Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=4[CH:13]=3)[CH:10]=2)[CH:5]=[C:4]([C:26]([OH:28])=[O:27])[CH:3]=1.[H-].[Na+].[CH3:31]I.Cl>C1COCC1.O.CN(C)C=O>[CH3:31][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:18]([CH3:22])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:24])([CH3:25])[C:14]=4[CH:13]=3)[CH:10]=2)[CH:5]=[C:4]([C:26]([OH:28])=[O:27])[CH:3]=1
Reactant: CI
Reactant: CC1(C)CCC(C)(C)c2cc(-c3ccc4cc(C(=O)O)cc(O)c4c3)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)cc2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
0.8 g (2.1 mmoles) of the acid obtained in Example 2, dissolved in 10 ml of THF, are added drop by drop to a suspension of sodium hydride (0.113 g; 4.7 mmoles) in 10 ml of THF. After stirring for two hours at room temperature, 10 ml of dimethylformamide and 0.90 g (6.3 mmoles) of methyl iodide are added. After stirring for one hour, the mixture is poured into water and brought to pH 1 (concentrated hydrochloric acid). Following extraction by ether, the organic phase is decanted, then dried and evaporated. The solid thus formed is recrystallized in a mixture of diisopropyl ether (50%) and cyclohexane (50%). In this manner is obtained 0.60 g (74%) of 4-methoxy-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2 naphthoic acid which melts at 242° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[C:19]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1)(=[NH:21])[NH2:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[CH:4]=[CH:3][N:20]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=3)[N:21]=2)=[CH:8][CH:9]=1
Reactant: N=C(N)Nc1ccc(C(N)=O)cc1
Reactant: CN(C)/C=C/C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: NC(=O)c1ccc(Nc2nccc(-c3ccc(Cl)cc3)n2)cc1
Temperature: 25 °C

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-(4-chlorophenyl)prop-2-en-1-one (0.10 g, 0.48 mmol), 4-(amidinoamino)benzamide nitrate (0.116 g, 0.48 mmol), and potassium carbonate (0.132 g, 0.96 mmol) in ethanol (10 ml) with was heated to 120° C. overnight in a sealed vessel. The reaction mixture was cooled to room temperature and the resulting solid was collected then washed with ethanol, water, and diethyl ether to provide the title compound as a beige solid, identical in all respects with the compound prepared in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27](OCC)=O)[CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]2[NH:10][CH2:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:11]=2)[CH:22]=1)#[N:20]
Reactant: NCC(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(C#N)ccn1
Product: N#Cc1ccnc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)CN2)c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The mixture of 1,1-bis(4-fluorophenyl)-1,2-ethanediamine (153 mg) and 4-cyano-2-ethoxycarbonylpyridine (95 mg) was stirred at 180° C. for 2 hours. The obtained oily compound was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=3:2) to give the objective compound (103 mg).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@@H:47]([CH3:50])[CH2:48][OH:49].Cl.NCC(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C@@H:47]([CH3:50])[CH2:48][OH:49])=[CH:35][CH:36]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: C[C@H](N)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)N[C@@H](C)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and (S)-2-amino-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}-methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Br:15]Br.C(Cl)(Cl)[Cl:18]>C1COCC1>[ClH:18].[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[Br:15])=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: BrBr
Reactant: Brc1ccc2c(c1)[nH]c1cnccc12
Solvent: C1CCOC1
Product: Brc1ccc2c3ccncc3n(Br)c2c1
Product: Cl
Reaction time: 0.17 h

Procedure:
A solution of the product from example 1 (140 mg, 0.58 mmol) in THF (2 ml) was treated with bromine (0.50 ml). After 10 min at RT, the reaction was diluted with chloroform and the product was filtered. The filtered product was taken up in methanol and treated with 1M HCl in ether and concentrated. The residue was triturated with ether to provide 160 mg of 7,9-dibromo-β-carboline hydrochloride.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:16][C:17]1[N:22]=[C:21](F)[C:20]([F:24])=[CH:19][N:18]=1.CCOC(C)=O.CCCCCCC>CN(C=O)C>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19]1[C:20]([F:24])=[CH:21][N:22]=[C:17]([F:16])[N:18]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Reactant: Fc1ncc(F)c(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1nc(F)ncc1F
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 68.1 %

Procedure:
To a solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (6.35 g, 33.9 mmol) in DMF (170 mL) under a nitrogen atmosphere at 0° C. was added sodium hydride (2.14 g, 50.9 mmol, 60%) portion wise over 3 minutes. The reaction mixture was then stirred for 2 hr at 0° C. whereupon 2,4,5-Trifluoropyrimidine (5 g, 37.3 mmol) was added and the reaction mixture allowed to stir 75 minutes at 0° C. then the mixture was allowed to warm to RT and stirred for 1 hr at RT. The reaction mixture was quenched with the slow addition of saturated solution of NH4Cl and the aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 50%) provided a colorless oil of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (6.97 g, 23.1 mmol, 68% yield) which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) 1.10 (d, J=6.26 Hz, 3H) 1.18 (s, 9H) 4.25-4.35 (m, 1H) 4.49-4.62 (m, 2H) 4.65-4.73 (m, 1H) 8.45 (d, J=1.57 Hz, 1H). LCMS m/z 246.1 (-t-butyl fragment) (M+H)+, Rt 0.91 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][CH:33]([O:1][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1cc(O)ccc1N
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To 4-hydroxy-2-(methoxycarbonyl)benzenamine (6.8 g), triphenylphosphine (14.2 g) and 4-hydroxy-N-(t-butoxycarbonyl)piperidine (9.06 g) in THF (200 mL) was added DEAD (9.51 g) drop-wise at ambient temperature. The reaction was stirred at ambient temperature for overnight, concentrated and re-dissolved in ether. The ether layer was washed with 0.5 N NaOH aqueous solution, water and brine. It was then concentrated and purified on silica gel column (ethyl acetate/hexane, gradient) to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-2-(methoxycarbonyl)benzenamine (7.31 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=3)[CH:9]=2)=[C:4]([CH3:23])[CH:3]=1.ClCCCl.C([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][CH2:41][CH:38]4[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]4)=[CH:3][C:4]=3[CH3:23])[NH:13][C:12](=[O:14])[CH:11]=2)=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(-c2cc(-c3ccc(N)cc3C)[nH]c(=O)c2)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(-c2cc(-c3ccc(NCC4CCNCC4)cc3C)[nH]c(=O)c2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a round bottom flask was added 6-(4-amino-2-methylphenyl)-4-(4-hydroxy-3-methylphenyl)pyridin-2(1H)-one (76 mg, 0.25 mmol), 1,2 Dichloroethane (5.0 mL), acetic acid (0.1 mL), and N-Boc-4-Formyl piperidine (0.65 mg, 0.30 mmol). The reaction was stirred at room temperature for 15 minutes before adding sodium triacetoxy borohydride (85 mg, 0.40 mmol). Stirring was continued at room temperature for 10 min. The reaction was then concentrated down under reduced pressure. The resulting oil was then dissolved in 4N HCl/dioxane (5.0 mL) and stirred at 45° C. for 1 h. The resulting slurry was cooled down to room temperature and the precipitate was filtered off. The resulting solid was then dissolved in MeOH and purified by preparatory HPLC (15-40% gradient of NH4OAc/ACN) to give 4-(4-hydroxy-3-methylphenyl)-6-{2-methyl-4-[(piperidin-4-ylmethyl)amino]phenyl}pyridin-2(1H)-one as the acetate salt (16 mg, 14% yield over 2 steps). 1H NMR (400 MHz, d6-DMSO) δ 7.47 (s, 1H), 7.39 (dd, 1H), 7.06 (d, 1H), 6.85 (d, 1H), 6.45 (m, 2H), 6.36 (s, 1H), 6.27 (s, 1H), 5.95 (t, 1H), 2.98 (m, 2H), 2.91 (t, 1H), 2.48 (m, 2H), 2.22 (s, 3H), 2.16 (s, 3H), 1.72 (m, 4H), 1.09 (m, 1H); MS (EI) for C25H29N3O2: 404 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:13]=1.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[C:32]([Cl:34])[C:31](Cl)=[N:30][CH:29]=1.CCN(CC)CC>CN(C=O)C.O>[Cl:34][C:32]1[CH:33]=[C:28]([C:27]([O:26][CH3:25])=[O:36])[CH:29]=[N:30][C:31]=1[N:10]1[CH2:11][CH2:12][C:6]2[C:5]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)=[N:4][C:3]([S:2][CH3:1])=[N:13][C:7]=2[CH2:8][CH2:9]1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNCC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCc3nc(SC)nc(Nc4ccc(C(F)(F)F)cc4)c3CC2)c(Cl)c1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of (2-methylsulfanyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine (187 mg, 0.53 mmol), 5,6-dichloro-nicotinic acid methyl ester (129 mg, 0.58 mmol), and Et3N (0.2 mL, 1.58 mmol) in DMF (1.2 mL) was heated at 120° C. for 2 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was purified (FCC) to give the title compound (203 mg, 74%). MS (ESI): mass calcd. for C23H21ClF3N5O2S, 523.11; m/z found, 524.1 [M+H]+. 1H NMR (CDCl3): 8.57 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 6.73-6.59 (m, 1H), 3.89-3.65 (m, 7H), 3.19-3.07 (m, 2H), 2.95-2.87 (m, 2H), 2.40 (s, 3H).
Reaction SMILES: [OH:1]O.[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:29])[CH2:7]1)[CH:4]=[CH2:5].[OH-].[Na+].Cl>C(O)C>[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]([NH2:25])=[O:1])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:29])[CH2:7]1)[CH:4]=[CH2:5]
Reactant: OO
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C#N)c2)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(N)=O)c2)C[C@H]1C
Temperature: 60 °C
Yield: 79 %

Procedure:
Hydrogen peroxide (0.5 mL of a 30% by weight solution) was added to a mixture of the benzonitrile (0.50 g, 1.4 mmol), 0.7 mL of 10N aqueous sodium hydroxide and 3 mL of ethanol. The reaction was exothenic with gas evolution and formation of a white precipitate. After a few minutes, the mixture was carefully heated under a reflux condenser in an oil bath at 60° C. for three hours. After cooling to room temperature, 6N aqueous hydrochloric acid was added to adjust the pH to 8. The mixture was evaporated to dryness under vacuum, and the residue was extracted between ethyl acetate and pH 8 buffer solution. The organic layer was washed with pH 8 buffer and brine, dried over sodium sulfate, and the solvent was evaporated to give 0.42 g (79%) of (±)-3-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide as a bright yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[N:11]1.[CH2:19]=O>CCO>[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH2:19][NH:4][C:3]3[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:2]=3[CH3:1])[C:13]=2[N:12]=[N:11]1
Reactant: C=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccc(C)c(N)c1
Solvent: CCO
Product: Cc1ccc(C)c(NCc2cccc3[nH]nnc23)c1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A mixture of 2,5-dimethylaniline (27.4 g, 0.2 mol) and benzotriazole (23.8 g, 0.2 mol) in EtOH (300 mL) was stirred at 20° C. as 37% aqueous formaldehyde (16.1 g, 0.2 mol) was added gradually. After 30 minutes, the white solid which precipitated was collected and washed with EtOH to give N-(1-benzotriazolylmethyl)-2,5-dimethylaniline (33.9 g, 67% yield); mp (EtOH) 147°-149° C.
Reaction SMILES: C([Li])CCC.C(O[CH:9]([O:15]CC)[N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)C.[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1C(N1CCCC1)=O.[Cl-].[NH4+]>O1CCCC1.CO>[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1[C:9]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[O:15]
Reactant: Cc1ccccc1OCc1ccccc1C(=O)N1CCCC1
Reactant: CCOC(OCC)n1ccnn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1OCc1ccccc1C(=O)n1ccnn1
Reaction time: 0.25 h
Yield: 34.1 %

Procedure:
At −20° C., 2.8 g (0.01 mol) of 23% pure n-butyllithium are added dropwise within 15 minutes to a solution of 1.7 g (0.01 mol) of N-diethoxymethyltriazole in 10 ml of tetrahydrofuran. Stirring is continued for 15 minutes at −20° C., and 1.48 g (0.005 mol) of N-[2-(2-methylphenoxymethyl)-benzoyl]-pyrrolidine dissolved in 10 ml of tetrahydrofuran are then added, and the mixture is stirred for a further 30 minutes at −20° C. 2 g of ammonium chloride and 10 ml of methanol are added and the mixture is heated under reflux for 15 minutes. The volatile components are removed under reduced pressure, the residue is admixed with water and extracted with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The residue crystallizes when treated with a mixture of diethyl ether and petroleum ether in the ratio of 1:1. 0.5 g (17% of theory) of 3-[2-(2-methylphenoxymethyl)-benzoyl]-triazole of melting point 179° C. is obtained.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][S:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][S:27][CH2:28][CH2:29][CH2:30][CH2:31]OS(C)(=O)=O)(=[O:20])=[O:19]>C(#N)C>[CH3:17][S:18]([O-:21])(=[O:20])=[O:19].[CH3:17][S:18]([O-:21])(=[O:20])=[O:19].[S:27]([CH2:28][CH2:29][CH2:30][CH2:31][N+:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)[S:26][CH2:25][CH2:24][CH2:23][CH2:22][N+:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1
Reactant: c1cc2c(cn1)CCCC2
Reactant: CS(=O)(=O)OCCCCSSCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)[O-]
Product: c1c[n+](CCCCSSCCCC[n+]2ccc3c(c2)CCCC3)cc2c1CCCC2
Temperature: 100 °C

Procedure:
2.1 g of 5,6,7,8-tetrahydroisoquinoline and 0.5 g of potassium carbonate were mixed in 2 ml of acetonitrile and brought to 100° C. A solution of 2.7 g of disulfanediyldibutane-4,1-diyl dimethane sulfonate in 2 ml of acetonitrile was added in 5 min. Stirring was maintained for 3 h at 100° C. and then the reaction medium was brought back to ambient temperature and concentrated under vacuum. 10 ml of dichloromethane were added and the solution was filtered and then poured dropwise into 100 ml of ethyl ether. The oil that had separated by settling out was reprocessed by diluting in 10 ml of dichloromethane and adding to 500 ml of ethyl ether. After drying under vacuum, 3.3 g of a brown oil were recovered. The analyses were in compliance with the expected structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[OH-].[NH4+:34]>C(O)C>[NH2:34][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1cnccc1Cl)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccncc1S(=O)(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 72.3 %

Procedure:
To a 2-mL microwave vial was added 2-(4-(4-((4-chloro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (90 mg, 0.18 mmol), ethanol (1.5 mL) and aqueous ammonium hydroxide (1.5 mL, 39 mmol). The solution was then heated in the microwave at 110° C. for 2 h and then concentrated. The residue was diluted with saturated aqueous NaHCO3 and DCM. The solution was stirred for 5 min and then transferred onto a phase separation cartridge (Radleys Discovery Technologies) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was concentrated and purified by silica gel chromatography (0 to 5.0% MeOH/DCM) afforded 2-(4-(4-((4-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (63 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:20].Cl[CH2:22][CH:23]=O.O>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[NH:20][CH:22]=[CH:23][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CNC(=O)OC(C)(C)C
Reactant: O=CCCl
Reactant: N
Solvent: O
Product: CC(C)(C)OC(=O)NCc1[nH]ccc1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
Tert-butyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (755 g, 2.76 mol) was treated with ammonia (2 M in MeOH, 7.0 L) and NH4OAc (851 g, 11.04 mol) at RT. The resulting mixture was heated at 40° C. for 1 h, then treated with chloroacetaldehyde, 50% in water (1083 g, 5.52 mol, Sinopharm Chemical Reagent Co., Ltd, China) and stirred at 50° C. for 4 h and cooled to RT. The solvent was removed in vacuo and the crude material was diluted with water and EtOAc (water: EtOAc=1:1,5 L: 5 L). The organic layer was separated, dried (Na2SO4) and concentrated. Similarly another 2 batches were carried out on 755 g scale. The combined residue was purified by flash column chromatography (eluted by 5-20% EtOAc in petroleum ether) to afford tert-butyl 2-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrrole-3-carboxylate (820 g, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 6.91 (s, 1H), 6.58-6.57 (m, 1H), 6.26-6.24 (m, 1H), 4.34-4.33 (m, 2H), 1.44 (s, 9H), 1.36 (s, 9H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18].O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CCCCCCCCOc1ccc(O)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In pyridine was dissolved 2 g of p-octyloxyphenol, and a solution of p-acetoxybenzoic acid chloride in chloroform was added dropwise to the thus-obtained solution and the mixture was stirred at room temperature for 3 hours. Water was added to the thus-obtained solution and the mixture was extracted with chloroform, and the extract was washed with a 0.5N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of sodium chloride in succession, followed by concentration. The concentrate was recrystallized from n-hexane to obtain 2.35 g of 4-octyloxyphenyl 4-acetoxybenzoate. The product was dissolved in a liquid mixture comprising tetrahydrofuran and methanol at a volume ratio of 10/1, 6.2 ml of a 1N aqueous solution of lithium hydroxide was added to the solution, the mixture was stirred at room temperature for 1 hour, and the mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. Then, the liquid was dehydrated on anhydrous magnesium sulfate and concentrated, and the concentrate was recrystallized from ethyl acetate to obtain 1.1 g of 4-octyloxyphenyl 4-hydroxybenzoate.
Reaction SMILES: FC1(F)[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.F[B-](F)(F)F.N1([O:44]C(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N1CCOCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:25]([N:22]1[CH2:23][CH2:24][CH:19]([O:18][C:16]2[CH:17]=[C:12]3[CH:11]=[C:10]([C:8]([N:5]4[CH2:4][CH2:3][O:44][CH2:7][CH2:6]4)=[O:9])[NH:28][C:13]3=[N:14][CH:15]=2)[CH2:20][CH2:21]1)([CH3:27])[CH3:26]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Yield: 70 %

Procedure:
The title compound was synthesized in analogy to example 9, intermediate a), from (1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride (example 13, intermediate b)), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, morpholine and N,N-diisopropylethylamine (7 eq.) in DMF to give the desired product as a yellow solid (70%).