Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([N+:14]1[C:18]2[CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=[CH:22][C:17]=2[S:16][C:15]=1[CH3:29])[CH3:13].O=[C:31]1[CH2:38][C:35]([CH3:37])([CH3:36])[CH2:34][C:33]([CH3:39])=[CH:32]1.C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH2:12]([N+:14]1[C:18]2[CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=[CH:22][C:17]=2[S:16][C:15]=1[CH:29]=[C:31]1[CH2:38][C:35]([CH3:37])([CH3:36])[CH2:34][C:33]([CH3:39])=[CH:32]1)[CH3:13]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CC[n+]1c(C)sc2ccc(-c3ccccc3)cc21
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC[n+]1c(C=C2C=C(C)CC(C)(C)C2)sc2ccc(-c3ccccc3)cc21
Temperature: 25 °C

Procedure:
4.3 g of 3-ethyl-2-methyl-5-phenylbenzothiazolium paratoluene sulfonate, 2.7 ml of isophorone, 1 g of ammonium acetate and 3.4 ml of acetic acid were dissolved in 35 ml of toluene and then heated under reflux for 1.5 hours while removing water by azeotropy. After leaving the solution standing to cool to room temperature, 50 ml of water was added. The resulting solution was extracted by 50 ml of methylene chloride, the organic layer was dried over sodium sulfate, the solvent was distilled off, 30 ml of ethyl acetate was added, and 4.7 g of 3-ethyl-2-(3,5,5-trimethyl-2-cyclohexenylidene)methyl-5-phenylbenzothiazolium paratoluene sulfonate produced as a solid was collected by filtration. 4.7 g of the solid obtained and 4.2 g of 1,3-diphenyl-1,3-diazapropene were dissolved in 20 ml of acetic anhydride, the reaction solution was heated under reflux for 8 hours and then left standing to cool to room temperature, 5 g of sodium iodide and 50 ml of water were added, and the resulting solution was extracted by methylene chloride. The organic layer was dried over sodium sulfate and the solvent was distilled off to obtain 2.9 g of 3-ethyl-2-[3-(2-acetanilidoethenyl)-5,5-dimethyl-2-cyclohexenylidene]methyl-5-phenylbenzothiazolium iodide salt as a solid. 0.7 g of the solid obtained and 0.6 g of 2-methyl-3-[2-(1-naphthoxy)ethyl]-5-phenylbenzothiazolium paratoluene sulfonate were dissolved in 10 ml of pyridine at 80° C., and thereto 1 ml of triethylamine was added. The reaction solution was stirred at room temperature for 1 hour, and 30 ml of ethyl acetate was added thereto. The crude crystals produced were collected by filtration and then recrystallized from methylene chloride and isopropyl alcohol to obtain 0.2 g of Compound 39.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)(O)[O-].[Na+]>>[CH3:17][O:16][C:14](=[O:15])[CH2:13][NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1
Reactant: COC(=O)CCl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CNc1ccc(C(F)(F)F)cc1
Yield: 59.2 %

Procedure:
4-Trifluoromethylaniline (5.84 g), methyl chloroacetate (13.1 g) and sodium bicarbonate (3 g) were treated according to the method of Intermediate 5. The product was purified by FCC eluting with System B (1:3) to give the title compound (5.00 g), t.l.c. (System B, 1:3) Rf 0.32.
Reaction SMILES: C([N:3](CC)[CH:4]=[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6](=[O:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)C.[NH2:24]N>C(O)(C)C>[C:9]1([C:7]2[C:6](=[O:15])[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:4][NH:3][N:24]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(C=C(C(=O)C(=O)c1ccccc1)c1ccccc1)CC
Reactant: NN
Solvent: CC(C)O
Product: O=c1c(-c2ccccc2)c[nH]nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product solution from Example 1 was cooled to 0°C. and mixed with 20 ml. of isopropyl alcohol and 2 ml. of hydrazine. The mixture was stirred for 10 minutes, and was then warmed to room temperature and stirred for 15 hours. The product was then collected by filtration. The yield was 6.0 g. of 3,5-diphenyl-4(1H)-pyridazinone, m.p. 328°-32°C., which was identified by infrared and nuclear magnetic resonance analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH:16]=[CH:15][CH2:14][C@@H:13]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[OH-:30].[Na+].OO>O1CCCC1>[CH2:22]([O:21][C:19]([NH:18][C@@H:13]1[CH2:14][CH2:15][CH:16]([OH:30])[CH2:17][C@@H:12]1[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(N[C@H]1CC=CC[C@H]1NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC(O)CC[C@H]1NC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
cis-N1,N2-Bis(benzyloxycarbonyl)-4-cyclohexene-1,2-diamine (10 g) was dissolved in absolute tetrahydrofuran (70 ml), borane-dimethyl sulfide complex (7.4 ml) was added at 0° C., and the mixture was gradually heated to room temperature and stirred for 14 hours. Ice was added to the reaction mixture to decompose excessive borane, and a 1N aqueous solution (80 ml) of sodium hydroxide and 30% aqueous hydrogen peroxide (80 ml) were added to stir the mixture for 1 hour. The reaction mixture was extracted with ethyl acetate, and the resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=2:1) to obtain the title compound (9.2 g) as a colorless wax.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([OH:43])=[C:38](B(O)O)[CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:36]3[CH:35]=[C:34]([Cl:33])[CH:39]=[CH:38][C:37]=3[OH:43])[CH:16]=2)[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Reactant: OB(O)c1cc(Cl)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nn(C(=O)OC(C)(C)C)c2ccc(-c3cc(Cl)ccc3O)cc12
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of tert-butyl 3-[bis(tert-butoxycarbonyl)amino]-5-bromo-1H-indazole-1-carboxylate (2.97 g, 5.81 mmol) in dimethoxyethane (25 mL) was added (5-chloro-2-hydroxyphenyl)boronic acid (1.00 g, 5.81 mmol), tetrakis(triphenylphosphine)palladium (0.67 g, 0.58 mmol) and 2 M aqueous sodium carbonate (5.8 mL, 11.6 mmol). The mixture was heated at refluxed for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 30-60% gradient of ethyl acetate in hexanes to afford tert-butyl 3-[bis(tert-butoxycarbonyl)amino]-5-(5-chloro-2-hydroxyphenyl)-1H-indazole-1-carboxylate as a colorless solid in 84% yield (2.57 g): 1H NMR (300 MHz, DMSO-d6) δ8.21 (d, J=7.8 Hz, 1H), 7.62-7.59 (m, 2H), 7.46 (s, 1H), 6.90-6.86 (m, 2H), 5.33 (br s, 1H), 1.72 (s, 9H), 1.42 (s, 18H); MS (ES+) m/z 560.0 (M+1), 562.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:5]=3[C:4]=2[N:3]=1.[CH2:18]([O:20][C:21]([C:23]1[C:24]([NH2:28])=[N:25][NH:26][CH:27]=1)=[O:22])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O>[CH2:18]([O:20][C:21]([C:23]1[C:24]([NH2:28])=[N:25][N:26]([C:2]2[N:11]=[CH:10][C:9]3[CH2:8][CH2:7][C:6]4[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:5]=4[C:4]=3[N:3]=2)[CH:27]=1)=[O:22])[CH3:19]
Reactant: COc1ccc2c(c1)CCc1cnc(Cl)nc1-2
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2ncc3c(n2)-c2ccc(OC)cc2CC3)nc1N
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 54.1 %

Procedure:
A mixture of 2-Chloro-8-methoxy-5,6-dihydro-benzo[h]quinazoline (2, 5.0 g, 20.27 mM), 3-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (3.14 g, 20.27 mM), Cs2CO3 (8.59 g, 26.35 mM) in DMF (40 ml) was stirred at 100° C. for 2.5 hr then cooled to room temperature and diluted with water (400 ml). The resulting precipitate was isolated via filtration and the solid washed with water (3×50 mL) then methanol (3×30 ml). The solid was dried under reduced pressure which was comprised of a 7:3 mixture of 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester(3) and it's isomer 5-Amino-1-(5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester identical to the material prepared in preparation 6 below. The solid was then crystallized from dichloromethane (40 ml) to give the slower (TLC, EtOAc) of two isomers 3-Amino-1-(8-methoxy-5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (3, 4.0 g, 2 crops, 54% yield). ES-MS MH+ 366. The mother liquors may be purified via chromatography on silica eluting with ethyl acetate to provide the faster isomer 5-Amino-1-(5,6-dihydro-benzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: C=O.S(=O)(=O)(O)O.[CH:8]1[CH:17]=[C:16]2[C:18]([O:20][C:21](=[O:22])[C:14]3=[C:15]2[C:10](=[CH:11][C:12]([OH:23])=[CH:13]3)[CH:9]=1)=[O:19].[O:24]1[CH2:29]COC[CH2:25]1>>[CH:9]1[C:10]2[C:15]3[C:16]([C:18](=[O:19])[O:20][C:21](=[O:22])[C:14]=3[CH:13]=[C:12]3[C:11]=2[CH2:29][O:24][CH2:25][O:23]3)=[CH:17][CH:8]=1
Reactant: C1COCCO1
Reactant: O=C1OC(=O)c2cc(O)cc3cccc1c23
Agent: C=O
Agent: O=S(=O)(O)O
Product: O=C1OC(=O)c2cc3c(c4cccc1c24)COCO3
Temperature: 80 °C

Procedure:
Paraformaldehyde (16.0 g, 530.0 mmol) and concentrated sulfuric acid (80 mL) were added to a suspension of 3-hydroxy-1,8-naphthalic anhydride (10.24 g, 48.0 mmol) in dioxane (500 mL). The mixture was heated to 80° C. for 2 hours under stirring. After cooling, the reaction mixture was poured into ice water (1000 mL). The precipitate was filtered and dried to give 12.0 g of the title compound.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][N:59]1[CH2:64][CH2:63][N:62]([C:65]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[O:66])[CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][N:59]5[CH2:60][CH2:61][N:62]([C:65]([O:67][CH2:68][C:69]6[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=6)=[O:66])[CH2:63][CH2:64]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCN(C(=O)OCc3ccccc3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and benzyl 4-aminopiperazine 1-carboxylate.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([O:38][CH3:39])=[O:37])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][CH2:27][N:28]([CH3:35])[C:29](=O)[CH2:30][CH2:31][NH:32][CH3:33])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([O:38][CH3:39])=[O:37])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][CH2:27][N:28]([CH3:35])[CH2:29][CH2:30][CH2:31][NH:32][CH3:33])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCCC(=O)N(C)CCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Solvent: C1CCOC1
Product: CNCCCN(C)CCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of methyl 14-cyclohexyl-7(R,S)-{2-[methyl(N-methyl-β-alanyl)amino]ethyl}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.02 M) in THF was treated dropwise with BH3-DMS complex (2M in THF; 10 eq). The resulting solution was stirred at RT for 3 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution refluxed for 2 h. The mixture was cooled before concentrating in vacuo. The crude material was purified by FC (EtOAc/MeOH/Et3N 90:8:2) affording the product as a yellow oil (48%, over steps 8, 9). (ES+) m/z 518 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH2:35][CH2:36][S:37]([CH3:39])=[O:38])=[CH:23][N:22]=3)[C:5]=2[CH3:40])[CH2:3][CH2:2]1.OO.N(C(OCC)=O)=NC(OCC)=[O:46]>O1CCCC1>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH2:35][CH2:36][S:37]([CH3:39])(=[O:46])=[O:38])=[CH:23][N:22]=3)[C:5]=2[CH3:40])[CH2:3][CH2:2]1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: OO
Solvent: C1CCOC1
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)(=O)=O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
100 mg of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-[2-(methylsulfinyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (2-8-1, 0.176 mmol, 1.0 eq.) were suspended in 0.93 mL dry tetrahydrofuran under a nitrogen atmosphere. 90 μL hydrogen peroxide (30%, 0.879 mmol, 5.0 eq.) and 33 μL diethyl azodicarboxylate (0.211 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 50° C. for 2 hours and concentrated in vacuo. The crude product was purified by flashcromatography to provide 31.9 mg (0.05 mmol, 31%) of the analytically pure target compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([C:22]2[CH2:23][C@H:24]([C:28](O)=O)[CH2:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.O.OC1C2N=NNC=2C=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCl.O1CCCC1.CCOCC.O>[C:16]1([C:22]2[CH2:23][C@H:24]([CH2:28][N:40]3[CH2:41][CH2:42][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)[CH2:38][CH2:39]3)[CH2:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)[C@@H]1CCC=C(c2ccccc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Agent: [Al+3]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: C1=C(c2ccccc2)C[C@H](CN2CCN(c3ccccn3)CC2)CC1
Reaction time: 8 h
Yield: 32.2 %

Procedure:
Dicyclohexylcarbodiimide (0.506 g) in dichloromethane (10 mL) is added to (R)-3-phenyl-3-cyclohexenecarboxylic acid (0.414 g, Example D), 2-pyridylpiperazine (0.410 g) and hydroxybenzotriazole hydrate (0.332 g) in dichloromethane (40 mL) and stirred overnight. The mixture is filtered and evaporated. The residue is dissolved in ethyl acetate, filtered, washed with saturated sodium bicarbonate, 5% citric acid, 2N sodium carbonate, brine, dried over magnesium sulfate, filtered, and evaporated to leave a yellow solid. This solid is dissolved in tetrahydrofuran (5 mL) and added to lithium aluminum hydride (78 mg) in tetrahydrofuran (5 mL) pretreated with aluminum chloride (90 mg) in ether (5 mL) at 0° C. and stirred for 2 hours. Water (0.1 mL) and 25% sodium hydroxide (0.4 mL) are added and the mixture filtered, washed with brine, dried over magnesium sulfate, filtered, and evaporated to a yellow oil. This oil is purified by medium pressure liquid chromatography on silica gel eluting with 50% ethyl acetate in hexane to give 0.22 g of (R)-1-[(3-Phenyl-3-cyclohexen-1-yl)methyl]-4-(2-pyridinyl)piperazine as an off-white solid; mp 106°-108° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1(O)[C:18]2[C:13](=[CH:14][C:15]([C:23]([NH2:25])=[O:24])=[CH:16][C:17]=2[C:19]([F:22])([F:21])[F:20])[N:12]([CH2:26][C@H:27]2[CH2:30][C@H:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:28]2)[C:11]1=[O:36].C(=O)(O)[O-].[Na+].C(N(S(F)(F)[F:49])CC)C>>[ClH:2].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1([F:49])[C:18]2[C:13](=[CH:14][C:15]([C:23]([NH2:25])=[O:24])=[CH:16][C:17]=2[C:19]([F:20])([F:21])[F:22])[N:12]([CH2:26][C@H:27]2[CH2:28][C@H:29]([N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])[CH2:30]2)[C:11]1=[O:36]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C(N)=O)cc3C(F)(F)F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(F)(c3ccc(Cl)cc3Cl)c3c2cc(C(N)=O)cc3C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the compound of Example 1-4 (150.0 mg, 0.26 mmol) was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane (2.6 mL), and thereto was added diethylaminosulfur trifluoride (207.9 mg, 1.29 mmol) at −78° C., and the mixture was allowed to warm to room temperature and stirred for 24 hours. To the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and then purified by silica gel column chromatography (chloroform/methanol/ammonia water 20/1/0 to 10/1/0 to 100/10/1), and then by preparative liquid chromatography. To the purified substance were added tetrahydrofuran and 1M hydrochloric acid (0.5 mL), and the mixture was concentrated. The resulting solid was suspended in diethyl ether and filtered to give the titled compound (65.0 mg, 43%).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([O-:15])=[O:14])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([OH:15])=[O:14])[CH2:4][CH2:3]1
Reactant: O=C([O-])C1=Cc2ccccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2ccccc2S(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
Into a solution. of methyl 7-(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (650 mg) in THF/methanol (5/2.5 ml) was added at room temperature an aqueous solution (2.1 ml) of potassium carbonate (622 mg), and the resulting mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (379 mg) as colorless crystals.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]C(=O)C)=[C:10]([C:18]#[C:19][Si](C)(C)C)[CH:9]=1)(=[O:5])=[O:4].CC(C)([O-])C.[K+].O.CCCCCCC>CN1CCCC1=O>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][CH:19]=[CH:18]2)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)CCc1ccc(NC(C)=O)c(C#C[Si](C)(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CN1CCCC1=O
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2[nH]ccc2c1
Temperature: 82.5 °C
Reaction time: 0.5 h

Procedure:
N-[4-(2-methylsulfamoyl-ethyl)-2-trimethylsilanylethynyl-phenyl]-acetamide (100 gm) was dissolved in N-methylpyrrolidone (900 ml) at 25° C. under inert atmosphere. Potassium tert-butoxide (49 g) was added and heated to 80-85° C. for 120-150 minutes. The reaction mass was cooled gradually to 25° C., water (3000 ml) was added and stirred for 30 minutes. The solution was extracted with ethyl acetate (2000 ml). The organic layer was dried over sodium sulfate and vacuum distilled to obtain a residue. The residue was treated with heptane (300 ml) to obtain a solid. The solid was filtered, washed with heptane and dried at 50-55° C. under vacuum to obtain title compound. (Yield: 74 g, HPLC Purity: 98%)
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[NH:18][C:19]2[C:25](=[CH:26][C:14]=1[CH2:13]3)[C:23](=O)[CH:22]=[CH:21][CH:20]=2)=[O:11].C(N(CC)CC)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(O)=O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO.C(Cl)(Cl)Cl>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:25]([CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:26][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(=O)cccc-3[nH]c2-1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of 9-hydroxycamptothecin (9-HC; 300 mg, 0.82 mmol) in N,N-dimethylformamide (15 ml), triethylamine (0.68 ml, 4.92 mmol. 6.0 eq.) and N-phenyl trifluoromethanesulfonimide (879 mg, 2.46 mmol, 3.0 eq.) were added, and the mixture was stirred at 60° C. for 0.5 hr under argon gas atmosphere. After confirmation of the disappearance of the starting material by thin layer chromatography (chloroform:methanol=20:1), this reaction solution was added with triethylamine (1.14 ml, 8.20 mmol. 10.0 eq.), dichlorobis(triphenylphosphine)palladium (58 mg, 0.08 mmol, 10 mol %), formic acid (189 mg, 4.10 mmol, 5.0 eq.) and heated at 60° C. for 3 hr. After the disappearance of 9-OTfC was confirmed by thin layer chromatography (chloroform:methanol=50:1), and the reaction mixture was cooled, followed by evaporation of the solvent under reduced pressure. The residue was added with chloroform (5 ml) and n-hexane (200 ml) and the resulting precipitate was taken by suction filtration to give camptothecin (CPT) (209 mg, yield 73%) as a yellow solid.