Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10](=[O:35])[NH:11][C:12]1[CH:13]=[N:14][C:15]([C:18](=O)[CH2:19][O:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([C:30]=2[NH2:31])=[N:28][C:27]([O:32][CH3:33])=[CH:26][CH:25]=3)=[CH:16][CH:17]=1)([CH3:8])([CH3:7])[CH3:6].C([BH3-])#N.[Na+].ClCCl>CO>[C:5]([O:9][C:10](=[O:35])[NH:11][C:12]1[CH:13]=[N:14][C:15]([CH:18]2[NH:31][C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH3:33])[N:28]=4)[N:23]=[CH:22][C:21]=3[O:20][CH2:19]2)=[CH:16][CH:17]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: COc1ccc2ncc(OCC(=O)c3ccc(NC(=O)OC(C)(C)C)cn3)c(N)c2n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2ncc3c(c2n1)NC(c1ccc(NC(=O)OC(C)(C)C)cn1)CO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Acetic acid (110 mg, 1.83 mmol, 1.7 eq) is added at room temperature to a stirred solution of {6-[2-(4-amino-6-methoxy-[1,5]naphthyridin-3-yloxy)-acetyl]-pyridin-3-yl}-carbamic acid tert-butyl ester (470 mg, 1.10 mmol 1.0 eq) in methanol (20 mL) and the resulting mixture is stirred at room temperature for 1 hour before the addition of sodium cyanoborohydride (370 mg, 5.89 mmol, 5.3 eq). After 4 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and a saturated sodium hydrogen carbonate aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 200:1 to 50:1, v/v) to afford [6-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester as a light yellow solid (222 mg, 49% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[C@@H:14]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:13][NH:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.CCN(CC)CC.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1COCC1>[C:38]([N:12]1[CH2:13][C@H:14]([NH:15][C:16](=[O:30])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=[O:29])=[CH:21][CH:22]=2)[C@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:11]1)(=[O:40])[CH3:39]
Reactant: O=C(N[C@H]1CNC[C@H]1NC(=O)c1ccc(Cl)s1)c1ccc(-n2ccccc2=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1C[C@H](NC(=O)c2ccc(-n3ccccc3=O)cc2)[C@H](NC(=O)c2ccc(Cl)s2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
To a solution of Example 75 (6 mg, 0.013 mmol) in THF (200 μl) at 0° C. was added Et3N (3 μl, 0.021 mmol) followed by the acetic anhydride (5 μl, 0.04 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and then at rt for 10 minutes. The solvent was evaporated under pressure, and the residue was purified by preparative HPLC using 0 to 100% B over 10 minutes (Column, Luna 10μ, C18 25×100 mm; Solvent A, 10% ACN +90% H2O with 0.1% TFA; Solvent B, 90% ACN+10% H2O with 0.1% TFA) to afford the title compound (2.8 mg, 48%) as a white lyophilite. MS m/z 486 ([M+H]+).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH2:29][SH:30])[CH:20]=[CH:19][C:18]1=2>>[CH3:16][C:17]1([CH3:31])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH2:29][S:30][C:11]([C:10]3[CH:9]=[CH:8][C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:15][CH:14]=3)=[O:13])[CH:20]=[CH:19][C:18]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CS)ccc21
Reactant: C=CCOC(=O)c1ccc(C(=O)O)cc1
Product: C=CCOC(=O)c1ccc(C(=O)SCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 2 g (10 mmol) of 4-(allyloxycarbonyl)benzoic acid with 2.34 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylmethanethiol, 3.4 g (81%) of the expected allyl ester, melting point 79°-80° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1(Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12][NH:11]1.[CH2:21]([NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1)[CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH:26]1([CH2:25][N:24]([CH2:21][CH2:22][CH3:23])[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=3[CH3:9])=[N:11][N:12]=2)[CH2:28][CH2:27]1
Reactant: Cc1cc(C)c(C2(Cl)NN=Cc3ccccc32)c(C)c1
Reactant: CCCNCC1CC1
Solvent: Cc1ccccc1
Product: CCCN(CC1CC1)c1nnc(-c2c(C)cc(C)cc2C)c2ccccc12

Procedure:
A mixture of the product of step C (100 mg), N-propyl-N-cyclopropylmethylamine (0.5 mL) and in 1 mL of toluene was heated at 100° C. overnight. The mixture was cooled and concentrated. The residue was purified through silica gel column chromatography to give 40 mg of the title compound as an oil. 1H NMR (CDCI3): δ0.08 (q, 2H), 0.50 (q 2H), 0.95 (t, 3H), 1.20 (m, 1H), 1.76 9m, 2H), 1.92 (s, 6H), 2.36 )s, 3H), 3.45 (d, 2H), 3.68 (m, 2H), 6.90 (s, 2H), 7.36 (d, 1H), 7.64 (t, 1H), 7.74 (t, 1H), 8.19 (d, 1H)ppm.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28].C(N(CC)CC)C>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.[Cu]I.CN1CCCC1=O>[CH3:22][N:19]1[CH2:20][CH2:21][CH:16]([O:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:4]2[CH:3]=[C:2]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][CH2:23][N:29]3[C:33](=[O:34])[C:32]4[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:30]3=[O:39])[CH:7]=[CH:6][CH:5]=2)[CH2:17][CH2:18]1
Reactant: CN1CCC(OC(c2cccc(I)c2)c2ccccn2)CC1
Reactant: C#CCCCCN1C(=O)c2ccccc2C1=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCC(OC(c2cccc(C#CCCCCN3C(=O)c4ccccc4C3=O)c2)c2ccccn2)CC1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A screw-cap tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]pyridine (105 mg, example 37), tetrakis(triphenylphosphine)palladium (52 mg), copper(I) iodide (26 mg), N-5-hexynylphthalimide (186 mg), triethylamine (400 μL) and 1-methyl-2-pyrrolidinone (4 mL). The tube is evacuated, filled with argon and sealed. After stirring at 90° C. for 14 h, the mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5) to give 2-(6-{3-[(1-methylpiperidin-4-yloxy)-pyridin-2-ylmethyl]phenyl}hex-5-ynyl)isoindole-1,3-dione as an brown oil.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[C:1]([NH:9][C:10]([NH:16][CH2:15][CH:12]1[CH2:14][CH2:13]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCC1CC1)c1ccccc1
Yield: 100.4 %

Procedure:
Add benzoyl isothiocyanate (500 g, 3.06 mol) to chloroform (5 L) and cool to <5° C. Add a solution of cyclopropylmethylamine (230 g, 3.22 mol) in chloroform (500 mL) with vigorous stirring maintaining a temperature below 20° C. Remove the ice-water bath, and stir the mixture at room temperature overnight. Concentrate the mixture in vacuo to obtain the desired intermediate as a white solid (720 g, 100%). MS (APCI) m/z: 235 (M+H)+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10]CCl.Cl.Cl.[CH3:15][N:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]1=[O:41].[C:42]1([N:48]=[C:49]=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[ClH:10].[CH3:15][N:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([CH2:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[C:49]([NH:48][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:50])=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]1=[O:41]
Reactant: O=C=Nc1ccccc1
Reactant: ClCCl
Reactant: Cn1c(=O)ccc2cc(OCCCCCNCCc3cccnc3)ccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)ccc2cc(OCCCCCN(CCc3cccnc3)C(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-Ethyldiisopropylamine (0.192 ml) was added to a dichloromethane solution (5 ml) of 1-methyl-6-[5-(2-pyridin-3-ylethylamino)pentyloxy]-1H-quinolin-2-one dihydrochloride (219 mg). The mixture was stirred at room temperature for 5 minutes. The reaction mixture was condensed under reduced pressure. Phenylisocyanate (0.065 ml) and toluene (2 ml) were added to the residue. The mixture was stirred at 100° C. for 1 hour. The reaction mixture was purified by NH silica gel column chromatography (ethyl acetate:hexane=1:1→1:0). The purified product was concentrated under reduced pressure. A 1N-hydrogen chloride ethanol solution was added to the solution of the residue in ethanol, and stirred for 30 minutes at room temperature. The precipitated insoluble matter was collected by filtration, washed with ethyl acetate, and dried to give the title compound (147 mg) as a pale yellow flakes.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1.[CH3:15][NH2:16]>CO.[OH-].[Na+].C(O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([NH:16][CH3:15])=[CH:9][N+:10]([O-:12])=[O:11])[CH2:2]1
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCC1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCC1CCOC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture comprising 7.0 g of (tetrahydro-3-furanyl)methylamine, 12.5 g of 1,1-bis(methylthio)-2-nitroethylene and 100 ml of acetonitrile was refluxed for 5 hours. The reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to give 6.6 g of 1-[{tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene. Then, a mixture comprising 4.0 g of the 1-[{(tetrahydro-3-furanyl)methyl}amino]-1-methylthio-2-nitroethylene obtained above, 6.0 ml of 40% methylamine in methanol solution, 20 ml of 1 N aqueous sodium hydroxide solution and 20 ml of ethanol was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated under a reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate/methanol=9/1) to obtain 3.2 g of 1-[{(tetrahydro-3-furanyl)methyl}amino]-l-methylamino-2-nitroethylene.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][NH:14][O:15][CH3:16].CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: CNOC
Agent: Cl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a cooled solution of 2,4-dihydroxybenzoic acid (8 g, 52 mmol), N,O-dimethylhydroxylamine hydrochloride (6.1 g, 62 mmol) and N-methylmorpholine (13.18 g, 130 mmol) in methylene chloride (50 mL) at 0° C. was added EDC batchwise (11.95 g, 62.3 mmol). Stirred at room temperature for 3 days. The reaction was quenched by the addition of water and then extracted with methylene chloride (2 times). The combined organic extracts were successively washed with a 10% aqueous citric acid solution, a 5% sodium bicarbonate solution, water and saturated salt solution and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-33% ethyl acetate in hexanes to yield the title compound, mass spectrum (CI) m/e=198 (M+1)+.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OCCCC)(=O)C.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Mg+2].C([O-])(=O)C>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was mixed with 30 parts by volume of n-butyl acetate and 10.7 parts acetic anhydride. A solution of 0.20 parts anhydrous magnesium acetate in 2.0 parts by volume of glacial acetic acid was added and the slurry was stirred for 30 minutes at 25° C. The mixture was stirred for 2.5 hours at 40°-50° C. and then was cooled to 25° C. The solid was collected on a filter under nitrogen, it was rinsed with n-butyl acetate, and then was dried at 0.1 mm to afford 19.3 parts N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])(C)C)=[O:14])[CH2:9][CH2:8]1.Cl.C(OC(Cl)=O)[C:22]1[CH:27]=[CH:26]C=[CH:24][CH:23]=1>O1CCOCC1>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:19]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[O:14])[CH2:11][CH2:12]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCO)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCC(C2CC2CCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
Cis tert-butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (2.0 g, 7.44 mmol) was treated with 4M HCl in dioxane (200 mL) at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue taken up in 200 mL DCM. To this solution was added TEA (10.0 mL, 7.64 mmol) followed by benzylchloroformate (1.30 g, 7.64 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was washed with 1N aqueous HCl (75 mL), followed by saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via Biotage (40M+ silica gel) eluting with a gradient of 0-80% ethyl acetate to afford the title compound (2.06 g, 91%) as a viscous oil.
Reaction SMILES: [Cl-:1].[C:2]([N:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:7]=[N+:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:5])([CH3:4])[CH3:3].[C:25]12(N([Si](C)(C)C)C3C=CC=CC=3)[CH2:34][CH:29]3CC(C[CH:27]([CH2:28]3)[CH2:26]1)C2>>[Cl-:1].[C:15]12([N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:7]=[N+:6]([C:2]34[CH2:3][CH:11]5[CH2:12][CH:13]([CH2:14][CH:9]([CH2:10]5)[CH2:5]3)[CH2:4]4)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:18][CH:27]3[CH2:28][CH:29]([CH2:34][CH:25]([CH2:26]3)[CH2:17]1)[CH2:16]2
Reactant: C[Si](C)(C)N(c1ccccc1)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)N(C=[N+](c1ccccc1)C(C)(C)C)c1ccccc1
Agent: [Cl-]
Product: C(N(c1ccccc1)C12CC3CC(CC(C3)C1)C2)=[N+](c1ccccc1)C12CC3CC(CC(C3)C1)C2
Yield: 71.5 %

Procedure:
With the same method used in the synthesis of 4a except for adding 3b (2 equiv), 4b (71.5%) was obtained as a white solid. 1H NMR (300 MHz, CD2Cl2) δ=8.71 (s, 1H), 7.24-6.90 (m, 6H), 6.78 (d, J=7.4 Hz, 4H), 2.21 (br. s, 6H), 2.07-1.99 (m, 12H), 1.66 (br. s, 12H); 13C NMR (75 MHz, CD2Cl2) δ 152.7, 135.0, 130.3, 129.0, 128.9, 66.6, 41.8, 35.4, 30.5. HRMS-DART (m/z): [M]+ calcd for C33H41ClN2, 465.3264. found, 465.3249.
Reaction SMILES: [CH:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C=O.Cl.[OH:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25](N(CC)CC)C>C1(C)C=CC=CC=1.CCO>[C:19]1([CH2:18][N:17]2[CH2:25][C@H:4]3[CH2:5][C@H:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C@H:3]3[O:16]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)C1CC=CC1
Reactant: ONCc1ccccc1
Agent: C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H]2CN(Cc3ccccc3)O[C@@H]2C1
Reaction time: 24 h
Yield: 85.7 %

Procedure:
To a solution of 1,1-dimethylethyl 3-cyclopentene-1-carboxylate (8.4 g, 50.0 mmole) [JACS, 1983, 105, 2435-2439] in toluene (150 mL) and EtOH (75 mL) was added paraformaldehyde (11.0 g, 250 mmole), N-hydroxybenzylamine hydrochloride (11.8 g, 75 mmole) and triethylamine (10.4 mL, 75 mmole). After 24 hours at 80° C., the reaction solution was concentrated under vacuum and redissolved in hexanes/EtOAc, 4:1 (200 mL) and filtered. The organic solution was concentrated and then purified on silica (hexanes/EtOAc, 4:1) to give the title compound (13.0 g, 86%) as a light yellow oil: LC-MS (ES) m/e 304 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:14])[C:7]([C:12]#[N:13])=[CH:8]OCC)C.[CH2:16]([O:18][C:19]([O:24][CH2:25][CH3:26])([CH3:23])[CH2:20][CH2:21][NH2:22])[CH3:17]>O>[CH2:25]([O:24][C:19]([O:18][CH2:16][CH3:17])([CH3:23])[CH2:20][CH2:21][N:22]1[CH:8]=[C:7]([C:12]#[N:13])[C:6](=[O:14])[NH:5][C:4]1=[O:3])[CH3:26]
Reactant: CCOC(C)(CCN)OCC
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: O
Product: CCOC(C)(CCn1cc(C#N)c(=O)[nH]c1=O)OCC
Temperature: 80 °C
Yield: 83 %

Procedure:
(2-Cyano-3-ethoxy-acryloyl)-carbamic acid ethyl ester (Prep32, 500 mg, 2.3 mmol) was suspended in water (20 mL) and 3,3-diethoxybutylamine (816 μl, 4.7) was added and the mixture warmed at 80° C. for 10 minutes. The reaction mixture was lyophilized and the residue was purified by flash chromatography with petroleum ether-ethyl acetate (1-1) to give 553 mg of the title compound as a white solid (83% yield).
Reaction SMILES: [OH-:1].[K+].Cl[CH2:4][C:5]([OH:7])=[O:6].[C:8]1(C)[C:9](C)=[CH:10][CH:11]=[CH:12][CH:13]=1>>[O:1]([CH2:4][C:5]([OH:7])=[O:6])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccccc1C
Reactant: O=C(O)CCl
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)COc1ccccc1
Reaction time: 0.67 h

Procedure:
304 g of alkyl phenol derived by partial hydrogenation of distilled cashew nut shell liquid and 600 ml of xylene was charged to a 2 liter reactor equipped with agitator and condenser. The contents were warmed to 40 degree C. Subsequently 168 g of potassium hydroxide was added to the reactor and stirred for 40 minutes. Later, 94 g of chloro acetic acid was added slowly in 30 minutes. After the completion of addition of reactants, the reaction mixture was refluxed for 6 hours. On completion of the reaction, the solvent was removed and contents taken in water and acidified with dilute sulfuric acid. The product got separated from the aqueous mixture, which was filtered and recrystallised from methanol, having melting point 104° C.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=1[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16])(=[O:9])=[O:8].[H-].[Na+].[CH3:25]I>CN(C)C=O>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=1[CH:6]([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16])(=[O:8])=[O:9])[CH3:25]
Reactant: CI
Reactant: O=S(=O)(Cc1cc(Cl)ccc1OC(F)F)c1cccc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1cc(Cl)ccc1OC(F)F)S(=O)(=O)c1cccc[n+]1[O-]

Procedure:
In the same manner as in Example 1, 8.86 g of 2-(2-difluoromethoxy-5-chlorobenzylsulfonyl)pyridine-N-oxide, 1.11 g of 55% sodium hydride and 3.60 g of methyl iodide were mixed with 150 ml of dimethylformamide and the mixture was reacted followed by the same after-treatment as in Example 1, whereby 7.00 g of Compound No. 15 of the present invention was obtained. The product was white crystals having a melting point of from 145°-147° C.
Reaction SMILES: NCCCN.O.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[N:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[OH:25])([O-])=O>C1(C)C(C)=CC=CC=1.[Cu].II.CC(O)=O>[OH:25][C:19]1[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[N:17]1[N:16]=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:7]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: [Cu]
Agent: II
Agent: NCCCN
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
11.6 g of 1,3-diaminopropane (0.16 mol) and 2 g of copper-II-acetate (0.01 mol) are placed into 50 ml of water and the whole is heated, with the exclusion of air and with stirring, to 85°-90° C. A solution of 10 g of 2-nitro-2'-hydroxy-5'-methyl-azobenzene (0.04 mol) in 100 ml of xylene heated to 60° C. is then added, and after 20 hours the reaction mixture is cooled to room temperature. The aqueous phase is separated, and the organic phase is extracted with aqueous hydrochloric acid, and then washed with water until neutral. The xylene is distilled off to leave 7.7 g of crude product. Analysis of the crude product by means of LC (liquid chromatography) gives 86% of theory of 2-(2'-hydroxy-5'-methylphenyl)-benzotriazole.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]([CH2:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[C:7]2[C:12]([C:13]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:11][CH:10]=[C:9]([C:20]([O:22]C)=[O:21])[CH:8]=2)=O.[C:33]([NH:37][C:38]([NH2:40])=[S:39])([CH3:36])([CH3:35])[CH3:34].[OH-].[Na+].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>CS(C)=O>[C:33]([NH:37][C:38]1[S:39][CH:2]=[C:3]([C:5]2[N:6]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[C:7]3[C:12]([C:13]=2[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:11][CH:10]=[C:9]([C:20]([OH:22])=[O:21])[CH:8]=3)[N:40]=1)([CH3:36])([CH3:35])[CH3:34].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]
Reactant: CC(C)(C)NC(N)=S
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(C(=O)CBr)n(CC(=O)N3CCOCC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)(C)Nc1nc(-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC(=O)N2CCOCC2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The bromomethylketone of example 11 (39.6 mg, 0.078 mmol, 1 equiv.) was dissolved in DMSO (1 mL) and N-tertbutylthiourea (12.4 mg, 0.094 mmol, 1.2 equiv.) was added. The mixture was stirred for 2 h at room temperature. 10 N NaOH (24 μL) was added and after stirring for 4 h at room temperature, another portion of 10 N NaOH (24 μL) was added and the mixture stirred 24 h at room temperature to complete the hydrolysis. The reaction mixture was then neutralized by addition of TFA and the title product of example 12 isolated directly from the reaction mixture by preparative HPLC as a white amorphous TFA salt (21 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[CH2:43][NH2:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:44][CH2:43][CH:39]3[CH2:40][CH2:41][CH2:42][O:38]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NCC1CCCO1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CCCO3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and C-(tetrahydrofuran-2-yl)-methylamine according to conditions described in general procedure C. 1H NMR (400 MHz, DMSO-d6) δ 1.40-1.65 (m, 10 H), 3.00-3.85 (m, 9 H), 6.327 (bs, 1 H), 6.96 (d, 1 H), 7.15 (d, 1 H), 7.38 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.54-7.60 (m, 3 H), 7.78-7.82 (m, 1 H), 7.96 (d, 1 H), 8.20 (s, 1 H), 10.41 (s, 1 H).