Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C@H:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)[CH:39]=2)[O:34]1)[CH2:9][C@H:10]([O:24][Si](C(C)(C)C)(C)C)[C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[CH3:23])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:32][C@H:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=3)[CH:39]=2)[O:34]1)[CH2:9][C@@H:10]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]2[CH3:22])=[CH:15][CH:16]=1)[OH:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(-n4c(C)ccc4C)nc2)C(=O)OC(C)(C)C)O3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O)c2ccc(-n4c(C)ccc4C)nc2)C(=O)OC(C)(C)C)O3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 120.1 %

Procedure:
To a solution of methyl 4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-{[tert-butyl(dimethyl)silyl]-oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl}-amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate (Example 371, 213 mg, 0.29 mmol) in THF (5 mL) was added a solution of 1 M tetrabutylammonium fluoride (0.59 mL, 0.59 mmol). The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. Flash chromatography of the residue over silica gel using 40% ethyl acetate/hexanes afforded 213 mg (92%) of the desired product. The product had: 1H NMR (CDCl3δ): 8.62 (s, 1 H), 8.06 (d, J=8.9 Hz, 2 H), 7.92 (d, J=7.2 Hz, 1 H), 7.58 (d, J=8.8 Hz, 2 H), 7.31-7.40 (m, 2 H), 7.22 (d, J=7.8 Hz, 1 H), 6.89 (d, J=7.9 Hz, 1 H), 5.89 (s, 2 H), 5.10-5.26 (m, 2 H), 4.21-4.50 (m, 1 H), 3.93 (s, 3 H), 3.56-3.88 (m, 4 H), 3.15-3.42 (m, 1 H), 2.78-3.04 (m, 2 H), 2.12 (s, 6 H), 1.65-1.83 (m, 2 H), 1.50 (s, 9 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([N+:29]([O-])=O)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[CH:8]=1)[CH3:2]>[Pd].C(Cl)(Cl)Cl.CCO>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:29])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccccc12)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(N)Cc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
2-Amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester (33) was prepared as follows: Palladium on carbon (10% wet, 0.4 g) was added to a solution of compound 32 (1.2 g) in CHCl3 (10 mL) and EtOH (30 mL). The reaction mixture was shaken under hydrogen (50 PSI) for 24 hours at room temperature. After filtration on Celite, HCl (4N in 1,4-dioxane, 4 mL) was added and the solvents were evaporated under vacuum to give compound 33 as a blue solid (1.1 g, 90%): LC/MS: m/z=401.1 [M+H]+ (Calc: 400.5).
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([OH:22])[CH:16]=1>C(O)C>[Cl:12][C:11]1[C:10](=[O:13])[C:9]2[C:4]([C:3](=[O:14])[C:2]=1[NH:21][C:20]1[CH:15]=[CH:16][C:17]([OH:22])=[CH:18][CH:19]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Product: O=C1C(Cl)=C(Nc2ccc(O)cc2)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,3-Dichloro-1,4-naphthoquinone (1.0 g, 4.4 mmol) was dissolved in 80 ml ethanol at 60° C., to which p-aminophenol (1.44 g, 13.2 mmol) in 20 ml ethanol was added. The reaction mixture was stirred at room temperature for 16 h. The precipitated product was filtered off and recrystallized from ethanol to afford pure purple crystals. Yield: 1.30 g (99%), Mp: 233° C.
Reaction SMILES: [C:1]1([C@H:7]2[NH:11][C@@H:10]([CH2:12][OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23].O>C(Cl)Cl>[C:1]1([C@H:7]2[CH2:8][CH2:9][C@@H:10]([CH2:12][O:13][Si:22]([CH3:24])([CH3:23])[CH3:21])[NH:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC[C@H]1CC[C@@H](c2ccccc2)N1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC[C@@H]1CC[C@H](c2ccccc2)N1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 89.3 %

Procedure:
To a solution of (2R,5S)-(5-phenyl-pyrrolidin-2-yl)-methanol (0.78 g, 4.4 mmol) in CH2Cl2 (7 mL) at 0° C. was added 0.72 mL (5.2 mmol, 1.2 eq) of Et3N followed by a slow addition of 0.66 mL (5.2 mmol, 1.2 eq) of TMSCl. The mixture was stirred at 0° C. for 45 min. Water (3 mL) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2 mL×2). The combined organic layer was dried (Na2SO4) and concentrated under vacuum to give 0.98 g (89%) of (2R,5S)-2-phenyl-5-trimethylsilanyloxymethyl-pyrrolidine as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.60–7.30 (5H, m), 4.30 (1H, m), 3.85 (2H, m), 3.50 (1H, m), 2.25 (1H, m), 2.05 (1H, m), 0.25 (9H, m).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl(O)(=O)(=O)=[O:23]>C(OC(=O)CCC)(=O)CCC>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:11]([O-:21])(=[O:23])[CH2:8][CH2:9][CH3:10]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CCCC(=O)OC(=O)CCC
Agent: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CCCC(=O)[O-]
Reaction time: 3 h

Procedure:
225 g of florfenicol was suspended in 330 ml of butyric anhydride in one liter round bottom flask equipped with a over head stirrer and a drying tube. To this suspension was added one ml of perchloric acid, while stirring vigorously, with a pipette. A clear solution was obtained in a few minutes. Stirring was continued for another 3 hours during which the florfenicol butyrate pro-drug was crystallized. The solid product was filtered using a Buckner funnel under vacuum, and washed thoroughly with hexane. The product was finally crystallized in ethanol and the crystallized product was washed with hexane and dried to obtain around 230 g of solid florfenicol butyrate.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.[Si:9](OC1CCC(N2CC(B3OC(C)(C)C(C)(C)O3)=CN2)C1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[C:12]([Si:9]([CH3:11])([CH3:10])[O:7][CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([OH:8])[CH2:2]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC1(C)OB(C2=CNN(C3CCC(O[Si](C)(C)C(C)(C)C)C3)C2)OC1(C)C
Reactant: OC1CCCC(O)C1
Product: CC(C)(C)[Si](C)(C)OC1CCCC(O)C1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 1,3-cyclohexanediol by a procedure analogous to Intermediate 28, Step A. 1H NMR (300 MHz, CDCl3): δ 4.0-4.2 (m, 1H), 3.8-3.95 (m, 1H), 1.3-2.4 (m, 9H), 0.86 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31]O)=[CH:25][CH:24]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C.CCCCCC>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][Br:20])=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: OCCCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Clc1ccc(CCCBr)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 4.15 g (15.8 mmol) of triphenylphosphine in 100 ml of toluene at 0° C., 1.51 ml (15.8 mmol) of bromine was added dropwise. This mixture was stirred for 3 hours then a solution of 3.90 g (22.9 mmol) of Part (a) alcohol and 1.63 ml (15.8 mmol) of pyridine in 20 ml of toluene was added. A solution of 25 ml hexane and 25 ml diethyl ether was added, and a brown mass was formed. The liquid was decanted and concentrated in vacuo. The residue was triturated with hexane:ethyl acetate and triphenylphosphine oxide was precipitated. The solid was filtered and the filtrate was concentrated in vacuo to give a yellow oil. The oil was purified by flash chromatography to obtain 1.80 g 7.72 mmol, 49%) of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[N-]=[C:21]=[S:22]>>[OH:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N:1]=[C:21]=[S:22])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCCO)CC2)cc1
Reactant: [N-]=C=S
Product: OCCCN1CCN(c2ccc(N=C=S)cc2)CC1

Procedure:
This compound was prepared from 4-(4-nitrophenyl)-1-piperazine-propanol (which can be prepared according to the procedure of Loewe and Mieth Arzneim.-Forsch. 1966, 16, 1306-1310) using the hydrogenation and isothiocyanate-forming reactions used in Example 4. MS (ES) MH+=277.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[C:36]3[CH:37]=[N:38]N[CH:40]=3)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1.[O:41]1C=C(B(O)O)C=N1.CC1(C)C(C)(C)OB(C2C=NN(C(OC(C)(C)C)=O)C=2)O1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[C:36]3[CH:37]=[N:38][O:41][CH:40]=3)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cnoc1
Reactant: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1-c1cn[nH]c1
Agent: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1-c1cnoc1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine of using isoxazol-4-ylboronic acid instead tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate. LC-MS: (M+1=557, obsd.=557).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=2)[N:14]=[CH:13][N:12]=1.[CH2:22]([C:24]1[NH:41][C:27]2=[N:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[C:26]2[N:25]=1)[CH3:23].C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.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>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]3[CH:31]=[C:26]4[N:25]=[C:24]([CH2:22][CH3:23])[NH:41][C:27]4=[N:28][CH:29]=3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: CCc1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2[nH]1
Reactant: Ic1ccc2ncnc(N3CCc4ccccc4C3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc2cc(-c3ccc4ncnc(N5CCc6ccccc6C5)c4c3)cnc2[nH]1
Yield: 19.1 %

Procedure:
0.25 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline, 0.35 g of 2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine, 0.52 g of sodium hydrogencarbonate and 0.29 g of Pd(PPh3)2Cl2 in 17 ml of dioxane and 2 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 3 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient EA: methanol 0-45% in 16 min), giving 0.05 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline (“A10”) as white powder (yield 92%, content 94%); MS-FAB (M+H+)=407.2; Rf (polar method): 1.40 min;
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][C:5]([CH2:9][OH:10])([CH3:8])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[C:20](F)=[CH:21][C:22]([F:32])=[C:23]([CH:31]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:19]1[C:20]([O:10][CH2:9][C:5]2([CH3:8])[CH2:4][CH2:3][C:2]([F:11])([F:1])[CH2:7][CH2:6]2)=[CH:21][C:22]([F:32])=[C:23]([CH:31]=1)[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(CO)CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CCC(F)(F)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
A mixture of (4,4-difluoro-1-methylcyclohexyl)methanol (3.05 g, 18.56 mmol)(PCT Int. Appl., WO2012025857, 2012), cesium carbonate (12.09 g, 37.12 mmol), and tert-butyl 5-chloro-2,4-difluorobenzoate (6.0 g, 24.13 mmol) in dimethylsulfoxide (70 mL) was stirred at 70° C. for 16 hours, cooled to ambient temperature and diluted with ethyl acetate (150 mL); washed with water (2×300 mL), brine (150 mL); dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-5%) afforded the title compound (3.69 g, 51%) as colorless oil: MS (ES+) m/z 393.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4](OC(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2OC(C2C=CC=CC=2)=O)[C@:11]2(OC(C)=O)[CH2:51]O[C@@H:10]2[CH2:9][C@@H:8]1O)=O.C/C=C(/C(N[C@H]([C@@H](O)C(O[C@@H]1C(C)=C2C(C)(C)[C@](O)([C@@H](OC(C3C=CC=CC=3)=O)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C([C@@H]2OC(C)=O)=O)C1)=O)C1C=CC=CC=1)=O)\C>C(OCC)(=O)C.C(Cl)Cl>[CH3:51][C@H:11]1[C@H:12]2[CH2:13][C@H:14]3[C:15]([CH3:16])([CH3:17])[C@@H:3]([CH2:4][CH2:5][C@:7]2([CH3:58])[CH2:8][CH2:9][CH2:10]1)[C@H:2]([CH3:1])[CH2:19][CH2:18]3
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: C/C=C(\C)C(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C(=O)[C@H](OC(C)=O)C(=C1C)C2(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]1CCC[C@@]2(C)CC[C@H]3[C@H](C)CC[C@@H](C[C@H]12)C3(C)C

Procedure:
dissolving any fraction comprising taxol and cephalomannine from step (7) in a mixture of about 20% ethyl acetate and 80% methylene chloride to form a taxane-containing solution;
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[C:27]([NH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:29])[CH3:28]>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=[C:2]([C:35]3[CH:36]=[C:31]([NH:30][C:27](=[O:29])[CH3:28])[CH:32]=[CH:33][CH:34]=3)[C:3]=2[CH:17]=[CH:16][C:15]1=[O:18]
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2nc(NC(CO)CO)nc3c2ccc(=O)n3-c2ccc(F)cc2F)c1

Procedure:
The title compound was prepared by following the procedure in example 96d from 4-chloro-8-(2,4-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one and [3-(acetylamino)phenyl]boronic acid: LC-MS m/z 482 (M+H)+, retention 2.69 min.
Reaction SMILES: [C:1]([C:4]1[C:5](Cl)=[N:6][C:7]([NH:23][C:24]2[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][C:27]([CH:34]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]3)=[C:26]([CH3:47])[CH:25]=2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])(=O)[CH3:2].[Cl-].[Cl-].[NH2:51][NH2:52].C([O-])(=O)C.[Na+]>CCO>[CH:31]([O:30][C:29]1[CH:28]=[C:27]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:26]([CH3:47])=[CH:25][C:24]=1[NH:23][C:7]1[N:6]=[C:5]2[NH:51][N:52]=[C:1]([CH3:2])[C:4]2=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])[N:8]=1)([CH3:32])[CH3:33]
Reactant: CC(=O)c1c(Cl)nc(Nc2cc(C)c(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC(C)C)nc1Nc1ccccc1S(=O)(=O)C(C)C
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(4-(5-acetyl-4-chloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-2-ylamino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate (81 mg, 0.12 mmol) in EtOH (2 mL) was added hydrazine dichloride (36 mg, 0.34 mmoL) and sodium acetate (47 mg, 0.57 mmol) sequentially, and the reaction mixture was heated at 80° C. overnight. The reaction was cooled to room temperature and concentrated in vacuo. The crude was dissolved in the solution of TFA (2 mL) in DCM (2 mL), and the reaction was stirred for 30 min, followed by concentration and purification by RP-HPLC to afford N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine. MS (ES+): 578.3 (MH+).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1.C(#N)C.P([O-])([O-])([O-])=[O:16].S([O-])(O[O-])(=O)=O.[K+].[K+]>O.CC(C)=O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][N+:2]([O-:16])=[O:1])=[CH:5][N:6]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: COc1ccc(C=NO)cn1
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C[N+](=O)[O-])cn1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a mixture of 2 g of N-hydroxy-1-(6-methoxypyridin-3-yl)methanimine, 50 ml of acetonitrile, and 50 ml of an aqueous phosphate buffer solution (pH 6.9) was added a mixed liquid of 20 g of potassium peroxymonosulfate (Oxone: 2KHSO5.KHSO4.K2SO4) in 50 ml water and 50 ml of acetone at room temperature, followed by stirring at 45° C. for 4 hours. The insoluble materials were separated by filtration and washed with diethyl ether. The organic layer was washed with a saturated aqueous sodium sulfite solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 251 mg of 2-methoxy-5-(nitromethyl)pyridine.
Reaction SMILES: CC(=NO)C(C)=NO.[BH4-].[Na+].[CH:11]1([CH2:16][O:17][C:18]2[CH:31]=[CH:30][C:21]([CH:22]=[C:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C>O.[OH-].[Na+].C1COCC1.CN(C=O)C>[CH:11]1([CH2:16][O:17][C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCC3CCCC3)cc2)S1
Agent: CC(=NO)C(C)=NO
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(=O)C(Cc2ccc(OCC3CCCC3)cc2)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To the suspension containing CoCl2.6H2O (4.6 mg, 0.016 mmol) and dimethylglyoxime (76.4 mg, 0.65 mmol) in 10 ml of water, 4 drops of 1.0N NaOH and NaBH4 (427.6 mg, 11.12 mmol) were subsequently added. The mixture was cooled to 0° C., and 5-(4-(cyclopentylmethoxy)benzylidene)thiazolidine-2,4-dione (1 g, 3.27 mmol) in 15 ml of THF-DMF (2:1) was added thereto over 20 minutes. The mixture was stirred at room temperature for 18 hours, to which acetic acid was then added until the pH thereof reached about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on silica gel to afford 5-(4-(cyclopentylmethoxy)benzyl)thiazolidine-2,4-dione (Derivative 115 of the above formula) as white solid (0.8 g, yield: 79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([NH:27][C@@H:28]([CH3:32])[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH:11][C:29](=[O:30])[C@@H:28]([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH3:32])[C:5]=1[NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1c(F)ccc(N)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1c(F)ccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-6-fluoro-2-phenylaminobenzoic acid methyl ester (2.0 g, 7.7 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.6 g, 8.45 mmol), HOAt (760 mg, 8.45 mmol), 4-methylmorpholine (1.86 mL, 16.9 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.07 g, 8.45 mmol) in DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford 3-((S)-2-tertbutoxycarbonylaminopropionylamino)-6-fluoro-2-phenylaminobenzoic acid methyl ester. LCMS (Method B): RT 3.65 min [M+H]+ 432.3.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:13][CH:14]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[C:22]1([S:28]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:13][CH:14]=2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CCCc1ccc(N)cn1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cn1
Reaction time: 4 h
Yield: 52.6 %

Procedure:
Triethylamine (1 ml) in chloroform (10 ml) was added over 10 minutes to a solution of methyl 4-(5-aminopyrid-2-yl)-butanoate (1.5 g, 8.3 mmole) and benzene sulphonyl chloride (2.2 g, 12 mmole) in chloroform (20 ml). The solution was stirred for 4 hours. Chromatography on silica gel eluted with 5% v/v methanol in chloroform gave the title compound (1.46 g) as a straw coloured oil.