Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=O>>[F:18][C:17]([F:19])([F:20])[C:4]1[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:12][C:13]1[N:16]=[C:27]([C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=2)[O:15][N:14]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(OC(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-[(trifluoromethyl)oxy]benzoic acid: MS (APCl): m/z 453 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](COCC[Si](C)(C)C)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(N3CCNC(=O)C3)n2)c2cc(-c3cccnc3)ncc21
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of 4-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperazin-2-one (70 mg, 0.14 mmol) in dioxane (5 mL), was added 10% HCl 1 mL. The reaction mixture was stirred at 25° C. for 16 h, and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via reverse phase prep-HPLC eluting with 40% to 80% MeOH in aqueous 0.1% NH4OH solution to afford 279 as a yellow solid (13 mg, 25%). 1H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 9.13 (s, 1H), 9.02 (s, 1H), 8.58-8.53 (m, 2H), 7.76-7.73 (t, 1H), 7.64-7.60 (m, 2H), 6.88-6.87 (d, J=6.4, 1H), 4.39 (s, 2H), 3.99-3.98 (t, J=4, 2H). ESI MS m/z=371.15 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:34]>C(#N)C>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([NH2:34])[N:19]=2)=[N:6]1
Reactant: N
Reactant: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C(F)(F)F
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
690 mg (1.768 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-(trifluoromethyl)-1,2,4-triazin-5-ol were admixed with 9 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 123 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the acetonitrile was removed on a rotary evaporator, water was added, the precipitate was filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 125 mg (18% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:12]2=[N:13][NH:14][C:15](=[O:20])[C:16]3[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=32)[NH:9][CH:8]1[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C(O)(=O)C.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.[BH3-]C#N.[Na+]>C(#N)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[C:12]2=[N:13][NH:14][C:15](=[O:20])[C:16]3[CH:17]=[CH:18][CH:19]=[C:10]([C:11]=32)[NH:9][CH:8]1[C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][CH:28]=1
Reactant: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(C=O)cc1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
A mixture of 4-(9-(1-methyl-1H-imidazol-2-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.22 mmol), acetic acid (60 uL) and pyrrolidine (1.05 g, 15 mmol) in acetonitrile (7 mL) was stirred at room temperature for 4 hr. To this mixture was added NaCNBH3 (36 mg, 0.67 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 4 hr. Upon removal of solvents under reduced pressure, the residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give the title compound as a white solid (21 mg, yield 22%). LC-MS (ESI) m/z: 427 (M+1)+. 1H-NMR: (400 MHz, DMSO-d6&D2O) δ (ppm): 1.66 (d, J=2.8 Hz, 4H), 2.37 (s, 4H), 3.38 (s, 3H), 3.50 (s, 2H), 4.62 (d, J=10 Hz, 1H), 4.90 (d, J=10.4 Hz, 1H), 6.72 (s, 1H), 6.87 (s, 1H), 7.15-7.20 (m, 3H), 7.29-7.32 (m, 3H), 7.36-7.38 (m, 1H), 7.54-7.58 (m, 1H), 12.15 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])=[N:8][CH:7]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:24]O>>[CH3:24][O:2][C:1](=[O:3])[CH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])=[N:8][CH:7]=1
Reactant: O=C(O)CCc1cnc(-c2cccc(C(=O)O)c2)o1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cnc(-c2cccc(C(=O)O)c2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-[5-(2-carboxyethyl)-1,3-oxazol-2-yl]benzoic acid (317 mg, 1.2 mmol) in methanol (5 mL) is added thionyl chloride (4.4 μL, 0.06 mmol), and the reaction is stirred at room temperature 16 h. The solution is concentrated under reduced pressure to give the title compound. ESI MS m/z 274.1 [M−H]−.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 64.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (268 mg, 0.447 mmol) prepared in Example 25a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (130 mg, 65%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:5]2[N:6]([C:8]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=3)=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1.C[O-].[Na+:43]>>[Na+:43].[Cl:1][C:2]1[CH:3]=[C:4]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[C:5]2[N:6]([C:8]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O-:33])=[O:32])=[CH:28][CH:29]=3)=[C:9]([C@@H:11]3[CH2:13][C@@H:12]3[C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:10]=2)[N:7]=1
Reactant: COC(=O)Cc1ccc(-c2c([C@@H]3C[C@@H]3c3ccc4ccccc4n3)nc3c(N4CCOCC4)cc(Cl)nn23)cc1
Agent: C[O-]
Agent: [Na+]
Product: O=C([O-])Cc1ccc(-c2c([C@@H]3C[C@@H]3c3ccc4ccccc4n3)nc3c(N4CCOCC4)cc(Cl)nn23)cc1

Procedure:
Compound 82a (30 mg, 0.054 mmol) was treated with NaOMe (36 μL, 0.10 mmol) using the procedures described in Example 73, Step H to afford title compound 173. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.18 (d, J=8.6 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.49 (t, J=6.8 Hz, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.6 Hz, 1H), 6.34 (s, 1H), 4.02-4.11 (m, 4H), 3.85-3.95 (m, 4H), 3.49 (s, 2H), 2.79-2.89 (m, 1H), 2.68-2.79 (m, 1H), 1.84-1.94 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H26ClN5O3: 540.1 (M+H). found: 539.8.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH3:22])=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1CCOCC1>>[C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]=[O:23])=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Reactant: C1COCCO1
Product: O=Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
A mixture of SeO2 (500 mg, 4.51 mmol) and 1,4-dioxane (10 mL) was heated to over 80° C. 8-Bromo-2-methylquinolin-7-yl benzenesulfonate (15, 1.70 g, 4.49 mmol) in 1,4-dioxane (5 mL) was added. After stirring at 80° C. for 24 h, the reaction was cooled and vacuum filtered. The filtrate was collected and concentrated to yield a yellow solid. Purification by SiO2 column chromatography (CHCl3) gave 16 as a white solid (1.60 g, 4.08 mmol, 91% yield). 1H NMR (500 MHz, CDCl3) δ 10.25 (s, 1H), 8.37 (d, 1H, J=7.5 Hz), 8.09 (d, 1H, J=8.5 Hz), 7.99 (d, 2H, J=7.0 Hz), 7.91 (d, 1H, J=9.0 Hz), 7.79 (d, 1H, J=9.0 Hz), 7.72 (t, 1H, J=7.5 Hz), 7.57 (t, 2H, J=8.0 Hz). 13C NMR (500 MHz, CDCl3) δ 193.33, 153.80, 149.08, 146.10, 138.35, 135.82, 135.17, 129.79, 129.66, 128.99, 128.37, 125.61, 119.93, 118.51.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH2:24][CH2:25][CH:26]([OH:28])[CH3:27]>C(O)C>[OH:28][CH:26]([CH3:27])[CH2:25][NH:24][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CC(O)CN
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCC(C)O)ncc2c(=O)[nH]1
Yield: 83.4 %

Procedure:
In a similar manner to Example 38 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.41 g) and 1-amino-2-propanol (0.97 g) in ethanol (15 ml) for 40 hours yielded the title compound 0.37 g, m.p. 212.5-214° C. (recrystallized from methanol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:28][C:25]1[N:24]=[CH:23][C:22]([C:21]#[C:20][C:19]2[C:18]([CH3:29])=[N:17][C:16]([NH2:30])=[N:15][C:14]=2[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:27][CH:26]=1
Reactant: Cc1nc(N)nc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)nc(C2=CCNCC2)c1C#Cc1ccc(N)nc1
Reaction time: 3 h
Yield: 55.3 %

Procedure:
630 mg (1.5 mmol) of 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester are dissolved in DCM (40 mL) and 2 mL TFA are added. The reaction mixture is stirred for 3 h, concentrated aqueous Na2CO3 solution is added until pH 7 is reached and DCM is evaporated at reduced pressure. The residue is washed with water, taken up in acetonitrile and freeze dried yielding 253 mg (0.83 mmol) of the desired product which is used for the next step without further purification.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:14].[OH-].[Na+]>CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:12]/[C:13]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:14])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)/C=C/c2ccc3c(c2)OCO3)cc(OC)c1OC
Reaction time: 18 h

Procedure:
To a stirred solution of piperonal (1.13 g, 7.5 mmol) and 3,4,5-trimethoxyacetophenone (1.58 g, 7.5 mmol) in methanol (15 ml) was added aqueous NaOH (6 ml, 50% w/v) and the mixture stirred for 18 h. The resultant solid was collected by filtration and recrystallised from methanol (100 ml) as pale yellow crystals (1.98 g, 77%): mp 135° C.; 1H NMR δ (CDCl3) 3.92 (3H, s, OCH3), 3.93 (6H, s, OCH3), 6.01 (2H, s, CH2), 6.83 (1H, d, J=8.0 Hz, H-5), 7.11 (1H, dd, J=1.6, 8.0 Hz, H-6), 7.15 (1H, d, J=1.6 Hz, H-2), 7.25 (2H, s, H-2′,6′), 7.30 (1H, d, J=15.5 Hz, CH), 7.72 (1H, d, J=15.5 Hz, CHCO); 13C NMR 56.42, 60.99, 101.69, 106.06, 106.68, 108.72, 119.77, 125.26, 133.72, 142.43, 144.60, 148.44, 149.96, 153.17, 189.07; MS (rel intensity) m/z 343 ([M+H]+, 100%); Anal. Calcd (C19H18O6): C, 66.66; H, 5.30. Found C, 66.43; H, 5.45.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([OH:15])=O)=[CH:5][N:4]=1)#[N:2].C(Cl)(=O)C([Cl:19])=O>CN(C=O)C.ClCl>[C:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([Cl:19])=[O:15])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(C(=O)O)c(C(F)(F)F)n1
Reactant: O=C(Cl)C(=O)Cl
Agent: ClCl
Solvent: CN(C)C=O
Product: N#Cc1ncc(C(=O)Cl)c(C(F)(F)F)n1
Yield: 83.1 %

Procedure:
A solution of 2-cyano-4-trifluoromethylpyrimidine-5-carboxylic acid (2.0 g, 9.2 mmol), oxalyl chloride (1.4 g, 11 mmol) and DMF (4 drops) in CH2 Cl2 (46 mL) was stirred at room temperature under N2 for 0.75 h. The reaction was concentrated and distilled (b.p. 100° C., 1.5 mm/Hg) to give the title compound (1.8 g, 82% yield); 1HNMR (CDCl3) δ 9.49 (s, 1H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.N1C=CC=CC=1.[O:24]=[C:25]1[CH2:42][C@@:40]2([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]2[OH:43])[C:35]2[CH2:34][CH2:33][C:32]3[CH:31]=[C:30]([O:44][CH3:45])[CH:29]=[CH:28][C:27]=3[C:26]1=2.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:45][O:44][C:30]1[CH:29]=[CH:28][C:27]2[C:26]3[C:25](=[O:24])[CH2:42][C@@:40]4([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]4[O:43][CH:6]4[CH2:5][CH2:4][CH2:3][CH2:2][O:1]4)[C:35]=3[CH2:34][CH2:33][C:32]=2[CH:31]=1
Reactant: COc1ccc2c(c1)CCC1=C2C(=O)C[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC1=C2C(=O)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Reaction time: 2 h

Procedure:
47 ml of dihydropyran and 0.96 g of pyridine toluenesufonate were added at room temperature to 15.29 g of 11-keto-3-methoxy-estra-1,3,5(10),8-tetraen-17β-ol (1) in 35 ml of dichloromethane, and it was stirred for 2 hours. Then, the reaction solution was shaken several times with saturated sodium bicarbonate solution, washed with water and dried with magnesium sulfate. The solvent was evaporated in a vacuum, and the residue was purified on silica gel (solvent mixture: cyclohexane/ethyl acetate=8/2). 16.8 g (83%) of light yellowish, viscous oil was thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N@:13]1[CH2:15][CH:14]1[C@H:16]1[O:20][C:19](=[O:21])[C@H:18]([CH2:22][CH2:23][CH3:24])[CH2:17]1)(=[O:12])=[O:11])([O-:3])=[O:2].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][CH2:34][C:33]1=[O:40]>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:33](=[O:40])[CH2:34][N:35]([CH2:15][C@H:14]([NH:13][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C@@H:16]2[CH2:17][C@@H:18]([CH2:22][CH2:23][CH3:24])[C:19](=[O:21])[O:20]2)[C:36]([CH3:39])([CH3:38])[CH2:37]1
Reactant: CCC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: CC1(C)CN(c2ccccc2Cl)C(=O)CN1
Solvent: Cc1ccccc1
Product: CCC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 75.6 %

Procedure:
A solution of 700 mg of (3R,5S)-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]-3-propyldihydrofuran-2-one obtained in Example (116g) (1.98 mmol) and 611 mg of 1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (1k) (2.57 mmol) in toluene (20 ml) was stirred at 110° C. for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone 5/1) to obtain 888 mg of the title compound (yield: 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1>CC#N.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](OC)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Product: COCCCC[C@@](OC)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A quarter of the (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)piperidine-1-carboxylate obtained in Step 1 (ca. 75 mg, ca. 0.1 mmol) was dissolved in CH3CN (30 mL) and 2 N HCl (25 mL). The mixture was vigorously stirred at rt for 2 d. The solvents were removed in vacuo to give the HCl salt of (R)-3-((S)-1-(3-chlorophenyl)-1,5-dimethoxypentyl)-piperidine, which was used without further purification. LC-MS (3 min) tR=1.22 min, m/z 328, 326 (M+H+).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH2:41][CH2:42][N:43]3[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(CCN3CCN(C)CC3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCc2n[nH]c3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c23)CC1
Temperature: 70 °C
Yield: 34.7 %

Procedure:
A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (4 mg, 0.006 mmol) and TFA (0.5 mL) was heated to 70° C. for 18 hours. The mixture was concentrated in vacuo, using toluene (2×5 mL) to azeotrope residual TFA. The residue was partitioned between EtOAc (5 mL) and a 1:1 water/saturated aqueous NaHCO3 (5 mL) mixture. The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×2 mL). The combined organic phases were concentrated in vacuo. The residue was loaded on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was further purified on a Waters SepPak silica gel column (2 g silica), eluting with DCM, 5% MeOH/DCM, then 5% MeOH (containing 7N NH3) in DCM to elute the product. The product was obtained as a waxy solid (1.2 mg, 34%). LCMS (ESI+): 93% purity, 220 nm, m/z 576 (M+1) detected; 1H NMR (400 MHz, MeOD-d3) δ 8.27 (d, J=6 Hz, 1H), 7.84 (m, 1H), 7.55 (m, 2H), 7.43 (m, 1H), 7.37 (t, J=9 Hz, 1H), 7.07 (t, J=9 Hz, 2H), 6.29 (d, J=6 Hz, 1H), 3.65 (m, 1H, overlaps MeOD), 3.57 (m, 1H), 2.94 (m, 2H), 2.64 (m, 8H), 2.37 (s, 3H), 1.64 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][CH:36]1[CH2:40][CH2:39][CH2:38][NH:37]1.C(OCC)(=O)C>C(#N)C>[CH3:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:16]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CN1CCCCC1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1CN1CCCCC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A solution of ethyl 2-[4-(3-chloropropoxy)phenyl]-4-(piperidin-1-ylmethyl)-1,3-oxazole-5-carboxylate i95 (0.22 g, 0.56 mmol, 1 eq) in acetonitrile (10 ml) is treated with potassium carbonate (0.31 g, 2.24 mmol, 4 eq) and 2-methylpyrrolidine (60 μl, 0.67 mmol, 1.2 eq) and the resulting mixture is stirred at 110° C. overnight. Ethyl acetate is then added and the organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Purification over silicagel (eluent: dichloromethane/methanol/ammonia) affords 90 mg of ethyl 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4-(piperidin-1-ylmethyl)-1,3-oxazole-5-carboxylate i96.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[N+:27]([O-])([OH:29])=[O:28]>S(=O)(=O)(O)O>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:20]([N+:27]([O-:29])=[O:28])=[CH:19][CH:18]=[CH:17][C:16]2=[CH:15][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cccc([N+](=O)[O-])c3nc2-1

Procedure:
Japanese Kokai Patent Application No. 59-51288 provides one method of making 9-nitro-camptothecin by treating camptothecin with a slight excess of concentrated nitric acid in concentrated sulfuric acid. However, when following this procedure, a yield of about 3% to about 7% of the 9NC product which is capable for medicinal use is obtained. Further, this procedure results in unwanted byproducts such as the inactive isomer, 12-nitrocamptothecin (12NC), in a ratio of about 1 to 3 of 9NC to 12NC. The following scheme shows the reaction from the use of nitric acid and sulfuric acid. ##STR1##