Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:13]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][CH3:22])[C:14]=2[NH2:15])=[O:12])[N:4]=1.O1CCCC1.B.[Na]>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([OH:12])[C:13]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][CH3:22])[C:14]=2[NH2:15])[N:6]=1
Reactant: COCc1cccc(C(=O)c2nc(OC)cc(OC)n2)c1N
Agent: B
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cccc(C(O)c2nc(OC)cc(OC)n2)c1N
Temperature: 25 °C
Yield: 89.7 %

Procedure:
3.1 g (10 mM) of the 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-methoxymethylaniline obtained in the above (4) was dissolved in 50 ml of a 1:1 (by volume ratio) mixed solvent of tetrahydrofuran and water. While the solution was stirred at room temperature, thereto was added 0.6 g (16 mM) of sodium boron hydride. The mixture was stirred at room temperature for 2 hours. 50 ml of ice water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and subjected to vacuum distillation to remove the solvent. The residual crystals were washed with diisopropyl ether to obtain 2.8 g (yield: 92%) of 2-[(4,6-dimethoxypyrimidine-2-yl)hydroxymethyl]-6-methoxymethylaniline as a white powder (melting point: 40 to 42° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([CH3:19])=[CH2:18])[CH:16]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1.CS(O)(=O)=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([OH:22])([CH3:19])[CH3:18])[CH:16]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: C=C(C)c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(O)c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
To a solution of 3-(5-chloropyridin-2-yl)-5-isopropenylbenzoic acid (0.18 g, 0.46 mmol) in water (4.6 mL) was added methanesulfonic acid (1.5 mL, 23.1 mmol). The mixture was heated to 50° C. After 18 h, the mixture was cooled to ambient temperature and sodium carbonate was added to adjust pH to 3-4. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 100% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (80 mg). MS 292.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:26][C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Product: Cc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1

Procedure:
The product from Example 4a (5.00 g, 17.53 mmol) was reacted with 4-methylthiophenol (2.17 g, 17.53 mmol) in place of thiophenol following the procedure from Example 1e for 18 h giving the crude title compound which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane providing a solid (3.53 g, 78%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:23](=[O:24])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:26])[CH:18]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc3oc4c(c3c2)CCCCCC4)c1
Yield: 81.4 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.70 mmol), m-toluoyl chloride (0.096 mL, 0.73 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (17 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-3-methylbenzamide (0.19 g). MS (ESI) m/z 334 ([M+H]+).
Reaction SMILES: C([O:3][C:4]([NH:6][C:7]1[C:8](=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[C:9]([OH:11])=[O:10])=O)C.S(Cl)(Cl)=O>O1CCOCC1>[Cl:16][C:15]1[C:7]2[NH:6][C:4](=[O:3])[O:10][C:9](=[O:11])[C:8]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)Nc1c(Cl)cccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1

Procedure:
468 gm of N-ethoxycarbonyl-3-chloro-anthranilic acid (m.p. 111°-114° C) were refluxed in 1500 ml of dioxane with 420 ml of thionyl chloride for 3 hours while stirring. Thereafter, the reaction solution was evaporated in vacuo until crystallization started, and then cooled. The precipitate was collected by suction filtration and washed with ether. 8-Chloro-2H-3,1-benzoxazine-2,4(1H)-dione, m.p. 225°-230° C, was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c2cc(Br)c(OCc3ccccc3)cc2n1
Reactant: C1CCNC1
Product: Cc1cc(N2CCCC2)c2cc(Br)c(OCc3ccccc3)cc2n1
Yield: 62.9 %

Procedure:
A mixture of 7-benzyloxy-6-bromo-4-chloro-2-methyl-quinoline (10.0 g, 27.6 mmol) and pyrrolidine (47 mL, 0.562 mol) was refluxed during 3 h. The mixture was cooled down and the pyrrolidine was evaporated under high vacuum. The residue was taken up in dichloromethane, washed with water and brine, dried over sodium sulfate, filtered and the solvents were evaporated under vacuum. 6.9 g of the title compound were obtained. Brown solid, ISP-MS: m/e=399.2 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:30])[CH:6]=1)[CH2:25][C:26]([F:29])([F:27])[F:28])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(CC(F)(F)F)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6 and Step 7, using the following starting materials: {6-methoxy-2′-[(2,2,2-trifluoro-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[ClH:14]>CO.[Pt](=O)=O>[ClH:14].[CH3:7][C:2]([CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)([CH3:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)c1ccncc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)C1CCNCC1
Reaction time: 46 h

Procedure:
0.115 g of methyl 2-methyl-2-pyridin-4-ylpropionate (CAS 79757-27-0) is dissolved in an autoclave in 5 ml of methanol. The solution is admixed with 0.35 ml of 1.2M HCl in methanol and 0.012 g of platinum(IV) oxide, and the reaction mixture is hydrogenated at 4 bar and 23° over 46 hours. The catalyst is filtered off through Hyflo and the filtrate is concentrated by evaporation. The title compound is obtained as a light brown solid. Rf0.05 (200:20:1 dichloromethane-methanol-25% conc. ammonia).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][C@@H:12]([CH3:16])[NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>>[CH:17]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][C@@H:12]([CH3:16])[NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCC(O)CC1
Reactant: C[C@@H]1Cn2c(cc3cc(O)ccc32)C(=O)N1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@@H](C)NC2=O)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 1, from (R)-8-hydroxy-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butyl-azodicarboxylate, to give the desired product as a light yellow solid (34%).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[C:14]1[NH:15][C:16]([S:20](Cl)(=[O:22])=[O:21])=[C:17]([CH3:19])[N:18]=1.O>O1CCOCC1>[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[C:14]1[NH:15][C:16]([S:20]([NH2:1])(=[O:22])=[O:21])=[C:17]([CH3:19])[N:18]=1
Reactant: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1S(=O)(=O)Cl
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1S(N)(=O)=O
Reaction time: 3 h

Procedure:
Aqueous ammonia solution (approximately33% w/w, 1.2 ml) was added dropwise with stirring to a solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-methyl-imidazole-5-sulphonyl chloride (2.0 g, 0.005 mol) in dioxane (15 ml) and the mixture was stirred for 3 hours. It was poured into water (50 ml) and extracted with diethyl ether (3×25 ml). The combined extracts were washed with water (2×50 ml) dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluted with.a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.) (1:2). Recrystallization from a mixture of ethyl acetate and petroleum spirit (b.p. 60°-80° C.) (1:3) gave 2-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-methylimidazole-5-sulphonamide (0.45 g), m.p. 266°-267° C., as an off-white solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH:12](C)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:4]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COCc1cccnc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a suspension of 1.24 g of sodium hydride (60% oil dispersion; 31 mmol) in 90 mL of THF were added dropwise 3.27 g of 3-pyridinemethanol (30 mmol) in 10 mL of dry THF at room temperature over 5 min. The resulting white suspension was stirred at room temperature for an hour, to which was then added dropwise 6.27 g of tert-butyl 2-bromopropionate (30 mmol) in 10 mL of dry THF at room temperature over 5 min. The mixture was stirred at room temperature for 11.5 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate=1:1) to give 4.01 g of tert-butyl (pyridin-3-yl)methoxyacetate (Yield: 56.3%) as a dark brown oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[N:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid tert-butyl ester (0.45 g, 1.49 mmol) in dioxane (3.0 mL) at room temperature was added 4M HCl in dioxane (8 mL). The reaction mixture was stirred at room temperature 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue treated with ether. The titled compound was collected by filtration. MS (CI) m/z 203 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([C:5](C(OC)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:4])=[O:3].[Cl-].[Na+].CN(C)C=O>O>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:4])=[O:3]
Reactant: COC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OCc1ccccc1)(C(=O)OC)S(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OCc1ccccc1)S(C)(=O)=O
Temperature: 160 °C

Procedure:
A mixture of methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13-(4-fluorophenoxy)tridecanoate (2.60 g., 4.5 mmoles), sodium chloride (0.5 g., 8.5 mmoles), dimethylformamide (8 ml.) and water (0.2 ml.) is heated with an oil bath at 160° C. overnight (ca. 15 hours). The reaction mixture is allowed to cool to room temperature, quenched with cold water, and then extracted with chloroform three times. The combined extracts are washed with brine and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo leaving the desired product as a viscous oil residue (2.30 g., 4.4 mmoles, 98%). ir (neat) 3.40, 5.72, 6.20, 6.62, 6.87, 7.71, 8.00, 8.28, 8.90, 12.04, 13.17, 14.37μ; pmr (CCl4)δ1.0-2.0 (22H, m, containing a methyl singlet at 2.60δ), 3.54 (3H, s); 3.5-4.1 (3H, m), 4.47 (1H, d, J=12Hz), 4.70 (1H, d, J=12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: Cl[CH:2]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:2]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[C:3]2[CH:4]=[CH:5][C:6]3[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:7]=3[CH:20]=2)=[CH:22][CH:23]=1
Reactant: c1c[nH]cn1
Reactant: O=C1CN=C(c2ccccc2)c2cc(C(Cl)c3ccc(Cl)cc3)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN=C(c2ccccc2)c2cc(C(c3ccc(Cl)cc3)n3ccnc3)ccc2N1
Yield: 44.6 %

Procedure:
A mixture of intermediate (29) (0.0125 mol), 1H-imidazole (0.0375 mol) and K2CO3 (8.62 g) in acetonitrile (150 ml) was stirred and refluxed for 3 h. The mixture was cooled, filtered off and the filtrate was evaporated till dryness. The residue was taken up in DCM. The organic layer was washed with water, dried (MgSO4), filtered off and evaporated. The residue (5.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1) (15–40 μm). The pure fractions were collected and evaporated. The residue (2.71 g) was crystallized from DIPE, yielding 2.38 g (51%) of (±)-7-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, mp. 144° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]([S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[CH2:10][CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:6]([CH2:8][N:9]([S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[CH2:10][CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])([OH:7])=[O:5]
Reactant: COC(=O)C=CCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)C=CCN(CC(=O)O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
A solution of methyl 4-[(tert-butoxycarbonylmethyl)(6-chloro-naphthalene-2-sulfonyl)amino]-2-butenoate (22.7 g) in toluene (30 ml) was combined with trifluoroacetic acid (30 ml) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the resultant residue was crystallized from ether-hexane to obtain methyl 4-[carboxymethyl(6-chloro-naphthalene-2-sulfonyl)amino]-2-butenate (19.35 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH:20]([CH3:22])[CH3:21])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOCC>[C:1]([O:5][C:6](=[O:23])[CH:7]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH3:27])[CH:20]([CH3:21])[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(C)C(C(=O)OC(C)(C)C)C(C)C)cc1
Reaction time: 15 h
Yield: 95.3 %

Procedure:
To a solution of 1.00 g (2.915 mmol) of N-[(4-methoxyphenyl)sulfonyl]-D-valine tert-butyl ester (J. Med. Chem. 1997, 40, 2525) in 10 mL of DMF was added 0.128 g (3.207 mmol) of 60% sodium hydride. After 30 minutes at room temperature 0.45 mL (7.289 mmol) of iodomethane was added and the reaction was stirred for 15 h. The reaction mixture was then diluted with ether and washed with water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.993 g (95%) of the N-methyl sulfonamide as a colorless oil. Electrospray Mass Spec: 357.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Cc1cc(N)c(N)cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2nc(C(O)C(F)(F)F)[nH]c2cc1C
Temperature: 108 °C

Procedure:
4,5-Dimethyl-benzene-1,2-diamine (5.04 g; 37.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (8.01 g; 55.6 mmoles) were suspended in 6N HCl (9 mL; 54 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (6.90 g; 81.00 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:16]3[O:17][C:18]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[N:19][N:20]=3)[C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:29]I>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:16]3[O:17][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:29])[CH2:23][CH2:22]4)=[N:19][N:20]=3)[C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cnc(N)c(-c3nnc(C4CCNCC4)o3)c2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2cnc(N)c(-c3nnc(C4CCN(C)CC4)o3)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 19.3 %

Procedure:
To a solution of 5-(3-methoxyphenyl)-3-[5-(4-piperidyl)-1,3,4-oxadiazol-2-yl]-pyridin-2-amine (150 mg, 0.42 mmol) in THF (20 mL) was added 60% NaH (25.0 mg, 064 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 10 min. Then MeI (54.5 mg, 0.38 mmol) was added at 0° C. and stirred the reaction mixture at 0° C. for 2 h. The reaction mixture was poured into ice-water (30 mL), extracted with ethyl acetate (3×20 mL), organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude product was purified by preparative TLC to afford the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:57][C@H:56]([CH2:55][O:54][C:51]1[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=1)[CH2:58][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH2:13][CH2:14]2)=[CH:28][CH:29]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 23.1 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]acetamide (0.500 g, 1.08 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.4 g, 0.973 mmol) according to Procedure G to give the title compound (0.185 g, 0.225 mmol).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[OH:32][CH2:33][C@H:34]1[CH2:39][NH:38][CH2:37][CH2:36][N:35]1C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:38]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH2:33][OH:32])[CH2:39]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@@H](CO)C3)c2c1
Reaction time: 16 h

Procedure:
A mixture of the product of Example 75 step i) (300 mg), (R)-2-(hydroxymethyl)piperazine-1-carboxylic acid, tert-butyl ester (465 mg) and sodium triacetoxyborohydride (608 mg) in dichloromethane (20 mL) was stirred under nitrogen for 16 hours. The reaction was partitioned between dichloromethane and water, the organics were then collected and concentrated to dryness. The residue was purified by HPLC to give the title compound (230 mg) as a solid.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:17]2[C:18]3[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:27]([C:24]1[S:23][C:19]2[N:20]=[CH:21][N:22]=[C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[O:8][CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:30])[CH2:7][CH2:6]3)[C:18]=2[C:25]=1[CH3:26])=[O:28]
Reactant: CN(C)CCCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12

Procedure:
Prepared analogously to 33.3 from 0.050 g 4-[2-(4,4-difluoro-cyclohexyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 33.2) and 0.126 ml N,N-dimethyl-propane-1,3-diamine.