Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[NH2:5][C:6]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][CH2:11]2.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:5][C:6]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]([CH:1]([CH3:3])[CH3:2])[CH2:11]2
Reactant: CC(C)Br
Reactant: Nc1c2c(cc3ccccc13)CNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N1CCc2c(cc3ccccc3c2N)C1
Reaction time: 6 h

Procedure:
A solution of 5.2 g of isopropyl bromide in 10 ml of ethanol is added dropwise at room temperature to a mixture of 8.0 g of 5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinoline [see Example 4]and 4.5 g of anhydrous sodium carbonate in 30 ml of ethanol. The reaction mixture is then boiled for 6 hours. The solvent is removed by evaporation, and the residue is treated with water. The resulting mixture is extracted with methylene chloride. The organic phase is washed with water, dried over potassium carbonate and evaporated. The title compound is obtained as a residue which is recrystallized from hexane/isopropanol (M.Pt. 112° - 113°).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]([OH:22])[CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[CH2:1]([O:22][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCCOCCO
Reactant: CCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCOCCOCCO

Procedure:
Using 13.9 g of tetradecyl bromide and 15.9 g of diethylene glycol and proceeding as in Example 17, there is obtained the title compound. Yield 6.1 g.
Reaction SMILES: NCC(O)=O.[OH-].[K+].[O-]S([O-])(=O)=O.[Mg+2].[CH:14]1[CH:19]=[N+:18]([C@@H:20]2[O:24][C@H:23]([CH2:25][O:26][P:27]([O:30][P:31]([O:34][CH2:35][C@H:36]3[O:40][C@@H:39]([N:41]4[C:45]5[N:46]=[CH:47][N:48]=[C:49]([NH2:50])[C:44]=5[N:43]=[CH:42]4)[C@H:38]([OH:51])[C@@H:37]3[OH:52])([OH:33])=[O:32])([OH:29])=[O:28])[C@@H:22]([OH:53])[C@H:21]2[OH:54])[CH:17]=[C:16]([C:55]([NH2:57])=[O:56])[CH:15]=1>>[CH:47]1[N:48]=[C:49]([NH2:50])[C:44]2[N:43]=[CH:42][N:41]([C@@H:39]3[O:40][C@H:36]([CH2:35][O:34][P:31]([O:30][P:27]([O:26][CH2:25][C@H:23]4[O:24][C@@H:20]([N:18]5[CH:17]=[C:16]([C:55]([NH2:57])=[O:56])[CH2:15][CH:14]=[CH:19]5)[C@H:21]([OH:54])[C@@H:22]4[OH:53])([OH:29])=[O:28])([OH:33])=[O:32])[C@@H:37]([OH:52])[C@H:38]3[OH:51])[C:45]=2[N:46]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Temperature: 45 °C
Reaction time: 0.07 h

Procedure:
Alcohol dehydrogenase activities were measured spectrophotometrically essentially as described previously (Hektor, Kloosterman et al. (2002) Chem 277(49): 46966-46973) and the reaction mixture contained: 100 mM Glycine-KOH pH 9.5 (unless otherwise stated), 5 mM MgSO4, 0.5 mM NAD+ and 500 mM alcohol (methanol, ethanol, propanol, 1,3-propanediol, or butanol). NAD+ was substituted with equal concentrations of NADP+, FMN+, and FAD+, when indicated. The reaction mixture for measurements of formaldehyde reductase activity contained: 50 mM Potassium-phosphate buffer pH=6.7, 0.15 mM NADH, 1 mM DTT and 11.6 mM (0.1-116 mM) formaldehyde. The assay components were mixed in the cuvette and pre-warmed to 45° C., unless otherwise stated. The reactions were started by addition of 5-40 μg of the purified MDH proteins, and the production of NADH was monitored at 340 nm for 4 minutes. One unit of MDH activity was defined as the amount of enzyme needed to produce 1 μmol NADH per minute under the conditions described above. Purified Act (0.1-40 μg) or NudF (20 μg) proteins were added to the reaction mixtures as indicated in the text.
Reaction SMILES: C([Li])CCC.[CH:6]1[CH:11]=[C:10]2[CH:12]=[CH:13][O:14][C:9]2=[CH:8][CH:7]=1.[Br:15][C:16]1[C:17]([O:25][CH3:26])=[C:18]([C:21]([F:24])=[CH:22][CH:23]=1)[CH:19]=[O:20].[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[O:14]1[C:13]([CH:19]([C:18]2[C:21]([F:24])=[CH:22][CH:23]=[C:16]([Br:15])[C:17]=2[O:25][CH3:26])[OH:20])=[CH:12][C:10]2[CH:11]=[CH:6][CH:7]=[CH:8][C:9]1=2
Reactant: COc1c(Br)ccc(F)c1C=O
Reactant: c1ccc2occc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(Br)ccc(F)c1C(O)c1cc2ccccc2o1
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
In an atmosphere of nitrogen gas, 3.56 ml of a 2.66 M solution of n-butyllithium in hexane was added to a solution of 1.12 g of 2,3-benzofuran in 10 ml tetrahydrofuran at −78° C. After stirring at the same temperature for 10 minutes, the mixture was stirred under ice-cooling for 15 minutes and was then stirred at −78° C. for 8 minutes. Then, a solution of 2 g of 3-bromo-6-fluoro-2-methoxy-benzaldehyde in 3.5 ml tetrahydrofuran was added dropwise at the same temperature. After stirring at the same temperature for 30 minutes, saturated aqueous ammonium chloride solution was added at the same temperature. Water was added at room temperature and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography, to give 2 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=2)[CH2:16][CH2:15]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][C:19]2[CH:18]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[NH:21][N:20]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
A mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (3.6 g, 16.3 mmol, 1.0 equiv.) and 5-cyclopropyl-1H-pyrazol-3-amine (3.0 g, 24.45 mmol, 1.5 equiv.) in EtOH (6 mL) was stirred at 20° C. under a nitrogen atmosphere for 10 min. The reaction mixture was filtered and the solid was washed by EtOH (10 mL) and MeOH (3 mL) to afford ethyl 2-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylate (3.5 g, 70%) as a white solid. LC-MS (m/z)=308.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[S:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: S=c1[nH]c2ccccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CSc1nc2ccccc2[nH]1
Reaction time: 6 h
Yield: 30947.1 %

Procedure:
To a stirred solution of 1H-benzo[d]imidazole-2(3H)-thione (20.0 g, 0.13 mol, 1.0 eq.) in anhydrous ethanol (500 mL) at room temperature, was added potassium carbonate (9.25 g, 0.07 mol, 0.5 eq.) and ethyl bromoacetate (26.7 g, 0.16 mmol, 1.2 eq.). The reaction was heated to reflux and stirred at that temperature for 6 hours. The solvent was removed in vacuo and water (200 mL) was added. The aqueous phase was extracted with dichloromethane (3×100 mL), and the combined organic extracts were washed with water (200 mL) and brine (200 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a colorless oil which solidified on standing. Purification by flash chromatography (CHCl3→10% MeOH:90% CHCl3) gave 4a as a white solid (11.7 g, 37%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Mg]Cl)[CH2:22][CH3:23]>C1COCC1>[CH2:1]([O:8][C:9]1[C:17]([CH:18]([OH:19])[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[Mg]Cl
Reactant: Cn1ccc2c(OCc3ccccc3)c(C=O)ccc21
Solvent: C1CCOC1
Product: CCCC(O)c1ccc2c(ccn2C)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(benzyloxy)-1-methyl-1H-indole-5-carbaldehyde (4.57 g, 17.22 mmol) in THF (60 mL) at −78° C. was slowly added a solution of n-PrMgCl (2M Et2O, 13.00 mL, 26 mmol). The mixture was stirred at this temperature for 15 min and then allowed to warm to 0° C. After 1 h the reaction was quenched with NH4Cl (aqueous saturated, 50 mL) and the product was extracted with EtOAc (3×100 mL). The combined organics were washed with NaCl (aqueous saturated, 100 mL) and dried over Na2SO4. The solvents were concentrated to yield 1-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)butan-1-ol as an oil which was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15](I)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].C([Si](CC)(CC)[C:23]([F:26])([F:25])[F:24])C.[F-].[K+]>CN(C)C=O.CN1CCCC1=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:23]([F:26])([F:25])[F:24])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC[Si](CC)(CC)C(F)(F)F
Reactant: CCOC(=O)c1cnn(-c2cc(C)c(I)cn2)c1C
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnn(-c2cc(C)c(C(F)(F)F)cn2)c1C

Procedure:
1-(5-Iodo-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (395 mg), copper(I) iodide (1.13 g), triethyl(trifluoromethyl)silane (1.11 ml), and potassium fluoride (345 mg) were suspended in N,N-dimethylformamide (6.2 ml) and N-methylpyrrolidone (6.2 ml), and stirred at 70° C. for 9 hours. After completion of the reaction, the mixture was allowed to cool, extracted with ethyl acetate, the obtained organic layer was sequentially washed with 28% ammonia water, water, and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 5-methyl-1-[4-methyl-5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (271 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28](O)=[O:29])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([NH2:37])([CH3:36])([CH3:35])[CH3:34].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28](=[O:29])[NH:37][C:33]([CH3:36])([CH3:35])[CH3:34])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CCC(=O)CC2C(=O)O)OC1(C)C
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NC(=O)C1CC(=O)CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.1 %

Procedure:
A solution of 4-Benzyl-5-(2-carboxy-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.66 g, 3.74 mmol) in dry dichloromethane (20 ml) was stirred at 0° C. during sequential treatment with tert-butyl amine (1.4 ml, 12.7 mmol), 1-hydroxybenzotriazole hydrate (570 mg, 5 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (970 mg, 5 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for 20 hours and then concentrated in vacuo. The crude mixture was dissolved in ethyl acetate and the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution, 1 M hydrochloric acid and brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/hexane: 1/3 to 4/6) provided 4-benzyl-5-(2-tert-butylcarbamoyl-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.2 g, 61%). Mass spectrum 502 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[N:5]=1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([CH:9]([C:8]2[C:4]([CH2:3][O:2][CH3:1])=[N:5][N:6]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][N:12]=3)[CH:7]=2)[OH:10])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COCc1nn(-c2cc(C(F)(F)F)ccn2)cc1C=O
Solvent: C1CCOC1
Product: COCc1nn(-c2cc(C(F)(F)F)ccn2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
To a solution (10 mL) of 3-(methoxymethyl)-1-[4-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbaldehyde (0.59 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (4.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (0.23 g, 30%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH2:15][CH2:16]Br)([CH3:14])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2].[CH3:22][NH:23][CH3:24].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH2:15][CH2:16][N:23]([CH3:24])[CH3:22])([CH3:14])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCBr)O2
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCN(C)C)O2
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 3.55 g (0.01 mol) of 3,4-dihydro-2-(2- bromoethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-yl acetate and 2.0 g of liquid dimethylamine in 50 ml of dimethylformamide is stirred at room temperature for 40 hours. Water is added and the product is extracted with ethyl acetate and ethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting oil crystallizes from a mixture of ethyl ether and pentane to give 2.05 g of 3,4-dihydro-2-(2-dimethylaminoethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-yl acetate as the free base. The hydrochloride salt prepared by standard methods and recrystallized from isopropanol has m.p. 263°-270° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9](O)([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
To a mixture of 3-aminophenol (1.50 g, 13.8 mmol), isopropanol (3.3 g, 55 mmol), and triphenylphosphine (14.4 g, 54.9 mmol) in THF (15 mL), was added dropwise diethylazodicarboxylate (9.60 g, 55.0 mmol) over a 30 min period. The mixture was stirred at room temperature for 3 h and concentrated. The residue was diluted with water, acidified with aqueous 2N HCl and extracted with ether. The aqueous phase was basified with aqueous 2N NaOH and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The resulting crude product was purified by silica gel column chromatograph (petroleum ether/EtOAc 10:1 to 5:1) to afford 3-isopropoxybenzenamine as yellow oil (1.3 g, 64%).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([S:5][CH2:4][C:3]([OH:15])=[O:2])=[CH:11][CH:10]=1)(=[O:14])[CH3:13]
Reactant: COC(=O)CSc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(SCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
(4-Acetyl-phenylsulfanyl)-acetic acid methyl ester (1.48 g, 6.6 mmol) is dissolved in THF (40 ml). To this solution is added LiOH (415 mg, 9.9 mmol) in water (10 ml), and the mixture was stirred at ambient temperature overnight. The mixture was acidified to pH 5 using 1N HCl and then extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield (4-acetyl-phenylsulfanyl)-acetic acid as a white solid (1.27 g, 91%).
Reaction SMILES: [CH2:1]([O:4][P:5](Cl)([O:7][CH2:8][CH2:9][CH3:10])=[S:6])[CH2:2][CH3:3].[OH-:12].[K+:13]>C(O)CC>[K+:13].[P:5]([O-:12])([O:7][CH2:8][CH2:9][CH3:10])([O:4][CH2:1][CH2:2][CH3:3])=[S:6]
Reactant: [OH-]
Reactant: CCCOP(=S)(Cl)OCCC
Agent: [K+]
Solvent: CCCO
Product: CCCOP([O-])(=S)OCCC
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To 100 g (460 mmole) of di-n-propylchlorothiophosphate in 300 ml of 1-propanol was added 58.8 g (920 mmole) of 88% potassium hydroxide pellets. The reaction mixture was refluxed overnight and then cooled to room temperature. The precipitated potassium chloride was filtered off and the solvent was stripped in vacuo. The resulting solid was slurried in 20% diethyl ether/80% hexanes and filtered yielding 67 g of the title compound, a fluffy white solid, mp 205°-207° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1[N:23]=[C:22]([C:24]([O:26]CC)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.[OH-].[K+].Cl>O>[NH2:3][CH2:12][CH2:13][C:14]1[N:23]=[C:22]([C:24]([OH:26])=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CCOC(=O)c1nc(CCN2C(=O)c3ccccc3C2=O)nc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NCCc1nc(C(=O)O)c2ccccc2n1

Procedure:
Into a 250-mL 4-necked round-bottom flask, was placed ethyl 2-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl]quinazoline-4-carboxylate (7 g, 18.65 mmol, 1.00 equiv). This was followed by the addition of KOH (20.9 g, 372.51 mmol, 19.98 equiv) in water (20 mL) dropwise with stirring. The resulting solution was stirred for 18 h at 100° C. The reaction was then poured into 250 mL of water. The pH value of the solution was adjusted to 7 with hydrogen chloride (2 mol/L). The resulting solution was extracted with 5×100 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.2 g (79%) of 2-(2-aminoethyl)quinazoline-4-carboxylic acid as a white solid. MS (ESI) m/z 218 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:29][CH2:30][CH2:31][N:32]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34](OCC)=[O:35].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:29]2[CH2:30][CH2:31][N:32]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34]2=[O:35])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CCOC(=O)CN(CCN)C(=O)OCC[Si](C)(C)C
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN1CCN(C(=O)OCC[Si](C)(C)C)CC1=O)CCCN2
Reaction time: 12 h

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 2.50 g, 10.58 mmol), ethyl 2-((2-aminoethyl)((2-(trimethylsilyl)ethoxy)carbonyl)amino)acetate para-toluene sulphonate (intermediate 124, 8.37 g, 18.09 mmol) and triethylamine (3.23 ml, 23.28 mmol) in 1,2-dichloroethane (10 ml) at room temperature was stirred for 12 h and sodium triacetoxyborohydride (4.72 g, 21.16 mmol) added. The reaction mixture was stirred for 18 h at room temperature, partitioned between saturated aqueous NaHCO3 solution and EtOAc, the EtOAc phase washed with brine, dried over MgSO4 and evaporated. The residue was applied to a RediSep® silica column and purified by normal phase chromatography, eluting with a gradient from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a yellow oil. (UPLC-MS 6) tR 0.42; ESI-MS 322.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Br>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([OH:28])=[O:18])=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1ccccc1CBr
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Product: O=C(O)c1ccccc1COc1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
2-(2′-Nitro-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4′-hydroxy-2-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 2-bromomethyl-benzoic acid methyl ester (Intermediate 1). Yield: 69 mg. Mass spectrum (ES) MH+=350.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].CCO.Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1>O>[CH2:2]([O:3][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)[CH3:1]
Reactant: CC[O-]
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOCc1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of NaOEt in dry EtOH (45 mL, 114.90 mmol) under inert atmosphere was added 4-chloromethyl-1-methyl-2-nitro-benzene (7.0 g, 38.30 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water was added and ethanol was removed under reduced pressure. The crude product was extracted with DCM (2 times) and the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgSO4 and concentrated to give I-g as brown oil in 96% yield. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 4.52 (s, 2H), 3.56 (q, J=7.0 Hz, 2H), 2.57 (d, J=10.1 Hz, 3H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][N:16]([CH3:19])[C:15](=[O:20])[C:14]=1[N+:21]([O-:23])=[O:22]>O1CCCC1>[CH3:19][N:16]1[CH:17]=[CH:18][C:13]([CH:3]([C:2](=[O:1])[CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:14]([N+:21]([O-:23])=[O:22])[C:15]1=[O:20]
Reactant: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)c1ccn(C)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a stirred solution of ethyl 3-oxobutanoate (2.5 g, 19 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% w/w, 0.96 g, 23.9 mmol) in batches at 0° C. The mixture was stirred at room temperature for 30 minutes. Then the solution of 4-chloro-1-methyl-3-nitropyridin-2(1H)-one (3.0 g, 16 mmol) in tetrahydrofuran (50 mL) was added in one portion. The resultant solution was stirred and heated to 50° C. for 12 hours. Once the starting material had been consumed, the reaction solution was quenched with water (100 mL) at 0° C., and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give ethyl 2-(1-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-yl)-3-oxobutanoate (2.5 g, 56%) as a yellow solid. LRMS (M+H+) m/z: calcd 282.09. found 282.