Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[C:9]=2[C:23]#[C:24][C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1.[N+](=[CH2:30])=[N-]>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[C:9]=2[C:23]#[C:24][C:25]([O:27][CH3:30])=[O:26])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C#CC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C#Cc1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C

Procedure:
11.0 g of the crude 3-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)prop-2-ynoic acid were dissolved in 400 ml of diethyl ether, and ethereal diazomethane solution was added in portions until the reaction was complete according to TLC. The solvent was evaporated off and then the remaining crude ester was purified by column chromatography (silica gel; cyclohexane/dichloromethane 1:1). The title compound was obtained in a yield of 8.85 g, corresponding to 98% based on the dibromide employed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22](Br)=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[O:8])=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2cc(Cl)ccc2=O)sc1C(=O)NCc1ccccc1
Yield: 39 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 5-chloro-2-hydroxypyridine in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 39% yield: mp 173-174° C.; 1H NMR (300 MHz, CDCl3) δ 8.79 (d, J=2.4 Hz, 1H), 7.36-7.23 (m, 6H), 6.61 (d, J=9.9 Hz, 1H), 6.43 (s, 1H), 4.55 (d, J=5.4 Hz, 2H), 2.66 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 158.8, 152.4, 152.0, 141.0, 131.7, 128.7, 128.5, 127.8, 127.6, 123.8, 121.9, 115.5, 44.1, 17.2; MS (ES+) m/z 360.1 (M+1), 362.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[C:4]=1[NH2:22].[OH-].[Na+].[C:25](OC(=O)C)(=O)[CH3:26]>C(Cl)(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]3[C:6]([N:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:25]([CH3:26])=[N:22][C:4]=3[C:3]=1[O:2][CH3:1])=[N:7][CH:8]=[N:9]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)N=C(C)N3c1ccccc1

Procedure:
A solution of 6,7-dimethoxy-N4-phenyl-quinazoline-4,5-diamine (60 mg, 0.20 mmol) (from Example 1, Step C, supra) in acetic anhydride (2 mL) was heated at 150° C. for 2 hours. Aqueous NaOH solution was then added to the reaction mixture to a pH 10–12. The solution was diluted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/Et3N (1:0.04) as eluent to give the desired 8,9-dimethoxy-2-methyl-3-phenyl-3H-1,3,4,6-tetraaza-phenalene as a yellow solid. (Yield 20 mg, 62%).
Reaction SMILES: N1CCCCC1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O.[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:15]>O1CCOCC1>[C:14]([C:16](=[CH:12][C:8]1[S:7][CH:11]=[CH:10][CH:9]=1)[C:17]([O:19][CH3:20])=[O:18])#[N:15]
Reactant: O=Cc1cccs1
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: COC(=O)C(C#N)=Cc1cccs1

Procedure:
A solution of 1.0 ml of piperidine in 10 ml of dioxane was added carefully to a stirred solution of 33.65 g thiophene-2-carboxaldehyde and 29.7 g of methyl cyanoacetate in 40 ml of dioxane. On standing the reaction mixture overnight at room temperature a crystalline precipitate was obtained which was filtered off, washed with cold dioxane and dried in vacuo to give 1, as a solid, mp 104°-106° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][C:30]=1[C:39]#[N:40]>O1CCCC1>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:36])=[O:37])=[CH:31][C:30]=1[C:39]#[N:40]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Br)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a nitrogen purged solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 448 mg, 1.78 mmol) in tetrahydrofuran (7.5 mL) at −78° C. was added lithium hexamethyl disilazane (1.0 M in tetrahydrofuran, 1.96 mL). The reaction was stirred for 15 minutes before a solution of 4-bromo-3-cyanobenzenesulfonyl chloride (Preparation 27, 500 mg, 1.78 mmol) in tetrahydrofuran (7.5 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (3×10 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The material was purified by silica gel column chromatography (ISCO™ companion, 40 g column, 0-30% ethyl acetate in heptane gradient elution). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a colourless solid (883 mg, 73%)
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH3:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH:9]=1>O>[CH:4]([O:6][C:8]1[N:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[CH:21]=[CH:22][C:23]([C@@H:26]([NH:28][C:29]([CH:31]4[CH2:32][CH2:33]4)=[O:30])[CH3:27])=[CH:24][CH:25]=3)[CH2:18][CH2:19]2)[CH:9]=1)([CH3:5])[CH3:3]
Reactant: CC(C)O
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(C2CCN(c3cc(Cl)ncn3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(N2CCC(c3ccc([C@H](C)NC(=O)C4CC4)cc3)CC2)ncn1
Temperature: 80 °C

Procedure:
25 mg (1.04 mmol) Sodium hydride are added to 2 mL 2-propanol and heated at 80° C. for 10 min. After that time, 80 mg (0.21 mmol) (S)-cyclopropanecarboxylic acid (1-{4-[1-(6-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-ethyl)-amide (XIV.6) are added. The mixture is heated at 80° C. for 12 h. After that time, water is added and the mixture is extracted with dichloromethane. The solvent is evaporated and the residue is purified using reversed phase HPLC (column: Waters XBridge 5 μM; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(OC([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)=O)(C)(C)C>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:19]3[CH2:26][CH:25]4[CH:21]([CH2:22][NH:23][CH2:24]4)[CH2:20]3)[S:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: Clc1ccc2nc(N3CC4CNCC4C3)sc2c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 23 utilizing 2,6-dichloro-benzothiazole and hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester as starting materials.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH2:17]([N:19]([CH2:36][CH3:37])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(O)[C:27]#[CH:28])=[CH:22][CH:21]=1)[CH3:18]>C1(C)C=CC=CC=1>[CH2:36]([N:19]([CH2:17][CH3:18])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:12][C:5]3[C:6]4[C:11]([C:2]([OH:1])=[C:3]([C:13]([O:15][CH3:16])=[O:14])[C:4]=3[CH:28]=[CH:27]2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:22][CH:21]=1)[CH3:37]
Reactant: C#CC(O)(c1ccccc1)c1ccc(N(CC)CC)cc1
Reactant: COC(=O)c1cc(O)c2ccccc2c1O
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(C2(c3ccccc3)C=Cc3c(C(=O)OC)c(O)c4ccccc4c3O2)cc1
Yield: 55.7 %

Procedure:
Methyl 1,4-dihydroxynaphthalene-2-carboxylate (4.00 g, 18.3 mmol), 1-(4-diethylaminophenyl)-1-phenyl-prop-2-yn-1-ol (4.67 g, 18.3 mmol) and Al2O3 (4.5 g) in toluene (150 mL) was refluxed for 3 hrs, filtered whilst hot and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (20% hexane) as eluent followed by a second filtration through silica using DCM as eluent. The residue was crystallised from acetone-MeOH and the product isolated as a yellow solid (4.89 g, 56%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:27]=[C:26]4[C:21]([CH:22]=[N:23][C:24]5[N:25]4[N:28]=[C:29]([CH3:31])[CH:30]=5)=[CH:20][C:19]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:31][C:29]1[CH:30]=[C:24]2[N:23]=[CH:22][C:21]3[CH:20]=[C:19]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH2:7])[CH2:11][CH2:10][CH2:9]5)=[CH:17][CH:16]=4)=[N:27][C:26]=3[N:25]2[N:28]=1
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)nc3n2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Compound (4-2) (7 mg, 0.14 mmol, 1 eq.) in CH2Cl2 (3 mL) was added trifluoroacetic acid (1 mL) and the mixture stirred at room temperature for 15 minutes. The volatiles were removed under reduced pressure and the residue was purified by reverse phase HPLC using TFA:CH3CN and water as the eluant to provide Compound (4-3). MS (M+H)+: observed=406.2027, calculated=406.2032
Reaction SMILES: [CH3:1][C:2]([S:7]([CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:9])=[O:8])([CH3:6])[C:3]([OH:5])=O.[NH2:17][C:18]1[O:22][N:21]=[C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])[CH:19]=1>>[C:24]([C:23]([CH3:27])([CH3:26])[C:20]1[CH:19]=[C:18]([NH:17][C:3](=[O:5])[C:2]([CH3:1])([S:7]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH3:6])[O:22][N:21]=1)#[N:25]
Reactant: CC(C)(C#N)c1cc(N)on1
Reactant: CC(C)(C(=O)O)S(=O)(=O)CC1CCOCC1
Product: CC(C)(C#N)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCOCC2)on1

Procedure:
Prepared according to procedure of example 1 starting from 100 mg (0.40 mmol) of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid (intermediate 2) and 66.4 mg (0.44 mmol) 2-(5-amino-isoxazol-3-yl)-2-methyl-propionitrile (intermediate 7).
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[C:6]([C:14]1[C:15](=[O:25])[CH:16]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:18][CH:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.OO>CN(C)C=O.O>[C:6]([C:14]12[O:3][CH:19]1[O:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][C:15]2=[O:25])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cc(=O)c(C(=O)c2ccccc2)co1
Agent: OO
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=CC(=O)C2(C(=O)c3ccccc3)OC2O1
Reaction time: 1 h

Procedure:
Solid sodium acetate (2.0 g) was added to a stirred solution of this ester (5.4 g) in dimethylformamide (80 ml) at 0°-5° C. 30% Hydrogen peroxide solution (10 ml) was added dropwise over 15 minutes and the mixture was stirred for a further 1 hour at 0°-5° C. then slowly diluted with water (240 ml). The solid product was dried and recrystallised from ether-petroleum ether 40°-60° C. to give the epoxide, ethyl 6-benzoyl-5-oxo-2,7-dioxabicyclo-[4.1.0]hept-3-ene-3-carboxylate (mp 96°-98° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[CH:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1.[Cl:36]N1C(=O)CCC1=O.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[Cl:36][C:7]1[C:8]2[N:9]([CH3:17])[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[C:13]=2[N:5]([CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[Cl:1])[C:6]=1[N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:19]1
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(c(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in N,N-dimethylformamide (20 ml) was added N-chlorosuccinimide (294 mg), and the resulting mixture was stirred overnight at room temperature. The reaction solution was adjusted to pH 2 with a 10% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (917 mg).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1C(C(O)=O)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=[CH:9]1>CN(C=O)C.C(Cl)Cl>[CH3:7][N:8]1[C:1]([C:2]([Cl:4])=[O:3])=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=[CH:9]1
Reactant: Cn1cnc(-c2ccccc2)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccccc2)c1C(=O)Cl
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.35 mL) followed by one drop of DMF was added to 1-methyl-4-phenyl-1H-imidazole-5-carboxylic acid (intermediate 3) (732 mg) suspended in anhydrous DCM (6 mL). After stirring for 1 hour under inert atmosphere the mixture was evaporated to dryness and used immediately without further purification (800 mg, 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C(OCC)C>[N+:10]([C:9]1[C:5]([CH2:3][OH:2])=[N:6][N:7]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1nn(C2CCCCO2)cc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
A stirred solution of 4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester [500 mg, Reference Example 54(a)] in tetrahydrofuran (20 ml) under nitrogen at −78° C. was treated dropwise with a solution of diisobutylaluminium hydride in tetrahydrofuran (8.82 ml, 1M). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was taken up in diethyl ether (100 ml) and quenched with water (150 ml). The resulting suspension was filtered through celite and the organic layer was collected from the filtrate, then dried over magnesium sulfate and then evaporated to yield [4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-methanol (349 mg) as a peach oil. LC-MS (Method H): RT=2.08 minutes, 250.29 (M+H+Na)+.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+]>[CH2:7]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](O)[C@@H](C)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](C)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
5.00 g (44.6 mmol) of potassium tert.-butylate was added to a solution of 4.00 g (44.4 mmol) (2R,3R)-butane-2,3-diol in 300 ml THF at room temperature and the mixture was refluxed for 15 minutes. The mixture was cooled to approx. 50° C. and 5.3 ml (44.6 mmol) benzyl bromide was added. It was refluxed for 3 hours, and was then stirred overnight at room temperature. The mixture was diluted with ethyl acetate and sodium chloride solution and then washed with 1N hydrogen chloride solution (1×) and sodium chloride solution (2×). The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 1:1). 3.41 g (18.9 mmol; yield: 43%) of the product was obtained.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:40])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].C(#N)C>O>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@@:14]2([OH:40])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:6].[OH2:6].[OH2:6]
Reactant: 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)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Solvent: O
Solvent: CC#N
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)OC(C)(C)C)c4ccccc4)C[C@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C

Procedure:
In accordance with the third aspect of the present invention, a process of producing docetaxel trihydrate is provided. The process comprises a) combining anhydrous docetaxel, and acetonitrile; b) heating the mixture of step a) to about 30-60° C.; c) adding water to the mixture of the heated mixture of step d); cooling the mixture of c) to about 10-30° C. to obtain a slurry; and e) filtering, washing, and drying the slurry of step d) to obtain docetaxel trihydrate.
Reaction SMILES: [S:1]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=O)[CH2:3][CH2:2]1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1>CCO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[NH:21][C:4]1[C:5]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=3[S:1][CH2:2][C:3]2=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCSc2ncccc21
Agent: Cl
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CSc1ncccc1-3

Procedure:
A mixture of 2,3-dihydro-thiopyrano[2,3-b]pyridin-4-one (2.24 g, 13.6 mmoL) and 4-methoxy-phenylhydrazine HCl salt (2.60 g, 14.9 mmoL) in EtOH (10 mL) was refluxed for 5 hours. The reaction mixture was cooled and filtrated through a pad of Celite to remove any solids in the mixture. The solvent was removed in vacuo. The remaining residue was partitioned between EtOAc and saturated NaHCO3. The aqueous phase was extracted two times with EtOAc. The organic layer of each extraction was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes:EtOAc1:1 as eluent) to yield the title compound as a pale solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[C:14][Si](C)(C)C)[CH:8]=2)[O:3]1.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[CH3:1][C:2]1([CH3:19])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[CH:14])[CH:8]=2)[O:3]1
Reactant: CC1(C)CC(=O)c2cc(C#C[Si](C)(C)C)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc2c(c1)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
To a solution of 2,2-dimethyl-6-trimethylsilanylethynyl-chroman-4-one (Compound 261, 4.05 g, 14.87 mmol) in 60.0 mL of MeOH was added K2CO3 (410.9 mg, 2.97 mmol) The resulting mixture was stirred at room temperature for 24 hours, diluted with EtOAc (100 mL) and washed with H2O and saturated aqueous NaCl, and dried over Na2SO4. Concentration of this solution under reduced pressure afforded 2.71 g (91%) of the product as a tan solid. 1H NMR (300 MHz, CDCl3) δ: 8.01 (1H, d, J=2.2 Hz), 7.56 (1H, dd, J=2.2, 8.6 Hz), 6.90 (1H, d, J=8.6 Hz), 3.02 (1H, s), 2.74 (2H, s), 1.47 (6H, s).
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].NC(N)=[S:13].[OH-].[K+]>C(O)C>[SH:13][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1S
Temperature: 25 °C

Procedure:
2-mercapto-3-nitropyridine was prepared by treating 3-nitro-2-chloro-pyridine (50 g, 0.0317 mol) with thiourea (24 g, 0.0317 mol) in 200 mL of ethanol at reflux for several hours. After the reaction mixture was allowed to cool, 7.19 mL solution of KOH (42.8 g in 115 mL of water) was added and the resulting mixture was heated at reflux for 3 hours. The crude reaction mixture was cooled to room temperature and then concentrated to 50% of its volume in vacuo. After diluting with 300 mL of water, the product was isolated by vacuum filtration as an orange solid that was used without further purification. MS (DCI/NH3) m/z 157 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 5.76 (m, 1H), 7.67 (dd, J=8.46, 4.78 Hz, 1H), 8.63 (dd, J=8.46, 1.47 Hz, 1H), 8.73 (dd, J=4.60, 1.65 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].CN(C=O)C.[CH:16]([NH:18][NH2:19])=O.[H-].[Na+]>O>[N:19]1[N:18]=[CH:16][N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[S:10][C:9]=12
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)sc1nncn12
Temperature: 160 °C

Procedure:
Five grams (30.0 mmoles) of o-chlorophenylisothiocyanate were dissolved in 50 ml. of dry DMF. A solution of 1.8 g. (30.0 mmoles) of formylhydrazine in 50 ml. of dry DMF was added dropwise rapidly to the stirred reaction mixture. The temperature of the reaction rose to about 45° C. The temperature was maintained between 60° C. and 100° C. for 24 hours. Thirty millimoles, 1.5 g., of sodium hydride as a 50% mineral oil suspension was added to the reaction mixture. The reaction was completed by heating at reflux temperature (160° C) for about 185 hours. The cooled mixture was poured into water. The aqueous mixture was extracted with n-hexane to remove mineral oil. The product was extracted with ethyl acetate. The ethyl acetate extract was washed (water), dried (MgSO4) and evaporated in vacuo to a residual oil. the oil was covered with dry ether an the product crystallized upon standing. The yield of s-triazolo[3,4-b]benzothiazole, m.p. about 175°-176° C., was 200 mg.