Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: COc1cccc(B(O)O)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: O
Solvent: COCCOC
Product: COc1cccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 73 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.052 g (73%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:17]C)=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=1)#N.[ClH:19]>>[ClH:19].[ClH:19].[CH3:1][NH:3][C:4]([NH2:17])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNC(=NCCSCc1ncccc1O)NC#N
Agent: Cl
Product: CNC(N)=NCCSCc1ncccc1O

Procedure:
A solution of N-cyano-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)-methylthio)ethyl]guanidine (2.2 g) in hydrochloric acid (25 ml) was heated on the steam bath for 2 hours. Concentration followed by recrystallisation of the product afforded N-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]guanidine dihydrochloride (1.6 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[C@H:41]2[N:37]([CH2:38][CH2:39][CH2:40]2)[CH2:36][C:35]2[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](O)=[O:49])[CH:44]=[N:45][C:34]=2[NH:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>CO>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:48](=[O:49])/[CH:47]=[CH:46]/[C:43]1[CH:44]=[N:45][C:34]2[NH:33][C:32](=[O:31])[C@H:41]3[N:37]([CH2:38][CH2:39][CH2:40]3)[CH2:36][C:35]=2[CH:42]=1
Reactant: CNCc1sc2ccccc2c1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Solvent: CO
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN2CCC[C@H]2C(=O)N3)sc2ccccc12
Yield: 62 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (S)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.15 g, 62%) was prepared as a tan powder: [α]25D +167.8° (c 1.05, methanol); 1H NMR (300 MHz, DMSO-d6) δ 12.33 (br s, 1H), 11.30 (br s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 7.89-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.65-7.55 (m, 1H), 7.42-7.31 (m, 3H), 5.13-4.90 (m, 2H), 4.47-4.22 (m, 2H), 3.61 (br s, 1H), 3.42-3.39 (br s, 4H), 3.17-2.95 (m, 3H), 2.42 (s, 3H), 2.10-1.88 (2H); MS (ESI) m/e 447 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18]C[CH2:16]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[CH:15]([N:12]1[CH2:11][CH2:10][N:9]([CH2:8][C:5]2[N:6]=[CH:7][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[CH:3][CH:4]=2)[CH2:14][CH2:13]1)([CH3:16])[CH3:18]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(CN2CCN(C3CCC3)CC2)nc1
Product: CC(C)N1CCN(Cc2ccc(-c3ccc(C#N)cc3)cn2)CC1

Procedure:
1-(5-Bromopyridin-2-ylmethyl)-4-isopropylpiperazine (1.163, 3.75 mmol) and 4-cyanophenyl-boronic acid (0.82 g, 5.6 mmol) were mixed with catalyst and reacted in the same manner as in example 18. The title compound was isolated as white crystals of the free amine. Yield: 241 mg (20%)
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)S([O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](O)[CH:26]=2)[CH:21]=1)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[C:1]1([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=3)[CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=S(=O)(Oc1ccc2cc(O)ccc2c1)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1ccc2cc(-c3cccc4ccccc34)ccc2c1
Yield: 120.9 %

Procedure:
Naphthalen-1-ylboronic acid (5.30 g, 30.8 mmol), 6-hydroxynaphthalen-2-yl trifluoromethanesulfonate (7.5 g, 25.7 mmol), potassium phosphate (10.90 g, 51.3 mmol) were mixed in 200 mL of THF and 20 mL of water and bubbled with nitrogen for 20 minutes. Pd2(dba)3 (0.235 g, 0.257 mmol) and [1,1′-biphenyl]-2-yldicyclohexylphosphine (0.180 g, 0.513 mmol) were added to the reaction mixture. The reaction was refluxed overnight. After cooling, the reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was separated and dried over MgSO4. The residue was purified by column using 1:2 hexanes:DCM (v/v) to give [1,2′-binaphthalen]-6′-ol (8.4 g, 95% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH2:10]2)=[C:4]([CH3:25])[CH:3]=1.Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=2)[C:30]([Cl:40])=[CH:29][N:28]=1.Cl.C([O-])(O)=O.[Na+]>CC(O)C>[Cl:40][C:30]1[C:31]([NH:33][C:34]2[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=2)=[N:32][C:27]([NH:1][C:2]2[C:7]([CH3:8])=[CH:6][C:5]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:11](=[O:24])[CH2:10]3)=[C:4]([CH3:25])[CH:3]=2)=[N:28][CH:29]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: COc1ccc(CN2CCC(c3cc(C)c(N)cc3C)CC2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(CN2CCC(c3cc(C)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2=O)cc1
Temperature: 130 °C

Procedure:
To a mixture of 4-(4-amino-2,5-dimethylphenyl)-1-(4-methoxybenzyl)piperidin-2-one (23 mg, 0.094 mmol) and 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (29 mg, 0.086 mmol) in iPrOH (1 mL) was added HCl (60 uL, 4N in dioxane). The reaction vessel was then sealed and heated to 130° C. for 4 hr. After cooling to room temperature, the mixture was treated with saturated NaHCO3 aqueous solution (3 mL) and extracted with EtOAc (3×4 mL). The organic layers were combined and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 0˜10% MeOH/CH2Cl2) to provide 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)-1-(4-methoxybenzyl)piperidin-2-one. ESMS m/z 546.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl>[C:17]([O:21][C:22](=[O:33])[NH:23][CH:24]1[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][N:13]2[CH2:14][CH2:15][C:10]([C:8](=[O:9])[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([OH:16])[CH2:11][CH2:12]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(c1ccc(F)cc1)C1(O)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCC(CCN2CCC(O)(C(=O)c3ccc(F)cc3)CC2)CC1

Procedure:
The title compound was prepared from ((4-Fluoro-phenyl)-(4-hydroxy-piperidin-4-yl)-methanone and trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester according to the procedure described for the synthesis of (4-{2-Trans-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (intermediate E, example 1) in 1,2 dichloroethane using triacetoxyborohydride. MS (m/e): 451.1 (M+H+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([CH2:12][S:13]([CH2:16][S:17]([CH2:20][C:21](O)=O)(=[O:19])=[O:18])(=[O:15])=[O:14])(O)=O>C(O)(=O)C>[CH:12](/[S:13]([CH2:16][S:17](/[CH:20]=[CH:21]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18])(=[O:15])=[O:14])=[CH:1]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccccc1)CS(=O)(=O)/C=C/c1ccccc1
Yield: 77 %

Procedure:
A solution of benzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 77% yield. m.p. 128-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: COc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3OC)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 50.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methoxyphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.054 g, 0.11 mmol) obtained in step 2 and ethanesulfonamide (0.059 g, 0.55 mmol), the title compound (0.031 g, 34%) was obtained.
Reaction SMILES: CCC1C=CC(CC[O:11]C2C=CC(CC3SC(=O)NC3=O)=CC=2)=NC=1.Cl.C(O)[C@H]1[O:33][C@H:32]([O:34][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:31]([OH:46])[C@@H:30]([OH:47])[C@@H:29]1[OH:48]>>[C:32]([OH:33])(=[O:34])[CH:31]([CH:30]([C:29]([OH:48])=[O:11])[OH:47])[OH:46]
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: Cl
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Compound A (24.8 g), sucrose (Osaka-Toka. Co., Ltd., 28.7 g), crystalline cellulose (Avicel PH-101, Asahi Kasei Corporation, 8.0 g) and L-HPC (LH-31, Shin-Etsu Chemical Co., Ltd., 12.5 g) were thoroughly mixed to give a dusting powder. Tartaric acid crystal (Wako Pure Chemical Industries, Ltd.) was sieved with a round sieve to give tartaric acid crystal on 30 mesh (aperture 0.50 mm). The tartaric acid crystal (150 g) was fed into a centrifugal fluidized-bed granulator (CF-mini, Freund Corporation) and coated with the above-mentioned dusting powder while spraying an aqueous solution (6 w/v %) of hydroxypropylcellulose (HPC-SL, NIPPON SODA CO., LTD.). The obtained spherical granules were dried under reduced pressure in a constant temperature vacuum drying oven (DP43, YAMATO SCIENTIFIC CO., LTD.) at 40° C. for 16 hr to give granules at the range of 16-30 mesh (aperture 0.50-1.00 mm). The granules (450 mg) were filled in No. 0 gelatin capsules (Capsugel) to give capsules having the following composition per capsule.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](O)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([O:7][C:6](=[O:8])[CH2:5][C@H:4]([OH:9])[CH2:3][C:1]#[N:2])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CO
Reactant: N#CC[C@@H](O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)COC(=O)C[C@H](O)CC#N
Yield: 92 %

Procedure:
(R)-4-cyano-3-hydroxybutyric acid (1.0 mol) in isobutanol (500 ml) and conc. sulfuric acid (5 g) were refluxed for 5 hours. The reaction mixture was neutralized with sodium carbonate and filtered. The filtrate was concentrated in vacuo to afford (R)-4-cyano-3-hydroxybutyric acid isobutyl ester (157 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6].C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:9]([CH:10]3[N:16]4[CH:17]=[N:18][CH:19]=[C:15]4[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1ccc(C2CCCCc3cncn32)c(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccc(C2CCCCc3cncn32)c(-c2ccc(F)cc2)c1
Reaction time: 0.01 h

Procedure:
To 3-bromo-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile (0.507 g, 1.59 mmol) is added DME (7.0 mL). To this is added aqueous 2M sodium carbonate (3.0 mL, 6 mmol) followed by 4-fluorophenylboronic acid (0.552 g, 3.97 mmol). This mixture is transferred to a microwave safe vial. Tetrakis(triphenylphosphine) palladium(0) (0.03 g, 0.025 mmol) is added, and the vessel sealed. The mixture is stirred briefly (30 seconds) and placed in a microwave for 25 minutes at 125° C. The vial is allowed to cool and unsealed. The mixture is extracted into ethyl acetate and washed with saturated sodium bicarbonate. The organic layer is removed in vacuo. The resulting material is subjected to chromatography (Silica gel, 1:50 to 1:25 methanol:methylene chloride) to give the desired product. MS (ESI) m/z 332 (M+H)
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:22]=3[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[C:1]1([C:7]2[O:11][C:10]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:22]=3[CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]4)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2cccc(Nc3ncc(-c4ccccc4)o3)c2C1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: OC1CCc2cccc(Nc3ncc(-c4ccccc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 11C for the product of Example 1I. 1H NMR (DMSO-d6) 9.11 (s, 1H), 7.59 (m, 3H), 7.41 (t, 2H, J=7.7 Hz), 7.37 (s, 1H), 7.25 (t, 1H, J=7.5 Hz), 7.09 (t, 1H, J=7.5 Hz), 6.84 (d, 1H, J=7.1 Hz), 4.80 (d, 1H, J=4.1 Hz), 3.93 (m, 1H), 2.73-2.99 (m, 4H), 1.86 (m, 1H), 1.62 (m, 1H); MS (ESI+) m/z 307 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.Cl.Cl.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35].C([O-])(O)=O.[Na+]>CCOC(C)=O.O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:34](=[O:35])[CH2:33][N:32]([CH3:37])[CH3:31])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CN(C)CC(=O)O
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2cc(NC(=O)CN(C)C)ccc2[nH]1
Temperature: 0 °C
Reaction time: 21 h
Yield: 67.6 %

Procedure:
A solution of 5-nitro-1H-indole-2-carboxylic acid ethyl ester (28) (750 mg, 3.20 mmol) in EtOAc (125 mL) was hydrogenated over Pd/C (10%, 300 mg) at 60 psi H2 for 5 h at room temperature. Then, the solid was removed by filtration through Celite, which was washed thoroughly with CH2Cl2 (400 mL) and MeOH (400 mL), and the filtrate was concentrated in vacuo. The residue was dissolved in DMF (30 mL) and the solution was cooled to 0° C. EDC.HCl (1.84 g, 9.60 mmol) and N,N-dimethylglycine hydrochloride (670 mg, 4.80 mmol) were added and the reaction mixture was allowed to warm to room temperature. After stirring for 21 h at this temperature, the solution was diluted with EtOAc (100 mL) and water (100 mL). The mixture was adjusted to pH 9 with a saturated aqueous solution of NaHCO3 and extracted with EtOAc (4×150 mL). The combined organic fractions were washed with water (4×200 mL) and brine (300 mL), dried (MgSO4), and the solvent was removed in vacuo. Purification by column chromatography (CH2Cl2/MeOH, 10:1) gave 29 (626 mg, 68% overall yield) as a pale brown solid. 1H NMR (200 MHz, CDCl3): δ=1.42 (t, J=7.1 Hz, 3 H, OCH2CH3), 2.40 (s, 6 H, NMe2), 3.11 (s, 2 H, 1′-H2), 4.41 (q, J=7.1 Hz, 2 H, OCH2CH3), 7.18 (d, J=1.8 Hz, 1 H, 3-H), 7.36 (d, J=8.8 Hz, 1 H, 7-H), 7.43 (dd, J=8.8, 1.8 Hz, 1 H, 6-H), 8.04 (sbr, 1 H, 4-H), 9.04 (sbr, 1 H, NH), 9.13 (sbr, 1 H, NH) ppm; 13C NMR (50.3 MHz, CDCl3): δ=14.3 (OCH2CH3), 46.0 (NMe2), 61.0 (OCH2CH3), 63.6 (C-1′), 108.5 (C-3), 112.2, 112.8 (C-4, C-7), 119.2 (C-6), 127.5, 128.2 (C-2, C-3a), 131.1 (C-5), 134.1 (C-7a), 162.0 (NHCO), 168.6 (CO2Et) ppm; MS (70 eV, EI): m/z (%)=289 (25) [M]+, 58 (100) [CH2NMe2]+; C15H19N3O3 (289.33): calcd. 289.1426, found 289.1426.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH:2]([CH3:4])[CH3:3].[CH2:42]([O:49][C:50]([NH:52][C@H:53]([C:58]([OH:60])=O)[CH2:54][C:55](=[O:57])[NH2:56])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([N:5]([C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:58]([C@@H:53]([NH:52][C:50]([O:49][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:51])[CH2:54][C:55]([NH2:56])=[O:57])=[O:60])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:33])=[O:34])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using commercially available Nα-benzyloxycarbonyl-L-asparagine (319 mg, 1.2 mmol). The final product was purified by preparative HPLC to yield 46 mg (41%) of the desired material.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19]>>[Cl:14][C:15]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:17]2[C:16]=1[C:21](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:18]2=[O:19]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Product: COC(=O)C(CN1C(=O)c2c(Cl)ccc(Cl)c2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.23 g, 30%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 2.30 mmol) and 3,6-dichlorophthalic anhydride (0.50 g, 2.30 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].N1C=CC=CC=1.Cl.[NH2:20][OH:21]>CO.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:20][OH:21])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NO
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: O=[N+]([O-])c1cc(C=NO)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of 4-bromo-3-nitro-benzaldehyde (commercially available) (10 g, 43.5 mmol) in methanol (28 ml) under a nitrogen atmosphere was added pyridine (7.74 g, 97.8 mmol) and hydroxylamine hydrochloride (6.04 g, 86.94 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with a mixture of ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3) to give 4-bromo-3-nitro-benzaldehyde oxime (5.34 g, 67% yield). 1H-NMR (CDCl3, 400 MHz): 8.11 (s, 1H), 8.05 (d, 1H), 7.75 (d, 1H), 7.62 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>O1CCOCC1.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(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(F)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 85 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (90 mg, 0.24 mmol), (4-fluorophenyl)boronic acid (33.7 mg, 0.24 mmol) in 1,4-dioxane (3 mL). PdCl2(dppf)-CH2Cl2 adduct (19.7 mg, 0.024 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium carbonate (77 mg, 0.72 mmol) was added, the vessel was sealed, and the mixture was heated at 85° C. for 2 hrs and then at 100° C. overnight. Added an additional 2 eq of boronic acid and 0.2 eq of PdCl2(dppf)-CH2Cl2 adduct. The contents were heated at 120° C. for 4 hr. and then irradiated (microwave) first at 160° C. for 90 min, and then at 190° C. for 2 hrs. After cooling to room temperature, the solids were filtered, washed with DMSO and the filtrate was evaporated. The crude product was purified first by reverse-phase HPLC (C18, 5% to 80% CH3CN in water with 0.1% TFA, 18 minute gradient) and then silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The collected solid was dried to afford the title compound (13 mg, 12%) as a white solid. LCMS E-S (M+H)=434.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (br. s., 1H), 8.96 (t, J=4.67 Hz, 1H), 8.38 (s, 1H), 8.33 (dd, J=8.84, 5.56 Hz, 2H), 8.16 (s, 1H), 7.40 (t, J=8.84 Hz, 2H), 5.91 (s, 1H), 5.33 (dt, J=13.26, 6.76 Hz, 1H), 4.41 (d, J=4.55 Hz, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (d, J=6.57 Hz, 6H).