Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:10][C:9]2[CH2:8][C:7](=[O:11])[CH:6]=[CH:5][C:4]=2[CH2:3]1.[N+:12]([O-])([O-:14])=[O:13].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[OH:1][CH:2]1[CH:10]([N+:12]([O-:14])=[O:13])[C:9]2[CH2:8][C:7](=[O:11])[CH:6]=[CH:5][C:4]=2[CH2:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1C=CC2=C(C1)CC(O)C2
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C=CC2=C(C1)C([N+](=O)[O-])C(O)C2
Reaction time: 24 h
Yield: 38.4 %

Procedure:
2-Hydroxy-5-indanone(3.00 g, 20.0 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.95 g, 21.0 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.5 g, 39%). 1H NMR (CD3COCD3): δ 7.70 (d, 1H), 7.04 (d, 1H), 3.04 (d, 2H), 2.74 (d, 2H).
Reaction SMILES: C([S:4][C:5]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([N:9]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=O)C>N>[SH:4][C:5]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([N:9]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)Sc1c(Cl)cccc1C(=O)N(CC(=O)O)C1CCCC1
Agent: N
Product: O=C(O)CN(C(=O)c1cccc(Cl)c1S)C1CCCC1
Reaction time: 3 h

Procedure:
To a chilled solution of methanolic ammonia (50 ml) was added 3.7 g (0.0104 m) of N-(2-acetylthio-3-chlorobenzoyl)-N-cyclopentylglycine. The reaction was covered with nitrogen and stirred 3 hours while warming slowly from 0° C. to room temperature.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]3[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[ClH:29]>O1CCOCC1>[ClH:29].[C:1]1([N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]3[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(c3ccccc3)C2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(c3ccccc3)C2)nc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (47 mg) in dioxane (1.4 mL) was added 1N sodium hydroxide (0.42 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O (7 mL) and acidified with 1N hydrochloric acid (to pH 4). A resulting precipitate was collected by filtration, and washed with water to give (2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid hydrochloride (39 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Solvent: C1COCCO1
Product: CC(C)(C)C1CCCCC1O
Temperature: 100 °C
Reaction time: 4.5 h

Procedure:
In the autoclave, the resulting 453.6 grams of the 4 mole ethoxylate of 4-nonyl, 2-tert butylphenol was mixed with 125 grams of dioxane and 3.5 grams of the above-prepared catalyst and then the vessel was purged with nitrogen. Hydrogen was charged until the pressure reached 100 psi and then the autoclave was heated to 100° C. With moderate agitation the hydrogenation process continued until no more hydrogen was taken up. This reaction took approximately 4.5 hours. The product was recovered by filtering out the catalyst under nitrogen and then vacuum stripping off the volatile solvent. A water white liquid identified as 4-nonyl, 2-tert butylcyclohexyl alcohol with 4.0 moles of EO (NTBCH-4) was produced with less than 150 ppm of free 4-nonyl, 2-tert butylcyclohexyl alcohol and at least 81% saturation of the aromatic rings.
Reaction SMILES: CO.[H-].[Na+].CN(C)C=O.[CH2:10]([O:17][C:18]1[C:23]([CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[N:22][C:21]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:20]([CH2:40][CH:41]([CH3:43])[CH3:42])[N+:19]=1[O-:44])C1C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[CH2:33]([O:32][C:21]1[C:20]([CH2:40][CH:41]([CH3:43])[CH3:42])=[N+:19]([O-:44])[C:18]([O:17][CH3:10])=[C:23]([CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:22]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)Cc1c(OCc2ccccc2)nc(COC2CCCCO2)c(OCc2ccccc2)[n+]1[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1c(COC2CCCCO2)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
There was stirred, for 1 hour at room temperature, a mixture of 55 μl of methanol, 11 mg of 60% sodium hydride, 22 mg of tetra-n-butylammonium bromide, 50 μl of dimethylformamide and 65 mg of 2,5-dibenzyloxy-6-isobutyl-3-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide (Compound B-14). The reaction mixture was mixed with diethyl ether. The mixture was washed with water several times and dried with magnesium sulfate, then the solvent was removed by evaporation. The residue was purified by silica gel thin layer chromatography (developing solvent: 30 volume % ethyl acetate-n-hexane) to obtain 50 mg of 3-benzyloxy-2-isobutyl-6-methoxy-5-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide (Compound B-15) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](N)[CH:6]=[C:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:8]=1.Cl.N([O-])=O.[Na+].[I-:20].[K+]>O>[I:20][C:5]1[CH:6]=[C:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: [I-]
Reactant: COc1cc(N)cc(-c2ccsc2)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(I)cc(-c2ccsc2)c1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a solution of 3-methoxy-5-thiophen-3-yl-phenylamine (2.45 g, 11.93 mmol) in water (7.2 mL) was added a concentrated hydrochloric acid (5.34 mL, 71.58 mmol, 36%) at 0° C. To this was added in a dropwise manner to a vigorously stirred, chilled solution of sodium nitrite (1.5 g, 21.47 mmol) in water (9.3 mL). Then, the resulting colored mixture was stirred for 15 min at 0° C., and a cold solution of potassium iodide (3.96 g, 23.86 mmol) in water (9.3 mL) was added carefully. During this addition, a black brown solid was formed and after addition the ice-cold bath was removed, and the reaction mixture was heated to reflux. When the production of purple vapor ceased, the mixture was cooled to room temperature and the organic compound was extracted into dichloromethane (3×100 mL). The combined organic extracts were washed with brine solution (200 mL) and dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Then, the crude residue was purified by using a LC 80 column, eluting with 0-10% ethyl acetate in hexanes to obtain 3-(3-iodo-5-methoxy-phenyl)-thiophene (2.19 g, 58%) as a white solid: ES(+)-HRMS m/e calculated for C11H9IOS (M+)+ 315.9419, found 315.9418.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]([O:20][CH3:21])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:22]([O-])([N+]([O-])=O)=[O:23]>>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:17][CH:18]([O:20][CH3:21])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: COC(C)CN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: COC(C)CN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 69.6 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-(2-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 10-(2). 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(2-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow powder.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:33])[C:12]([NH:14][C@@:15]1([C:28]([O:30]CC)=[O:29])[CH2:22][C:19]2([CH2:21][CH2:20]2)[C@@H:18]2[C@H:16]1[C@H:17]2[C:23]([O:25]CC)=[O:24])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH3:33])[C:12]([NH:14][C@@:15]1([C:28]([OH:30])=[O:29])[CH2:22][C:19]2([CH2:20][CH2:21]2)[C@@H:18]2[C@H:16]1[C@H:17]2[C:23]([OH:25])=[O:24])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)(C(=O)OCC)CC21CC1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Charge 2 N NaOH (37 mL, 5.0 equivalents) and diethyl (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylate (6.50 g, 14.81 mmol) to a reactor and allow to stir for at least 12 hours between 20-30° C. until the reaction is complete by HPLC. Transfer the reaction to a separatory funnel and allow it to settle for at least 10 minutes. Separate the phases and return the lower aqueous layer to the reactor. Add ethyl acetate (90 mL, 13.8 volumes) to the mixture, and then add 1 N NaHSO4 until pH reaches 2 to 2.5. Separate layers and wash the organic with water (45 mL, 6.9 volumes). Remove water in organic phase atmospheric distillation with ethyl acetate to remove residual water. Cool the resulting slurry between 20-30° C. over at least 2 hours and allowed to granulate at that temperature for at least 90 minutes. Filter the resulting solids and wash the wet cake with ethyl acetate (3×15 mL, 2.3 volumes). Dry under reduced pressure at 45° C. to provide the title compound as a white solid (4.45 g, 11.64 mmol, 78.6%) 1H NMR (DMSO-d6, 400 MHz, 50° C.): δ 12.01 (s, 2H), 8.22 (s, 1H), 6.49 (bs, 1H), 4.00 (bs, 1H), 2.43 (dd, J=6.5, 2.8, 1H), 1.83 (d, J=14.0, 1H), 1.68-1.62 (m, 2H), 1.42 (dd, J=6.5, 2.8, 1H), 1.36 (s, 9H), 1.15 (d, J=7.1, 3H), 0.67-0.61 (m, 1H), 0.56-0.51 (m, 1H), 0.46-0.36 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:15])[C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:16]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([OH:15])[C:8]([C:12]([OH:14])=[O:13])=[CH:9]3)=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)(=[O:18])[CH3:17]
Reactant: O=C(O)c1cc2cc(Br)ccc2cc1O
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(-c2ccc3cc(O)c(C(=O)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
To 7-bromo-3-hydroxynaphthalene-2-carboxylic acid (100 mg, 0.37 mmol) (example 340) was added a solution of 4-acetylphenylboronic acid (92 mg, 0.56 mmol) in acetone (2.2 mL) followed by a solution of sodium carbonate (198 mg, 1.87 mmol) in water (3.3 mL). A suspension of palladium(II) acetate (4 mg, 0.02 mmol) in acetone (0.5 mL) was filtered and added to the above solution. The mixture was purged with N2 and stirred vigorously for 24 hours at room temperature. The reaction mixture was poured into 1 N hydrochloric acid (aq.) (60 mL) and the precipitate was filtered off and rinsed with water (3×40 mL). The crude product was dissolved in acetone (25 mL) and dried with magnesium sulfate (1 h). Filtration followed by concentration furnished the title compound as a solid (92 mg). 1H-NMR (DMSO-d6): δ 12.60 (1H, bs), 8.64 (1H, s), 8.42 (1H, s), 8.08 (2H, d), 7.97 (2H, d), 7.92 (2H, m), 7.33 (1H, s), 2.63 (3H, s); HPLC-MS (Method (A): m/z: 307 (M+1); Rt=3.84 min.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH:18]2[CH2:20][CH:15]1[CH2:16][CH2:17]2)=[S:11])(=O)C1C=CC=CC=1.[OH-].[K+].O>CO>[CH:15]12[CH2:20][CH:18]([CH2:17][CH2:16]1)[CH2:19][CH:14]2[CH2:13][NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)NCC1CC2CCC1C2)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=S)NCC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 250 mL round-bottomed flask equipped with a magnetic stir bar was charged with 6.17 g (22.4 mmol) of 1-benzoyl-3-(bicyclo[2.2.1]heptan-2-ylmethyl)thiourea in 30 mL of MeOH. KOH was added (2.55 g, 45.4 mmol) and the reaction was stirred at ambient temperature for 4 h. Water (150 mL) was then added to the reaction mixture, and the solid was removed by filtration. The flask and filter cake were rinsed with 40 mL of H2O. The collected solid was then suspended in 15 mL of MTBE, and the solid was collected by filtration providing the desired thiourea. MS (ESI, pos. ion) m/z: 185.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH3:22])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:23])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CC#N.C(Cl)Cl>[CH3:22][C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:12][C:11](=[O:23])[N:10]([C@H:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:9])[CH2:15][CH2:14]1
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](c1cccc(O)c1)N1CCC(C)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1cccc([C@H](C)N2CCC(C)(c3ccccc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.2 %

Procedure:
A mixture of (R/S)-3-((S)-1-(3-hydroxyphenyl)ethyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (0.0955 g, 0.31 mmol, 1.0 equiv), Cs2CO3 (0.3307 g, 1.01 mmol, 3.3 equiv), and ethyl bromoacetate (0.1468 g, 0.88 mmol, 2.8 equiv) in CH3CN (1.5 mL) was stirred at rt for 3 d. The mixture was diluted with CH2Cl2, treated with H2O (2 mL), dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.1025 g (84%) of ethyl 2-(3-((S)-1-((R/S)-6-methyl-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenoxy)acetate. LC-MS Method 1, tR=1.75 min, m/z=398 (M+1). 1H NMR (CDCl3) 7.40-7.23 (m, 6H), 6.95-6.93 (m, 1H), 6.88 (m, 1H), 6.81-6.78 (m, 1H), 5.76 (q, J=7.1 Hz, 1H), 4.61 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 2.68-2.65 (m, 2H), 2.28-2.23 (m, 1H), 2.06-1.98 (m, 1H), 1.63 (s, 3H), 1.30 (t, J=7.2 Hz, 3H), 1.26 (d, J=7.3 Hz, 3H).
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[CH:10]1[CH:15]=[N+:14]([C@@H:16]2[O:20][C@H:19]([CH2:21][O:22][P:23]([O:26][P:27]([O:30][CH2:31][C@H:32]3[O:36][C@@H:35]([N:37]4[C:41]5[N:42]=[CH:43][N:44]=[C:45]([NH2:46])[C:40]=5[N:39]=[CH:38]4)[C@H:34]([O:47]P(O)(O)=O)[C@@H:33]3[OH:52])([OH:29])=[O:28])([OH:25])=[O:24])[C@@H:18]([OH:53])[C@H:17]2[OH:54])[CH:13]=[C:12]([C:55]([NH2:57])=[O:56])[CH:11]=1.C1C(C(O)=O)=C[C@@H](O)[C@@H](O)[C@@H]1O>>[CH:43]1[N:44]=[C:45]([NH2:46])[C:40]2[N:39]=[CH:38][N:37]([C@@H:35]3[O:36][C@H:32]([CH2:31][O:30][P:27]([O:26][P:23]([O:22][CH2:21][C@H:19]4[O:20][C@@H:16]([N:14]5[CH:13]=[C:12]([C:55]([NH2:57])=[O:56])[CH2:11][CH:10]=[CH:15]5)[C@H:17]([OH:54])[C@@H:18]4[OH:53])([OH:25])=[O:24])([OH:29])=[O:28])[C@@H:33]([OH:52])[C@H:34]3[OH:47])[C:41]=2[N:42]=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](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=C(O)C1=C[C@@H](O)[C@@H](O)[C@H](O)C1
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

Procedure:
Each of these crude enzyme solutions was added to a mixture of 0.1M Tris-HCl buffer (pH 7.4), 0.8 mM NADP and 4 mM shikimic acid, and shikimate dehydrogenase activity was determined by measuring the change in optical density at 300 mμ resulting from the conversion of NADH.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C@H:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:33](=[O:34])C1>ClCCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C@@H:12]([C:13]([CH3:16])([CH3:14])[CH3:15])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:33]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A solution of the product of Example 111-4 in 1,2-dichloroethane (1325 mL) was treated with triethylamine (37.5 mL, 269 mmol, 1.25 equivalents) and N,N-disuccinimidyl carbonate (68.9 g, 269 mmol, 1.25 eq). The reaction mixture was stirred at 20° C. overnight, washed with 10% Na2CO3 (2×1.5 L). The aqueous was back-extracted with dichloromethane (600 mL). The organics were combined and washed with 1.5 L of brine. The organic layer was concentrated to yield 76.8 gm of crude material. 1H NMR (CDCl3): δ 7.15-7.3(m, 5H), 4.25-4.4(m, 3H), 3.75(m, 1H), 3.67(residual dichloroethane), 3.48(m, 1H), 3.1(m, 2H), 1.4(s, 9H), 1.0(s, 9H).
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1.Cl.O>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C(=CNc1ccccc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
10 g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.1 g (118 mmol) of aniline were dissolved at 40° C. in 200 ml of isopropanol. The solution was admixed with 3.6 ml (43.5 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 10 min. 200 ml of deionized water were added, the suspension was cooled to 10° C. and the crystallized product was filtered off.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(Cl)Cl>CS(C)=O>[CH2:16]([N:23]1[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 61.8 g (0.3 mole) of dicyclohexylcarbodiimide in 400 ml of dry dimethylsulfoxide is dropwise added a solution of 19.10 g (0.1 mole) of 1-benzyl-3-hydroxymethylpyrrolidine [prepared in the manner described in J. O. C. 26, 1519 (1961) by YAO-HUA WU and R. F Feldkamp] under ice-cooling for 15 minutes, and the mixture is stirred at room temperature overnight. Dicyclohexylcarbodiimide (13.26 g; 60 mmoles) and phosphorus pentachloride (4.40 g; 30 mmoles) are added thereto and the mixture is stirred overnight, poured into ice water, mixed with 300 ml of methylene chloride and stirred for 30 minutes. The insoluble materials, which appear, are filtered off and washed with water. The combined filtrate and washings are washed twice with 200 ml of methylene chloride, adjusted to pH 9 with 20 (w/w) % aqueous sodium carbonate solution, and extracted four times with 200 ml of methylene chloride. The extract is washed with 20 (w/w) % aqueous sodium hydrogensulfite solution. The aqueous layer is separated, washed thrice with 100 ml of methylene chloride, mixed with 20 (w/w) % aqueous sodium carbonate solution, and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield crude oily 1-benzyl-3-formylpyrrolidine in 66% yield.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH:24]([CH3:26])[CH3:25])[C:12]2[CH:13]=[C:14]([CH3:23])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[CH:24]([N:11]([C:12]1[CH:13]=[C:14]([CH3:23])[C:15]2[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:27])=[O:3])=[CH:10][CH:9]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1ccc(N(c2cc(C)c3c(c2)C(C)(C)CO3)C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N(c2ccc(C(=O)O)cc2)C(C)C)cc2c1OCC2(C)C
Yield: 77.2 %

Procedure:
Following general procedure H using 4-[isopropyl-(3,3,7-trimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 37, 0.08, 0.21 mmol) and 2.5 mL of 4M potassium hydroxide solution in 4 mL of ethanol, the title compound (0.055 g, 77%) was obtained as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 7.87 (d, 2H, J=8.9 Hz), 6.69 (d, 1H, J=2.0 Hz), 6.66 (d, 1H, J=2.0 Hz), 6.52 (d, 2H, J=9.1 Hz), 4.36(heptet, 1H, J=6.5 Hz), 4.32 (s, 2H), 2.23(s, 3H), 1.35 (s, 6H), 1.17 (d, 6H, J=6.5 Hz).
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[C:10](#[N:13])[CH:11]=[CH2:12].[O-]CCCC.[Na+]>>[CH2:1]([P:3]([CH2:12][CH2:11][C:10]#[N:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: C=CC#N
Reactant: CCCCOP([O-])CC
Agent: CCCC[O-]
Agent: [Na+]
Product: CCCCOP(=O)(CC)CCC#N
Yield: 90.9 %

Procedure:
A 1 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel was charged with 447 g (3 mol) of butyl ethylphosphonite (produced as in Example 3) and 159 g (3 mol) of acrylonitrile. While stirring, 15 ml of sodium butoxide (30% strength in butanol) are added dropwise at a rate such that a reaction temperature of max. 120° C. becomes established. The crude product thus obtained is distilled in vacuo to obtain 554 g (91% of theory) of butyl ethyl(2-cyanoethyl)phosphinate as colorless liquid.
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C>[OH:1][CH:2]([CH2:28][N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CN1CCN(C)CC1
Temperature: 70 °C
Yield: 31.8 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy) quinazoline (100 mg, 0.27 mmol), (prepared as described for the starting material in Example 162), and N-methylpiperazine (200 ul, 1.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was recrystallised from acetonitrile. The solid was filtered, washed with diethyl ether and dried to give 7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (41 mg, 32%).