Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6](S(C)(=O)=O)[N:5]=1)([CH3:3])[CH3:2].Cl.[C@@H:20]12[CH2:26][C@@H:23]([CH2:24][CH2:25]1)[CH2:22][C@@H:21]2[NH2:27].O1CCOCC1.C(N(CC)C(C)C)(C)C>O>[C@@H:20]12[CH2:26][C@@H:23]([CH2:24][CH2:25]1)[CH2:22][C@@H:21]2[NH:27][C:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1C(C)C
Reactant: N[C@H]1C[C@@H]2CC[C@H]1C2
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N[C@H]2C[C@@H]3CC[C@H]2C3)nc1C(C)C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a mixture of ethyl 4-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (400 mg), (1S,2S,4R)-bicyclo[2.2.1]heptan-2-aminehydrochloride (347 mg), and 1,4-dioxane (8 mL) was added N,N-diisopropyl ethylamine (1 mL) at room temperature, followed by stirring at the same temperature for 16 hours. To the reaction mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain ethyl 2-[(1S,2S,4R)-bicyclo[2.2.1]hept-2-ylamino]-4-isopropylpyrimidine-5-carboxylate (417 mg) as a pale yellow solid.
Reaction SMILES: CO[C:3]1([O:10]C)[CH:8]=[CH:7][C:6](=[O:9])[CH:5]=[CH:4]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]2[C:3]2([OH:10])[CH:4]=[CH:5][C:6](=[O:9])[CH:7]=[CH:8]2)(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccc(F)cc1)n1ccc2ccccc21
Reactant: COC1(OC)C=CC(=O)C=C1
Product: O=C1C=CC(O)(c2cc3ccccc3n2S(=O)(=O)c2ccc(F)cc2)C=C1
Yield: 14 %

Procedure:
The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienone and 1-(4-fluoro-benzenesulfonyl)-1H-indole, according to Method C, described above. Yield 14%; mp 165-166° C.; 1H NMR (CDCl3) δ 7.82-7.93 (m, 3H), 7.49 (d, J=10 Hz, 2H), 7.35 (d, J=8 Hz, 1H), 7.12-7.28 (m, 2H), 6.99-7.05 (m, 2H), 6.73 (s, 1H), 6.25 (d, J=10 Hz, 2H), 5.31 (s, 1H);13C NMR (CDCl3) δ 185.2, 170.9, 170.5, 147.7, 141.0, 138.6, 133.6, 130.1, 129.9, 128.8, 128.1, 126.8, 125.2, 122.2, 117.3, 116.9, 115.6, 114.5, 69.5, 67.9; MS (AP+) m/z 384.04 (M++1).
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 76 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 76% of theory, Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1) C27H27N5O4 (485.6) ##EQU21##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[C:11]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6]C=CC=1.BrCC1CC1>>[CH:2]1([CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][C:17]4[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=4[N:31]=3)=[C:11]([O:32][CH2:33][C:34]([F:36])([F:37])[F:35])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)cc3OCC(F)(F)F)nc2cn1
Agent: BrCC1CC1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4)cc3OCC(F)(F)F)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-2-(2,2,2-trifluoroethoxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (bromomethyl)cyclopropane, and in the same manner as in Step D of Example 68, the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[NH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:16])[C:11]=2[C:12]=1[C:13]([OH:15])=O)([O-:3])=[O:2].[CH3:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[CH2:18]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:13]([C:12]2[C:11]3[C:10](=[O:16])[CH2:9][CH2:8][CH2:7][C:6]=3[NH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[O:15])=[CH:24][CH:25]=1)[CH3:17]
Reactant: O=C1CCCc2[nH]c([N+](=O)[O-])c(C(=O)O)c21
Reactant: CCOc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1ccc(NC(=O)c2c([N+](=O)[O-])[nH]c3c2C(=O)CCC3)cc1
Reaction time: 67 h
Yield: 18.6 %

Procedure:
A mixture of 2-nitro-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (0.18 g, 0.8 mmol), p-phenetidine (0.52 mL, 4 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (767 mg, 4 mmol) in 50% aqueous dioxane (10 mL) was stirred for 67 hours, then concentrated in vacuo. Aqueous 3.6N hydrochloric acid was added, the mixture cooled in an ice water bath, and the precipitate collected, rinsed with water then diethyl ether, and dried. Purification on Silica gel (10% methyl alcohol/dichloromethane) gave N-(4-ethoxyphenyl)-2-nitro-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 56) (51 mg).
Reaction SMILES: C1(C(=[N:14][CH:15]([C@H:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[CH:26]=[CH2:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl>C(OCC)C>[NH2:14][CH:15]([C@H:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[CH:26]=[CH2:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CC(C)CCC[C@@H](C)C(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Product: C=CC(C)CCC[C@@H](C)C(N)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of (3R)-ethyl 2-(diphenylmethyleneamino)-3,7 dimethylnon-8-enoate (14.5 g, 37 mmol) in diethyl ether (25 mL) was added aqueous 1.5 N HCl solution (125 mL) and the reaction mass was stirred at room temperature overnight. The reaction mass was washed with diethyl ether (100 mL). The aqueous solution was basified using saturated sodium bicarbonate solution and extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound (2.1 g, 23%). The crude compound was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ ppm 5.85-5.60 (m, 1H), 4.98-4.85 (dd, J=1.6, 2.8 Hz, 2H), 4.10-4.06 (m, 2H), 3.15-3.14 (m, 1H), 2.15-2.02 (m, 1H), 1.94-1.75 (m, 3H), 1.32-1.17 (m, 9H), 0.95-0.93 (m, 3H), 0.84-0.74 (m, 3H). MS: MS m/z 227.7 (M++1).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[C:22]1([CH:28]2[CH2:33][NH:32][CH2:31][CH2:30][NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:32]2[CH2:31][CH2:30][NH:29][CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:33]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: c1ccc(C2CNCCN2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5ccccc5)C4)cc3nc21
Temperature: 115 °C
Yield: 35.5 %

Procedure:
A suspension of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.84 g) in pyridine (20 cc), (RS)-2-phenylpiperazine (5.83 g) and triethylamine (1.24 g) is heated to a temperature in the region of 115° C. for 5 hours. After cooling to approximately 20° C., the precipitate formed is drained and washed with pyridine (2×5 cc), isopropyl alcohol (2×5 cc), ethanol (2×5 cc) and ethyl ether (1×20 cc). After 1 recrystallization in a mixture of dimethylformamide (40 cc) and ethanol (40 cc), (RS)-7-fluoro-1-methyl-4-oxo-8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.920 g) is obtained in the form of a yellow solid, m.p. 265° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][OH:45].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:45][CH2:44][CH2:43][C:37]3[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=3[F:35])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1ccc(F)cc1F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc(F)cc2F)cc1
Reaction time: 18 h
Yield: 34.9 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(2,4-difluorophenyl)ethanol (33.7 mg, 0.213 mmol) and Ph3P-resin (33.6 mg, 0.128 mmol) in THF (2 mL) was added DEAD (0.020 mL, 0.128 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(2,4-difluorophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (8.6 mg, 0.015 mmol, 34.7% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.53-7.45 (m, 1H), 7.28-7.15 (m, 2H), 7.11-6.90 (m, 4H), 5.82 (s, 1H), 4.31-4.18 (m, 2H), 3.08 (t, J=6.6 Hz, 2H), 2.84-2.76 (m, 1H), 2.43 (s, 3H), 2.17 (d, J=10.6 Hz, 1H), 2.05 (s, 3H), 1.49 (br. s., 1H), 1.34-1.27 (m, 1H), 1.17 (d, J=12.5 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=12.8 Hz, 1H), 0.85 (s, 3H), 0.60 (s, 3H). LCMS (M+H)=581.5.
Reaction SMILES: C1(C(C2C=CC=CC=2)O[P:9]2[O:14][CH2:13][C:12]3([CH2:19][O:18][P:17](OC(C4C=CC=CC=4)C4C=CC=CC=4)[O:16][CH2:15]3)[CH2:11][O:10]2)C=CC=CC=1.C1(C(Br)C2C=CC=CC=2)C=CC=CC=1>>[CH2:19]1[C:12]2([CH2:11][O:10][PH:9][O:14][CH2:13]2)[CH2:15][O:16][PH:17][O:18]1
Reactant: c1ccc(C(OP2OCC3(CO2)COP(OC(c2ccccc2)c2ccccc2)OC3)c2ccccc2)cc1
Agent: BrC(c1ccccc1)c1ccccc1
Product: C1OPOCC12COPOC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 208.9 %

Procedure:
560.5 g (1.0 mol) of 3,9-bis(diphenylmethoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane and 494.3 g (2.0 mol) of diphenylmethyl bromide were charged into a reactor equipped with a stirrer, thermometer and capacitor, and dry nitrogen was caused to flow into the reactor under agitation at room temperature. Thereafter, heating was started with an oil bath which was kept at 150° C. for 15 minutes. The oil bath was removed to cool the reactor to room temperature. 2,000 ml of acetone was added to the obtained reaction product which was a white solid and stirred to clean the reaction product, and the white powder was separated by filtration with a glass filter. Then, the separated white powder was cleaned with 2,000 ml of a 50 wt % aqueous solution of methanol and dried at 100 Pa and 120° C. for 8 hours to produce 409.6 g of 2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane, 3,9-bis(diphenylmethyl)-3,9-dioxide. It was confirmed from mass spectral analysis, 1H, 31P nuclear magnetic resonance spectral analysis and elemental analysis that the product was 2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]undecane, 3,9-bis(diphenylmethyl)-3,9-dioxide. This compound had a yield of 73%, an HPLC purity of 99.2% and an acid value of 0.63 mgKOH/g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[N:7]=1>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH:21][C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)[N:7]=1
Reactant: O=[N+]([O-])c1ccc(Nc2cccc3nc(-c4cccs4)c(-c4cccs4)nc23)cc1
Solvent: C1CCOC1
Product: Nc1ccc(Nc2cccc3nc(-c4cccs4)c(-c4cccs4)nc23)cc1

Procedure:
2.2 g (5.1 mmol) of 2,3-di(2-thienyl)-5-(4-nitrophenyl)aminoquinoxaline was dissolved in 50 ml of tetrahydrofuran, and a reaction container was purged with nitrogen. Thereafter, 0.7 g of 5% Pd/C (hydrous) was added, followed by sufficient purging with nitrogen again. This system was purged with hydrogen, followed by reaction at room temperature for 5 hours. After completion of the reaction, the system was filtered, and the resulting filtration residue was washed with tetrahydrofuran and filtered again. The solvent was removed from the resulting filtrate, and a reaction product was extracted with a silica gel column.
Reaction SMILES: [C:1]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:16]([O:25][CH3:26])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19]>>[C:1]([C:6](=[CH:12][NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH3:26])=[O:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1N
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccccc1C(=O)OC)C(=O)OCC
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 2-butyryl-3-ethoxyacrylate (21.4 g, 0.1 mol) and methyl anthranilate (12.9, ml, 0.1 mol) was heated to boiling for 20 minutes, then cooled and triturated with petroleum ether to obtain ethyl 2-butyryl3-(2-carbomethoxyphenylamino)acrylate as a mixture of E/Z isomers (18.0 g, 56%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]=[C:8]([NH:10][CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:16]=2)[N:7]([CH3:29])[N:6]=1.[CH3:30][NH:31][C:32](SC)=[CH:33][N+:34]([O-:36])=[O:35]>O.CO.C(OCC)(=O)C>[CH3:29][N:7]1[C:8]([NH:10][CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:16]=2)=[N:9][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][CH3:30])=[CH:33][N+:34]([O-:36])=[O:35])=[N:6]1
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: Cn1nc(CCCN)nc1NCC(O)COc1cccc(CN2CCCCC2)c1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=C[N+](=O)[O-])NCCCc1nc(NCC(O)COc2cccc(CN3CCCCC3)c2)n(C)n1
Reaction time: 3 h
Yield: 38.4 %

Procedure:
A solution of 1-[[3-(3-aminopropyl)-1-methyl-1H-1,2,4-triazol-5-yl]amino]-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol (0.25 g) and N-methyl-1-(methylthio)-2-nitroethenamine (0.1 g) in water (6 ml) and methanol (6 ml) was stirred at room temperature for 24 h. A further quantity of N-methyl-1-(methylthio)-2-nitroethenamine (0.01 g) was added and the mixture stirred for a further 3 h. The reaction mixture was concentrated to ca. 6 ml, diluted with water (10 ml), acidified to pH3 with acetic acid and washed with ethyl acetate. The aqueous solution was basified with excess potassium carbonate and extracted with ethyl acetate. The extract was dried and evaporated to leave a brown gum which was chromatographed on silica using methanol:ammonia (250:1) to give a gum which was dissolved in hot ethyl acetate and cooled to precipitate a gum. This gum was dissolved in chloroform and filtered through florosil and hyflo. The filtrate was evaporated to give the title compound (0.12 g) as a solid white foam m.p. 60°-63° (softens).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O.[Br-].[Br-].C([N+]1C=CC(C2C=C[N+](CCCCCCC)=CC=2)=CC=1)CCCCCC>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[CH:6]=[O:7]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: CCCCCCC[n+]1ccc(-c2cc[n+](CCCCCCC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: Nc1cc(C=O)ccc1Cl
Temperature: 5 °C
Reaction time: 4 h
Yield: 102.4 %

Procedure:
4-Chloro-3-nitrobenzaldehyde (4.00 mg, 21.6 mmol) in CH2Cl2 (150 mL) at 23° C. was treated with water (50 mL) and N, N′-diheptyl-4,4′-bipyridinium dibromide (220 mg, 10 mg/mmol of substrate). The biphasic mixture was cooled to 5° C. and treated with a solution of sodium dithionite (15.0 g, 86.0 mmol) and K2CO3 (13.4 g, 87.0 mmol) in water (45 mL). The cooling bath was removed and the biphasic mixture stirred vigorously at 23° C. for 4 hours. The mixture was partitioned between additonal CH2Cl2 (75 mL) and water (50 mL) and the aqueous layer was extracted with CH2Cl2 (75 mL). The organic portions were washed with brine (75 mL) and dried (Na2SO4). The residue was treated with ethyl acetate (25 mL) and silica gel (75 g) and the suspension was filtered through a small pad of Celite, rinsing with 10% ethyl acetate/CH2Cl2 (15 mL). The filtrate was concentrated to provide the title compound as an off-yellow powder (3.44 g, 22%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].[CH2:11]=[O:12]>>[OH:12][CH2:11][CH2:7][C:6]1[C@@H:8]2[CH2:9][C@@H:3]([CH2:4][CH:5]=1)[C:2]2([CH3:10])[CH3:1]
Reactant: C=O
Reactant: C=C1CCC2CC1C2(C)C
Product: CC1(C)[C@@H]2CC=C(CCO)[C@@H]1C2

Procedure:
A mixture of β-pinene (32 ml) and paraformaldehyde (4 g) in sealed tube was reacted for 18 hrs at 180° C. The reaction solution was distilled to give the title compound (15.5 g) having the following physical data:
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][CH2:6][C:5]([CH2:10][O:11]CC)([CH2:8][OH:9])[CH2:4][O:3]1.O>CO>[CH2:2]([O:3][CH2:4][C:5]([CH2:8][OH:9])([CH2:10][OH:11])[CH2:6][OH:7])[CH3:1]
Reactant: CCOCC1(CO)COC(C)(C)OC1
Solvent: O
Solvent: CO
Product: CCOCC(CO)(CO)CO
Reaction time: 4 h

Procedure:
A mixture consisting of 2,2-dimethyl-5-ethoxymethyl-5-hydroxymethyl-1,3-dioxane (15.0 g) and Amberlyst "15" (3.0 g) in methanol (500 ml) containing water (10 ml) was refluxed with stirring for 4 hours. The mixture was filtered and the filtrate was evaporated in vacuo. 2-Ethoxymethyl-2-hydroxymethylpropan-1,3-diol was obtained as a viscous oil (10.5 g) and was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.B.[Na]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: B
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(C(C)O)cc2)cc1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
32.2 g (0.12 mol) of ethyl 4'-acetyl-4-biphenylcarboxylate, 150 ml of chloroform and 50 ml of ethanol were supplied into a four-necked flask provided with a stirrer and a thermometer. Then 2.3 g (0.06 mol) of sodium boron hydride was added at 15°-25° C. over a period of 10 minutes. The mixture was maintained at the same temperature for 2 hours and the resulting reaction solution was poured into ice-water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to form 30.8 g (95% yield) of ethyl 4'-(1-hydroxyethyl)-4-biphenylcarboxylate (III-5).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[CH:7][CH:8]=1.C[O-].[Na+].[I-].[K+].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>CO.C1C=CC=CC=1.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:18]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 4.08 g of α,α,α-trifluoro-p-cresol, 1.19 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed overnight and then poured into 100 ml of water. The mixture is then extracted with 2 × 75 ml of ether. The combined extracts are washed with 2 × 50 ml of 5% NaOH, 50 ml of water, 50 ml of saturated brine and dried (MgSO4). Evaporation of the solvent yields a yellow oil. Chromatography on 100 g of silica gel (benzene, 400 ml) affords the product as a colorles oil.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].P([O-])(O)(O)=[O:10].[Na+].Cl([O-])=O.[Na+].[OH-].[Na+]>C(#N)C.O.OO>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:10])=[O:8]
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccsc1Br
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccsc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromo-3-methylthiophene (17.7 g), N-bromosuccinimide (17.7 g), 2,2'-azobis(isobutyronitrile) (0.32 g) and carbon tetrachloride (200 ml) was stirred for 4 hours under reflux. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-bromomethyl-2-bromothiophene (12.56 g). A suspension of 3-bromomethyl-2-bromothiophene (6.30 g), potassium acetate (9.8 g) in acetone (100 ml) was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-acetoxymethyl-2-bromothiophene (5.8 g). This crude product was dissolved in tetrahydrofuran (50 ml), and 1N aqueous sodium hydroxide (50 ml) and ethanol (20 ml) were added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-hydroxymethyl-2-bromothiophene (4.6 g). This crude product of 3-hydroxymethyl-2-bromothiophene was dissolved in methylene chloride (100 ml), manganese dioxide (15 g) was added. The mixture was stirred at room temperature for 6 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-bromo-3-thiophenecarbaldehyde (3.92 g). The crude product of 2-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.0 g) in water (15 ml) and 30% aqueous hydrogen peroxide (2.5 ml) were added. Further, sodium chlorite (2.7 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide (2.7 g) and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-bromo-3-thiophenecarboxylic acid (2.89 g) as crystals.