Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>>[OH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)[O:12][CH2:11][C:10]1([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=1)[CH3:15]
Reactant: C1CCOC1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCO)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
(3RS,4RS)-4-[4-(t-butyl dimethylsilyloxy)-1-butyl 3-(7-methoxymethoxy-3-(4-(methoxymethoxy)phenyl)-3-methylchroman (680 mg, 1.28 mmol) was dissolved in tetrahydrofuran (10 ml), and cooled to 0° C. To this solution was added tetrabutylammonium fluoride (2.6 ml, 2.56 mmol), and the reaction mixture was stirred at room temperature for 6 hours The solvent was removed by evaporation under vacuum, and the residue was dissolved in ethyl acetate, which was washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography on silica gel, eluting with 30% ethyl acetate in n-hexane to afford 487 mg of the title compound as a colorless oil. (yield: 92.4%)
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:12][CH2:13][CH2:14][Cl:15])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.CC1(C)C(C)(C)OB([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][N:31]3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:26][CH:25]=2)O1.[Cl-].[Li+].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:37]([O:36][C:34]([N:31]1[C:32]2[C:27](=[CH:26][CH:25]=[C:24]([C:2]3[S:3][C:4]([CH2:12][CH2:13][CH2:14][Cl:15])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=3)[CH:33]=2)[CH2:28][CH2:29][CH2:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)c1nc(Br)sc1CCCCl
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)sc1CCCCl
Temperature: 100 °C
Yield: 81.1 %

Procedure:
Ethyl 2-bromo-5-(3-chloropropyl)thiazole-4-carboxylate (23C) (0.790 g, 2.5 mmol) was dissolved in dioxane, the tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (23E) (0.910 g, 2.5 mmol) was added followed by lithium chloride (0.320 g, 7.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.290 g, 0.25 mmol), cesium carbonate (2.5 g, 7.6 mmol) and water. This was transferred to a sealed tube, the reaction was evacuated, flushed with nitrogen and heated at 100° C. overnight. The reaction was filtered through Celite, eluted with EtOAc, concentrated under reduced pressure, and dry loaded onto silica. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0 to 50% EtOAc in hexanes to provide 0.943 g (80%) of the desired product ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-chloropropyl)thiazole-4-carboxylate (23F): LC/MS (APCI): m/z 466.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Br-].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[Zn+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3[C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: [Zn+]c1cccs1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccs2)c1
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-t-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and 2-thienylzinc bromide (0.23 ml, 0.12 mmol). After stirring for 2 hours, the reaction was purified by silica gel chromatography, eluting with hexanes:ethyl acetate (3:1) to yield ethyl 2-(4-(4-((4-chlorophenethyl) carbamoyl)phenoxy)-3-(thiophen-2-yl)phenyl)acetate (20 mg, 83% yield) as a clear oil.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CCO>[CH2:1]([C:5]1[C:6]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 85.5 %

Procedure:
Ethyl ester 83 (0.30 g, 0.62 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.24 g (86%) of the title compound (84) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, J=7.3 Hz, 3H), 1.10-1.28 (m, 2H), 1.40-1.50 (m, 2H), 2.50-2.60 (m, 2H), 3.93 (s, 3H), 6.22 (d, J=16.0 Hz, 1H), 6.58 (d, J=8.6 Hz, 2H), 7.04 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.08-7.15 (m, 2H), 7.16 (d, J=2.4 Hz, 1H), 7.18-7.30 (m, 5H), 7.58 (s, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H). LCMS (ESI): m/z 453 (M+H)+, m/z 451 (M−H)−.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[F:20])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:5][CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=2[F:20])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:5][CH:4]=1)=[N+:22]=[N-:23]
Reactant: CN(C)C(=O)c1ccc(F)c(-c2ccc(CCl)nn2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(F)c(-c2ccc(CN=[N+]=[N-])nn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
3-(6-(Chloromethyl)pyridazin-3-yl)-4-fluoro-N,N-dimethylbenzamide (470 mg, 1.60 mmol) was treated with NaN3 (312 mg, 4.80 mmol) and DMF (5 mL) and stirred at RT for 15 h. The reaction mixture was extracted with EtOAc and the organic layer was washed with water and brine (2×30 mL), dried over MgSO4, filtered and concentrated. Purification of the crude material by silica gel chromatography (30-100% EtOAc in hexanes) afforded 3-(6-(azidomethyl)pyridazin-3-yl)-4-fluoro-N,N-dimethylbenzamide (341 mg, 1.14 mmol, 71.0% yield) as a clear colorless film. MS (ESI, pos. ion) m/z: 301.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (1 H, dd, J=7.3, 2.1 Hz), 8.02 (1 H, dd, J=8.8, 1.6 Hz), 7.57-7.69 (2 H, m), 7.22-7.31 (1 H, m), 4.81 (2 H, s), 3.08 (3 H, s), 3.13 (3 H, s). 19F NMR (376 MHz, CDCl3) δ ppm −115.30 (1F, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:37]1C=CC(O)=CC=1C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]2)=[C:15]([CH3:37])[CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(O)ccc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Product: Cc1cc(OCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC2CCCC2)ccc1B1OC(C)(C)C(C)(C)O1

Procedure:
Synthesised by analogous methods to Intermediate 2b, using 4-bromo-3-methyl-phenol at Stage 6 of Scheme 2. m/z 504 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:20]3[CH2:21][CH:22]([C:24]([O:26]CC)=O)[CH2:23][CH:12]2[CH2:13][C:14]2([CH2:19]3)[O:18][CH2:17][CH2:16][O:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:29][CH2:30][Mg+].[Br-]>CCOCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:23][CH:22]([C:24]4([OH:26])[CH2:30][CH2:29]4)[CH2:21][CH:20]2[CH2:19][C:14]2([CH2:13]3)[O:15][CH2:16][CH2:17][O:18]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC[Mg+]
Reactant: CCOC(=O)C1CC2CC3(CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1)OCCO3
Agent: [Br-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CC(C3(O)CC3)CC1CC1(C2)OCCO1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
Ethyl 9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane]-7-carboxylate (50) (395 mg, 0.918 mmol) was dissolved in Et2O (2 mL) and the resulting solution was cooled to −78° C. Ti(O-i-Pr)4 was added followed by EtMgBr dropwise over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 18 h. The resulting solution was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic phase was dried (Na2SO4), filtered, and concentrated to give 1-{9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolan]-7-yl}cyclopropanol (55). MS (ESI) 414.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:4]=[N:3]1.C(N(CC)CC)C.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>O1CCCC1>[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:8][NH:9]3)=[CH:14][CH:13]=2)=[CH:17][CH:18]=1)=[O:36]
Reactant: Cn1cc(-c2n[nH]c3cc(-c4ccc(CN)cc4)ccc23)cn1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cc(-c2n[nH]c3cc(-c4ccc(CNC(=O)c5cccc(F)c5)cc4)ccc23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 0° C. suspension of Example 31B (70 mg, 0.231 mmol) in tetrahydrofuran (15 ml) was treated with triethylamine (1.00 ml, 7.17 mmol) followed by 3-fluorobenzoyl chloride (0.014 ml, 0.115 mmol) added dropwise. The reaction was allowed to warm to room temperature slowly and after 2 hours was treated with an additional 14 uL acid chloride, stirred for 18 hours, then partitioned between brine and ethyl acetate. The organic extract was dried with MgSO4, concentrated and the residue was purified via by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H) 4.55 (d, J=5.95 Hz, 2 H) 7.35-7.81 (m, 10 H) 7.99 (s, 1 H) 8.06 (d, J=8.33 Hz, 1 H) 8.37 (s, 1 H) 9.19 (t, J=5.95 Hz, 1 H) 12.98 (s, 1 H). MS (ESI(+)) m/e 426 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:15]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]3[CH2:27][CH2:26][C:25](=O)[C:11]=3[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2].ClCCl.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[C:1]([O:4][CH2:5][C:6]1[N:15]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]3[CH2:27][CH2:26][CH:25]([NH:32][C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=4)[C:11]=3[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(=O)CC3
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OCc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
2-Acetoxymethyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione (0.140 g, 0.36 mmol) was suspended in anhydrous methanol (8 ml) and then anhydrous dichoromethane (4 ml) was added until a clear solution was obtained. Tert-butyl 4-aminobenzoate (0.084 g, 0.44 mmol) was then added followed by decaborane (0.014 g, 0.12 mmol). The reaction mixture was stirred overnight at room temperature under argon. The solvent was removed in vaciio, and the residue was purified by column chromatography on elution with 40% ethyl acetate in hexane. The product was obtained as a glass (0.127 g, 63%) 1H-NMR (CDCl3) 1.20 (s, 9H, POM C(CH3)3), 1.58 (s, 9H, CO2C(CH3)3), 2.20 (s, 3H, CH3CO), 2.02, 2.72 (2×m, 2H, 7-CH2), 3.13 (m, 2H, 8-CH2), 4.36 (d, J=7.7 Hz, 1H, NH), 5.15 (q, J=6.8 Hz, 1H, 6-H), 5.21 (s, 2H, 2-CH2), 6.12 (AB system, J=10.7 Hz, 2H, POM CH2), 6.67 (d, J=8.8 Hz, 2H, 3,5′-ArH), 7.57 (s, 1H, 9-H), 7.85 (d, J=8.9 Hz, 2H, 2′,6′-ArH), 8.25 (s, 1H, 5-H); MS (ESI, m/z) 564 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A solution of triphenylphosphine (48 mg, 0.183 mmol) in methylene chloride (700 μL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (33 mg, 0.183 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid (50 mg, 0.159 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (35 mg, 0.35 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (40.4 mg, 64%) as a pink solid: mp 200–202° C.; EI-HRMS m/e calcd for C18H21FN2O3S2 (M+) 396.0978, found 396.0976.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[C:11]2[C:19]3[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([CH:27]=[CH2:28])[C:20]=3[O:21][C:10]=2[CH:9]=1.CO.[H][H]>[Ni].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[C:11]2[C:19]3[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([CH2:27][CH3:28])[C:20]=3[O:21][C:10]=2[CH:9]=1
Reactant: C=Cc1cc(O)cc2c1oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(O)cc2c1oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 48.9 %

Procedure:
A solution of (863) (0.054 g, 0.167 mmol) prepared as described in example 444 in a methanol:tetrahydrofuran mixture (1:1, 4 mL) was hydrogenated over Raney nickel (100 mg) and hydrogen. The product was purified by column chromatography using a gradient of 0–100% ethyl acetate in dichloromethane to give (864) (0.032 g, 59%). 1H NMR δ [(CD3)2SO] 9.65 (s, 1H), 7.92 (m, 1H), 7.56 (d, J=3.0 Hz, 1H), 7.43 (m, 3H), 6.96 (d, J=2.5 Hz, 1H), 2.90 (q, 2H), 1.5 (t, 3H). MH−:392, 390.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2N)[N:9]=1.[N+:38](C1C=CC(CBr)=CC=1)([O-])=O>>[F:33][C:32]([F:35])([F:34])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH2:38])=[CH:26][CH:27]=2)[N:9]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Nc1ccccc1Cn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Product: Nc1ccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)cc1

Procedure:
Prepared as for the compound of Example 3 using p-nitrobenzyl bromide.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[F:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1>>[Cl:1][C:2]([C:12]([F:13])([F:14])[F:15])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH:17]([F:16])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:19]=2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)C(F)(F)F)C1C(=O)O
Product: CC1(C)C(C=C(Cl)C(F)(F)F)C1C(=O)OC(F)c1cccc(Oc2ccccc2)c1

Procedure:
This compound was prepared from 3-(2-chloro-2-trifluoromethylvinyl)-2,2-dimethylcyclopropanecarboxylic acid and α-fluoro-3-phenoxybenzyl bromide following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift δ ppm (solvent CDCl3): 1.26(6H, m, C(CH3)2); 1.72-2.44(2H, m, cyclopropyl protons); 5.80 and 6.18(1H, 2xd, vinyl proton); 7.20(1H, d, J=56Hz, CHF) and about 7.13(9H, m, aromatic protons).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13]C)=O)[C:5]([C:6]([OH:8])=O)=[C:4]([CH3:15])[C:3]=1[N+:16]([O-])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:52]1([CH2:57][CH2:58][NH2:59])[CH2:56][CH2:55][CH2:54][CH2:53]1>C1COCC1>[NH2:16][C:3]1[C:4]([CH3:15])=[C:5]2[C:9](=[CH:10][C:2]=1[NH2:1])[C:11](=[O:13])[N:59]([CH2:58][CH2:57][N:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1)[C:6]2=[O:8]
Reactant: NCCN1CCCC1
Reactant: COC(=O)c1cc(N)c([N+](=O)[O-])c(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N)c(N)cc2c1C(=O)N(CCN1CCCC1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
To a solution of 4-amino-6-(methoxycarbonyl)-2-methyl-3-nitrobenzoic acid (380 mg, 1.0 mmol), HATU (114 mg, 1.0 mmol) and DIPEA (129 mg, 1.0 mmol) in THF (20 mL) was added 2-(pyrrolidin-1-yl)ethanamine (114 mg, 1.0 mmol) and stirred at RT for overnight. The reaction mixture was evaporated in vacuo and the residue was triturated with MeOH (10 mL). The yellow precipitate was isolated by filtration and dried to afford the title compound (300 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:9][CH:10]([CH3:21])[CH2:11][N:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:13][CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O([CH2:30][CH3:31])S(C(F)(F)F)(=O)=O.[Cl-:32].FF>C(Cl)Cl.CO.O>[Cl-:32].[C:1]([O:9][CH:10]([CH3:21])[CH2:11][N+:12]([CH2:30][CH3:31])([CH2:13][CH3:14])[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC(C)OC(=O)c1ccccc1)C1CCCCC1
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: FF
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC[N+](CC)(CC(C)OC(=O)c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(cyclohexyl(ethyl)amino)propan-2-yl benzoate (0.427 g, 1.47 mmol) in dry DCM (20 mL) was added ethyl triflate (0.25 mL, 1.92 mmol) dropwise at ice-cold conditions. The resulting mixture was stirred at rt for 16 hours in a sealed tube. The reaction mixture was concentrated and the crude material was purified by Combiflash chromatography eluting with 3-4% methanol/DCM to provide a sticky liquid. Amberlite® IRA-400 (Cl) chloride form resin (3.0 g) was added to a solution of the liquid compound in methanol (15 mL) and stirred for 6 hours. The solution was then filtered, concentrated and lyophilized to provide a solid. Because the fluorine NMR spectrum showed incomplete counter ion exchange, the solid was again treated with Amberlite® IRA-400 (Cl) chloride form resin in water and filtered. The filtrate was concentrated and the crude material was lyophilized to provide N-[2-(benzoyloxy)propyl]-N,N-diethylcyclohexanaminium chloride as an off white solid. Yield: 0.05 g (9.62%). 1H NMR (DMSO-d6) δ 7.98 (d, J=8 Hz, 2H), 7.68 (t, J=7 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 5.52-5.49 (m, 1H), 3.95-3.89 (m, 1H), 3.55 (d, J=15 Hz, 1H), 3.44-3.35 (m, 5H), 2.19-2.17 (m, 1H), 2.09-2.06 (m, 1H), 1.80-1.78 (m, 2H), 1.54-1.51 (m, 3H), 1.36 (d, J=6 Hz, 3H), 1.25-1.07 (m, 9H). LCMS: m/z=318.0 [M+], RT=2.88 min, (Column: Y, Program: P1). UPLC: 98.70% (200 nm), RT=3.59 min, (Mobile Phase A. 0.05% TFA in water, B. Acetonitrile; Column: Zorbax® SB-C18 (4.6×50 mm) 1.8μ)
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>CN(C=O)C>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([N:23]2[CH2:22][CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=3[NH:13][C:6]2=[O:7])[CH2:25][CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1c(F)cccc1CCNC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1Nc2c(F)cccc2CCN1C1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
11.0 g (65.8 mmol) CDI were added to 13.1 g (40.0 mmol) [2-(2-amino-3-fluoro-phenyl)-ethyl]-(1-benzyl-piperidin-4-yl)-amine in 120 mL DMF. The mixture was heated to 100° C. and stirred for 1 h. After the reaction mixture had cooled to RT it was poured onto 300 mL ice water. The aqueous phase was extracted several times with DCM, the organic phases were combined, dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined and evaporated down.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S-:27].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][S:27][CH3:26])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (9.765 g, 26.43 mmol) in methanol (1 00mL) at room temperature was added sodium thiomethoxide (5.557 g, 79.29 mmol, Aldrich). The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken in methylene chloride and washed with water (3×) and brine (1×). The organic layer was dried over anhydrous sodium sulfate and concentrated to give a clear oil as crude product of 4-methylsulfanylmethyl-piperidine-1-carboxylic acid tert-butyl ester (6.37 g).