Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.[Cl:7][C:8]1[CH:9]=[C:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(OCC)(=[O:27])C>>[Cl:7][C:8]1[CH:9]=[C:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C:17]2=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(-n2ccc3ccccc32)cc1Cl
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(N2C(=O)Cc3ccccc32)cc1Cl

Procedure:
Using 3:2 hexane:ethyl acetate as eluant on chromatography, the procedure of the preceding preparation was used to convert 1-(3-chloro-4-methoxyphenyl)indole (0.93 g) to present title product, 0.71 g, m.p. 165°-167°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([C:22]3([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:24][O:23]3)([F:21])[F:20])=[CH:17][CH:18]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:33]1[CH:37]=[N:36][N:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])([OH:23])[CH2:24][N:33]3[CH:37]=[N:36][N:35]=[N:34]3)=[N:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Fc1ccc(C2(C(F)(F)c3ccc(Oc4ncc(C(F)(F)F)cc4Cl)cn3)CO2)c(F)c1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of 3-chloro-2-((6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)oxy)-5-(trifluoromethyl)pyridine (U) (356 mg, 0.744 mmol) and 1H-tetrazole (62.5 mg, 0.892 mmol) in dry DMSO (3.718 mL) was added potassium carbonate (206 mg, 1.487 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at 60° C. overnight, cooled to RT and diluted with ice-cold water/2N HCl and DCM and the layers were separated on a Phase Separator. The aq. layer was extracted again with DCM and the combined organic extracts were evaporated. The crude residue was purified on silica (ISCO, 40 gram column, gradient to 40% EtOAc/Hexanes over 20 minutes) to afford the title compound. Yield=119 mg (27.7%) of a brown glass. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.27 (dd, J=2.1, 0.9 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.74-7.63 (m, 2H), 7.34 (td, J=8.9, 6.4 Hz, 1H), 7.21 (s, 1H), 6.83-6.72 (m, 1H), 6.72-6.64 (m, 1H), 5.64 (d, J=14.3 Hz, 1H), 5.13 (d, J=14.1 Hz, 1H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ −61.74 (s), −103.20 (d, J=15.0 Hz), −103.72-−104.09 (m), −107.86 (d, J=10.9 Hz), −110.78 (d, J=45.0 Hz), −111.48 (d, J=45.0 Hz). MS (ESI): m/z 549.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:23]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:21]=[C:20](F)[C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH:29]([O-:32])([CH3:31])[CH3:30].[Na+]>>[F:1][C:2]1[C:23]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:21]=[C:20]([O:32][CH:29]([CH3:31])[CH3:30])[C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1F
Reactant: CC(C)[O-]
Agent: [Na+]
Product: CC(C)Oc1ccc(S(C)(=O)=O)c(F)c1C(=O)N1CCN(c2ccc(C#N)cc2)CC1

Procedure:
The compound was prepared in analogy to example 359 from 4-[4-(2,6-difluoro-3-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile and sodium isopropanolate. MS (m/e): 446.0 (MH+, 49%)
Reaction SMILES: [CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28]([CH:33]=O)[CH:27]=[CH:26]3)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:12]([CH:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28]([CH2:33][N:6]2[CH2:5][CH2:4][C:3]([CH2:1][CH3:2])([C:9]([OH:11])=[O:10])[CH2:8][CH2:7]2)[CH:27]=[CH:26]3)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCC1(C(=O)O)CCNCC1
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.7 %

Procedure:
4-ethylpiperidine-4-carboxylic acid (0.184 g, 1.17 mmol) was combined with 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.3 g, 0.9 mmol), Acetic acid (0.19 mL, 3.4 mmol) in Methanol (1.9 mL, 48 mmol) and stirred for 30 min. The reaction was then cooled to 0° C. on an icebath and sodium cyanoborohydride (90.9 mg, 1.4 mmol) was added. The reaction was then allowed to warm to room temperature while stirring overnight. Reaction was then concentrated to about 4-5 mL then purified directly via reverse phase chromatography (5-95% CH3CN/Water (0.1% TFA), C18, 150 mm). The product was then lyophilized to dryness to give 7 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid as a white solid (2%). ESI-MS: 452 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.75-8.00 (m, 3H), 7.47-7.61 (m, 1H), 7.43 (s, 1H), 7.07-7.28 (m, 1H), 4.44 (m, 3H), 3.29-3.54 (m, 2H), 2.74-3.03 (m, 2H), 2.20 (s, 3H), 1.64-1.98 (m, 3H), 1.02-1.65 (m, 9H), 0.89 (s, 9H), 0.76-0.83 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Cl:13]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc2c1CCCC2=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Cl)c2c1CCCC2=O
Reaction time: 60 h

Procedure:
A solution of 5-amino-1-tetralone (Itoh, K. Chem. Pharm. Bull. (1984), 32, 130-151) (0.50 g, 3.1 mmol) in dimethylformamide (15 mL) was treated with N-chlorosuccinimide (0.49 g, 3.7 mmol), stirred for 60 hours, treated with water and extracted with ether (4×30 mL). The combined ether extracts were washed with brine, dried (Na2SO4) and concentrated. Purification of the residue on silica gel with ethyl acetate:hexanes 1:1 provided the desired product.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)[CH:17]=[CH:16]4)[CH:7]=2)=[O:24])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2ccc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(1-oxo-1,2-dihydroisoquinolin-6-yl)benzamide (Example 11) (1.0 g), potassium carbonate (1.3 g) and methyl 4-(bromomethyl)benzoate (0.86 g) in DMF (10 mL) was stirred at room temperature for 17 hours.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[S:16][C:11]2[CH2:12][O:13][CH:14]([CH3:15])[C:10]=2[C:9]=1[C:17](O)=[O:18])=[O:6].Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[S:16][C:11]2[CH2:12][O:13][CH:14]([CH3:15])[C:10]=2[C:9]=1[C:17]([N:32]1[CH2:33][C:30]([F:34])([F:29])[CH2:31]1)=[O:18])=[O:6]
Reactant: CC1OCc2sc(NC(=O)c3c(C(F)(F)F)ccc(Cl)c3F)c(C(=O)O)c21
Reactant: FC1(F)CNC1
Agent: Cl
Product: CC1OCc2sc(NC(=O)c3c(C(F)(F)F)ccc(Cl)c3F)c(C(=O)N3CC(F)(F)C3)c21

Procedure:
The title compound was prepared from the product of Example 50A and commercially available 3,3-difluoroazetidine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (d, J=6.4 Hz, 3H), 4.30-4.51 (m, 4H), 4.89-5.02 (m, 2H), 5.17-5.26 (m, 1H), 7.80 (d, J=8.5 Hz, 1H), 8.03 (dd, J=8.0, 8.0 Hz, 1H), 11.85 (br s, 1H). MS (ESI+) m/z 499 (M+H)+. Anal. calcd. for C19H13ClF6N2O3S: C, 45.75; H, 2.63; N, 5.62. Found: C, 46.17; H, 2.51; N, 5.33.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: CN1CCNCC1
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2nnc3ccc(F)cn23)CC1
Yield: 32.3 %

Procedure:
A solution of Intermediate 24b (451 mg, 2.50 mmol) and N-methyl-piperazine (1.11 mL, 10.0 mmol) in DMA (10 mL) was heated in the microwave at 170° C. for 8 h. The mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM, to give the title compound as an orange gum (190 mg, 32%). LCMS (Method 3): Rt 0.43 min, m/z 236 [MH+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.Cl[C:10]1[CH:15]=[C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:13]([N+:29]([O-:31])=[O:30])=[CH:12][N:11]=1>>[CH:26]([NH:25][C:23]([C@H:20]1[CH2:19][CH2:18][C@@H:17]([NH:16][C:14]2[C:13]([N+:29]([O-:31])=[O:30])=[CH:12][N:11]=[C:10]([O:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:15]=2)[CH2:22][CH2:21]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CN1CCC(O)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OC3CCN(C)CC3)ncc2[N+](=O)[O-])CC1

Procedure:
Intermediate cis-N-isopropyl-4-(2-(1-methylpiperidin-4-yloxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide was prepared from 1-methylpiperidin-4-ol using a procedure analogous to that used for cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (95 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10]Cl.[C-:12]#[N:13].[Na+]>C(O)C.O>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:10][C:12]#[N:13]
Reactant: ClCc1c(Cl)cc(Cl)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(Cl)cc(Cl)cc1Cl
Yield: 69.4 %

Procedure:
To a stirred solution of 1,3,5-trichloro-2-chloromethyl-benzene (12.85 g, 58.8 mmole) in ethanol (45 ml), NaCN (3.20, 67.0 mmole) solution in water (15 ml) was added at ambient temperature. The reaction mixture was refluxed for 4 hours to complete the reaction. Ethanol was evaporated and the reaction mixture was diluted with water (50 ml). The aqueous layer was extracted with EtOAc (3×100 ml). The combined organic layer was washed with brine (30 ml) and dried over sodium sulfate. Organic layer was concentrated under vacuum to give white solid. Crude product was purified by chromatography on silica-gel column to afford 9.0 g (75.0% of theory) of (2,4,6-trichloro-phenyl)-acetonitrile
Reaction SMILES: [CH2:1]([N:8]=[CH:9][C:10]1[S:18][C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:12]=2[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:21]1[CH:22]=[C:23]([CH:36]=[CH:37][C:38]=1OC)[CH2:24][N:25]=[CH:26]C1SC2N=CN=CC=2C=1>>[CH2:1]([N:8]1[C:9]([C:10]2[S:18][C:13]3[N:14]=[CH:15][N:16]=[CH:17][C:12]=3[CH:11]=2)=[C:24]([C:23]2[CH:36]=[CH:37][CH:38]=[CH:21][CH:22]=2)[N:25]=[CH:26]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Reactant: C(=NCc1ccccc1)c1cc2cncnc2s1
Product: c1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3cncnc3s2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Example 6 but using N-benzyl-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine (Intermediate 51) in place of N-(3,4Dimethoxybenzyl)-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine (intermediate 14). Pale yellow solid (26 mg, 26%);
Reaction SMILES: [Li+].[BH4-].[C:3]1([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:18][CH2:19]O)[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:21]>>[C:3]1([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH2:18][CH2:19][Br:21])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Br
Reactant: OCCC1CC(c2ccccc2)c2ccccc21
Agent: [BH4-]
Agent: [Li+]
Product: BrCCC1CC(c2ccccc2)c2ccccc21

Procedure:
Ethyl 3-phenylindan-1-acetate (84.3 g, 0.3 mol) in THF (300 ml) was added dropwise with stirring to LiAlH4 (10 g) in THF (200 ml) under N2 and the mixture stirred at 80° C. overnight. Processing by standard conditions yielded 2-(3-phenylindan-1-yl)ethanol as an oil (47.3 g), IR 3100-3600 cm-1 (OH). This alcohol could also obtained by reduction of the ester in THF using LiBH4. The alcohol (43.15 g, 0.18 mol) was refluxed overnight with 48% HBr (280 ml), cooled, extracted with ether which, with standard processing, gave 2-(3-phenylindan-1-yl) ethyl bromide (50.8 g) as an oil. This bromo-compound (41.8 g, 0.14 mol) in Me2CO (160 ml) was added to a solution of NaCN (7 g, 0.143 mol) in H2O (40 ml) and the solution stirred and refluxed for 64 hours. The solution was evaporated to dryness and the product extracted with a mixture of AcOEt and H2O. After drying (Na2SO4), filtration and evaporation 3-(3-phenylindan-1-yl)propionitrile (26.8 g) was obtained as a solid, IR 2250 cm-1 (CN). This nitrile (24.3 g, 0.1 mol) in hot EtOCH2CH2OH (100 ml) was treated with NaOH (24.3 g, 0.6 mol) in H2O (40 ml) and the solution refluxed for 6 hours. It was then poured into conc. HCl (50 ml) in H2O (250 ml), extracted with Et2O and the Et2O extracted with 2N NaOH. Acidification gave the title compound. NMR (CCl4)δ1.5-3.3 (7H, CH2), 4.12 (1H, CH), 6.8-7.3 (9H,Ar), 11.92 (1H, exchangeable). cl EXAMPLE 3
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([CH3:17])=[C:9]([C:13]([CH3:16])=[CH:14][CH:15]=1)[C:10](O)=[O:11])=[O:4].C(Cl)(=O)C(Cl)=O.[NH3:26]>C1COCC1>[F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([CH3:17])=[C:9]([C:13]([CH3:16])=[CH:14][CH:15]=1)[C:10]([NH2:26])=[O:11])=[O:4]
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(=O)O
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(N)=O

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 3-((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzoic acid (1.0 g), oxalyl chloride (1.0 mL), THF (50 mL) and ammonia gas to afford 0.800 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]([N:9]([CH3:24])[C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH3:27][NH:28][CH2:29][CH2:30][CH3:31]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7](=[O:8])[N:9]([CH3:24])[C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][N:28]([CH3:27])[CH2:29][CH2:30][CH3:31])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Reactant: CCCNC
Solvent: CC(=O)N(C)C
Product: CCCN(C)CC#C[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 235 mg (corresponds to 0.5 mmol) of trans-Methanesulfonic acid 3-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-prop-2-ynyl ester in 2.5 ml of DMA was cooled at 0° C., treated with 0.76 ml (1 mmol) of N-methylpropylamine and stirred over night at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 98:2) gave 153 mg (81%) of pure trans-Methyl-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cyclohexyl}-carbamic acid 4-chloro-phenyl ester, MS: 377 (MH+, 1Cl).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:5]=2[O:4]1.[F:22][C:23]([F:31])([F:30])[C:24]([F:29])([F:28])C([O-])=O.[K+].CN(C)C=O>[Cu]I.C1(C)C=CC=CC=1>[F:28][C:24]([F:29])([C:16]1[CH:17]=[CH:18][C:5]2[O:4][C:3]([CH2:20][F:21])([CH2:2][F:1])[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:6]=2[CH:15]=1)[C:23]([F:31])([F:30])[F:22]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: FCC1(CF)C=C(c2ccccn2)c2cc(I)ccc2O1
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: FCC1(CF)C=C(c2ccccn2)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Temperature: 160 °C
Yield: 79 %

Procedure:
A mixture of 1.11 g of 2,2-bisfluoromethyl-6-iodo-4-(2-pyridyl)-2H-1-benzopyran, 1.17 g of potassium pentafluoropropionate, 1.18 g of copper (I) iodide, 20 ml of N,N-dimethylformamide and 7.ml of toluene was stirred at 160° C. under nitrogen gas atmosphere with heating for 3 hours while toluene was distilled off. Ether and water were added thereto and the mixture was filtered using Celite. The mother liquor was extracted with ether. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.86 g of oily 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([OH:30])[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([OH:28])([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)[C:17]([F:20])([F:19])[F:18]>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([OH:28])([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)[C:17]([F:19])([F:18])[F:20])[O:30][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Product: CC(=O)OCCOc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-bromoethyl acetate and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=433.1 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]1[O:20][C:19]2[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][C:11]=2[O:10]1>ClCCl.C(N(CC)CC)C>[CH2:9]1[O:20][C:19]2[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH:16][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[CH:12][C:11]=2[O:10]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1ccc2c(c1)OCO2)c1ccco1

Procedure:
N-[2-(3,4-methylenedioxyphenyl)ethyl]furan-2-carboxamide was prepared by condensation of 2-furoyl chloride and 3,4-methylenedioxyphenethylamine in dichloromethane with triethylamine as catalyst.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][C:14]1[CH:15]=[C:16]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH2:13][C:14]3[CH:15]=[C:16]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(c1cccc(CN)c1)S(C)(=O)=O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CN(c1cccc(CNc2cccn3nc(Cl)nc23)c1)S(C)(=O)=O

Procedure:
169 d) N-{3-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (184.0 mg, 0.7915 mmol) and N-(3-aminomethyl-phenyl)-N-methyl-methanesulfonamide (188.0 mg, 0.8773 mmol) in a manner analogous to Example 2d. Product isolated as a yellow resin (0.082 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.89 (d, J=6.7 Hz, 1H), 7.42-7.36 (m, 2H), 7.33-7.29 (m, 2H), 6.85 (t, J=7.4 Hz, 1H), 6.39 (d, J=7.8 Hz, 1H), 5.43-5.38 (m, 1H), 4.49 (d, J=5.7 Hz, 2H), 3.32 (s, 3H), 2.83 (s, 3H). MS=366, 368 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH2:16][OH:17])[N:5]=[C:4]2[C:18]([CH3:21])=[N:19][O:20][C:3]=12>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH:16]=[O:17])[N:5]=[C:4]2[C:18]([CH3:21])=[N:19][O:20][C:3]=12
Reactant: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)nc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)nc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(7-Chloro-6-((2R,6S)-2,6-dimethylmorpholino)-3-methylisoxazolo[4,5-b]pyridin-5-yl)methanol (Intermediate 352, 459 mg, 1.47 mmol) was dissolved in about 10 ml CH2Cl2. Manganese dioxide (1920 mg, 22.08 mmol) was added, and the slurry was stirred at room temperature for three days. The mixture was filtered through celite and concentrated. The crude was purified by chromatography on SiO2 using 10-30% EtOAc/hexanes. Recovered a yellow solid, 185 mg (41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[N:46]1([C@H:51]2[CH2:55][CH2:54][NH:53][CH2:52]2)[CH:50]=[N:49][CH:48]=[N:47]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:53]3[CH2:54][CH2:55][C@H:51]([N:46]4[CH:50]=[N:49][CH:48]=[N:47]4)[CH2:52]3)=[O:28])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: c1ncn([C@H]2CCNC2)n1
Agent: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](n4cncn4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 150.2 %

Procedure:
Following a procedure similar to that described in Preparation 18(a), but using 768 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 218 mg of pivaloyl chloride and 238 mg of (3S)-3-(1,2,4-triazol-1-yl)pyrrolidine trifluoroacetate, 803 mg of the title compound were obtained as a powder.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:5][N:6](C(OC(C)(C)C)=O)[CH2:7][CH2:8][C:9]=2[N:10]=1.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>ClCCl>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[Br:1][C:2]1[S:3][C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
2-Bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (890 mg) was dissolved in dichloromethane (2 ml), and to the solution trifluoroacetic acid (15 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. Precipitated solid materials were collected by filtration to obtain the title compound (867 mg) as a colorless solid.