Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](/[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)\[C:25]#[N:26])=[CH:19][C:17]=2[CH:18]=1.O.C(OCC)(=[O:37])C.Cl>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](/[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)\[C:25]([NH2:26])=[O:37])=[CH:19][C:17]=2[CH:18]=1
Reactant: CCOC(C)=O
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(/C=C(\C#N)Oc3ccccc3)ccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(/C=C(/Oc3ccccc3)C(N)=O)ccc2o1

Procedure:
A solution of (E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl)methyl-5-benzofuranyl]-2-phenoxy-2-propenenitrile (0.19 g, 0.44 mmol) in ethanol (10 ml) and sodium hydroxide (2 ml) was heated to reflux for 24 hours, then cooled, poured into a mixture of water (50 ml) and ethyl acetate and acidified with 6N hydrochloric acid. The layers were separated, the aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (hexanes/ethyl acetate/acetic acid, 48:8:1) followed by recrystallization from ethyl acetate/hexanes (30 mg, m.p. 171°-172.5° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]2>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]2)=[O:1]
Reactant: COC(=O)c1ccc2cc(CO)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
Activated manganese dioxide (2.1 g) was added to a solution of methyl 6-hydroxymethyl-2-naphthalenecarboxylate (266 mg, 1.23 mmol) obtained in example 3 (1) in dichloromethane (30 ml). The resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time the reaction mixture was chromatographed on a silica gel column using ethyl acetate-hexane (1:2) as the eluant to obtain methyl 6-formyl-2-naphthalenecarboxylate (237 mg, yield 90%) as a white solid which was recrystallized from ethyl acetate-hexane to give white fluffy crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19](=O)[CH3:20])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[CH:19]([NH2:28])[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1nc(C)c2ccccc2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1nc(C(C)N)c(-c2cccc(F)c2)c2ccccc12
Temperature: 65 °C

Procedure:
A mixture of 1-[4-(3-fluorophenyl)-1-methylisoquinolin-3-yl]ethanone (222 mg, 0.795 mmol) and ammonium acetate (613 mg, 7.95 mmol) in methanol (4.5 mL) and acetonitrile (4.5 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (99.9 mg, 1.59 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in the next step (215 mg, 97%). LCMS calculated for C18H18FN2 (M+H)+: m/z=281.1; Found: 281.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: BrCCOC1CCCCO1
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)c(OCCOC2CCCCO2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 2-fluoro-5-nitrophenol (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.4 mL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50° C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H2O (5×'s to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes—1:1 hexanes:EtOAc to provide 2-(2-(2-fluoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[SH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1>C1C=CC=CC=1>[N:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[S:47][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: Sc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(CSc2ccccn2)C1
Reaction time: 0.08 h

Procedure:
To a stirred solution of tert-butyl 3-(hydroxymethyl)-1-piperidinecarboxylate (Preparation 52, 1.0 g, 5 mmol) in benzene (40 ml) under nitrogen was added triphenyl phosphine (1.44 g, 5.5 mmol). Diethyl azodicarboxylate (0.86 ml, 5.5, mmol) in benzene (4 ml) was added dropwise and the reaction mixture was stirred for 5 min. 2-mercapto pyridine (0.61 g, 5.5 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture washed with sodium hydroxide (1M), water, and saturated brine. The organic extracts were dried (Na2SO4) and concentrated to an oil which was purified by flash chromatography on silica gel eluting with dichloromethane:ethyl acetate (9:1). The title compound was obtained as an oil (1.0 g, 65%).
Reaction SMILES: [C:1]([N:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[CH2:7][CH2:6][C@H:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:9][C@@H:8]([CH2:10][CH3:11])[CH2:7][CH2:6][C@H:5]1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])(=[O:3])[CH3:2]
Reactant: C=CC1=CN(C(C)=O)[C@H](C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC[C@H]1CC[C@@H](C(=O)OC(C)(C)C)N(C(C)=O)C1
Yield: 3.4 %

Procedure:
4.08 g (16.3 mmol) of the t-butyl (S)-N-acetyl-5-vinyl-1,2,3,4-tetrahydropyridine-2-carboxylate obtained in Synthesis Example 16 was dissolved in 150 mL of ethanol, followed by the addition of 4.0 g of 10% Pd/C. It was treated in a hydrogen atmosphere of 3 kg/cm2 by the use of medium pressure catalytic reaction equipment to conduct hydrogenation. The catalyst was removed by filtration and the filtrate was concentrated to give 140 mg of the title compound. Yield 100%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(OS(C)(=O)=O)(=O)=O.[Br-:28].[Li+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][Br:28])[N:7]=1
Reactant: [Br-]
Reactant: OCc1cccc(Br)n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: BrCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 498 mg of (6-bromo-pyridin-2-yl)methanol in 6 ml of N,N-dimethylformamide were successively added 1.15 ml of diisopropylethylamine and a solution of 695 mg of methanesulfonic anhydride in 2 ml of N,N-dimethylfornamide under cooling with ice, followed by stirring the reaction mixture at room temperature for 20 minutes. Then 693 mg of lithium bromide was added to the solution, followed by stirring the reaction mixture at room temperature for 1 hour. After adding saturated aqueous sodium bicarbonate solution to the reaction mixture, the mixture was extracted with ethyl acetate. The resulting ethyl acetate solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1-3/2) to give the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([OH:26])(=O)[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5].C(Cl)(=O)C([Cl:30])=O>C(Cl)Cl>[C:1]([Cl:30])(=[O:26])[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C[C@H](CCC(=O)Cl)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C

Procedure:
A mixture of 0.5 g (1.39 mmol) of 5β-cholanic acid (Aldrich), 0.4 mL (4.6 mmol) of oxalyl chloride, and 10 mL of methylene chloride was heated in a sealed reaction vessel at 60° C. for 15 minutes. The volatiles were distilled off to give 5β-cholanoyl chloride as a colorless solid in quantitative yield. m.p. 104-106° C. 1H NMR (CDCl3, 500 MHz): δ 2.94 (m, 1H), 2.83 (m, 1H), 2.00-0.67 (m, 37H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]1[CH2:58][CH2:57][C@@:56]([F:62])([C:59](O)=[O:60])[CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[F:62][C@@:56]1([C:59](=[O:60])[NH:41][C@@H:40]([CH:42]([CH3:44])[CH3:43])[C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])[CH2:57][CH2:58][N:54]([C:52]([O:51][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:53])[CH2:55]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(F)CCN(C(=O)OC(C)(C)C)C1)C(C)C
Yield: 37.9 %

Procedure:
According to the general procedure D, from #86 (300 mg, 0.45 mmol, 1 eq.), #169 (106 mg, 0.45 mmol, 1 eq.), dichloromethane (10 mL), HATU (194 mg, 0.54 mmol, 1.2 eq.) and diisopropylethylamine (117 mg, 0.9 mmol, 2 eq.) was synthesized the crude desired material, which was purified by reverse phase chromatography (Method P) to afford #193 (149 mg, 37%) as a white solid. HPLC (Protocol X): m/z 873.4 [M+H+], retention time=3.34 minutes (purity=98%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:9]=1[CH2:10][N:11]1[CH:15]=[C:14]([C:16](O)=[O:17])[N:13]=[N:12]1.[Cl-].[NH4+:25].C(=O)(O)[O-].[Na+]>C1COCC1.O>[F:7][C:8]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:9]=1[CH2:10][N:11]1[CH:15]=[C:14]([C:16]([NH2:25])=[O:17])[N:13]=[N:12]1
Reactant: [NH4+]
Reactant: O=C(O)c1cn(Cc2c(F)cccc2F)nn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 55.8 %

Procedure:
1.9 ml (22.4 mmol) of oxalyl chloride were added drop wise, to a suspension of 5 g (20.9 mmol) of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid in 12.5 ml of anhydrous THF, at 20-25° C. and under nitrogen atmosphere. Once the addition of oxalyl chloride was completed, the mixture was stirred at 20-25° C. for 4 h. Afterwards, the resulting mixture was concentrated under vacuum to dryness, in order to eliminate HCl and unreacted oxalyl chloride. The obtained residue was dissolved in ml of fresh anhydrous THF and treated with 4.0 g (75.2 mmol) of ammonium chloride and 5.26 g (62.7 mmol) of sodium bicarbonate over 16 h at 20-25° C. The resultant suspension was treated with 30 ml of water. The solid was filtrated and washed with 30 ml of a saturated aqueous sodium bicarbonate solution and twice with 30 ml of water. The solid was dried in a vacuum drier at 50° C. to yield 2.78 g (55.8%) of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide as Form R-5.
Reaction SMILES: C(O)C.C(O)(=O)C.[CH3:8][C:9]1[S:32][C:12]2[N:13]=[C:14]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[C:11]=2[CH:10]=1>[Fe].O>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]1[C:11]2[CH:10]=[C:9]([CH3:8])[S:32][C:12]=2[N:13]=[C:14]([N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[N:15]=1
Reactant: Cc1cc2c(-c3ccccc3[N+](=O)[O-])nc(N3CCNCC3)nc2s1
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2c(-c3ccccc3N)nc(N3CCNCC3)nc2s1
Yield: 81.3 %

Procedure:
Into a mixed solvent of 8 ml of ethanol, 3.5 ml of water and 4 ml of acetic acid, 1.25 g of 6-methyl-4-(2-nitrophenyl)-2-piperazinyl-thieno[2,3-d]pyrimidine is dissolved, and 1.5 g of iron powder is gradually added at 90° C. over one hour. After the reaction at 90° C. further for 20 minutes, 25 ml of ethanol and 6 ml of water are added. The reaction mixture is filtered by a Celite layer. The Celite layer is washed with hot ethanol and the washings and the filtrate are combined and distilled off under reduced pressure. The residue is treated with 20 ml of 10% aqueous solution of sodium carbonate and with 80 ml of chloroform and filtered by a Celite layer. The chloroform layer is separated and dried over anhydrous sodium sulfate. Chloroform is removed to concentrate and crystallization from chloroform/cyclohexane gives the desired product (0.93 g) which has a melting point of 232°-236° C.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Si:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:33])[CH3:32])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[CH3:34][C:35]1([CH3:43])[O:39][CH:38]([CH2:40][CH:41]=[O:42])[CH2:37][O:36]1>C1COCC1.O>[Si:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:33])[CH2:32][CH:41]([OH:42])[CH2:40][CH:38]1[CH2:37][O:36][C:35]([CH3:43])([CH3:34])[O:39]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(=O)CCCCO[Si](C)(C)C(C)(C)C
Reactant: CC1(C)OCC(CC=O)O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC1(C)OCC(CC(O)CC(=O)CCCCO[Si](C)(C)C(C)(C)C)O1
Reaction time: 0.33 h

Procedure:
A solution of n-butyl lithium in hexane (119 ml, 1.6M, 0.19 mol) is added dropwise to a solution of diisopropylamine (19.3 g, 0.191 mol) in THF (100 ml) cooled in an ice bath. After the addition, the mixture is stirred for 20 minutes then cooled to -78°. A solution of 6-t-butyldimethylsilyloxy-hexan-2-one (40.0 g, 0.174 mol) in THF is added dropwise. The resultant mixture is stirred for 90 minutes then a solution of 2,2-dimethyl-1,3-dioxolane-4-acetaldehyde (25.1 g, 0.174 mol) in THF (100 ml) is added dropwise. After the addition, the mixture is stirred for 2 hours, then water (10 ml) slowly added. The mixture is warmed to 0°, diluted with water (300 ml) and extracted with ether (2×500 ml). The extracts are washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to leave the crude product (63.5 g) an oil. A portion of this material (46 g) is chromatographed on silica gel (2.5 Kg) eluting with 25% ethyl acetate/hexane to give the title compound, 8-t-butyldimethylsiloxy-1-(2,2-dimethyl-1,3-doxolan-4-yl)-2-hydroxyoctan-4-one; (23 g, 49%) an oil.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CC(N(C)C)=O>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)=[CH:18][CH:17]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Reaction time: 0.33 h

Procedure:
To a solution of 16.3 g. of isatoic anhydride in 200 ml. of dimethylacetamide at room temperature is added sodium hydride obtained from 5.0 g. of 57% solution in mineral oil. The resulting mixture is stirred for 20 minutes and 16 g. of p-fluorobenzyl chloride is added followed by stirring at room temperature for about 15 hours. The resulting mixture is concentrated in vacuo to about one half its volume, a mixture of ice and water added and the resulting precipitate filtered off, washed with water, dried under suction and washed with pentane. The solid material is then dissolved in methylene chloride, dried with sodium sulfate, treated with charcoal and about twice the volume of diethyl ether added to crystallize N-(p-fluorobenzyl)isatoic anhydride, m.p. 142°-145°C.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([OH:23])=O)[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:23])[N:15]=2)[CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)N3CCOCC3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.3 %

Procedure:
A mixture of 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (1 g, 2.8 mmol), morpholine (0.366 g, 4.2 mmol), HATU (1.28 g, 3 mmol) and DIPEA (0.58 g, 4 mmol) in DMF (5 mL) was allowed to stir at RT overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (8×25 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc gave an oily residue which was purified by reverse phase HPLC followed by chiral HPLC to afford 15 mg of (R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(morpholino)methanone, and its enantiomer. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.29 (d, 6H), 1.92-2.15 (m, 5H), 2.30-2.42 (m, 1H), 2.67-2.81 (m, 4H), 2.90-3.04 (m, 1H), 3.41-3.90 (m, 10H), 4.98-5.08 (m, 1H), 5.85 (brs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:3]=1[NH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[N:37]=[C:36]([C:38]([NH:41][C:42]2[C:47]([CH:48]([CH3:50])[CH3:49])=[CH:46][CH:45]=[CH:44][C:43]=2[CH:51]([CH3:53])[CH3:52])([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1(C)C=CC=CC=1.CO>[CH:51]([C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH:48]([CH3:50])[CH3:49])[C:42]=1[NH:41][C:38]([C:36]1[N:37]=[C:32]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:6]=2[CH2:5][NH:4][C:3]2[C:2]([CH3:1])=[CH:28][C:27]([CH3:29])=[CH:26][C:25]=2[CH3:30])[CH:33]=[CH:34][CH:35]=1)([CH3:40])[CH3:39])([CH3:53])[CH3:52]
Reactant: CC(C)c1cccc(C(C)C)c1NC(C)(C)c1cccc(Br)n1
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C(C)(C)Nc3c(C(C)C)cccc3C(C)C)n2)c(C)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.26 g (5.64 mmol) of 2,4,6-trimethyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 2.11 g (6.00 mmol) of N-[1-(6-bromopyridin-2-yl)-1-methylethyl]-2,6-diisopropylaniline, 4.03 g (14.1 mmol) of Na2CO3×10H2O, 63 ml of water, 18 ml of methanol, and 76 ml of toluene was purged with argon for 30 min. To the obtained solution 0.32 g (0.30 mmol) of Pd(PPh3)4 was added. In argon atmosphere, this mixture was stirred for 12 h at 80° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 2.60 g (81%) of yellow oil. Anal. calc. for C40H47N3: C, 84.31; H, 8.31; N, 7.37. Found: C, 84.50; H, 8.51; N, 7.22. 1H NMR (CDCl3): δ 7.88 (m, 1H, 8-H in naphtalene), 7.85 (d, J=8.4 Hz, 1H, 4-H in naphtalene), 7.80 (t, J=7.7 Hz, 1H, 4-H in pyridine), 7.67 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 5-H in naphtalene), 7.37-7.49 (m, 4H, 3, 5, 6, 7-H in naphtalene), 7.24 (dd, J=7.7 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 7.04-7.06 (m, 3H, 3, 4, 5-H in 2, 6-iPr2C6H3), 6.76 (s, 2H, 3, 5-H in mesityl), 4.14 (br.s, 1H, NH), 4.00 (m, 2H, CH2N), 3.48 (br.s, 1H, NH), 3.23 (sep, J=6.7 Hz, 2H, CHMe2), 2.22 (s, 3H, 4-Me in mesityl), 2.06 (s, 6H, 2, 6-Me in mesityl), 1.57 (s, 3H, CMeMe′), 1.45 (s, 3H, CMeMe′), 1.04 (d, J=6.7 Hz, 6H, CHMe2), 1.02 (d, J=6.7 Hz, 6H, CHMe2).
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])=[O:10])=[CH:7][N:8]=1)[CH3:2].[OH:18]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])=[O:10])=[CH:7][N:8]=1)=[O:18])[CH3:2]
Reactant: C#CCCCCNC(=O)c1cnc(SCC)s1
Reactant: OO
Solvent: CC(=O)O
Product: C#CCCCCNC(=O)c1cnc(S(=O)CC)s1

Procedure:
In this preparation a mixture of 0.064 mole of 2-ethylthio-5-(hex-5-ynylaminocarbonyl) thiazole; 40 ml. of 30% aqueous hydrogen peroxide and 200 ml. of acetic acid is stirred at a temperature of from 40° to 50° C for 4 hours. The mixture is concentrated by evaporation of a large portion of the acetic acid, under vacuum, at room temperature (about 20° C) and the resulting residue poured into 500 ml. of ethyl acetate and then washed with aqueous sodium bicarbonate solution until no acetic acid is present in the organic layer. The ethyl acetate layer is then separated, dried with anhydrous magnesium sulfate, filtered, and the resulting filtrate evaporated to dryness, under vacuum, affording 2-ethylsulfinyl-5-(hex-5-ynylaminocarbonyl)thiazole.