Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH2:31]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:31][CH2:30][S:32]([CH3:35])(=[O:34])=[O:33])[C:7]=2[CH:6]=1)=[O:4]
Reactant: C=CS(C)(=O)=O
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(ncn2CCS(C)(=O)=O)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (1.55 g, 3.89 mmol) is dissolved in 15 mL DMF under N2, K2CO3 (0.70 g, 5.06 mmol) is added followed by methyl vinyl sulfone (0.41 mL, 4.67 mmol). After stirring 16 hours at room temperature, the reaction mixture is diluted with ethyl acetate and water. The layers are separated and the organic layer is washed with water (3×) and brine. The combined aqueous washes are extracted with ethyl acetate. The combined organic extract are dried (MgSO4) and concentrated under reduced. Purification by dissolving the residue in methylene chloride and precipitating with diethyl ether, repeated several times, gives 1.16 g (50%) pure desired product as a yellow solid: MS APCI (+) m/z 506, 504 (M+ Br pattern) and 400, 398 (M− methyl ethyl sulfone Br pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13]1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:14]3[CH:15]=[CH:16][O:12][CH:13]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccoc1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccoc1
Yield: 49.6 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2 g, 11.9 mmol) (Alfa) was reacted with 3-furaldehyde (1.04 mL, 11.9 mmol) and piperidine (1.18 mL, 11.9 mmol) in methanol to give E/Z-6-chloro-3-furan-3-ylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.45 g, 55%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[Cl:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:33][CH2:34][S:35]([NH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:30])([F:29])[F:31])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32])(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)CCl
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNS(=O)(=O)CCl

Procedure:
1-Chloro-N-{2-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}methanesulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and chloromethanesulfonyl chloride following General Procedure U.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[OH:18])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.N1(C(OC(C)(C)C)=O)CCNCC1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[O:18][C:9]2=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1CCCCC1O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC2CCCCC2C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3-chlorophenyl)(2-hydroxycyclohexyl)acetic acid (Reference Example 2-d) (1.25 g, 4.66 mmol), benzotriazol-1-yloxytris(dimethylaminop)phosphonium hexafluorophosphate (3.1 g, 7.0 mmol), and tert-butyl 1-piperazinecarboxylate (0.87 g, 4.66 mmol) in methylene chloride (12 mL) was treated with triethylamine (0.98 mL, 7.0 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 25% EtOAc/hexane) to yield 0.97 g (83%) the lactone, 3-(3-chlorophenyl)hexahydro-1-benzofuran-2(3H)-one as a clear oil. HRMS: calcd for C14H15ClO2+H, 251.0861; found (ESI, [M+H]+), 251.0844.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19](O)=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].Cl.[CH2:36]([NH2:38])[CH3:37].C1C=CC(P(OC2C(F)=C(F)C(F)=C(F)C=2F)(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([NH:38][CH2:36][CH3:37])=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: Cc1ccc(-c2cn(CC(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCN
Agent: Cl
Agent: O=P(Oc1c(F)c(F)c(F)c(F)c1F)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of compound 111 (39 mg, 0.08 mmol) in DMF (1.0 mL) was added ethylamine hydrochloride (20 mg, 0.08 mmol), FDPP (43 mg, 0.11 mmol), and DIEA (68 μL, 0.4 mmol). The flask was flushed with argon and the reaction mixture was stirred at RT for 72 h and then poured into a mixture of water (4 mL), HCl (4N, 2 mL), and EtOAc. The phases were separated. The organic phase was concentrated on silica in vacuo. The crude product was purified by chromatography eluting with EtOAc/petroleum ether (40-60) 50:50 to 100:0 as the eluent to afford the title compound as white foam. 13C NMR (DMSO-d6) δ 194.9, 164.8, 149.3, 145.2, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.6, 126.4 (dd), 125.0, 124.2 (dd), 123.0, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 51.7, 33.6, 19.4, 14.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][NH2:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1.F[C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[N+:29]([O-:31])=[O:30].C(N(C(C)C)CC)(C)C>C(#N)C.O>[I:28][C:25]1[CH:26]=[CH:27][C:22]([NH:20][CH2:19][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:23]([N+:29]([O-:31])=[O:30])[CH:24]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Reactant: COc1ccc(COc2ccc(CN)cc2OC)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(COc2ccc(CNc3ccc(I)cc3[N+](=O)[O-])cc2OC)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a stirred solution of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (5.00 g, 18.23 mmol) in acetonitrile (75 mL) was added 1-fluoro-4-iodo-2-nitrobenzene (4.55 g, 17.04 mmol) and diisopropylethylamine (3.30 g, 25.56 mmol). The yellow solution was heated to reflux and stirred. After 4 h, the orange-brown mixture was allowed to cool to room temperature and was diluted with water (150 mL). The resulting bright orange precipitate was isolated by filtration and washed with water. The moist solids were dissolved in dichloromethane, and a small amount of water separated and was removed. The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 7.10 g (80%) of 4-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-2-nitroaniline as a bright orange solid.
Reaction SMILES: C([C@H](C(O)CC([O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1)CCCCCCCCCCC)C(O)=O)CCCCC.[OH2:33].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37](S(O)(=O)=O)=[CH:36][CH:35]=1>C(O)C>[OH:33][C@@H:31]1[CH2:30][CH2:29][CH:28]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:34][CH3:44])[O:27][C:26]1=[O:25]
Reactant: O
Reactant: CCCCCCCCCCCC(CC(O)[C@@H](CCCCCC)C(=O)O)OC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCCCCCCCCCCC1CC[C@@H](O)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
M)a) 15.4 g of a diastereomer mixture of 2-hexyl-3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoic acid were dissolved in 160 ml of ethanol and 800 mg of toluene-4-sulfonic acid monohydrate were added. The reaction mixture was heated to 55°-60° C. until the reaction was finished. The solvent was removed in vacuo and the residue was dissolved in 160 ml of dichloromethane. The solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated. The material obtained was chromatographed on silica gel. There was obtained tetrahydro-3-hydroxy-(R)-6-undecyl-2H-pyran-2-one, m.p. 95°-96° C.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.CC(C)=O.[CH:41]1[CH:46]=[CH:45][C:44]([C:47]([O:49][C@H:50]([C:64]([OH:66])=[O:65])[C@H:51]([O:55][C:56]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:57])[C:52]([OH:54])=[O:53])=[O:48])=[CH:43][CH:42]=1>C(#N)C>[C:56]([O:55][C@@H:51]([C@H:50]([O:49][C:47](=[O:48])[C:44]1[CH:43]=[CH:42][CH:41]=[CH:46][CH:45]=1)[C:64]([OH:66])=[O:65])[C:52]([OH:54])=[O:53])(=[O:57])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Agent: O=C(O[C@H](C(=O)O)[C@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
A solution of racemic (4-(1-(2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 200 mg, 0.47 mmol) in a mixture of acetonitrile, tetrahydrofuran, and acetone (4 mL, 6:1:1) at room temperature was warmed to 50° C. before being treated with (+)-2,3-dibenzoyl-D-tartaric acid (16, 84 mg, 0.235 mmol, 0.5 equiv) in one portion. The resulting homogeneous solution was then stirred at 50° C. for 10 minutes before being cooled gradually to room temperature and stirred at room temperature for 23 hours. The solids were then collected by filtration, rinsed with a small volume of hexane, and dried under reduced pressure to afford (2S,3S)-2,3-bis(benzoyloxy)succinic acid-(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (1:1; 22, 145 mg, 183 mg theoretical, 79.2% yield) as white crystals. The enantiomeric purity of the isolated salt was analyzed by chiral HPLC and found to be in a ratio of 87:13 favoring the desired R-enantiomer. For 22: C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).
Reaction SMILES: [F:1][CH2:2][C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.CN(C)C=O.[CH3:22][Si:23]([CH3:26])([CH3:25])Cl>CCCCCC>[F:1][CH2:2][C:3]([O:11][Si:23]([CH3:26])([CH3:25])[CH3:22])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C#CCC(O)(CF)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(CF)(CCCC)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
To a solution of 4.38 g. of 4-fluoromethyl-4-hydroxy-1-octyne and 4.8 g. of imidazole in 19 ml. of dimethylformamide, cooled in an ice bath under nitrogen is added 4.5 ml. of trimethylchlorosilane via a syringe during a few minutes. The mixture is stirred in the ice bath for 30 minutes and then at room temperature under nitrogen overnight. The solution is poured into hexane, washed with saturated aqueous sodium bicarbonate, water, then brine and dried over anhydrous sodium sulfate. The solvents are removed in vacuo giving the product as a colorless liquid.
Reaction SMILES: C([Cl:4])(=O)C.[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[C@@H:7]([NH:13][C:14]([CH:16]1[CH2:29][CH2:28][C:19]3([CH2:24][CH2:23][N:22](C([O-])=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]1)=[O:15])[CH2:6]2>C(O)C>[ClH:4].[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[C@@H:7]([NH:13][C:14]([CH:16]1[CH2:29][CH2:28][C:19]3([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[CH2:18][CH2:17]1)=[O:15])[CH2:6]2
Reactant: CC(=O)Cl
Reactant: O=C(N[C@H]1CN2CCC1CC2)C1CCC2(CC1)CCN(C(=O)[O-])CC2
Solvent: CCO
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)C1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Acetyl chloride (5 eq.) was added to an ice-cold solution of 9-((R)-quinuclidin-3-ylcarbamoyl)-3-azaspiro[5.5]undecane-3-carboxylate (0.271 mmol, 1 eq.) in ethanol. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in acetone/ethanol (1:3, 3 ml) and diethyl ether (20 ml) was added. The white solid was filtered out, washed with diethyl ether and dried in vacuo. Yield: 86%
Reaction SMILES: [CH2:1]([C:5]1([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:11]=2)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:24]([Mg]Br)[CH:25]=[CH2:26]>O1CCCC1>[CH2:1]([C:5]1([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:11]=2)[C:6]1([C:25]([CH3:26])=[CH2:24])[OH:18])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCCCC1(CCCC)Cc2cc(OCOC)ccc2C1=O
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCCCC1(CCCC)Cc2cc(OCOC)ccc2C1(O)C(=C)C
Temperature: 25 °C

Procedure:
A solution of 2-butyl-5-(methoxymethoxy)-2-(4-pentenyl)-1-indanone (400 mg, 1.27 mmol) in anhydrous tetrahydrofuran (THF, 5 mL) was placed under a N2 atmosphere, cooled in a dry ice-acetone bath, stirred, and treated with 2-propenyl magnesium bromide, (1M in THF, 1.9 mL, 1.9 mmol). After warming to room temperature, the mixture was treated with additional 2-propenyl magnesium bromide (1M in THF, 6 mL, 6 mmol) and stirred at room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl, dried over MgSO4, filtered through a pad of silica, and concentrated under vacuum to afford an oil. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4.0×7.0 cm) silica gel column, eluting with 19:1 hexanes-EtOAc. The product-containing fractions were evaporated under vacuum to afford 2-butyl-1-isopropenyl-5-(methoxymethoxy)-2-(4-pentenyl)-1-indanol as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][C@@H:37]([C:42]([OH:44])=[O:43])[C:38]([SH:41])([CH3:40])[CH3:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])[C:15]([SH:18])([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N(CC)CC)C>C(#N)C.O>[CH3:16][C:15]1([CH3:17])[S:18][S:41][C:38]([CH3:39])([CH3:40])[C@H:37]([C:42]([OH:44])=[O:43])[NH:36][C:34](=[O:35])[C@@H:26]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:25][C:23](=[O:24])[CH2:22][NH:21][C:19](=[O:20])[C@@H:14]1[NH:13][C:11]([C@@H:2]([NH2:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:12]
Reactant: CC(C)(S)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(C)(C)S)C(=O)O
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)SSC(C)(C)[C@@H](NC(=O)[C@@H](N)Cc2ccc(O)cc2)C(=O)NCC(=O)N[C@H](Cc2ccccc2)C(=O)N[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
3.0 mg of DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen) was dissolved in 5 ml of anhydrous acetonitrile. A 20% molar excess of PEG reagent (either mPEG-SPA 5K [27.9 mg] or mPEG-SPA 2K [11.1 mg]) and triethylamine (0.8 μl) was added to the DPDPE. The reaction was allowed to proceed at room temperature under an argon atmosphere for 2 days. The sample was diluted to 15 ml with deionized water and lyophilized. The PEG-DPDPE powder was reconstituted in 5 ml of deionized water and purified on a Superdex 30 size exclusion column. The pertinent fractions were pooled together, dialyzed against water and frozen until in situ perfusion experiments.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[F:11])=[O:3].[CH:12](OC)(OC)[O:13]C.[C:19](=O)([O-])O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH3:19][O:3][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[F:11])([O:13][CH3:12])[CH3:1]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: O=C([O-])O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COC(C)(OC)c1ccc(F)cc1F

Procedure:
In a solution composed of 15.7 g of 2,4-difluoroacetophenone, 35 g of trimethyl ortho-formate and 15 g of methanol, 0.96g of p-toluenesulfonic acid was added, and reacted at 40° C. to 45° C. for 2 hours. This was added to an aqueous solution of 5% by mass sodium hydrogen carbonate, which was then extracted with ethyl acetate. An extract was washed with water, and dried on Na2SO4. Then, ethyl acetate was concentrated to yield 18.2 g of 1-(1,1-dimethoxyethyl)-2,4-difluorobenzene. It was confirmed that the 1-(1,1-dimethoxyethyl)-2,4-difluorobenzene had NMR data of (CDCl3, δppm) 1.62 (s, 3H), 3.9 (s, 6H), 6.74-6.9 (m, 2H), 7.56-7.7 (m, 1H) by NMR (supplied from Varian Technologies Japan Limited).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=[O:22]>O1CCCC1.CCCCCC>[Br:19][C:20]([CH3:25])([CH3:24])[C:21]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1])=[O:22]
Reactant: CC(C)(Br)C(=O)Br
Reactant: C=CCCCCCCCCCO
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCOC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 4.257 g (25 mmol) of ω-undecylenyl alcohol in 25 mL of dry tetrahydrofuran was added 2.1 mL of pyridine (26.5 mmol) followed by dropwise addition of 3.10 mL of 2-bromoisobutyryl bromide (25 mmol) over 5 min. The mixture was stirred at room temperature overnight and then diluted with hexane (50 mL) and washed with 2 N HCl and twice with water. The organic phase was dried over sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure, and the colorless oily residue was purified by flash column chromatography (hexane/ethyl acetate 25/1 v/v) to give 7.34 g (92%) of the ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42].B1(C=C)OB([CH:49]=[CH2:50])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:10]([CH:49]=[CH2:50])=[CH:9][C:8]([C:19]2[N:20]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:23][CH:22]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:42]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: O
Product: C=Cc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Yield: 59.8 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (70.0 mg, 0.111 mmol) was dissolved in dimethoxyethane (3.5 mL), and the solution was treated with 2,4,6-trivinylcyclotriboroxane-pyridine complex (53.6 mg, 0.222 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (7.3 mg, 0.0090 mmol), potassium carbonate (76.7 mg, 0.355 mmol) and water (0.060 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=9/1) to obtain 4-chloro-5-vinyl-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (33.6 mg, yield 60%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Br:12][C:13]1[CH:14]=[C:15]([NH2:20])[CH:16]=[N:17][C:18]=1[CH3:19].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]([N:20]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:16]=[N:17][C:18]=1[CH3:19]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ncc(N)cc1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C

Procedure:
A mixture of phthalic anhydride (3.7 g, 25 mmol), 5-bromo-6-methylpyridin-3-amine (3.9 g, 20.85 mmol) and sodium acetate (1.5 g, 25 mmol) in glacial acetic acid (44 ml) was refluxed for overnight. After cooling down to room temperature, the precipitate was collected by vacuum filtration, washed with water, and dried to afford the title compound. MS (m/z) 318.91 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=1>CN(C)C=O.O.CO>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)[O:10][C:11]1[C:12](=[O:21])[N:13]([CH2:29][C:30]2[C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=2)[CH:14]=[CH:15][C:16]=1[C:17]([F:18])([F:19])[F:20]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)n1nc(Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(C#N)c3)c2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with 3-chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (3C, 2.03 g, 6.45 mmol) and potassium carbonate (0.891 g, 6.45 mmol) was added dimethylformamide (20 mL). To this under N2 was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (2.01 g, 6.45 mmol) as a solution in dimethylformamide (10 mL). This was allowed to stir at room temperature for 16 hours. After this time the reaction mixture was diluted with water (50 mL) and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with brine (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 120 gram column, eluting with 0-5% methanol in CH2Cl2 to give a solid. This was suspended in methanol (100 mL) and filtered to recover the title compound as a solid. 1H NMR (DMSO-d6) δ 8.71 (d, J=4.4 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.11 (d, J=7.1 Hz, 1H), 7.74-7.70 (m, 1H), 7.56-7.52 (m, 1H), 7.50-7.45 (m, 1H), 7.44-7.38 (m, 1H), 6.70 (d, J=7.1 Hz, 1H), 5.59 (s, 2H), 1.62 (s, 9H). LRMS (M+1)=545.8.