Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[S:28][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:31][CH2:32][N:33]([C:9]([NH:8][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH3:7])=[O:16])[CH2:34][CH2:35]2)[S:28][CH:29]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: Clc1ccc(-c2csc(N3CCNCC3)n2)c(Cl)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccc(Cl)cc4Cl)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (201 mg, 0.700 mmol), 1-[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.636 mmol) and diisopropylethylamine (0.222 ml, 1.27 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 116 mg (40.3%) of the desired product as a solid.
Reaction SMILES: [OH2:1].[H-].[Na+].[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)([O:6][C:7]([CH3:10])(C)C)=[O:5]>CCOC(C)=O.C(Cl)Cl>[C:4]([NH:11][C@H:12]([C:4]([OH:6])=[O:5])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:1])=[CH:18][CH:19]=1)([O:6][CH2:7][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: O
Reactant: CC(C)(C)OC(=O)NCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reaction time: 16 h

Procedure:
H2O (1.5 g, 4.29 mmole) was dissolved in EtOAc/CH2Cl2, dried over MgSO4, filtered and evaporated. The residue was dissolved in DMF and treated with NaH (50% dispersion in oil, 0.43 g, 8.96 mmole) for 1 hour. N-BOC-8-amino-1-bromooctane (1.33 g, 4.34 mmole) was added and the reaction was stirred for 16 hours. The DMF was removed in vacuo, the residue dissolved in water, acidified to pH 3 and extracted with EtOAc. The EtOAc layers were combined, dried and concentrated. Column chromatography (SiO2, 97:3:1 CHCl3 /MeOH/HOAc) gave 2-5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH3:8][S:9]([O:12][CH2:13][CH2:14][S:15][S:16][CH2:17][CH2:18]OS(C)(=O)=O)(=[O:11])=[O:10].C(O[CH2:28][CH3:29])(=O)C>CN1CCCC1=O>[CH3:8][S:9]([O-:12])(=[O:11])=[O:10].[CH3:8][S:9]([O-:12])(=[O:11])=[O:10].[S:16]([CH2:17][CH2:18][N+:1]1[CH:6]=[CH:5][C:28]([CH3:29])=[CH:3][CH:2]=1)[S:15][CH2:14][CH2:13][N+:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccncc1
Reactant: CS(=O)(=O)OCCSSCCOS(C)(=O)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)[O-]
Product: Cc1cc[n+](CCSSCC[n+]2ccc(C)cc2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3.51 g of 4-picoline and 5 g of disulfanediyldiethane-2,1-diyl dimethanesulfonate are diluted in 5 mL of N-methylpyrrolidinone (NMP) and then heated at 80° C. with stirring for 2 hours. Stirring is continued at room temperature for 17 hours. The reaction medium is made up with 50 mL of ethyl acetate and then filtered, washed with three times 100 mL of EtOAC and dried under vacuum over P2O5. 7.29 g of brown powder are collected. The analyses indicate that the product is in accordance and pure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[CH3:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7]([NH:31][CH3:30])=[O:27])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: CN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.1 %

Procedure:
To a solution of the benzoxazinone product of Example 6, Step D (4.50 g, 10.18 mmol) in tetrahydrofuran (THF; 70 mL) was added methylamine (2.0 M solution in THF, 15 mL, 30.0 mmol) dropwise and the reaction mixture was stirred at room temperature for 5 minutes. The tetrahydrofuran solvent was evaporated under reduced pressure and the residual solid wag purified by chromatography on silica gel to afford 4.09 g of the title compound, a compound of the present invention, as a white solid melting at 185-186° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1Cl.[CH3:12][O-:13].[Na+]>CO>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1[O:13][CH3:12]
Reactant: C[O-]
Reactant: CCn1ncc(Cl)c(Cl)c1=O
Agent: [Na+]
Solvent: CO
Product: CCn1ncc(OC)c(Cl)c1=O

Procedure:
The title compound, white crystalline solid, was prepared in accordance with the general method of example 23e by treatment of 4,5-dichloro-2-ethyl-2H-pyridazin-3-one with sodium methoxide in methanol.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1O)[CH:27]=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:20][C@H:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:27]=[O:28]
Reactant: CCCC[C@@H](O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: O=Cc1ccc(O)c(Cl)c1
Product: CCCC[C@H](Oc1ccc(C=O)cc1Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 19.7 %

Procedure:
Prepared according to the procedure used to prepare Intermediate 103 from (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (208 mg, 0.67 mmol) and 3-chloro-4-hydroxybenzaldehyde (141, 0.90 mmol) to afford the title compound (59 mg).
Reaction SMILES: [CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.Cl[CH2:41][CH2:42][N:43]([CH3:45])[CH3:44].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[CH3:44][N:43]([CH3:45])[CH2:42][CH2:41][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:38][C:6]=3[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[C:8]2=[O:22])=[CH:20][CH:19]=1
Reactant: CN(C)CCCl
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(O)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OCCN(C)C)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 60 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
To a mixture of 4′-{[6-ethyl-3-[2-(4-hydroxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile, 2-chloro-N,N-dimethylethanamine hydrochloride (0.62 g) and N,N-dimethylformamide (7 mL) was added cesium carbonate (2.8 g), and the mixture was stirred at 60° C. for 12 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.41 g, 48%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1([CH2:17][CH2:18]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH2:18][CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][C:31]=3[C:5]=2[CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN1CCC(=O)CC1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccccc2)C1
Yield: 1.7 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. 4-Chlorophenylhydrazine hydrochloride (500 mg, 2.79 mmol), 2-phenyl ethyl bromide (0.38 ml, 2.79 mmol), triethyl amine (0.39 ml, 2.79 mmol) and N-methyl-4-piperidone hydrochloride (623 mg, 4.18 mmol) were combined in ethanol (2 ml) to obtain 15 mg of 8-chloro-2,3,4,5-tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole as a trifluoroacetate salt after purification on neutral alumina using ethyl acetate-hexane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH:1]([OH:3])=O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.Cl.[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]2[CH2:39][CH2:40][CH2:41][CH:42]([NH2:43])[C:31]=12.O>O1CCCC1>[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]2[CH2:39][CH2:40][CH2:41][CH:42]([NH:43][CH:1]=[O:3])[C:31]=12
Reactant: O=CO
Reactant: Cc1c2n(c3ccccc13)CCCC2N
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2n(c3ccccc13)CCCC2NC=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of formic acid (b 6 mL) and acetic anhyride (12 mL) was heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-amine hydrochloride (7.5 g, 37.5 mmol), in dry tetrahydrofuran (60 mL) was added upon cooling to the resultant mixed anhydride. The reaction mixture was stirred at 25° C. for 2 hours, poured into water (150 mL) and extracted with ether (3×100 mL). The combined extracts were washed successively with 5% hydrochloric acid, 5% sodium bicarbonate, and water. The ethereal solution was dried over MgSO4, filtered, and evaporated. The solid residue was crystallized from benzene/hexane to give 8.5 g (99%) of the title formamide as a yellow solid, m.p. 133°-5° C. Analytical sample melted at 136° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:25]Br>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Clc1cc(Cl)cc(CBr)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Cl)cc(Cl)c2)c1
Yield: 55.6 %

Procedure:
5-isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (250 mg, yield: 55.6%).
Reaction SMILES: [NH3:1].[C:2]1([C:7]([C:9]2[CH:19]=[CH:18][C:12]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:11][CH:10]=2)=[O:8])[S:6][CH:5]=[CH:4][CH:3]=1>CCOCC>[C:2]1([C:7]([C:9]2[CH:19]=[CH:18][C:12]([CH:13]([CH3:17])[C:14]([NH2:1])=[O:15])=[CH:11][CH:10]=2)=[O:8])[S:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(C(=O)Cl)c1ccc(C(=O)c2cccs2)cc1
Solvent: CCOCC
Product: CC(C(N)=O)c1ccc(C(=O)c2cccs2)cc1

Procedure:
Gaseous ammonia is introduced through a solution of 5.8 parts of p-(2-thenoyl)hydratropoyl chloride in 80 parts of ether: the product is precipitated as an oil. The solvent is decanted and the oil is stirred twice in petroleumether. The solvent is decanted each time. The oily residue is dissolved in 2-propanol and the solvent is evaporated. The residue is dissolved in ether and upon the addition of petroleumether, the product is precipitated. It is filtered off and purified by column-chromatography over silicagel, using a mixture of chloroform, methanol and acetone (8:1:1 by volume). The pure fractions are collected and the solvent is evaporated. The oily residue is triturated in ether. The solid product is filtered off and dried, yielding p-(2-thenoyl)hydratropamide; m.p. 108°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:15].CCOC(C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N+:7]([O-:15])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C)nc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-methoxy-2-methylpyridine (15 g, 0.121 mol) in DCM (200 mL) was added 3-chloro peroxybenzoic acid (23.14 g, 0.134 mol, Aldrich). The reaction was stirred at rt for 3 h. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of reaction, the reaction mixture was concentrated under reduced pressure providing the product as a yellow oil. The oil was dissolved in EtOAc (50 mL) and passed through a silica gel plug (60-120 mesh) and the plug eluted with 10% MeOH in CHCl3 to give the title compound as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (d, J=2.4 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 6.98 (dd, J=2.7 and 8.7 Hz, 1H), 3.78 (s, 3H), 2.26 (s, 3H). MS (ESI, positive ion) m/z: 140.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:27]>ClCCl>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N+:9]2[O-:27])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccccc2)c2c1ccc[n+]2[O-]
Temperature: 27.5 °C
Reaction time: 2 h

Procedure:
5-Acetyl-8-benzyloxyquinoline (200 gms/0.72 moles) was dissolved in dichloromethane (4 liters) at room temperature. To this solution was added m-chloroperoxybenzoic acid (355.64 gms/1.44 moles) in 90 minutes under stiffing. The mixture was stirred at 25-30° C. for 2 hours. After completion of reaction, reaction mass was quenched with 8% sodium bicarbonate solution (3.04 liter) slowly in 30 minutes and stirred for 5-10 minutes at same temperature. The organic layer was separated and aqueous layer was extracted with dichloromethane (2.5 liters). The organic layers were combined and washed with brine solution (2.5 liters). The dichloromethane was distilled out under vacuum at 40° C. The residue was stripped with acetone (500 ml) to remove traces of dichloromethane. The residue was stirred with acetone (200 ml) and chilled to 0-5° C. for 2 hours. The resulting 5-Acetyl-8-benzyloxyquinoline-N-oxide was isolated by filtration and washed with diethyl ether (200 ml), dried under vacuum at 60-65° C. for 2-3 hours. Yield-116 gms.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C1C(=O)N([I:30])C(=O)C1.C(O)(=O)C>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)=[CH:11][C:12]=1[I:30]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)c(I)c2)CC1
Temperature: 25 °C

Procedure:
Sulfuric acid (0.708 mL, 13.29 mmol) was added into a cold (ice bath) mixture of methyl trans-4-(4-chlorophenyl)cyclohexanecarboxylate (3.3588 g, 13.29 mmol) and n-iodosuccinimide (2.99 g, 13.29 mmol) in acetic acid (0.798 g, 13.29 mmol). The reaction mixture was stirred in an ice bath and was allowed to warm to ambient temperature overnight. The reaction crude was poured into an ice water and extracted with EtOAc. The separated organic phase was dried over Na2SO4, filtered and evaporated to afford a dark mixture. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by a EtOAc/hexanes mixture (0% to 10%). Related fractions were pooled and evaporated to afford a crystalline solid as the titled compound. LCMS calc.=377.99. found=379.00 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]([Si](C)(C)C)([F:17])([F:16])[F:15].C1COCC1>CCOCC>[F:15][C:14]([F:17])([F:16])[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of methyl 4-acetylbenzoate (5.0 g, 28.1 mmol) and CF3SiMe3 (12.5 mL, 84.2 mmol) in THF (150 mL) TBAF (1.0 M, 78.6 mL, 78.6 mmol) was added dropwise at 0° C. The mixture was then stirred for 2.5 h at room temperature, diluted with Et2O (100 mL). The solution was washed with saturated aqueous NaHCO3, and brine, dried, and concentrated. Flash chromatography of the residue, using 2:8 EtOAc-hexane, gave methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate: 1H NMR (CDCl3) δ 8.07 (d, J=8.5 Hz, 2H), δ 7.67 (d, J=8.5 Hz, 2H), 3.93 (s, 3H), 2.70 (br, 1H), 1.80 (s, 3H); ms 249.1 (M+H+).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH3:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].[CH3:38][C:39]1[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=1[C:41]([O:43]CC)=O>O1CCCC1>[OH:43][C:41]1([C:40]2[CH:46]=[CH:47][CH:48]=[CH:49][C:39]=2[CH3:38])[CH2:36][C:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29](=[O:37])[N:28]1[CH3:27]
Reactant: CCOC(=O)c1ccccc1C
Reactant: CNC(=O)c1cccnc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1C1(O)Cc2ncccc2C(=O)N1C
Reaction time: 2 h

Procedure:
109 ml. of 1.6 M. n-butyl lithium in hexane (174.4 mmol.) were added to a solution of 24.4 ml. of diisopropylamine in 200 ml. of dry tetrahydrofuran stirred at -10°--30° C. under nitrogen. To the resulting solution of lithium diisopropylamide, 13.1 g. (87.3 mmol.) of 2-methylnicotinic acid N-methylamide (Compound XII), dissolved in 110 ml. of dry tetrahydrofuran, were added slowly at -30°--20° C. with stirring under nitrogen. Stirring under nitrogen was continued for 2 hours at -30°--20° C. Then 14.3 g. (87.2 mmol.) of freshly distilled ethyl 2-methylbenzoate dissolved in 60 ml. of dry tetrahydrofuran were slowly added at the same temperature and stirring under nitrogen was continued for a further 2 hours at the same temperature. The reaction mixture was then quenched with 150 ml. of concentrated sodium chloride solution and the reaction mixture was extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed six times with water, once with concentrated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a crude material (20.4 g.). The crude material was dissolved in ethyl acetate and filtered through silica gel. Evaporation at reduced pressure yielded 16.3 g. of material which was separated into neutral and basic components by dissolving in toluene and cold 2 N. hydrochloric acid and extracting the toluene phase twice with cold 2 N. hydrochloric acid. The three aqueous phases were combined, made basic with sodium hydroxide solution and extracted twice with methylene chloride. The methylene chloride extracts were combined, dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain the basic component (8.7 g.), i.e., the crude hydroxylactam of Formula XV.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:9]=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:7])=[CH:4][CH:3]=1.[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([S:26]([O:29][NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[C:20]1([CH3:31])[CH:21]=[CH:22][C:23]([S:26]([O-:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[NH2:30][N+:9]1[C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)ON)cc1
Reactant: O=C(c1ccc(Cl)cc1)c1cc2ccccc2cn1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: N[n+]1cc2ccccc2cc1C(=O)c1ccc(Cl)cc1
Yield: 69.4 %

Procedure:
5 g (19 millimoles) of 3-(4-chlorobenzoyl)-isoquinoline are dissolved in 10 ml of dichloromethane, then 4 g (22 millimoles) of O-(p-toluenesulfonyl)-hydroxylamine are added, and the mixture is allowed to stand for an hour. 6 g (73%) of 2-amino-3-(4-chlorobenzoyl)-isoquinolinium-p-toluene sulfonate are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[CH3:26][OH:27]>C(N)C1OC=CC=1>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:10][CH2:7][C:6]3[O:27][CH:26]=[CH:3][CH:4]=3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: CO
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: NCc1ccco1
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCc4ccco4)C3=O)N1CC1NC12
Product: NC(=O)O
Reaction time: 3 h
Yield: 42.7 %

Procedure:
To a solution of 60 mg (0.17 mmol) of mitomycin A in 8 ml of anhydrous methanol, 0.5 ml of furfurylamine was added with stirring. The progress of the reaction was periodically checked by TLC and the reaction appeared to be complete in 3 hours. The solvent was removed by evaporation under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with ethyl acetate was evaporated. Recrystallization from a mixture of chloroform and hexane gave 30 mg (42.7% yield) of the desired product as purple-colored crystals having a melting point of 62°-63° (decomposing) and providing the following analysis:
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[NH2:1][C:2]1[C:6]([NH:7][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:5][S:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: Nc1cscc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1cscc1N
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
3.06 g of 3,4-diaminothiophene were mixed with 45 ml of methylene chloride and 9 ml of triethylamine and a solution of 3.6 g of valeroyl chloride in 45 ml of methylene chloride was added at a temperature of 20° C. over one hour. The mixture was stirred for 30 minutes, followed by evaporation to dryness. After separation by chromatography (eluant: methanol/methylene chloride 5/95), 3.2 g of the expected monoamide were obtained which was crystallized from 15 ml of a 50/50 mixture of isopropyl ether and cyclohexane. The crystals were separated, washed with this mixture and dried under reduced pressure at 100° C. to obtain 2.14 g of the expected product melting at 110° C.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C[C:7](=[O:11])[C:8]([O-:10])=[O:9].[CH3:12]C(C)=O>>[C:1]([NH:5][CH:7]([OH:11])[C:8]([O:10][CH3:12])=[O:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(=O)C(=O)[O-]
Reactant: CC(C)=O
Reactant: C=CC(N)=O
Product: C=CC(=O)NC(O)C(=O)OC

Procedure:
Acrylamide (141.7 parts), methylglyoxylate (144 parts), acetone (1200 ml) and henothiazine (0.05 parts) were mixed and heated to reflux for 6 hours. After filtration and crystallization 180 parts MAG were received as confirmed by chemical analysis.