted with toluene and the organic phase washed with water, dried and evaporated. The residue, dissolved in ethyl acetate, was passed through a short silica column to yield the title compound. (3.8 g) mp. 88°-90° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1CC[CH2:22][CH2:21][N:20]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCC1CCN(C(OCC2C=CC=CC=2)=O)CC1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:19][CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(bromomethyl)-1-piperidinecarboxylate.