Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[NH:38]1[CH2:43][CH2:42][CH2:41][C@@H:40]([NH2:44])[CH2:39]1>C(C(C)=O)C(C)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:38]2[CH2:39][C@H:40]([NH2:44])[CH2:41][CH2:42][CH2:43]2)=[N:18][C:17]2[N:16]([CH3:29])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: N[C@@H]1CCCNC1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 95 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine dihydrochloride (11.5 gm) were added to the reaction mixture at 30° C. The reaction mixture was heated to 95° C. and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30° C. and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at room temperature. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution was added drop-wise at 30° C. The mixture was stirred for one hour at 30° C. and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45° C. Isopropyl alcohol (100 mL) was added to the residue and stirred for 3 hours at room temperature. Filtered the compound and washed with isopropyl alcohol (20 mL) and dried the compound at below 60° C. under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: FIG. 2, Purity: 99.0%
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N+:13]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[OH:26])([O-:15])=[O:14].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CCOC(C)=O>[C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:26][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DEAD (2.6 ml)was added to a mixture of 2-nitro-4-tert-butylphenol (2 g) and N,N-dimethylethanolamine (1.3 g) and Ph3P (4 g) in THF (50 ml). The reaction was stirred at RT for 1 h, diluted with EtOAc (50 ml) and washed with 1 N HCl twice. The aqueous layer was basified with NaHCO3, extracted with EtOAc twice and washed with H2O and brine. The organic layer was dried over Na2SO4 and evaporated to give {2-[4-(tert-butyl)-2-nitrophenoxy]ethyl}-dimethylamine. It was hydrogenated under H2 atmosphere to give {2-[4-(tert-butyl)-2-aminophenoxy]ethyl}-dimethylamine.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CCN(CC)CC>[O:11]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[N:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)Cl
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a solution of isoindoline-1,3-dione (2 g, 13.6 mmol) in Et3N (60 mL) was added ClCOOEt (2.55 g, 16.33 mmol) at 0° C. The mixture was warmed to room temperature and stirred at room temperature for 4 h. The mixture was filtered and the solid was partitioned between water (150 mL) and EtOAc (50 mL) and adjusted pH value to 6 with 1 N HCl. The organic layer was washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 1,3-dioxoisoindoline-2-carboxylate (1.67 g, 53.08%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[NH2:17][C:18]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][NH:20][N:19]=1>C(#N)C>[NH2:17][C:18]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:19]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1N
Temperature: 60 °C
Yield: 53.5 %

Procedure:
According to Scheme 15 Step 1: 1-(Chloromethyl)-4-methoxybenzene (12.9 mmol, 2.02 g) followed by K2CO3 (25.8 mmol, 3.56 g) were added to a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (12.9 mmol, 2.00 g) in acetonitrile (10 mL) and then the reaction mixture was heated at 60° C. for 3 hours. After evaporation of the solvent, a saturated solution of Na2CO3 was added and the aqueous phase was extracted with AcOEt. The organic phase was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (100:0 to 20:80) as eluent to afford ethyl 3-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (6.90 mmol, 1.90 g, 53%) as a white powder.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].CCN(CC)CC.[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][O:24][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
TBSCl (18.7 g, 124.3 mmol), Et3N (14.08 g, 139.2 mmol) and DMAP (194.3 mg, 8.9 mmol) were dissolved in CH2Cl2 (120 mL) and the solution was cooled to 0-5° C. (3-Bromophenyl)methanol (18.5 g, 99.4 mmol) was added dropwise to the solution. After the addition of the (3-bromophenyl)methanol, the mixture was warmed to room temperature and stirred for 2 h. 5% HCl was added to the reaction mixture to adjust the pH=4-5. Then the organic phase was separated and the aqueous layer was extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with water and dried over Na2SO4. After removing the solvent, 28.5 g of {[(3-bromophenyl)methyl]oxy}(1,1-dimethylethyl)dimethylsilane was obtained (Yield: 95.1%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:18]2[CH2:19][CH2:20][CH:15]([N:14]([CH3:21])[CH3:13])[CH2:16][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]

Procedure:
A solution of 4-fluoro-2-methoxy-1-nitrobenzene (1.711 g, 10 mmol), N,N-dimethylpiperidin-4-amine (1.410 g, 11.00 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.48 mL, 20.00 mmol) in anhydrous N,N-dimethylformamide (25 mL) was stirred at 70° C. overnight. The mixture was concentrated and the residue was mixed with water (60 mL), adjusted to pH 12, then extracted with CH2Cl2. The crude product was purified on a silica gel column eluting with 7.5% methanol in CH2Cl2 saturated with NH3 to provide the title compound. (ESI+) m/e 280.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>CN(C=O)C>[CH3:14][CH2:13][CH:12]([N:8]1[C:6]2=[N:7][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:3][N:4]=[C:5]2[N:10]=[C:9]1[OH:11])[CH2:15][CH3:16]
Reactant: CCC(CC)n1c(O)nc2ncc(Br)nc21
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CC)n1c(O)nc2ncc(C#C[Si](C)(C)C)nc21
Temperature: 80 °C
Yield: 80.2 %

Procedure:
A mixture of 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (3.75 g, 13.2 mmol)), trimethylsilylacetylene (2.8 mL, 19.8 mmol), PdC12(PPh)2 (0.93g, 1.32 mmol), Cul (0.5 g, 2.64 mmol) and triethylamine (5.5 mL, 39.5 mmol) in DMF (50 mL) was purged with N2 for 30 seconds followed by stirring at 80° C. After 3 hours the reaction mixture was diluted with EtOAc, washed with NH4Cl solution, dried over Na2SO4, and concentrated in vacuo. Purification with over silica gel (Biotage MPLC 10-80% EtOAc/hexanes) provided the title compound (3.2 g, 80%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([O-:14])=[O:13].[Na+].C(=O)(O)[O-].[Na+]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C([O-])CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
54.0 g (0.46 mol) of 4-aminobenzonitrile and 107.2 g (0.92 mol) of sodium chloroacetate were suspended in 730 mL of water, and the resulting mixture was stirred at reflux temperature for 4 hours. After cooling to room temperature, pH was adjusted to 8-9 with sodium bicarbonate. The resulting solution was washed with 2×200 mL of ethyl acetate, and 5M hydrochloric acid was added to the aqueous phase until pH=3. The precipitated solid was isolated by filtration, washed with 100 mL of water and dried to yield 57.1 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 70.9%. Purity (HPLC, method 3): 92.9%.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[C@@H:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].C([O-])(=O)C.[NH4+]>O1CCCC1.O.[Zn]>[OH:22][C@@H:18]([CH:19]([CH3:21])[CH3:20])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]1)=[O:24])=[O:23]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Zinc dust (1.30 g, 20.32 mmol) was added to a solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (400 mg, 0.92 mmol) in tetrahydrofuran (20 mL). This suspension was treated with a solution of ammonium acetate (1.10 g, 13.9 mmol) in water (7 mL). After stirring at room temperature for 16 h, zinc residues were filtered off and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and saturated potassium hydrogen sulfate solution, the aqueous layer was extracted with ethyl acetate (2×), the organic layers were combined and the volatiles were removed in vacuo. The residual acetic acid was azeotroped off with toluene (3×10 mL) to give crude (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid which was combined with crude [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-methyl-amine hydrochloride in anhydrous acetonitrile (15 mL) and N,N-diisopropylethylamine (0.801 mL, 4.60 mmol). This solution was then treated with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (464 mg, 1.22 mmol). After stirring at room temperature for 2 h, the volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and subsequently washed with saturated ammonium chloride solution and sodium bicarbonate solution. The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/acetone 1:0 to 0:1 to afford the title compound (318 mg, 58%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 0.85 (d, J=6.9 Hz, 3H), 1.00 (d, J=6.9 Hz, 3H), 1.33 (d, J=6.9 Hz, 3H), 1.69 (d, J=6.9 Hz, 3H), 1.72-2.15 (m, 6H), 2.98 (s, 3H), 2.85-2.95 (m, 1H), 3.80-3.90 (m, 1H), 4.30-4.40 (m, 1H), 5.25-5.35 (m, 1H), 5.95-6.10 (m, 1H), 7.45-7.78 (m, 1H), 7.65-7.72 (m, 1H), 7.80-7.90 (m, 1H), 8.18-8-38 (m, 2H). LCMS (m/z) 548.1, 550.1 [M+H], Tr=2.60 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N)ccc1Cl
Temperature: 86 °C
Yield: 93 %

Procedure:
2-Chloro-5-aminobenzoic acid (1.5 g, 8.74 mmol) was dissolved in methanol (8 ml) and sulphuric acid (1 ml) was added drop wise with stirring. The reaction mixture was then heated to 86° C. for 18 hr then allowed to cool to room temperature before solvent was removed in vacuo. The resultant purple solid was then dissolved in water and 5M NaOH solution was added until pH 7 was reached. This was then washed with ethyl acetate. The organics were dried over Na2SO4 and solvent was removed in vacuo to give the title compound as a purple oil (1.51 g, 8.12 mmol, 93%): LCMS: [M+H]+=186, Rt=0.88 min, 95% purity.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC#N.C([O-])(=O)C.[NH4+].C1C(=O)N([Br:26])C(=O)C1>>[Br:26][C:8]1[CH:9]=[C:2]([F:1])[C:3]([OH:10])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(F)c1O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: O=Cc1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
This material was prepared as reported in J. Molecular Catalysis A, 2007, 30-33. Commercial 3-fluoro-2-hydroxybenzaldehyde (0.280 g, 2 mmol) was dissolved in MeCN (10 mL, 191 mmol) and ammonium acetate (0.015 g, 0.200 mmol) and NBS (0.392 g, 2.200 mmol) were added at rt. The mixture was stirred at rt for 1 h. The reaction mixture was then concentrated and the crude compound was dissolved in a small amount of dichloromethane and charged to a 12 g silica gel cartridge which was eluted with a 25 min gradient of from 0% to 30% ethyl acetate in hexanes at 30 mL/min. Fractions containing product were pooled and concentrated in vacuo to give 5-bromo-3-fluoro-2-hydroxybenzaldehyde (0.43 g, 1.963 mmol, 98% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 10.89 (s, 1H) 9.87 (s, 1H) 7.39-7.65 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][C:12]([CH3:18])([CH2:16][OH:17])[C:13]([OH:15])=[O:14]>CN(C1C=CN=CC=1)C.CCOCC>[C:1]([O:17][CH2:16][C:12]([CH3:18])([CH3:11])[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(C)(CO)C(=O)O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (4.52 g, 58.2 mmol) was added dropwise to a cold (0° C.) pyridine solution (10 ml) of 2,2-dimethyl-3-hydroxypropionic acid (5.5 g, 46.5 mmol) and 4-DMAP (0.57 g, 4.65 mmol). After stirring overnight at ambient temperature, the reaction was poured into ether (200 ml). This mixture was washed with 10% HCl (2×20 ml), and saturated brine (2×25 ml) and the resulting ethereal solution was dried (MgSO4). Evaporation gave the title compound as a pale yellow solid which was used in the next step without further purification. NMR (CDCl3) δ4.13 (2H, s), 2.08 (3H, s), 1.26 (6H, s).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[CH3:8].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1>>[CH3:7][C:5]1[S:6][C:2]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([CH3:18])=[CH:10][CH:11]=2)=[C:3]([CH3:8])[N:4]=1
Reactant: Cc1nc(C)c(Br)s1
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNc2sc(C)nc2C)cc1

Procedure:
In analogy to the procedure described for the synthesis example 32 (step 1), the title compound (2,4-dimethyl-thiazol-5-yl)-(2-p-tolyl-ethyl)-amine (MS m/e: 247.0 [M+H]+) was prepared from 5-bromo-2,4-dimethyl-1,3thiazole and 2-(p-tolyl)ethylamine.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O.[NH2:21][NH2:22]>C(O)COCCO>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8](=[N:21][NH2:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: NN
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1ccccc1)c1cc(C(F)(F)F)ccc1N

Procedure:
In the manner given in Preparation 1, 5-(trifluoromethyl)-2-aminobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 5-(trifluoromethyl)-2-aminobenzophenone hydrazone.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH:12][OH:13]>C(OCC)C>[CH:9]1[CH:10]=[C:2]([C:1]([OH:6])=[O:11])[C:3]([C:4]([O:12][OH:13])=[O:5])=[CH:7][CH:8]=1
Reactant: OO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOCC
Product: O=C(O)c1ccccc1C(=O)OO
Temperature: 25 °C

Procedure:
To the mixture containing phthalic anhydride (2.22 g, 0.015 mole) and diethyl ether (25 mL), hydrogen peroxide solution (3.4 g; 0.03 moles; as 30% aqueous solution) was added and the reaction mixture was stirred at 25° C. to dissolve the anhydride. The reaction mixture was transferred to a separating funnel, ether layer was separated and aqueous layer was extracted with ether (3×10 mL). Combined ether extracts are dried over sodium sulfate and this solution of monoperphthalic acid was used.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].C([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)#N.O>C1(C)C(C)=CC=CC=1>[N:21]1[CH:22]=[CH:23][C:18]([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:8])=[CH:19][CH:20]=1
Reactant: N#Cc1ccncc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Benzophenone (54.6 grams, 0.3 mole) was charged into a 1 liter roundbottom three neck flask equipped with a mechanical stirrer, reflux condenser and dropping funnel. Xylene (300 ml) and sodium metal (16.6 grams, 0.72 mole) cut into small pieces were then added. The flask was heated slowly and refluxed under an inert atmosphere (nitrogen) with mechanical stirring for 30 minutes. 4-cyanopyridine (38.2 grams, 0.37 mole) dissolved in xylene (200 ml) was then added over a period of 1 hour, whereafter the mixture was refluxed for an additional three hours. The reaction mixture was then cooled to room temperature and water (300 ml) was carefully added. The solid was then filtered and washed with water and acetone to give 4-pyridyl diphenyl carbinol (73.1 grams, 93% yield)
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>CCCCCC.CCOC(C)=O>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:12]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Yield: 44 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 30 from 0.293 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one, (+) isomer and 0.290 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent gives 0.24 g of the expected product after crystallization from a DCM/iso ether mixture. αD25 =+127° (c=0.24; chloroform).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-].[NH4+]>C(#N)C.O>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([C:13]2[CH:12]=[N:11][N:10]([C:8]3([CH2:32][C:33]#[N:34])[CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:9]3)[CH:14]=2)=[N:20][CH:19]=1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (6, 327 g, 655 mmol) in acetonitrile (3 L) and water (300 mL) was added LiBF4 (614 g, 6.55 mol, 10.0 equiv). The resulting reaction mixture was stirred at 75° C. for overnight. The reaction mixture was cooled to 0° C. before a solution of ammonium hydroxide (NH4OH, 570 mL) in water (2.2 L) was added slowly to keep the temperature below 10° C. (pH 9-10). The mixture was stirred at room temperature for overnight. When the reaction was deemed complete, water (10 L) was added and the resulting mixture was vigorously stirred for 3 h at room temperature. The solids were collected by filtration, washed with water (6.7 L) and heptane (6.7 L), and dried in vacuum oven at 45° C. over the weekend. The dried solid was then dissolved in 20% MeOH in dichloromethane (12 L), and was purified by column chromatography on 1.3 Kg of silica gel eluting with a 20% MeOH in dichloromethane solution (18 L) to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 243.3 g theoretical, 83.8% yield) as an off-white solid. For 7: 1H NMR (300 MHz, d6-DMSO) 81.25 (t, 3H), 3.25 (q, 2H), 3.75 (s, 2H), 4.25 (d, 2H), 4.65 (d, 2H), 7.10 (d, 1H), 7.65 (dd, 1H), 8.50 (s, 1H), 8.70 (s, 1H), 8.95 (s, 1H), 12.2 (bs, 1H); MS: m/z calcd. 372.12. found: 372.0.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20](=[CH2:22])[CH3:21])[CH3:15].Cl>>[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20]([C:10]1[CH:11]=[C:6]([F:5])[CH:7]=[CH:8][C:9]=1[O:12][CH3:13])([CH3:22])[CH3:21])[CH3:15]
Reactant: COc1ccc(F)cc1
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 40 h

Procedure:
0.8 g of anhydrous aluminum chloride is added to 5 ml of 4-fluoranisole and 0.9 g of 2-hydroxy-4-methylene-2-trifluoromethyl-valeric acid ethyl ester. After 40 hours of stirring at room temperature, it is added to ice-cooled 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with 1N hydrochloric acid and water, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel with hexane/ethyl acetate (1:1), 1 g of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, melting point 38-390° C., is obtained.