Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][OH:28]>CC(=O)CC.O>[OH:28][CH2:27][CH2:26][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: OCCBr
Reactant: O=c1[nH]cc(C2CCNCC2)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=c1[nH]cc(C2CCN(CCO)CC2)c2ccccc12
Yield: 55.9 %

Procedure:
4-(Piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (0.8 g) obtained in Example 31, potassium carbonate (2.0 g) and 2-bromoethanol (1.88 g) were dissolved in 2-butanone and water (1 mL), and the mixture was heated under reflux for 4 hrs. After the completion of the reaction, the solvent was evaporated, and water was added to the obtained residue. The mixture was extracted with chloroform, the organic layer dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1+triethylamine 2%) to give 4-(1-(2-hydroxyethyl)piperidin-4-yl)-2H-isoquinolin-1-one (0.46 g) as white crystals.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:31])=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([Cl:31])=[O:27])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (500 mg, 1.38 mmol) in chloroform (10 ml) were added oxalyl chloride (0.15 ml, 1.66 mmol) and several drops of N,N-dimethylformamide. The mixture was stirred at room temperature for 2 hr and concentrated. Hexane was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was washed with hexane to give 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl chloride (476 mg, yield 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[BH4-].[Na+]>C(O)C.O>[OH:17][CH:10](/[CH:9]=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)/C=C/c1ccccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(O)/C=C/c1ccccc1C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (E)-5-(2-methylphenyl)-3-oxo-4-pentenoate (37.24 g, 160.3 mmol) in ethanol (100 ml) was added sodium borohydride (3.03 g, 80.2 mmol) by small portions under ice-cooling, and the mixture was stirred as it was for 10 min. The reaction solution was diluted with water, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of ethyl (E)-3-hydroxy-5-(2-methylphenyl)penta-4-enoate as a yellow liquid.
Reaction SMILES: [CH:1]1([N:4]([CH2:30][C:31]2[CH:36]=[C:35]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:34]=[C:33]([O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:32]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]([CH3:21])[C:15](=[O:22])[CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[CH:1]1([N:4]([CH2:30][C:31]2[CH:36]=[C:35]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:34]=[C:33]([O:42][CH2:43][CH2:44][O:45][CH3:46])[CH:32]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]([CH3:21])[C:15](=[O:22])[CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: COCCCc1cc(CN(C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2c2cc(=O)n(C)c(C)c2C)C2CC2)cc(OCCOC)c1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)[C@@H]2CNCC[C@H]2c2cc(=O)n(C)c(C)c2C)C2CC2)cc(OCCOC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a CH2Cl2 solution (0.06 M) of trans-1,1-dimethylethyl 3-{[cyclopropyl({3-{[2-(methyloxy)ethyl]oxy}-5-[3-(methyloxy)propyl]phenyl}methyl)amino]carbonyl}-4-(1,5,6-trimethyl-2-oxo-1,2-dihydro-4-pyridinyl)-1-piperidinecarboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 4 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 94:6 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+, M+H): 540. Human Renin IC50 (buffer): 25 nM. Human Renin IC50 (plasma): 80 nM.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([N:11]([CH3:33])[C:12](=[O:32])[CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22]CC4C=CC(OC)=CC=4)[N:16]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:22][C:17]1[N:16]=[C:15]([NH:14][CH2:13][C:12]([N:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7]2)[CH3:33])=[O:32])[C:20]([CH3:21])=[CH:19][N:18]=1
Reactant: COc1ccc(CNc2ncc(C)c(NCC(=O)N(C)C3CCN(CC4CC4)CC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(N)nc1NCC(=O)N(C)C1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Compound 107 (24.9 mg) was dissolved in methylene chloride (1 mL). While the solution was cooled with ice, trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature (20 to 30° C.) overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1 to 4:1) to give 12.6 mg (68% yield) of the desired product as a white amorphous.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[N:14][CH:15]=1)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:42])[CH3:41])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[K+].[ClH:45]>CCO>[ClH:45].[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:35]=[CH:36][C:37]([C:40](=[O:42])/[CH:41]=[CH:8]/[C:10]3[CH:15]=[N:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=3)=[CH:38][CH:39]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=Cc1ccc(/C=C/C(=O)O)nc1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid trifluoroacetate (272 mg, 0.93 mmol), 4-(4-acetyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (obtained as described in Preparation 9, 283 mg, 0.93 mmol) and 1.7 M KOH (0.820 ml) in EtOH (10 ml) was stirred at 0° C. for 8 h and then at room temperature for 6 days. The mixture was acidified with 10% HCl until reaching a pH value of 3 and the resulting precipitate was filtered to give 184 mg of 4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester hydrochloride.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([CH:28]=[CH:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([CH:28]=[CH:29][CH:30]3[CH2:35][CH2:34][N:33]([C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:10])[CH2:32][CH2:31]3)(=[O:26])=[O:27])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: O=S(=O)(C=CC1CCNCC1)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CCC(C=CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Reaction time: 3 h

Procedure:
3-Phenylpropionyl chloride (0.21 ml) was added dropwise to a solution of 4-(4-fluorophenyl)-1-[2-(piperidin-4-yl)-ethenylsulphonyl]-piperazine (0.5 g) in dichloromethane containing triethylamine (0.2 ml). The mixture was stirred for 3 hours, evaporated to dryness, diluted with water and extracted with ethyl acetate (2×15 ml). The ethyl acetate extracts were combined and washed with aqueous sodium bicarbonate, water and dried. Removal of the solvent gave 4-(4-fluorophenyl)-1-[2-(1-phenethylcarbonylpiperidin-4-yl)-ethenylsulphonyl]-piperazine as a gum, M+H=486 (485).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]1([C:48]2[S:49][CH:50]=[C:51]([CH2:53]O)[N:52]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:53][C:51]5[N:52]=[C:48]([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[S:49][CH:50]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: -50 °C
Reaction time: 5 h
Yield: 113.3 %

Procedure:
A mixture of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.800 g, 2.52 mmol), triphenylphosphine (0.992 g, 3.78 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 0.555 g, 2.90 mmol) in a 200 mL flask fitted with an addition funnel was maintained under vacuum for ten minutes. The mixture was then flushed with nitrogen and charged with dry tetrahydrofuran (60 mL, distilled over lithium aluminum hydride). The solution was warmed to −50° C. and then sonicated for 5 min. The cooled heterogeneous mixture was then treated at 22° C. with a solution of diisopropyl azodicarboxylate (0.663 g, 3.28 mmol) in tetrahydrofuran (15 mL), added dropwise over 2.5 h. The reaction was homogeneous (pale yellow) at the end of the addition. The mixture was then stirred for another 2.5 h (total 5 h). The reaction mixture was then diluted with dichloromethane (400 mL), washed with saturated sodium bicarbonate (20 mL), brine and dried (anhydrous magnesium sulfate). Evaporation gave a white solid which was chromatographed on silica gel (3×12 cm, elution dichloromethane-ethyl acetate 98.5:1.5 to 97:3). The fractions were collected and evaporated to give the desired compound (1.40 g) as a white solid, contaminated with hydrazide by tlc. Crystallization in ethyl acetate (40 mL) gave the pure title material (0.838 g, 68%) as a white solid. The mother liquors (0.475 g) were chromatographed on silica gel (3×12 cm, elution dichloromethane-ethyl acetate 98.5:1.5 to 97:3) to give after crystallization from ethyl acetate (30 mL) to provide additional desired compound (0.160 g, 13%, total 81%) as a white solid. LC (Method C): 2.480 min. HRMS (ESI) calcd for C24H19N4O4S2 [M+H]+ m/z 491.0842, found 491.0865. 1H NMR (CDCl3, 400 MHz) 3.85 (s, 3H) 4.21 (s, 3H) 5.33-5.55 (m, 2H) 6.48 (d, J=1.96 Hz, 1H) 6.72 (dd, J=1.96, 0.78 Hz, 1H) 7.12 (s, 1H) 7.36-7.39 (m, 1H) 7.41-7.50 (m, 3H) 7.86 (s, 1H) 7.95-8.02 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+]=[N-].[ClH:12].N[CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19]>Cl.[Pd].[Pt]>[ClH:12].[NH2:1][CH2:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:18]([OH:20])(=[O:19])[CH2:17][CH2:16][C:15]([CH3:14])=[O:21]
Reactant: [N-]=[N+]=NCC(=O)CCC(=O)O
Agent: [Pd]
Agent: [Pt]
Agent: Cl
Product: CC(=O)CCC(=O)O

Procedure:
In the following step, the key compound 5-azido levulinic acid will be reduced to 5-amino levulinic acid hydrochloride without any difficulties. The reduction is preferably carried out as a catalytic hydrogenation in the presence of a metal catalyst (preferably palladium or platinum on a suitable carrier, such as active carbon) in aqueous hydrochloric acid without any arise of undesireable organic by-products. The catalyst can be regenarated. 5-Amino levulinic acid hydrochloride is obtained absolutly pure with an overall yield of 31-35% (starting from levulinic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Br:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>O1CCCC1>[Br:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Br
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Br)c1cccc(C(F)(F)F)c1
Yield: 27.2 %

Procedure:
Using N-[6-(3-amino-4-bromophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (178 mg, 0.46 mmol), 3-(trifluoromethyl)benzoyl chloride (92 mg, 0.44 mmol), triethylamine (0.14 mL, 1.00 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (67 mg, 24%) was obtained as a white powder.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](O)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:27]1[C:30]2([CH2:33][O:32][CH2:31]2)[CH2:29][CH2:28]1.C([O-])(=O)C([O-])=O>>[CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:14]([N:27]3[C:30]4([CH2:33][O:32][CH2:31]4)[CH2:29][CH2:28]3)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C1CC2(COC2)N1
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Agent: O=C([O-])C(=O)[O-]
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)N1CCC12COC2

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and 6-Oxa-1-azaspiro[3.3]heptane, ethanedioate (1:2) (CAN 1380571-72-1) as starting materials and isolated (27 mg, 46%); MS (ESI, m/z): 456.6 (M+H+).
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([NH2:36])[CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]2)=[CH:30][C:31]=1[NH:36][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CCCCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(N)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(NC(=O)CCCCC(=O)c3ccccc3)c2)CC1
Reaction time: 12 h
Yield: 50.8 %

Procedure:
A 25-mL RB-flask was charged with 6-oxo-6-phenylhexanoic acid (51.0 mg, 0.250 mmol), tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidinecarboxylate (59.0 mg, 0.200 mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.400 mmol, 62.0 mg), 4-dimethylaminopyridine (10 mg) in DMF:DCM (0.2:2.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (10.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by chromatography (silica gel, hexanes:EtOAc 6:1) to afford tert-butyl 4-{4-fluoro-3-[(6-oxo-6-phenylhexanoyl)amino]phenyl}-1-piperidinecarboxylate (49.0 mg, 51.0%): 1H NMR (400 MHz, CDCl3) δ 8.30-8.14 (m, 1H), 8.04-7.89 (m, 2H), 7.62-7.50 (m, 1H), 7.50-7.37 (m, 3H), 7.09-6.93 (m, 1H), 6.93-6.76 (m, 1H), 4.38-4.01 (br, 2H), 3.13-2.95 (m, 2H), 2.89-2.69 (m, 2H), 2.65-2.54 (m, 1H), 2.54-2.35 (m, 2H), 1.95-1.74 (m, 6H), 1.69-1.48 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[C:17](=O)[C:18]([NH2:20])=O)=[CH:14][CH:13]=[CH:12][CH:11]=2.O.[OH-].[Na+]>C1COCC1>[CH3:7][C:8]1[NH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]=1[CH2:17][CH2:18][NH2:20]
Reactant: Cc1[nH]c2ccccc2c1C(=O)C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c2ccccc2c1CCN
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of LiAlH4 (17 g, 445 mmol) in dry THF(1000 mL) is cooled to 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) is added in portions over 30 min. The mixture is stirred at room temperature for 30 min. and then maintained at reflux for 3 h. The reaction is cooled to 0° C. and treated with H2O (17 ml), 15% NaOH (aq., 17 ml) and H2O (51 ml). The mixture with MgSO4, filtered and the filtrate evaporated to give 2-methyltryptamine which is dissolved in MeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to the solution, followed by NaBH3CN (8.4 g) and AcOH (1 equiv.). After 1 h the reaction is diluted with NaHCO3 (aq.) and extracted with EtOAc. The organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by chromatography to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane (1-1.5 eqiv.) is added followed by Et2O. The resulting precipitate is filtered and the solid washed with Et2O and dried thoroughly to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to an ice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol) and HONH2 (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 h, the ice cold solution is diluted with H2O and NH4Cl (aq., 0.86 M, 100 mL). The resulting precipitate is filtered, washed with H2O and dried to afford N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 350 [MH+]).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[SH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Sc1ccccn1
Product: O=C(O)CNC(=O)c1nc(Sc2ccccn2)c2ccccc2c1O

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 2-mercaptopyridine under conditions analogous to Example D-110. The final product was purified by column chromatography on silica gel using a gradient of 3-15% methanol in dichloromethane with 0.5% acetic acid to elute the product; MS (−) m/z 354.10 (M−1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)[CH:5]=O.[C:11]([S@:15]([NH2:17])=[O:16])([CH3:14])([CH3:13])[CH3:12]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)/[CH:5]=[N:17]/[S@@:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:16]
Reactant: O=Cc1cc(F)cc(I)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(F)cc(I)c1
Temperature: 60 °C

Procedure:
To a solution of 3-fluoro-5-iodobenzaldehyde (8.75 g, 35 mmol) and (R)-(+)-t-Butylsulfinamide (4.67 g, 38.5 mmol) in DCE (117 mL) was added copper(II) sulfate (anhydrous) (16.76 g, 105 mmol) and the resulting suspension was heated at 60° C. overnight. LCMS indicated desired product formation. Reaction mixture was filtered through Celite and the filtrate concentrate in vacuo and then taken to the next step as such. LCMS (m/z): 354.1 (MH+), 1.08 min.
Reaction SMILES: [N+](C1C=CC([C:10]2[C:11]([S:20](C3C(C4C=CC([N+]([O-])=O)=CC=4)=CC4C(=CC=CC=4)N=3)(=O)=[O:21])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=CC=1)([O-])=O.C[N:43]([CH:45]=O)C>C(O)C.[Pd]>[NH2:43][C:45]1[CH:17]=[CH:18][C:13]([S:20]([C:11]2[CH:10]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[O:21])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3ccccc3nc2S(=O)(=O)c2nc3ccccc3cc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CN(C)C=O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)c2ccc3ccccc3n2)cc1

Procedure:
4-Nitrophenyl-2-quinolylsulfone (9.0 mmoles, 2.7 g) was dissolved in 200 ml ethanol and 75 ml DMF and was then hydrogenated over 2.2 g 5% Pd/C at room temperature for 3 hr. The reaction mixture was then filtered through celite and condensed to afford 2-(4-aminophenylsulfinyl)quinoline
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])([CH3:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.C(O[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1)(C)C>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C:9]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:10])[CH3:11])[CH:3]=[C:2]([F:1])[C:7]=1[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1
Reactant: CC(C)[Si](OC(C)(C)c1cc(F)cc(F)c1)(C(C)C)C(C)C
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](OC(C)(C)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of (2-(3,5-difluorophenyl)propan-2-yloxy)triisopropylsilane (1.0 eq) in dry THF (0.2 M) under an atmosphere of N2 at −78° C. was added n-butyllithium (1 eq, 1.6 M in hexanes) slowly keeping the internal temperature below −65° C. The reaction was stirred for 2 hrs at −78° C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield (2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yloxy)triisopropylsilane in 99%. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.03-1.08 (m, 21H) 1.24 (s, 12H) 1.38 (s, 3H) 1.57 (s, 3H) 6.92-7.03 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:14]([CH3:15])=[O:16]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
4-Aminobiphenyl (15 g, 88.76 mmol)in toluene (250 ml) was added acetic anhydride (8.5 ml, 90 mmol). The mixture was stirred at ambient temperature for 1 hour. Following the reaction the mixture was poured into petroleum ether (500 ml), the product was filtered off, washed with petroleum ether and dried to yield 4-acetaminobiphenyl (18.7 g).