Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:13]([N:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH:8]=[CH:7][C:6]2[CH:20]=[C:2]([C:26]3[CH:25]=[N:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[CH:3]=[N:4][C:5]=2[CH2:12]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1Cc2ncc(Br)cc2C=Cc2ccccc21
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: COc1ccc(-c2cnc3c(c2)C=Cc2ccccc2N(C(C)=O)C3)cn1
Yield: 95.9 %

Procedure:
Compound 52D (20.9 mg, 91%) was prepared from 52C (20 mg, 0.061 mmol) and 2A (14.3 mg, 0.061 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.419 min; LCMS Found: (M+H)+=358.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[C:1]([O:9][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(ON1C(=O)CCC1=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Nicotinic acid (4.025 g, 0.0327 mol) and N-hydroxysuccinimide (3.763 g, 0.0327 mol) were dissolved in 130 ml of dioxane. Dicyclohexylcarbodiimide (6.75 g, 0.032 mol in 20 ml of dioxane was added. The reaction mixture was then stirred at room temperature for 3 hours. The dicyclohexylurea which precipitated was removed by filtration and the solvent was removed by rotary evaporation. The crude product was recrystallized from ethyl acetate to give light yellow crystals which are then washed with anhydrous ether. The product, obtained in 72% yield (5.2 g) and melting at 129°-131° C., has the formula: ##STR1619##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH3:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:11])[CH3:21]
Reactant: CNCCc1ccc(F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C)CCc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A solution of [2-(4-fluoro-2-nitro-phenyl)-ethyl]-methyl-amine (10.4 g, 0.053 mole) and ethyl bromoacetate (8.8 g, 0.053 mole) in acetonitrile (200 mL) containing potassium carbonate (3.64 g, 0.026 mole) was stirred at room temperature overnight. The mixture was evaporated in vacuo, water was added to the residue and then extracted with dichloromethane (2×200 mL). The combined organic layers were washed with saturated sodium chloride (300 mL), dried and concentrated. Purification by flash column chromatography (silica gel, methylene chloride:hexanes 1:1 to methylene chloride) provided 10.0 g of the title compound as a light brown oil. 1H NMR (CDCl3): 7.65 δ (dd, 1H); 7.40 δ (dd, 1H); 7.25 δ (dd, 1H); 4.20 δ (m, 2H); 3.30 δ (s, 2H); 3.05 δ (t, 2H); 2.80 δ (t, 2H); 2.45 δ (s, 3H); 1.25 δ (t, 3H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:8]=[C:7]([NH:19][CH3:20])[N:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:29])[N:12]=3)=[CH:9][N:8]=[C:7]([NH:19][CH3:20])[N:6]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1ncc(-c2ccnc(SC)n2)c(CC2CC2)n1
Product: CNc1ncc(-c2ccnc(S(C)=O)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfanyl)-4,5′-bipyrimidin-2′-amine (4-1) (770 mg, 2.68 mmol), m-CPBA (925 mg, 5.36 mmol) was added and the reaction mixture was stirred at rt for 2 hours. The reaction was partitioned between water and DCM. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [50 g SNAP column, 100% DCM to 10% MeOH/DCM] to obtain a mixture of the desired product and the corresponding sulfone (645 mg, 79% yield). MS (ES+): m/z=304.2/305.2 (100/20) [MH+]. HPLC: tR=0.85 minute over 3 minutes. Purity: 73.2% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f7) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+]>C(O)CO>[ClH:29].[ClH:29].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:18]2[C:19]3[C:20]4[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=4[NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:24][CH:25]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccc(Cl)cc4)c3c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: Cl
Product: Clc1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)cc1
Temperature: 170 °C

Procedure:
3-benzoyl-10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and KOH (3.0 g) were stirred in ethylene glycol (10 ml) and the reaction mixture was heated at 170° C. for 1 h. The reaction mixture was cooled to RT, partitioned between H2O and EtOAc, separated, dried over MgSO4, filtered and concentrated. The product was dissolved in EtOAc and HCl (4 ml, 1N in Et2O) was added. The precipitate was filtered and recrystallized from EtOAc/MeOH to give the title compound as a solid: 1H NMR (DMSO-d6) δ 3.09, 3.18, 3.30, 4.48, 6.78, 7.08, 7.32, 7.38, 7.52, 9.60, 11.3. HRMS (FAB) calcd for C18H17ClN2 (MH+) 297.1158, found 297.1137.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.N1[CH:27]=[C:26]([C:28]2[S:32][C:31]([O:33][C@@H:34]3[CH:41]4[CH2:42][N:37]5[CH2:38][CH:39]([CH2:43][CH:35]3[CH2:36]5)[CH2:40]4)=[N:30]C=2)[CH:25]=N1.[NH3:44]>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:26]([C:28]1[S:32][C:31]([O:33][C@H:34]2[CH:41]3[CH2:42][N:37]4[CH2:38][CH:39]([CH2:43][CH:35]2[CH2:36]4)[CH2:40]3)=[N:30][N:44]=1)([CH3:25])([CH3:12])[CH3:27]
Reactant: N
Reactant: c1n[nH]cc1-c1cnc(OC2C3CC4CC2CN(C4)C3)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)c1nnc(OC2C3CC4CC2CN(C4)C3)s1

Procedure:
The free base of the title compound was prepared from the product of Example 57A (106 mg, 0.34 mmol) according to Method C, and then converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.42 (s, 9H), 2.05-2.32 (m, 5H), 2.36 (s, 3H), 2.71 (s, 2H), 3.42-3.63 (m, 4H), 3.81 (d, J=12.5 Hz, 2H), 5.41 (s, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H). MS (DCI/NH3) m/z=294 (M+H)+. Anal. Calcd. for C15H23N3OS.C7H8O3S: C, 56-75; H, 6.71; N, 9.02. Found: C, 54.04; H, 6.43; N, 8.41.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:25][C@H:26]([C@H:28]([N:36]1[CH:40]=[C:39]([C:41]([NH2:43])=[O:42])[N:38]=[CH:37]1)[CH2:29][CH2:30]OS(C)(=O)=O)[CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:25][C@H:26]([C@H:28]([N:36]1[CH:40]=[C:39]([C:41]([NH2:43])=[O:42])[N:38]=[CH:37]1)[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCOS(C)(=O)=O)n1cnc(C(N)=O)c1
Reactant: Oc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](OCc1ccccc1)[C@@H](CCOc1ccc2ncccc2c1)n1cnc(C(N)=O)c1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
Under N2, to a solution of 6-hydroxyquinoline (43 mg, 0.296 mmol) in DMF (3 ml) was added potassium carbonate (82 mg, 0.593 mmol) at room temperature. The reaction mixture was stirred for 30 minutes. 1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamide was added and the resulting mixture was stirred for 6 h at 70° C. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (8 g) chromatography eluting with chloroform/methanol (100:1 to 30:1) to give 1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide (1) (62.5 mg, 48.9%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:27])=[O:28])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: COC(CNS(=O)(=O)NC(=O)OC(C)(C)C)OC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 24.2 %

Procedure:
A mixture of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (103 mg, 0.302 mmol, 1.5 equiv.; Step D) and tert-butyl N-(2,2-dimethoxyethyl)sulfamoylcarbamate (57.2 mg, 0.201 mmol) in dichloromethane (1.0 mL) was stirred under N2 at room temperature. To this mixture was added trifluoroacetic acid (0.50 mL, 6.5 mmol) and triethylsilane (80.2 μL, 0.502 mmol, 2.5 equiv.) drop-wise. This reaction mixture was stirred at room temperature for 2 h. HPLC indicated approximately 30% conversion. The reaction mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate to pH ˜8. The mixture was extracted in ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by preparative TLC (50% ethyl acetate/hexane) to give the desired product (27.5 mg, 29.5%) as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.6 Hz, 1H), 6.58 (t, J=5.7 Hz, 1H), 3.38 (dd, J=12.7, 6.2 Hz, 2H), 3.10 (dd, J=12.1, 5.9 Hz, 2H), 1.41 (s, 9H). C17H19BrFN7O7S (MW 564.34), LCMS (EI) m/e 485.8/487.8 (M+-C5H8O2+Na).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]2[CH:20]([CH:21]2[CH2:24][OH:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]2[CH:22]([CH:21]2[CH:24]=[O:25])[CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC2C(CO)C2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2C(C=O)C2C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To a stirring solution of oxalyl chloride (7.8 mL, 89.5 mmol) in 370 mL of anhydrous CH2Cl2 at −78° C., under Nitrogen, was added DMSO (13.8 mL, 193.9 mmol) dropwise. After 10 minutes, 6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15.9 gm, 74.5 mmol) in 72 mL anhydrous CH2Cl2 was added. After the mixture stirred 30 minutes, triethylamine (52.0 mL, 372.9 mmol) was added and the mixture was allowed to slowly warm to 0° C. over 1 hour. The mixture was concentrated, the resulting solid was taken up in saturated NaHCO3 and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated to give a quantitative crude yield of 6-Formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15.8 gm), which was used in the next step without purification. 400 MHz 1H NMR (CDCl3) δ 9.4 (d, J=4.1 Hz, 1H), 3.6 (dd, J=11.2 Hz, 37.8 Hz, 2H), 3.4 (d, J=9.95, 2H), 2.1 (m, 2H), 1.8-1.7 (q, J=3.32 Hz, 1H), 1.4 (s, 9H); GCMS (M+0) 211.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:27]([NH:29][NH2:30])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1.O>O1CCCC1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:30][NH:29][C:27]([C:10]2[N:11]=[C:12]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:28])=[O:46])=[CH:40][CH:39]=1
Reactant: NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a mixture of the product of example 15 (807 mg, 1.97 mmol) and sodium carbonate (418 mg, 3.95 mmol) in tetrahydrofuran (25 ml), 4-fluorophenylacetyl chloride (374 mg, 2.17 mmol) was added drop-wise. The resulting mixture was stirred overnight at room temperature. Then water (25 ml) was added and the mixture was stirred for 1 hour. The resulting solids were collected by filtration, washed with water and PE successively and dried to give the titled product (697 mg, 64.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:30])[CH:10]([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:32](Br)[CH:33]=C.[Li+].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[CH2:31]([C@@:10]1([CH3:37])[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:11]1=[O:30])[CH:32]=[CH2:33]
Reactant: C=CCBr
Reactant: CC[C@@H](COCC1CC1)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)COCC2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.2 g (0.434 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-3-methylpiperidin-2-one (Example 68, Step C, mixture of diastereomers) and allyl bromide (0.147 mL, 1.737 mmol) in THF (5 mL) was added LHMDS, (1.0M solution in THF, 1.3 mL, 1.3 mmol) at RT. Let it stir at RT for 5 min. Then the reaction mixture was heated at 50° C. for 3 h. The reaction mixture was diluted with satd. NH4Cl. and extracted with CH2Cl2. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by chromatography, eluting with a gradient of 0% to 20% EtOAc in hexane, to provide the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:33][C:32]([C:34]([NH2:36])=O)=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.P(Cl)(Cl)([Cl:39])=O.Cl>ClCCl>[ClH:39].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:19]=1)=[C:8]([C:29]1[S:33][C:32]([C:34]#[N:36])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(N)=O)s3)ccc2c1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C#N)s3)ccc2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Add 5-(6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl)thiophene-2-carboxamide (79 mg, 0.16 mmol) and phosphoryl chloride (13 mL, 139.9 mmol) to a round bottom flask under nitrogen. Warm the resulting mixture to 100° C. and stir for 15 min. Cool the mixture to room temperature and concentrate in vacuo to give a yellow residue. Carefully quench the resulting residue with methanol and load onto an SCX acidic ion exchange column. Flush the column with methanol then elute desired material with 2M ammonia in methanol. Concentrate the ammonia containing eluent in vacuo to give a pale yellow solid. Dissolve the resulting solid in dichloromethane and treat with HCl (1M in ether, 5 mL). Concentrate in vacuo to obtain the title compound (81.5 mg, 0.16 mmol) 1H NMR (d6-DMSO) δ 0.82-0.73 (m, 1H), 1.33-1.23 (m, 4H), 2.88-2.80 (m, 2H), 3.36-3.31 (m, 5H), 3.81 (s, 3H), 4.23-4.19 (m, 2H), 6.73-6.63 (m, 2H), 6.87-6.77 (m, 2H), 7.15-7.09 (m, 1H), 7.41-7.36 (m, 1H), 7.62-7.54 (m, 1H), 7.87-7.77 (m, 3H), 8.09-8.05 (m, 1H), 10.58-10.45 (m, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:11]1[CH:12]=[C:13]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH:14]=[CH:15][C:16]=1[F:17].C([O-])(=O)C([O-])=O.[CH3:39][CH:40]1[CH2:44][CH2:43][C:42](=O)[C:41]1=[O:46]>C(O)C.O.[OH-].[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)[C:11]1[CH:12]=[C:13]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]=[C:42]2[C:41]([OH:46])=[C:40]([CH3:39])[CH2:44][CH2:43]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CC1CCC(=O)C1=O
Reactant: CN1CCC(OC(c2nc3ccccc3[nH]2)c2cc(C#CCCCCN)ccc2F)CC1
Agent: O=C([O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=C(O)C(=NCCCCC#Cc2ccc(F)c(C(OC3CCN(C)CC3)c3nc4ccccc4[nH]3)c2)CC1

Procedure:
A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 50 mg), 3-methyl-1,2-cyclopentanedione (11.8 mg) in ethanol (2 mL) is refluxed for 2 h. The mixture is then cooled, diluted with water and 1N sodium hydroxide and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5) to afford 5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.30.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 82.5 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 3.17 g (19.8 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), and 10 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.41 g (reaction yield: 98.9%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:14]([C:15]4C=CC=C[C:20]=4[CH:21]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=1.[CH2:22]([Li])[CH2:23][CH2:24][CH3:25].[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>ClCCl.CCCCCC.C1COCC1>[CH:22]1[C:20]2[CH:21]=[C:8]([C:4]3[CH:3]=[C:2]([B:27]([OH:32])[OH:28])[CH:7]=[CH:6][CH:5]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:25]=[CH:24][CH:23]=1
Reactant: Brc1cccc(-c2cc3ccccc3c3ccccc23)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]CCCC
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(-c2cc3ccccc3c3ccccc23)c1
Temperature: -60 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
In argon atmosphere, a liquid mixture of 15.45 g (46.4 mmol) of 9-(3-bromophenyl)phenanthrene and 150 ml of dry THF was cooled to −60° C., and 35.9 ml (55.6 mmol) of a 1.55 M hexane solution of n-butyllithium was added dropwise under stirring. Then, the reaction mixture was stirred at −60° C. for 2 h. The reaction solution was cooled again to −60° C., and 26.2 g (139 mol) of triisopropyl borate was added dropwise. The reaction mixture was heated up to room temperature, stirred for one hour, and left standing overnight. The solvent was removed by distillation under reduced pressure to concentrate the reaction mixture. The concentrated reaction mixture was cooled to 0° C., added with hydrochloric acid, and stirred at room temperature for one hour. After the reaction, dichloromethane was added to the reaction mixture, and the aqueous phase was removed. The organic phase was dried over sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 13.4 g (yield: 67%) of 3-(9-phenanthrenyl)phenylboronic acid.
Reaction SMILES: [NH2:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20].[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:24]([O:23][C:22]([NH:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20])=[O:26])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CC(N)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)NC(C)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
4.2 g of 2-(2-aminopropyl)-4-phenyl-1(2H)-isoquinolone, 2.7 g of ethyl chlorocarbonate, 4.1 g of potassium carbonate and 60 ml of ethanol were mixed and stirred at room temperature for 3 hours. The solvent was then distilled off, and the residue was extracted with dichloromethane. The crystals obtained by distilling off the solvent were recrystallized from ethanol to obtain 3 g (57% yield) of 2-(2-ethoxycarbonylaminopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 182° C. as colorless prisms.