Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][S:8](=[O:11])(=O)[O-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C1(C)C=CC=CC=1>[C:1]1([NH:7][S:8]([Cl:14])(=[O:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)([O-])Nc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)Nc1ccccc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A suspension of sodium phenylsulfamate (200 mg, prepared according to the procedure of Audrieth and Sveda, J. Org. Chem., 1944, 9, 89) in dry toluene (5 mL), under a blanket of nitrogen, was treated with PCl5 (267 mg). After stirring at 80° C. for 20 hours the reaction mixture was allowed to cool to room temperature and then evaporated to give the title compound (100 mg) as a brown oil, which was used without further purification.
Reaction SMILES: [I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([CH3:14])=[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:8]=[C:7]2SC.[I-].[CH3:24][C:25]1[S:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[N+:29]=1[CH3:30].C(N(CC)CC)C>CN(C)C=O>[I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[N:8][C:7]2=[CH:24][C:25]1[S:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[N+:29]=1[CH3:30]
Reactant: Cc1sc2ccccc2[n+]1C
Reactant: COc1ccc2c(c1)c(SC)nc(-c1ccccc1)[n+]2C
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(=Cc1sc3ccccc3[n+]1C)N=C(c1ccccc1)N2C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
600 mg (1.41 mmol) 6-Methoxy-1-methyl-4-methylsulfanyl-2-phenyl-quinazolin-1-ium iodide and 412 mg (1.41 mmol) 2,3-dimethyl-benzothiazol-3-ium iodide were dissolved in 2.0 ml dimethylformamide and 571 mg (0.79 ml, 5.64 mmol) triethylamine were added. The solution was stirred for 1 h at 80° C., filtrated and the residue was washed with water and methanol.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[C:9]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[N:8]=3)[CH:6]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
5-{1-[4-Trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.68) (0.73 g, 1.5 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.62 g, 1.8 mmol) according to the general procedure VI. Obtained as a light brown solid (0.43 g), which was subsequently deprotected.
Reaction SMILES: [CH2:1]([C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:35]=[CH:34][C:14]2[C:15](=[O:33])[CH2:16][C:17]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[O:18][C:13]=2[C:12]=1[CH2:36][CH2:37][CH3:38])[CH2:2][CH3:3].ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>>[CH2:1]([C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:35]=[CH:34][C:14]2[C:15](=[O:33])[CH2:16][C:17]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[O:18][C:13]=2[C:12]=1[CH2:36][CH2:37][CH3:38])[CH2:2][CH3:3]
Reactant: CCCc1ccccc1OCCCOc1ccc2c(c1CCC)OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Product: CCCc1ccccc1OCCCOc1ccc2c(c1CCC)OC(CCC(=O)O)(CCC(=O)O)CC2=O

Procedure:
The title compound was prepared by the method of Example 22 substituting the title product of Example 40 (446 mg) for the title product of Example 21. Crystallization from ethyl acetate/hexane produced 252 mg as a solid, m.p. 163°-165° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:18])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([N:12](S(O)(=O)=O)[NH2:13])[C:5]=2[O:4]1>C(O)C>[CH3:2][C:3]1([CH3:18])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][NH2:13])[C:5]=2[O:4]1
Reactant: CC1(C)Cc2cccc(N(N)S(=O)(=O)O)c2O1
Agent: Cl
Solvent: CCO
Product: CC1(C)Cc2cccc(NN)c2O1
Reaction time: 3 h

Procedure:
18 g of hydrogen chloride was introduced into a stirred slurry of 56 g of (1B) in 250 ml of ethanol. The resulting mixture was stirred for 3 hours, and the solvent was evaporated. The residue was dissolved in 50 ml of water, the solution was made basic with aqueous sodium hydroxide, and extracted with ether. The extract was washed with cold water, dried (MgSO4), and filtered, and the solvent was evaporated to give 2,3-dihydro-2,2-dimethyl-7-hydrazinobenzofuran (1C) as a dark oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[NH:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]1=O>COCCOC>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: O=c1cccc[nH]1
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccccn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 2-pyridone, using dry DME as reaction solvent: MS (APCI) m/z 390 (M+1).
Reaction SMILES: [CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N)CC1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[CH:1]1([C@H:7]2[C@@H:16]3[CH2:17][CH2:18][CH2:19][O:20][C@@H:15]3[C:14]3[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Agent: NC1CC1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc2c(c1)[C@H]1OCCC[C@H]1[C@H](C1CCCCC1)N2
Reaction time: 8 h
Yield: 19.8 %

Procedure:
To a stirred solution of (4aSR*,5SR*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline-9-carboxylic acid (50 mg, 0.16 mmol, 1 equiv.) in dry CH2Cl2 (1.6 mL) under argon atmosphere at 0° C. was added cyclopropanamine (12.1 μL, 0.17 mmol, 1.1 equiv.) followed by DIPEA (41 μL, 0.24 mmol, 1.5 equiv.) and EDC (33.5 mg, 0.17 mmol, 1.1 equiv). The reaction mixture was allowed to reach r.t. and stirred overnight. The solvent was removed under reduced pressure and the residue directly purified by Combiflash chromatography (SiO2, c-Hexane/AcOEt) to afford (4aS,5S,10bS)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline-9-carboxylic acid (10 mg, 17%). The compound was prepared as hydrochloride salt following the method described in example 1.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[C:4]([CH3:17])=[N:3]1.[H][H]>[Ni].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]2=[O:7])=[CH:13][CH:12]=1
Reactant: Cc1nn(C)c(=O)n1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1nn(C)c(=O)n1-c1ccc(N)cc1
Yield: 95 %

Procedure:
A mixture of 9 parts of 2,4-dihydro-2,5-dimethyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 7.5 parts (95%) of 4-(4-aminophenyl)-2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazol-3-one; mp. 160° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:33])([CH3:32])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1.CO.[Li+].[OH-].O>C1COCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:20]3[C:11](=[CH:12][C:13]4[C:18]([CH:19]=3)=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:16]=[CH:15][CH:14]=4)[C:10]([CH3:33])([CH3:32])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2cccc3cc4c(cc23)C(c2ccc(C)s2)=CCC4(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc4cccc(-c5ccc(C(=O)O)cc5)c4cc32)s1
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 4-[1-(5-methyl-thien-2-yl)-3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoate (Compound 3, 33 mg, 0.07 mmol), in THF (2 mL), MeOH (2 mL), was added aqueous LiOH (1M solution, 0.2 mL, 0.2 mmol). After 16 hours, water (2 mL) was added to the reaction mixture, about 50% of the organic solvents were removed by distillation, and the mixture was further diluted the mixture with water (5 mL). The reaction mixture was washed with ether (10 mL) and the aqueous layer was acidified to pH 4 and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed water (5 mL), brine (10 mL), dried with MgSO4 and the solvent was removed by distillation. The product was recrystallized from acetone to obtain the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:20]([C:19]3[CH:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:18]=3[F:17])=[O:21])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1c(-c2ccc(N)cc2)csc1N
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1c(-c2ccc(NC(=O)c3cc(C(F)(F)F)ccc3F)cc2)csc1N
Temperature: 25 °C

Procedure:
Crude 2-amino-4-(4-amino-phenyl)-thiophene-3-carboxylic acid amide (0.15 mmoles, 1 eq) is dissolved in 1 mL DMF and added to a solution of 2-fluoro-5-trifluoromethylbenzoic acid (0.20 mmoles, 1.3 equiv) and HBTU (0.20 mmoles, 1.3 equiv) in 1 mL DMF. To this solution is added 0.5 mL triethylamine. The solution is stirred at room temperature until the reaction is complete, as judged by TLC. The crude reaction mixture is purified by preparative HPLC, affording the desired 2-amino-4-{4-[(1-[2-fluoro-5-trifluoromethyl-phenyl]-methanoyl)-amino]-phenyl}-thiophene-3-carboxylic acid amide. Biological Data
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16].[CH2:17]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13].[CH2:17]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: CC[Mg]Br
Solvent: CCCCOCCCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 25 °C

Procedure:
Air inside the reaction vessel as in Example 1 was replaced with a nitrogen gas in a satisfactory manner. Then, 180 ml of dibutyl ether solution containing 0.354 mol of ethyl magnesium bromide as hydrocarbon magnesium halide was charged to the reaction vessel. Further, 0.365 mol of bromopentafluorobenzene was charged to the dropping funnel as fluoroarylhalide. Next, after dropping the bromopentafluorobenzene in the dropping funnel over 120 minutes at 25° C., the content of the reaction vessel was stirred for thirty minutes at 25° C., thereby obtaining pentafluorophenyl magnesium bromide as the fluoroaryl magnesium halide, obtained as a colorless dibutyl ether solution.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]([OH:5])[CH3:4].[O-:12][C:13]#[N:14].[K+]>O>[OH:5][CH:3]([CH3:4])[C@@H:2]([NH:1][C:13]([NH2:14])=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(O)[C@@H](N)c1ccccc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: CC(O)[C@@H](NC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S)-1-amino-1-phenylpropan-2-ol (0.43 g, 2 mmol) in H2O (2 mL) was added potassium cyanate (0.23 g, 2.7 mmol) and the contents were stirred at ambient temperature for 2 hr. The solid thus obtained was filtered and washed successively with H2O (2×5 mL) and dried in air to afford 1-((1S)-2-hydroxy-1-phenylpropyl)urea. MS: [M+H]+ m/z 195.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[CH2:11])[C:9]2[C:4](=[C:5]([N+:12]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15]>C1COCC1.[Pd]>[NH2:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3](=[O:15])[N:2]([CH3:1])[CH:10]2[CH3:11]
Reactant: C=C1c2cccc([N+](=O)[O-])c2C(=O)N1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1c2cccc(N)c2C(=O)N1C

Procedure:
2-methyl-3-methylene-7-nitro-2,3-dihydro-isoindol-1-one (13.96 g) is suspended in THF and mixed with a spatula tip of Pd/C (5%) and hydrogenated under H2 pressure (3 bar). For working up the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12])=[O:6])(=O)C>ClCCl.C(Cl)(=O)[O-]>[O:33]=[S:30]1(=[O:34])[CH2:31][CH2:32][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:5]([O:7][CH2:8][O:9][C:10]([CH:11]4[CH2:23][CH2:22][CH2:21][CH2:26][CH2:12]4)=[O:13])=[O:6])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Agent: O=C([O-])Cl
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)OCOC(=O)C1CCCCC1
Yield: 80 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (589.0 mg, 1.72 mmol) in dichloromethane (14 mL) and cyclohexanecarbonoylmethyl carbonochloridate (7j) gave the titled product in 80% yield (722.9 mg, 1.37 mmol). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H), 7.23 (t, 1H), 7.16 (dd, 1H), 5.72 (q, 2H), 5.29 (t, 1H), 4.76-4.82 (m, 1H), 4.05 (t, 1H), 3.78 (dd, 1H), 3.64-3.70 (m, 1H 3.57 (dt, 1H), 3.13-3.19 (m, 4H), 3.09 (dt, 1H), 2.29-2.46 (m, 4H), 2.16-2.22 (m, 2H), 1.58-1.98 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2([OH:10])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of 4-fluorophenylmagnesium bromide (1M in THF, 11 mL, 11 mmol) was added gradually to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.85 g, 10 mmol) in diethyl ether (40 mL) during 5 min at ambient temperature. The mixture was stirred for 30 min and thereafter slowly quenched with NH3Cl (10 mL, 3M). The organic phase was isolated and evaporated. The residue was purified by flash chromatography (SiO2 2:1 heptane/EtOAc) to afford the title compound, which was used without further purification. MS (EI) 208 (M-tBuO)
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:18][CH2:19]2)=[CH:24]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cc1ccn2c(=O)c(CCCl)c(C)nc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cc1ccn2c(=O)c(CCN3CCC(c4c[nH]c5ccccc45)CC3)c(C)nc2c1

Procedure:
A mixture of 3.8 parts of 3-(2-chloroethyl)-2,8-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 3 parts of 3-(4-piperidinyl)-1H-indole, 10 parts of sodium carbonate, 0.1 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed for 20 hours. The reaction mixture is filtered hot over Hyflo and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanol, 2,2'-oxybispropane and 4-methyl-2-pentanone, yielding 4.7 parts of 3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,8-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 235.9° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=2)=[C:16]([F:29])[CH:15]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C>[F:29][C:16]1[CH:15]=[C:14]([CH2:12][N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)[CH:28]=[CH:27][C:17]=1[O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2F)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: N#Cc1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2F)nc1
Yield: 74.9 %

Procedure:
Using a method similar to Example 365 step 2, using 3-phenyl-pyrolidine (0.169 g, 1.15 mmol), 6-(4-formyl-2-fluoro-phenoxy)-nicotinonitrile (compound of example 375 step 1), (0.200 g, 0.826 mmol), sodium triacetoxyborohydride (0.262 g, 1.24 mmol), and acetic acid (0.071 mL, 1.24 mmol) in 1,2-dichloroethane (8.0 mL), after silica gel chromatography (3:1 hexanes:ethyl acetate), provides 0.231 g (75%) of the title compound as a clear syrup: mass spectrum (electrospray): m/z=374.2 (M+1); 1H NMR (CDCl3): 8.40 (d, 1H, J=2.9 Hz), 7.91 (dd, 1H, J=2.4, 8.3 Hz), 7.30-7.24 (m, 2H), 7.24-7.21 (m, 3H), 7.20-7.09 (m, 3H), 7.06 (d, 1H, J=8.8 Hz), 3.70-3.61 (m, 2H), 3.40-3.31 (m, 1H), 3.01 (t, 1H, J=8.8 Hz), 2.84-2.77 (m, 1H), 2.75-2.67 (m, 1H), 2.53 (dd, 1H, J=7.8, 9.3 Hz), 2.39-2.28 (m, 1H), 1.95-1.84 (m, 1H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23](OC)=[O:24])[N:18]=2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH:23]=[O:24])[N:18]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1nccc(-c2ccc(F)cc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1nccc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
DIBAL-H (3.62 mL, 3.62 mmol, 1.0 M in toluene) was slowly added to a suspension of Example 32A (700 mg, 3.01 mmol) in toluene (30 mL) at −75° C. After 2 hours, DIBAL-H (1.507 mL, 1.507 mmol, 1.0 M in toluene) was added to the reaction mixture and warmed slowly to ambient temperature overnight. The reaction was a clear orange-red solution and the methyl ester was consumed, yielding a mixture of aldehyde and alcohol. Additional DIBAL-H (1.507 mL, 1.507 mmol, 1.0 M in toluene) was added at ambient temperature. After 4 hours, the reaction was quenched with 5% acetic acid in water (200 mL), extracted twice with EtOAc (200 mL), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 12 g column, eluted with 0-60% EtOAc in dichloromethane (25 mL/min) to provide the title compound (62 mg, 0.307 mmol, 10.17% yield) as an off-white solid. MS (ESI+) m/z 234.8 (M+H-MeOH); 1H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.12 (d, J=5.3, 1H), 8.38 (dd, J=9.0, 5.5, 2H), 8.32 (d, J=5.4, 1H), 7.45 (t, J=8.9, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]([NH2:15])=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: COc1ccccc1C1(C(N)=O)CCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2O)CCC1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To 1-(2-methoxyphenyl)cyclobutanecarboxamide (Example 268a, 4.19 g) at 0° C. in dichloromethane (20 mL) was added boron tribromide (40.8 mL, 1 M in dichloromethane) and the reaction warmed to room temperature over 3 h. It was poured into ice, extracted with dichloromethane (×3) and the combined organics were dried (MgSO4) and the solvent was removed in vacuo to give crude 1-(2-hydroxyphenyl)cyclobutanecarboxamide (2.96 g). This was dissolved in DMF (20 mL) and potassium carbonate (2.14 g) and benzyl bromide (1.84 mL) were added and the reaction stirred for 16 h. Water and ethyl acetate were added and the organic layer separated. The aqueous layer was extracted further with ethyl acetate. The combined organics were washed with water (×3), brine, dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified (SiO2 chromatography eluting with 5-50% ethyl acetate in iso-hexane) to afford the subtitle product (1.98 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[F:19][C:20]([F:43])([F:42])[O:21][C:22]1[CH:23]=[C:24]([CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=2)[C:29]#[N:30])[CH:25]=[CH:26][CH:27]=1.[F:44][C:45]([F:50])([F:49])[C@@H:46]1[CH2:48][O:47]1>C1COCC1.O>[F:44][C:45]([F:50])([F:49])[C@@H:46]([OH:47])[CH2:48][C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:42])([F:43])[F:19])[CH:23]=1)[C:29]#[N:30]
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: N#CC(C[C@H](O)C(F)(F)F)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reaction time: 0.08 h
Yield: 34.8 %

Procedure:
To a solution of diisopropyl amine (0.305 mL, 2.16 mmol) in THF (6 mL) at −78° C. was added dropwise a 1.6 M solution of n-BuLi in hexane (1.35 mL, 2.16 mmol) and the mixture was stirred for 5 min. To this mixture was added a solution of 2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile (600 mg, 1.7 mmol), prepared as described in Example 10 (Procedure 13 and 14). The reaction mixture was stirred at −78° C. for 1 h and then (S)-2-(trifluoromethyl)oxirane (2.8 g, 25.0 mmol, 70% ee, purchased from TCI America) was added dropwise to the mixture. The cooling bath was removed and the reaction mixture was stirred at rt for 1 h. Additional (S)-2-(trifluoromethyl)oxirane (0.12 g, 1.1 mmol, 70% ee, purchased from TCI America) was added and the reaction mixture was stirred for an additional 1 h then poured into H2O and extracted with EtOAc (50 mL). The combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (RT=23.65 min, YMC Sunfire 5μ column, 30×100 mm eluting with 20-100% MeOH/H2O over 25 minutes containing 0.1% TFA; 30 mL/min, monitoring at 220 nm) to give (S)-5,5,5-trifluoro-4-hydroxy-2,2-bis(3-(trifluoromethoxy)phenyl)pentanenitrile (280 mg, 36% yield, 70% ee) as a clear colorless oil. LCMS: RT=3.898 min [M+H] 474.0 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 10 mM NH4OAc; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1 H(CDCl3) ppm 2.55-2.64 (m, 1 H) 2.66-2.78 (m, 2 H) 3.87-3.95 (m, 1 H) 7.10-7.21 (m, 4 H) 7.23-7.27 (m, 1 H) 7.30-7.42 (m, 3 H).