Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][C:35]1([CH3:52])[O:39][CH:38]([CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[CH2:37][O:36]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:22])[N:44]([CH2:43][CH2:42][O:41][CH2:40][CH:38]2[CH2:37][O:36][C:35]([CH3:52])([CH3:34])[O:39]2)[C:45]2[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CC1(C)OCC(COCCNc2ccc(F)cc2)O1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOCC2COC(C)(C)O2)c2ccc(F)cc2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.6 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.115 ml) and DMF (0.005 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in anhydrous dichloromethane (5 ml). The reaction was stirred at room temperature for 1.5 h then [2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-ethyl]-(4-fluoro-phenyl)-amine (0.078 g) as a solution in dichloromethane (0.5 ml), DMAP (0.002 g) and DIPEA (0.080 ml) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with further dichloromethane and extracted with saturated aqueous sodium bicarbonate. The aqueous layer was removed and the organic phase washed with water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (1:1, 2:1 and 4:1 v/v), to give the title compound as a colourless gum (0.037 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([Cl:13])[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[C:5]2[Cl:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:31]2[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=2)=[O:30])=[CH:25][CH:24]=1.[Li]CCCC>>[Cl:13][C:7]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:5]([Cl:21])[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)[OH:30])[CH:3]=2)[N:8]=1
Reactant: Cn1cncc1C(=O)c1ccc(F)cc1
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Agent: [Li]CCCC
Product: Cc1cc(C(O)(c2ccc(F)cc2)c2cncn2C)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A round bottom flask was charged with 6-bromo-2,4-dichloro-3-(3-fluorophenyl)-8-methylquinoline (1.00 g, 2.60 mmol, Intermediate 50, step c) and (4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (583 mg, 2.86 mmol, Intermediate 49, step b) and was evacuated and re-filled with argon (three times). THF (20 mL) was added, and the solution was cooled in a dry ice acetone bath for 2 minutes. At this point the mixture began to turn cloudy and n-BuLi (1.6 M in hexane, 2.11 mL, 3.38 mmol), was added over about 1 minute. The mixture was stirred at −78° C. for 10 minutes, then in an ice water bath for 1 hour. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 30-60% acetone-DCM) to afford slightly impure title compound as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.09 (s, 1H), 7.60 (s, 1H), 7.44-7.55 (m, 1H), 7.30-7.39 (m, 3H), 7.15-7.23 (m, 1H), 7.01-7.12 (m, 4H), 6.40 (s, 1H), 4.00 (br. s., 1H), 3.40 (s, 3H), 2.74 (s, 3H). MS m/e 510.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[C:21]([CH3:27])=[C:22]([NH:23][C:40](=[O:41])[C:39]4[CH:43]=[CH:44][CH:45]=[C:37]([C:36]([F:35])([F:46])[F:47])[CH:38]=4)[CH:24]=[CH:25][CH:26]=3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-c2cc3nccc(-c4cccc(N)c4C)c3o2)cc1OC
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3nccc(-c4cccc(NC(=O)c5cccc(C(F)(F)F)c5)c4C)c3o2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
To a 20-mL glass vial was added 3-[2-(3,4-dimethoxyphenyl)furo[3,2-b]pyridin-7-yl]-2-methylaniline (19.20 mg; 0.05 mmol), triethylamine (0.01 ml; 0.11 mmol) suspended in DCM (2.00 ml). 3-(trifluoromethyl)benzoyl chloride (16.67 mg; 0.08 mmol) was then added. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture which was then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mixture was purified using Biotage column chromatography (20-100% EtOAc/Hexanes). Fractions containing the desired product were combined and concentrated. The mixture was then purified using preparative HPLC to afford the title compound as a yellow solid (3.80 mg, 13%). HPLC (method F): 100%, RT=4.531 min. 1H NMR (CDCl3) δ [ppm] 8.58 (d, 1H), 8.19 (s, 1H), 8.12 (d, 1H), 7.96 (d, 1H), 7.88-7.84 (m, 2H), 7.71-7.68 (m, 2H), 7.60-7.47 (m, 3H), 7.39-7.38 (m, 2H), 7.00-6.97 (m, 1H), 4.01 (s, 3H), 3.96 (s, 3H), 2.27 (s, 3H). MS: m/z=533 [M+H]+, RT=3.91 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[OH:30]O.O.C1(C)C=CC=CC=1>C(O)(=O)C.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=2)=[O:30])=[CH:17][CH:18]=1
Reactant: COCCOCCOc1ccc(Sc2ccc(OCCOCCOC)cc2)cc1
Reactant: OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COCCOCCOc1ccc(S(=O)c2ccc(OCCOCCOC)cc2)cc1
Reaction time: 12 h
Yield: 95 %

Procedure:
In 200 g of acetic acid was dissolved 26.6 g of bis[4-[2-(2-methoxyethoxy)ethoxy]phenyl]sulfide obtained in Synthesis Example 1-42. While the solution was maintained at an internal temperature of 30° C., 6.4 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 12 hours, after which under ice cooling, a mixture of 0.5 g sodium thiosulfate pentahydrate and 20 g water was added dropwise to quench the reaction. The solution was combined with 200 g of toluene and 100 g of water. The organic layer was separated, washed with water, and concentrated in vacuum, obtaining 26.1 g of the target compound, bis[4-[2-(2-methoxyethoxy)ethoxy]phenyl]sulfoxide as oily matter. Yield 95%.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[F:22])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Br[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:11][CH2:12][CH3:13])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([O:21][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:15]=2[F:22])=[CH:24][CH:25]=1)#[N:2]
Reactant: CCC(Br)CC
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(O)c1F
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(OC(CC)CC)c1F
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution under Ar of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-ethoxy-acetamide (200 mg) in DMF (10 ml) was added CSCO3 (226 mg) and 3-bromopentane (105 mg). The solution was stirred over night at 80° C. The solvent was evaporated and the residue was taken up in H2O (50 ml). The product was extracted with AcOEt (2×100 ml). The organic layers were washed with H2O (2×50 ml) and dried (NaaSO4) and the solvent was evaporated. CC (AcOEt/Hept 2:3 to AcOEt) afforded 190 mg (79%) of (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-[3-(1-ethyl-propoxy)-2,6-difluoro-phenyl]-acetamide. This material was converted to (RS)-N-(4-carbamimidoyl-benzyl)-2-ethoxy-2-[3-(1-ethyl-propoxy)-2,6-difluoro-phenyl]-acetamide acetate by the sequence of procedures G and H. Off-white solid. MS 434.4 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[CH:30][C:31]=1[OH:32]>C(OCCO)C>[OH:32][C:31]1[CH:30]=[C:29]([CH3:33])[CH:28]=[CH:27][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Cc1ccc(N)c(O)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(C)cc3O)c2cc1OC
Yield: 85.7 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.2 mmol) of 6-amino-m-cresol to give 287.5 mg (85.8%) of the product as a light brown solid, m.p.>250° C., mass (electrospray, m/e): M+H 335.9.
Reaction SMILES: [F:1][C:2]([F:14])([C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>ClCCl>[CH3:22][S:23]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:14])([F:1])[C:10]([F:11])([F:12])[F:13])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCC(F)(F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
7,7,8,8,8-Pentafluorooctan-1-ol (25 g, 113 mmol) was dissolved in dichloromethane (250 ml) and cooled to 0° C. To this solution, triethylamine (47.4 ml, 339 mmol) and methanesulfonyl chloride (17.6 ml, 227 mmol) were added dropwise, followed by stirring for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to give 1-methanesulfonyloxy-7,7,8,8,8-pentafluorooctane (30 g, Yield 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[CH:23][CH:22]=2)=[CH:17][N:16]=1.CC1C=CC(S(O)(=O)=O)=CC=1.Cl>O1CCOCC1>[F:30][CH:28]([F:29])[O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[N:20][C:15]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=3)=[N:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1

Procedure:
A mixture of ethyl 2-(4-aminophenyl)acetate (8 mmol), 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30 (4 mmol), and p-TSA (2 mmol) in 1,4-dioxane (4 mL) are heated at reflux for 4 h. The mixture is poured onto 1 N HCl. The solid is filtered, washed with 1 N HCl and dried to afford ethyl 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)acetate 31 as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 2H), 7.92 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.18 (d, J=9.1 Hz, 2H), 6.49 (t, J=73.5 Hz, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.54 (s, 2H), 1.19 (t, J=7.1 Hz, 3H). MS (m/z) (M+1)+: 400.1.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9](=[O:16])[C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(O)(=O)C>O>[C:12]([C:11]1[O:17][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9](=[O:16])[C:10]=1[OH:15])(=[O:14])[CH3:13]
Reactant: CC(=O)CC(=O)C(=O)CC(=O)c1ccccc1
Solvent: Ic1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1oc(-c2ccccc2)cc(=O)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
A mixture of 1-phenylheptane-1,3,4,6-tetrone (2.3 g), iodobenzene diacetate (6.7 g) and acetic acid (80 mL) was stirred at room temperature for 16 hr, the reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.32 g).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:16]=3)=[CH:14][C:9]=2[CH:8]=[C:7]([C:28]([O:30]C)=[O:29])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:20]=3)=[CH:14][C:9]=2[CH:8]=[C:7]([C:28]([OH:30])=[O:29])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of methyl 1-allyl-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (262 mg) in a mixture of tetrahydrofuran (19 ml) and methanol (19 ml) was added 1N sodium hydroxide solution (6.3 ml), and the mixture was stirred at room temperature overnight. Then, water and 1N hydrochloric acid were added to make acidic (pH=4) at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give the solid, which was washed with hexane to give 1-allyl-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (199 mg) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16](N)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:10]([NH:9][O:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)ON[C@H]1CCCNC1
Product: CC(C)(C)OC(=O)ON[C@H]1CCCN(Cc2ccccc2)C1

Procedure:
a method, wherein the amino group of L-aspartic acid is protected, the carboxy group is reduced, the resulting hydroxyl group is converted into a leaving group, the resultant is reacted with ammonia to produce (S)-3-(tert-butoxycarbonyloxyamino) piperidine, the piperidine is reacted with benzylamine instead of ammonia to obtain (S)-1-benzyl-3-(tert-butoxycarbonyloxyamino) piperidine, and deprotection is carried out using trifluoroacetic acid to produce (S)-1-benzyl-3-aminopiperidine (Non-patent Document 3).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=O)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH2:28]([NH2:31])[CH2:29][CH3:30]>C1COCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:31][CH2:28][CH2:29][CH3:30])=[O:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCCN
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Solvent: C1CCOC1
Product: CCCNC(=O)CCCCCn1c(COCC)nc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
A solution of ethyl 6-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (3.73 g, 10.1 mmol, prepared in Parts A and B of Example 13), n-propylamine (5 mL), and THF (5 mL) was heated at 80° C. for three days in a high-pressure vessel, allowed to cool to ambient temperature, and concentrated under reduced pressure. The work-up procedure described in Part C of Example 13 was followed to provide 4.1 g of 6-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-N-propylhexanamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CO>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:26]4[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:25]=4[F:24])[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1

Procedure:
A mixture of 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg), 2-fluoro-4-(methanesulfonyl)phenylboronic acid (97 mg), 2 M aqueous Na2CO3 solution (0.33 mL), methanol (0.5 mL), and 1,4-dioxane (1.5 mL) is sparged with Ar for 10 min. PdCl2 [1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (22 mg) is added and the mixture is stirred at reflux temperature for 2 h. The mixture is diluted with water and methanol and purified by HPLC on reversed phase (methanol/water) to give the title compound. LC (method 5): tR=1.29 min; Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#N.[OH2:27]>C(O)=O.[Pt](=O)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:27]
Reactant: O
Reactant: CN1CCC(OC(c2cccc(C#N)c2)c2nc3ccccc3[nH]2)CC1
Agent: O=[Pt]=O
Solvent: O=CO
Product: CN1CCC(OC(c2cccc(C=O)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile (example 172, 740 mg) in 80% aqueous formic acid (3 mL) is added platinum(IV) oxide (48 mg). The reaction mixture is heated at 60° C. for 7 h, then at room temperature for 2 days. As the reaction is not complete, 80% aqueous formic acid (3 mL) and platinum (IV) oxide (48 mg) are added and the reaction mixture is heated at 60° C. overnight. Water is added and the reaction mixture is filtered on celite. The phase is basified by adding a solution of 1N sodium hydroxide and extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated to give 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde. 1H NMR: 9.99 (s, 1H), 9.67 (sl, 1H), 8.01 (s, 1H), 7.85-7.65 (m, 2H), 7.60-7.40 (m, 2H), 7.32-7.15 (m, 3H), 5.95 (s, 1H), 3.65-3.50 (m, 1H), 2.82-2.65 (m, 2H), 2.26 (s, 3H), 2.20-1.65 (m, 6H).
Reaction SMILES: [NH3:1].[CH3:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6]>C(Cl)(Cl)Cl>[CH3:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([NH2:1])=[O:6]
Reactant: N
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(N)=O)c(C)c1
Reaction time: 0.33 h

Procedure:
Saturated with anhydrous ammonia, a solution of 50 g (0.3 mole) of 2,4-dimethylbenzoyl chloride and 500 ml of AR chloroform, while maintaining a temperature of 15°. Stirred for 20 min., then filtered, washed with cold distilled water and oven-dried at 60° to give 29.1 g, m.p. 184°-186°.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:5]2[CH:6]=[C:7]([C:14]3[CH:15]=[N:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][CH:19]=3)[CH:8]=[C:9]([C:10]([NH:12][NH2:13])=[O:11])[N:4]2[N:3]=1.[C:24](Cl)(=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>C1COCC1.O1CCOCC1>[CH3:27][CH:26]([CH3:28])[CH2:25][C:24]([NH:13][NH:12][C:10]([C:9]1[N:4]2[N:3]=[C:2]([NH2:1])[N:23]=[C:5]2[CH:6]=[C:7]([C:14]2[CH:19]=[N:18][C:17]([N:20]([CH3:21])[CH3:22])=[N:16][CH:15]=2)[CH:8]=1)=[O:11])=[O:29]
Reactant: CN(C)c1ncc(-c2cc(C(=O)NN)n3nc(N)nc3c2)cn1
Reactant: CC(C)CC(=O)Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)CC(=O)NNC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(N)nn12

Procedure:
The product of Step 2 (0.11 g, 0.35 mmol) was combined with isovaleryl chloride (0.04 mL, 0.35 mmol) and 5 mL of a 1:1 solution of THF/dioxane in a tube. The mixture was microwaved at 130° C. for five minutes. The reaction mixture was cooled, then the solid was collected by filtration to give 2-amino-7-(2-dimethylamino-pyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid N′-(3-methyl-butyryl)-hydrazide. MS (APCI+): m/z 398.1.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[N:24]1[C:32]2[C:27](=[C:28]([N:33]3[CH:37]=[C:36]([C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)[N:35]=[CH:34]3)[CH:29]=[CH:30][CH:31]=2)[C:26]([CH:44]([CH3:46])[CH3:45])=[N:25]1)[C:19]#[N:20].FC(F)(F)C(O)=O.[CH3:54][C:55]([CH3:57])=O>ClCCl>[CH:44]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][C:28]=2[N:33]2[CH:37]=[C:36]([C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[N:35]=[CH:34]2)[N:24]([C:23]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[NH:15][CH:55]([CH3:57])[CH3:54])[N:25]=1)([CH3:46])[CH3:45]
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2N)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1cc(C#N)ccc1-n1nc(C(C)C)c2c(-n3cnc(-c4cccnc4)c3)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyborohydride (192 mg) was added to a solution of compound (10b) (190 mg) in dichloromethane (2.7 mL), and the mixture was cooled to 0° C. Then trifluoroacetic acid (0.45 mL) and acetone (67 μL) were added thereto and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (10c) (208.6 mg, yield 990) as a white foamy substance.