Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl[S:19]([OH:22])(=[O:21])=[O:20].CCOCC>C(OC)(=O)C1C(=CC=CC=1)C(OC)=O>[CH3:17][O:16][C:14]1[CH:15]=[C:2]([OH:1])[C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[CH:12][C:13]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Solvent: CCOCC
Solvent: COC(=O)c1ccccc1C(=O)OC
Product: COc1cc(O)c(C(=O)c2ccccc2)cc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
11.4 g of 2-hydroxy-4-methoxybenzophenone were dissolved in 30 ml of dimethyl phthalate at 80° C., and 3.5 ml of chlorosulfonic acid were added dropwise at this temperature. Stirring was carried out for a further 4 hours at 80° C., the mixture was cooled to room temperature and 25 ml of ether were added to the solution. The precipitate was filtered off under suction, washed with ether and hexane and dried under reduced pressure at 30° C. 10 g of 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid of melting point 112°-114° C. were obtained (water content 7.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][CH:23]([O:25]C(=O)C)[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])[CH2:12][CH2:13][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][CH:23]([OH:25])[CH2:22]3)(=[O:19])=[O:20])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OC1CN(S(=O)(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CC(O)C1
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
To a stirred solution of acetic acid 1-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexylmethanesulfonyl]-azetidin-3-yl ester (Example 29) (185 mg, 0.33 mmol.) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide (16 mg, 0.67 mmol.) in water (5 mL) and the mixture stirred for 45 minutes. The solvent was removed in vacuo and the residue diluted with 1N aqueous sodium hydroxide (10 mL) and extracted into ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4) and evaporated to leave the desired compound (171 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:21][CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].Cl>ClCCl>[O:25]=[S:24]1(=[O:26])[CH2:23][CH2:22][CH2:21][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-aminobenzoate (0.92 g) and triethylamine (1.5 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.9 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, 1N hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (8 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue (1.5 g) was dissolved in ethanol (20 mL), 1N aqueous sodium hydroxide solution (8.4 mL) was added, and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture were added 1N hydrochloric acid (9.2 mL) and water, and the precipitate was collected by filtration to give the title compound (0.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:31]=[CH:32][N:33]=[C:10]12.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:31]=[CH:32][N:33]=[C:10]12
Reactant: COC(=O)c1ccc(Nc2ncc3c(=O)n(-c4c(Cl)cccc4Cl)c4nccn4c3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Nc2ncc3c(=O)n(-c4c(Cl)cccc4Cl)c4nccn4c3n2)cc1

Procedure:
To a suspension of Example 216 (0.6 g, 1.24 mmol) in 10 mL methanol and 3 mL water was added KOH (0.28 g, 4.99 mmol). The reaction was heated at 50 degrees overnight and at 60 degrees for 1.5 hours. The reaction mixture was cooled and concentrated. The crude material was suspended in ethyl acetate, acidified with 1M aqueous HCl, and the aqueous layer was extracted with dichloromethane (2×). The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated. The material in the aqueous layer was filtered and the solid was dried to provide the title compound. MS (ESI+) m/z 467.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[Si:9](OS(C(F)(F)F)(=O)=O)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(Cl)Cl>[CH3:13][C:12]([Si:9]([CH3:11])([CH3:10])[O:7][C:6]1[CH:5]=[C:4]([CH3:8])[O:3][C:2]=1[CH3:1])([CH3:15])[CH3:14]
Reactant: CC1=CC(=O)C(C)O1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)c(C)o1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
2,5-Dimethyl-3(3H)-furanone (2.00 g, 17.8 mmol) was dissolved in methylene chloride (180 mL). TEA (7.43 mL, 53.5 mmol) was added followed by TBSOTf(4.92 mL, 21.4 mmol) at 25° C. After 1 h, the reaction was concentrated in vacuo and the resulting slurry was run through a silica gel column conditioned with 3% TEA in hexanes. The product was eluted with 3% TEA/hexanes to give 3.6 g (89%) of compound 222A as an orange oil which was used directly in subsequent reactions.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[F:16][C:17]([F:23])([F:22])[C:18](OC)=[O:19]>CO>[F:16][C:17]([F:23])([F:22])[C:18]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COC(=O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)C(F)(F)F)CC1
Temperature: 0 °C

Procedure:
A solution of tert-butyl cis-4-aminocyclohexanecarbamate (22.1 g, 103 mmol) and methyl trifluoroacetate (11 ml, 110 mmol) in 110 ml of methanol is stirred at RT for 4 h. After the reaction mixture has been cooled down to 0° C., the precipitate is filtered off, washed with diethyl ether and dried. Yield: 17.6 g.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[C:18]([CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=2)[NH2:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26]>ClCCl.N1C=CC=CC=1>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[C:18]([N:19]=[CH:25][CH3:26])[CH:17]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CC=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC=Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reaction time: 5 h
Yield: 80.1 %

Procedure:
3-(9-acridinylamino)-5-(hydroxymethyl)aniline was dissolved in dichloromethane/pyridine(1/1, v/v, 40 ml), and thereto acetaldehyde (2.09 g, 47.56 mmol) was added. The resulting mixture was stirred for 5 hours, and the solvent used was removed under the reduced pressure. Then, the resulting product was purified by column chromatography to give the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=1)([O-:3])=[O:2].[CH3:17][O-:18].[Na+]>CO>[CH3:17][O:18][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 90.7 %

Procedure:
To a solution of 1,3-dinitro-5-(trifluoromethyl)benzene (10 g, 42.4 mmol) in absolute methanol (100 mL) was added sodium methanolate (3.43 g, 63.5 mmol) in absolute methanol (20 mL). The red alcoholic solution was refluxed for 1 h, then concentrated to remove solvent, diluted with ethyl acetate (80 mL) and water (30 mL). Separated organic part was dried over Na2SO4, filtered and concentrated to get the title product (8.5 g) as a red solid
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=O)=[CH:14]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[N:22]1([CH2:20][C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][C:2]2[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=2)=[CH:19][CH:18]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(c1cc2cc(Oc3nc4ccccc4s3)ccc2[nH]1)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2sc(Oc3ccc4[nH]c(CN5CCCCC5)cc4c3)nc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a cooled (−78° C.) solution of [5-(benzothiazol-2-yloxy)-1H-indol-2-yl]-piperidin-1-yl-methanone (150 mg, 0.40 mmol) in THF (5 mL) was added LAH (2 M in THF, 0.2 mL, 18 mg, 0.40 mmol) and the reaction mixture was stirred (−78° C., 1 h) and allowed to warm (rt, 1 h). The reaction mixture was cooled (0° C.) and treated with H2O (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH:DCM (0-8%) to provide the title compound as a colorless foam (78 mg, 54%). MS (ESI): mass calcd. for O21H21N3OS, 363.1; m/z found, 364.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.64 (s, 1H), 7.77-7.70 (m, 1H), 7.61 (dd, J=7.9, 0.7, 1H), 7.48 (d, J=2.3, 1H), 7.40-7.32 (m, 2H), 7.22 (dd, J=11.0, 4.3, 1H), 7.10 (dd, J=8.7, 2.4, 1H), 6.35 (s, 1H), 3.62 (s, 2H), 2.60-2.30 (m, 4H), 1.65-1.54 (m, 4H), 1.53-1.41 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1.[H+].[B-:28]([F:32])([F:31])([F:30])[F:29]>C(OCC)C.C(Cl)Cl>[F:29][B-:28]([F:32])([F:31])[F:30].[CH3:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][S+:7]([CH2:18][C:19]2[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][CH:16]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(CSCc2ccc(C)cc2)cc1
Reactant: Cc1ccc(CO)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C[S+](Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1
Reaction time: 1 h

Procedure:
85.1 g (0.351 mol) of di-(p-methylbenzyl) sulfide and 51.5 g (0.421 mol) of p-methylbenzyl alcohol are initially introduced into 250 ml of methylene chloride under an N2 atmosphere in a reaction vessel (750 ml) provided with a stirrer and thermometer. 142.7 g of an approximately 54% by weight HBF4 solution in diethyl ether is added dropwise at an internal temperature of 20°-30° C. in the course of 40 min, while stirring. The reaction mixture is stirred at RT for 2 h. The reaction mixture is diluted with methylene chloride and extracted 4 times by shaking with deionized water (pH 5-6). The organic phase is dried with MgSO4 and the methylene chloride is removed on a rotary evaporator. The product, which has not been completely freed from methylene chloride, is stirred in 250 ml of toluene at RT for about 1 h and then at 0°-5° C. for 1 h. The crystals which have now precipitated are filtered off with suction and washed with a little toluene. The product is dried under a high vacuum at room temperature for 19 h. 118.6 g of tris-(p-methylbenzyl)-sulfonium tetrafluoroborate are obtained as white crystals of melting point 168°-170° C.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[C:14]([C:15]2[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20](C=O)=[CH:19][CH:18]=3)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C1C[O:36][CH2:35][CH2:34]1>>[Cl:4][C:5]1[C:14]([C:15]2[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH2:34][CH2:35][OH:36])=[CH:19][CH:18]=3)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(C=O)ccc21
Agent: C[Mg]Br
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CCO)ccc21
Reaction time: 0.5 h

Procedure:
A solution of methylmagnesium bromide in THF (3 M, 0.85 mL, 2.56 mmol, 1.3 equiv) was added to a solution of 2-(2-chloro-3-quinolinyl)-5-formyl-1H-indole-1-carboxylate (8-1, 800 mg, 2.0 mmol, 1 equiv) in THF (25 mL) at 0° C., and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between pH 7 phosphate buffer solution and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane, grading to 70% EtOAc in hexane) to provide tert-butyl 2-(2-chloro-3-quinolinyl)-5-(1-hydroxyethyl)-1H-indole-1-carboxylate (8-2) as a white foam. 1H NMR (500 MHz, CDCl3) δ8.29 (d, 1H, J=8.8 Hz), 8.18 (s, 1H), 8.08 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.78 (br t, 1H, J=7.1 Hz), 7.64 (s, 1H), 7.61 (br t, 1H, J=7.1 Hz), 7.42 (dd, 1H, J=8.6, 1.5 Hz), 6.66 (s, 1H), 5.05 (m, 1H), 1.58 (d, 3H, J=6.6 Hz), 1.27 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(F)cc1F
Temperature: 37 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
2,4-difluorobenzaldehyde (20-a, 10 g, 70.4 mmol) in dichloromethane (300 ml) were added (R)-2-methylpropane-2-sulfinamide (8.5 g, 70.4 mmol), PPTS (1.85 g, 7.4 mmol) and anhydrous CuSO4 (22.5 g, 0.14 mol). The resulting mixture was stirred at 37° C. overnight. The mixture was then filtrated and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=8/1) to provide the product, 20-b, (15.77 g, 91%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:13][C:3]=12.[NH:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:3]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
To a vial containing 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (714.2 mg, 2.115 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 645.9 mg, 3.225 mmol), 1-butanol (8.00 mL) was added followed by DIPEA (582.8 mg, 4.509 mmol). The reaction mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as a yellow solid (719.5 mg, 68%). LCMS calc. for C23H28N5O6S (M+H)+: m/z=502.2. found 502.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[C:17]([Cl:25])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:25].[ClH:25].[Cl:25][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)cc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cc2ccccc2c(NC2CCNCC2)n1

Procedure:
A solution of 4-(3-chloro-isoquinolin-1-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.14 g, 3.15 mmol) in 4 M HCl in dioxane (100 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 262.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.[Cl-].[Na+].C(OCC)(=O)C>C(COC)OC.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>[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(-c2ccccc2O)cc1
Yield: 74.8 %

Procedure:
Methyl (4-bromophenyl)acetate (2.79 g, 12.2 mmol), tetrakis(triphenylphosphine)palladium (0) (170 mg), potassium phosphate (9.71 g, 45.75 mmol) and dimethoxyethane (50 ml) were degassed under nitrogen in a 100 ml flask fitted with a reflux condenser. 2-Hydroxybenzene boronic acid (2.52 g, 18.3 mmol) in dimethoxyethane (5 ml) was added and the mixture was heated at reflux overnight then mixed with 1:1 saturated sodium chloride/ethyl acetate (25 ml). The organic materials were separated, dried (MgSO4), then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient hexane to 3:1 hexane/ethyl acetate) which provided 2.21 g (75%) of methyl (4-(2-hydroxyphenyl)phenyl)acetate.
Reaction SMILES: [CH3:1][S:2]([OH:4])=[O:3].[Na].[Cl:6][C:7]1[N:12]=[C:11]([CH2:13]I)[CH:10]=[C:9]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[N:8]=1>C(#N)C>[Cl:6][C:7]1[N:8]=[C:9]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[CH:10]=[C:11]([CH2:13][S:2]([CH3:1])(=[O:4])=[O:3])[N:12]=1
Reactant: CS(=O)O
Reactant: C[C@H]1COCCN1c1cc(CI)nc(Cl)n1
Agent: [Na]
Solvent: CC#N
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
Methanesulfinic acid, sodium salt (11.75 g, 115.11 mmol) was added in one portion to 2-chloro-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (37 g, 104.64 mmol), in acetonitrile (900 mL) and the resulting solution stirred at 85° C. for 24 hours. The organic layers were combined and washed with water (3×100 mL), dried over MgSO4, filtered, and the solvent was removed by evaporation to give the crude product as a dark brown oil, which solidifed (36 g). The crude solid was purified by flash silicachromatography, elution gradient 0 to 30% ethyl acetate in DCM, to give the desired material (22 g) as a cream solid which was identical to previous samples.
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=[O:9])C=1.C(=O)([O-])O.[K+].[CH2:17]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]3[CH:42]=[CH:41][C:40](C(=O)C)=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH2:17]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]3[CH:42]=[CH:41][C:40]([O:10][C:8](=[O:9])[CH3:4])=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCOc1ccc(-c2nc3cc(C(C)=O)ccc3o2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(-c2nc3cc(OC(C)=O)ccc3o2)cc1
Temperature: 25 °C

Procedure:
In a 50 ml-round-bottomed flask, 1.50 g of (3.81 mM) of 2-(4-decyloxyphenyl)-5-acetylbenzoxazole was dissolved in 10 ml of dichloromethane, followed by successive addition of 0.66 g of (3.82 mM) of m-chloroperbenzoic acid and 0.40 g (4.00 mM) of potassium hydrogencarbonate and heat-refluxing for 7 hours and 40 minutes under stirring. After cooling to room temperature, 0.33 g (1.91 mM) of m-chloroperbenzoic acid and 0.20 g (2.00 mM) of potassium hydrogencarbonate was successively added, followed by heat-refluxing for 12 hours under stirring. After the reaction, the insoluble was filtered off and the filtrate was subjected to reduced pressure distillation to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) to obtain 2-(4-decyloxyphenyl)-5-acetoxybenzoxazole. Then, 0.51 g (7.73 mM) of potassium hydroxide was dissolved in 50 ml of ethanol under heating. To the solution, the above-prepared 2-(4-decyloxyphenyl)-5-acetoxybenzoxazole was added, followed by stirring for 30 minutes at about 60° C. After the reaction, ethanol in the reaction mixture was distilled off under reduced pressure. To the resultant residue, 50 ml of water was added, followed by addition of 0.7 ml of hydrochloric acid under stirring on an ice bath to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from methanol to obtain 0.27 g of 2-(4-decyloxyphenyl)-5-hydroxybenzoxazole (Yield: 19.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:22].FC(F)(F)C(O)=O>ClCCl>[F:22][C:3]1[CH:4]=[C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[CH:20]=[CH:21][C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(CC2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 118.4 %

Procedure:
Tert-butyl 4-(4-amino-3-fluorobenzyl)piperidine-1-carboxylate (6.49 mmol, 2 g) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (3 mL) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction mixture was purified by SCX chromatography to give the intermediate 2-fluoro-4-(piperidin-4-ylmethyl)aniline (1.6 g) as a colourless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][N:14]=[CH:13]1.C(N(CC)CC)C>COCCOC>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCCCn1ccnc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1cc(NCCCn2ccnc2)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
A mixture of 31.2 g (0.2 mol) of 4-fluoro-2-methyl-1-nitrobenzene, 37.5 g (0.3 mol) of 3-imidazol-1-ylpropylamine and 34.8 ml (0.25 mol) of triethylamine in 30 ml of 1,2-dimethoxyethane was heated with stirring for 3 hours on a boiling water bath.