Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]12[O:32][CH:25]([CH:26]([O:30][CH3:31])[CH2:27][CH:28]1[CH3:29])[CH:24]([O:33][CH3:34])[CH2:23][CH:22]([CH3:35])[CH2:21][C:20]([CH3:36])=[CH:19][CH:18]([CH2:37][CH3:38])[C:17](=[O:39])[CH2:16][CH:15]([OH:40])[CH:14]([CH3:41])[CH:13]([C:42]([CH3:50])=[CH:43][CH:44]1[CH2:49][CH2:48][CH:47]=[CH:46][CH2:45]1)[O:12][C:11](=[O:51])[CH:10]1[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]1)[C:4](=[O:52])[C:3]2=[O:53]>CO.[Pd]>[OH:1][C:2]12[O:32][CH:25]([CH:26]([O:30][CH3:31])[CH2:27][CH:28]1[CH3:29])[CH:24]([O:33][CH3:34])[CH2:23][CH:22]([CH3:35])[CH2:21][C:20]([CH3:36])=[CH:19][CH:18]([CH2:37][CH3:38])[C:17](=[O:39])[CH2:16][CH:15]([OH:40])[CH:14]([CH3:41])[CH:13]([C:42]([CH3:50])=[CH:43][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1)[O:12][C:11](=[O:51])[CH:10]1[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]1)[C:4](=[O:52])[C:3]2=[O:53]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CC=CCC3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Pd]
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCCCC3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of the product of Example 50 (15 mg) in dry methanol (4 ml) was added 104 Pd-on-C (6 mg) and the resulting suspension was stirred in an ice bath for one hour under an atmosphere of hydrogen. The reaction mixture was then filtered and concentrated to an oil in vacuo. Chromatography on silica eluting with hexane in an increasing acetone gradient then gave the title compound as a foam (14 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][CH:4]1[NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1.Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:8][C:6]1([F:9])[CH2:5][CH:4]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[CH:3]([NH:2][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:7]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NC1CC(F)(F)CC1Nc1ccc(C(F)(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 140 °C

Procedure:
To a solution of N-(2-amino-4,4-difluorocyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 42; 120 mg, 0.349 mmol) in dry DMSO (1.2 ml) was added 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 70 mg, 0.38 mmol) and DIPEA (183 μl, 1.05 mmol). The reaction mixture was heated in a sealed vial at 140° C. for 17 hours then partitioned between ethyl acetate and water. The organics were washed with water, filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (basic silica, 0-100% ethyl acetate in petrol) and then was chirally separated using SFC (Waters prep30/MS system using 10% Ethanol, Daicel AD 10 mm id×250 mm long columns at 30 ml/min, 40° C. and 100 bar) to afford the title compound as a single enantiomer.
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:16][CH2:17][C:18]1[CH:37]=[CH:36][C:21]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][C:26]=2[O:34][CH3:35])=[O:23])=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.Br>C(O)(=O)C>[NH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:32])[NH2:33])=[CH:27][C:26]=2[O:34][CH3:35])=[O:23])=[CH:36][CH:37]=1
Reactant: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.7 %

Procedure:
To 1.5 g of 4-amidino-2-methoxyphenyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate, was added 15 ml of acetic acid followed by 1 ml of anisole. To the mixture, while being cooled in ice, was added 3.0 ml of an acetic acid solution containing 30% of hydrogen bromide. The mixture was then stirred overnight at room temperature. The insoluble substance precipitated from the reaction mixture was collected by filtration and recrystallization from a methanol-ethyl ether mixture to obtain 1.1 g of colorless crystals of 4-amidino-2-methoxyphenyl 4-aminomethylbenzoate dihydrobromide.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl[C:9]1[CH:14]=[C:13]([Cl:15])C=C(Cl)C=1>>[Cl:15][C:13]1[CH:14]=[CH:9][C:1]([O:4][C:5]2[CH:3]=[CH:2][C:1]([OH:4])=[C:7]([CH2:7][CH:6]=[CH2:5])[CH:6]=2)=[CH:2][CH:3]=1
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: C=CCOCC=C
Product: C=CCc1cc(Oc2ccc(Cl)cc2)ccc1O
Temperature: 25 °C

Procedure:
The crude allyl ether from step 3 (20.0 g) was dissolved in 2,4,6-trichlorobenzene (60 mL) and the solution was heated at reflux for 4 h. After being cooled to room temperature, the solution was directly loaded onto a column of silica gel and eluted sequentially with hexane and a 8:2 mixture of hexane and ethyl acetate to give 4-(4-chlorophenoxy)-2-(2-propenyl)phenol.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:16]([C:18]1[CH:26]=[C:25]([F:27])[C:21]([C:22](Cl)=[O:23])=[C:20]([F:28])[CH:19]=1)#[N:17]>>[C:16]([C:18]1[CH:19]=[C:20]([F:28])[C:21]([C:22]([C:3]2[C:4]3[C:5](=[C:6]([NH:10][C:11]([CH:13]4[CH2:14][CH2:15]4)=[O:12])[N:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:23])=[C:25]([F:27])[CH:26]=1)#[N:17]
Reactant: O=C(Nc1nccc2cc[nH]c12)C1CC1
Reactant: N#Cc1cc(F)c(C(=O)Cl)c(F)c1
Product: N#Cc1cc(F)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(F)c1

Procedure:
N-[3-(4-Cyano-2,6-difluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropane carboxamide (Compound No. 51) was prepared from N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide and 4-cyano-2,6-difluorobenzoyl chloride.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:43][C:44]1[N:45]=[CH:46][NH:47][CH:48]=1.[CH3:49][CH:50]([O:52][C:53](=[O:70])[NH:54][C@H:55]1[C:64]2[C:59](=[CH:60][CH:61]=[C:62](Br)[CH:63]=2)[N:58]([C:66](=[O:68])[CH3:67])[C@@H:57]([CH3:69])[CH2:56]1)[CH3:51].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)(C)(C)C>[C:66]([N:58]1[C:59]2[C:64](=[CH:63][C:62]([N:47]3[CH:48]=[C:44]([CH3:43])[N:45]=[CH:46]3)=[CH:61][CH:60]=2)[C@H:55]([NH:54][C:53](=[O:70])[O:52][CH:50]([CH3:49])[CH3:51])[CH2:56][C@@H:57]1[CH3:69])(=[O:68])[CH3:67]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: Cc1c[nH]cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 1.5 %

Procedure:
A stock solution of tert-butanol (5 mL) and water (10 μl) was prepared and degassed under house vacuum and quenched several times with nitrogen. A mixture of palladium(II) acetate (6 mg, 5 mmol) and Xantphos (38 mg, 0.081 mmol) in the stock solvent (4 mL) was heated at 80° C. for 1 min under microwave irradiation then cooled to room temperature. The solution was then added to a mixture of 4-methylimidazole (53 mg, 0.65 mmol), 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Example 4) (200 mg, 0.54 mmol) and potassium carbonate (112 mg, 0.81 mmol). The resulting mixture was stirred at 110° C. for 15 h under microwave irradiation then cooled to room temperature and the insoluble were filtered off. Most of the solvents were removed in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) gave 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (3 mg, 0.0081 mmol, 1.5%)
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-])=[O:2].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C.[CH2:22]([Sn:26]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[C:27]#[CH:28])[CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1.O>[CH3:5][C:4]1[CH:28]=[C:27]([Sn:26]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[O:2][N:1]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: CC[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Temperature: 50 °C

Procedure:
To a solution of nitroethane (0.0952 ml, 1.33 mmol) in benzene (2 mL) was added phenyl isocyanate (0.291 ml, 2.66 mmol). The solution was stirred at 50° C. for ten minutes followed by the addition of triethylamine (0.00925 ml, 0.0666 mmol) and tributyl(ethynyl)stannane (0.365 ml, 1.27 mmol). The mixture was left to stir at 50° C. overnight. The solution was diluted with water and filtered though a celite plug, the resulting filtrate was extracted with toluene. Organic extracts were dried over magnesium sulfate and filtered then concentrated to yield the product as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:27]=1[C:28](O)=[O:29]>>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[C:27]=1[C:28]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: O=C(O)c1c(F)cccc1C(F)(F)F
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3C(F)(F)F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
N-[(2-fluoro-6-(trifluoromethyl)phenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2-fluoro-6-(trifluoromethyl)benzoic acid using the general procedures described in example 7 and was obtained as a white solid: mp 218-220° C. ES-HRMS m/e calcd for C25H23F4N3O5 (M+Na) 530.1310, found 530.1317.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)=[O:11])=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[N:23]=2)=[CH:18][C:17]=1[O:39][CH3:40].FC(F)(F)C1C=CC(C(Cl)=O)=CC=1>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[N:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([NH:15][C:10](=[O:11])[C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)=[C:17]([O:39][CH3:40])[CH:18]=3)[C:30]=12
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
4-(Trifluoromethoxy)-1-benzenecarbonyl chloride (38 mg, 0.170 mmol) in dichloromethane (0.3 mL) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.17 mmol) in pyridine (1.2 mL) at 0° C. After 5 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 1 hours then, more 4-(trifluoromethyl)-1-benzenecarbonyl chloride (19 mg, 0.085 mmol) was added. After 2 hours, the solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give N1-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethoxy)benzamide (70 mg, 76%). 1H NMR (CDCl3) δ 2.06 (d, J=11.79 Hz, 2H), 2.28 (m, 2H), 2.40 (s, 3H), 2.50 (m, 2H), 3.07 (d, J=10.8 Hz, 2H), 4.02 (s, 3H), 4.80 (m, 1H), 5.71 (s, 2H), 7.27 (m, 2H), 7.36 (d, J=8.20 Hz, 2H), 7.98 (d, J=6.20 Hz, 2H), 8.37 (s, 1H), 8.59 (s, 1), 8.67 (d, J=8.55 Hz, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=542.3, Rt=1.98 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1>Cl>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[O:16][C:17]=2[CH3:18])(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3cc(C)cc(C)c3)c(C)o2)cc1
Agent: Cl
Product: Cc1cc(C)cc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Yield: 99.9 %

Procedure:
Reaction of benzoate 25 (346 mg, 0.87 mmol) and 6 M HCl (10 mL) gave acid 26 (335 mg, 100%) as a white solid: mp (H2O) 265-268° C.; 1H NMR δ 13.16 (br s, 1H, CO2H), 8.05 (dd, J=8.5, 1.8 Hz, 2H, H-2, H-6), 7.93 (ddd, J=8.5, 1.8 Hz, 2H, H-3, H-5), 7.41 (br s, 2H, H-2′, H-6′), 7.37 (br s, 1H, H-4′), 4.62 (s, 2H, CH2SO2), 2.32 (s, 6H, 2×CH3), 2.19 (s, 3H, CH3); MS m/z 386.5 MH+, 100%). Anal. calcd for C20H19NO5S: C, 62.32; H, 4.97; N, 3.63. Found: C, 62.59; H, 4.84; N, 3.58%.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1>CN(C)C=O.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([O:8][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:6][N:7]=1
Reactant: Oc1cnc(F)cc1I
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(I)c(OCCOC2CCCCO2)cn1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Add 6-fluoro-4-iodo-pyridin-3-ol (0.5 g, 2.09 mmol) to a suspension of sodium hydride (60% dispersion in mineral oil, 0.1 g, 2.51 mmol) in dimethylformamide (6 mL). Stir the mixture for 1 hour. Add 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.51 g, 2.34 mmol). Stir the solution at room temperature overnight. Dilute the mixture with ethyl acetate and water. Wash the organic layer with saturated aqueous sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to give yellow oil. Purify the oil by column chromatography (10% ethyl acetate in hexane) to afford the title compound (0.58 g, 75.5%) as a light yellow oil. MS (EI) m/z 368 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:37]O)[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:37][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: OCc1ccc(CO)cc1
Product: O=C1c2ccccc2C(OCc2ccc(CO)cc2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 57.4 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (541 mg, 1.37 mmol, 1 equiv.) and 1,4-benzenedimethanol (946 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (405 mg, 78%). 1H NMR (300 MHz, CDCl3): 8.01-7.85 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.61-7.53 (m, 2H, Ar—H), 7.37-7.18 (m, 9H, Ar—H), 6.93 (d, J=7.8 Hz, 2H, Ar—H), 4.85 and 4.67 (d: AB, J=15.0 Hz, 2H, N—CH2), 4.66 (d, J=5.7 Hz, CH2—OH), 3.90 and 3.68 (d: AB, J=11.7 Hz, 2H, OCH2), 2.12 (t, J=6.0 Hz, 1H, OH). 13C NMR (75 MHz, CDCl3): 168.52, 147.63, 145.39, 144.90, 141.16, 137.34, 136.39, 135.37, 133.42, 131.73, 130.57, 130.32, 129.19, 128.38, 127.30, 127.11, 124.34, 123.69, 95.52, 65.26, 65.12, 42.89. m/z (ES): 515 [M+H]+. HPLC: Rt=3.56 min. Anal.: calc. for C29H23ClN2O5: C, 67.64; H, 4.50; N, 5.44, Found: C, 67.38; H, 4.43; N, 5.26.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1>>[NH2:12][C:8]1[C:7]([Cl:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1)=[N:3]2
Reactant: Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(c2ccc3c(N)c(Cl)ccc3n2)CC1
Yield: 71.8 %

Procedure:
Prepared according to the method of example 30, using 2,6-dichloroquinolin-5-amine (Example 1(d)) (800 mg) and 4-piperidinecarboxylic acid, ethyl ester (1.8 g). Purification (SiO2, miethanol:dichloromethane 1:99 as eluant) gave the sub-title compound as a solid (900 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCCCCBr
Reactant: Nc1ccc(Br)c(OCCN2CCCCC2)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc(N2CCCC2)cc1OCCN1CCCCC1
Temperature: 110 °C

Procedure:
4-Bromo-3-(2-{piperidin-1-yl}ethoxy)aniline (2.99 g), 1,4-dibromobutane (1.2 ml), diisopropylethylamine (4.18 ml) and toluene (15 ml) were stirred and heated at 110° C. for 18 h. When cool, water (20 ml) was added, and the mixture was extracted with ethyl acetate (2×30 ml). The combined organic phase was washed with water, brine, dried (MgSO4) and evaporated to give the product as an orange-brown oil (2.25 g).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-])=O)([CH3:3])[CH3:2]>[Pt].C(OCC)(=O)C>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[NH2:19])([CH3:3])[CH3:2]
Reactant: CC(C)OCCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)OCCCNc1c(N)cnc2cccnc12
Reaction time: 2.5 h
Yield: 95.4 %

Procedure:
N4-(3-Isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine (4.2 g, 14.5 mmol), platinum on carbon (1.1 g of 5%), and ethyl acetate (100 mL) were placed in a hydrogenation flask. The mixture was shaken under a hydrogen pressure of 50 psi (3.5 Kg/cm2) for 2.5 hours. The reaction mixture was filtered and the catalyst was washed with ethyl acetate. The filtrate was dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 3.6 g of N4-(3-isopropoxypropyl)[1,5]naphthyridine-3,4-diamine as a bright yellow oil. 1H NMR (300 MHz CDCl3): δ 8.70 (dd, J=4.1, 1.6 Hz, 1H), 8.39 (s, 1H), 8.17 (dd, J=8.4, 1.6 Hz, 1H), 7.37 (dd, J=8.4, 4.1 Hz, 1H), 5.99 (broad s, 1H), 3.98 (broad s, 2H), 3.63-3.55 (m, 5H), 1.87 (pentet, J=6.2 Hz, 2H), 1.17 (d, J=6.1 Hz, 6H); MS (EI): m/e 260.1630 (260.1637 calc'd for C14H20N4O).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][O:30][CH3:31]>C(#N)C>[F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][O:30][CH3:31])[CH2:17][CH2:16]1
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). MS m/z (rel. intensity, 70 eV) 369 (M+, 1), 325 (15), 324 (bp), 191 (37), 133 (14).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.C([O-])([O-])=[O:27].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].O.C(O)(=O)C>CO.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:27])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: O=C([O-])[O-]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: O=[Mo](=O)([O-])[O-]
Agent: OO
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: 20 °C
Reaction time: 4 h
Yield: 204 %

Procedure:
310 mg of 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazol were dissolved in 1.5 ml of methanol and 12 mg of ammonium molybdate added. The solution was cooled to 51C and 0.11 g of sodium percarbonate were added, then kept stirred at the same temperature for 4 h. After the reaction ended 3 ml of water were added, then heating to 20° C. and adjusting the mixture of the pH to 7.5 with acetic acid. The mixture is extracted with 5 ml of dichloromethane and the organic phase separated, then washed with 10 ml of water. The solvent was evaporated at a reduced pressure. 274 mg of pantoprazol were obtained (yield: 88%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.N1C=CC=CC=1>[CH3:23][S:24]([NH:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][S:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[CH:8]2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cccc2cc(NS(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide is dissolved in methylene chloride and pyridine, and the mixture is cooled in an ice bath. Methanesulfonyl chloride is added dropwise, and the reaction mixture is stirred at ice bath temperature, then allowed to warm to room temperature. The reaction mixture is quenched by addition of water and extracted with methylene chloride. The organic layer is washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give N-[5-(Methanesulfonylamino-methyl)-naphthalen-2-yl]-benzenesulfonamide. 5-(Methanesulfonylamino-methyl)-naphthalene-2-sulfonic acid phenylamide may be similarly prepared.