Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][CH:14]([N:17]([CH3:32])[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)S(C)(=O)=O
Temperature: 50 °C

Procedure:
The product of Example 1 (52 mg, 0.11 mmol) in tetrahydrofuran (3 ml), cooled to 0° C. was treated with sodium hydride (11 mg, 0.28 mmol) After 10 minutes methyl iodide was added (70 μL, 1.1 mmol) and the reaction heated to 50° C. for 4 hours, then extracted into ethyl acetate and washed with H2O, dried (MgSO4) and evaporated. Product was purified by chromatography (25% ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3) δ 7.36-7.26 (4H, m), 7.04-7.01 (2H, m), 6.79-6.71 (1H, m), 3.91-3.84 (1H, m), 3.24-3.19 (2H, d, broad), 2.91 (3H, s), 2.86 (3H, s), 2.64-2.57 (2H, dd, J=12.5, J=3.8), 2.06-2.01 (2H, m), 1.85-1.76(2H, m). m/z=500, 502 [MNa]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.C[Si](C)(C)[O:32][C@@H:33]1[C@@H:38]([O:39][Si](C)(C)C)[C@H:37]([O:44][Si](C)(C)C)[C@@H:36]([CH2:49][O:50][Si](C)(C)C)[O:35][C:34]1=O>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:34]2[C@H:33]([OH:32])[C@@H:38]([OH:39])[C@H:37]([OH:44])[C@@H:36]([CH2:49][OH:50])[O:35]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCCC2)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-(cyclopentyloxy)ethoxy)benzyl)benzene (Intermediate AC) (0.41 g) in anhydrous toluene/THF (v/v=2:1, 10 mL), n-BuLi (1.3 eq) was added dropwise at −78° C. and stirred for 1 h. Then the mixture was transferred to a solution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one) (1.5 eq) in anhydrous toluene (10 mL) at −78° C. The mixture was stirred at −78° C. for 2 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH), and the mixture was allowed to warm to room temperature and stirred overnight. Then 20 mL of water was added. The organic phase was separated, and the water phase was extracted with EtOAc. The organic phases were combined, washed with saturated NaHCO3, water and brine, and then dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified on a flash column (0.8 g, Rf=0.1-0.2, EA:PE=2:1) to collect the crude product. The crude product was dissolved in anhydrous CH3CN (10 mL), Et3SiH (1 mL) was added, the mixture was cooled to −5° C., and BF3.Et2O (0.6 mL) was added dropwise. Then the reaction was allowed to warm to 20° C. and stirred overnight. After the reaction reached completion, it was quenched with saturated aqueous NaHCO3. The solvent was removed under reduced pressure and the residue was extracted with EtOAc and washed with water and brine. The product was dried with anhydrous Na2SO4, filtered, concentrated to a solid, and purified by preparative HPLC to obtain compound AD as a white powder upon freeze-drying. 1H NMR (CD3OD): δ 7.30 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.07 (m, 5H), 3.87 (s, 1H), 3.71 (m, 3H), 3.15 (m, 1H), 3.10 (m, 2H), 3.07 (m, 6H), 1.72 (m, 6H), 1.55 (m, 2H); MS ESI (m/z): 494 (M+H)+, calc. 493.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[Cl:20][C:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[C:26]([NH:27][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Reactant: Nc1cccnc1Cl
Product: CN(C)C1CCc2[nH]c3ccc(C(=O)Nc4cccnc4Cl)cc3c2C1
Yield: 9 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and 2-chloro-3-aminopyridine, 1.2 mg (9%) of the title compound were recovered.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[CH3:29][CH:30]([CH3:50])[C:31](=[O:49])[CH2:32][NH:33][C:34]([CH2:36][CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O>ClCCl>[CH:30]([C:31]1[O:49][C:34]([CH2:36][CH2:37][NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N:33][CH:32]=1)([CH3:50])[CH3:29]
Reactant: CC(C)C(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cnc(CCNC(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
100.00 g (215 mmol) PS-triphenylphosphine are suspended in 1000 ml dichloromethane, 59.92 g (236.06 mmol) iodine are added. The mixture is stirred for 0.1 hours at ambient temperature, then 65.32 ml (470.24 mmol) triethylamine are added dropwise. 28.80 g (94.91 mmol) benzyl [2-(3-methyl-2-oxo-butylcarbamoyl)-ethyl]-carbamate dissolved in 200 ml dichloromethane are added. The reaction mixture is stirred for 16 hours at ambient temperature. If the reaction is incomplete, a further 0.1 eq triphenylphosphine and 0.1 eq iodine are added. The mixture is stirred for 16 hours at ambient temperature, then the precipitate is filtered off. The filtrate is evaporated down, the residue is extracted with water and chloroform, the organic phase is dried and evaporated to dryness. The residue is purified by chromatography.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C1C(=O)N([Cl:17])C(=O)C1>>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(N)c1
Reactant: O=C1CCC(=O)N1Cl
Product: CCc1cc(N)ccc1Cl

Procedure:
Prepared from 7.36 g of 3-ethyl-phenylamine and 8.12 g NCS. Yield: 4.4 g. LC-MSD, m/z for C8H10ClN [M+H]+=156.0, 158.0;
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:39].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:17][CH2:18][C:19]([OH:39])=[O:20])[S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1(N(CCCO)S(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)CCCC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of the crude 1-[(4'-fluorobiphenyl-4-sulfonyl)-(3-hydroxypropyl)amino]cyclopentanecarboxylic acid benzyl ester (22.1 grams) in acetone (400 mL) was cooled in an ice bath and treated with Jones reagent (about 20 mL) until an orange color persisted. The mixture was stirred from 0° C. to room temperature over 2 hours. After quenching excess oxidant with isopropanol (1 mL), Celite™ was added and the mixture was filtered. The filtrate was concentrated under vacuum. The residue was taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated to afford crude 1-[(2-carboxyethyl)-(4'-fluorobiphenyl-4-sulfonyl)amino]-cyclopentanecarboxylic acid benzyl ester as an oil (21.4 grams).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[S:3][C:4]=3[CH:10]=2)[CH:13]=[CH:14][C:15]=1[CH3:32])=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CO)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 53 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.452 mmol) produced in Example A7(vi) in pyridine (4.0 mL) was added 2-chloro-2-oxoethyl acetate (107 μL, 0.994 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (4.0 mL). 1N Aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine (50 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (120 mg, 53%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(Br)cc(C)c1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1O[Si](C)(C)C(C)(C)C
Yield: 86.6 %

Procedure:
Dissolve 4-bromo-2,6-dimethylphenol (30.16 g, 150 mmol) and imidazole (26.6 g, 390 mmol) in CH2Cl2. Added t-butyldimethylchlorosilane (36.17 g, 240 mmol) and stirred mechanically for 3 h. The solids were vacuum filtered and the filtrate concentrated. Suspended the resulting residue in water and extracted with ethyl acetate (2×150 mL). The combined organic portions were washed with water (150 mL) and brine (150 mL) and then dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. Purify on a Waters Prep 2000 LC (hexanes) to give 40.96 g of the title compound as a clear liquid. 1H NMR(CDCl3): δ6.91 (s, 2H), 2.00 (s, 6H), 0.86 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: CO[N:3]1[C:7]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=2[N:5]=[C:4]1[C:18]([F:21])([F:20])[F:19].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(Cl)(Cl)Cl>CO>[N+:12]([C:11]1[C:6]2[NH:5][C:4]([C:18]([F:21])([F:20])[F:19])=[N:3][C:7]=2[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1)([O-:14])=[O:13]
Reactant: COn1c(C(F)(F)F)nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc21
Reactant: C1CCNCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2[nH]c(C(F)(F)F)nc2c1N1CCCCC1
Reaction time: 3 h

Procedure:
A 450 mg. portion of 1-methoxy-4,6-dinitro-2-(trifluoromethyl) benzimidazol was dissolved in methanol, and 150mg. of piperidine was added at room temperature. The reaction mixture was constantly stirred, and the progress of the reaction was monitored by thin-layer chromatography. After about 3 hours, the solvent was evaporated under vaccum, and the residue was taken up in water and acidified to pH 3. The mixture was then extracted with ethyl acetate, and the product was isolated by chromatography of the organic layer, using chloroform as the eluent. The product was recrystallized from ethanol-water, and was identified as 4,6-dinitro-7-piperidino-2-(trifluoromethyl) benzimidazole, m.p. 207° -209° C., by nuclear magnetic resonance analysis and elemental microanalysis, the results of which follow. The yield was about 70 mg.
Reaction SMILES: [CH3:1][C:2](=[O:5])[C:3]#[CH:4].[N+:6](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N-:7]>CCOCC>[CH2:12]([O:11][C:9]([C:8]1[CH:4]=[C:3]([C:2](=[O:5])[CH3:1])[NH:7][N:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#CC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1cc(C(C)=O)[nH]n1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
A 500 ml Erlenmeyer flask was charged with 25.0 g of 3-butyne-2-one and ethyl ether (200 ml). To the resulting solution, 41.9 g of ethyl diazoacetate were added slowly with stirring. After 30 minutes of stirring, the ether solution began refluxing by itself. After stirring for 1 hour, the mixture was chilled at 0° C. for 1 hour and filtered to yield 28.5 g of 5-acetylpyrazole-3-carboxylic acid ethyl ester as white solids, mp 114°-115° C. NMR: 1.42 (t, 3H), 2.62 (s, 3H), 4.44 (q, 2H), 7.36 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(N(CC)CC)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:37]([NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:38])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and phenyl isocyanate in substantially the same manner as described in Example 61 with one change: no triethylamine was used; off-white solid: MS (EI) m/z 512.2 (M+H)+; 1H NMR (DMSO-d6): δ 6.90 (d, J=7.7 Hz, 1H), 6.96 (t, J=7.3 Hz, 1H), 7.20-7.30 (m, 3H), 7.35-7.47 (m, 6H), 7.57 (t, J=7.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.83 (d, J=7.7 Hz, 1H), 8.35 (d, J=6.9 Hz, 1H), 8.66 (s, 1H), 8.74 (s, 1H), 9.14 (s, 1H).
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[OH:3].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13]>O>[OH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][C:1](=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: NCCOCCO
Reactant: CC(O)C(=O)O
Solvent: O
Product: CC(O)C(=O)NCCOCCO

Procedure:
Equimolar quantities of lactic acid and 2-(2-aminoethoxy)ethanol were mixed together. This mixture was then heated to 120° for 2 hours and the resulting water of reaction was continuously removed. The final product was a viscous, amber colored liquid.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][C:5](O)([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[Cl-].[NH4+]>N1C=CC=CC=1>[F:1][C:2]1([F:19])[CH2:7][CH2:6][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)C1(O)CCC(F)(F)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(OCc1ccccc1)C1=CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl 4,4-difluoro-1-hydroxycyclohexanecarboxylate (1.8 g, 6.66 mmol) in 13 ml of pyridine was added phosphorous oxychloride (1.12 g, 7.33 mmol). The resulting solution was stirred under nitrogen at room temperature for 18 hours, and then poured into 70 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with 2 molar hydrochloric acid solution and brine and then dried over sodium sulfate. Filtration and concentration under vacuum afforded the crude product which was purified by chromatography on silica gel eluting 2% ethyl acetate in hexanes to give benzyl 4,4-difluorocyclohex-1-ene-1-carboxylate as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(OCc3ccccc3)nc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCc3ccccc3)nc21
Yield: 95.2 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.00 g of 5-{4-(5-benzyloxy-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 95) was treated with 12 ml of a 3:1 by volume mixture of acetic acid and water. After working up the product as described in Example 12, the resulting crude product was crystallized by trituration with ethyl acetate, to give 0.63 g of the title compound, melting at 210°-211° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH:10]=O)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].[CH2:27]([NH2:29])[CH3:28]>CCOCC.C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][NH:29][CH2:27][CH3:28])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CNCC)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and ethylamine, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): δ 7.06 (m, 4 H), 3.18 (m, 4 H), 2.32 (q, J=7.4 Hz, 2 H), 2.15 (t, J=5.2 Hz, 2 H), 1.13 (m, 18 H), 0.839 (t, J=7.4 Hz, 3 H), 0.698 (t, J=6.6 Hz, 3 H). FAB-MS: calcd for (C25H37FN2) 384, found 385 (M+H). Anal. Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.85; H, 9.50; N, 6.99; F, 4.79. mp 48-50° C. Rf=0.1 (20% ether/CH2Cl2).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:46]([CH3:45])[N:47]=[N:48][N:49]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Cn1nnnc1CCl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cn1nnnc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as white solid. MS (m/e): 379.3 (MH+).
Reaction SMILES: [C:1]1([NH:11][C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1cccc2ccccc12
Solvent: C1CCOC1
Product: c1ccc(COc2cccc(CCNc3cccc4ccccc34)c2)cc1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of N-naphthyl-2-[3-(phenylmethoxy)phenyl]acetamide (3.00 g, 8.16 mmol) in tetrahydrofuran (25 mL) under nitrogen was added a solution of 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran (12.3 mL, 12.3 mmol) and heated to reflux for 5 hours. The reaction was quenched with a 5% hydrochloride solution. After stirring 30 minutes, the reaction was basified with a 10% sodium carbonate solution and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound (2.724 g, 94% yield): 1H NMR (CDCl3) 7.78 (d, 1H), 7.67 (d, 1H), 7.18-7.46 (m, 10H), 6.89 (m, 3H), 6.66 (d, 1H), 5.01 (s, 2H), 4.40 (br, 1H), 3.55 (t, 2H), 3.05 (t, 2H); ES−MS (m/z) 354 [M+H]+.