Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Br)ccc1OCc1ccccc1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (505 mg, 2.348 mmol) and cesium carbonate (1339 mg, 4.11 mmol) in DMF (5 ml) was added benzyl bromide (0.351 ml, 2.94 mmol) and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed 2 times with water, followed by brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford 709 mg of 1-[2-(benzyloxy)-5-bromophenyl]ethanone, 703 mg (2.304 mmol) of which were combined with BISPIN (731 mg, 2.88 mmol), PdCl2(dppf) (202 mg, 0.276 mmol), and potassium acetate (452 mg, 4.61 mmol) in 1,4-dioxane (2 ml)/DMSO (10 ml). The mixture was heated at 80° C. overnight. The solids were filtered through a silica plug washing with EtOAc. Water was added and the filtrate was extracted 3 times with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford 634 mg of 1-[2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone. A mixture of 64 mg (0.182 mmol) of 1-[2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone, 63 mg (0.105 mmol) of (4S,5R)-3-{[6-azetidin-1-yl-3-(5-chloro-2-methoxyphenyl)pyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 27), potassium carbonate (1M aqueous) (0.400 ml, 0.400 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (15 mg, 0.023 mmol) in 1,4-dioxane (1.5 ml) was heated at 120° C. with microwaves for 4 hours, then transferred to an oil bath at 120° C. overnight. The mixture was filtered through a silica plug, washing with EtOAc. The filtrate was concentrated and purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the title compound. Mass spectrum (ESI) 790.6 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH:7]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([N:16]([CH3:30])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:12][CH2:11]1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][N:16]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C@H:13]1[CH2:14][CH2:15][C@H:10]([O:9][CH:7]([CH3:8])[C:6]([OH:31])=[O:5])[CH2:11][CH2:12]1
Reactant: CC(O[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)C(=O)O
Reaction time: 3 h

Procedure:
A solution of 300 mg (0.64 mmol) of from trans-2-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid tert-butyl ester in 3 ml of CH2Cl2 was treated wit 0.5 ml (6.7 mmol, 10 eq) of trifluoroacetic acid and stirred at 40° during 3 h. Evaporation of the solvent gave 266 mg (quantitative) of trans-2-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid as an off-white solid, MS: 408 (M−H−).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][CH:26]=2)[NH:21]1>>[F:29][C:24]1[CH:23]=[C:22]2[C:27]([CH2:28][CH:20]([CH3:19])[N:21]2[C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:26][CH:25]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2ccc(F)cc2N1
Agent: [Na+]
Product: CC1Cc2ccc(F)cc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 74 %

Procedure:
The product is prepared by following the procedure described in example 21c using 115 mg of sodium (4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate (obtained in step 2c of example 1c) and 62 mg of (−)-2-methyl-6-fluoro-2,3-dihydro-1H-indole [reference example 9c, step 5c]. After silica column purification: eluent 98/02 then 95/05 dichloromethane/methanol, 113 mg of 2-[2-((+)-6-fluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][C:25]3[NH:26][CH:27]=[CH:28][N:29]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30]I.[H-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][C:25]3[N:29]([CH3:30])[CH:28]=[CH:27][N:26]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCc3ncc[nH]3)CC[C@H]2c2ccc(F)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCc3nccn3C)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=428.2 (M+H+) and [α]D20=−69.7° (c=0.2770 in chloroform), was prepared by methylation of (2R,5S)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole in accordance with the general method of example 8 (methyl iodide, sodium hydride).
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:7].[CH3:9][C:10]1([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH2:7][C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[NH:8][CH:26]1[CH2:25][CH2:24][N:23]([C:10]2([CH3:9])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Reactant: N[C@@H]1CCCC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@@H]3CCCC[C@@H]3N)CC2)CC1
Temperature: 25 °C

Procedure:
To a solution of cis-cyclohexane-1,2-diamine (0.850 mL, 7.22 mmol) in dichloromethane (10 mL) was added with tert-butyl 4-methyl-4-(4-oxo-1-piperidyl)piperidine-1-carboxylate (1.39 g, 3.61 mmol) in dichloromethane (5 mL) followed by sodium triacetoxyborohydride (0.918 g, 4.33 mmol) and the mixture stirred at room temperature over night. The mixture was then quenched with 1 N NaOH and dichloromethane was added. The phases were separated and aqueous phase was extracted with dichloromethane. The combined organic phases were dried and concentrated in vacuo to give the title product, which was used for the subsequent step without further purification. MS (M+1): 395.37.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:10]1[O:18][CH:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[O:7]([CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][OH:18])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: c1ccc(C2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC(Oc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A mixture of phenol (28.2 g), NaOH (4.0 g) and water (15 ml) was heated on a boiling water bath until the mixture became homogeneous. Styrene oxide (12.0 g) was added dropwise over a period of 15 minutes and the mixture was heated with stirring on a boiling water bath for 1 hr. The mixture was poured into a solution of NaOH (12.0 g) in ice water (200 ml) and extracted with ether (50 ml) 2 times. The ether solution was dried over anhydrous sodium sulfate and the solvent distilled off to obtain a crystalline product. Recrystallization from methylene chloride-hexane gave white crystals (6.6 g) of 2-phenoxy-2-phenylethanol.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10](O)=[O:11]>C1COCC1>[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[CH2:10][OH:11]
Reactant: Nc1cccc(F)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(F)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
LAH (987 mg, 26 mmol) was added slowly to a solution of 2-amino-6-fluoro-benzoic acid (2.69 g, 17.3 mmol) in dry THF (20 mL) at 0° C. The mixture was stirred at room temperature for approximately 1 hr and cooled to 0° C. again. Na2SO4.10H2O (10 g) was added slowly with stirring for 20 minutes. The mixture was filtered, the solid was washed with THF. The solution was concentrated to yield a yellow solid as (2-amino-6-fluoro-phenyl)-methanol (2.49 g). MS [M-OH]+: 124.1; tR=0.57 min. (method 1)
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].C([BH3-])#N.[Na+]>>[CH3:1][O:2][NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11]
Reactant: CON=Cc1ccccc1C
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccccc1C
Yield: 83 %

Procedure:
Reduction of 2-methylbenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (83% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.42 (3H, s, CH3), 3.55 (3H, s, OCH3), 4.11 (2H, s, NCH2), 5.64 (1H, s, NH), 7.19–7.32 (4H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 148–150° C. Anal. calcd. for C9H13NO—HCl: C, 57.60; H, 7.51; N, 7.46. Found: C, 57.59; H, 7.69; N, 7.52.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12](=[NH:18])[S:13][C:14]=2[CH2:15]OC)[N:9]=1)[NH2:3].[S:19]([NH2:23])([NH2:22])(=[O:21])=[O:20]>COCCO>[NH2:18][C:12]1[S:13][C:14]([CH:15]=[N:22][S:19]([NH2:23])(=[O:21])=[O:20])=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[N:11]=1
Reactant: COCc1sc(=N)[nH]c1-c1csc(N=C(N)N)n1
Reactant: NS(N)(=O)=O
Solvent: COCCO
Product: NC(N)=Nc1nc(-c2nc(N)sc2C=NS(N)(=O)=O)cs1
Temperature: 70 °C
Yield: 28.7 %

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-[2-(imino)(methoxy)methylthiazol-4-yl]thiazole (1.0 g) and sulfamide (1.36 g) in a 2-methoxyethanol (10 ml) was heated at 70° C. for 7 hours. The resulting precipitate was removed by filtration. The filtrate was chromatographed on a silica gel column eluting with ethyl acetate:methanol=3:1. Recrystallization from a mixture of N,N-dimethylformamide and water afforded 4-[2-(amino)(aminosulfonylimino)methylthiazol-4-yl]-2-(diaminomethyleneamino)thiazole (0.35 g).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(O)[CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(CC1CCNCC1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
The title compound was prepared by dissolving 20 g of alpha,alpha-diphenyl-4-piperidineethanol in 40 mL of anhydrous trifluoroacetic acid and stirring for 15 minutes. The volatiles were removed under vacuum and the residue was partitioned between toluene and 2N sodium hydroxide solution. The organic layers were dried over sodium sulfate, evaporated, and the residue was crystallized from hexane to give 17.2 g (92%) of 4-(2,2-diphenylethenyl)piperidine, mp 98°-99° C. Anal. Calcd for C19H21N: C, 86.65; H, 8,.04; N, 5.32. Found: C, 86.35; H, 7.97; N, 5.26.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].CN1C(=O)CCC1.[CH2:20]([Mg]Br)[CH:21]([CH3:23])[CH3:22]>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccnc(CC(C)C)c1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-isonicotinic acid ethyl ester (10.0 g, 63.3 mmol) in THF (150 mL), NMP (8.78 g, 88.6 mmol) and Fe(acac)3 (2.46 g, 6.96 mmol) is added under argon. The mixture is cooled to −74° C. before isobutylmagnesium bromide (47 mL of a 2 M solution in THF, 94.9 mmol) is added. The temperature rises to −65° C. The mixture is stirred at −75° C. for 1 h, then warmed to rt and carefully quenched with water. The mixture is extracted with EA, the org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-isobutyl-isonicotinic acid ethyl ester (3.00 g) as an oil, LC-MS: tR=0.74 min, [M+1]+=208.11.
Reaction SMILES: Br[CH:2]([C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CC(C)([O-])C.[K+]>CS(C)=O>[C:2]([C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(Br)C(Br)c1ccccc1OCCCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCC#Cc1ccccc1OCCCC(=O)OCC
Reaction time: 15 h

Procedure:
A solution of ethyl 4-[2-(1,2-dibromooctyl)-phenoxy]butanoate, (2.01 g, 4.20 mmole), potassium t-butoxide, (1.33 g, 11.1 mmole) and 18 crown6 (5 mg) in dry dimethylsulphoxide (25 ml) was stirred at ambient temperature for 4 h, then at 100° C. for 15 h. The reaction was evaporated in vacuo to a low volume, poured into saturated brine and acidified with dilute hydrochloric acid. The product was extracted with ethyl acetate (three times) and the combined organic phases washed with water (three times), and dried, (MgSO4). Evaporation in vacuo yielded the crude product as a pale brown oil, which was purified by column chromatography using silica gel and eluting with dichloromethane/petroleum ether 60°-80° C., (1:1). The intermediate bromoalkane was collected first, followed by 0.380 g (29%) of the acetylene as a colourless oil.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:10](Cl)[CH:11]=[C:12]([CH3:14])[CH3:13]>>[CH2:10]([C:3]1[C:4]([OH:5])=[CH:6][C:7]([OH:8])=[CH:9][C:1]=1[OH:2])[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: CC(C)=CCCl
Reactant: Oc1cc(O)cc(O)c1
Product: CC(C)=CCc1c(O)cc(O)cc1O

Procedure:
Phloroglucinol was treated with prenylchloride using the same procedure as described in Example 2 to yield prenylphloroglucinol. Prenylphloroglucinol was treated with butyrylchloride, according to the same procedure as described for the preparation of 2,4-dibutyrylphloroglucinol in Example 34 (Method 2) to yield 5,7-dihydroxy-6,8-dibutyryl-2,2-dimethylchroman (36) after chromatography with silica gel (petroleum ether, ethyl acetate, 4:1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH2:13][C@H:14]([CH2:19][NH2:20])[CH2:15][C:16]([OH:18])=[O:17])[CH3:12]>C1COCC1>[C:1]([NH:20][CH2:19][C@@H:14]([CH2:13][CH:11]([CH3:12])[CH3:10])[CH2:15][C:16]([OH:18])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](CN)CC(=O)O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C[C@H](CNC(=O)c1ccccc1)CC(=O)O
Reaction time: 18 h
Yield: 47 %

Procedure:
Benzoyl chloride (0.88 ml, 7.6 mmol) was added to a stirred suspension of pregabalin (1.0 g, 6.3 mmol) in THF (80 ml) at room temperature under argon and the reaction mixture was stirred for 18 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was chromatographed (SiO2, heptane-ethyl acetate, 1:1 to 3:7) to give 4 (0.78 g, 47%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)=[N:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>C(O)(C)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([OH:18])[CH2:16][CH2:17]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OC1CCN(CCCc2noc3cc(F)ccc23)CC1
Yield: 89.3 %

Procedure:
A solution of 5 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone and 1.4 g of sodium borohydride in 50 ml of isopropanol was stirred at ambient temperature for twenty hrs. The reaction mixture was quenched with methanol and concentrated. The residue was stirred with water and extracted with ether. The organic extracts were washed with water (2×), saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give 4.5 g (90%) of product. Recrystallization from ether gave the analytical sample, mp 88°-89° C.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3CCC#N)=[CH:17][C:16]=2[F:33])[CH2:11][CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:24]=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][NH:22]3)=[CH:17][C:16]=2[F:33])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCC#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2nc3[nH]cc(C(=O)O)c(=O)c3cc2F)CC1
Reaction time: 0.17 h

Procedure:
A solution of Example 66B was treated with trifluoroacetic acid (20 mL), stirred for 10 minutes and concentrated; and the concentrate was azeotroped with toluene and dried under vacuum. NMR (300 MHz, DMSO-d6) δ 15.26 (s, 1H), 13.36 (br s, 1H), 8.57 (s, 1H), 8.09 (m, 1H), 7.91 (br s, 3H), 4.46 (m, 2H), 4.02 (br s, 1H), 3.22 (m, 2H), 2.04 (m, 2H), 1.61 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:15]=2[N:16]=1>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: COC(=O)CO
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 54.1 %

Procedure:
To a suspension of 79 mg (3.30 mmol) of sodium hydride in 2 mL of benzene was added 225 mg (2.75 mmol) of methyl glycolate and a solution of 320 mg (0.91 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidine in 2 ml of benzene. The mixture was then heated at 60° C. After 24 hours the reaction was cooled to ambient temperature and an additional 40 mg of sodium hydride and 110 mg of methyl glycolate were added. After 3 days, the reaction was partitioned by the addition of 2 mL of 2 M sodium hydrogen sulfate and 20 mL of ethyl acetate. The organic phase was washed with 10 mL of water, dried with sodium sulfate and concentrated. The product was purified by flash chromatography (30 g silica, methylene chloride-heptane gradient 2:1 to 100:0) to provide 200 mg (54%) of [[2-(methylthio)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.26 (t, J=7.4 Hz, 3H), 2.53 (s, 3H), 2.56 (q, J=7.4 Hz, 2H), 3.79 (s, 3H), 5.05 (s, 2H), 5.35 (s, 2H), 6.31 (s, 1H), 6.92 (d, J=6.7 Hz, 1H), 7.08 (s, 1H), 7.21 (m, 2H)
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([NH2:19])[C:15]([Cl:18])=[N:16][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([NH:19][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:15]([Cl:18])=[N:16][CH:17]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzenesulfonyl chloride (2.24 ml, 17.5 mmol) was added dropwise over 5-10 mins to a solution of 5-bromo-2-chloro-3-pyridinamine (2.5 g, 12.1 mmol) and pyridine (1.5 ml, 18.56 mmol) in DCM (25 ml). The reaction was stirred for 18 h at RT before evaporation to dryness in vacuo. The residue was split in two and purified by silica gel chromatography, eluting with 0-100% DCM in cyclohexane. Appropriate fractions were combined and evaporated to give title compound, 1.81 g.
Reaction SMILES: O[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:2]2[CH2:6][CH2:5][S:4][CH2:3]2)=[C:10]([Cl:17])[N:9]=1
Reactant: Oc1ccsc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Reaction time: 8 h
Yield: 24.8 %

Procedure:
312 mg of 3-hydroxythiophene, 380 mg of 2,6-dichloropurine, 6 ml of tetrahydrofuran, 786 mg of triphenylphosphine (P(phenyl)3) are mixed together at ambient temperature then 0.47 ml of DEAD (diethyl-azodicarboxylate) is added over 10 minutes and agitation is carried out overnight at ambient temperature. Then 10 ml of NaH2PO4 in aqueous solution 1M is added, followed by extracting 3 times with 10 ml of methylene chloride, washing with 10 ml of water with 5 of an aqueous solution of sodium chloride, drying and evaporating to dryness. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 75/25 then 90/10, impasting is carried out at ambient temperature in 5 ml of isopropyl ether, followed by separating, washing with 5 ml of isopropyl ether and drying at ambient temperature. In this way 137 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C1CCNCC1.CC=C(C)C.[C:37](Cl)(=[O:41])[CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl>[C:37]([N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)=[O:8])[CH2:25][CH2:24]1)(=[O:41])[CH2:38][CH2:39][CH3:40]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: CCCC(=O)Cl
Agent: CC=C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CCCC(=O)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 24 h
Yield: 12.5 %

Procedure:
A small sample of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (60 mg, 0.16 mmol) was weighed out in a 4 mL sealable vial, followed by (piperidinomethyl)polystyrene (0.12 g, 0.32 mmol). To this was added 10 mL of amylene-stabilized chloroform and butyryl chloride (18.0 μL, 0.17 mmol). The vial was capped and placed in a shaker, where it was kept at room temperature for 24 h, then at 50° C. for 36 h. The crude reaction mixture was then applied to a 2 g SCX column, washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo to a dry residue, which was purified by preparative thin layer chromatography. Elution with 9:1 dichloromethane-methanol provided the title compound (9 mg, 13%), isolated in 98% purity by HPLC analysis (Method C: gradient from 50% acetonitrile-50% water with 0.1% trifluoroacetic acid to 90% acetonitrile-10% water with 0.1% trifluoroacetic acid over 10 min; hold 2 min; back to 50% acetonitrile-10% water with 0.1% trifluoroacetic acid over 1 min; hold 2 min; 0.5 ml/min; Waters Symmetry Cl18, 3.5 μM column, 4.6 by 75 mm; 25° C.).