Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH2:25][CH3:26])[C:5]1=[O:33])[CH:2]=[CH2:3].[CH3:35][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])([CH3:35])[CH3:31])[CH2:25][CH3:26])[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)=O)C1=O
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-7-oxooctan-3-yl)piperidin-2-one prepared above in Step C (122 mg, 0.244 mmol) in THF (2.4 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (522 μL, 0.731 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure and purification of the residue by chromatography on silica gel (12 g SiO2, 30% and 40% EtOAc/Hex) provided the title compound as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH:48]([CH3:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH:48]([CH3:49])[CH3:50])=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.3 %

Procedure:
p-Methoxyaniline (0.077 g, 0.626 mmol), triethylamine (0.063 g, 0.626 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.106 g, 0.626 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-isopropoxybenzoic acid (0.117 g, 0.313 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexane:ethyl acetate=1:2) to obtain the titled compound (0.095 g, 0.198 mmol, 63%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:6]([C:15]([OH:17])=O)[CH2:5][O:4][CH2:3]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:6]([C:15]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H]1COCC(=O)N1Cc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NCc1ccccc1)[C@@H]1COCC(=O)N1Cc1ccccc1
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To a solution of (3S)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (4.611 g, 19.60 mmol) in DCM (65 mL) was added benzylamine (2.6 mL, 23.80 mmol), N-methylmorpholine (11 mL, 100.0 mmol), 1-hydroxy-7-azabenzotriazole (3.20 g, 23.51 mmol), and EDC (4.51 g, 23.53 mmol). The solution was stirred overnight and then diluted with DCM (100 mL). The solution was washed with 6 N aq. HCl (2×100 mL), and the organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide crude (3S)-5-oxo-N,4-bis(phenylmethyl)-3-morpholinecarboxamide (6.454 g, >100% crude yield) as a pale yellow foam. LCMS: (M+H)+: 325.2.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:35])[C:11]([C:32]([OH:34])=O)=[CH:12][N:13]([CH2:26][CH:27](OC)OC)[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)C1C=CC=CC=1.S(Cl)(Cl)=O.[CH:40]([NH2:43])([CH3:42])[CH3:41].S([O-])(O)=O.[K+]>O1CCCC1.C(N(CC)CC)C>[CH:40]([NH:43][C:32]([C:11]1[C:10](=[O:35])[C:9]([OH:8])=[C:14]2[C:15](=[O:25])[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH:27]=[CH:26][N:13]2[CH:12]=1)=[O:34])([CH3:42])[CH3:41]
Reactant: COC(Cn1cc(C(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Reactant: CC(C)N
Agent: O=S([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cn2ccn(Cc3cccc(Cl)c3)c(=O)c2c(O)c1=O

Procedure:
To a solution of 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (25.4 mg) obtained in Example 161, Step 4 in tetrahydrofuran (0.3 ml) were successively added triethylamine (0.021 ml) and thionyl chloride (0.0056 ml) at 0° C. with stirring. After stirring at room temperature for 10 min, the mixture was ice-cooled again and isopropylamine (0.0086 ml) was added. After stirring at room temperature for 30 min, 5% aqueous potassium hydrogen sulfite solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated. Trifluoroacetic acid was added to the obtained residue and the mixture was stirred at 70° C. for 5.5, hr. Trifluoroacetic acid was evaporated, toluene was added and the mixture was concentrated, which operations were performed twice. Crystallization from ethyl acetate (2 ml) gave 2-(3-chlorobenzyl)-9-hydroxy-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid isopropylamide (13.6 mg)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[CH2:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[CH2:23]([O:28][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:31]1[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=1)=[CH:7][CH:6]=3)[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)CO
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Product: CC(C)(C)COc1cc2c(cn1)Oc1ccc(-c3cccnc3)cc1[C@@]21COCC(N)=N1

Procedure:
The title compound was synthesized by steps analogous to those described in Method A4, but using Intermediate 10B, neopentyl alcohol, and pyridin-3-ylboronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9](Cl)[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[S:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[CH:4][N:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: Cc1cc(Br)ncc1C(Cl)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 2-bromo-5-[chloro(2,5-difluorophenyl)methyl]-4-methylpyridine (6.44 g, 19.4 mmol) in N,N-dimethylformamide (100 ml), 4-fluorobenzenethiol (2.06 ml, 19.4 mmol), and then potassium carbonate (2.94 g, 21.3 mmol) were added in an argon atmosphere, at 0° C., and the mixture was stirred for 1 hour at room temperature. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, and then the organic layer was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution of hexane:ethyl acetate=30:1 was concentrated under reduced pressure, to obtain the title compound (8.20 g, 19.3 mmol, 100%) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:12](=[O:14])[CH3:13])[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(Br)cc2s1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
6-Bromobenzo[d]thiazol-2-amine (Aldrich, St. Louis, Mo.; 10.02 g, 43.7 mmol) was suspended in DCM (175 mL) to which DMAP (6.107 g, 50.0 mmol) was added. The flask was cooled in an ice water bath under argon, and acetic anhydride (4.60 mL, 48.8 mmol) was added, and the reaction was warmed to RT and stirred overnight. The reaction was washed with 10% HCl and water. The precipitate in the organic phase was filtered. The aqueous washings were extracted with DCM and 10:1 DCM/MeOH. These extracts were concentrated, combined with the filtrate from the above filtration, and concentrated again. The solid was collected (from the filtration as well as the aqueous workup), concentrated, and dried under vacuum to afford the desired N-(6-bromobenzo[d]thiazol-2-yl)acetamide (12.30 g, 45.39 mmol, 88% purity, 91% yield). MS (ESI pos. ion) m/z: 271 (MH+, 79Br), 273 (MH+, 81Br). Calculated exact mass for C9H7BrN2OS: 270 (79Br), 272 (81Br).
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.COCOC.C[C:20]([O:22][CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[C@H:28]([NH2:31])[C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=O>S1(CCCC1)(=O)=O>[NH2:31][CH:28]1[C:29](=[O:30])[N:26]2[C:25]([C:34]([OH:36])=[O:35])=[C:24]([CH2:23][O:22][CH3:20])[CH2:33][S:32][C@H:27]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: O=S1(=O)CCCC1
Solvent: COCOC
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
16.7 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2), 2.18 g of trimethyl borate and 2.45 g of methylal (prepared as described in Preparation 5) were added to 20 ml of sulfolane. The mixture was cooled to 10° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 10° C. for 1.5 hours. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2. 1.94 g (yield 79%) of the title compound were produced with high purity.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:4][NH:5][C:6]([NH2:8])=[O:7].[C:17](OC(C)(C)C)(=[O:22])[CH2:18][C:19]([CH3:21])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[C:3]=1[CH2:4][N:5]1[C:19]([CH3:21])=[CH:18][C:17](=[O:22])[NH:8][C:6]1=[O:7]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: NC(=O)NCc1c(F)cccc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
(2-Fluoro-6-trifluoromethyl-benzyl)-urea (2.568 g, 10.9 mmol) in toluene (125 mL) was heated briefly to reflux under a Dean-Stark trap. T-butyl acetoacetate (5.0 g) was added and the mixture heated to reflux for 4 hrs. p-Toluenesulfonic acid monohydrate (2.82 g, 14.8 mmol) was added and the reflux was continued for one additional hour. Toluene was displaced with i-PrOH and the volume of the solution was reduced to approximately 30 mL. The solution was stirred overnight at room temp. The crystalline product was filtered and washed with a few mL of i-PrOH to provide 2.01 g (63% yield) of 1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione. LCMS (ESI) m/z 303.0 (MH+)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)COB([C:35]2[CH:36]=[CH:37][C:38]([N:41](C)[C:42](=O)OC(C)(C)C)=[N:39][CH:40]=2)OC1>>[CH3:42][NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:40][N:39]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OCC(C)(C)CO2)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CNc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-methanesulfonyl-piperazin-1-yl)methyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with tert-butyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-2-yl(methyl)carbamate (Kumar et al (2003) J. Label Compd. Radiopharm., 46:1055-1065) via General Procedure A. Purification on silica yielded 195 (note BOC group cleaved during Suzuki reaction). NMR (CDCl3): 2.66-2.68 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.00 (s, 3H, CH3), 3.28-3.30 (m, 4H, 2×CH2), 3.86-3.88 (m, 6H, 3×CH2), 4.00-4.02 (m, 4H, 2×CH2), 4.12 (s, H, NH), 6.57 (d, H, ArH, J=9.03 Hz), 7.26 (s, H, ArH), 8.62 (d, H, ArH, J=9.04 Hz), 9.00 (s, H, ArH). MS: (ESI+): MH+504.33
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(CN)OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(CNC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzyl chloroformate (231.3 g, 1.3 mol) was added gradually to a mixture of aminoacetaldehyde dimethyl acetal (152.0 g, 1.3 mol) in toluene (750 mL) and aqueous NaOH (72.8 g, 1.82 mol; in 375 mL of water) at 10-20° C. After the addition was complete, the mixture was stirred at ambient temperature for 4 h. The organic layer was separated, washed with brine (2×100 mL) and concentrated to provide the title compound. MS (DCl/NH3): m/z 240 (M+1)+, 257 (M+18)+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH:14]([OH:35])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>>[C:29]1([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:14]([OH:35])[CH2:13][S:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][CH:2]=[N:1]4)[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Sc1cccc2ncccc12
Product: OC(CSc1cccc2ncccc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 20.3 %

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 220 mg of 5-quinolinethiol and 1.2 g of 4-(3-chloro-2-hydroxypropyl)-1-(diphenylmethyl)piperzine, in order to obtain 130 mg of 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropylthio]quinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=3)=[CH:21][CH:22]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)n2ccnc12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)n2ccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A mixture of methyl [5-(4-aminobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (17 mg, 0.06 mmol), p-trifluoromethylbenzoyl chloride (0.01 mL, 0.07 mmol) and triethylamine (0.016 mL, 0.11 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour. The reaction was quenched with water, and extracted with chloroform. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (silica gel, chloroform:methanol, 95/5) to give methyl [5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (21.5 mg, 80%) as slightly yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][S-:12].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][CH3:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: C[S-]
Reactant: COc1cc(F)ccc1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1Br
Temperature: 85 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methoxybenzene (4.0 g) in DMF (40 mL) was added sodium methanethiolate (2.76 g). The mixture was stirred at room temperature for 30 minutes and at 85° C. for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 280 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/C(O)=O)=[CH:22][CH:21]=2)=[C:4]([CH3:31])[CH:3]=1.NN.C[N:35]([C:37]([O:41]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C[N:68]([CH:70]=[O:71])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:70]3[O:71][C:37](=[O:41])[NH:35][N:68]=3)=[CH:24][CH:25]=2)=[C:4]([CH3:31])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3C)sc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(Oc3ccc(/C=C/c4n[nH]c(=O)o4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (40 mg, 0.092 mmol) was dissolved in DMF (1 mL). The vial was charged with hydrazine (5.90 mg, 0.184 mmol), HATU (52.5 mg, 0.138 mmol), and DIEA (0.048 mL, 0.276 mmol). The reaction mixture was stirred for 10 min at room temperature. The reaction was quenched with sat. aq. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to afford to crude product. The crude material was purified by column chromatography (SiO2, 1-20% MeOH/DCM) to afford (E)-5-(4-((2-(4-fluor-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one (38 mg, 0.085 mmol, 92% yield). LC/MS (m/z, MH+): 449.1
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:18])[CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:8][CH2:7]2.[Br:19]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:5]1[C:4](=[O:18])[NH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:10]2
Reactant: BrBr
Reactant: Cc1[nH]c(=O)cc2c1CC(c1ccncc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(Br)c2c1CC(c1ccncc1)CC2
Yield: 39.5 %

Procedure:
2,3,5,6,7,8-Hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline (0.4 g) obtained in Example 1 was dissolved in 6 ml of acetic acid, and a solution of 0.27 g of bromine and 1.3 ml of acetic acid was dropwise added at 45° C. After the reaction was completed, the reaction mixture was poured into water and an aqueous solution of sodium hydroxide was added to adjust the pH to 9-10. The deposit was filtered out and recrystallized from methanol. Thus, there was obtained 0.21 g of 4-bromo-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:25](=[O:26])[O:27][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)COC(=O)Cl
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Solvent: C1CCOC1
Product: CC(C)COC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 0.89 mmol) and TEA (360 mg, 3.6 mmol) in THF (200 mL) at −20° C. was slowly added iso-butyl chloroformate (121 mg, 0.89 mmol) in THF (10 mL). Then the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 15%-40%, 25 min) to give the title compound (185 mg, 38%) as TFA salt. 1H NMR DMSO 400 MHz δ 9.98 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.43 (q, 2H), 7.20 (d, J=8.8 Hz, 1H), 7.11 (q, 1H), 6.48 (s, 1H), 6.35 (q, 1H), 4.84 (s, 2H), 4.50 (s, 2H), 3.75 (d, J=7.2 Hz, 2H), 1.84 (q, 1H), 0.88 (q, 6H).