Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:47][NH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][S:58]([CH3:61])(=[O:60])=[O:59].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:10]([C:11](=[O:12])[N:48]([CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH3:47])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CNCCc1ccccc1NS(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccc1NS(C)(=O)=O)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3(2-naphthyl)propionic acid (444 mg, 1.35 mmol) and successively 1-hydroxy-7-azabenzotriazole (184 mg, 1.35 mmol) were dissolved in N,N-dimethylformamide (5 ml) and dichloromethane (7 ml). The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (259 mg, 1.35 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of N-(2-(2-(methylamino)ethyl)phenyl)methanesulfonamide (308 mg, 1.35 mmol) was added. Ethyldiisopropylamine (0.23 ml, 1.35 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate and washed with 10% aqueous sodium hydrogen sulfate solution (70 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (150 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using ethyl acetate/heptane (1:1) as eluent, to give 245 mg of N-((1R)-1-(N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl-ester.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=3)[C:7]1=2
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Reactant: Brc1cccc2ccsc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Clc1cc(-c2cccc3ccsc23)ccn1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
In a flask, combine 7-bromo-benzo[b]thiophene (1.7 g, 12 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.6 g, 7 mmol), Pd(dppf)Cl2 (285 mg, 0.3 mmol), 2-(di-tert-butylphosphino)biphenyl (63 mg, 0.2 mmol), sodium carbonate (2 M, 8 mL, 16 mmol) and THF (20 mL). Heat the mixture at 100° C. for 3 h. Dilute the mixture with chloroform/IPA (3/1). Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo to a dark residue. Purify by column chromatography (DCM to 20% THF in DCM) to afford the title compound (1.14 g, 66%) as a yellow solid. MS (ES) m/z 246 [M+1]+.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CS(C)=O.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][CH2:21][CH2:22][OH:23])[C:14]=2[N:13]=[CH:12]1.O>C(Cl)Cl>[CH2:15]([N:11]([CH2:12][CH2:1][CH3:2])[CH:20]([C:19]1[C:14]2[N:13]=[CH:12][NH:11][C:15]=2[CH:16]=[CH:17][CH:18]=1)[CH2:21][CH:22]=[O:23])[CH2:14][CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCCCc1cccc2[nH]cnc12
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCN(CCC)C(CC=O)c1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (1.2 mL, 0.014 mol) was added with stirring to methylene chloride (20mL) at -78° C. Ten minutes after addition was complete, DMSO (2 mL) was added and stirring was continued for an additional 10 minutes. β-Dipropylamino)-1H-benzimidazole-4propanol (2.1 g, 7.5 mmol) in methylene chloride was added and, after 30 minutes, the solution was allowed to warm to room temperature. Water was added, the methylene chloride was separated and evaporated, and the residue was chromatographed on silica gel to give β-(dipropylamino)-1H-benzimidazole-4-propanal as an oil.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][CH:12]=[C:11]([CH2:14]O)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[CH:10]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[S:13][CH:12]=1
Reactant: CC1(c2cc(CO)cs2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cc(CCl)cs2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-methanol (460 mg, 2.30 mmol) in dry CH2Cl2 (4.6 mL) was treated at 0° C. with Et3N (0.42 mL, 2.99 mmol) followed by DMAP (28 mg, 0.23 mmol) and Ms-Cl (0.21 mL, 2.76 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (20 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a pale yellow oil. TLC:rf (1:4 EA-Hept)=0.35.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4](C)[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[CH3:25])(=[O:15])=[O:14].CO.[OH-].[Li+]>O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH3:25])[C:16]([S:13]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])(=[O:14])=[O:15])=[C:21]([CH3:22])[CH:20]=1
Reactant: COC(=O)C(C)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 4-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)butanoic acid methyl ester (1.65 g, 4.3 mmol) was dissolved in water (10 ml) and methanol (35 ml) and lithium hydroxide (0.3 g, 12.9 mmol) was added. The mixture was stirred for 3 d at room temperature, then methanol was distilled off under vacuum and ethyl acetate (50 ml) and HCl solution (1 mol/l, 10 ml) added to the residue. Phase separation, extraction with ethyl acetate (2×50 ml), the combined organic phases were dried over sodium sulfate and concentrated to small volume under vacuum. Yield: 1.56 g (98%)
Reaction SMILES: [CH2:1]([C:4]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8](O)=[O:9])[CH:2]=[CH2:3].S(Cl)([Cl:21])=O>>[CH2:1]([C:4]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([Cl:21])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OCC(=O)O)cccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: C=CCc1c(OCC(=O)Cl)cccc1C(F)(F)F

Procedure:
7 g of the product of Step D in 50 ml of thionyl chloride was refluxed for 2 hours and after concentrating, the residue was taken up in toluene. The solvents were eliminated under reduced pressure and the crude product obtained was used as is for Step F.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7]CCCCC(O)=O.Br[CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: Cn1ccnc1SCCCCC(=O)O
Reactant: O=C(O)CCBr
Product: Cn1ccnc1SCCC(=O)O

Procedure:
3-(1-methyl-1H-imidazol-2-ylthio)propanoic acid 28a was prepared as described for 5-(1-methyl-1H-imidazol-2-ylthio)pentanoic acid (Tweit, et al. (1973) J. Med. Chem. 16:1161), except that 3-bromopropanoic acid was used as the starting material. 1H NMR (400 MHz, CDCl3): 2.62-2.65 (t, 2H, J=6.4 Hz), 3.13-3.16 (t, 2H, J=6.4 Hz), 3.73 (s, 3H), 7.34-7.35 (d, 1H, J=2.1 Hz), 7.38-7.39 (d, 1H, J=2.1 Hz), 11 (br s, 1H). MS (ESI): 187 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[C:6]([CH3:16])[CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[C:6]([CH3:16])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NCC(O)CO
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)ccc1NCC(O)CO

Procedure:
The 3-(4-nitro-2-methylphenylamino)propane-1,2-diol (7) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH2:10][CH:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][C:20]4[N:16]([N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[CH:19]=4)[C:15]=3[CH:32]=2)[CH2:8]1)([CH3:6])[CH3:5].CC(C[AlH]CC(C)C)C>C1COCC1>[CH:29]([N:25]1[C:24]([C:18]2[CH:19]=[C:20]3[N:16]([C:15]4[CH:32]=[C:11]([CH:9]5[CH2:10][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:8]5)[CH:12]=[CH:13][C:14]=4[O:23][CH2:22][CH2:21]3)[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: COC(=O)C(C)(C)N1CC(c2ccc3c(c2)-n2nc(-c4ncnn4C(C)C)cc2CCO3)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(C(C)(C)CO)C3)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (200 mg, 0.55 mmol), 2-bromo-2-methyl propionate (71 L, 0.55 mmol), triethylamine (75 L, 0.55 mmol) in DMF was heated at 55° C. for 30 h before concentrating in vacuo. The residue was partitioned between 10% MeOH in DCM and water, the aqueous extracted with 10% MeOH in DCM and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester 63 (56 mg, 23%). To a solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester 63 (56 mg, 0.12 mmol) in THF (1.5 mL) at −78° C. was added DIBAL (1.5 M solution in toluene, 0.24 mL, 0.36 mmol) and the mixture allowed to warm to RT over 18 h. The mixture was cooled to 0° C., further DIBAL (0.12 mL, 0.18 mmol) added dropwise and stirring continued for 45 min. The reaction was quenched by the addition of MeOH (0.5 mL) followed by Rochelle's salt saturated aqueous solution (0.5 mL), then diluted with ethyl acetate and filtered through Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH (+2M NH3) in DCM) to give 170 as a white solid, as illustrated in FIG. 13 (27 mg, 53%). 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1 H); 7.85 (d, J=2.18 Hz, 1 H); 7.23 (d, J=2.23 Hz, 1 H); 7.17 (d, J=8.29 Hz, 1 H); 6.87 (s, 1 H); 5.74-5.66 (m, 1 H); 4.55 (t, J=6.02 Hz, 2 H); 3.71 (s, 3 H); 3.43 (s, 2 H); 3.28 (s, 2 H); 3.16 (t, J=6.03 Hz, 2 H); 1.59 (d, J=6.62 Hz, 6 H); 1.04 (s, 6 H). 1 Exchangeable proton not observed. LCMS: RT=6.43 min, M+H+=423
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH:40]1[CH:44]=[C:43]([C:45]2[N:50]=[N:49][C:48]([C:51]3([NH2:54])[CH2:53][CH2:52]3)=[CH:47][CH:46]=2)[CH:42]=[N:41]1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:11](=[O:13])[NH:54][C:51]1([C:48]2[N:49]=[N:50][C:45]([C:43]3[CH:44]=[N:40][NH:41][CH:42]=3)=[CH:46][CH:47]=2)[CH2:52][CH2:53]1)[CH3:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1(c2ccc(-c3cn[nH]c3)nn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ccc(-c3cn[nH]c3)nn2)CC1
Reaction time: 2 h

Procedure:
To a solution of the N-Boc-alanine (89 mg, 0.48 mmol), HATU (199 mg, 0.52 mmol), and 1-[6-(1H-pyrazol-4-yl)-pyridazin-3-yl]-cyclopropylamine dihydrochloride (130 mg, 0.48 mmol) in CH2Cl2 (1.9 mL) was added diisopropylethylamine (0.33 mL, 1.9 mmol). The brown mixture was stirred for 2 h then 10% (w/w) aqueous Na2CO3 (5 mL) was added and stirring continued for 20 min. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford a brown oil. This was purified via normal phase flash chromatography on silica gel (1→20% MeOH/CH2Cl2) to yield mg of ((S)-1-{1-[6-(1H-pyrazol-4-yl)-pyridazin-3-yl]-cyclopropylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester, m/z 373.7 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].C[O:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:31])/[C:17](/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO.ClCCl.O>[C:25]1(/[C:17](=[CH:18]\[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[C:16]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:2][OH:3])=[O:7])=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NO
Reactant: COC(=O)CCCCCCNC(=O)/C(=C/c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(CCCCCCNC(=O)/C(=C/c1ccccc1)c1ccccc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
Hydroxylamine hydrochloride (1.4 g, 19.7 mmol) in methanol (3 mL) was mixed with KOH (1.1 g, 19.7 mmol) in methanol (2.5 mL) at 0° C. and the reaction mixture was sonicated for 5 minutes. A white precipitate was formed which was filtered. The filtrate was immediately added to the methyl-(2E)-7-(2,3-diphenylacrylamido)heptanoate (0.4 g, 1.1 mmol) in dichloromethane (1 mL) and the mixture was stirred at room temperature for 30 min. Reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate, (200 mL). The organic layer was washed successively with water (3×50 mL) and brine solution (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude compound, triturated with dichloromethane (20 mL), to afford the title compound as a pure colorless solid (0.230g, 58% yield). 1H NMR (DMSO-d6) δ (ppm): 1.23 (4H, m, —CH2), 1.42-1.49 (41-1, m, —CH2), 1.91-1.94 (2H, t, —CH2), 3.09-3.14 (2H, q, —CH2), 6.96-6.98 (2H, t, Ar—H), 7.15-7.17 (5H, m, Ar—H), 7.34 (1H, s, ═CH), 7.36-7.44 (4H, m, Ar—H & —NH), 9.00 (1H, s, —NH), 10.34 (1H, s, —NH). MS m/z: 367.0 (M++1). The following compounds were prepared according to the above procedure
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[CH2:30]([CH:33]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[F:47])[CH2:36][NH:35]/[C:34]/1=[N:48]\[NH2:49])[CH:31]=[CH2:32].[F:50][C:51]([F:57])([F:56])[CH2:52][C:53](O)=O>C(#N)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:30]([CH:33]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[F:47])[CH2:36][N:35]2[C:53]([CH2:52][C:51]([F:57])([F:56])[F:50])=[N:49][N:48]=[C:34]12)[CH:31]=[CH2:32]
Reactant: O=C(O)CC(F)(F)F
Reactant: C=CCC1CCC(c2cccc(F)c2F)CN/C1=N\N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCC1CCC(c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
Triethylamine (142 μL, 1.02 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (196 mg, 1.02 mmol), and 1-hydroxy-7-azabenzotriazole (139 mg, 1.02 mmol) were added to a solution of (2Z)-3-allyl-6-(2,3-difluorophenyl)azepan-2-one hydrazone (285 mg, 1.02 mmol) and 3,3,3-trifluoropropanoic acid (90 μL, 1.02 mmol) in acetonitrile (25 mL). After 18 h, additional triethylamine (0.14 mL, 1.02 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol), 1-hydroxy-7-azabenzotriazole (70 mg, 0.51 mmol) and 3,3,3-trifluoropropanoic acid (45 μL, 0.51 mmol) were added. After 5.5 h, the reaction mixture was heated to 60° C. After 2.5 h, the mixture was cooled to ambient temperature. After 18 h, the reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with saturated brine, dried with sodium sulfate, filtered and concentrated. Purification by reverse phase HPLC (100% water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compounds (275 mg). MS 372.1 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.CC1C=CC(S(O[CH2:55][C@@H:56]2[CH2:61][O:60][CH2:59][CH2:58][O:57]2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:57]1[CH2:58][CH2:59][O:60][CH2:61][C@H:56]1[CH2:55][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COCCO2)cc1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(C[C@@H]2COCCO2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, (8S)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (84%) as a colorless solid: mp 207-210° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.30 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 7.15 (dd, J=7.5 Hz, 0.9 Hz, 1H), 7.08-7.02 (m, 2H), 6.49 (s, 1H), 6.21 (s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.63 (d, J=9.0 Hz, 1H), 4.21-4.16 (m, 2H), 4.13-4.09 (m, 2H), 3.98-3.77 (m, 4H), 3.75-3.56 (m, 4H), 3.41 (dd, J=11.7, 9.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.3, 144.7, 142.7, 138.4, 132.3, 128.9, 123.9, 123.5, 121.1, 111.6, 109.4, 99.5, 80.2, 73.3, 69.4, 66.8, 66.5, 64.6, 64.0, 58.0, 41.9; MS (ES+) m/z 396.0 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[C:16]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CN([CH:31]=[O:32])C>C1COCC1.CCOC(C)=O.O.CC(O)=O>[F:13][C:14]1[CH:15]=[C:16]([CH:24]=[C:25]([F:27])[C:26]=1[CH:31]=[O:32])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(F)c(C=O)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a stirred solution of diisopropylamine (5 mL, 35.5 mmol, 1.2 eq) in THF (100 mL, anhyd) was slowly added BuLi (1.6M in hexanes, 20 mL, 32.3 mmol, 1.1 eq) at below 0° C. After addition was completed, the solution was cooled to −78° C. and then charged dropwise with a solution of tert-butyl 3,5-difluorobenzoate (6.3 g, 29 mmol) in THF (50 mL, anhyd) over 1 h. The resulting solution was stirred for another 2 h at −78° C. Next anhyd DMF (2.5 mL, 32.3 mmol, 1.1 eq) was added dropwise and, after 30 min, AcOH (4 mL) and water were added successively to quench the reaction. The reaction mixture was warmed to room temperature and diluted with EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-formylbenzoate (5.8 g, 83%) as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:24]1[N:25]=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[Cu](I)I>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:27]3[CH:26]=[N:25][C:24]5[C:29]([CH:28]=3)=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCc2cc(OC3CCN(C4CCC4)CC3)ccc2N1
Reactant: Brc1cc2ccccc2cn1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(OC3CCN(C4CCC4)CC3)ccc2N1c1cnc2ccccc2c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A suspension of 6-(1-cyclobutylpiperidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one synthesized in Example 4-(1) (0.10 g), 3-bromoisoquinoline (0.10 g), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.047 g), copper iodide (0.016 g) and cesium carbonate (0.22 g) in toluene (1 mL) was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with chloroform and filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: hexane/ethyl acetate=4/1 to 1/4) and OH-type preparative TLC (on two plates of 1 mm thickness, developing solvent: chloroform/methanol=4/1) to give the titled compound (0.061 g, 44%) as a colorless amorphous substance.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8](=[O:23])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17]OS(C)(=O)=O)[CH:11]=1)[CH3:6]>CN(C)C=O>[CH2:5]([O:7][C:8](=[O:23])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][N:1]=[N+:2]=[N-:3])[CH:11]=1)[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)Cc1cccc(CCOS(C)(=O)=O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(CCN=[N+]=[N-])c1
Temperature: 60 °C
Yield: 91.9 %

Procedure:
Sodium azide (2.82 g, 43.3 mmol) was added in one portion to a stirred solution of ethyl(3-{2-[(methylsulfonyl)oxy]ethyl}phenyl)acetate (Preparation 56) (6.20 g, 21.7 mmol) in N,N-dimethylformamide (400 ml) at room temperature. The reaction was heated at 60° C. for 1 hour and then allowed to cool to room temperature and the solvent removed in vacuo. Ethyl acetate (200 ml) and water (75 ml) was added and the organics separated, the aqueous was washed with ethyl acetate (2×100 ml) and the combined organics evaporated in vacuo to yield an oil that was purified by flash column chromatography on silica gel eluting with ethyl acetate:penatane (5:95, by volume) to give the title compound as a colourless oil (4.65 g). 1H NMR (400 MHz, CDCl3): δ=7.27-7.23 (1H, t), 7.17-7.12 (3H, m), 4.15-4.06 (2H, m), 3.60 (2H, s), 3.51-3.47 (2H, t), 2.87-2.84 (2H, t), 1.24-1.20 (3H, t) ppm. LRMS (electrospray): M/Z [M+NA]+256, [M−H]− 232.