Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(Cl)Cl>[CH3:9][S:10]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:12])=[O:11]
Reactant: COCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COCCOCCOS(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution of 2-(2-methoxyethoxy)ethanol (300 mg, 2.5 mmol) in DCM (5 mL) was added methanesulfonyl chloride (370 mg, 2.6 mmol) dropwise at 0° C. After stirred at this temperature for 5 min, TEA (505 mg, 5.0 mmol) was added. It was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude oil product, which was used without purification. Product tlc [petroleum ether/ethyl acetate [1:1) developed with iodine, Rf 0.5]
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[O:13][C:12]([C:14]([O:16]C)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:21][CH2:20][CH2:19]1>CO>[N:18]1([C:14]([C:12]2[O:13][C:9]([S:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:7])=[O:8])=[CH:10][CH:11]=2)=[O:16])[CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(S(=O)(=O)NC(C)(C)C)o1
Reactant: C1CNC1
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc(C(=O)N2CCC2)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 5-[(tert-butylamino)sulfonyl]-2-furoate (the product of step i) (2.15 g) in methanol (80 mL) was added azetidine (1.15 mL). After stirring at room temperature for 5 h the mixture was evaporated to dryness in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and H2O (50 mL). The separated organic layer was dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting crude material was purified by column chromatography (EtOAC as eluent) to give the subtitle compound as a pale yellow oil. Yield: 3 g.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1)=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-c2ccc(C(F)(F)F)cn2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccc(C(F)(F)F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzoic acid. MS (ESI) 392 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][C@@H:27]4[O:53][C@H:52]([CH2:54][O:55]C(=O)C(C)(C)C)[C@@H:44]([O:45]C(=O)C(C)(C)C)[C@H:36]([O:37]C(=O)C(C)(C)C)[C@H:28]4[O:29]C(=O)C(C)(C)C)[C:18]=23)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][C@@H:27]4[O:53][C@H:52]([CH2:54][OH:55])[C@@H:44]([OH:45])[C@H:36]([OH:37])[C@H:28]4[OH:29])[C:18]=23)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OCc5ccccc5)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OCc5ccccc5)cc4)c23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
To a solution of 4-[2-(4-benzyloxyphenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (49 mg) in methanol (4 mL) was added sodium methoxide (0.056 mL), and the mixture was stirred at 50° C. for 5 hours. To the reaction mixture was added acetic acid (0.033 mL), and the resulting mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give 4-[2-(4-benzyloxyphenyl)ethyl]-3-(β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (25 mg). This material was dissolved in methanol (4 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (16 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:19][CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:14][CH:15]([CH3:18])[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:19][CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([CH2:14][CH:15]([CH3:18])[CH:16]=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(CO)CC1(OCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C=O)CC1(OCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Yield: 45 %

Procedure:
A mixture of tert-butyl-4-((benzyloxy)methoxy)-4-(3-hydroxy-2-methylpropyl)piperidine-1-carboxylate (1.97 g, 5.0 mmol) and Dess-martin reagent (3.18 g) was stirred in dichloromethane (60 mL) at r.t for 16 hrs. The reaction mixture was quenched by adding 25% sodium bicarbonate solution (100 mL), then the mixture was extracted by EtOAc (60 mL×2). The organic phase was combined and concentrated to give a residue, which was further purified by a standard method to give the product (0.88 g). LC-MS: m/z 392.5 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([O:12][CH3:13])[C:4]=1[O:14][CH3:15].[CH3:16][O:17]C(Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:14][CH3:15])=[C:5]([O:12][CH3:13])[C:6]([O:10][CH3:11])=[C:7]([CH3:9])[C:8]=1[CH:16]=[O:17]
Reactant: COc1cc(C)c(OC)c(OC)c1OC
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3,4-tetramethoxy-5-methylbenzene (20.0 g) in methylene chloride (100 ml) was dropwise added titanium tetrachloride (20.6 ml) with cooling with ice, followed by addition of 1,1-dichlorodimethylether (11.0 ml) with cooling with ice. The reaction mixture was allowed to warm to room temperature and further stirred for 8 hr. The reaction mixture was poured into ice-water, and extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=10:1) to give the entitled compound(21.5 g) as an oil.
Reaction SMILES: [N:1]([C@@H:4]([CH3:24])[C@H:5]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]([O:8]CC1C=CC=CC=1)=[O:7])=[N+]=[N-]>CO>[NH2:1][C@@H:4]([CH3:24])[C@H:5]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: CO
Product: C[C@H](N)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Yield: 103.7 %

Procedure:
A solution of (2S,3S)-benzyl 3-azido-2-(tert-butoxycarbonylamino)butanoate (1.7 g, 5.08 mmol) and PdC (5%, wet) (340 mg, 319 μmol) in MeOH (16.4 g, 20.7 ml) was shaken under H2 (50 PSI) for 3.5 h, then filtered through a bed of celite and concentrated to give (2S,3S)-3-amino-2-(tert-butoxycarbonylamino)butanoic acid (1.15 g, quant.) as a white solid.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.C(N(CC)[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])C>C1COCC1>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CCN(CC)C(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 1.25 h
Yield: 65 %

Procedure:
To a stirred solution of the (4-bromobenzyloxy)-(tert.-butyl)-dimethylsilane (24.94 g, 82.8 mmol) in THF (420 mL) at −78° C. was added dropwise a 1.6 M solution of nBuLi in hexane (62 mL, 99.2 mmol) over a 1 h period. After stirring the mixture at the same temperature for 75 min, a solution of N,N-diethyltrifluoroacetamide (19.19 g, 113 nmol) in THF (60 mL) was added dropwise over 1 h. Following the addition the mixture at −78° C. for a further 75 min before the reaction was quenched with an aqueous solution of NH4Cl. Ether was added and the organic layer was extracted 3 times with ether (3×300 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuum. The resulting pale yellow liquid was distillated in vacuo to give the 1-(4-((tert-butyldimethylsilyloxy)methyl)phenyl)-2,2,2-trifluoroethanone (65%) as a colorless liquid; b.p. 170-180° C. (10 torr), 1H NMR (CDCl3): δ 0.12 (s, (CH3)2Si), 0.96 (s, CH3)3C), 4.83 (s, CH2), 7.50 (d, J=8.2 Hz, C6H4), 8.05 (d, J=8.2 Hz, C6H4); 13C NMR (CDCl3): δ −5.4 (CH3Si), 18.3 (C(CH3)3), 25.8 (C(CH3)3), 64.2 (CH2O), 116.7 (q, J=289.7 Hz, CF3), 126.2 (C6H2), 128.6 (C6H2), 130.2 (C6H2), 150.1, (C6H2), 180.2 (q, J=34.5 Hz, CO).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=2[O:10][CH3:11])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(Cl)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=CC=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)CCC.C1(=O)CCCCC1.C([O:43][C:44](=[O:47])CC)C>>[CH2:21]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][CH2:17][C:44]([OH:47])=[O:43])=[CH:13][N:14]=1)[CH2:22][CH2:23][CH3:28]
Reactant: CCOC(=O)CC
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Solvent: CCCCN
Solvent: O=C1CCCCC1
Product: CCCCN(C(=O)Nc1ncc(SCCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from n-butylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 100-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5.0 g, 21.73 mmol), triethylamine (4.39 g, 43.38 mmol), 3-phenylpropanoyl chloride (3.67 g, 21.76 mmol) in dichloromethane (50 mL). The resulting mixture was stirred for 12 hours at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (2:1) to give the title compound as a white solid.
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6](=[S:9])([NH2:8])[CH3:7].Cl[CH2:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([NH:23][C:24](=[O:40])[C:25]3[C:30]([F:31])=[CH:29][CH:28]=[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[C:26]=3[F:39])[CH:21]=2)[NH:16][CH:15]=1)=O.CO>C1COCC1>[F:39][C:26]1[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:34])=[O:35])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:20]1[CH:21]=[C:22]2[C:14]([C:12]3[N:8]=[C:6]([CH3:7])[S:9][CH:11]=3)=[CH:15][NH:16][C:17]2=[N:18][CH:19]=1)=[O:40]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Reactant: CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(-c4csc(C)n4)c3c2)c1F
Temperature: 70 °C
Reaction time: 9 h
Yield: 18.5 %

Procedure:
NaHCO3 (0.00098 g, 0.012 mmol) and ethanethioamide (0.00096 g, 0.013 mmol) were added to N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.011 mmol) in THF (0.1 mL), and the reaction mixture was warmed to 70° C. for 4 hours. MeOH (0.2 mL) was added, along with another equivalent of ethanethioamide (0.00096 g, 0.013 mmol) and NaHCO3 (0.00098 g, 0.012 mmol). After 9 hours at 70° C., the reaction mixture was cooled and partitioned between EtOAc and aqueous sodium bicarbonate. The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified via column chromatography (10% MeOH-DCM) to provide 2,6-difluoro-N-(3-(2-methylthiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (1 mg, 19%). 1H NMR (400 MHz, CHCl3-d1) δ 8.84-8.85 (m, 1H), 7.86 (s, 1H), 7.60-7.66 (m, 1H), 7.32 (s, 1H), 7.02-7.06 (m, 1H), 3.06-3.12 (m, 2H), 2.80 (s, 3H), 1.85-1.93 (m, 2H), 1.04-1.08 (m, 3H); m/z (APCI-pos) M+1=492.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 73.4 %

Procedure:
To a stirred solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 332) (0.100 g, 0.28 mmol) in DMF (2.8 mL) was added benzyl chloride (0.32 mL, 0.28 mmol). The resulting solution was stirred with heating to 60° C. overnight. The solvent was removed in vacuo and the resulting residue partitioned between ethyl acetate and 10% citric acid. After extracting with ethyl acetate, the combined organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography (SiO2, 1:1 ethyl acetate:hexanes) to provide the desired product (yield: 0.096 g, 76%). mp 110–113° C. 1H NMR (300 MHz, DMSO d6) δ 3.39 (s, 3H), 5.48 (s, 2H), 7.29 (m, 4H), 7.59–7.71 (m, 3H), 7.76 (m, 3H), 8.00 (m, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 467 (M+H)+, 484 (M+NH4)+. Anal. calc. for C24H19ClN2O4S: C, 61.73; H, 4.10; N, 6.00. Found: C, 62.00; H, 4.18; N, 5.93.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[C:33]([O:37][C:38](=[O:46])[NH:39][CH:40]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41]1)([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[C:33]([O:37][C:38](=[O:46])[NH:39][CH:40]1[CH2:44][CH2:43][CH:42]([NH:45][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=2)=[O:22])[CH2:41]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NC1CCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(NC(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (300 mg, 0.66 mmol) and (3-aminocyclopentyl)-carbamic acid tert-butylester hydrochloride (233 mg, 0.98 mmol). DMF (3 ml) was added followed by HATU (274 mg, 0.72 mmol) and N,N-diisopropylethylamine (0.30 ml, 1.72 mmol). The reaction mixture was stirred at room temperature for 30 min. Additional DMF (2 ml) was added and the light yellow suspension was stirred at room temperature overnight. Water was added and the resulting suspension was filtered, washed with water and petroleum ether and dried under high vacuum to afford 413 mg (99%) of (3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclopentyl)-carbamic acid tert-butyl ester as an off-white powder. The isolated product was determined to be a single diastereomer of unknown relative stereochemistry by NMR analysis.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([CH:15]=O)=[C:13]([Cl:17])[N:12]=[CH:11][N:10]=1.Cl.Cl.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([N:27]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([Cl:17])=[C:14]2[CH:15]=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNCc1ccccc1
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1ncnc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
Triethylamine (1.181 mL, 8.48 mmol) was added to 4,6-dichloropyrimidine-5-carbaldehyde (CAS no. 5305-40-8) (500 mg, 2.83 mmol) and benzylhydrazine dihydrochloride (CAS no. 20570-96-1) (551 mg, 2.83 mmol) in THF (15 mL) at room temperature under nitrogen. The resulting suspension was stirred at room temperature for 10 minutes and then heated at 65° C. for 50 mins. Silica was added to the reaction mixture and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (500 mg, 72.3%). 1H NMR (400 MHz, CDCl3) 5.67 (2H, s), 7.28-7.38 (5H, m), 8.16 (1H, s), 8.79 (1H, s); m/z (ES+) (M+H)+=245; HPLC tR=2.29 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=3)[C:43]2=[O:57])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:54])([CH3:53])[CH3:55])[CH:48]=3)[C:43]2=[O:57])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CC(O)C3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC(O)C4)cn3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 27 %

Procedure:
A 100-mL flask equipped with a reflux condenser was charged with 147c (285 mg, 0.81 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (669 mg, 1.62 mmol), Pd(dppf)Cl2 (66.2 mg, 0.081 mmol), K3PO4 (343.4 mg, 1.62 mmol), sodium acetate (132.8 mg, 1.62 mmol), water (0.5 mL), and acetonitrile (15 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 147d as a brown solid (140.0 mg, 27%). MS-ESI: [M+H]+ 640.3.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[N+](=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C(Cl)Cl>[C@H:1]12[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@H:8]1[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]2
Reactant: C1=CCCC=CCC1
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)OCC
Agent: CCOC(=O)C1(C(=O)OCC)[C@@H]2CC/C=C\CC[C@@H]21
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)[C@@H]2CCC=CCC[C@@H]21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1,5-cyclooctadiene (5.27 mL, 43.0 mmol) and Rh2(OAc)4 (100 mg, 0.23 mmol) in CH2Cl2 (5 mL) was added dropwise in 3 h a solution of diethyl diazomalonate (1.0 g, 5.37 mmol) in CH2Cl2 (5 mL). This solution was stirred for 24 h at rt. The CH2Cl2 was evaporated and the excess of cyclooctadiene was removed by filtration over a glass filter filled with silica (eluens: heptane). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EtOAc:heptane, 1:10) to afford IIa.8 (1.03 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl.[CH3:40][CH:41]([CH3:44])[CH2:42][NH2:43]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([NH:43][CH2:42][CH:41]([CH3:44])[CH3:40])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CC(C)CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 2-(2-fluorobiphenyl-4-yl)propanoic acid (Aldrich) (172.3 mg), HOBt (133.2 mg, 1.4 eq) and triethylamine (196.5 mL, 2 eq) in dichoromethane (7 mL) was added at room temparature EDC (270.4 mg, 2.0 eq). The reaction was stired at room temperature for 30 minutes and 2-methylpropan-1-amine (0.1 mL, 1.5 eq) was added. The solution was stirred overnight then diluted with dichlorometahne and washed successively with aqueous NaHCO3, water, aqoueous HCL (1N), water, dried over MGSO4, filtered and evaporated. Chromatogarphy on silica gel (eluent:ethyl acetate/hexane 1:1) afforded 170 mg of 2-(2-fluorobiphenyl-4-yl)-N-isobutylpropanamide. Yield: 80%. 1H NMR (500 MHz, CDCl3): δ 0.83-0.79 (d, 6H), 1.55-1.56 (d, 3H), 1.69-1.74 (m, 1H), 3.04-3.07 (m, 2H), 3.56-3.58 (m, 1H), 5.4 (s br, 1H), 7.11-7.16 (m, 2H), 7.37-7.46 (m, 4H), 7.53-7.55 (m, 2H).