Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)OC1.[CH3:20][N:21]1[CH2:26][CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[CH2:23][CH2:22]1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][N:21]1[CH2:22][CH:23]=[C:24]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)COB(c2cc(N)cc(C(F)(F)F)c2)OC1
Reactant: CN1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CN1CC=C(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 80 °C

Procedure:
3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine (8.8 g, 0.032 mol) was added to trifluoro-methanesulfonic acid 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (7.91 g, 0.032 mol) and 2N Na2CO3 aqueous solution (25 mL) was bubbled through N2 for 5 min. Pd(PPh3)4 (3.7 g, 3.2 mmol) was added and the reaction was heated to 80° C. for 16 h. The reaction was cooled to RT and diluted with Et2O (100 mL). The mixture was filtered through Celite® and the filtrate was washed with NaHCO3 aqueous solution (25 ml) followed by brine (25 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The desired product was isolated by passing through silica gel column chromatography (EtOAc, then (2M NH3) in MeOH/EtOAc) to provide a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[NH:50][CH2:49][CH2:48]2>CN(C)C=O>[Br:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[N:50]([C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:49][CH2:48]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
To a mixture of phenylacetic acid (0.687 g, 5.05 mmol) and HATU (2.112 g, 5.55 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added Hunig's base (0.882 mL, 5.05 mmol), and the resulting mixture was stirred for 15 minutes at room temperature. 5-bromo-2,3-dihydro-1H-indole (1 g, 5.05 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was poured onto water, and the resulting precipitate was filtered and air dried to afford the 5-bromo-1-(phenylacetyl)-2,3-dihydro-1 H-indole (1.24 g) as a tan solid.
Reaction SMILES: C(OC([NH:8][C:9]1([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:16][CH:15]2[N:17]([CH2:18][C:19]3[NH:24][C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[N:22][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[Cl:37])[C:20]=3[C:38]([O:40][CH3:41])=[O:39])[CH:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:10][CH:11]2[N:17]([CH2:18][C:19]3[NH:24][C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[N:22][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[Cl:37])[C:20]=3[C:38]([O:40][CH3:41])=[O:39])[CH:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1
Reactant: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2CC1=C(C(=O)OC)[C@H](c2ccc(F)cc2Cl)N=C(c2nccs2)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1(N)CC2COCC(C1)N2CC1=C(C(=O)OC)[C@H](c2ccc(F)cc2Cl)N=C(c2nccs2)N1
Reaction time: 2 h

Procedure:
A mixture of 146b (0.14 g, 0.20 mmol), TFA (2 mL) in DCM (5 mL) was stirred for 2 hours. The solvents were removed under reduced pressure to give crude methyl (4R)-6-[[7-amino-7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate in TFA salt form. MS: calc'd (MH +) 592, exp (MH+) 592. This TFA salt (35 mg, 0.051 mmol) was dissolved in a mixture of TEA (20.6 mg, 0.204 mmol) in DCM (3 mL). To it was added CH3SO2Cl (11.7 mg, 0.102 mmol). The resulting mixture was stirred for 12 hours at room temperature, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give two products, Example 146 and Example 147.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[C:19](C)[CH:20]=[CH:21][CH:22]=3)[C:3]=12.[F:25]C1C=C(C=CC=1)C=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[CH:18]=3)[C:3]=12
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1
Product: Cn1nc(-c2cccc(F)c2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 32 was synthesised following similar procedures outlined in Example 24 (Compound 19), using 3-fluorobenzaldehyde instead of 3-methylbenzaldehyde in Step 1.
Reaction SMILES: [ClH:1].[Cl-].[CH3:3][N+:4]([CH3:22])([CH2:11][CH2:12][N:13]([CH2:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][NH:8]C=O>>[Cl-:1].[CH3:22][N+:4]([CH3:3])([CH2:11][CH2:12][N:13]([CH2:20][CH3:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: CCN(CC[N+](C)(C)CCCNC=O)c1ccccc1
Reactant: Cl
Agent: [Cl-]
Product: CCN(CC[N+](C)(C)CCCN)c1ccccc1

Procedure:
Dilute hydrochloric acid hydrolysis of N,N-dimethyl-N-2-(N'-ethylanilino)ethyl-N-3-formamidopropylammonium chloride following a procedure similar to that of B-4 above gives N,N-dimethyl-N-2-(N'-ethylanilino)ethyl-N-3-aminopropylammonium chloride.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[F:26][C:27]1([F:42])[CH2:32][CH2:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:30]3[CH2:31][CH2:32][C:27]([F:42])([F:26])[CH2:28][CH:29]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC1(C)OB(C2=CCC(F)(F)CC2)OC1(C)C
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(c1ccc(Oc2nccnc2C2=CCC(F)(F)CC2)cc1)c1nc2ccccc2[nH]1
Reaction time: 8 h

Procedure:
To a round bottomed flask was added (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (0.5018 g, 1.431 mmol), 2-(4,4-difluorocyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.698 g, 2.86 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.080 g, 0.114 mmol), and sodium carbonate (0.455 g, 4.29 mmol) in DME (3.58 mL) and water (1.192 mL) at 80° C. to stir overnight. Upon completion, solvent was removed. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 15 min to provide (1H-benzo[d]imidazol-2-yl)(4-(3-(4,4-difluorocyclohex-1-enyl)pyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 433.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[CH3:9])=[CH:18][CH:17]=2)=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1ccccc1OC(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3C)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.2 %

Procedure:
To the solution of 4-(1-(o-tolyloxy)ethyl)benzoic acid (127 mg, 0.5 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mmol). then the 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added, the solution was stirred at room temperature for 12 hours, then washed with water (50 mL*3), the organic layer was evaporated and purified by column chromatography (silica gel, dichloromethane/meth anol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(o-tolyloxy)ethyl)benzamide (57 mg, 30%). LRMS (M+H+) m/z: calcd: 390.19. found 390; 1H-NMR (300 MHz, CD3OD) δ 7.75 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.71-7.08 (m, 1H), 6.97-6.92 (m, 1H), 6.77-6.66 (m, 2H), 6.10 (s, 1H), 5.46-5.44 (m, 1H), 4.48 (s, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 1.62 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].CCN(C(C)C)C(C)C.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CCCC(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 100 %

Procedure:
3-Nitroaniline (6.00 g, 43.4 mmol) was sealed in a flask with stir bar under nitrogen and dissolved with dichloromethane (DCM, 145 mL). The solution was cooled on ice before (i-Pr)2NEt (8.35 ml, 47.8 mmol) and butyryl chloride (5.00 ml, 47.8 mmol) were added. The flask was removed from the ice and stirred for 16 h. The reaction was then diluted with DCM and aq. 1 M HCl, the layers were separated, and the combined organics were washed again with 1 M aq. HCl, then twice with half-saturated aq. NaHCO3, then brine. The organic phase was dried over MgSO4, filtered, and concentrated, yielding a yellow oil (9.04 g, 100%). LRMS (ESI−) (M−H): 207.06. The crude oil was used without further purification in the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])([C:10]([OH:13])([CH3:12])[CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH2:22]([O:24][C:25](OCC)(OCC)OCC)[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:9])[C:10]([CH3:12])([CH3:11])[O:13][C:25]([O:24][CH2:22][CH3:23])=[N:17][S:14]2(=[O:15])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)(OCC)OCC
Reactant: CC(C)(O)C(C)(c1cccc(Br)c1)S(N)(=O)=O
Solvent: CC(=O)O
Product: CCOC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A suspension of 14.40 g of 2-(3-bromophenyl)-3-hydroxy-3-methylbutane-2-sulfonamide (50%, contaminated with 1-(3-bromophenyl)ethanesulfonamide)) in 100 ml of tetraethoxymethane was admixed with 12 ml of acetic acid and stirred at 100° C. under a strong argon stream for 6 hours. After the removal of the solvent under reduced pressure (bath temperature 70° C.), the viscous residue was dried at 50° C. in a vacuum drying cabinet for 16 hours. The conversion was checked by LCMS and found to be incomplete. Therefore, the oily residue was left to react on the rotary evaporator under reduced pressure (bath temperature 80° C.) for 4 hours. After the addition of 10 ml of acetic acid, the bath temperature was increased to 85° C. and the pressure was adjusted to 150 mbar. Subsequently, the volatile constituents were removed, again under reduced pressure, and the crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (5.97 g) with a molecular weight of 376.3 g/mol (C14H18BrNO4S).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]=O)[CH:3]=1.[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>C(O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][N:13]=3)[CH:14]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])[CH:3]=1
Reactant: Cc1cc(Nc2ncccc2C=O)no1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2n(-c2cc(C)on2)c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
3.3 g (16 mmol) of (2-(5-methyl-3-isoxazolyl)amino)nicotinaldehyde was dissolved in ethanol (60 mL), and 3.9 g (24 mmol) of diethyl malonate and 0.56 g (6.5 mmol) of piperidine were added thereto. The resulting mixture was stirred overnight at 90° C. The reaction mixture was cooled, and then the solvent was distilled off. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 7:3), and thus 2.7 g of the title compound was obtained as pale yellow crystals (yield: 55%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[CH2:13][C:14]1[C:15]2[N:16]([CH:20]=[CH:21][N:22]=2)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:22]1[CH:21]=[CH:20][N:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=3)[CH:7]=[O:8])[C:15]=12
Reactant: COc1ccc(O)cc1C=O
Reactant: ClCc1cccn2ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OCc2cccn3ccnc23)cc1C=O
Temperature: 125 °C

Procedure:
A mixture of 5-hydroxy-2-methoxybenzaldehyde (723.6 mg, 4.7 mmol), 8-(chloromethyl)-imidazol[1,2-a]pyridine (785 mg, 4.7 mmol), and K2CO3 (1.9 g, 14.1 mmol) in DMF (20 mL) was heated at microwave reactor at 125° C. for 15 min. The mixture was filtered and concentrated. The residue was purified on silica gel (50-100% EtOAc in hexanes) to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxybenzaldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:21])([CH3:20])[CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2].F[B-](F)(F)F.[O:29]=[N+:30]=[O:31]>C(Cl)Cl>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:20])([CH3:21])[CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([CH2:17][O:18][N+:30]([O-:31])=[O:29])[CH:14]=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2]
Reactant: O=[N+]=O
Reactant: CC1(C)C=C(n2cc(CO)ccc2=O)c2cc(C#N)ccc2O1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(C)C=C(n2cc(CO[N+](=O)[O-])ccc2=O)c2cc(C#N)ccc2O1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
In 10 ml of anhydrous methylene chloride, is suspended 581 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro- 2-oxo-5-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 14. Then, 270 mg of nitronium tetrafluoroborate is added at room temperature and reacted at that temperature for 30 minutes. After stopping the reaction by adding ice water, the reaction mixture is extracted with methylene chloride, and the organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/25 mixture of ethyl acetate/ether as a developing solvent. Thus, 328 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-5-nitroxymethyl-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:23])=[CH2:22]>CC(C)=O>[Br: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][CH2:22][C:21]([CH3:23])=[CH2:20]
Reactant: C=C(C)CBr
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1cc(C(=O)OC)ccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a heterogeneous mixture of methyl 4-bromo-3-hydroxybenzoate (1.5 g, 6.49 mmol) and potassium carbonate (1.795 g, 12.98 mmol) in anhydrous acetone (50 mL) was added 3-bromo-2-methylprop-1-ene (2.62 mL, 26.0 mmol) at rt. The mixture was stirred rt for 4 h. The insoluble material was removed by filtration. The filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (100 mL), washed sequentially with 1 N NaOH solution (30 mL), water (2×40 mL), and brine (30 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was applied to ISCO (80 g silica gel, 5-10% ethyl acetate/hexane) to provide the desired product, methyl 4-bromo-3-(2-methylallyloxy)benzoate (1.81 g, 6.35 mmol, 98% yield), as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7].[C:42]([O:46][C:47](=[O:55])[NH:48][CH2:49][CH2:50][NH:51][CH:52]1[CH2:54][CH2:53]1)([CH3:45])([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:42]([O:46][C:47]([NH:48][CH2:49][CH2:50][N:51]([CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7])[CH:52]1[CH2:53][CH2:54]1)=[O:55])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCl)c4)sc4c3CCCC4)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCNC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN(CCNC(=O)OC(C)(C)C)C5CC5)c4)sc4c3CCCC4)cc2)cc1
Yield: 97.7 %

Procedure:
By using 2.0 g of methyl 4-[2-(4-{[(2-{[3-(chloromethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 1.0 g of tert-butyl[2-(cyclopropylamino)ethyl]carbamate, 0.76 g of potassium carbonate, and 40 mL of DMF, 2.5 g of methyl 4-(2-{4-[({2-[(3-{[{2-[(tert-butoxycarbonyl)amino]ethyl}(cyclopropyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate was obtained by the method similar to Preparation Example 9.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].[ClH:12].Cl[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([Cl:12])([CH:6]=[N:7][OH:8])[CH2:4][C:3]=1[CH3:11]
Reactant: Cl
Reactant: Cc1cc(C=NO)ccc1Br
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: CC1=C(Br)C=CC(Cl)(C=NO)C1
Reaction time: 0.75 h
Yield: 97.4 %

Procedure:
In a solution of 82.0 g of 4-bromo-3-methylbenzaldoxime in 450 ml of tetrahydrofuran, 120.0 g of concentrated hydrochloric acid was added adropwise with stirring under ice cooling over 45 minutes. Then, 220 ml of 8% sodium hypochlorite aqueous solution was carefully added dropwise over 75 minutes so that the temperature of the reaction mixture would not exceed 5° C., after the completion of the addition, continued to stir at 10° C. or less further for 90 minutes. After the completion of the reaction, nitrogen gas was blown through the reaction mixture for 45 minutes and precipitated insoluble material was filtered off, and tetrahydrofuran was distilled off under reduced pressure. The remaining aqueous solution was extracted with 240.0 g of ethyl acetate. The organic phase was washed with water (240 ml×2) and then insoluble material was filtered off, the solvent was distilled off under reduced pressure to obtain 93.5 g of the aimed product as pale yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:19]([CH2:35][NH:36][CH3:37])[CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[CH2:24][CH2:23]2)[CH:15]=[CH:16][C:17]=1[Cl:18]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[CH2:26][CH2:27]2)[CH2:35][N:36]([CH3:37])[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CNC[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cccc(F)c1

Procedure:
3-Fluorobenzoyl chloride (0.088 mL) was reacted with (S)-1′-[3-(3,4-dichloro-phenyl)-4-methylamino-butyl]-[1,4]bipiperidinyl-2-one (0.30 g) in dichloromethane (78 mL) overnight. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic extracts were dried, evaporated, and purified by chromatography, with dichloromethane:methanol (gradient 97:3, 94:6) as eluent to give the title compound (0.28 g). Rf=0.36 in methylene chloride:methanol (95:5). MS: m/z=534 (M+). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue was triturated with ether. The product was obtained as a white foam (0.093 g).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH2:23][C:24]([O:26]CC)=[O:25])=[N:15]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH2:23][C:24]([OH:26])=[O:25])=[N:15]3)=[CH:11][CH:10]=2)=[O:7])=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc12
Yield: 96.6 %

Procedure:
Ethyl 2-[1-[4-(4-chlorobenzamido)benzyl]-1H-indazol-3-yl]acetate (159 mg, 0.355 mmol) was dissolved in tetrahydrofuran (10 mL). In an ice bath, 10 mL aqueous solution dissolving lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated. It was filtered, and dried to obtain a white solid 144 mg, at a yield of 96.6%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:40]([N:47]1[CH2:51][CH2:50][C@@H:49]([C:52](O)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:40]([N:47]1[CH2:51][CH2:50][C@@H:49]([C:52]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:53])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)[C@@H]1CCN(Cc2ccccc2)C1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)[C@@H]1CCN(Cc2ccccc2)C1
Yield: 33.9 %

Procedure:
This compound was prepared according to method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.181 g; 0.476 mmol), (R)-1-benzylpyrrolidine-3-carboxylic acid hydrochloride (0.119 g; 0.476 mmol), and N,N-diisopropylethylamine (0.189 mL; 1.08 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of a solution of 5% ammonium hydroxide in methanol, in dichloromethane) to afford 0.056 g (34%) of (R)-1-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)pyrrolidine-3-carboxamide as a white solid.