Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][N:28]=1)[CH3:26])(=O)=O>O1CCCC1.CS(C)=O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=3)[CH3:26])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(C)OS(C)(=O)=O)nc1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4′-(trifluoromethyl)biphenyl-4-ol (263 mg, 1.1 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (44.2 mg, 60 wt % in mineral oil, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. A solution of the crude methyl 6-(1-(methylsulfonyloxy)ethyl)nicotinate prepared above in DMSO (6 mL) was added. The mixture was heated to 60° C. for 48 hours. The mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(1-(4′-(trifluoromethyl) biphenyl-4-yloxy)ethyl)nicotinic acid (60 mg). 1H NMR (400 MHz, CD3OD, 5): 8.98 (m, 1H), 8.19-8.21 (m, 1H), 7.54-7.61 (m, 4H), 7.42-7.44 (m, 3H), 6.86-6.89 (m, 1H), 5.42-4.43 (q, 1H), 1.58 (d, 9H).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:9]3[N:44]=[C:42]([NH:41][C:31]4[CH:32]=[CH:33][C:34]([N:35]5[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]5)=[C:29]([O:28][CH3:27])[CH:30]=4)[N:43]=[CH:3][C:4]=3[CH2:5][CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: CN(C)C=C1CCCC(c2ccc(F)cc2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2ccc(F)cc2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(4-fluoro-phenyl)-cyclohexanone (143 mg, 0.53 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (195 mg, 0.53 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (71 mg, 31%). MS ISP (m/e): 430.5 [(M+H)+]. mp 191-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]1[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])=[CH:7]2.[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]1[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])=[C:7]2[F:34]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(=O)[nH]1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1[nH]c(=O)c2c(Cl)cccc2c1F
Temperature: 25 °C

Procedure:
A mixture of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate 79 (2.75 g, 6.1 mmol, 1.0 eq) and selectfluor (2.16 g, 6.1 mmol, 1.0 eq) in anhydrous acetonitrile (100 mL) was stirred at reflux under argon for 12 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and filtered through celite. The filtrate was washed with water, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate-hexanes) to afford the product (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-4-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate 80.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[CH2:22](O)[CH2:23][OH:24]>C1C=CC=CC=1>[CH2:22]1[CH2:23][O:24][CH:10]2[CH:11]([C@:12]3([CH2:14][CH2:15][C@H:16]4[C@@H:7]([CH2:6][CH2:5][CH:4]5[C@:17]4([CH3:20])[CH2:18][CH2:19][C@H:2]([OH:1])[CH2:3]5)[C@@H:8]3[CH2:9]2)[CH3:13])[O:21]1
Reactant: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: OCCO
Solvent: c1ccccc1
Product: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12

Procedure:
A solution of 10.0 g of 3β-hydroxyandrostan-17-one (Elisberg E. et al., J. Amer. Chem. Soc., 1952, 74, 2814) and 0.10 g of p-toluensolfonic acid in 50 ml of benzene and 10 ml of ethylene glycol was kept on standing at reflux temperature for 10 hrs (water was removed by azeotropic distillation). The mixture was pured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated to dryness under reduced pressure and the crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 9.0 g of 17-ethylenedioxy-androstan-3β-ol as a colourless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[Cl:31][C:32]1[C:33]([CH:42]=O)=[N:34][CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:31][C:32]1[C:33]([CH2:42][NH:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH:21]3[C:30]4[N:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:24][CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[N:34][CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=1
Reactant: O=Cc1ncc(C(F)(F)F)cc1Cl
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1cnc(CNCc2ccc(CN(Cc3nc4ccccc4[nH]3)C3CCCc4cccnc43)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.4 %

Procedure:
Using General Procedure B: To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (133 mg, 0.34 mmol) and 3-chloro-5-(trifluoromethyl)-pyridine-2-carboxaldehyde (66 mg, 0.32 mmol) in CH2Cl2 (5 mL) was added NaBH(OAc)3 (93 mg, 0.44 mmol) and the mixture was stirred at room temperature for 16 h. Purification of the crude material by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 75:1:1) afforded the desired amine (48 mg, 26%) as a yellow foam.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29]Br.[H-].[Na+]>O1CCCC1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]=[C:14]([C:22]4([C:23]([O:25][CH3:26])=[O:24])[CH2:29][CH2:28]4)[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2cc(OC3CCC4(CC3)OCCO4)nc(C(F)(F)F)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
Methyl [6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]acetate (0.46 g, 1.2 mmol) was dissolved in tetrahydrofuran (23 mL), then 1,2-dibromoethane (300 μL, 3.4 mmol) was added and the reaction mixture cooled to 0° C. NaH in mineral oil (136 mg, 3.4 mmol) was then added and the reaction mixture was heated to 67° C. for 18 h. LCMS showed 50% reaction. The reaction was quenched with saturated NH4Cl and was partitioned between EtOAc and water. The EtOAc extract was washed with brine, dried (Na2SO4), and stripped in vacuo. The ester was purified by automatic silica gel chromatography on a 40 g silica gel column, using solvent A=hexane; solvent B=EtOAc; flow 40 mL/min; A, 2 min; Gradient to 30% B in 30 min; detector set at 254 nm; collected 47 mL fractions; retention time starting ester, 26 min; product, 19 min. The solvent was removed by rotary evaporation to give 0.17 g of product. 1H NMR (300 MHz, CDCl3) δ 7.35 (s, 1H); 5.30 (m, 1H); 3.97 (s, 4H); 3.74 (s, 3H); 1.8-2.0 (m, 6H); 1.6-1.8 (m, 6H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:15])([OH:14])[C:11]([CH2:16][CH:17]=[CH2:18])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:28][O:29][CH2:30]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:15])([O:14][CH2:28][O:29][CH3:30])[C:11]([CH2:16][CH:17]=[CH2:18])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)O
Reactant: COCCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)OCOC
Yield: 82 %

Procedure:
To a solution mixture of 4.7 g of (1RS,4RS)-3-allyl-4-methyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether, 6.8 g of N,N-diisopropylethylamine and 50 ml of chloroform was added 2.66 ml of chloromethyl methyl ether under ice-cooling and the resulting mixture was allowed to react at room temperature for 8 hours. Then the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted two times with diethyl ether. The combined ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 4.5 g of (1RS,4RS)-3-allyl-4-methyl-4-methoxymethoxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 82%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][C:15]3=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[O:23][CH2:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][C:15]3=[N:19][C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=3)[O:23][CH2:24][C:25]([O:27][CH:28]([CH3:29])[CH3:30])=[O:26])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Reactant: O=C1CCCc2ccc(-c3cccc(F)c3)cc21
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)COc1cccc(N=C2CCCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
Approximately forty oven dried 3 Å molecular sieves were added to a solution of 7-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one (174 mg, 0.724 mmol) and isopropyl 2-(3-aminophenoxyl)acetate (644 mg, 3.08 mmol) in toluene (15 mL) at 25° C. The reaction was heated in an 120° C. oil bath and allowed to stir overnight for approximately 16 hours. The reaction was cooled to room temperature and concentrated. The resulting crude residue was purified by combiflash (4 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 25 mg (4%) of isopropyl 2-(3-((7-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-ylidene)amino)phenoxy)acetate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=3)=[O:24])[CH:17]=2)([CH2:14][F:15])[N:13]=1)(C)(C)C>Cl.CO>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:17]=[C:18]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=3)=[O:24])[CH:19]=[CH:20][CH:21]=2)([CH2:14][F:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(CF)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1
Agent: Cl
Solvent: CO
Product: NC1=NC(CF)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1

Procedure:
A solution of (5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (48 mg, 0.095 mmol) in 2 ml of 3N HCl in MeOH was stirred at 40° C. for 2 h. The mixture was evaporated, and the residue was purified by chromatography on silica gel with a gradient of dichloromethane and 2-10% MeOH/NH4OH (0.5%), yielding the title compound in the form of a colorless foam. TLC (dichloromethane/MeOH/25% aqueous NH4OH=90:9:1): Rf=0.28; HPLC: RtH1=2.755 min; 1H-NMR (400 MHz, CDCl3): 8.58 (d, 1H), 8.10 (d, 1H), 7.96 (dd, 1H), 7.76 (s, 1H), 7.71 (d, 1H), 7.31 (t, 1H), 7.21 (d, 1H), 4.55-4.33 (m, 2H), 4.13-3.95 (m, 3H), 3.65 (d, 1H), 4.0-3.3 (br, NH2); MS: 407, 409 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CCN(C(C)C)C(C)C.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:43][CH2:42][C:31]3[N:32]=[CH:33][N:34]=[C:35]([O:36][C@H:37]4[CH2:41][CH2:40][NH:39][CH2:38]4)[C:30]=3[CH2:29]2)=[CH:24][C:23]=1[CH3:44]>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]([C:8]([N:39]2[CH2:40][CH2:41][C@H:37]([O:36][C:35]3[C:30]4[CH2:29][N:28]([C:25]5[CH:26]=[N:27][C:22]([O:21][CH3:20])=[C:23]([CH3:44])[CH:24]=5)[CH2:43][CH2:42][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38]2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C
Reactant: Cc1nc(C)c(C(=O)O)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)c5oc(C)nc5C)C4)c3C2)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
A mixture of 2,4-dimethyl-oxazole-5-carboxylic acid (36.4 mg, 0.258 mmol), HTBU (98 mg, 0.258 mmol), DIPEA (86p1, 0.49 mmol) in DMF (5 mL) was stirred at rt for 20 min. then a solution of 6-(6-methoxy-5-methyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared in example 1, method 1b, step 2) (80 mg, 0.23 mmol) and DIPEA (86 μl, 0.49 mmol) in DMF (0.4 mL) was added. The reaction mixture was stirred 30 min at rt. The reaction mixture was directly purified by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions over PL-HCO3 MP gave (2,4-dimethyl-oxazol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone (91 mg, 84% yield) as a white lyophilized powder. 1H-NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.27-2.52 (m, 8H) 2.95-3.03 (m, 2H) 3.44-3.55 (m, 2H) 3.70-4.26 (m, 9H) 5.76-5.92 (m, 1H) 7.40 (br. s., 1H) 7.64 (br. s., 1H) 8.55-8.62 (m, 1H), LCMS: [M+H]+=465.2, Rt(1)=1.51 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]Cl.C(=O)=O.CC(C)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:11])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: ON=Cc1ccc(F)cc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: ON=C(Cl)c1ccc(F)cc1
Reaction time: 1 h
Yield: 48.1 %

Procedure:
A solution of 25 g of 4-fluorobenzaldoxime in 200 ml of chloroform was cooled to 0° to -10°. From a pressure bottle, 14.2 g of chlorine was run into a flask cooled by dry ice-acetone and allowed to distill into the aldoxime solution, the solution being maintained at 0° ± 5°. The reaction mixture was stirred for one hour in an ice bath while nitrogen was bubbled through the solution. The chloroform was evaporated to leave an oil to which hexane was added quickly. The solid which separated was recrystallized from hexane to give 15.0 g of 4-fluorobenzohydroximoyl chloride, m.p. 74.5°-75°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[C:3]([CH3:17])=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Cc1c(Br)c(C)c(OC(C)C)c2c1CC(C)O2
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(c3c(C)c4c(c(OC(C)C)c3C)OC(C)C4)CC2)cc1
Yield: 33.6 %

Procedure:
By using 5-bromo-2,4,6-trimethyl-7-(1-methylethoxy)-2,3-dihydro-1-benzofuran (598 mg, 2.0 mmol) synthesized in Reference example 85 and 1-(4-methoxyphenyl)piperazine (768 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 276 mg (yield 34%). Melting point was 110 to 112° C. (ethanol-water).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]C#N)=[CH:6][C:5]([CH2:11][C:12]2[S:13][C:14]3[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:15]=3[N:16]=2)=[C:4]([CH3:24])[N:3]=1.O.[C:26]([O-:29])(O)=[O:27].[Na+]>Cl>[CH3:1][C:2]1[C:7]([CH2:8][C:26]([OH:29])=[O:27])=[CH:6][C:5]([CH2:11][C:12]2[S:13][C:14]3[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:15]=3[N:16]=2)=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1nc(C)c(Cc2nc3c(F)c(F)cc(F)c3s2)cc1CC#N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1nc(C)c(Cc2nc3c(F)c(F)cc(F)c3s2)cc1CC(=O)O
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 2,6-dimethyl-5-(4,5,7-trifluorobenzothiazole-2-yl-methyl)-pyridin-3-yl-acetonitrile (0.50 g, 1.43 mmol) in 50% hydrochloric acid (HCl) (8 ml, 0.2 M) under nitrogen is warmed (90° C. bath) and stirred overnight. The reaction mixture is added to H2O (20 mL) and brought to pH 5 with NaHCO3. The solids are filtered and the aqueous extracted with ethyl acetate (5×30 mL). The solid and extracts are combined and purified by reverse-phase HPLC (acetonitrile/water, 0.05% HCl)to give 2,6-Dimethyl-5-(4,5,7-trifluoro-benzothiazole-2-ylmethyl)-pyridin-3-yl-acetic acid as a white solid (0.40 g, 75%): mp 211° C. dec 1H NMR (DMSO-d6, 300 MHz) δ 8.29 (s, 1 H), 7.85-7.74 (m, 1 H), 4.80 (s, 2 H), 3.86 (s, 2 H), 2.73 (s, 3 H), 2.67 (s, 3 H), ESI-LCMS m/z calcd for C17H13F3N2O2S: 366.1; found 367.0 (M+1)+. Anal. Calcd for C17H14ClF3N2O2S: C, 50.69; H, 3.50; N, 6.95; Cl, 8.80; S; 7.96. Found: C, 50.48; H, 3.63; N, 6.89; Cl, 8.97; S, 7.84.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[CH:33]=[CH:34][C:28]=3[F:27])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 25.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 2-fluoro-5-(trifluoromethyl)aniline (0.069 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.035 g of desired product. 1HNMR (DMSO-d6): δ 4.06 (s, 3H), 7.59 (d, J=7.8 Hz, 1H), 7.77-7.68 (m, 5H), 7.84 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 8.67 (d, J=6.9 Hz, 1H), 10.38 (s, 1H), 12.79 (br s, 1H); MS (m/z): 540.92 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:21][CH:17]4[CH2:18][CH:19]([CH2:20]2)[C:15]([NH2:22])([CH2:16]4)[CH2:14]3)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[C:39]#[N:40])=[O:33]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:21][CH:17]4[CH2:16][C:15]([NH:22][CH2:31][C:32]([N:34]5[CH2:38][CH2:37][CH2:36][C@H:35]5[C:39]#[N:40])=[O:33])([CH2:14]2)[CH:19]([CH2:18]4)[CH2:20]3)=[CH:11][CH:12]=1
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
To a stirred mixture of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.03,7]nonan-3-amine (0.4 g, 1.2 mmol) and K2CO3 (0.48 g, 3.6 mmol) in DMSO (4.8 mL) at ice bath temperature was added (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.25 g, 1.44 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.28 g) in 50% yield. M.R, 214-216° C. m/z (M+1) 469; IR cm−1 3436, 2932, 2240, 1658, 1517, 1414, 1308, 1137, 952, 740. 1H NMR (300 MHz, CD3OD) δ: 7.35 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.85 (t, J=5.4 Hz, 1H), 4.15-3.95 (m, 2H), 3.81-3.70 (m, 3H), 3.60-3.50 (m, 1H), 3.42 (t, J=7.4 Hz, 2H), 2.65-2.45 (m, 4H), 2.40-1.75 (m, 14H).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[N:20]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH3:19][N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:33])=[O:5])=[C:8]([N:20]([CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])[CH:9]=2)[CH2:18][CH2:17]1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl ester (12.1 g, 25.7 mmol), trifluoroacetic acid (48.5 mL) and dichloromethane (195 mL) was stirred at room temperature for 2 hours. The volatiles were then evaporated, the residue taken up with diethylether and evaporated again. The procedure was repeated for 5 times, then the solid was triturated with diethylether, filtered and dried in oven at 40° C. affording the title compound as a pale brown solid (13.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([CH3:13])[C:11]#N)=[CH:4][CH:3]=1.[CH3:14][OH:15].Cl.C[OH:18]>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([CH3:13])[C:11]([O:15][CH3:14])=[O:18])=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)ccc1C(C)C#N
Reactant: CO
Agent: Cl
Product: COC(=O)C(C)c1ccc(Cl)nc1OC
Yield: 67 %

Procedure:
To a stirred solution of 2-(6-Chloro-2-methoxypyridin-3-yl)propanenitrile (1850 g, 9439 mmol) in MeOH (20 L) was added MeOH/HCl (about 2 M) at r.t. After the addition, the resulting mixture was heated at reflux for 12 hours. The reaction mixture was evaporated to move most of MeOH, and the residue was diluted with H2O (6 L) and basified to pH=9˜10 with solid NaHCO3. The aqueous layer was extracted with CH2Cl2 (15 L). The organic layer was washed with water (10 L) and brine (10 L), dried over Na2SO4 and concentrated to dryness. The crude residue was purified by column chromatography (petroleum ether/EtOAc=100:0˜80:20) to afford methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (1450 g, 67%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.44 (d, 3H), 3.67 (s, 3H), 3.91 (q, 1H), 3.95 (s, 3H), 6.89 (d, 1H), 7.45 (d, 1H).