Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:27][C:28]3[CH:35]=[CH:34][C:31]([CH3:32])=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: Cc1ccc(C=O)cc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(C)cc2)CC1
Yield: 98.3 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 4-methylbenzaldehyde (0.69 g) were reacted and treated in the same manner as in Example 121 to give 2.5 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-methylbenzylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[N-:16]=[N+:17]=[N-:18].[Li+]>CN(C)C=O>[N:16]([CH:2]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)nc1
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(Cn1ccnc1)c1ccc(Cl)cn1
Reaction time: 18 h

Procedure:
0.92 g of 1-chloro-(5-chloro-2-pyridyl)-2-(1H-imidazol-1-yl)ethane are added under argon to a solution of 0.37 g of lithium azide in 2 ml of dry dimethylformamide and the reaction mixture is stirred at 60° for 18 hours. Working up according to process A (see Example 1) gives the substance as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[B-](F)(F)(F)[F:12].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:12][C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: F[B-](F)(F)F
Reactant: Cc1csc2ccccc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1c(F)sc2ccccc12
Temperature: 70 °C
Yield: 72 %

Procedure:
A stirred solution of 3-methylbenzothiophene (0.51 g, 3.37 mmol) in acetonitrile (5 μL) under nitrogen was treated with SELECTFLUOR™ (1.25 g, 3.35 mmol) and heated to 70° C. overnight. The solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with sodium hydrogen carbonate solution, water and brine, dried over MgSO4 and evaporated in vacuo. Purification by flash column chromatography on silica, eluting with isohexane, gave 2-fluoro-3-methyl-1-benzothiophene (72% pure, 190 mg, 0.82 mmol) which was treated according to the method of Example 29 Step 2 to give 3-(bromomethyl)-2-fluoro-1-benzothiophene (95 mg, 12%). 1H NMR (500 MHz, CDCl3) δ 7.75 (1H, d, J=8.0 Hz), 7.68 (1H, d, J=8.0 Hz), 7.46 (1H, t, J=7.6 Hz), 7.39–7.35 (1H, m), 4.65 (2H, s).
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([NH2:23])=[C:18]([CH3:24])[C:17]=1[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(O)(=O)C.[N:41](OCCC(C)C)=O.C([O-])(=O)C.[K+]>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:25][O:26][C:27](=[O:29])[CH3:28])=[C:18]2[C:19](=[C:20]([Cl:22])[CH:21]=1)[NH:23][N:41]=[CH:24]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)OC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
(R)-3-(2-(acetoxymethyl)-4-amino-5-chloro-3-methylphenyl)-1-methoxy-1-oxopropan-2-yl benzoate (16.33 g, 38.9 mmol) in toluene (100.0 ml, 939 mmol) was added acetic acid (5.0 ml, 87 mmol) followed by isoamyl nitrite (5.76 ml, 42.8 mmol) at 0° C. After 15 min, potassium acetate (7.64 g, 78 mmol) was added and the reaction mixture was stirred for 12 h. The solvent was removed and the crude product was dissolved in dichloromethane (250 mL) and washed with aqueous NaHCO3. The solvent was dried (Na2SO4), evaporated and the crude product was purified by flash chromatography using 40% EtOAc in hexane to give (R)-3-(4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate in 88% yield. MS (ESI) 453 (M+Na); Rf=2.46.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH:4]([CH3:10])[C:3]1=[O:11].[CH3:13][Li].Cl>CCOCC>[OH:11][C:3]1([CH3:13])[CH:4]([CH3:10])[C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7][C:2]1([CH3:1])[CH3:12]
Reactant: CC1C(=O)C(C)(C)CCC1(C)C
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Product: CC1C(C)(C)CCC(C)(C)C1(C)O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
26 g of 2,2,5,5,6-pentamethylcyclohexanone are dissolved in 500 ml of ether and treated slowly at -20° C. with 113.5 ml of methyl lithium (1.5 molar in ether). After stirring for 3.5 hours at 0° C., the mixture is poured on to ice, acidified with 1N hydrochloric acid, extracted with ethyl acetate, dried and evaporated. Distillation of the crude product gives 25.9 g of 1-hydroxy-1,2,2,5,5,6-hexamethylcyclohexane as a colourless liquid of boiling point 87°-92° C./10 mm Hg.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][N:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[NH:16]2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].Cl.[CH3:26][O:27][NH2:28].C([O-])(=O)C.[K+].CO>O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([O:23][CH3:24])[NH:16][N:15]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:1](=[N:28][O:27][CH3:26])[CH3:2])[C:5]=2[C:6]([O:8][CH3:9])=[O:7])[N:20]=1
Reactant: COC(=O)c1c(ON2N=C(OC)C=C(OC)N2)cccc1C(C)=O
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CON=C(C)c1cccc(ON2N=C(OC)C=C(OC)N2)c1C(=O)OC
Yield: 48 %

Procedure:
0.9 of methyl 2-acetyl-6-[(4,6-dimethoxytriazin-2-yl)oxy]benzoate, 0.68 g of methoxyamine hydrochloride and 0.80 g of potassium acetate were added to 30 ml of methanol, and the resultant mixture was stirred for one day and one night at room temperature. The resultant reaction liquor was poured into water, and was extracted with ethyl acetate. After washing the extracted product with water, the washed product was dried and concentrated to obtain an oily product. This was then purified by column chromatography to obtain 0.47 g of the aimed compound (melting point=131° to 135° C.) at a yield of 48%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Cl-].[NH4+]>CO.O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To 1,1-dimethylethyl (2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D21) (15 g, 44.8 mol) in MeOH (150 mL) and water (150 mL) at 80° C. was added ammonium chloride (11.9 g, 0.224 mol) and iron powder (7.5 g, 0.134 mol) with vigorous stirring. The reaction was stirred at 80° C. for 2 h then filtered through Celite® while still hot and the filter cake was washed with further DCM. The filtrate layers were separated and the aqueous layer was washed with DCM (×3). The DCM layers were combined, dried (Na2SO4) and concentrated to give the crude product which was purified by column chromatography. Elution with 20-70% EtOAc/petroleum ether gave the title compound as a white solid (9.46 g).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.[CH2:17]([N:24]1[CH2:29][C@@H:28]2[CH2:30][C@H:25]1[CH2:26][NH:27]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[OH-]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH:28]2[CH2:30][CH:25]1[CH2:26][N:27]2[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3CC2CN3C2=Nc3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 11-oxo-dibenz[b,f][1,4]oxazepine (Aldrich) (0.149 g, 0.0007 mol) in dry toluene (10 mL), was added (1S,4S)-2-benzyl-2,5-diazabicyclo(2.2.1)heptane (0.54 g, 0.003 mol) and TiCl4 (0.75 mL, 0.0008 mol) via syringe. The mixture was stirred at room temperature for 30 min then refluxed for 5 hrs. The reaction mixture was cooled and dumped into conc. NH4OH and extracted with CHCl3. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed (hexane:EtOAc, 1:1) to give 11-(2-benzyl-2,5-diazabicyclo(2.2.1) hept-5-yl)-dibenz[b,f][1,4]oxazepine (yield 0.1319, mp 70°-72° C.).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-fluoronitrobenzene (6.0 mL, 56.9 mmol) and N-methylpiperazine (8.11 mL, 56.9 mmol) was stirred at 0° C. for 20 minutes, then at room temperature for 3 days. The crude mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate and the organic layer was then washed with saturated sodium chloride (NaCl), dried and concentrated in vacuo to provide 2-(4-methylpiperazin-1-yl)-1-nitrobenzene as an orange oil, 12.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[C:32]([CH2:34][F:35])[CH:33]=2)[CH2:27][N:28]=[N+]=[N-])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[C:32]([CH2:34][F:35])[CH:33]=2)[CH2:27][NH2:28])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:36]=[CH:37][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C(OCc2cc(CF)cc(CN=[N+]=[N-])c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(OCc2cc(CN)cc(CF)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.2 %

Procedure:
To a solution of 3-(4,4′-dimethoxytrityloxy)methyl-5-fluoromethylbenzylazide (39) (247 mg, 0.50 mmol) in THF (5.00 mL) were added water (0.20 mL) and then triphenylphosphine (264 mg, 1.01 mmol). The air was evacuated from the reaction system, and then Ar was charged therein. The reaction mixture was stirred for 15 hours at a room temperature. TLC was used to confirm the progress of the reaction. Then, the reaction mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (EtOAc, then EtOAc: MeOH=2:1) to isolate 3-(4,4′-dimethoxytrityloxy)methyl-5-fluoromethylbenzylamine (40) (234 mg, 100%) as a white opaque oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]12([CH2:23][CH2:24]O)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:23][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[CH:12][CH:11]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-hydroxybenzoate (83 mg) and 1-adamantaneethanol (90 mg) were combined in tetrahydrofuran (2 mL). Polymer-supported triphenylphospine (250 mg of 3 mmol/g) and di-tert-butyl azodicarboxylate (173 mg) were added. The reaction was stirred at room temperature overnight. The resin was removed by filtration through celite. The filtrate was concentrated under vacuum, and the residue was triturated with 95/5 hexanes/ether to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.[OH-].[Na+].O>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Yield: 83.4 %

Procedure:
To a solution of ethyl(1RS,2SR,3SR)-1-(4-methoxyphenyl)-3-phenylindane-2-carboxylate, (5.5 g, 14.8 mmol) in EtOH (70 ml) was added SM NaOH (9 ml, 45 mmol). The resulting mixture was stirred under an argon atmosphere for 1 d, at which time H2O (70 ml) was added. The mixture was concentrated under reduced pressure. The aqueous residue was extracted with Et2O, and the Et2O extracts were discarded. The aqueous phase was acidified with 6M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to provide an oily residue which crystallized upon standing. The solid material was recrystallized from EtOAc/hexanes to afford the title compound (4.25 g, 83%); m.p. 164°-166° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:47]=[CH:46][C:39]2[S:40][C:41](B(O)O)=[CH:42][C:38]=2[CH:37]=1>O1CCOCC1.C([O-])(O)=O.[Na+].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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:41]2[S:40][C:39]3[CH:46]=[CH:47][C:36]([F:35])=[CH:37][C:38]=3[CH:42]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc2cc(F)ccc2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
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: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3cc(F)ccc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (300 mg, 0.601 mmol), 5-fluorobenzo[b]thiophen-2-ylboronic acid (236 mg, 1.202 mmol) and tetrakis(triphenylphosphine)palladium(0) (695 mg, 0.601 mmol) in dioxane and saturated aqueous NaHCO3 (1:1, 5 mL) was heated to 120° C. via microwave irradiation for 30 minutes. After the solvent was removed, the crude product was purified by silica gel column chromatography, eluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes. The fractions were collected to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was first dissolved in DCM (3 mL) then TFA/DCM (1:1, 10 mL) and the mixture was stirred at 60° C. for 1 hour. After solvent was removed, the resulting crude material was reconstituted in MeOH/DMF/DCM (30.0 mL) and purified via preparative mass trigger LCMS, eluting with gradient of 30-40 ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and ACN was removed via rotary evaporation. The mixture was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×300 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to give the title compound (77 mg, 31%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-2.09 (m, 8H), 3.82 (br s, 1H), 4.31 (d, J=1.95 Hz, 1H), 4.42-4.53 (m, 2H), 7.13 (d, J=5.86 Hz, 1H), 7.27 (td, J=8.91, 2.69 Hz, 1H), 7.56-7.82 (m, 3H), 7.94-8.04 (m, 1H), 8.64 (s, 1H), 9.41 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H20F2N4OS, 415. found, 415.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[CH2:11][CH2:10]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2cccc(F)c2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc(F)c3)CC2)cc1
Yield: 81.8 %

Procedure:
0.5 g (0.00239 mol) of 1-(3-fluoro-benzyl)-piperidin-4-ol and 0.67 ml (0.00478 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.632 ml (0.00478 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.64 g (82%) of 1-(3-fluoro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil. MS: me/e=328 (C20H23FNO2+).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][OH:45])=[CH:39][CH:38]=1>CCOC(C)=O>[OH:45][CH2:44][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:38][CH:39]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(CCO)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCO)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 300 mg, 0.746 mmol) and THF (7.5 mL). To the resulting solution was added 2-(4-amino-phenyl)-ethanol (120 mg, 0.875 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and the resulting suspension was filtered. The solids collected were washed with 0° C. iPrOH (5 mL) and set aside. The filtrate was concentrated in vacuo and the residue obtained was dissolved in EtOAc (5 mL). The resulting solution was triturated with Hexanes (˜50 mL) to yield a precipitate. This precipitate was then filtered and washed with 0° C. iPrOH (5 mL). The solids collected were combined with those previously set aside to afford the title compound in 20% yield (0.078 g, 0.149 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:33])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
2.23 g of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio-1H-benzimidazole(6 mmol) prepared in Example 1 was dissolved in 20 ml of chloroform, 1.24 g of m-chloroperbenzoic acid(1.2 equivalent) dissolved in 20 ml of chloroformwas added thereto dropwise at below 5° C., and stirred at the same temperature for about 10 minutes. The reaction mixture was washed with aqueous NaHCO3 and dried over MgSO4. The residue obtained after removing the solvent under a reduced pressure was purified by silica gel column chromatography and recrystallization, to obtain 1.33 g of lansoprazole as a white-light brown solid (yield: 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([OH:18])[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:28]=[C:27]([Br:29])[C:26]([O:30][CH3:31])=[C:25]([Br:32])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Cl)=[CH:43][CH:42]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([O:18][CH2:45][C:44]3[CH:47]=[CH:48][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:24]=[C:25]([Br:32])[C:26]([O:30][CH3:31])=[C:27]([Br:29])[CH:28]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1c(Br)cc(CC2c3cc([N+](=O)[O-])c(O)cc3CCN2C(=O)OC(C)(C)C)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc3c(cc2[N+](=O)[O-])C(Cc2cc(Br)c(OC)c(Br)c2)N(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-(3,5-dibromo-4-methoxy-benzyl)-6-hydroxy-7-nitro-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (0.002 mol), K2CO3 (0.331 g, 0.0024 mol) and 4-methoxybenzyl chloride (0.376 g, 0.0024 mol) in 10 mL of DMF was heated for 4 h at 100° C. 0.17 g (0.00109 mol) of 4-methoxybenzyl chloride was added additionally. The reaction mixture was heated for 5 h at 100° C., cooled, poured in water, cooled, filtered and dried in vacuum. The residue was dissolved in ethyl acetate and filtered through silica gel. The solution was concentrated. The residue was crystallized from chloroform-hexanes mixture. Yield 0.96 g (72%).
Reaction SMILES: [CH3:1]/[C:2](/[C:5]([CH3:7])=[O:6])=[N:3]\[OH:4].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.C(O)(=O)C.Cl>C(OCC)C>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]2[O:6][C:5]([CH3:7])=[C:2]([CH3:1])[N+:3]=2[O-:4])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C

Procedure:
1.00 g (9.89 mmol) of diacetyl monoxime and 1.53 g (10.88 mmol) of 4-chlorobenzaldehyde are initially charged in 2 ml (34.94 mmol) of glacial acetic acid. With ice-cooling, hydrogen chloride gas is then introduced into the reaction mixture for 30 min 10 ml of diethyl ether are then added to the reaction mixture. A precipitate is formed, which is filtered off with suction and washed twice with in each case 2 ml of diethyl ether. The precipitate is suspended in about 5 ml of water, and the suspension is made basic using aqueous ammonia. The suspension is then extracted four times with in each case 10 ml of dichloromethane. The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator. Without further purification, the product obtained in this manner is used for the subsequent step.