Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[O:14][C:15]=2[CH3:16])=[N:7][CH:8]=1.[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([OH:39])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([O:39][CH2:2][C:3]2[CH:8]=[N:7][C:6]([O:9][CH2:10][C:11]3[N:12]=[C:13]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[O:14][C:15]=3[CH3:16])=[CH:5][CH:4]=2)=[N:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A mixture of 5-chloromethyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridine (1.30 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.06 g), potassium carbonate (0.59 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl 1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazole-4-carboxylate as colorless crystals (2.00 g, yield 90%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 140-141° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:6][C:5]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1.Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:17]([O:16][C:14]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:5]=2[CH2:6][S:2]1(=[O:12])=[O:1])=[O:15])[CH3:18]
Reactant: O=S1(=O)Cc2c(O)cccc2N1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2cccc(O)c2CS1(=O)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 26.6 %

Procedure:
Sultam 1c (100 mg, 0.54 mmol) was dissolved in pyridine (2.5 mL) and cooled to 0° C. Ethyl chloroformate (62 μL, 0.65 mmol) was added and the solution was warmed to room temperature and allowed to age for 16 hours. The pyridine was removed in vacuo and the reaction mixture was diluted with EtOAc, washed twice with 1.0 N HCl, once with water and once with brine. The solution was then dried over MgSO4, filtered and the solvent removed in vacuo. Purification via flash chromatography gave the desired phenol 1d (37 mg, 27%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:11])=[O:12])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1

Procedure:
In analogy to the procedure described in example 409f, (2S,4R)-4-cyclopropylmethanesulfonyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (example 423c) was reacted with trifluoroacetic acid to give the title compound as yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O: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].[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][N:42]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN(C)[C@@H]1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (R)—N,N-dimethylpyrrolidin-3-amine according to conditions described in general procedure C. Mp: 115-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.70-2.10(m, 2 H), 2.13(s, 6H), 2.68-3.10 (m, 5 H), 3.25(t, J=4.4 Hz, 4 H), 3.74(t, J=4.8 Hz, 4 H), 6.15(bd, 1 H), 7.04(d, J=12.0 Hz, 1 H), 7.24(d, J=8.4 Hz, 1 H), 7.40-7.61(m, 5 H), 7.84(d, J=8.0 Hz, 1 H), 7.98(d, J=8.4 Hz, 1 H), 8.22(d, J=5.5 Hz, 1 H), 10.45(s, 1 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[C:20]([C:21](=[O:23])[CH3:22])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([C:9]1[C:20]([CH:21]([OH:23])[CH3:22])=[C:12]2[C:13]3[CH2:19][CH2:18][O:17][C:14]=3[CH:15]=[CH:16][N:11]2[N:10]=1)[CH3:8]
Reactant: CCc1nn2ccc3c(c2c1C(C)=O)CCO3
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn2ccc3c(c2c1C(C)O)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a suspension of 80% lithium aluminum hydride (233 mg, 5.03 mmol) in tetrahydrofuran (13 mL) was added a solution of 1-(2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanone (290 mg, 1.26 mmol) in tetrahydrofuran (13 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (2.9 g) was added under ice-cooling, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (265 mg, yield 90%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@:4]1([C:15]([O:17]C)=[O:16])[CH2:8][CH2:7][C@@H:6]([C:9]([O:11]C)=[O:10])[C:5]1([CH3:14])[CH3:13]>CO>[CH3:3][C@@:4]1([C:15]([OH:17])=[O:16])[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[C:5]1([CH3:13])[CH3:14]
Reactant: COC(=O)[C@@H]1CC[C@@](C)(C(=O)OC)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(C(=O)O)CC[C@@]1(C)C(=O)O
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A 1 N aqueous solution of sodium hydroxide (36.8 mL, 36.8 mmol) was added to a solution of the crude di-ester mixture from Step 2 (1.4 g) in methanol (40 mL) at room temperature. The resulting mixture was heated to reflux for a total of 30 h then cooled to room temperature. After removal of methanol in vacuo, the aqueous residue was washed with dichloromethane (2×20 mL), acidified with 6 N hydrochloric acid and extracted with dichloromethane (3×80 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give the crude product (730 mg), which was taken to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][S:10][C:11](SC)=[C:12]([C:17]#[N:18])[C:13]([O:15][CH3:16])=[O:14]>>[C:17]([C:12](=[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[S:10][CH3:9])[C:13]([O:15][CH3:16])=[O:14])#[N:18]
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C(C#N)=C(SC)SC
Product: COC(=O)C(C#N)=C(Nc1ccc(F)cc1)SC
Temperature: 150 °C

Procedure:
0.5 g (4.5 mmol) of 4-fluoroaniline is thoroughly mixed with 0.91 g (4.5 mmol) of methyl 3,3-bis(methylthio)-2-cyanoacrylate (R. Gompper, W. Toepfl, Chem. Ber. 1962, 95, 2861-2870). The reaction mixture is heated at 150° C. for 2 h, resulting in a melt. After cooling, a pale solid is obtained and is washed several times with methanol. 0.68 g (55.7% of theory) of the desired product is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C:3]1=[O:27].C(O)C.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[O:15])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C:3]1=[O:27]
Reactant: CCOC(=O)c1ccc(C(=O)Nc2ccc3c(c2)N(C)C(=O)CCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1C(=O)CCCc2ccc(NC(=O)c3ccc(C(=O)O)cc3)cc21
Temperature: 35 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
850 mg of ethyl p-[(2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepine-8-yl)carbamoyl]benzoate were dissolved in 20 ml of tetrahydrofuran and 10 ml of ethanol and treated with 10 ml of 1.2N NaOH yielding a two-phase mixture. The mixture was stirred intensively at 35° C. for 8 hours, poured into an ice/conc. HCl solution and extracted thoroughly with ethyl acetate. The resulting product was washed with a small amount of NaCl solution, dryed, and concentrated, and the remaining residue was repeatedly boiled in ethyl acetate and dryed yielding 400 mg of p-[(2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-8-yl)carbamoyl]benzoic acid as beige crystals, m.p. >270° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])=[O:3].[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:12][C:5]3[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=3[C:2](=[O:3])[CH3:1])=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(OC)cc23)c(C(C)=O)c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
2-Hydroxy-5-methoxyacetophenone (3.00 g), 7-benzyloxy-4-chloro-6-methoxyquinoline (6.65 g), and 4-dimethylaminopyridine (4.90 g) were suspended in o-dichlorobenzene (30 ml), and the suspension was stirred at 180° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 1-[2-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-ethanone (2.53 g, yield 59%).
Reaction SMILES: [CH3:1][C:2]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([C:4]#[CH:5])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]2[N:30]=[C:29]([NH:31][CH2:32][CH2:33][CH3:34])[C:28](I)=[CH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1.C(OCC)(=O)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.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>[F:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]2[N:30]=[C:29]([NH:31][CH2:32][CH2:33][CH3:34])[C:28]([C:5]#[C:4][C:2]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])[CH3:1])=[CH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1I
Reactant: C#CC(C)(C)C(C(=O)OCC)C(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CC(C)(C)C(C(=O)OCC)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-(2-methyl-3-butyn-2-yl)malonate synthesized according to the method described in Chemistry A European Journal, 2005, 11, pp. 308-320 (3.3 g), N2-(3-fluorophenyl)-5-iodo-N4-propylpyrimidine-2,4-diamine (F2, 868 mg), bis(triphenylphosphine)palladium(II) dichloride (161 mg) and copper(I) iodide (88 mg) in N,N-dimethylformamide (15 mL), triethylamine (1.6 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. To the reaction mixture, tetrakis(triphenylphosphine)palladium(0) (132 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour and 40 minutes. To the reaction mixture, ethyl acetate and saturated aqueous ammonium chloride were added. The organic layer was separated, washed successively with saturated aqueous ammonium chloride, water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 94 to 64% hexane in ethyl acetate) to obtain diethyl 2-(4-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-2-methyl-3-butyn-2-yl)malonate (F13, 803 mg) as yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(Cl)Cl.Cl.[OH:12][C:13]1[CH:37]=[C:36]([O:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:35]=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])=[O:16]>N1C=CC=CC=1>[C:1]([N:42]1[CH2:41][CH2:40][CH:39]([O:38][C:36]2[CH:35]=[CH:34][C:14]([C:15]([NH:17][C:18]3[CH:27]=[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])=[O:16])=[C:13]([OH:12])[CH:37]=2)[CH2:44][CH2:43]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCNCC2)cc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCN(C(C)=O)CC2)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, pyridine (0.010 mL) and acetic anhydride (4.0 μL) were sequentially added to a methylene chloride (1 mL) suspension of the obtained methyl 2-(2-hydroxy-4-(piperidin-4-yloxy)benzamido)-4-phenylbenzoate hydrochloride (0.017 g), followed by stirring at room temperature for 1 hour. Pyridine (0.49 mL) and acetic anhydride (4.0 μL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of citric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a 10% aqueous solution of citric acid, and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 0.016 g of methyl 2-(4-((1-acetylpiperidin-4-yl)oxy)-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Nc1ccncc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: c1ccc2c(Nc3ccncc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and pyridin-4-ylamine to give N3-(1H-pyrazol-3-yl)-N1-pyridin-4-yl-isoquinoline-1,3-diamine. LC-MS m/e 303(MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]([CH:9]([CH2:11][CH2:12][CH3:13])[CH3:10])[S:6][CH2:7][CH:8]=1)([O-:3])=[O:2].S(Cl)(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]([CH2:11][CH2:12][CH3:13])[CH3:10])([O-:3])=[O:2]
Reactant: CCCC(C)C1SCC=C1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCC(C)c1sccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.4 %

Procedure:
After dissolving 78 mg of 3-nitro-2-(pentan-2-yl)-2,5-dihydrothiophene in 2 ml of dichloromethane, a solution prepared by dissolving 78 mg of sulfuryl chloride in 2 ml of dichloromethane was added thereto, and the solution was stirred at room temperature for 2.5 hours. After adding an aqueous solution of saturated sodium bicarbonate, the solution was extracted with dichloromethane. The organic layer was washed with saturated saline, dried with magnesium sulfate and concentrated, and then purified by NH-silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 69 mg of 3-nitro-2-(pentan-2-yl)thiophene (yield: 88.7%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]([NH2:23])([CH3:22])[CH3:21]>>[C:20]([NH:23][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:22])([CH3:21])[CH3:19]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-methylpropan-2-amine (CAN 75-64-9) as starting materials and isolated (12.5 mg, 17%) as colorless oil; MS (ESI, m/z): 317.1 (M+H+).
Reaction SMILES: [ClH:1].[NH:2]=[C:3]1[NH:9][CH:8]([CH2:10][CH:11]=[CH:12][C:13]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4]1>CO.[Pd]>[ClH:1].[ClH:1].[NH2:23][C:20]1[CH:21]=[CH:22][C:13]([CH:12]=[CH:11][CH2:10][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[NH:2])[NH:9]2)=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C=CCC1CCCCC(=N)N1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(N)ccc1C=CCC1CCCCC(=N)N1

Procedure:
The title material of Example 161 in MeOH is hydrogenated over Pd on carbon in a standard Parr apparatus selectively reducing the nitro function to generate the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([I:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19][C:20]([CH3:22])=O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:25]([O:24][C:18](=[O:23])/[CH:19]=[C:20](/[NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])=[CH:10][C:11]=1[I:16])\[CH3:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)c(I)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C/C(=C\C(=O)OCc1ccccc1)Nc1ccc(CNC(=O)OC(C)(C)C)cc1I
Yield: 100.5 %

Procedure:
To a solution of (4-amino-3-iodo-benzyl)-carbamic acid tert-butyl ester (3.5 g, 10 mmol) and benzyl acetoacetate (1.92 g, 10 mmol) in benzene (80 mL) was added p-toluenesulfonic acid (95 mg, 0.5 mmol). The mixture was heated at reflux overnight using a Dean Stark condenser. The mixture was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 5.25 g (99%) of crude desired product as a light brown oil: MS(APCI+): m/z 523.1 (MH+). The compound was taken to Step D without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(=O)CC>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([O:11][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(O)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCCCCCCCCC
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A mixture of 15.0 g of product from Example 102, 53.2 g of 1-bromotetradecane, 37 g of potassium carbonate, 1.04 g of potassium iodide and 350 ml of 2-butanone is heated at reflux for 28.5 hours. The reaction is cooled to room temperature, filtered and the filtrate concentrated in vacuo. The residue is recrystallized from methylene chloride/hexane to give 49.33 g of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C.Cl>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CN(C)CCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCCCCCCCCCCN
Yield: 66.7 %

Procedure:
N,N-Dimethyl N-(11-phthalimidoundecyl)amine (22.9 g) (Example 11) was added to hydrazine hydrate (3.54 g) in ethanol (200 ml), and refluxed for 7 hours. The solvent was removed leaving a white solid, which was partially dissolved in dilute hydrochloric acid and filtered. The pH of the filtrate was adjusted to pH 14 using NaOH (1M) whereupon a brown oil separated from the aqueous phase and was extracted with ether. The organic extract was dried and evaporated to give N,N-dimethyl-N-(11-aminoundecyl)-amine as a brown oil (9.5 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH:5]([O:22][CH3:23])[C:6]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].O>O1CCCC1CO>[CH3:23][O:22][CH:5]([O:4][CH3:3])[C:6]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:11]=[CH:10][C:7]=1[CH2:8][OH:9]
Reactant: COCOc1c(C(F)(F)F)ccc(C=O)c1C(OC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: OCC1CCCO1
Product: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Reaction time: 8 h
Yield: 52 %

Procedure:
Sodium borohydride (5.11 g, 135 mmol) was added to a solution of crude 2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzaldehyde obtained in Example (6-5) in a mixture of tetrahydrofuran-methanol (5:1, 100 ml) under ice-cooling and the mixture was stirred overnight. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate (four times), the organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the sol-vent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1-2/1) to give [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol as an orange oil (22.6 g, two-step total yield: 52%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].N[C@H](C(O)=O)C>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: C[C@H](N)C(=O)O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
[Aspartate β-decarboxylase activity is indicated in terms of micromoles of L-alanine which are produced by reaction with 0.2 M L-aspartic acid. The reaction with L-aspartic acid is conducted by adding 12 g of the immobilized preparation to 30 ml of an aqueous 0.2 M ammonium L-asparaginate solution (pH 5.5) containing 10-4M pyridoxal phosphate, and shaking the mixture at 37° C. for one hour. The amount of L-alanine produced is bioassayed by using Leuconostoc mesenterioides P-60.]