Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CN1CCc2ccccc21
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: Cn1ccc2ccccc21
Temperature: 25 °C
Yield: 57 %

Procedure:
The N-methyl indoline product in Example 47 (70 mg, 0.22 mmol) was dissolved in toluene (9 mL) in a 50-mL flask under N2 fitted with a condenser. MnO2 (199 mg, 2.3 mmol) was added, and the mixture was heated to ref lux for 1.5 h. The mixture was cooled to rt, Celite, and the pad was washed several times with liberal amounts of MeOH. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (gradient 25-35% EtOAc/hexane) to provide the N-methyl indole product (39 mg, 57%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 6.93-7.11 (m, 5H), 6.72 (d, J=8.5 Hz, 1H), 6.42 (d, J=3.1 Hz, 1H), 4.29 (t, J=5.8 Hz, 1H), 3.84-3.96 (m, 2H), 3.77 (s, 3H), 2.99 (dd, J=11.3, 5.0 Hz, 1H), 2.67 (dd, J=11.3, 6.7 Hz, 1H), 2.49 (s, 3H); ESI MS m/z=313 [C19H18F2N2+H]+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:9]1(=[O:16])O[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.OCCCCCC(O)=O>C1CCCCC1>[C:6]1(=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]1.[CH:9]1([OH:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C1CCCCCO1
Reactant: OCCCCCCO
Agent: O=C(O)CCCCCO
Solvent: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
A process for preparing 1,6-hexanediol and ε-caprolactone from a carboxylic acid mixture comprising adipic acid, 6-hydroxycaproic acid and small amounts of 1,4-cyclohexanediols which is obtained as a by-product in the oxidation of cyclohexane to cyclohexanone/cyclohexanol using oxygen or oxygen-containing gases by water extraction of the reaction mixture, by esterifying and hydrogenating a substream to give hexanediol and cyclizing 6-hydroxycaproic esters to give caprolactone, wherein
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH:7]2[C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:4][CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[O:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH:7]2[C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:4][CH2:3]1
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(O)C3C4)nc2n(CCC)c1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(=O)C3C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
8-(4-Hydroxy-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (140 mg) from step 1 was taken in CH2Cl2 (5 ml). Celite (2 g) was added, followed by PCC (90 mg) and stirred at room temperature for 1 hr. Additional PCC (90 mg) was added and stirred for 2 hrs at room temperature. The reaction mixture was diluted with ether (100 ml) and filtered through celite and concentrated. Purified on silica column eluted with ethyl acetate:hexane (25:75) to yield 65 mg of the desired product. Mass (ES+ 369).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])[CH3:2].C(OC(=O)C)(=O)C.[N+:23]([O-])([OH:25])=[O:24]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([N+:23]([O-:25])=[O:24])[CH:13]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)OC)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of methyl 4-ethoxy-3-methoxybenzoate (7.12 g, 33.9 mmol) and acetic anhydride (40 mL) in acetic acid (40 mL) at room temperature was dropped fume nitric acid (90%, 3.15 g). After stirring at room temperature for 15 minutes, it was heated at 50° C. for 1 hour. The reaction mixture was poured into ice and a solid was formed. It was filtered, washed with water, and dried under vacuum with P2O5 to give methyl 4-ethoxy-5-methoxy-2-nitrobenzoate as white solid (8.392 g, 97%). 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.07 (s, 1H), 4.19 (q, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 1.52 (t, 3H); LC-MS (ESI) m/z 256 (M+H)+.
Reaction SMILES: [N+:1]1([O-:9])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].[N+:10]([O-])([OH:12])=[O:11].OS(O)(=O)=O>>[CH3:8][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:7])[N+:1]=1[O-:9]
Reactant: Cc1cccc(C)[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Temperature: 80 °C

Procedure:
Lutidine-N-oxide (19 g, 155 mmol) is cooled at 0° C. and a mixture of fuming HNO3 (100%, 37.5 mL) and conc. H2SO4 (95-97%, 52.5 mL), prepared by addition of H2SO4 to HNO3 at 0° C., is added slowly. The mixture is heated at 80° C. for 3 h. The cooled mixture is carefully poured into ice-water (500 mL). A white precipitate forms that is filtered. The precipitate is dissolved in CH2Cl2 (100 mL) and the filtrate is extracted with CH2Cl2 (4×75 mL). The organic extracts are combined with the dissolved precipitate and washed with sat. aq. NaCl (2×75 mL), dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([CH3:13])=[CH:4][C:3]=1[CH3:14].[Li]CCCC.C[O:21][B:22](OC)[O:23]C>C1COCC1>[CH2:9]([O:8][C:6]1[C:5]([CH3:13])=[CH:4][C:3]([CH3:14])=[C:2]([B:22]([OH:23])[OH:21])[CH:7]=1)[CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCOc1cc(Br)c(C)cc1C
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCOc1cc(B(O)O)c(C)cc1C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In the glovebox, a 100-mL round bottomed flask is charged with 1-bromo-5-(but-3-enyloxy)-2,4-dimethylbenzene (3.142 g, 13.6 mmol) and THF (100 mL). The flask is sealed with a septum and removed from the glovebox. The flask is cooled to −70° C. under nitrogen purge. BuLi (1.6M in hexanes, 8.2 mL, 13 mmol) is added slowly, keeping the temperature below −68° C., and the reaction mixture is stirred for one hr at −70° C. Trimethylborate (1.3 mL, 12 mmol) is added, and the mixture is stirred as it slowly warms to room temperature. Solvents are removed on a rotovap, and ice (60 g) containing hydrochloric acid (HCl) (conc, 5 mL) is added, and then ether (60 mL). A white precipitate forms, and this is collected on a fine frit. Yield=1.283 g of a white solid. 1H NMR is taken by suspending the solid in d6-dimethylsulfoxide (d6-DMSO) and adding a trace of HCl.
Reaction SMILES: [CH2:1]=O.[OH-].[Na+].[NH2:5][CH2:6][C:7]([OH:9])=[O:8].[P:10]([O-:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].Cl>O>[C:7]([CH2:6][NH:5][CH2:1][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([OH:9])=[O:8]
Reactant: C=O
Reactant: NCC(=O)O
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOP(=O)(CNCC(=O)O)OCC
Reaction time: 0.17 h

Procedure:
8.6 g. of 37% formaline (= 0.1 moles of formaldehyde) are added to a stirred solution of 4.0 g. (0.1 moles) of sodium hydroxide and 7.5 g. (0.1 moles) of glycine in 40 ml. of water. After 10 minutes of stirring at 0° to 5° C, 13.8 g. (0.1 moles) of diethyl phosphite are added, and stirring is continued for 2 hours at 90° to 100° C. The reaction mixture is cooled, acidified with hydrochloric acid, and extracted to obtain diethyl N-carboxymethyl-aminomethyl-phosphonate. The product melts at 132°-134° C with decomposition.
Reaction SMILES: N[C@H:2]([CH:7]=O)[CH2:3]CSC.[C:9]1([C:15]2[CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:26]([OH:28])=[O:27])[CH:21]=3)[N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C>C(O)(C)C>[C:9]1([C:15]2[CH2:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:26]([O:28][CH:2]([CH3:7])[CH3:3])=[O:27])[CH:21]=3)[N:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CSCC[C@H](N)C=O
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Temperature: 0 °C
Yield: 78.8 %

Procedure:
Metal sodium (0.33 gram) is dissolved in 40 ml of anhydrous isopropyl alcohol and the solution is heated to reflux for one hour with 2 grams of the 2-phenyl-4-quinolone-6-carboxylic acid obtained in Example 2. After cooling, the solution is mixed with ice water, acidified with acetic acid, the crystals which separate out therefrom are collected by filtration. The crystals are washed with water, washed with methanol, and dried to give 0.6 gram of isopropyl 2-phenyl-4-quinolone-6-carboxylate, colorless powder, melting at above 300° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH2:15][OH:16])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)C.ClCCl.[O-2].[O-2].[Mn+4]>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH:15]=[O:16])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cnc(CO)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cnc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 83.3 %

Procedure:
Manganese dioxide (6.0 g) is added to a solution of 4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (2.0 g) in diethyl ether (80 mL) and dichloromethane (10 mL) and the mixture stirred at room temperature for 90 hours. After filtering the filter pad is washed with dichloromethane and the combined filtrate and washings are evaporated to give a white solid. The solid is dried under high vacuum to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g). [1Hnmr in D6-DMSO shifts relative to Me4Si: 1.55-1.79, 6H, m; 1.97, 2H, m; 3.96, 3H, s; 5.03, 1H, m; 7.45, 1H, s; 8.41, 1H, s; 9.83, 1H, s.].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28]CC)=[O:27])=[CH:18][C:17]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([O:11][C:14]2[C:13]([Cl:12])=[CH:31][C:17]3[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]([C:22]([F:24])([F:25])[F:23])[O:21][C:16]=3[CH:15]=2)=[C:2]([Cl:1])[CH:3]=1)([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(=O)O)cc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-chloro-4-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to Example 183, Step 3, an additional equivalent of potassium carbonate was added.) mp >300° C. 1H NMR (acetone-d6/300 MHz) 8.18 (d, 1H, J=2.0 Hz), 8.03 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.93 (s, 1H), 7.78 (s, 1H), 7.23 (d, 1H, J=8.7 Hz), 6.77 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz). ESHRMS m/z 446.9625 (M−H, Calc'd 446.9650). Anal. Calc'd for C18H9Cl2F3O6: C, 48.13; H, 2.02 ; Cl, 15.79. Found: C, 47.96; H, 1.90; Cl, 15.65.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12]2[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)([O-:3])=[O:2].[CH2:21](O)[CH2:22][OH:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:22]1[O:23][CH:19]([C:18]2[C:12]3[NH:11][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])=[N:14][C:13]=3[CH:15]=[CH:16][CH:17]=2)[O:20][CH2:21]1
Reactant: OCCO
Reactant: O=Cc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1nc2cccc(C3OCCO3)c2[nH]1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
2-(2-Nitrophenyl)-benzimidazole-4-carboxaldehyde 4 (6.27 g, 23.5 mmol) was dissolved in benzene (150 mL), and mixed with ethylene glycol (6.5 mL, 118 mmol) and p-toluenesulfonic acid monohydrate (0.450 g, 2.35 mmol). The mixture was heated to reflux overnight and the water was removed by azeotropic distillation. The resulting solution was allowed to cool to room temperature, and was then neutralized with saturated NaHCO3, washed with water and brine and dried over Na2SO4. The compound was purified by column chromatography on silica gel using hexane/ethyl acetate (1:2) as the eluent to give 2-(2-nitrophenyl)-benzimidazole-4-carboxaldehyde ethylene acetal (4.552 g, 62.2%) as a yellow solid. Rf=0.24 (hexane/ethyl acetate=1:2); 1H NMR (200 MHz, CDCl3) δ 4.11 (m, 2H), 4.20 (m, 2H), 6.15 (s, 1H), 7.30 (m, 2H), 7.57-7.83 (m, 3H), 7.93 (d, J1=7.8 Hz, J2=1.3 Hz, 1H), 8.13 (d, J1=7.7 Hz, J2=1.5 Hz, 1H), 10.48 (broad s, 1H). HRMS: Calcd. for C16H13N3O4 311.0906, found 311.0915.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[C:32]3[C:27](=[N:28][C:29]([NH:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:30][CH:31]=3)[N:26](COCC[Si](C)(C)C)[N:25]=2)[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:36]1([CH2:35][CH2:34][NH:33][C:29]2[N:28]=[C:27]3[NH:26][N:25]=[C:24]([C:20]4[CH:19]=[C:18]([NH:17][CH:10]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH2:9][CH2:8][NH2:7])[CH:23]=[CH:22][CH:21]=4)[C:32]3=[CH:31][N:30]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3nc(NCCN4CCOCC4)ncc23)c1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(Nc1cccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of crude (3-{3-[6-(2-morpholin-4-yl-ethylamino)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-phenylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester (329 mg, crude) in dichloromethane (1.5 mL) was added TFA (1.5 mL) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure and partitioned between saturated NaHCO3 solution and ethyl acetate. The water phase was extracted with ethyl acetate again. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, MeOH:dichloromethane, 1:100 to 1:10). The obtained solid was dissolved in a solution of HCl in MeOH and concentrated to give N1-{3-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-phenyl}-1-phenyl-propane-1,3-diamine; hydrochloride. (Yield 20 mg).
Reaction SMILES: ClC(OC(C)C)=O.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH3:20])[C:17](O)=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[OH-:28].[Na+].Cl.[NH2:31]O>CO.O1CCCC1>[OH:28][NH:31][C:17](=[O:18])[C@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:20]
Reactant: [OH-]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NO
Agent: CC(C)OC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
At about 0° C., isopropyl chloroformate (86.05 g, 702.16 mmol, 1.00 equiv.) was added dropwise, over a period of 60 minutes, to a stirred mixture of (S)-2-(tert-butoxycarbonylamino)propanoic acid (118 g, 623.65 mmol, 1.00 equiv.), tetrahydrofuran (500 mL), and triethylamine (63.63 g, 628.82 mmol, 1.00 equiv.). The resulting mixture was then stirred at about 0° C. for about 2 hours, and then the solids were removed by filtration. The resulting filtrate was then added to a hydroxylamine solution (formed by first stirring a mixture of sodium hydroxide (37.6 g, 940.00 mmol, 1.50 equiv.), methanol (500 mL), and hydroxylamine hydrochloride (65 g, 935.39 mmol, 1.50 equiv) at about 0° C. for about 2 hours, and then removing the resulting solids by filtration). The resulting mixture was stirred at about 0° C. for about 2 hours, the solids were removed by filtration, and the resulting filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:1)) to give the title product as a white solid (70 g; yield=55%). 1H NMR (300 MHz, CDCl3) δ: 5.18 (b, 1H), 4.21 (m, 1H), 2.06 (s, 1H), 1.46 (s, 9H), 1.40 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:31]([O:34][CH2:35]OC)(=O)C>CCCCCC>[C:1]([O:7][CH2:8][CH:9]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[O:10][CH2:31][O:34][CH3:35])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCC(O)COC(=O)C(C)(C)C
Reactant: COCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Product: COCOC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
50.45 g of 1,3-dipivaloyl glycerol was dissolved in 200 ml of methoxymethyl acetate. After the addition of 2.5 g of p-toluenesulfonic acid monohydrate, the mixture was stirred for 1 hr then diluted with 200 ml of hexane and washed twice with 200 ml saturated aqueous sodium carbonate, once with aqueous NaCl solutions, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 1,3-dipivaloyl-2-methoxymethyl glycerol as a colorless oil.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][NH2:9])[CH3:5]>CCOCC>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[CH2:8][NH:9][C:2]#[N:1])[CH3:5]
Reactant: CCOC(CN)OCC
Reactant: N#CBr
Solvent: CCOCC
Product: CCOC(CNC#N)OCC
Temperature: 0 °C
Yield: 109.7 %

Procedure:
A solution of cyanogen bromide (2.12 g., 0.02 moles) in ether (20 ml.) was added dropwise over 35 minutes to a stirred ice-cooled solution of aminoacetaldehyde diethyl acetal (5.32 g., 0.04 moles) in ether (20 ml.). During this addition a white precipitate was formed. The resulting suspension was stirred at 0° C. for a further hour, filtered and the filtrate evaporated to dryness under reduced pressure to give 2,2-diethoxyethylcyanamide (3.47 g., 110%) as a colourless oily liquid having the following n.m.r. spectrum in CDCl3 : 1.24 (t, 6H); 3.1 (d, 2H); 3.65 (m, 4H); 4.0 (br s, 1H); 4.57 (t, 1H).
Reaction SMILES: Cl.Cl.[N+]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)([O-])=O.Cl.[N+](C1C=CC=C2C=1N=CC=C2)([O-])=O>C(OCC)(=O)C.CN(C)C=O>[N:11]1[C:12]2[C:7](=[CH:6][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc2ncccc12
Agent: Cl
Agent: O=[N+]([O-])c1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
A crude nitration mixture (50 g) created in the manner of Preparation I was dissolved in 500 mL of ethyl acetate. Approximately 10.4 g (0.29 mole) of hydrogen chloride gas was added giving a yellow precipitate. (Note: The amount of hydrogen chloride gas added could only be approximated as it was measured by weighing the flask.) This precipitate was analyzed and found to contain 5-nitroquinoline hydrochloride and 8-nitroquinoline hydrochloride in a ratio of 51:41. The precipitate was collected by filtration and dried affording 54 g. The crude product was suspended in 270 mL of wet dimethylformamide (0.5 parts water in 99.5 parts dimethylformamide) to form a slurry. The slurry was heated to dissolution (95° C.-100° C.) to form a solution and this solution was cooled to 25° C. Crystallization of a cream colored solid commenced at about 85° C.-95° C. The solid was collected by filtration, washed with ethyl acetate (2×25 mL) and dried and found to be 99.0% 5-nitroquinoline hydrochloride and 0.41% 8-nitroquinoline hydrochloride. The yield of 5-nitroquinoline hydrochloride was 20.8 g (34.5% overall yield from quinoline).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH2:11]([O:13][C:14](=[O:22])[CH2:15][C:16]([CH2:18][O:19][CH2:20][CH3:21])=O)[CH3:12].[CH2:23]([O:25][C:26](=[O:32])[CH:27]=[C:28]([NH2:31])[CH2:29][CH3:30])[CH3:24]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=2)[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:32])=[C:28]([CH2:29][CH3:30])[NH:31][C:16]=1[CH2:18][O:19][CH2:20][CH3:21])=[O:22])[CH3:12]
Reactant: CCOC(=O)C=C(N)CC
Reactant: CCOCC(=O)CC(=O)OCC
Reactant: N#Cc1cccc(C=O)c1
Solvent: CCO
Product: CCOCC1=C(C(=O)OCC)C(c2cccc(C#N)c2)C(C(=O)OCC)=C(CC)N1
Yield: 42 %

Procedure:
6.5 g of 3-cyanobenzaldehyde, 8.7 g of γ-ethoxyacetoacetic acid ethyl ester and 7.2 g of β-amino-β-ethylacrylic acid ethyl ester in 80 ml of ethanol are heated overnight under reflux, the mixture is cooled, and after filtration, and washing with cold ethanol, 2-ethoxymethyl-6-ethyl-4-(3'-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained in the form of light yellow crystals of melting point 125°C, in a yield of 42% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][S:30][CH2:31][CH2:32]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:29][S:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CSCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
To a mixture of 1.00 g of 3-hydroxybenzaldehyde, 25 ml of tetrahydrofuran, 2.40 g of triphenylphosphine and 0.78 ml of 2-methylthioethanol was added dropwise 3.50 ml of diethyl azodicarboxylate (40% toluene solution), and the mixture was stirred at room temperature for 15.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.71 g of oily 3-(2-methylthioethoxy)benzaldehyde [Compound No. (f)].
Reaction SMILES: CSC1SC(C(OC)=O)=CC=1C1[N:13]=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[S:15]C=1.[Br:32][CH2:33][C:34]([C:36]1[CH:37]=[C:38]([C:42]([O:44][CH3:45])=[S:43])[S:39][C:40]=1[CH3:41])=O.C(OC1C=CC(NC(N)=S)=CC=1)C1C=CC=CC=1>>[BrH:32].[C:26]1([CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:14]3[S:15][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([C:42]([O:44][CH3:45])=[S:43])[S:39][C:40]=4[CH3:41])[N:13]=3)=[CH:19][CH:20]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Reactant: COC(=O)c1cc(-c2csc(Nc3ccc(OCc4ccccc4)cc3)n2)c(SC)s1
Agent: NC(=S)Nc1ccc(OCc2ccccc2)cc1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccc(OCc4ccccc4)cc3)n2)c(C)s1
Yield: 76 %

Procedure:
Methyl 5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylate: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (336.3 mg, 1.08 mmol) was allowed to react with 4-benzyloxyphenyl thiourea (279 mg) as described in Example 154, step (a) to give 450 mg (76% yield) of methyl 4-(2-{[4-phenylmethoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C23H20N2O3S3, 468.61 (M+H), found 469.2.