Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]S([O-])(=O)=O.[Na+].[Na+].[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1.[CH3:32][N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][CH:17]([C:11]2[CH:10]=[C:9]([NH:8][CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:25][CH:26]=1)#[N:31]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(N)cc(CC)c1
Reactant: CN1CCC(=O)CC1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(NC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
Na2SO4 (1.09 g, 7.7 mmol) was added to a solution of the ethyl (RS)-(3-amino-5-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (250 mg, 0.77 mmol) obtained in Example 223.4 and 1-methyl-4-piperidone (174 mg, 1.54 mmol) in acetic acid (5 ml) and the mixture was stirred for 15 min. at room temperature. The mixture was subsequently cooled to 0° C. and NaHB(OAc)3 (489 mg, 2.31 mmol) was slowly added portionwise. After 30 min. a saturated solution of NaHCO3 was added and the mixture was extracted with EtOAc. The organic phase was dried and filtered, and the filtrate was concentrated. The residue was purified by chromatography (SiO2, CH2Cl2MeOH 9:1). There were obtained 287 mg (89%) of ethyl (RS)-(4-cyano-phenylamino)-[3-ethyl-5-(1-methyl-piperidin-4-ylamino)-phenyl]-acetate as a yellowish solid; MS: 421 ([M+H]+).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][NH2:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3].[C:28](OCC)(OCC)(OCC)[CH3:29]>>[CH2:1]([C:4]1[N:9]=[C:28]([CH3:29])[N:11]2[N:12]=[C:8]([CH3:10])[N:7]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCc1nc(C)n2nc(C)nc2c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
6 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 12, are heated to 90° C. for 5 hours in 100 ml of triethyl orthoacetate. The mixture is then evaporated under vacuum and the residue is taken up in 75 ml of formic acid. The solution obtained is heated to reflux for 5 hours, the formic acid is then evaporated off under vacuum and the residue is crystallised in an ether/pentane mixture to give 5 g of 7-n-propyl-2,5-dimethyl-8-[(2'-cyano-4biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidine in the form of crystals of melting point 132° C.
Reaction SMILES: [C:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)(=O)C>O1CCCC1>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[O:23])[CH2:2][C:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[O:3])[CH3:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C1COc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)C1COc2ccccc2C1=O
Temperature: -40 °C

Procedure:
A solution of 3-acetyl-4-chromanone (1.8 g, 9.5 mmoles, described in Example 5) in dry tetrahydrofuran (20 ml) is added dropwise to a suspension of 57% sodium hydride (1.17 g, 28.5 mmoles) in tetrahydrofuran (30 ml) and the mixture is heated at reflux temperature for 15 min. A solution of diethyl oxalate (1.39 g, 9.5 mmoles) is added dropwise under an atmosphere of nitrogen. The reaction mixture is heated at reflux temperature overnight and cooled to -40° C. A solution of 50% aqueous acetic acid (4 ml) is added and the reaction mixture evaporated. The residue is partitioned between chloroform and water, the organic phase is separated and the aqueous phase is re-extracted with chloroform. The combined chloroform extracts are dried and evaporated. The residue is subjected to chromatography on silica gel. Elution with chloroform affords 4-(4-chromanon-3-yl)-2,4-dioxobutyric acid ethyl ester (VII; R1, R2, R3R4 and R17 = H, R19 = C2H5 and X = O), which is crystallized from ether, m.p. 117°-119° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)=[CH:20][C:19]=1[O:32][CH2:33][CH3:34]>CN(C=O)C>[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)=[CH:20][C:19]=1[O:32][CH2:33][CH3:34]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(CN2CCC(NC(=O)c3ccccc3)CC2)ccc1Cl
Yield: 59 %

Procedure:
Benzoyl chloride (17 mg, 0.11 mmol), Et3N (20 μL, 0.15 mmol) and 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine (27 mg, 0.1 mmol) were shaken in DMF (0.5 ml) for 16 h, after which time the solvent was evaporated and the residue purified by reversed phase HPLC (MeCN:H2O) affording the title compound (22 mg, 60%). MS: 373.4 (MH+)
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH:10][C@H](C2C=CC=CC=2)CO)[CH2:8][CH3:9])=[CH:4][CH:3]=1.CN.[O-][O-].[Na+].[Na+].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>CCO.O.C1COCC1.CC(OC)(C)C>[C:26]1([CH3:36])[CH:27]=[CH:28][C:29]([S:32]([OH:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1.[CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH2:10])[CH2:8][CH3:9])=[CH:4][CH:3]=1
Reactant: CC[C@@H](N[C@@H](CO)c1ccccc1)c1ccc(C)o1
Agent: CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](N)c1ccc(C)o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
80 g of (R)-2-[(R)-1-(5-Methyl-furan-2-yl)-propylamino]-2-phenyl-ethanol are dissolved in 160 ml of EtOH and the reaction mixture obtained is cooled to 5°. 40% methylamine in 23.5 ml of H2O are added and 70 g of sodium peroxide dissolved in 400 ml of H2O are added dropwise over a period of 1.5 hours at 5°. The reaction mixture obtained is stirred for 1.5 hours at rt, filtered and the filtrate obtained is washed with TBME, H2O and brine and the organic portion is dried over Na2SO4, filtered and solvent is evaporated. A residue obtained is dissolved in 80 ml of THF and is added dropwise to a solution of para-toluenesulfonic acid in 150 ml of THF at 0°. The reaction mixture obtained is stirred for 1 hour at rt, 200 ml of TBME are added and stirring is continued overnight. A solid is obtained and collected by filtration, washed with TBME and dried. The title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[NH:4][CH2:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18]>>[Cl:15][C:13]1[CH:14]=[C:2]2[C:3](=[CH:11][CH:12]=1)[N:4]([CH2:5][CH:6]([CH2:7][CH3:8])[CH2:9][CH3:10])[C:17](=[O:18])[C:16](=[O:22])[NH:1]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(CC)CNc1ccc(Cl)cc1N
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Yield: 76 %

Procedure:
35 g (0.124 mol) of 2-amino-4-chloro-N-(2-ethylbutyl)aniline were refluxed in 350 ml of diethyl oxalate for 2.5 h. After cooling, the precipitate was filtered off with suction and dried to yield 33 g (76%) of the product. Melting point 253°-255°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Cl.CN(C)CCCN=C=NCC.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]2[CH:39]([NH:40][CH3:41])[CH2:38][N:37]([C:42]([CH:44]3[CH2:49][CH2:48][N:47]([C:50]([C:52]4([CH3:55])[CH2:54][CH2:53]4)=[O:51])[CH2:46][CH2:45]3)=[O:43])[CH2:36]2)[CH:31]=[CH:32][C:33]=1[Cl:34]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:40]([CH:39]2[CH:35]([C:30]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:28]([Cl:27])[CH:29]=3)[CH2:36][N:37]([C:42]([CH:44]3[CH2:45][CH2:46][N:47]([C:50]([C:52]4([CH3:55])[CH2:54][CH2:53]4)=[O:51])[CH2:48][CH2:49]3)=[O:43])[CH2:38]2)[CH3:41])=[O:8])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 72 h
Yield: 88.8 %

Procedure:
To a mixture of 4-chloro-3-(trifluoromethyl)benzoic acid (31 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 0.14 mmol) was added at 0° C. under an atmosphere of nitrogen a solution {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (50 mg, 0.11 mmol) in dichloromethane (1 mL). The solution was stirred for 3 d in a thawing ice bath. The resulting solution was diluted with dichloromethane and was washed twice with water (10 mL). The aqueous layers were extracted with dichloromethane (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (63 mg, 86%) as a light brown foam. MS m/e: 646.3 [M+H]+.
Reaction SMILES: C(Cl)Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])[CH3:13].[CH2:24]([O:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36](Cl)[CH:35]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C.O1CCOCC1>[CH2:24]([O:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([C:18]2[CH:19]=[CH:20][C:15]([C:12](=[O:14])[CH3:13])=[CH:16][CH:17]=2)[CH:35]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OCc1ccccc1)c1cc(Cl)nc2ccccc12
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cc(C(=O)OCc3ccccc3)c3ccccc3n2)cc1
Temperature: 85 °C
Reaction time: 10 h
Yield: 67.9 %

Procedure:
PdCl2(dppf).CH2Cl2 (138 mg, 0.17 mmol), tripotassium phosphate (715 mg, 3.37 mmol), and 4-acetylphenylboronic acid (414 mg, 2.52 mmol) were added to a 1,4-dioxane (5 mL)/DMF (1 mL) mixed solution of 2-chloro-4-quinolinecarboxylic acid benzyl ester (500 mg, 1.68 mmol) obtained in Reference Example 4, and the mixture was heated with stirring at 85° C. for 10 hours in an argon atmosphere. After the reaction solution was concentrated, to the residue, a saturated aqueous solution of sodium chloride and methylene chloride were added, and insoluble matter was filtered off through celite. After that, the residue was subjected to extraction with methylene chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 2-(4-acetylphenyl)-4-quinolinecarboxylic acid benzyl ester (434 mg, 1.14 mmol).
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22].O>C(O)CCC>[S:17]1[CH:21]=[CH:20][N:19]2[C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:22]=[C:18]12
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: Nc1nccs1
Solvent: CCCCO
Solvent: O
Product: CSc1nc2ccc(Cc3cnc4sccn34)cc2s1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (500 mg, 1.84 mmol) and thiazol-2-amine (370 mg, 3.68 mmol) in 1-butanol (22 mL) was heated at reflux overnight. The mixture was cooled to rt and water (120 mL) was added. The mixture was extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylthio)benzo[d]thiazole as a yellow solid (350 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.4 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.16 (d, J=0.9 Hz, 1H), 6.99 (d, J=4.5 Hz, 1H), 6.71 (dd, J=0.9 Hz, J=4.5 Hz, 1H), 4.24 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 318 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59]C(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].OO.C(=O)(O)[O-].[Na+].ClCCl.O>O1CCCC1>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:59])[C:5]([C@@:7]1([CH3:58])[CH:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)C12)C3(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
To a solution of paclitaxel (1.0 g, 1.17 mmol) in tetrahydrofuran (20 mL) was added hydrogen peroxide (30%, 20 mL) followed by sodium bicarbonate (1.92 g, 22.85 mmol). After stirring at room temperature for 18 hrs, the mixture was treated with dichloromethane/water (1:1(v/v), 100 mL). The organic phase was washed with water (2×30 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with 3% methanol/dichloromethane (v/v) to yield 10-deacetylpaclitaxel (890 mg, 93% yield) as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:17][C@H:18]([N:20]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][CH3:39])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)(=[O:3])[NH2:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH2:17][C@H:18]([N:20]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH2:38][CH3:39])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])[CH3:19])[CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH:10]=[CH:9]2)(=[O:3])[NH2:2]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc(C(N)=O)c2c(ccn2CCCO)c1
Yield: 92.6 %

Procedure:
tert-Butyl (R)-N-[2-[7-carbamoyl-1-(3-hydroxy-propyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]carbamate (4.93 g) was dissolved in methanol (150 ml), and 10% palladium on carbon (490 mg) and ammonium formate (2.96 g) were added to the solution. After the mixture was heated under reflux for 36 hours and cooled, the insoluble material was filtered off. The solvent was removed in vacuo, and the residue was dissolved in methanol (150 ml). 10% Palladium on carbon (490 mg) and ammonium formate (2.96 g) were added to the solution. After the mixture was heated under reflux for 24 hours and cooled, the insoluble material was filtered off. The filtrate was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give white amorphous tert-butyl (R)-N-[2-[7-carbamoyl-1-(3-hydroxypropyl)-1H-indol-5-yl]-1-methylethyl]-N-[2-(2-ethoxyphenoxy)ethyl]-carbamate (4.55 g).
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.O>CCO.[O-2].[Mn+4].[O-2]>[N:1]1[C:2]([CH:10]=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: OCc1cn2ccccc2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Solvent: O
Product: O=Cc1cn2ccccc2n1
Temperature: 25 °C
Yield: 15.4 %

Procedure:
To a solution of imidazo[1,2-a]pyridin-2-ylmethanol (3.0 g, 20 mmol) in EtOH (50 mL) was added manganese (IV) oxide (8.8 g, 100 mmol). The mixture was refluxed for 2 days. After cooling to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by reverse phase column chromatography (eluting with acetonitrile in water 25% v/v, with 0.01% NH3. H2O) to afford the title compound (0.45 g, 15% yield) as a yellow solid. ESI MS: m/z 147 [M+H]+.
Reaction SMILES: [CH2:1]([O:4]N1C(=O)N2C[C@H]1C=C(C)[C@H]2C(N)=O)C=C.[CH2:18]([O:21][NH:22][C@H:23]1[CH2:28][NH:27][C@H:26]([C:29]([NH2:31])=[O:30])[C:25]([CH:32]([CH3:34])[CH3:33])=[CH:24]1)[CH:19]=[CH2:20]>>[CH2:18]([O:21][N:22]1[C:1](=[O:4])[N:27]2[CH2:28][C@H:23]1[CH:24]=[C:25]([CH:32]([CH3:34])[CH3:33])[C@H:26]2[C:29]([NH2:31])=[O:30])[CH:19]=[CH2:20]
Reactant: C=CCON[C@@H]1C=C(C(C)C)[C@@H](C(N)=O)NC1
Reactant: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2C(N)=O
Product: C=CCON1C(=O)N2C[C@H]1C=C(C(C)C)[C@H]2C(N)=O
Yield: 77 %

Procedure:
(2S,5R)-6-(allyloxy)-3-isopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (0.46 mg, 77%) was prepared a similar manner as described in Intermediate 86 as a pale yellow oil, using (2S,5R)-5-(allyloxyamino)-3-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 96, 0.54 mg, 0.23 mmol) as a starting material.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:31](=[O:32])[CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Cc3ccccc3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and phenylacetyl chloride provided the title compound. ESMS [M+H]+: 422.2
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:33])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:33])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1c(CO)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCOc1c(CCl)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Yield: 94.8 %

Procedure:
To a suspension of 6-benzyloxy-4-butoxy-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (6.96 g, 17 mmol) in toluene (50 mL)) was added thionyl chloride (2.5 mL, 34 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-4-butoxy-3-chloromethyl-2-isobutyl-1(2H)-isoquinolinone (6.90 g, 94.8%) as crystals.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH:5]=1>CO.[OH-].[Na+]>[CH3:17][O:16][CH:13]([O:14][CH3:15])[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11])[C:3]([OH:18])=[O:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(OC)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(OC)c1cc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.49 g (21.5 mmol) of Compound 5 in 200 mL of methanol, 50 mL of 1M NaOH were added and the mixture was stirred at room temperature for 2 h. The reaction mixture was then evaporated to dryness, the residue was dissolved in 100 mL water, acidified with 1 M HCl to pH 3-4. The precipitate was then filtered off, washed with water (4×), and dried. Yield: 4.96 g (95%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:7][C:6]=12.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)cc1
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 101.3 %

Procedure:
Prepared from 3-iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (87.5 g, 191 mmol) and trimethylsilylacetylene (54 mL, 390 mmol) as described in Example C.1, method 1, step 3a, to give the 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (82.71 g, 100%) as a yellow-orange solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3].[NH:18]([C:20](=[S:22])[NH2:21])[NH2:19]>O=P(Cl)(Cl)Cl>[CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[S:22][C:20]([NH2:21])=[N:18][N:19]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Oc1ccc(-c2nnc(N)s2)cc1C(F)(F)F
Temperature: 90 °C
Yield: 120.3 %

Procedure:
To a suspension 4-[(1-methylethyl)oxy]-3-(trifluoromethyl)benzoic acid (D2) (3 g) in POCl3 (11.27 mL) was added hydrazinecarbothioamide (1.652 g). The reaction mixture was heated at 90° C. for 3 h. The reaction was quenched with ice water, the pH value was adjusted to about 9 with NaOH solid. The mixture was extracted with EA/THF for 3 times. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated to afford 5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-amine (D3) (4.41 g). MS (ES): C12H12F3N3OS requires 303. found 304.1 (M+H+).