Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=O>C(OC(=O)C)(=O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:14](=[O:15])[O:16][C:7]2=[O:9]
Reactant: COc1cc(C(=O)O)c(C(=O)O)cc1OC
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)C(=O)OC2=O
Temperature: 120 °C
Yield: 100 %

Procedure:
A suspension of 4,5-dimethoxyphthalic acid (600 mg, 2.65 mmol) in acetic anhydride (5 ml) was heated to 120° C. for 1 hour. The solvent was then removed under vacuum to afford 5,6-dimethoxyisobenzofuran-1,3-dione as a yellow solid (552 mg, 2.65 mmol, quantitative yield). MS/ESI+ 208.9 [MH]+. This compound was used as such in the next step.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C([O-])(=O)C.[K+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][CH2:27][C:28]2[NH:37][C:31]3=[N:32][CH:33]=[C:34](I)[CH:35]=[C:30]3[N:29]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][CH2:27][C:28]2[NH:37][C:31]3=[N:32][CH:33]=[C:34]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:7][CH:8]=4)[CH:35]=[C:30]3[N:29]=2)[CH:21]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCc4cc(OC)ccn4)nc3c2)cc1
Temperature: 90 °C
Yield: 53 %

Procedure:
A mixture of 0.375 g of N-methyl-4-bromobenzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 16 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphos-phine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 90° under N2 for 8 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 20-15:1). Concentration of the chromatographically pure fractions and crystallisation from ethyacetate gives 0.219 g of the title compound as a solid of m.p. 225-227° C. The mass spectrum shows the molecular peak MH+ at 424.3 Da.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH:11]([C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[CH2:12][CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>ClCCl.C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([CH:11]([C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:18][CH:19]=1)[CH2:12][CH3:13])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(CC)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C(=O)O)C(CC)c1ccc(NC(=O)OC(C)(C)C)nc1
Reaction time: 16 h
Yield: 82.3 %

Procedure:
2-[1-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-propyl]-malonic acid diethyl ester (3.23 g, 8.19 mmol) was dissolved in a mixture of dichloromethane (12 mL) and ethanol (24 mL, 99.5%). To this solution was added dropwise a solution of potassium hydroxide (0.528 g, 87%, 8.20 mmol) in ethanol (16 mL, 99.5%) at 0° C. over 0.5 h. Stirring was continued for 16 h while the mixture was allowed to warn up to room temperature. After concentration under reduced pressure to 5-10 mL, water (50 mL) was added and the resulting emulsion was stirred for 0.5 h, and then filtered. The filtrate was washed twice with a mixture of ethyl acetate and diethyl ether (2:1, vol/vol). The aqueous layer was acidified by addition of a solution of citric acid in water (10%) to reach a pH of 4 to 5, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate, and the solvent was removed under reduced pressure to yield 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-propyl]-malonic acid monoethyl ester (2.47 g, 82%)
Reaction SMILES: [N+:1]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.C[CH:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:17][CH2:16][N:15](CC(NC(=O)C2C=CC(C)=CC=2)C(C)C)[CH2:14]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][N:18]1[CH2:13][CH2:14][N:15]([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[N+:1]([O-:3])=[O:2])[CH2:16][CH2:17]1
Reactant: O=[N+]([O-])C1=CCCCC1
Reactant: Cc1ccc(C(=O)NC(CN2CCN(Cc3ccc(Cl)c(Cl)c3)C(C)C2)C(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])C1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.5 %

Procedure:
A mixture of 1-nitrocyclohexene (311 mg, 2.45 mmol), dichlorobenzylpiperazine [prepared as described in Example 1](600 mg, 2.45 mmol), and triethylamine (512 μl, 3.68 mmol) in methylene chloride (10 ml) was stirred at room temperature under nitrogen atmosphere for 17 h. The reaction mixture was diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed with hexanes/ethyl acetate (2:1) as the eluant to provide 1-(3,4-dichlorobenzyl)-4-(2-nitrocyclohexyl)piperazine (461 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].CC#N>CN(C)C1C=CN=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[C:6]([CH3:11])=[CH:5]2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc2cc(Br)ccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
5-Bromo-2-methylindole (4.2 g, 200.0 mmol), di-t-butylcarbonate (4.37 g, 20 mmol), 4-dimethylaminopyridine (2.93 g, 24 mmol) and CH3CN (50 mL) were mixed and stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (300 mL) and the organic solution was washed successively with water (50 mL), a 1N HCl solution (50 mL), a saturated NaHCO3 solution (2×50 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford an oil (6.11 g, 99% yield): 1H NMR (CDCl3, 300 MHz): 7.98 (d, 1H, J=9), 7.56 (d, 1H, J=1), 7.32 (dd, H, J=9, 1), 6.27 (s, 1H), 2.60 (d, 3H, J=1), 1.69 (s, 9H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]1)=[N+:2]=[N-:3].[CH:13](OCC)=[S:14]>CCOCC>[CH:13]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])=[S:14]
Reactant: CCOC=S
Reactant: [N-]=[N+]=NCCCC1CCCCN1
Solvent: CCOCC
Product: [N-]=[N+]=NCCCC1CCCCN1C=S
Reaction time: 8 h

Procedure:
To a solution of 2-(3'-azidopropyl)-piperidine (1.8 g) in ether (10 ml) was added ethyl thioformate (1.5 ml). The solution was kept at 4° C. overnight and evaporated to leave an oil which was purified by chromatograpy on silica gel. The IR-spectrum (CHCl3) showed strong bands at 2950, 2100, 1485, 1445 and 1250 cm-1.
Reaction SMILES: [NH:1]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C@H:2]([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][O:4]C(C)(C)C.C(O)(C(F)(F)F)=O>>[NH:1]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][OH:4]
Reactant: CC(C)(C)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H](CO)NN1CCOCC1

Procedure:
Morpholino-Ser(OAloc) was prepared from SER(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholineacarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHCl3 (1:1) to yield morpholino-Ser(OAloc).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([CH:38]=[N:39]O)[CH:36]=4)[CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:38]#[N:39])[CH:36]=4)[CH2:31][CH2:30]3)[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: ON=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 70.1 %

Procedure:
Trifluoromethanesulfonic anhydride (0.72 ml) was added dropwise at −78° C. into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxyiminomethylindoline (1.5 g) and triethylamine (1.2 ml) in methylene chloride (1 l) and the resultant mixture was warmed to room temperature. Next, a saturated aqueous solution of sodium bicarbonate and chloroform were added thereto and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate and the residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (1.0 g) as a white powder (yield: 67%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:12][C:13]([O:15]CC)=[O:14])=[O:4].O[Li].O>C1COCC1.CCO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:12][C:13]([OH:15])=[O:14])=[O:4]
Reactant: CCOC(=O)CC(Nc1cc(-c2ccccc2)sc1C(=O)OC)C1CCCCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(CC(=O)O)C1CCCCC1
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(1-cyclohexyl-2-ethoxycarbonyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (300 mg, 0.72 mmol, 1.0 equiv) in THF (2.0 mL), EtOH (1.0 mL) and water (2.0 mL) was added LiOH.H2O (152 mg, 3.6 mmol, 5.0 equiv). The mixture was stirred at 55° C. for 20 minutes. The organic solvent was then evaporated. To the resulting solution was added 3.0 N HCl aq. solution until pH=5˜6. The solid was then collected by filtration and washed with water. The filtrate was extracted with EtOAc and the organic layer was washed with sat. NaHCO3 aq. solution, brine, dried over Na2SO4, and concentrated in vacuo. The crude material was continued to the next step with no further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[CH:13][C:14]([C:15]([O:17]CC)=[O:16])=[C:10]3[N:9]=[CH:8][CH:7]=2)=[CH:2]1.[OH-].[K+].Cl>C(O)C.O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[N:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CCOC(=O)c1cnn2c(-c3ccsc3)ccnc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn2c(-c3ccsc3)ccnc12

Procedure:
A mixture of 0.05 mole of ethyl 7-(3-thienyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 0.20 mole of potassium hydroxide in 50 ml. of ethanol-water is heated at reflux temperature for 4 hours. The mixture is acidified with concentrated hydrochloric acid and concentrated to give 7-(3-thienyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. The preceding compound in tetrahydrofuran is added dropwise to a solution of 0.10 mole of diborane in tetrahydrofuran chilled in an ice bath. After stirring for 2 hours the bath is removed and the mixture allowed to stand 6 hours at room temperature. The mixture is poured into ice to give the product of the example.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[F:22])C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][C@H:10]1[F:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2)[C@H](F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Reaction time: 16 h

Procedure:
Pd/C 10% (4.5 g) was added to a solution of (3R,4R) tert-butyl 4-(benzyl amino)-3-fluoropiperidine-1-carboxylate, 2.10 (19.6 g, 0.063 mol) in EtOH (500 mL). The reaction was stirred under hydrogen atmosphere (balloon pressure) for 16 hour. After completion of reaction by TLC, the mixture was filtered through celite-bed and concentrated under reduced pressure to obtain the title compound (3R,4R) tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate, 2.12 (12.6 g, 92% yield). 1HNMR (CDCl3, 400 MHz): δ 4.33-4.14 (m, 1H), 4.13-4.02 (m, 2H), 2.94-2.78 (m, 3H), 1.89-1.86 (m, 1H), 1.48 (s, 9H), 1.42-1.34 (m, 1H); LCMS: 100%, m/z 163.1 (M−55, tert-But), HPLC: 99.62%, rt=5.214 min.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OCc3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Temperature: 67.5 °C
Reaction time: 23 h
Yield: 77.3 %

Procedure:
Into a solution of methyl 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg) in THF/methanol (3/1.5 ml) was added at room temperature an aqueous solution (0.7 ml) of potassium carbonate (140 mg), and the resulting mixture was stirred at 65-70° C. for 23 hours. After cooling to room temperature, 1 N hydrochloric acid was added to the reaction mixture until the pH was adjusted to 5, and the precipitated crystals were collected by filtration. The crystals were washed with water, 2-propanol and diisopropyl ether to obtain 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (149 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
N,N-Dimethylethylenediamine (3.30 ml) was added to 4-chloro-N-methyl-3-nitrobenzamide (3.220 g) and the mixture was stirred for 14 hours at 100° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (3.687 g) as yellowish orange solid.
Reaction SMILES: F[C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:17]=1)[O:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[NH2:23][C:24]1[S:25][C:26]([C:36]([NH2:38])=[O:37])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C)C=O>[Cl:35][C:31]1[CH:30]=[C:29]([C:27]2[N:28]=[C:24]([NH:23][C:2]3[CH:17]=[C:6]([O:7][CH2:8][CH2:9][O:10][CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[C:5]([O:18][CH3:19])=[CH:4][C:3]=3[N+:20]([O-:22])=[O:21])[S:25][C:26]=2[C:36]([NH2:38])=[O:37])[CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1OCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1OCCOC1CCCCO1
Yield: 73.2 %

Procedure:
A mixture of 0.370 g of 2-[2-(5-fluoro-2-methoxy-4-nitro-phenoxy)-ethoxy]-tetrahydro-pyran (IV.44), 0.296 g (1.17 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 1.14 g (3.51 mmole) of cesium carbonate and 5 mL of dimethylformamide was heated at 70 degrees for 3 hours. The cooled mixture was poured into 30 mL of dilute ammonium chloride solution and the precipitated orange solid was collected by filtration, washed with water, and air-dried to give 0.470 g 4-(3-chloro-phenyl)-2-{4-methoxy-2-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenylamino}-thiazole-5-carboxylic acid amide (VI.44).
Reaction SMILES: [CH:1]1([C:5]2([C:8]3[N:13]=[C:12]4[S:14][C:15]([C:17]5[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=5[F:25])=[N:16][C:11]4=[CH:10][CH:9]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:27]1[CH2:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28]1>>[CH:1]1([C:5]2([C:8]3[N:13]=[C:12]4[S:14][C:15]([C:17]5[CH:24]=[CH:23][C:20]([CH2:21][N:27]6[CH2:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28]6)=[CH:19][C:18]=5[F:25])=[N:16][C:11]4=[CH:10][CH:9]=3)[CH2:6][CH2:7]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(C5CCC5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)C1CNC1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(C6CCC6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 4-(5-(1-cyclobutylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzaldehyde (66.2 mg, 0.188 mmol) and methyl azetidine-3-carboxylate hydrochloride (42.7 mg, 0.282 mmol) according to Reference R and the general procedure for reductive amination to give methyl 1-(4-(5-(1-cyclobutylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate as a white solid. MS (ESI) m/z: Calculated: 451.2; Observed: 451.9 (M++1).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]([CH3:27])[N:17]=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][CH:8]=1>O.C1COCC1.CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:18]=[N:17][N:16]([CH3:27])[C:15]=2[CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][N:9]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A solution of lithium hydroxide monohydrate (101 mg, 2.41 mmol) in water (3 mL) was added dropwise to a suspension of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid methyl ester (413 mg, 1.21 mmol) in THF (3 mL) and MeOH (0.6 mL). The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (380 mg, 96%) as a white solid. MS: m/e=327.3 [M−H]−.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1([OH:33])C[CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]4[CH:32]=[N:31][N:30]=[CH:29]4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=C1>CS(C)=O>[CH2:1]([NH:8][CH2:9][C:10]1([OH:33])[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]4[CH:32]=[N:31][N:30]=[CH:29]4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(CNCc2ccccc2)CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Agent: c1ccc2[nH]ccc2c1
Solvent: CS(C)=O
Product: OC1(CNCc2ccccc2)CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)C1

Procedure:
The title compound was prepared from the foregoing t-butyloxycarbonyl-protected compound as described for 4-(benzylamino)methyl-4-hydroxy-1-(3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl)piperidine. mp>61° C. MS, ES+, m/z=431 for (M+H)+ ; δ (360 MHz, D6 -DMSO) 1.57-1.67 (1H, m, CH), 1.72-1.86 (3H, m, CH and CH2CH2CH2)), 2.31-2.65 (8H, m 4×CH2 N), 2.72 (2H, t, J=7 Hz, CH2 -indole), 3.72 (2H, s, NHCH2Ph), 4.55 (1H, s, OH), 7.15-7.32 (7H, m, Ar--H), 7.47 (1H, d, J=8 Hz, Ar--H), 7.77 (1H, d, J=2 Hz, Ar--H), 9.00 (2H, s, triazole-H), 11.06 (1H, s, indole-NH). (Found: C, 68.40; H, 6.53; N, 18.73. C25H30N6O.0.15(CH2Cl2) requires C, 68.14; H, 6.89; N, 18.96%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:16]4([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC2(CCCCCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), cycloheptanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 2 h at 110° C. in a sealed tube. Then, this mixture was poured into sat. aqueous sodium hydrogen carbonate. Extraction with ethyl acetate, washing with brine, drying over magnesium sulfate, filtration and concentration at reduced pressure were carried out. This residue was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol), then recrystallized from methanol-ethyl acetate and the crystals were collected by filtration to afford the title compound (0.0226 g, 14%) as a yellow solid:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:17]=1[F:23])[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:19]=[CH:18][C:17]=1[F:23])[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Br)ccc1F)N2
Reactant: C1COCCN1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(N3CCOCC3)ccc1F)N2
Temperature: 120 °C
Yield: 15.6 %

Procedure:
A mixture of 2-(5-bromo-2-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.76 g, 1.87 mmol), morpholine (1.63 g, 18.7 mmol), copper (I) iodide (0.21 g, 1.1 mmol), L-proline (0.11 g, 0.94 mmol) and potassium carbonate (0.78, 5.61 mmol) in DMSO (3 mL) was heated for 4 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 2-(2-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.12 g, 16%) as a white solid: LC/MS m/e calcd for C24H29FN2O3 (M+H)+: 413.5, observed: 413.4.