Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:39]=[CH:38][S:37][CH:36]=3)[CH:30]=2)=[N:26][C:25]=1[CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:41][CH2:40][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[CH:39]=[CH:38][S:37][CH:36]=4)[CH:30]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccsc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4ccsc4)c3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.90 (dt, J=7.6 Hz, J=1.2 Hz, 1H), 7.64 (dt, J=7.6 Hz, J=1.2 Hz, 1H), 7.56–7.55 (m, 1H), 7.48–7.39 (m, 3H), 7.23–7.14 (m, 5H), 6.96 (t, J=7.2 Hz, 1H), 6.83–6.81 (m, 4H), 4.24 (t, J=6.8 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 3.00 (t, J=6.4 Hz, 2H), 2.39 (s, 3H), 1.38 (s, 3H) 1.21 (t, J=7.2 Hz, 3H); MS (EI) 568.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19]
Reactant: Cc1cccnc1C(=O)CBr
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2ncccc2C)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromoacetyl-3-methylpyridine (step 1). 1H-NMR (CDCl3) δ: 8.36 (1 H, dd, J=1.1, 4.8 Hz), 8.14 (1 H, d, J=1.8 Hz), 7.64 (1 H, ddd, J=0.7, 1.5, 7.0 Hz), 7.51 (1 H, dd, J=0.7, 8.4 Hz), 7.24 (1 H, d, J=1.8, 8.8 Hz), 7.22 (1 H, d, J=7.7 Hz), 6.05 (2 H, br s), 3.78 (2 H, q, J=7.3 Hz), 2.63 (3 H, s), 1.01 (3 H, t, J=7.3 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:17])([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:25]O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]([O:16][CH3:25])=[O:15])[CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:17])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c(=O)[nH]cnc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc([N+](=O)[O-])cc2c(=O)[nH]cnc12
Temperature: 25 °C
Yield: 84 %

Procedure:
6-nitro-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (500 mg, 2.13 mmol) was treated with a solution of sulfuric acid ((1.2 equiv.) in anhydrous MeOH (10 mL) under refluxing overnight. After cooling to rt, 2N NaOH solution was added to the reaction mixture to adjust pH˜8. After removal of MeOH, methyl ester was collected by filtration, and washing with water and as yellow solid in 84% yield. 1HNMR (in DMSO): 3.91 (s, 3H), 8.38 (s, 1H), 8.74 (d, J=2.6 Hz, 1H), 8.88 (d, J=2.6 Hz, 1H). Mass: M+H+: 250.
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[C:11]([CH2:19]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:44]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[CH2:2]([O:9][C:10]1[C:11]([CH:19]=[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: c1ccc(COc2cc3c(cc2C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)OCC3)cc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=C(c1ccccc1)c1ccccc1)c1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 22.2 %

Procedure:
A mixture of (5-benzyloxy-2,3-dihydro-benzofuran-6-yl)methyl triphenylphosphine iodide (2.0 g, 0.0033 mol) in tetrahydrofuran (20 ml) was cooled to an internal temperature of 5° C. under nitrogen and a solution of n-butyllithium (1.55M in hexane, 1.9 ml, 0.0030 mol) was added dropwise. The resulting mixture was stirred for 10 minutes then benzophenone (0.47 g, 0.0030 mol) was added portionwise. The ice bath was removed and the reaction was allowed to stir for 18 hours, then heated to reflux for 4 hours. The reaction mixture was concentrated to a dark oil which was dissolved in ethyl acetate (20 ml), washed with water (10 ml), saturated sodium chloride (10 ml). The combined organic layers were dried (MgSO4), concentrated then chromatographed over silica gel (hexane/ethyl acetate, 90/10, an eluent) to afford 1-(5-benzyloxy-2,3-dihydrobenzofuran-6-yl)-2,2-diphenyl-ethene (0.27 g, 22%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C@H:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH3:2][CH2:1][O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C@H:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O
Temperature: 62.5 °C
Reaction time: 2.5 h
Yield: 83.2 %

Procedure:
Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-amino carbonylmethyl]-benzoate (4.5 g, 0.0093 mol) was dissolved in methanol (45 ml), followed by the addition of sodium hydroxide solution (0.75 g of sodium hydroxide dissolved in 6 ml water). The reaction mixture was heated at 60-65° C. for 3-4 hours. Methanol (80-85%) was removed from the reaction mixture under vacuum. The remaining reaction mixture was diluted with water (45 ml) and pH was adjusted to 6.5-7.0 with 1N HCl. The precipitated solid was stirred for 2-3 hours followed by filtration and washing with water (45 ml). The product was further dried at 50-55° C. under vacuum for 6-8 hours to produce Repaglinide (Yield=83.2%; HPLC Purity: 99.89%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:6]([CH3:23])=[N:5][CH:4]=1.CC(C)([O-])C.[K+].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K]>O1CCCC1>[CH3:23][C:6]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:3]([CH2:2][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])=[CH:4][N:5]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ncc(CCl)n1-c1ccc(Cl)cc1Cc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Product: Cc1ncc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1Cc1ccccc1F
Temperature: 10 °C

Procedure:
To a suspension of 89.4 g (0.232 mole) of 5-(chloromethyl)-2-methyl-1-[4-chloro-2-(2-fluorobenzyl)phenyl]-1H-imidazole in 900 ml of tetrahydrofuran cooled to 10° C. was added 26.2 g (0.232 mole) of potassium t-butoxide. The temperature was maintained at 20° C. by means of an ice water bath during this addition. The bath was removed. To this mixture was added 51.5 g (0.278 mole) of potassium phthalimide. The reaction mixture was stirred under reflux for 2 hr. The mixture was cooled to room temperature and poured onto 1.2 l of ice-water and extracted with 3×600 ml of methylene chloride. The organic phases were combined and dried over sodium sulfate. The solution was filtered free of drying agent and the filtrate concentrated to dryness giving an oil. The oil was crystallized from 180 ml of ether. The resulting crystals were collected and dried to give end product of m.p. 152°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([C:14]#[N:15])=[CH:12][C:11]2[NH:16][N:17]=[C:18]([N:19]3C(=O)C4C(=CC=CC=4)C3=O)[C:10]=2[C:9]1=[O:30].O.NN.O>C(O)C>[NH2:19][C:18]1[C:10]2[C:9](=[O:30])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:13]([C:14]#[N:15])=[CH:12][C:11]=2[NH:16][N:17]=1
Reactant: N#Cc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c(=O)n1-c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: N#Cc1cc2[nH]nc(N)c2c(=O)n1-c1ccccc1Cl
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 75.3 %

Procedure:
To a solution of 5-(2-chlorophenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-carbonitrile obtained in Step K (203 mg) in ethanol (1.63 mL) was added hydrazine monohydrate (29.3 mg) at room temperature. The reaction mixture was stirred at 50° C. for 20 min, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/dichloromethane) to give the title compound (105 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].C(NCC)C.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>O>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[NH:21][CH:18]1[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Solvent: O
Solvent: CCNCC
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Reaction time: 16 h
Yield: 79.9 %

Procedure:
1-Chloro-2,5-difluoro-4-nitrobenzene (3.69 g, 19 mmol) is treated at 0° with diethylamine (2.3 g, 23 mmol) and cyclopropylamine (1.3 g, 23 mmol). After 1 hour at 0° the suspension obtained is stirred at 25° for 16 hours. The reaction mixture is taken up in water (150 ml) and extracted with ethyl acetate. The organic phase is washed with 10 percent sodium chloride solution and dried over magnesium sulfate. After distillation of the solvent the residue is recrystallized from ethanol (50 ml). There are obtained 3.5 g (79%) of 5-chloro-N-cyclopropyl-4-fluoro-2-nitroaniline with a m.p. of 73.5°-75.5°.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].[CH3:11]I>C(O)(=O)C>[CH3:11][S:3][C:2]1[NH:4][C:5](=[O:6])[CH:7]=[CH:8][N:1]=1
Reactant: CI
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSc1nccc(=O)[nH]1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Thiouracil (33.3 g, 0.26 mol) was dissolved in an aqueous solution of sodium hydroxide (20.8 g in 183 mL of water; ˜0.52 mol). The mixture was placed in an ice bath until the internal reaction temperature was 0° C. Methyl iodide (18.5 mL, 0.29 mol) was slowly added. The resulting reaction mixture was allowed to return to room temperature and then stirred for 16 hours. The pale yellow solution was cooled to 0° C. and acidified with glacial acetic acid. The white precipitate that formed was collected by vacuum filtration, washed with cold water (3×150 mL), and dried to afford 2-methylsulfanyl-3H-pyrimidin-4-one as a white powder. (37.4 g, 98%).
Reaction SMILES: [K].[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([OH:8])=[O:7].[CH2:17](C(C)=O)C.CI>O>[Cl:2][C:3]1[C:4]([C:15]#[N:16])=[C:5]([C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:6]([O:8][CH3:17])=[O:7]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reactant: CCC(C)=O
Agent: [K]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N

Procedure:
12.9 g of the potassium salt of 3,4,5,6-tetrachloro-2-cyanobenzoic acid are heated for 20 hours under reflux in a mixture of 30 ml of water, 60 ml of methyl ethyl ketone and 11.4 g of methyl iodide. The aqueous phase is separated and the organic phase is concentrated by evaporation. Recrystallisation of the crude product (which contains only a small amount of impurities according to analysis by thin-layer chromatography) from ethanol affords 7.5 g of pure methyl 3,4,5,6-tetrachloro-2-cyanobenzoate with a melting point of 83°-84° C.
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:24]1[CH:37]=[N:36][C:27]2[NH:28][C:29]3[CH:34]=[N:33][C:32]([Br:35])=[CH:31][C:30]=3[C:26]=2[CH:25]=1>C(=O)([O-])[O-].[Na+].[Na+].CC1CCCO1.C(OCC)(=O)C>[Br:35][C:32]1[N:33]=[CH:34][C:29]2[NH:28][C:27]3[N:36]=[CH:37][C:24]([C:10]4[CH:11]=[CH:12][C:13]([CH2:16][N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)=[CH:14][CH:15]=4)=[CH:25][C:26]=3[C:30]=2[CH:31]=1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCOCC4)cc3)cc12
Temperature: 85 °C
Yield: 30.2 %

Procedure:
A degassed mixture of 4-(4-morpholinomethyl)phenylboronic acid pinacol ester (486 mg, 1.61 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (400 mg, 1.07 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (131 mg, 0.16 mmol) in 2N aqueous sodium carbonate solution (8 mL) and 2-methyltetrahyrdofuran (16 mL) was heated at 85° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-15% methanol in DCM) to afford the title compound as an off-white solid (137 mg, 30%). 1H NMR (CDCl3, 300 MHz): 12.41 (s, 1H), 9.04 (d, J=2.3 Hz, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.72 (d, J=1.0 Hz, 1H), 8.53 (s, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 3.65-3.56 (m, 4H), 3.53 (s, 2H), 2.44-2.29 (m, 4H).
Reaction SMILES: C[C:2](C)=[O:3].[CH3:5][C:6]1[C:12](=[O:13])[C:11]2[N:14]3[C@@:18]([O:25][CH3:26])([C@H:19]([CH2:20][O:21][C:22]([NH2:24])=[O:23])[C:10]=2[C:8](=[O:9])[C:7]=1N)[C@H:17]1[NH:27][C@H:16]1[CH2:15]3>CO>[CH3:5][C:6]1[C:12](=[O:13])[C:11]2[N:14]3[C@@:18]([O:25][CH3:26])([C@H:19]([CH2:20][O:21][C:22]([NH2:24])=[O:23])[C:10]=2[C:8](=[O:9])[C:7]=1[O:3][CH3:2])[C@H:17]1[NH:27][C@H:16]1[CH2:15]3
Reactant: CC(C)=O
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(=O)C(C)=C(N)C3=O)N1C[C@@H]1N[C@@H]12
Solvent: CO
Product: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21

Procedure:
TLC (ETOAC:Acetone) one spot Rf =0.91; UV (MeOH) 216 and 358 mu NMR(CDCl3); appearance of singlet at 4.04 corresponding to the 7-methoxy group which is not present in the parent compound mitomycin C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][NH:23][O:24][CH3:25])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:23]([CH2:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[O:24][CH3:25])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCCCc1ccc(F)cc1
Product: CON(CCCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[3-(4-fluorophenyl)-propyl]-O-methyl-hydroxylamine as described in the preparation of compound 1-C gave the title amide as white crystals (97% yield): mp 90-91° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.77 (6H, s, CH3), 1.98 (2H, m, CH2), 2.64 (2H, t, J=7.9 Hz, CH2), 3.71 (2H, t, J=7.6 Hz, NCH2), 3.73 (3H, s, OCH3), 6.41 (1H, broad s, CH), 6.98 (2H, m, aromatics), 7.16 (2H, m, aromatics). Anal. calcd for C17H20FNO5: C, 60.53; H, 5.98; N, 4.15. Found: C, 60.43; H, 5.99; N, 4.09.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].C(O)=[O:40]>C(O)CO.C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH2:35][CH2:36][OH:40])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: O=CO
Agent: [H-]
Agent: [Na+]
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CCCCc1nc2cccc(C(=O)OCCO)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of ethyl 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.72 g) in ethylene glycol (15 ml) was added, while stirring at room temperature, sodium hydride (60% oil, 0.25 g) and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added ice-water (100 ml), which was made acidic with formic acid. Precipitates then formed were dissolved in ethyl acetate (100 ml) and the solution was washed with water, dried and concentrated to dryness to give a crystalline product. The crystals were recrystallized from acetone to afford colorless crystals (0.49 g, 66%), m.p. 145°-147° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[ClH:15].[N+:16]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O-:18])=[O:17].C(N(CC)CC)C.Cl>C(O)C>[ClH:15].[N+:16]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[O:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)=[O:4])[CH2:27][CH2:28]1)([O-:18])=[O:17]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1cccc(OC2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CN1CCC(Oc2cccc([N+](=O)[O-])c2)CC1)c1ccc2ccccc2c1

Procedure:
0.63 g of 2-bromo-2'-acetonaphthone, 0.65 g of 4-(m-nitrophenoxy)piperidine hydrochloride, and 1 g of triethylamine were added to 100 ml of ethanol. The mixture was refluxed for 30 min. The solvent was distilled off, and dichloromethane was added to the residue. The mixture was washed with water and dried. The dichloromethane was distilled off, and the residue was purified by column chromatography (silica gel) to prepare an oleaginous intended compound. The compound was converted into a hydrochloride by an ordinary method and then recrystallized to prepare 0.15 g of an intended hydrochloride.
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: CCOC(=O)CBr
Reactant: S=c1[nH]c2ccccc2[nH]1
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: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]3)[O:3]1.CC([O-])=O.[NH4+].CC(C)=O>O>[CH2:21]([O:20][C:18]([CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([B:4]([OH:5])[OH:3])[CH:10]=2)[CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1Cc2ccc(B(O)O)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A mixture of ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene-2-carboxylate (16 g, 50% purity, 25.3 mmol), NaIO4 (24 g, 0.112 mol), CH3COONH4 (5.2 g, 0.068 mol), acetone (100 mL), and water (10 mL) was stirred at room temperature overnight. The acetone was evaporated, and the aqueous residue was extracted with EtOAc (3×100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound as white solid (3.5 g). 1HNMR (400 MHz, DMSO-d6): δ 7.91 (s, 2H), 7.62 (s, 1H), 7.57 (d, 1H), 7.17 (d, 1H), 4.10 (q, 2H), 3.36-3.32 (m, 1H), 3.09-3.07 (m, 4H), 1.20 (t, 3H).
Reaction SMILES: [CH2:1]([C:8]1([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:28](B)#N.[Na].C(O)(=O)C>C(#N)C>[CH2:1]([C:8]1([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:13][CH2:12][C:11]([N:14]([CH3:28])[CH3:15])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BC#N
Reactant: CNC1(c2ccccc2)CCC(Cc2ccccc2)(CN(C)C)CC1
Agent: C=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)CC1(Cc2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the title compound from Example 33 (1.40 g, 4.16 mmol) and formalin (5.8 mL, 37% aqueous solution) in acetonitrile (40 mL) was mixed in portions with sodium cyanoboron hydride (1.03 g, 16.6 mmol) and stirred for 45 min at room temperature. Concentrated acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 min at room temperature. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (40 mL) and then extracted with ether (3×40 mL). The organic phase was dried over Na2SO4, filtered and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with ethyl acetate (methanol→methanol+2% TEA).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:2]=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:11]=2)=[N:5][CH:6]=1)#[N:9]
Reactant: CCCCCCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
5.2 G. of 4-chloro-5-cyano-2-(4-n-heptylphenyl)-pyrimidine are reacted in 220 ml. of 50% dioxane with 19.3 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-heptylphenyl)-pyrimidine having a melting point of 96.3° C. (smectic) and clearing point 109.0° C. The substance is identical with the compound obtained according to Example 11.