Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[C:12]([O:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:16]4[C:11](=[C:12]([O:17][C:18](=[O:20])[CH3:19])[CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9]3)=[CH:6][CH:7]=2)=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)Oc1cccc2c1ccn2-c1ccc(N)cc1
Product: CC(=O)Oc1cccc2c1ccn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from acetic acid 1-(4-aminophenyl)-1H-indol-4-yl ester and 4-chloro-3-(trifluoromethyl)phenyl isocyanate in the same manner as in Step C of Example 1.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:32]=[C:33]=[O:34])(C)C>O1CCCC1>[O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:20]=[CH:21][C:22]([NH:23][C:33]([NH2:32])=[O:34])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: NC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and trimethylsilyl-isocyanate (0.11 ml, 0.84 mmol) in 3 ml of tetrahydrofuran is stirred for 24 hours at ambient temperature. Aminomethylpolystyrene resin EHL (Novabiochem, 200-400 mesh, 2% DVB) (200 mg, approximately 1 mmol) is added and stirring is maintained for three hours. After filtration on frit, the filtrate is concentrated in a rotavapor. Isopropyl acetate and traces of isopropanol are added to the residue obtained. The mixture is heated to dissolution followed by filtration on frit then left to crystallize for 24 hours. After filtration then drying under a bell jar, a light beige-coloured powder is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([C:33]([F:38])=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH2:20][CH:31]([C:30]1[C:33]([F:38])=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:29]=1)[OH:32]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1cc(F)c(C=O)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(F)c(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a solution of diisopropylamine (0.16 g) in tetrahydrofuran (2 mL) at −78° C. is added a 2.5 N solution of n-butyl lithium in hexanes (0.62 mL). The solution is allowed to warm to −10° C. and cooled back to −78° C. A solution of 3,5-dichloro-4-methylpyridine (0.25 g) in dry tetrahydrofuran (4 mL) is added, stirred for 0.5 hours at −60° C. and treated with 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (0.25 g) in dry tetrahydrofuran (4 mL). The reaction mixture is allowed to warm to room temperature over 1 hour and stirred overnight. The mixture is treated with 2N ammonium chloride (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried (magnesium sulfate) and evaporated to give 2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanol (0.22 g). [NMR (CDCl3):— 8.44 (s, 2H), 6.97 (d, 1H, J=7 Hz), 6.56 (d, 1H, J=12 Hz), 5.34 (m, 1H), 4.74 (m, 1H), 3.83 (s, 3H), 3.5 (dd, 1H, J=8 Hz, 8 Hz), 3.32 (dd, 1H, J=5 Hz, 6 Hz), 2.07 (d, 1H, J=6 Hz), 1.93-1.55 (m, 8H)].
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CS(O[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)=[CH:20][C:18]=2[CH:19]=1)(=O)=O>>[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:30]#[N:31])=[CH:20][C:18]=2[CH:19]=1
Reactant: C[C@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Agent: Br
Product: C[C@H]1CCCN1CCc1cc2cc(-c3cccc(C#N)c3)ccc2o1

Procedure:
(2S)-2-Methylpyrrolidine hydrobromide and the product from Example 112D are processed as described in Example 1D to provide the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:15]Br>O.C(Cl)(Cl)Cl>[Br:15][C:8]1[C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: BrBr
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C=O)c(Br)c(OC)c1OC
Yield: 98.2 %

Procedure:
To a stirred refluxing solution of 3,4,5-trimethoxybenzaldehyde (17.0 g, 86.6 mmol) in water (3 mL) and chloroform (100 mL) was added a solution of bromine (14.7 g, 92 mmol) in chloroform (30 mL) dropwise. The solution was heated under reflux overnight, cooled, washed with water (2×100 mL) and saturated aqueous sodium hydrogen carbonate (50 mL), dried over MgSO4, filtered and evaporated. The residual orange oil (27 g) crystallised on standing. The solid was washed with petroleum ether, b.p. 40-60° C., to obtain 2-bromo-3,4,5-trimethoxybenzaldehyde as white crystals (23.4 g, 98%); m.p. 69° C. (literature value 69.5-71° C., see Brown, E.; Robin, J.-P.; Dhal, R. Tetrahedron 1982, 38, 2569-2579); NMR Spectrum δH (300 MHz, CDCl3) 10.40 (1H, s, 1-CHO), 7.29 (1H, s, 6-H), 4.00 (3H, s, OCH3), 3.95 (3H, s, OCH3) and 3.93 (3H, s, OCH3); NMR Spectrum δC (75 MHz, CDCl3) 56.6, 61.6, 106.9, 126.1, 128.1, 149.2, 150.3, 152.8, 189.2; νmax/cm−1 (thin film) 2940, 2843, 1685 (C═O), 1588, 1480, 1460, 1386, 1317, 1196, 1161, 1134, 1103 and 1002 (data in accordance with published values, see Brown, E.; Robin, J.-P.; Dhal, R. Tetrahedron 1982, 38, 2569-2579); Rf(hexane-ethyl acetate 4:1) 0.50.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][C:17]=1[S:26]([NH:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][C:2]([F:1])([F:13])[F:14])[N:11]=1)(=[O:28])=[O:27]
Reactant: Nc1cccc(COCC(F)(F)F)n1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Product: O=S(=O)(Nc1cccc(COCC(F)(F)F)n1)c1cc(C(F)(F)F)ccc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(2,2,2-Trifluoro-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 2-chloro-5-(trifluoromethyl)- benzenesulfonyl chloride (0.119 g) as alight yellow solid (0.123 g). MS (ESI−): 447.0 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc(C(C)=O)cc2)cc1
Yield: 74.5 %

Procedure:
Reaction of 4-aminoacetophenone (74 mg, 0.55 mmol) in THF (6 mL) with p-anisoyl chloride (90 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-4-methoxy-benzamide (110 mg, 0.41 mmol, 75% yield) as a white powder after washing by dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][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:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16](I)[N:15]=2)=[N:6]1.[NH2:30][CH2:31][CH2:32][OH:33]>CN1CCCC1=O>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][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:22]=[C:21]3[C:17]([N:18]([CH3:24])[C:19](=[O:23])[NH:20]3)=[C:16]([NH:30][CH2:31][CH2:32][OH:33])[N:15]=2)=[N:6]1
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: NCCO
Solvent: CN1CCCC1=O
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(NCCO)c21
Temperature: 150 °C

Procedure:
200 mg (0.399 mmol) of the compound obtained in example 107 were dissolved in N-methylpyrrolidone (4 ml) and admixed with 2-aminoethanol (1.5 ml), and then heated in a microwavable flask with septum in a microwave at 150° C. for 5 h. The reaction mixture was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 31 mg of the title compound were obtained (18% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:35])[C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([O:35][C:4]1[C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=[C:2]([Cl:1])[CH:3]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(O)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(OCc5ccccc5)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of tert-butyl {1-[4-(6-chloro-8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was in a manner analgous to that described for Intermediate Example Int-16 (1.90 g, 3.87 mmol) in DMF (50 mL) was added cesium carbonate (6.88 g, 11.6 mmol, 3.0 equiv.) and benzyl bromide (0.58 mL, 4.84 mmol, 1.25 equiv.), and the resulting mixture was irradiated in a microwave apparatus at 140° C. for 90 min. The resulting mixture stirred at room temperature for 16 h. The resulting mixture was added to ice water 100 mL). The aqueous mixture was extracted with a 4:1 DCM/isopropanol solution (3×50 mL). The combined organic phases were dried (Na2SO4 anh.), and concentrated under reduced pressure. The resulting oil was triturated with ethanol to give tert-butyl (1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate as a powder (0.93 g, 41%):
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].[OH-].[K+:12]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][CH:5]=1)[CH3:2].[K+:12]
Reactant: CCOc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc([O-])cc1

Procedure:
In a 50-ml flask at ambient temperature 4-ethoxy-phenol (Aldrich) (1492 mg, 10.8 mmoles) was stirred with 2.0 M aqueous KOH (5.50 ml) to form potassium 4-ethoxyphenolate. Methyl 4-chloro-3,5-dinitrobenzoate (Ullmann, 1909, Annalen der Chemie 366:92-93; commercial source: Spectrum Chemical Company, Gardena, Calif.; 2606 mg, 10.0 mmoles) was added, the mixture heated to reflux for 1 hour and chilled in an ice-bath, whereupon a rubbery mass of product deposited. Cold aqueous 1.0 M KOH (20 ml) was added, and upon continued chilling the product solidified. The yellow-orange solid was broken-up, collected on a suction filter, rinsed with water and dried. The material (3.08 g) was crystallized from hot 95% ethanol (50 ml) to give 2.56 g (70.6 % yield) of methyl 3,5-dinitro-4-(4'-ethoxyphenoxy)benzoate. Melting point: 101°-103° C.
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1.N.[H][H]>CO.[Ni]>[CH3:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][CH2:6][CH2:5][CH:4]2[NH2:3]
Reactant: CON=C1CCOc2ccc(C)cc21
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc2c(c1)C(N)CCO2
Yield: 61.3 %

Procedure:
A solution of the product of Example 7A (4.24 g) in 50 mL of a mixture of 20% ammonia in methanol was treated with 40 g Raney Nickel under 60 psi hydrogen for 4 hours at ambient temperature. The reaction mixture was filtered, and the solvent evaporated under reduced pressure. The residue was taken in diethyl ether, washed sequentially with water and saturated aqueous sodium bicarbonate, dried with magnesium sulfate, filtered and concentrated to give 2.22 g of the title compound. H NMR (300 MHz, CDCl3) δ 7.11 (s, 1H), 6.95 (d, 1H, J=8.5 Hz), 6.71 (d, 1H, J=8.5 Hz), 4.22 (m, 2H), 4.01 (m, 1H), 2.27 (s, 3H), 2.10-2.21 (m, 1H), 1.78-1.88 (m, 1H). MS (DCI) m/e 164 (M+H)+.
Reaction SMILES: [OH-].[K+:2].[C:3]([NH:13][NH2:14])(=[O:12])[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:15](=[S:17])=[S:16]>C(O)C>[C:3]([NH:13][NH:14][C:15]([S-:17])=[S:16])(=[O:12])[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[K+:2]
Reactant: S=C=S
Reactant: NNC(=O)c1ccc(O)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NNC(=S)[S-])c1ccc(O)c(O)c1
Yield: 75.3 %

Procedure:
10 g (178 mmol) of potassium hydroxide was dissolved in 400 ml of ethanol, and 20 g (119 mmol) of protocatechuhydrazide was added thereto under stirring at a temperature of at most 5° C. To this solution, 28.0 ml of carbon disulfide was dropwise added over a period of 10 minutes at a temperature of at most 10° C., and the mixture was stirred at a temperature of from 0° to 10° C. for 30 minutes. Then, the precipitates were collected by filtration, washed with ethanol and dried to obtain 25.3 g (yield: 75.3%) of potassium 3-protocatechuoyldithiocarbazate.
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[OH:10][CH2:11][C:12]1([CH2:16][CH2:17][CH3:18])[CH2:15]O[CH2:13]1>>[CH2:16]([C:12]12[CH2:11][O:10][C:7]([CH2:6][CH2:5][S:4][CH2:1][C:2]#[CH:3])([O:9][CH2:15]1)[O:8][CH2:13]2)[CH2:17][CH3:18]
Reactant: CCCC1(CO)COC1
Reactant: C#CCSCCC(=O)O
Product: C#CCSCCC12OCC(CCC)(CO1)CO2

Procedure:
4-n-Propyl-1-[2-(prop-2-ynylthio)ethyl]-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 3-(prop-2-ynylthio)propionic acid and 3-hydroxymethyl-3-n-propyloxetane using methodology described in Example I.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12][CH3:13])[NH:6][C:5]2=O.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12][CH3:13])[N:6]=[C:5]2[Cl:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc2ccc(Br)cc2c(=O)[nH]1
Solvent: c1ccncc1
Product: CSc1nc(Cl)c2cc(Br)ccc2n1
Temperature: 110 °C
Yield: 75 %

Procedure:
To a suspension of compound 5a (0.65 g, 2.4 mmol) in 6.2 mL of POCl3 was added 10 μL of pyridine and the mixture was heated at 110° C. for 18 hours. The reaction mixture was cooled to rt. and concentrated under reduced pressure. A saturated solution of 50 mL of aqueous NaHCO3 was added to the crude solid and the mixture was extracted with 50 mL of EtOAc. The organic layer was dried over MgSO4, concentrated under reduced pressure and purified by chromatography on a silica gel column. Elution with n-heptane/EtOAc (4:1) as eluent afforded 11a as a white solid (0.52 g, 75%). mp: 124° C.,
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([CH3:19])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:21].[K+].[OH2:26]>C(O)(C)(C)C>[OH2:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][N:10]=[C:11]([C:19]([OH:21])=[O:26])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A mixture of 4-[3-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)pyridine (5.8 g, 24.0909 mmol; prepared as set forth in Example A-4) and potassium permanganate (7.6916 g, 48.1818 mmol) in water (7.5 mL) and tert-butanol (10 mL) was heated to reflux at 95 to 100° C. for 6 hours (or until all the potassium permanganate was consumed) and stirred at room temperature overnight. The mixture was diluted with water (150 mL) and filtered to remove manganese dioxide. The aqueous filtrate (pH>10) was extracted with ethyl acetate to remove unreacted starting material. The aqueous layer was acidified with 1N HCl to a pH of about 6.5. A white precipitate was formed. This precipitate was collected by filtration, dried in air, and then dried in a vacuum oven overnight at 50° C. to give 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate (2.7677 g, 40.6%). The remaining product (0.21 g, 3.1%) was isolated from the mother liquid by reverse phase chromotograhpy. The total isolated yield of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate was 43.7%. Anal. Calc'd for C15H10N3FO2.H2O: C, 59.80; H, 4.01; N, 13.95; Found: C, 59.48; H, 3.26; N, 13.65. MS (MH+): 284 (base peak).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CC(O)=O>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C

Procedure:
To a stirring mixture of methyl 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetate (570 mg) in HOAc (5 mL) was added 6N HCl (10 mL). The reaction mixture was warmed to 80° C. for 2 h. The crude product mixture was concentrated under reduced pressure and directly taken to the next reaction without further purification. Method[1], MS (ESI) 278.1 [M+H], Retention time=0.666 min.
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].I([O-])(=O)(=O)=O>>[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]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:59])[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]
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-][I+3]([O-])([O-])[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)[C@H]21)C3(C)C

Procedure:
where R represents C6H5 (taxol analogue A or xyloside A), or CH3C=CHCH3 (taxol analogue B or xyloside B) or C5H11 (taxol analogue C or xyloside C) in a polar solvent (b) reacting the resultant solution with periodate for 20-40 hours at 20-40° C. to cleave the diol system of the xyloside into dialdehyde, (c) treating the generated dialdehyde in a mixture of polar solvent-organic acid mixture with salts of amines at 0-40° C. for 12-18 hours and (d) isolating the 10-deacetyl taxol A,B,C by chromatography.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si](C)(C)C)=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:36])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([S:21]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:16](=[O:36])[CH2:17]2)(=[O:23])=[O:22])=[CH:29][CH:28]=1)#[CH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(C#C[Si](C)(C)C)cc3)CC2=O)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1ccc(S(=O)(=O)N2CCN(CC3CCNCC3)C(=O)C2)cc1
Reaction time: 1 h
Yield: 124.4 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)-4-(4-iodobenzenesulfonyl)-4-piperidylmethyl]-2-piperazinone (1.13 g), which was produced according to a method described in Reference Example 54 using 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone and 4-iodobenzenesulfonyl chloride, in diethylamine (20 ml)-DMF (5 ml) were added trimethylsilylacetylene (244 mg), bis(triphenylphosphine)palladium chloride (II) (69 mg) and copper iodide (2 ml), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (hexane:acetone=1:1) to give brown crystals of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-[2-(trimethylsilyl)ethynyl]benzenesulfonyl]-2-piperazinone (825 mg). To a solution of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-[2-(trimethylsilyl)ethynyl]benzenesulfonyl]-2-piperazinone (534 mg) in toluene (10 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred for 1 hour. The reaction solution was concentrated, and the residue was dissolved in ethanol (20 ml). To the solution was added 1N sodium hydroxide (2 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added ethyl acetate, and the mixture was washed with 10% sodium carbonate solution and saturated brine, dried (MgSO4) and concentrated. Precipitated crystals were washed with ethanol-ether to give brown crystals of 4-(4-ethynylbenzenesulfonyl)-1-[4-piperidylmethyl]-2-piperazinone (450 mg). To 10% sodium carbonate solution was added bromopyridine hydrochloride (272 mg), and the mixture was extracted with ethyl acetate, dried and concentrated. To the residue were added 4-(4-ethynylbenzenesulfonyl)-1-[4-piperidylmethyl]-2-piperazinone (289 mg) and isoamylalcohol (10 ml), and the mixture was allowed to react at 130% overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added 10% sodium carbonate solution. The mixture was extracted with ethyl acetate-THF, and the extract was washed with saturated brine, dried and concentrated. The residue was purified with silica gel column chromatography (acetone:methanol=9:1→1:1), washed with water, and precipitated crystals were washed with acetone-ether to give powder of 4-(4-ethynylbenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (85 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)([O-])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]2[CH:16]=[C:15]3[C:14]([CH:21]=[CH:20][CH:19]=[CH:18]3)=[N:11]2)=[C:5]([CH3:10])[CH:4]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COc1ccc(-n2cc3ccccc3n2)c(C)c1
Yield: 62.9 %

Procedure:
A mixture of 4-methoxy-2-methylaniline (1.37 g, 10.0 mmol) and 2-nitrobenzaldehyde (1.51 g, 10.0 mmol) in tetrahydrofuran (30 mL) was stirred at reflux for 4 hours. The reaction was concentrated. To the residue was added triethyl phosphite (10 mL) and the mixture was stirred at reflux for 40 hours. The reaction was concentrated and purification by flash column chromatography gave 2-(4-methoxy-2-methylphenyl)-2H-indazole (1.5 g, 63%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.05 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.31-7.35 (m, 2H), 7.12-7.16 (m, 1H), 6.82-6.88 (m, 2H), 3.87 (s, 3H), 2.20 (s, 3H).