Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]([N:10]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:11]1[C:12]([CH3:25])=[C:13]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:9].[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:8]([N:10]([CH:26]1[CH2:31][CH2:30][N:29]([CH:33]([CH3:35])[CH3:32])[CH2:28][CH2:27]1)[C:11]1[C:12]([CH3:25])=[C:13]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:9]
Reactant: CC(C)=O
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C(C)C)CC1
Temperature: 23 °C
Reaction time: 144 h
Yield: 16.9 %

Procedure:
To a stirred solution of methyl 3-[ethyl(piperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoate TFA salt (crude material, 1.30 g, 3.36 mmol) in CH2Cl2 (20 mL) and AcOH (5 mL) was added acetone (590 mg, 10.1 mmol) and sodium triacetoxyborohydride (1.80 g, 8.40 mmol). The reaction mixture was stirred at 23° C. for 6 days and then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2 heptane/ethylacetate=5/1) to give the titled compound as oil (220 mg, 17% yield). 1HNMR (400 MHz, CDCl3) δppm; 7.79 (br. s., 1H), 7.44 (d, J=1.6 Hz, 1H), 3.91 (s, 3H), 3.10 (q, J=7.0 Hz, 2H), 2.86 (m, 2H), 2.61-2.75 (m, 2H), 2.53 (s, 3H), 2.06 (m, 2H), 1.70-1.80 (m, 2H), 1.58-1.69 (m, 2H), 1.00 (s×2, 6H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M+H] 387.2.
Reaction SMILES: C([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:25][CH3:26])[C:19]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=O)C.[CH3:27][NH:28][CH3:29]>>[ClH:24].[ClH:24].[CH3:26][O:25][C:18]1[C:19]([S:21](=[O:22])(=[O:23])[N:28]([CH3:29])[CH3:27])=[CH:20][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:17]=1
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2c1ccccc1
Reactant: CNC
Product: COc1cc2c(cc1S(=O)(=O)N(C)C)CCNCC2c1ccccc1
Product: Cl

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is treated with dimethylamine and then with refluxing hydrochloric acid to give 8-methoxy-7-(N,N-dimethylsulfamoyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH:12]=[CH:13][C:14](OC)=O)[CH:3]=1.[CH3:18][O-:19].[Na+].C[OH:22]>>[C:18]([CH2:14][CH:13]1[CH2:12][C:4]2[C:5](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[C:6]1=[O:8])([OH:22])=[O:19]
Reactant: CO
Reactant: COC(=O)C=Cc1cc(Cl)ccc1C(=O)OC
Reactant: C[O-]
Agent: [Na+]
Product: O=C(O)CC1Cc2cc(Cl)ccc2C1=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
108 g of methyl 4-chloro-2-(3-methoxy-3-oxo-1-propenyl)-benzoate are dissolved in 300 ml of methanol, and 80 g of sodium methoxide are then added. The mixture is then heated at 70° C. and some of the methanol is distilled off, such that the reaction mixture can still be stirred. After 2 h, 400 ml of toluene are added slowly, and the remaining methanol is removed. The mixture is then stirred for another 0.5 h and then cooled to room temperature. 10 g of acetic acid are then added dropwise to the mixture, which is then diluted with 500 ml of water and adjusted to pH 4-5 using 1 N hydrochloric acid. The toluene phase is concentrated until the product precipitates. Following filtration, the product can be recrystallized from hexane. This gives 93.5 g of 2-carboxymethyl-5-chloroindan-1-one.
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[CH:8]=1)[CH:3]([OH:6])CO.C(Cl)(Cl)(Cl)Cl.O.CC(O)(C)C>C(Cl)(Cl)(Cl)Cl.CC(O)(C)C.O>[F:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[CH:8]=1)[CH:3]=[O:6]
Reactant: O=C1OCc2cc(C(F)C(O)CO)ccc21
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: O=CC(F)c1ccc2c(c1)COC2=O
Reaction time: 1.5 h

Procedure:
NaIO4 (71 mg, 0.33 mmol) was added to a stirring solution of 5-(1-Fluoro-2,3-dihydroxypropyl)-2-benzofuran-1(3H)-one (30 mg, 0.13 mmol) in 5:2:2 CCl4-H2O-t-BuOH (5 mL) (the starting material was dissolved in CCl4-t-BuOH, and H2O was added last). After stirring 1.5 hours, the suspension was diluted with H2O (3 mL) and extracted with CH2Cl2 (50 mL). The combined organic extracts were washed with 10% aqueous NaHSO3 (8 mL) and water (8 mL), dried over Na2SO4 and evaporated. The residue was purified by prep-TLC to give the title product
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:34]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]([CH2:12][Br:34])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1
Reactant: Cc1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(-n2nc3ccccc3n2)c1O
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-3′-tert-butyl-5′-bromomethyphenyl)benzotriazole was prepared from the bromination of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)benzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 6.274 g (0.0223 mol) 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)benzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-3′-tert-butyl-5′-methyphenyl)benzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-3′-tert-butyl-5′-bromomethyphenyl)benzotriazole was 6.6 g (82%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1ccccc1
Yield: 34.6 %

Procedure:
Using the general method of Example 186 except that chloroform was used as the solvent, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with benzoyl chloride (972 mg, 5.55 mmol) to provide 700 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzamide as a white solid, m.p. 183.0-186.0° C. Analysis: Calculated for C23H25N5O2 0.5H2O: % C, 66.97; % H, 6.35; % N, 16.98; Found: % C, 67.16; % H, 6.18; % N, 17.07.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[C:23]([C@:25]1([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31])#[CH:24]>>[OH:32][C@@:25]1([C:23]#[C:24][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:22]=2)[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31]
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: NC(=O)c1nc2n(c1C(F)(F)F)CCOc1ccc(Br)cc1-2
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(F)(F)F)n2CCO3)C1=O
Yield: 48.3 %

Procedure:
10-bromo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 56 mg (48.3%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: [C:1]1([OH:21])[C:2]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[CH2:22]=[CH:23][CH3:24].[CH:25]1[C:30](Cl)=CC=C(Cl)[CH:26]=1>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W]>[CH:23]([C:3]1[CH:4]=[C:5]2[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:1]([OH:21])[C:2]=1[C:11]1[C:20]([CH:25]([CH3:30])[CH3:26])=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:24])[CH3:22]
Reactant: Oc1c(-c2ccc3c(c2)CCCC3)ccc2c1CCCC2
Reactant: Clc1ccc(Cl)cc1
Reactant: C=CC
Agent: [W]
Agent: P
Solvent: O
Product: CC(C)c1cc2c(cc1-c1c(C(C)C)cc3c(c1O)CCCC3)CCCC2
Temperature: 130 °C

Procedure:
A mixture of 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol (44.0 g), dichlorobenzene (10 ml) and phosphotungstic acid (2.3 g) was heated to 130° C. To the mixture was added excess propylene via a dry-ice condenser. The reaction was monitored by GC analysis. The reaction mixture contained 6% of monoisopropylated product and 83% of diisopropylated product. The mixture was purified by flash column to give 20.0 g of 3,3′-diisopropyl-5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1([CH3:21])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].CCOCC>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1([CH3:21])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:20][C:23](=[O:25])[CH3:24])=[C:16]([CH2:17][CH2:18][CH3:19])[C:9]=2[O:8]1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCc1c(OC(C)=O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.3 %

Procedure:
To a stirred solution of 0.8 g of racemic-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester in 8 ml of pyridine was added 0.37 ml of acetic anhydride. The solution was stirred at room temperature for 5 hours then poured into ice-water and worked up with ether in the usual manner (the combined ether extracts were additionally washed with 1N hydrochloric acid and saturated sodium bicarbonate solutions). The oily product (1.0 g) was chromatographed on 50 g of silica gel. Elution with 19:1 toluene-ethyl acetate afforded 0.575 g (63.3%) of racemic-7-acetoxy-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.N.O1CCOCC1>C1COCC1>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: Cc1cc(F)cc(C(=O)O)c1N
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(F)cc(C(N)=O)c1N
Reaction time: 3 h

Procedure:
To a solution of 2-amino-5-fluoro-3-methyl-benzoic acid (4.80 g, 28.4 mmol) in THF (60 ml) is added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.9 g, 56.8 mmol), 1-hydroxybenzotriazole hydrate (4.34 g, 28.4 mmol) and ammonia as 5 M solution in dioxane (283 ml, 142 mmol). The resulting slurry is stirred for 3 hours. The reaction mixture is filtered through Celite and washed with THF. The filtrate is evaporated and partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is crystallized from 2-propanol to afford 2-amino-5-fluoro-3-methyl-benzamide as beige crystals; HPLC/MS 1.68 min (B), [M+H] 169.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][C:8]([Cl:19])=[CH:7][CH:6]=2.[CH3:20][S:21][C:22]1[C:27]([N:28]=[C:29]=[O:30])=[C:26]([S:31][CH3:32])[CH:25]=[C:24]([CH3:33])[N:23]=1.C[N:35](C)C=O>C(OCC)(=O)C>[CH3:20][S:21][C:22]1[C:27]([NH:28][C:29](=[O:30])[NH:35][C:3]2[CH:2]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([Cl:19])[CH:9]=3)[N:4]=2)=[C:26]([S:31][CH3:32])[CH:25]=[C:24]([CH3:33])[N:23]=1
Reactant: CN(C)C=O
Reactant: CSc1cc(C)nc(SC)c1N=C=O
Reactant: Nc1cnc2ccc(Cl)cc2c1-c1ccccc1Cl
Solvent: CCOC(C)=O
Product: CSc1cc(C)nc(SC)c1NC(=O)Nc1cc(-c2ccccc2Cl)c2cc(Cl)ccc2n1
Temperature: 25 °C
Yield: 45 %

Procedure:
A solution of 3-amino-6-chloro-4-(2-chlorophenyl)quinoline (174 mg, 0.6 mmol) and 2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate (136 mg, 0.6 mmol) in 3 ml dimethylformamide was heated at 80° C. under nitrogen overnight. The reaction mixture was then cooled to room temperature, diluted with 30 ml ethyl acetate and washed with 2×30 ml water, 30 ml brine, dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The solid residue was triturated with 10 ml 4:1 hexane/ethyl acetate and filtered to yield the title compound as a white solid (140 mg, 45% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.Cl.CN(C)[CH2:15][CH2:16][CH2:17][N:18]=C=NCC.C1(N)CC1.O>CN(C)C=O>[CH:17]1([NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:15][CH2:16]1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1I
Yield: 98 %

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (10.5 g, 40 mmol), 1-(3-dimethlaminopropyl)-3-ethylcarbodiimide hydrochloride (9.2 g, 48 mmol) and cyclopropylamine (2.6 g, 45.6 mmol) in N,N-dimethylformamide (70 ml) was stirred at room temperature for 4 h. Water (250 mL) was added. The solution was extracted with ethyl acetate (200 mL×2), washed with saturated K2CO3 solution (200 mL) and water (200 mL). Organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the desired product (11.8 g, 98%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](OB(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].FC(F)(F)S(O[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26]([F:30])=[C:25]([O:31][C:32]([F:35])([F:34])[F:33])[C:24]([F:36])=[CH:23]2)(=O)=O.O.C1(C)C=CC=CC=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:26]1[C:27]2[C:22](=[CH:21][C:20]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[CH:29][CH:28]=2)[CH:23]=[C:24]([F:36])[C:25]=1[O:31][C:32]([F:35])([F:33])[F:34]
Reactant: O=S(=O)(Oc1ccc2c(F)c(OC(F)(F)F)c(F)cc2c1)C(F)(F)F
Reactant: CCCc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccc(-c2ccc3c(F)c(OC(F)(F)F)c(F)cc3c2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
7.3 g of 4-propylphenylboric acid and 11 g of 1,3-difluoro-2-trifluoromethoxynaphthalene-6-yl trifluoromethanesulfonate (obtained by triflating 1,3-difluoro-2-trifluoromethoxynaphthalene-6-ol with trifluoromethanesulfonic anhydride) were dissolved in 50 ml of DMF. To the solution was then added 0.4 g of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was stirred at a temperature of 85° C. for 8 hours. To the reaction solution were then added water and toluene. The resulting aqueous phase was then extracted with toluene. The material thus extracted and the organic phase were together washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain an oily matter. The oily matter thus obtained was purified through silica gel column chromatography (hexane/ethyl acetate=9/1), and then recrystallized from ethanol to obtain 6.3 g of 1,3-difluoro-2-trifluoromethoxy-6-(4-propylphenyl)naphthalene in crystal form.
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:30]=[CH:29][CH:28]=[CH:27][CH:26]=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:49]=[CH:48][CH:47]=[CH:46][CH:45]=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>C(O)(=O)C>[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:26]=[CH:27][CH:28]=[CH:29][CH:30]=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:49]=[CH:48][CH:47]=[CH:46][CH:45]=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: CC(=O)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
Product: O
Temperature: 45 °C
Yield: 328.1 %

Procedure:
Docetaxel anhydrous (about 0.8 Kg), acetonitrile (about 3.8 Kg) and glacial acetic acid (about 7.6 g) are charged into a suitable vessel. The mixture is heated to NMT 45° C., and purified process water (about 9.6 Kg) is added for precipitation. The slurry is filtered, washed and dried under a moist environment to provide docetaxel trihydrate (about 0.7 Kg).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]([C:26]([O:28]CC)=[O:27])=[C:23]([CH3:25])[N:24]=3)[CH2:16][C@H:15]2[F:31])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10].Cl.O>CO.O1CCCC1>[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]([C:26]([OH:28])=[O:27])=[C:23]([CH3:25])[N:24]=3)[CH2:16][C@H:15]2[F:31])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](F)C2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2F)nc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A 2 N aqueous lithium hydroxide solution (1.18 mL, 2.37 mmol) was added to a mixed solution of ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (196c) (105 mg, 0.237 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) at room temperature, and the mixture was stirred at 70° C. for two hours. The reaction solution was concentrated under reduced pressure. A 1 N aqueous hydrochloric acid solution (2.37 mL, 2.37 mmol) and water were added to the resulting residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure to obtain 72 mg of the title compound (73%) as a colorless solid.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[N:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27].Cl.CCOC(C)=O.N>C1COCC1>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[N:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27]
Reactant: COCCOCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Temperature: 65 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
6-(4-((2-Methoxyethoxy)methoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (6.31 mmol, 2.57 g) was dissolved in THF (42 ml) and hydrochloric acid (2M aq) (31.5 mmol, 15.77 ml) added. The mixture was heated to 65° C. for 4 hours, after which time LCMS indicated no reaction. THF (21 ml) was added and heating continued for 16 hours then EtOAc was added and the solution basified with aqueous ammonia. Organics were separated and solvent evaporated under reduced pressure. The resulting pale yellow solid was washed with EtOAc/ether (1:1) and dried to afford product 6-(4-hydroxy-3-(trifluoromethyl)-phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (82% yield). 1H NMR (DMSO) δ: 8.85 (s, 1H), 8.36 (s, 1H), 8.32 (d, 1H), 7.18 (d, 1H), 4.45 (s, 3H).
Reaction SMILES: [C:1]1(=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:31])(=[O:30])[N:21]=3)[C:10]2=[O:32])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:1]1([NH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:30])(=[O:31])[N:21]=3)[C:10]2=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 240C (0.099 g, 0.22 mmol) in tetrahydrofuran (4.0 mL) (0.099 g, 0.22 mmol) in tetrahydrofuran (4.0 mL) and methanol (0.020 mL, 0.49 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.16 mL, 0.32 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43 (m, 11 H) 1.87 (m, 1 H) 3.25 (m, 1 H) 5.53 (d, J=3.68 Hz, 1 H) 7.04 (m, 1 H) 7.28 (m, 2 H) 7.51 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.73 (d, J=8.46 Hz, 1 H) 8.05 (dd, J=7.72, 1.47 Hz, 1 H) 16.30 (s, 1 H). MS (ESI−) m/z 451 (M−H)−.