Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[Cl:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:23]=1[C:24]([O:26][CH3:27])=[O:25].CN(C)[CH:35]=[O:36]>C1COCC1>[Cl:21][C:22]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:28]([F:32])[C:29]([CH:35]=[O:36])=[CH:30][CH:31]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1c(F)cccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1c(Cl)ccc(C=O)c1F
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
An oven-dried round bottom flask successively purged and evacuated with N2 was charged with anhydrous THF (13.3 ml), and diisopropyl amine (6.6 ml, 46 mmol). The mixture was placed in a −78° C. dry ice/acetone bath before n-butyllithium (2.5 M in hexanes) (17 ml, 43 mmol) was added. The LDA solution was then placed in a 0° C. bath for 10 minutes before recooling to −78° C. Then, a solution of methyl 2-chloro-6-fluorobenzoate (3.50 g, 19 mmol) in THF (56 ml) was added dropwise over 30 minutes. The resulting mixture was stirred at −78° C. for 2.5 hrs, warmed to −50° C. over 30 min, and stirred for 30 minutes at −50° C. The mixture was then recooled to −78° C. before adding anhydrous dimethylformamide (14 ml, 186 mmol). The resulting mixture was stirred for 30 minutes at −78° C. and then gradually warmed to RT over 1 h. The reaction was quenched with 10% aqueous acetic acid, diluted with EtOAc and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organics were washed with water, brine, and dried over Na2SO4, filtered and concentrated to a yellow oil, which was purified by chromatography using 12:1 hexanes/EtOAc to give the title compound as a light yellow oil, which solidified upon exposure to reduced pressure.
Reaction SMILES: [C:1]1([C:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:13]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([CH:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[N:13]=2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1nc(-c2ccncc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccccc1)c1nc(-c2ccncc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of 1-phenyl-1-[4-(4-pyridyl)-2-thiazolyl]methanone (675 g, 0.0025 mol) in methanol (40 mL) was added sodium borohydride (300 mg, 0.0079 mol) in portions and the mixture allowed to stir at room temperature for one hour. The reaction mixture was concentrated, diluted with water, and extracted with ether (3×25 mL). The combined extracts were washed with brine, dried over magnesium sulfate, concentrated, and chromatographed. Recrystallization from hexane/ethyl acetate afforded 1-phenyl-1-[4-(4-pyridyl)-2-thiazolyl]methanol (300 mg, 45%). mp. 146°-147° C.
Reaction SMILES: ClC[C:3]([N:5]([CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])[CH2:6][CH2:7][N:8]1[C:16](=O)C2C(=CC=CC=2)C1=O)=[O:4].O.NN>CCO>[O:4]=[C:3]1[CH2:16][NH:8][CH2:7][CH2:6][N:5]1[CH2:19][CH2:20][N:21]1[C:22](=[O:31])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]1=[O:30]
Reactant: O=C(CCl)N(CCN1C(=O)c2ccccc2C1=O)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: O=C1CNCCN1CCN1C(=O)c2ccccc2C1=O
Reaction time: 12 h
Yield: 34.4 %

Procedure:
To a solution of 2-chloro-N,N-bis[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]acetamide (2 g, 4.55 mmol) in EtOH (230 mL) was added hydrazine hydrate (213 μL, 6.83 mmol). After 12 h at 85° C., the solution was concentrated and the residue purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound (428 mg, 34%) as a yellow foam: LCMS (ES) m/e 274 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:45])=[C:15]([C:19]2[N:20]=[C:21]([C:31]3([CH3:44])[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]=[C:21]([C:31]3([CH3:44])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=2)[C:14]=1[F:45])(=[O:10])=[O:11]
Reactant: Cc1nccc(-c2sc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccc(-c2sc(C3(C)CCNCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (72 mg, 0.109 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to obtain the title compound (38 mg). MS (ESI): 560.0 [M+1]+.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[CH:29]([NH:31][C@H:32]([C:37](O)=[O:38])[CH2:33][CH2:34][S:35][CH3:36])=[O:30]>>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][S:18][C:37](=[O:38])[CH:32]([NH:31][CH:29]=[O:30])[CH2:33][CH2:34][S:35][CH3:36])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Reactant: CSCC[C@H](NC=O)C(=O)O
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 24.5 %

Procedure:
The title compound (0.34 gm) was prepared from 9-fluoro-11β,17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-thiol (1.00 gm) and N-formyl-L-methionine (1.30 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.S(Cl)(Cl)=O.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>C(Cl)Cl>[OH:23][CH2:22][C:21]([NH:20][C:7]([C:2]1[C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])([CH3:25])[CH3:24]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(CO)NC(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
6 Parts of biphenyl-2-carboxylic acid is added to 15 parts by volume of thionyl chloride and the mixture is stirred at ambient temperature for about 22 hours. The thionyl chloride is distilled off under reduced pressure, then benzene is added and distilled off under reduced pressure leaving an oil. The oil is dissolved in 15 parts by volume of methylene chloride and added dropwise with stirring to a solution of 5.5 parts of 2-amino-2-methylpropanol in 15 parts by volume of methylene chloride at 0° C. The resultant mixture is stirred at ambient temperature overnight, filtered and the filtrate washed with water, twice with 25 parts by volume of 5% hydrochloric acid, twice with 25 parts by volume of 5% sodium hydroxide, and water. The filtrate is then dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure to give N-(2-hydroxy-1,1-dimethylethyl)-2-biphenylcarboxamide, as white crystals, melting at about 72.5°-74° C. after recrystallization from ether.
Reaction SMILES: [CH:1](=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:11]/1([CH3:12])[CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:13])\[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.CCCCCCC>[CH3:2][C@@H:1]1[O:22][C@@:3]21[C@:11]1([CH3:12])[C@H:6]([C@@H:7]([OH:13])[CH2:8][CH2:9][CH2:10]1)[CH2:5][CH2:4]2
Reactant: C/C=C1/CC[C@H]2[C@@H](O)CCC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H]1O[C@@]12CC[C@H]1[C@@H](O)CCC[C@@]12C
Temperature: 4.400000095367432 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
(Z,3aR,4S,7aS)-1-ethylidene-octahydro-7a-methyl-1H-indene-4-ol (Compound 6: 663.1 mg, 3.18 mmol) synthesized in accordance with the method described in J. Org. Chem. 2001, 66, 626-628 was dissolved in ethyl acetate (3.1 ml), and the solution was cooled to 4.4° C. Meta-chloroperbenzoic acid (913 mg, 3.44 mmol) was added to the reaction solution over 9 minutes. After stirring the reaction solution at 2° C. for 1 hour, aqueous sodium hydrogen carbonate solution (2 ml) and aqueous sodium sulfite solution (1 ml) were added thereto, and the mixed solution was stirred and separated. The obtained organic layer was washed with aqueous sodium hydrogen carbonate solution (2 ml) and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. To the obtained reaction mixture, seed crystals were added, and heptane (1.8 ml) was added thereto, followed by collecting the precipitated crystals by filtration to obtain (1R,3aR,4S,7aS,3′S)-3′,7a-dimethyl-4-hydroxyoctahydrospiro(indene-1,2′-oxirane) (382.8 mg, 61%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])=[CH:18][N:17]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reactant: NN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCOCC1)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added 4-aminomorpholine (31 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4) and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (41 mg, 47%) as a colorless oil. MS: m/e=412.2 [M+H]+.
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:17])[O:13][CH2:14][CH2:15][NH2:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[C:1]1([NH:11][C:12](=[O:17])[O:13][CH2:14][CH2:15][NH:16][S:28]([CH:27]=[CH2:26])(=[O:30])=[O:29])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCCOC(=O)Nc1cccc2ccccc12
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCCOC(=O)Nc1cccc2ccccc12

Procedure:
To a solution of 2-aminoethyl N-(1-naphthyl)carbamate [2.30 g(10.0 mmol.)] and triethylamine [1.53 ml(11.0 mmol.)] in chloroform(20 ml) was added, while stirring under ice-cooling, 2-chloroethanesulfonyl chloride [1.06 ml(10.0 mmol.)]. The mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was washed with a 1N aqueous solution of sodium hydroxide, and dried, followed by distilling off the solvent under reduced pressure. The residue was subjected to a silica gel colum chromatography, eluting with hexane-ethyl acetate(1:1) to obtain the compound(270) [1.50 g(46.9%)] as a yellow oily product.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.Cl[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][CH2:28][OH:29].C(Cl)[Cl:34]>>[Cl:34][C:32]1[CH:31]=[CH:30][C:26]([CH2:27][CH:28]=[O:29])=[CH:25][CH:24]=1
Reactant: OCCc1cccc(Cl)c1
Reactant: ClCCl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: O=CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Dess-Martin periodinane (1.02 g, 2.4 mmol) was diluted in anhydrous CH2Cl2 (25 mL) under argon, and when solution was affected, 4-chlorophenethyl alcohol (33, 0.313 g, 2 mmol) was added dropwise. The mixture was stirred for 2 h and 15 min at room temperature, and was then quenched by addition of 20 mL sat. aq. Na2S2O3. After stirring at room temperature for 15 min, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with H2O and sat. aq. NaCl (50 mL each) and was dried over anhydrous sodium sulfate and concentrated. The resulting semisolid residue was triturated with 10% EtOAc in hexanes, and the solid was filtered and discarded. The filtrate was concentrated, and the oily residue was purified by flash column chromatography (SiO2), eluting with a gradient of hexanes to 15% EtOAc in hexanes to afford the title compound as a clear yellow volatile oil (0.211 g, 88%). 1H-NMR (500 MHz; CDCl3): δ 9.75 (t, J=2.1 Hz, 1 H), 7.34 (d, J=8.3 Hz, 2 H), 7.15 (d, J=8.2 Hz, 2 H), 3.69 (d, J=2.0 Hz, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[C:36](Cl)[N:35]=[N:34][C:33]=2[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:36]2[N:35]=[N:34][C:33]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:31][CH:30]=3)[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.13 mmol, 240 mg) in THF (10 mL) at room temperature was added NaH (100 mg, 4.5 mmol). Stirring continued for 10 min then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.56 mmol, 200 mg) was added. The resulting mixture was stirred at 50-55° C. over night, then was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified by flash silica gel column chromatography using 30% ethyl acetate in hexanes to provide 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[S:27][C:10]2[CH2:11][CH2:12][CH:13]3[C:18]([C:9]=2[CH:8]=1)=[N:17][N:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:15](=[O:26])[CH2:14]3)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][CH2:5][CH2:6][C:7]1[S:27][C:10]2[CH2:11][CH2:12][CH:13]3[C:18]([C:9]=2[CH:8]=1)=[N:17][N:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)[C:15](=[O:26])[CH2:14]3
Reactant: CC(=O)OCCc1cc2c(s1)CCC1CC(=O)N(c3ccc(C)cc3)N=C21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(N2N=C3c4cc(CCO)sc4CCC3CC2=O)cc1
Yield: 97.4 %

Procedure:
To a suspension of 1.5 g of 8-(2-acetoxyethyl) -4,4a, 5,6-tetrahydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one in 50 ml of methanol was added 5 ml of aqueous solution of 0.7 g of potassium carbonate under ice-cooling. The mixture was stirred for an hour, and poured into water and then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting solid was recrystallized from a mixed solvent of chloroform and ethanol to give 1.3 g of 4,4a,5,6-tetrahydro-8-(2-hydroxy-ethyl)-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one as a white powder, melting at 159°-160° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:17])([F:16])[CH2:8][CH2:9][O:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:18](=O)(O)[O-:19].[Na+]>CN(C)C=O>[F:17][C:7]([F:6])([F:16])[CH2:8][CH2:9][O:10][C:11]1[S:12][C:13]([CH:18]=[O:19])=[CH:14][CH:15]=1
Reactant: FC(F)(F)CCOc1cccs1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(OCCC(F)(F)F)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
To 8 mL dimethylformamide at room temperature was added phosphorous oxychloride (4.0 mL, 43.33 mmol) dropwise. After stirring for 10 minutes at room temperature, 2-(3,3,3-trifluoropropoxyl)thiophene (1.70 g, 8.67 mmol) as a solution in 8 mL dimethylformamide. The resulting solution was heated to 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was poured into 100 mL of ice-water and stirred vigorously for 5 minutes. Sodium bicarbonate (11 g) was added carefully and the mixture stirred until homogeneous. Organics were extracted with ether (3×100 mL), washed with water (3×50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (0-20% ethyl acetate in hexanes) to give 5-(3,3,3-trifluoropropoxyl)thiophene-2-carbaldehyde (761 mg, 39%) as an off-white solid. Used without further characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([NH:20][C:21]([C:23]2([CH3:26])[CH2:25][O:24]2)=[O:22])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:26][C:23]([OH:24])([CH3:25])[C:21]([NH:20][C:13]2[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[C:11]([CH3:10])[CH:12]=2)=[O:22])=[CH:3][CH:4]=1)#[N:7]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(N)cc1
Product: Cc1cc(NC(=O)C(C)(O)CNc2ccc(C#N)cc2)ccc1[N+](=O)[O-]

Procedure:
3-(4-Cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 52 starting from 4-aminobenzonitrile and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-5% methanol). 1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.52 (3H, s), 3.25 (1H, dd, J=13.5 Hz, J=5.3 Hz), 3.52 (1H, dd, J=13.5 Hz, J=7.0 Hz), 6.08 (1H, s), 6.53 (1H, m), 6.75 (2H, d, J=8.8 Hz)), 7.39 (2H, d, J=8.8 Hz), 7.79-7.83 (2H, m), 8.01 (1H, d, J=8.9 Hz), 10.02 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:22](=[O:23])[C:20](=[O:21])[C:5]2[C@@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C@@:7]3([O:13][CH3:14])[C@H:11]4[NH:12][C@H:10]4[CH2:9][N:8]3[C:4]=2[C:3]=1[OH:24].[CH3:25]NN=NC1C=CC(C)=CC=1>>[CH3:1][C:2]1[C:3](=[O:24])[C:4]2[N:8]3[C@@:7]([O:13][CH3:14])([C@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C:5]=2[C:20](=[O:21])[C:22]=1[O:23][CH3:25])[C@H:11]1[NH:12][C@H:10]1[CH2:9]3
Reactant: CNN=Nc1ccc(C)cc1
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(O)=C(C)C(=O)C3=O)N1C[C@@H]1N[C@@H]12
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:
7-Hydroxy-9a-methoxymitosane was alkylated with 3-methyl-1-p-tolyltriazene to give mitomycin A or with diazodiphenylmethane to give 7-(diphenylmethyl)oxy-9a-methoxymitosane (hereinafter 7-ODPM mitomycin).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.Cl.[NH2:23][C:24]1[C:39]([Cl:40])=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:29])=[C:26]([O:41][CH3:42])[CH:25]=1.O>CN(C)C=O>[ClH:20].[NH2:23][C:24]1[C:39]([Cl:40])=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([CH2:19][CH2:18][CH2:17][CH2:16][S:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)(=[O:14])=[O:15])[CH2:36][CH2:37]2)=[O:29])=[C:26]([O:41][CH3:42])[CH:25]=1
Reactant: O=S(=O)(CCCCCl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Reaction time: 7.5 h
Yield: 13.4 %

Procedure:
Potassium carbonate (0.87 g) and 4-phenylsulfonylbutyl chloride (0.40 g) were added to a solution (15 ml) of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.52 g) in dimethylformamide, and the mixture was stirred at 70°-80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained oil was treated with hydrochloric acid-ethanol and the obtained crystals were recrystallized from ethyl acetate to give 0.10 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-phenylsulfonylbutyl)piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([F:48])=[CH:44][CH:45]=[C:46]([F:47])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1c(F)ccc(F)c1F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)ccc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 332. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.81 (s, 1H), 7.63-7.51 (m, 3H), 7.31-7.23 (m, 1H), 4.79 (dd, J=10.7, 3.5 Hz, 1H), 4.46-4.29 (m, 2H), 4.24-4.11 (m, 1H), 4.09-3.92 (m, 1H), 3.75 (s, 3H), 2.08-2.00 (m, 1H), 1.84-1.75 (m, 1H), 1.74-1.66 (m, 2H). LCMS (ES+) m/z 485 (M+1).