Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].CCN(CC)CC.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OCCBr
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 653.5 %

Procedure:
2-Bromo-ethanol (6.3 g, 5.0 mmol), Et3N (10 mL, 72 mmol) and trityl chloride (14.6 g, 52.5 mmol) in anhydrous CH2Cl2 (50 mL) was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, 4:1) to give the title product (12 g).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.Cl.CCOCC>[C:18]([C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:4]=1[CH:3]=[O:2])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=Cc1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1

Procedure:
A solution of crude ketone from Step 1 in acetone (250 mL) and HCl 10% (25 mL) was stirred for 6 hours, diluted with Et2O, washed with a saturated NH4Cl solution, H20 (3×), brine and dried (MgSO4). After evaporation of the solvent, the residue was saturated with hexane and filtered to afford the title compound as pale yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]([CH3:13])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:10]([C:9]4[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=[C:7]([CH3:13])[CH:8]=4)=[O:11])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cc1cc(C(=O)Cl)n(C(C)(C)C)n1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C(C)(C)C)n1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
A dry 250 mL flask was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carbonyl chloride (1.00 g, 4.98 mmol) and THF (40 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.0 g, 3.96 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a tan solid (0.984 g, 2.363 mmol, 60%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[C:23]([F:33])[CH:22]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:24]=[C:23]([F:33])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1cc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)ccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1cc(F)cc(N2CCOCC2)c1
Yield: 48 %

Procedure:
Using an analogous procedure to that described in Example 2, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-3-fluoro-5-morpholinobenzamide to give the title compound in 48% yield; NMR Spectrum: (DMSOd6) 3.23 (m, 4H), 3.74 (m, 4H), 6.97 (d, 1H), 7.12 (d, 1H), 7.26 (s, 1H), 7.54 (d, 1H), 7.71 (d, 2H), 8.07 (s, 1H), 8.35 (d, 1H), 8.95 (s, 1H), 10.37 (m, 2H); Mass Spectrum: M+H+ 487.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=3)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:35])=[O:26])=[CH:20][CH:19]=3)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(N(C)C(=O)OC(C)(C)C)cc3)nc2c1
Temperature: 0 °C
Yield: 100.9 %

Procedure:
A solution of 3-(4-(t-butoxycarbonyl(methyl)amino)phenyl)-2-phenylquinoxaline-6-carboxylic acid (213.5 mg, 0.46 mmol, 1.00 equiv, 99%) and K2CO3 (324.2 mg, 2.35 mmol, 5.00 equiv) in DMF (8 mL) was stirred 45 min at room temperature under an inert atmosphere. CH3I (333.7 mg, 2.35 mmol, 5.00 equiv) was added dropwise, with stirring, at 0° C. The resulting solution was stirred for 1 h at room temperature, then quenched by water. The solution was extracted with 5×10 mL of CH2Cl2, and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out, and the resulting mixture was concentrated under vacuum affording 218 mg (98%) of methyl 3-(4-(t-butoxycarbonyl(methyl)amino)phenyl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Br.[Br:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[C:4]=1[O:24][CH3:25].[CH:26]1([C:32](O)=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[BH4-].[Na+]>>[Br:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([CH2:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:9][CH:8]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[C:4]=1[O:24][CH3:25]
Reactant: O=C(O)C1CCCCC1
Reactant: COc1ccc(C2CNCCc3c2cc(OC)c(OC)c3Br)cc1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(C2CN(CC3CCCCC3)CCc3c2cc(OC)c(OC)c3Br)cc1

Procedure:
6-Bromo-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3 g) is reacted with cyclohexylcarboxylic acid in the presence of sodium borohydride as in Example 1 to give 6-bromo-3-cyclohexylmethyl-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine base and, after treatment with boron tribromide, 6-bromo-3-cyclohexylmethyl-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH:37]=[CH:36][N:35]=[CH:34]5)[CH:28]=4)[CH2:24][C:23](=[O:38])[NH:22][C:9]=3[CH:10]=2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1-c1ccc2c(c1)NC(=O)CC(c1cccc(-n3ccnc3)c1)=N2

Procedure:
Prepared from {4′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2′-methyl-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K50) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (82 mg).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]([C:37]1[N:38]=[CH:39][N:40](C(OC(C)(C)C)=O)[CH:41]=1)=[CH2:36]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:8]2[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2](/[CH:36]=[CH:35]/[C:37]4[N:38]=[CH:39][NH:40][CH:41]=4)=[CH:3][CH:4]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:10][C:9]=2[CH:20]=1
Reactant: C=Cc1cn(C(=O)OC(C)(C)C)cn1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3c[nH]cn3)cc2)cc1
Temperature: 150 °C
Yield: 79.6 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (50 mg, 0.113 mmol) was dissolved in DMF (2 mL) and triethyl amine (0.474 mL, 3.40 mmol). To the solution was added tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (66.0 mg, 0.340 mmol) and Pd(PPh3)2Cl2 (7.95 mg, 0.011 mmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and sat. NH4Cl. The organic layer was collected (phase separator) and concentrated onto silica gel and the material was purified by column chromatography (SiO2, 0-30% DCM/MeOH) to afford (E)-4-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole (41 mg, 0.090 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J=1.52 Hz, 1H), 7.51-7.62 (m, 2H), 7.46-7.51 (m, 1H), 7.39 (d, J=9.09 Hz, 2H), 7.32 (d, J=2.53 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 7.08 (d, J=16.67 Hz, 1H), 6.76-6.95 (m, 6H), 3.77 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C1C(=O)N([Br:32])C(=O)C1>>[Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[C:18]=3[Br:32])[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)cc(OC)c1OC
Product: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)c(Br)c(OC)c1OC

Procedure:
Bromination of 7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine) with NBS (1.5 equivalents) was done following the general procedure 3 to give the title compound: HPLC RT was 6.541 min. 1HNMR (CDCl3): δ 6.52 (s, 1H), 5.74(s, 2H), 5.46 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[C:6]([CH3:8])[S:5][C:4]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:7]=[C:6]([CH3:8])[S:5][C:4]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1cc(Cl)c(C2CC(=O)c3c(C)ccnc3C2)s1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cc(Cl)c(C2CC(=NNC(=N)N)c3c(C)ccnc3C2)s1
Temperature: 110 °C
Reaction time: 3 h
Yield: 199.9 %

Procedure:
To a mixture of 7-(3-chloro-5-methylthiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (1 g) and aminoguanidine hydrochloride (0.366 g) were added ethanol (12 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath temperature) for 3 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(3-chloro-5-methylthiophen-2-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 172) (1.17 g) as colorless crystals.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:33])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.ClCCl.[Pd]>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[O:33])[CH:24]=1
Reactant: COc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
4-[6-(2-Methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XI) (0.45 g, 1.00 mmol) was dissolved in methanol:dichloromethane (4:1) (24 ml) and 10% Pd/C (0.2 g) was added under an atmosphere of nitrogen. The reaction was stirred at room temperature under hydrogen balloon pressure for 18 hours. The catalyst was removed from the reaction mixture by filtration through a celite bed and the filtrate was evaporated to dryness. Then the crude product was treated with dry diethyl ether (10 ml) and the solid was filtered to obtain piperidine-4-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #6A) (0.19 g, 42%) as a white solid.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18][NH:19][CH:20]([CH3:22])[CH3:21]>CO>[CH:20]([N:19]([CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:18])([CH3:22])[CH3:21]
Reactant: CNC(C)C
Reactant: c1ccc(-c2ccccc2OCC2CO2)cc1
Solvent: CO
Product: CC(C)N(C)CC(O)COc1ccccc1-c1ccccc1

Procedure:
22.7 g (0.1 mole) of 2,3-epoxy-1-(2-phenylphenoxy)-propane is dissolved in 30 ml of methanol. Then 15 ml (0.2 moles) of methylisopropylamine is added to the reaction mixture slowly while stirring. The mixture is refluxed over a steam bath for 48 hr after which time the solvent and excess amine are evaporated under reduced pressure. The residue remaining is dissolved in 200 ml of ether and the solution washed with water. The ether phase is extracted with 5% aqueous hydrochloric acid and the aqueous extracts washed once with ether. The aqueous phase is neutralized with ammonium hydroxide, then extracted with methylene chloride. The methylene chloride extract is dried over anhydrous potassium carbonate and the solvent evaporated under reduced pressure to afford 1-(N-isopropyl-N-methylamino)-3-(2-phenylphenoxy)-propan-2-ol, as a blue-green oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)Cc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 23.8 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), phenylacetyl chloride (53.5 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (31.0 mg, yield 24%).
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6]1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[CH2:53][C:54]([O-])=[O:55].[Na+]>C1COCC1.C(Cl)Cl>[S:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[CH2:53][C:54]([NH:11][C@H:8]1[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:22])[CH2:6][C@H:7]1[CH2:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:15])=[O:55]
Reactant: O=C([O-])Cc1nc2ccccc2s1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)Cc2nc3ccccc3s2)[C@H](CS(=O)(=O)c2ccccc2)C1
Yield: 60.2 %

Procedure:
A solution of (1R,3R,4S)-N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)-cyclohexane-1,4-diamine (see 30b) (70 mg, 0.216 mmol), EDCI (50 mg, 0.260 mmol), HOBT (35 mg, 0.260 mmol), and sodium 2-(benzo[d]thiazol-2-yl)acetate (56 mg, 0.260 mmol) in THF (5 mL) was stirred overnight at room temperature. The mixture was dilute with CH2Cl2 (25 mL) and washed with water, brine and evaporated. The residue was chromatographed on silica gel (6% NH4OH/MeOH/CH2Cl2) to give the product (65 mg). MS found: (M+1)+: 500.49.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=S)[CH2:11][S:10](=[O:16])(=[O:15])[CH2:9]2)[CH:7]=1.[NH3:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[CH2:9][S:10](=[O:16])(=[O:15])[CH2:11][C:12]([NH2:19])=[N:13]2)[CH:7]=1
Reactant: N
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(=S)N1
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(N)=N1
Temperature: 60 °C
Reaction time: 5 h
Yield: 69.2 %

Procedure:
A mixture of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1λ6-thiomorpholin-3-thione (2.7 g, 7.67 mmol, Eq: 1.00) in ammonia (7 M in MeOH) (47.2 g, 60 ml, 420 mmol, Eq: 54.8) was stirred at 60° C. in a sealed tube for 5 hours. The yellow solution was evaporated, then chromatographed on 20 g silica gel with 0-80% ethyl acetate in heptane to give the (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (1.78 g, 5.31 mmol, 69.3% yield) as a white foam. MS (ISP): m/z=335.0 [M+H]+ and 337.0 [M+2+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:5]=[C:4]([C:18]#[N:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:6]2[C:7]([O:8][CH3:9])=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=[C:4]([C:18]#[N:19])[N:5]=2)=[CH:12][CH:13]=1
Reactant: COc1c(Cl)nc(C#N)nc1Nc1ccc(Cl)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: COc1c(Nc2ccc(Cl)cc2)nc(C#N)nc1N1CCNCC1

Procedure:
A solution of the product from step (v) (0.25 g) and piperazine (0.366 g) in tetrahydrofuran (8 ml) was heated at 60° C. for 6 h then the solvent removed under reduced pressure. The residue was purified by RPHPLC 15–75% acetonitrile in aqueous trifluoroacetic acid. Yield 0.139 g
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])[CH2:3][CH2:2]1.[BH3-]C#N.[Na+].[CH:31]([C:34]1[C:39]([CH:40]=O)=[C:38]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:37]([CH2:49][O:50][CH3:51])=[C:36]([CH:52]([CH3:54])[CH3:53])[N:35]=1)([CH3:33])[CH3:32].O>CO>[CH:31]([C:34]1[C:39]([CH2:40][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:26])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])[CH2:3][CH2:2]2)=[C:38]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:37]([CH2:49][O:50][CH3:51])=[C:36]([CH:52]([CH3:54])[CH3:53])[N:35]=1)([CH3:32])[CH3:33]
Reactant: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCNCC1
Reactant: COCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCN(Cc2c(C(C)C)nc(C(C)C)c(COC)c2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
Step 2): N-(Piperidin-4-yl)-2-(N'-n-heptylureido)benzamide (0.96 g, 2.7 mmol) and NaBH3CN (0.17 g, 2.7 mmol) were added into a solution of 2.6-diisopropyl-4-(4-fluorophenyl)-3-formyl-5-methoxymethylpyridine (0.9 g, 2.7 mmol) in MeOH (30 ml). The mixture was stirred at room temperature for 72 hours, and then water was added at 0° C. extracted with dichloromethane, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (10 to 50% ethyl acetate in hexane) to give N-[1-[2,6-diisopropyl-4-(4-fluorophenyl)-5-(methoxymethyl)pyridin-3-yl]methylpiperidin-4-yl]-2-(N'-n-heptylureido)benzamide (0.65 g, 35.7%): mp 123° C.: 1NMR (CDCl3)ppm: 0.88 (3H, t), 1.17-1.46 (22H, m), 1.49-1.66 (2H, m), 1.80-2.00 (4H, m), 2.57 (2H, d), 3.09-3.53 (9H, m), 3.68-3.89 (1H, m), 3.49 (2H, s), 4.53 (1H, t), 5.98 (1H, d), 6.93 (1H, t), 7.05-7.24 (4H, m), 7.33-7.48 (2H, m), 8.41 (1H, d), 10.30 (1H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH3:23])[CH:17]=2)[CH2:9]1)C1C=CC=CC=1.CN(C)P(N(C)C)(N(C)C)=O.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>C1(C)C=CC=CC=1>[CH3:23][S:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:36]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH2:9]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CSc1cccc(NCC2CN(Cc3ccccc3)CCO2)c1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CSc1cccc(NCC2CN(C(=O)Oc3ccccc3)CCO2)c1

Procedure:
To a solution of 4-benzyl-2-(3-methylthioanilino)methylmorpholine (1.7 g.) in toluene (50 ml.) is added hexamethylphosphoramide (1 ml.) and then phenyl chloroformate (1.5 ml.). The mixture is heated under reflux for 18 hours, the toluene is then removed under reduced pressure, the oily residue is dissolved in ether and the ethereal solution is washed successively with sodium hydroxide solution, water, hydrochloric acid and water before drying over anhydrous magnesium sulphate. Evaporation of the dried filtered ethereal solution gives yellow oil (2.4 g.) or 2-(3-methylthioanilino)methyl-4-phenoxycarbonylmorpholine, which is dissolved in dimethylsulphoxide (20 ml.) and this solution is added to a solution of sodium methylsulphinylmethide [prepared in the usual way from sodium hydride (2.4 g.) and dimethylsulphoxide (50 ml.) ]. Water (1.8 ml.) is then added when the temperature of the mixture rises to about 60°C. The solution is stirred for 1 hour and then poured into water containing ice and the mixture extracted with ether (3 × 100 ml.). The ethereal solution is washed with water, dried (MgSO4) and filtered and the filtrate is treated with an ethereal solution of oxalic acid to precipitate 2-(3-methylthioanilino)methylmorpholine oxalate, m.p. 114°-115°C. after recrystallisation from acetone.