Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:34][CH2:35][O:36][CH2:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:33]4[CH2:38][CH2:37][O:36][CH2:35][CH:34]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C3=CCOCC3)c2n1C
Temperature: 140 °C
Yield: 15.6 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (122 mg, 0.31 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (85 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (36 mg, 10 mol %) and caesium carbonate (204 mg, 0.63 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 432 as a white solid (19 mg, 15%). LCMS (Method K): RT 2.79 min [M+H]+ 394.16. 1H NMR (DMSO-d6, 400 MHz): δ 8.07 (1H, s), 7.69 (1H, m), 7.55 (1H, dd, J=8.76, 4.82 Hz), 7.30 (2H, br s), 7.04 (1H, dd, J=10.42, 8.75 Hz), 5.87 (1H br s), 5.70 (1H, m), 4.24 (2H, s), 3.86 (2H, m), 3.73 (3H, s), 2.45-2.23 (2H, m), 1.58 (3H, d, J=6.72 Hz)
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.ClC(OCC)=O.O>C1COCC1>[CH2:11]([C:10]1[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:9]=1[OH:8])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Oc1ccc(Cc2ccccc2)c(O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethyl amine (10 ml, 72.2 mmol) was added to a solution of 2,4-dihydroxybenzophenone (1) (5.4 g, 23.3 mmol) in THF (50 ml) and the solution cooled to 0° C. Ethyl chloroformate (6.9 ml, 72.2 mmol) was added slowly and the suspension stirred for ˜30 mins at 0° C., and for ˜3 hrs at room temperature. Water (150 ml) was added and the mixture extracted with diethyl ether (150 ml). The extracts were washed with water (2×150 ml) and saturated aqueous sodium chloride solution (100 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give 4-benzyl-benzene-1,3-diol as a pale green gum, solidified on standing, (8.2 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)=O.[CH3:24][C@H:25]1[NH:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1.C(O)(=O)C>C(Cl)Cl>[CH:21]1([C:19]([NH:18][C:16]2[CH:17]=[C:10]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][N:30]5[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:26][C@H:25]5[CH3:24])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][N:11]3[N:15]=2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1

Procedure:
N-(4-(4-Formylphenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (122 mg, 0.4 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (120 mg, 0.6 mmol) and (polystyrylmethyl)trimethylammonium cyanoborohydride (loading 4 mmol/g, 0.3 g, 1.2 mmol) were shaken in DCM (15 mL) and acetic acid (1.5 mL) at room temperature for 5 d. The beads were filtered off and the filtrate concentrated in vacuo to give (R)-tert-butyl 4-(4-(2-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-3-methylpiperazine-1-carboxylate which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(OCc2ccccc2)cc1)N1CCN(c2ncccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
To a stirred solution of 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (100 mg, 0.39 mmol) in anhydrous dichloromethane (2 mL) was added 4-benzyloxy-benzenesulfonyl chloride (110.27 mg, 0.39 mmol) then diisopropylethylamine (0.17 mL, 0.98 mmol). The mixture was stirred at room temperature for 4 hour. Reaction was complete as determined by TLC. The reaction mixture was purified with flash column chromatography to yield 1-{[4-(benzyloxy)phenyl]sulfonyl}-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine in 78.9% yield (147 mg) as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28]CC)=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.O[Li].O.Cl>C1COCC1.CO.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:12][C@@H:13]([C:26]([OH:28])=[O:27])[N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:15]3)[CH2:31][CH2:32]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:36])([F:38])[F:37])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.50 g, 1.94 mmol, See Ex. 1u) in THF (20 mL), MeOH (10 mL) and water (10 mL) was added LiOH—H2O (0.80 g, 19.4 mmol), and the reaction was stirred at RT for 4 h. The pH of the reaction mixture was adjusted to 6.5 with 6 N HCl, and the organic solvents were removed in vacuo to provide a white solid that is filtered away. The reaction mixture was then partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2SO4, filtered, then concentrated in vacuo to provide (2S)-8-[2-amino-6-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid that is used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:14](=[O:17])([O-])[O-].[Cs+].[Cs+].S(OC)(O[CH3:24])(=O)=O>C(#N)C.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:14])([CH3:12])[C:7](=[O:11])[N:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CC1(O)C(=O)Nc2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC1(C)C(=O)N(C)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-bromo-3-hydroxy-3-methylindolin-2-one 7.45 (200 mg, 0.826 mmol) in ACN/DMF (2:1, 6 mL) was cooled to 0° C. Cesium carbonate (942 mg, 2.89 mmol) and dimethyl sulfate (274 μL, 2.89 mmol) were added. The reaction was stirred at 0° C. for 90 min then at room temperature for 4 hours. The mixture was filtered over celite, concentrated and the residue was purified by flash column chromatography on silica gel to afford 6-bromo-3-methoxy-1,3-dimethylindolin-2-one 7.46. 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.25 (m, 3H), 3.14 (s, 3H), 2.85 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: [CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18][NH2:19])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[Si]([O:35][CH2:36][CH2:37][O:38][C:39]1[CH:48]=[C:47]2[C:42]([CH:43]=[CH:44][C:45]([CH:49]=O)=[N:46]2)=[CH:41][C:40]=1F)(C(C)(C)C)(C)C.[C:52](O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CCO>[CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:49]([C:45]4[CH:44]=[CH:43][C:42]5[C:47](=[CH:48][C:39]([O:38][CH2:37][CH2:36][O:35][CH3:52])=[CH:40][CH:41]=5)[N:46]=4)=[N:19][N:18]=3)[CH:13]=2)[C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc2nc(C=O)ccc2cc1F
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: CC(=O)O
Solvent: CCO
Solvent: Ic1ccccc1
Product: COCCOc1ccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.50 g, 4.01 mmol), 7-(2-(tert-butyldimethylsilyloxy)ethoxy)-6-fluoroquinoline-2-carbaldehyde (1.40 g, 4.01 mmol) and EtOH (30 mL) was stirred at ambient temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in DCM (30 mL) and iodobenzene diacetate (1.68 g, 5.21 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc) to give tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (1.45 g, 51%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[NH2:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(Br)s1
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc(Br)s1

Procedure:
2.63 g (12.3 mmol) 5-bromo-thiophene-2-carboxylic acid are refluxed in 15 ml dichloromethane together with 7.0 ml of thionyl chloride for 2 h with stirring. The mixture is then evaporated down i. vac. and the residue is twice taken up in toluene and evaporated down completely i. vac. The residue is added dropwise to 10 ml dichloromethane with stirring at ambient temperature in a mixture of 2.41 g (12.3 mmol) tert.-butyl 2-amino-isobutyrate hydrochloride in 20 ml dichloromethane with 5.14 ml (36.9 mmol) TEA and stirred for 16 h. The mixture is poured into water and extracted with dichloromethane, the combined organic phases are dried over magnesium sulphate and evaporated down i. vac.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)=O>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=3)[N:8]=2)[CH:7]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Nc1cnc(Cl)cn1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Yield: 99.9 %

Procedure:
A solution of 5-chloropyrazin-2-amine (0.336 g, 2.6 mmol) and 2-bromo-1-[3-nitro-4-(trifluoromethyl)phenyl]ethanone (0.811 g, 2.6 mmol) in acetonitrile (15 mL) is stirred at 100° C. for 18 hr. The mixture is concentrated to give the title compound (890 mg), which is used without further purification. LCMS m/z=343.3 [M+H]+, tR=2.65 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:11][C@H:12]([OH:27])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.[C:37](=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([N:10]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:11][C@H:12]([O:27][CH3:37])[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CO[C@H](CN1CCN(C(=O)OC(C)(C)C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Sodium hydride (333 mg, 8.30 mmol) was dissolved in 50 mL of tetrahydrofuran, added dropwise with a solution of tert-butyl 4-[(2S)-3-(dibenzylamino)-2-hydroxy-propyl]piperazine-1-carboxylate 35a (3.65 g, 8.30 mmol) in tetrahydrofuran in an ice-water bath. The reaction solution was stirred for 10 minutes and warmed up to room temperature. The reaction solution was stirred for 1 hour and cooled down to 0° C. followed by the addition of methyl iodide (1.18 g, 8.30 mmol). The reaction solution was stirred for 12 hours. The resulting solution was added with 10 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-(dibenzylamino)-2-methoxy-propyl]piperazine-1-carboxylate 35b (2.10 g, yield: 56.0%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1(C)[C:12]([S:17]([O:20]C)(=[O:19])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1>CC(C)=O>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH3:11].[CH3:1][C:15]1[CH:14]=[CH:13][C:12]([S:17]([OH:20])(=[O:18])=[O:19])=[CH:11][CH:16]=1
Reactant: Cc1nc2ccccc2s1
Reactant: COS(=O)(=O)c1ccccc1C
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1sc2ccccc2[n+]1C
Reaction time: 0.17 h

Procedure:
2-Methylbenzothiazole (74.6 pbw) and methyl toluenesulfonate (93.1 pbw) are mixed with one another and heated with stirring. At about 120° C. an exothermic reaction starts, in which the temperature of the mixture rises to 180° C. The solution is kept at this temperature for 10 minutes and then cautiously poured into 1000 pbw of acetone. The suspension obtained is stirred for one hour. The precipitate is removed by filtration with suction and washed with acetone. The powder obtained is dried in vacuo over phosphorus pentoxide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH2:8]1[CH2:10][CH:9]1[CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[CH2:8]1[CH2:10][CH:9]1[CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:15][CH:14]=1
Reactant: Oc1ccc(OCC2CC2)nc1
Reactant: O=C1NCC[C@@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1NCC[C@H]1Oc1ccc(OCC2CC2)nc1

Procedure:
A mixture of (S)-3-hydroxy-pyrrolidin-2-one (3.00 g), 6-(2-cyclopropyl-methoxy)-pyridin-3-ol (4.90 g), triphenylphosphine (polymer, 8.56 g), DCM (30 mL) and THF (50 mL) was added DIAD (6.60 g) keeping the reaction temperature below 30° C. After 12 hours the mixture was filtered and the filtrate was evaporated. The residue was purified by SGC (eluent: EA/MeOH 9:1) to provide the title compound. MS ESI+: m/z=249 [M+H]+.
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].S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:44][OH:45].C(Cl)(Cl)Cl>CO>[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[C:14](=[C:15]([CH2:44][OH:45])[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CO
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Camptothecin (100 mg, 0.287 m-mol) was suspended in methanol (25 ml) and then dissolved therein by addition under ice-cooling of 75% sulfuric acid (10 ml). To the solution was added dropwise under reflux with stirring an aqueous solution (100 ml) of ammonium persulfate (15 g, 0.0657 mol) over 16 hours. The reaction mixture was poured into ice water (100 ml) and the organic matter was extracted with a mixture (1:1, 500 ml) of dioxane-chloroform and then thrice with chloroform (100 ml×3). The organic phases were combined, dried with anhydrous magnesium sulfate, filtered and then evaporated until dryness under reduced pressure. The remaining solid having an orange color was warmed (50°-60° C.) with methanol (200 ml) and stirred for 30 minutes. An insoluble matter was collected by filtration, dried under reduced pressure and recrystallized from dimethylformamide-dioxane whereupon 40 mg (36.9%) of 7-hydroxymethylcamptothecin were obtained as light yellow white prismatic crystals having a melting point of 274°- 276° C. (dec.). Rf value 0.125 (5% methanol-chloroform).
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH2:19].ClC([O:24][C:25]1C=CC(Cl)=CC=1)=O.[CH3:32][S:33]([NH:36][NH2:37])(=[O:35])=[O:34].CCN(C(C)C)C(C)C>O1CCOCC1>[O:14]1[C:10]([C:8]2[CH:9]=[C:4]3[C:5](=[CH:6][C:7]=2[C:15]([F:16])([F:17])[F:18])[NH:19][C:25](=[O:24])[N:37]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])[C:3]3=[O:20])=[CH:11][N:12]=[CH:13]1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(-c2cnco2)c(C(F)(F)F)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-c3cnco3)cc2c1=O
Temperature: 80 °C
Yield: 19.2 %

Procedure:
A mixture of 2-amino-5-oxazol-5-yl-4-trifluoromethyl-benzoic acid methyl ester (248 mg, 0.866 mmol) and 4-chlorophenyl chloroformate (121 μL, 0.886 mmol) in dioxane (4 mL) was heated to 80° C. for 1 h. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in dioxane (4 mL) and treated with CH3SO2NHNH2 (191 mg, 1.732 mmol) and i-Pr2NEt (454 μL, 2.60 mmol). After heating at 80° C. for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by two successive flash chromatographies (70 g of silica gel, 2% MeOH in DCM), then (20 g silica gel, DCM→MeOH in DCM (1% to 3%)) to give the title compound (65 mg) as an off-white powder. This solid was further purified by sonication in DCM to provide 24 mg of pure product. The filtrate was concentrated in vacuo and sonicated in Et2O to give a further 27.8 mg of title product, for a total of 51.8 mg (15%) of the title compound as an off-white powder. API-ES: m/z 408.0 [M+NH4]+, rt 2.89 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.O>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH3:22])[CH:20]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: Cc1cccc(CBr)c1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cccc(C)c1
Reaction time: 17.5 h
Yield: 103.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.44 g, 7.45 mmol) was added to a suspension of 5-chloro-1H-indole-2-carboxylic acid ethyl ester (2.00 g, 8.94 mmol) in N,N′-dimethylformamide (DMF) (20 ml) under nitrogen. The mixture was stirred for 1 h before addition of the 3-methylbenzyl bromide (2.07 g, 2.48 ml) and the reaction stirred for 17.5 h. Water was added to reaction mixture which precipitated product as a gummy solid. Supernatant liquid was decanted and the solid washed with water. The product was dissolved in dichloromethane (DCM), washed with water, dried over magnesium sulfate and concentrated. Purification by silica chromatography using DCM as eluent, yielded 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid ethyl ester (3.03 g, 95%).
Reaction SMILES: C([CH2:5][C:6]([NH2:8])=[O:7])C1OC1.[C:9]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:16]([F:26])[CH:15]=1)([O:11]C)=O.[CH3:27][C:28](C)([O-:30])[CH3:29].[Li+]>C1COCC1>[F:26][C:16]1[CH:15]=[C:14]([N:13]2[CH2:27][CH:28]([CH2:29][NH:8][C:6](=[O:7])[CH3:5])[O:30][C:9]2=[O:11])[CH:19]=[CH:18][C:17]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NC(=O)CCC1CO1
Reactant: COC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 17.5 h
Yield: 80 %

Procedure:
To a solution of (±)-glycidylacetamide (VIIIB, EXAMPLE 11, 0.1571 g, 1.365 mmol) in THF (1.63 ml) at −78° is added N carbomethoxy-3-fluoro-4-morpholinylaniline (IX, PREPARATION 2, 0.4358 g, 1.71 mmol, 1.26 eq) and lithium t-butoxide (0.1267 g, 1.583 mmol, 1.16 eq). The reaction mixture is then stirred at 0 to 11° for 17.5 hrs at which point HPLC showes an 80% yield of (±)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (retention time=0.97 min; method B; Stationary phase: 4.6×250 mm Zorbax RX C-8 column; mobile phase: 650 ml acetonitrile, 1.85 ml triethylamine, 1.30 ml acetic acid, water sufficient to make 1000 ml; flow rate: 3.0 mi/min; UV detection at 254 nm). The title compound is isolated by means known to those skilled in the art.