Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1([O:38][CH3:39])[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.Cl>O1CCOCC1>[CH3:39][O:38][C:25]1([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:22])[F:23])=[CH:20][C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:48])[F:47])[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of tert-butyl 4-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-4-methoxypiperidine-1-carboxylate (321 mg; 0.461 mmol) in 1,4-dioxane (2.5 mL) was added 4.0M hydrogen chloride in 1,4-dioxane (0.5 mL; 2 mmol). The reaction was stirred at room temperature for 2 hours. 4.0M hydrogen chloride in 1,4-dioxane (1.5 mL; 6 mmol) was added and stirred for 1 hour. 4.0M hydrogen chloride in 1,4-dioxane (1.5 mL; 6 mmol) was added and stirred for 1 hour. The solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue and was concentrated under reduced pressure. Isopropyl ether was added and let sit for 16 hours. The solvent was evaporated under reduced pressure to give a white solid. The white solid was triturated with isopropyl ether and filtered off to give 254 mg (87.1% yield) of a white solid. MS (ES+): Calc: 596.4, Found: 597.4 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (s, 2H), 7.87 (s, 1H), 7.59 (d, J=8.30 Hz, 1H), 7.54(d, J=7.88 Hz, 1H), 7.45 (s, 1H), 5.14 (s, 2H), 4.96 (s, 2H), 4.19 (s, 3H), 3.35 (m, 4H), 3.03 (s, 3H), 2.56(d, J=12.86 Hz, 2H), 2.14 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:16]([NH:23][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: COc1cccc(C2CCCC(=O)C2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1cccc(C2CCCC(NCc3ccccc3)C2)c1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
3-(3-Methoxyphenyl)cyclohexanone (13.1 g), benzylamine (6.88 g) and p-toluenesulfonic acid (1.22 g) were refluxed for 1.5 hours in benzene (200 ml) using a Dean-Stark apparatus while removing the water generated. After concentrating the reaction solution under reduced pressure, methanol (200 ml) was added and upon adding sodium borohydride (2.43 g) gradually under ice cooling, the mixture was stirred at room temperature for an hour. After concentrating the reaction solution under reduced pressure, water was added and extraction was performed with chloroform. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried with anhydrous magnesium sulfate. The crude product obtained from distilling off the solvent under reduced pressure was separated and purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to give 15.8 g of N-benzyl-N-[3-(3-methoxyphenyl) cyclohexyl]amine as a diastereomeric mixture (83.4% yield). Repeated silica gel column chromatography (n-hexane:ethyl acetate=5:1) allowed separation of the two diastereomers, with the trans form obtained from the earlier eluted fraction and the cis form obtained from the later eluted fraction.
Reaction SMILES: C(O)C.Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=3)[N:12]=[CH:13][C:6]=12.[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][NH2:29].C(OC(C)C)(C)C>C(#N)C>[CH3:21][C:16]1[CH:15]=[C:14]([N:11]2[C:7]3=[N:8][CH:9]=[N:10][C:5]([NH:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH3:22])=[C:6]3[CH:13]=[N:12]2)[CH:19]=[C:18]([CH3:20])[CH:17]=1
Reactant: Cc1cc(C)cc(-n2ncc3c(Cl)ncnc32)c1
Reactant: COCCOCCN
Solvent: CCO
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: COCCOCCNc1ncnc2c1cnn2-c1cc(C)cc(C)c1
Temperature: 27.5 °C
Yield: 56.8 %

Procedure:
60.0 ml of ethanol and 10.0 g (0.038 mol) of 4-chloro-1-(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound No. 79) were charged into a 250 ml of 4 necked round bottom flask connected to a mechanical stirrer, thermometer socket, condenser and addition funnel. 22.40 g (0.18 mol) of 2-(2-Methoxy-ethoxy)-ethyl amine was charged at 25-30° C. under stirring. Reaction mass temperature was raised to reflux. Maintained the mass temperature at reflux for 5 hours. Reaction mass temperature was cooled to 25-30° C. Maintained the mass temperature at 25-30° C. for 60 min. Reaction mass temperature cooled to 0-5° C. Maintained the mass temperature at 0-5° C. for 60 min. Solid does not formed. Distilled off Ethanol completely under vacuum. Crude oily mass was obtained. Oily mass was dissolved in 45 ml of acetonitrile. 300.0 ml of isopropyl ether was added. Solid was formed. Solid was filtered and solid was washed with 50.0 ml of isopropyl ether. Compound was dried under vacuum at 60-65° C. Dry weight of the compound: 7.50 g (yield—56.80%). Melting point: 90.4° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:36])[CH3:35]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:31])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical Product: m.p. 261°-263° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.ClS([N:32]=[C:33]=[O:34])(=O)=O.[OH-].[Na+]>[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[C:33]([NH2:32])=[O:34]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C(N)=O)c2cc(F)ccc21
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (300 mg, 0.82 mmol) in 2-Me-THF (7 mL) is treated with chlorosulfonyl isocyanate (CSI) (85 uL, 2.0 mmol) at 0° C., and the mixture is warmed to rt for 2 h. The mixture is then cooled to 0° C., treated with 1 M NaOH (1 mL), diluted with brine (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo to afford 5-fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indole-3-carboxylic acid amide (275 mg, 83%). MS: 408 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.35 (d, 1H), 8.26 (s, 1H), 8.20 (d, 1H), 7.95 (d, 1H), 7.59 (m, 3H), 7.15 (m, 1H), 2.78 (s, 3H). IC50=8 nM.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH:39]([C:51]#[N:52])[C:40]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])=C)[CH2:19][C@H:20]([N:23]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=C)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:32]([O:31][N:23]([C:24]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:30])[C@H:20]1[CH2:19][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[CH:39]([C:51]#[N:52])[C:40]([CH2:42][O:43][Si:44]([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:46])[CH3:45])=[CH:21]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C=C[C@H](CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C#N)C(=C)CO[Si](C)(C)C(C)(C)C)N(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(OCc1ccccc1)[C@@H]1C=C(CO[Si](C)(C)C(C)(C)C)C(C#N)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 90 °C
Yield: 40.7 %

Procedure:
A solution of tert-butyl ((2R)-1-((((9H-fluoren-9-yl)methoxy)carbonyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-1-cyanoallyl)amino)but-3-en-2-yl)(benzyloxy)carbamate (Intermediate 159, 3.32 g, 4.59 mmol) in toluene (150 mL) was bubbled with nitrogen for 15 minutes. Hoveyda-Grubbs Catalyst 2nd Generation (0.288 g, 0.46 mmol) was added and the mixture was bubbled with nitrogen for an additional 15 minutes. The resulting solution was heated under nitrogen at 90° C. for 2 days. The reaction mixture was evaporated. The residue was purified on silica gel column (0-30% EtOAc/hexane) to afford the title compound (1.300 g, 40.7%) as a light brown film.
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-l-p-tolyltriazene to give mitomycin A or with diazodiphenylmethane to give 7-(diphenylmethyl)oxy-9a-methoxymitosane (hereinafter 7-ODPM mitomycin).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[I-:17].[Na+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][I:17]
Reactant: [I-]
Reactant: COC(=O)CCCCCCCCCCCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCCCCCI
Yield: 97 %

Procedure:
12-Bromododecanoic acid methyl ester (5.65 g, 19.3 mmol) was dissolved in acetone (50 ml). Sodium iodide (14.4 g, 96 mmol) was added and the reaction was refluxed under nitrogen for 20 h. The sample was concentrated under vacuum. Water (100 ml) was added, and the mixture was extracted with AcOEt (2×100 ml). The organic extracts were pooled and washed with water plus a small amount of sat. NaCl and sat. NaCl (100 ml each), dried over MgSO4, and concentrated to yield a light yellow oil (6.37 g, 97%).
Reaction SMILES: [CH3:1][C@H:2]1[N:8]2[C:9]3[CH:10]=[C:11]([C:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=3[CH:15]=[C:7]2[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C@H:2]1[N:8]2[C:9]3[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[CH:12]=[CH:13][C:14]=3[CH:15]=[C:7]2[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1
Reactant: C[C@@H]1CCNC(=O)c2cc3ccc(C(=O)[O-])cc3n21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CCNC(=O)c2cc3ccc(C(=O)O)cc3n21
Yield: 57.3 %

Procedure:
To a solution of (5R)-5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (3.65 g, crude) in ethanol (30 mL) is added 1M NaOH solution (13.8 mL, 13.8 mmol). The reaction mixture is refluxed for 2 h. The reaction mixture is acidified with 1M HCl and ethanol is removed under vacuum. The resulting solid is collected by filtration, is washed with water and dried to afford the title compound (2.1 g, 41% for 3 steps) as a solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:16]=[C:15]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][C:27]=3[F:38])[CH:14]=2)=[CH:11][CH:12]=1)=O)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[N:34]1([C:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][C:15]3[CH:14]=[C:13]([C:10]4[NH:9][C:8]([C:6]5[O:3][C:1]([CH3:2])=[N:4][N:5]=5)=[CH:12][CH:11]=4)[CH:18]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:16]=3)=[C:27]([F:38])[CH:28]=2)=[O:33])[CH2:35][CH2:36][CH2:37]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NNC(C)=O)[nH]2)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(-c3nnc(C)o3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
N′-Acetyl-5-{3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carbohydrazide (86 mg, 0.16 mmol) synthesized in Example (66h) was dissolved in dichloromethane (5 mL), and triethylamine (0.1 mL, 0.72 mmol) and p-toluenesulfonic acid chloride (69 mg, 0.36 mmol) were added, followed by stirring at room temperature overnight. The reaction solution was diluted with dichloromethane (60 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-100%) to afford the desired product (57 mg, yield 69%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[C:23]([F:22])([F:32])[F:33]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccccc1C(F)(F)F
Product: O=C(C=Cc1ccccc1C(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 2-(trifluoromethyl)benzaldehyde (83 ul, 0.633 mmol) similar to Example 6 and isolated as a pale white-yellow solid (26 mg, 9%). 1H NMR (CDCl3): 8.02 (d, J=16.5 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.62-7.47 (m, 2H), 7.39 (d, J=15.6 Hz, 1H), 7.29 (d, J=3.3 Hz, 1H), 7.14 (dd, J=3.2, 8.9 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH2:45][C:46]5[CH2:51][CH2:50][C:49]([CH3:53])([CH3:52])[CH2:48][C:47]=5[C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=5)[CH2:41][CH2:40]4)[CH:36]=[CH:35][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[O:61]1[CH2:64][C:63](=O)[CH2:62]1.C([BH3-])#N>O1CCCC1.C(O)(=O)C>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([C:47]2[CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][CH2:51][C:46]=2[CH2:45][N:42]2[CH2:41][CH2:40][N:39]([C:37]3[CH:36]=[CH:35][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH:26]5[CH2:31][CH2:30][N:29]([CH:63]6[CH2:64][O:61][CH2:62]6)[CH2:28][CH2:27]5)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:38]=3)[CH2:44][CH2:43]2)=[CH:59][CH:58]=1
Reactant: O=C1COC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(C6COC6)CC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 139B (120 mg) in tetrahydrofuran (3 mL) and acetic acid (1 mL) was added oxetan-3-one (50.8 mg) and MP-cyanoborohydride (2.15 mmol/g, 150 mg). The mixture was stirred at room temperature overnight. The mixture was filtered. The filtrate was concentrated and the residue was loaded on a silica gel cartridge and eluted with 5-10% 7N NH3 in methanol in dichloromethane to give the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.62 (s, 1H), 8.51 (d, 1H), 8.20 (d, 1H), 7.99 (d, 1H), 7.74 (m, 1H), 7.48 (m, 3H), 7.35 (d, 2H), 7.05 (d, 2H), 6.66 (dd, 1H), 6.36 (dd, 1H), 6.20 (d, 1H), 4.54 (t, 2H), 4.43 (t, 2H), 3.66 (m, 1H), 3.44 (m, 3H), 3.04 (m, 5H), 2.73 (s, 2H), 2.61 (m, 2H), 2.12 (m, 11H), 1.61 (m, 2H), 1.38 (t, 2H), 0.93 (m, 6H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:24]4=[C:25]([C:27](=[O:30])[CH:28]=[CH:29][N:23]4[C:22]4[CH:21]=[CH:20][C:19]([Br:31])=[CH:18][C:17]3=4)[CH:26]=2)[CH:9]=[N:10][CH:11]=1)(=O)C.[OH-].[Na+]>CO.O>[Br:31][C:19]1[CH:20]=[CH:21][C:22]2[N:23]3[CH:29]=[CH:28][C:27](=[O:30])[C:25]4[CH:26]=[C:14]([O:13][CH2:12][C:8]5[CH:9]=[N:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=5)[CH:15]=[C:16]([C:17]=2[CH:18]=1)[C:24]3=4
Reactant: CC(=O)OCc1cncc(COc2cc3c(=O)ccn4c5ccc(Br)cc5c(c2)c34)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1ccn2c3ccc(Br)cc3c3cc(OCc4cncc(CO)c4)cc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
2-(5-acetoxymethyl-3-pyridylmethyloxy)-10-bromo-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 69 was suspended in methanol (12 ml), and a solution of sodium hydroxide (100 mg) in water (0.8 ml) was added to the suspension. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were washed with methanol and ether in succession, and recovered by filtration to obtain the title compound (170 mg, 93%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O>C1(C)C=CC=CC=1>[CH:1]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=CN[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Into a 500 ml four-necked flask with a stirrer, a dropping funnel, a Dimroth condenser, and a thermometer, 112.5 g (1.10 mol) of acetic anhydride were introduced, and 30 g (0.65 mol) of formic acid were added dropwise thereto while stirring at room temperature. After stirring was performed at room temperature for 2 hours, 66.5 g (0.5 mol) of L-aspartic acid with an optical purity of 99.5% e.e. were added thereto, the temperature was increased to 60 to 70° C., and stirring was performed for 10 hours. The temperature was decreased to room temperature while stirring, and 80 g of toluene were further added thereto, followed by stirring. The precipitated crystal was subjected to filtration under reduced pressure and was rinsed with 10 g of toluene. The crystal was subjected to vacuum drying, and thus 60.1 g of N-formyl-L-aspartic anhydride was obtained. The chemical purity was 99%, and the optical purity was 99% e.e. or more.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C=O.[CH3:13]C(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:13][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tetrahydroquinoline (4.0 g, 30.0 mmol) in MeOH (60 mL) was added CH2O (37% aqueous solution, 2.7 mL, 36.3 mmol, 1.2 eq) and HOAc (1.73 mL, 30.0 mmol, 1.0 eq). The mixture was stirred at room temperature for 10 min then was cooled to 0° C. before NaBH3CN (1.98 g, 31.5 mmol, 1.05 eq) was added. After 1 h, the solvent was removed under reduced pressure. The reaction was quenched with saturated aqueous NaHCO3 then extracted with CH2Cl2 (5×30 mL). The combined organic layers were dried over Na2SO4 then concentrated to give a crude product which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)CCCCC(Cl)=[O:15].[OH-].[Na+:20]>>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:8])=[O:15].[Na+:20]
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: O=C1CCCCCN1
Agent: [Na+]
Agent: [OH-]
Product: NCCCCCC(=O)[O-]
Yield: 70 %

Procedure:
The literature has described various syntheses for TOCAP and related compounds. German Patent 949,568 (Kruckenberg) describes the reaction of caprolactam with various acyl halides including adipoyl dichloride in the presence of sodium hydroxide. Once sodium 6-aminocaproate has formed, the reactor is charged with a first portion acyl halide, sodium hydroxide and then a final portion acyl halide. Example 1 best details this process. Synthesis of TOCAP is reported by Zinner et al in J. Prakt. Chem. 17, 147-153 (1962). The procedure requires the addition of all the sodium hydroxide to be charged to the reaction vessel at the beginning of the synthesis. The reported yield is 70% of theory. Plate-like crystals are recovered through recrystallization from dimethyl formamide/water (2:5).