Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:23])=[C:5]2[C:19](=[CH:20][C:21]=1[CH3:22])[C:8]1[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:15]=3[C:7]=1[CH2:6]2.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[C:4]([CH3:23])=[C:5]2[C:19](=[CH:20][C:21]=1[CH3:22])[C:8]1[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:15]=3[C:7]=1[CH2:6]2
Reactant: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccc(C(C)C)cc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1O)Cc1c-2[nH]c2ccc(C(C)C)cc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
5,10-Dihydro-2-methoxy-1,3-dimethyl-8-isopropylindeno[1,2-b]indole (0.50 g, 1.64 mmol) was dissolved in dry dichloromethane (DCM, 2 cm3) under anhydrous conditions and cooled to -78° C. Boron tribromide (2 cm3 1.2 eq of 1 M solution in DCM) was added, and warmed to room temperature, whereupon a suspension formed. After 20 minutes, this had re-dissolved. Water (2 cm3) was cautiously added, and the mixture extracted between more DCM, and saturated sodium bicarbonate solution (some solid around during extraction finally dissolved). The DCM layer was dried (Na2SO4) and filtered through a pad of "flash" silica, eluting with DCM to yield a white solid (0.43 g, 90%) M.p. 173° C.(dec.). 1H NMR (CDCl3)δ: 8.04 (1H, br), 7.43 (1H, br), 7.29 (1H, d, J=8.2), 7.04 (1H, br), 4.58 (1H, br), 3.55 (2H, br), 30.2 (1H, septet, J=7.0Hz, 2.30 (3H, s), 2.29 (3H,s), 1.33 (6H, d, J=7.0Hz).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[O:20][N:19]=1>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[O:20][N:19]=[C:18]([CH2:17][N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[N:22]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: COc1ccccc1-c1nc(CCl)no1
Product: COc1ccccc1-c1nc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[2-(methyloxy)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 399 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[C:18]([O:25][CH3:26])(OC)(OC)OC>C(O)(=O)C>[CH2:11]([O:10][C:9]1[C:2]2[N:1]=[C:18]([O:25][CH3:26])[N:4]([CH3:5])[C:3]=2[CH:6]=[CH:7][CH:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(OC)(OC)OC
Reactant: CNc1cccc(OCc2ccccc2)c1N
Solvent: CC(=O)O
Product: COc1nc2c(OCc3ccccc3)cccc2n1C
Reaction time: 4 h

Procedure:
To a solution of 2-amino-3-benzyloxy-N-methylaniline (318.5 mg) in acetic acid (3.2 ml) was added tetramethyl orthocarbonate (233 pl) at ambient temperature, and the mixture was stirred for 4 hours. The reaction mixture was concentrated in vacuo, and to the residue were added ethyl acetate and saturated sodium bicarbonate solution. The separated organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give 4-benzyloxy-2-methoxy-1-methyl-1H-benzimidazole (27.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([CH3:13])([CH3:12])[CH:8]=[CH:7]2.CO.C(=O)([O-])[O-:23].[K+].[K+]>[Pd](Cl)Cl.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]2=[O:23]
Reactant: COC(=O)C(C)c1cc(Cl)c2c(c1)C=CC(C)(C)N2
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(C)c1cc(Cl)c2c(c1)C(=O)CC(C)(C)N2
Reaction time: 6 h
Yield: 28.4 %

Procedure:
1.0 g of methyl 2-(8-chloro-1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate was added to 20 ml of methanol. 2.0 g of palladium chloride was further added to the solution, and the mixture was stirred at 55°-60° C. for 6 hours. After cooling, 2 g of potassium carbonate and benzene were added to the mixture, then the mixture was further stirred. The precipitates were filtered off and washed with benzene. The filtrate and the wash were combined and concentrated, followed by addition of dilute aqueous solution of sodium hydrogencarbonate, and extraction with ether. The ethereal solution was washed with water, saturated aqueous solution of sodium sulfate and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (benzene:ether=9:1) to give 0.3 g of methyl 2-(8-chloro-1,2,3,4-tetrahydro-2,2-dimethyl-4-oxoquinolin-6-yl)propionate (Compound 31).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:15]=[CH:14][S:13][C:17]=4[CH:18]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2ncsc2c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzothiazole-6-carboxylic acid (Maybridge); yield 129 mg, 0.33 mmol (91%) according to methods A and C: 1H NMR (300 MHz, methanol-d4) δ 2.10-2.30 (m, 6H), 2.50 (s, 2H), 3.51 (d, J=12 Hz, 2H), 3.57 (s, 2H), 3.87 (d, J=13 Hz, 2H), 4.31 (s, 1H), 8.08 (dd, J=9, 2 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.69 (d, J=2 Hz, 1H), 9.49 (s, 1H); MS (DCI/NH3) m/z 314 (M+H)+; Anal. C17H19N3OS.2HCl.0.4H2O: C, H, N.
Reaction SMILES: CI.CN([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1)C.[C-:22]#[N:23].[K+].O>CS(C)=O>[C:22]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:14]=2)[NH:9][CH:8]=1)#[N:23]
Reactant: CN(C)Cc1c[nH]c2ccc(CNS(C)(=O)=O)cc12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 2 h
Yield: 17.1 %

Procedure:
Methyl iodide (0.15 ml) was added to a stirred solution of N-[[3-[(dimethylamino)methyl]-1H-indol-5-yl]methyl]methanesulphonamide (0.5 g) in dimethyl sulphoxide (20 ml) followed by potassium cyanide (0.3 g) and the resulting solution stirred for 2 h, before pouring it into water (80 ml) and extracting with ethyl acetate (2×30 ml). The combined organic extracts were washed with water (30 ml), hydrochloric acid (2N, 30 ml) dried (Na2SO4) and evaporated to dryness to give a fawn foam which was purified on a silica column (kieselgel 60, 10 g) eluted with ethyl acetate to give the title compound as a white solid (0.08 g) m.p. 106°-9° after crystallisation from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH:27]([S:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([CH3:29])[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:27]([S:30][C:31]1[CH:36]=[CH:35][C:34]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:33][CH:32]=1)([CH3:29])[CH3:28]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Sc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1nc(C)n(-c2ccc(SC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), [4-(isopropylthio)phenyl]boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.20 g, 84%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][C@@H:7]([CH2:9][OH:10])[CH2:6][O:5]1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1.CN(C=O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:10][CH2:9][C@H:7]2[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]2)=[CH:16][CH:15]=1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(COC[C@H]2COC(C)(C)O2)cc1
Temperature: 0 °C
Yield: 89 %

Procedure:
Sodium hydride (0.8 g) was added with DMF (5 mL) and tetrahydrofuran (THF, 20 mL), and the solution was stirred at 0° C. The solution was added dropwise with a solution of (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol (2.4 g) in mixture of DMF (3 mL) and THF (3 mL), and stirred at 0° C. for one hour. The solution was added with 4-methoxybenzyl chloride (2.8 mL) and stirred at room temperature for three hours. The solution was added with saturated ammonium chloride solution, and extracted twice with ethyl acetate. The resulting organic layer was washed four times with water, once with saturated brine. After the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed to obtain a crude product of (S)-(+)-4-(4-methoxybenzyloxymethyl)-2,2-dimethyl-1,3-dioxolane (4.1 g, 89%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=2)=[C:20]([C:35]([F:38])([F:36])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(Br)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc(Br)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 40-4 (980 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (590 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21](=[O:31])[C:22]1[CH:30]=[CH:29][CH:28]=[C:24]([C:25](O)=[O:26])[CH:23]=1>>[CH3:19][O:20][C:21](=[O:31])[C:22]1[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=3)[CH2:8][CH2:9]2)=[O:26])[CH:23]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: COC(=O)c1cccc(C(=O)O)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(C(=O)OC)c3)CC2)ccc1Cl
Yield: 92 %

Procedure:
The title compound (80 mg, 92%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with isophthalic acid monomethyl ester. MS: 431.6 (MH+).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:35][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Reactant: NCC(F)(F)F
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.1 mL, 2.2 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (250 mg, 2.2 mmol) in dioxane (10 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) in dioxane (10 mL) was added. The resulting mixture was then heated at 85-95° C. for 16 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 1:1) afforded the title compound (150 mg, 63%) which was obtained as a white solid. MS: m/e=482.2 [M+H]|.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([CH3:22])[C@@H:17]2[CH:23]=O)=[O:15])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][CH2:23][C@H:17]2[C@@H:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:15])=[N:30][CH:31]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2C=O)c(-c2ccc(F)cc2)s1
Reactant: Nc1ccc(F)cn1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac-cis-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidine-2-carbaldehyde and 5-fluoropyridin-2-amine in methanol/acetic acid (50:1) was added sodium cyanoborohydride at 0° C. The reaction was then stirred at rt overnight. After ˜16 h, the reaction mixture was transferred to a seperatory funnel, diluted with EtOAc, saturated NaHCO3 and the layers separated. The organic layer was washed with water, brine, dried (MgSO4), and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 443.2 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].[C:9]([NH:19][CH2:20][C:21]([OH:23])=O)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:12]([O:11][C:9]([NH:19][CH2:20][C:21]([N:5]([CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])[CH3:6])=[O:23])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNCC(OC)OC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(CN(C)C(=O)CNC(=O)OCc1ccccc1)OC

Procedure:
A solution of N-(2,2-dimethoxyethyl)-N-methylamine (760 g, 6.38 mmol), N-CBZ-glycine (1337.6 g, 6.39 mol), EDC (1225.8 g, 6.39 mol), and HOBt (107.7 g, 0.70 mol), and N,N-diisopropylethylamine (172 mL) in anhydrous DMF (12 L) was stirred at room temperature overnight. The reaction mixture was diluted with water (24 L) and extracted with dichloromethane (3×10 L). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[CH:13][C:12]=1[O:31][CH:32]([CH3:34])[CH3:33])([O-:10])=[O:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)=[CH:13][C:12]=1[O:31][CH:32]([CH3:34])[CH3:33])([O-:10])=[O:9]
Reactant: CC(C)Oc1cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(N2CCC[C@@H](N)C2)ccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
6.25 ml of trifluoroacetic acid are added, at a temperature of about 20° C., to 5.32 g of 2-methylpropan-2-yl {(3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-yl}carbamate in solution in 106 ml of dichloromethane, and the mixture is left to stir for 15 h. A further 2 ml of trifluoroacetic acid are added and the stirring is continued for 1 h. The mixture is concentrated under reduced pressure, so as to obtain an oily residue which is precipitated by adding ethyl ether. The solid obtained is filtered off and then washed with ethyl ether, so as to obtain 5.42 g of (3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-amine trifluoroacetate in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:22]([C:19]3[CH:18]=[CH:17][C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)(=[O:24])=[O:23])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-biphenyl sulfonyl chloride (333 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12j as a solid (200 mg, 51.2%). HPLC: 99.88% (Rt=15.46 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([OH:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:29]([F:36])([F:35])C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([O:23][CH:29]([F:36])[F:35])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1O
Reactant: CCOC(=O)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a solution of 0.30 g of 5-(3,5-dichlorophenyl)-3-(3-hydroxy-4-nitrophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 20 mL of acetonitrile and 3 mL of water, 0.218 g of ethyl bromodifluoroacetate and 0.293 g of potassium carbonate were added, and stirred at 80° C. for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 mL of water was added in the residue, and extracted with ethyl acetate (20 mL×1). The organic phase was washed with water, and then dehydrated with and dried over saturated sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude aimed product as yellow resinous substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=O)cc1
Yield: 93 %

Procedure:
To the solution of 4-hydroxybenzaldehyde (10.0 g, 81.9 mmol) in 150 ml of pyridine was added acetic anhydride (60 ml). The resultant mixture was stirred at room temperature for 2 hours. After removal of the solvent, the compound was purified by flash chromatography using heptane/methylene chloride/ethyl acetate (20/20/10) as eluent in a yield of 93%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:7])=[O:6].C([Li])CCC>C1COCC1>[CH:4]1([S:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCCCOS(=O)(=O)CCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOS(=O)(=O)C1CC1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
Solutions of 1-butyl 3-chloro-1-propanesulfonate (4.6 g, 21.39 mmol in 25 ml THF) and of butyllithium (14.7 ml, 23.53 mmol, 1.6M, THF) were simultaneously added to THF (150 ml) at −78° C. under nitrogen atmosphere. The solution was allowed to warm to 0° C. and then quenched with water (2 ml). The volatiles evaporated under reduced pressure and the residue extracted with CH2Cl2 (150 ml). The extract was washed with water and dried (MgSO4) and evaporated to give crude desired product (3.23 g, 78.22%) in almost pure form as pale yellow oil which was used for next step without further purification. 1H NMR (300 MHz, CDCl3) δ 0.94 (t, J=7.5 Hz, 3H), 1.07 (m, 2H), 1.25 (m, 2H), 1.45 (sextet, 2H), 1.74 (quintet, 2H), 2.45 (heptet, 1H), 4.23 (t, J=6.6 Hz, 2H).
Reaction SMILES: [CH2:1](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([C:33]=1[OH:34])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:35])=[O:24])[CH3:21]>CN(C)C=O>[CH2:20]([O:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([C:33]=1[O:34][CH2:1][CH3:2])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:35])=[O:24])[CH3:21]
Reactant: CCOC(=O)c1[nH]c2c(C)cccc2c1O
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2c(C)cccc2c1OCC
Temperature: 50 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
Toluene-4-sulfonic acid ethyl ester (274 mg, 1.37 mmol) and potassium carbonate (378 mg, 2.74 mmol) were added to a solution of 3-hydroxy-7-methyl-1H-indole-2-carboxylic acid ethyl ester (300 mg, 1.37 mmol) in N,N-dimethylformamide (3 mL). The mixture was stirred at 50° C. for 16 h, then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, hexane/ethyl acetate 6:1) afforded the title compound (250 mg, 74%). White solid, ISP-MS: m/e=248.2 ([M+H+]).