Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:23]1([C:29]#[C:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:29]#[C:30][CH2:31][CH2:32][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC#Cc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCC#Cc2ccccc2)C1

Procedure:
The title compound, MS: m/e=355.1 (M+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and toluene-4-sulfonic acid 4-phenyl-but-3-ynyl ester.
Reaction SMILES: CN([CH:4]=[N:5][C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])C.[C:22]([O:26][C:27](=[O:31])[CH2:28][C:29]#[N:30])([CH3:25])([CH3:24])[CH3:23]>C(O)(C)(C)C>[C:22]([O:26][C:27](=[O:31])[C:28]([C:29]#[N:30])=[CH:4][NH:5][C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOc1cc(N=CN(C)C)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CC(C)(C)O
Product: CCOc1cc(NC=C(C#N)C(=O)OC(C)(C)C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A 3-L round-bottomed flask under N2 equipped with an overhead stirrer, a condenser and a thermocouple is charged with 2-[[(dimethylamino)methylene]amino]-4-ethoxy-5-nitrobenzoic acid, methyl ester (68 g, 230 mmol), t-butanol (500 mL) followed by t-butylcyanoacetate (65 g, 460 mmol). The reaction mixture is heated to reflux. After 4 hours the reaction is cooled to room temperature and the suspension is filtered. The filter cake is washed with heptane (2×100 mL) and dried under vacuum (50 mm Hg) at 40° C. to provide the title compound as a beige solid (83 g, 91% yield, >98% purity by NMR). 1H NMR (300 MHz, DMSO-d6): 12.7 (d, J=12.9 Hz, 1H), 8.77 (d, J=12.9 Hz, 1H), 8.50 (s, 1H), 7.47 (s, 1H), 4.37 (q, J=7 Hz, 2H), 3.91 (s, 3H), 1.52 (s, 9H), 1.40 (t, J=7 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[S:37])[C@H:4]([CH2:32][CH2:33][C:34](=[O:36])[NH2:35])[NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:15])=[CH:9][C:8]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].[Li+:38].[OH-]>>[Li+:38].[CH:18]1([CH2:17][CH2:16][N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:2])=[S:37])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:31])=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH:9]=2)[CH3:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=S)[C@H](CCC(N)=O)NC(=O)c1ccc(CN(C)CCC2CCCCC2)cc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccccc1-c1cc(CN(C)CCC2CCCCC2)ccc1C(=O)N[C@@H](CCC(N)=O)C([O-])=S

Procedure:
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)benzoyl]thioglutamine methyl ester (12 mg, 22.9 μmol) was saponified using the standard LiOH procedure, evaporated, and lyophilized from water to provide 9.8 mg of the title compound. MS m/e 514 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([F:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1C2C(=NC=CC=2)N(OC(N(C)C)=[N+](C)C)N=1.[NH2:66][CH2:67][C@@H:68]([OH:70])[CH3:69]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:24]=[C:23]([F:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:66][CH2:67][C@@H:68]([OH:70])[CH3:69])=[O:20])[CH:8]=1)=[O:5]
Reactant: C[C@H](O)CN
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CNC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Reaction time: 18 h
Yield: 16 %

Procedure:
To a solution of 5-(2-chloro-4-fluoro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 110, 100 mg, 0.22 mmol) in DMF (3 mL) was added DIPEA (0.23 mL, 1.32 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (92 mg, 0.26 mmol). The reaction was stirred at room temperature for 10 minutes before the addition of (S)-1-aminopropan-2-ol (20 mg, 0.22 mmol) and the reaction was continued stirring for 18 hours. The reaction was diluted with EtOAc (50 mL) and extracted with water (3×5 mL) and brine (25 mL). The organic layer was collected, dried over anhydrous Na2SO4 before concentration in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-80% MeCN in water to afford the title compound (18 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14](=[O:15])[CH2:13][C:12]3[C:8](=[N:9][N:10]([CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=3)[C:6]=2[CH:7]=1.[OH-].[Na+]>CO>[C:17]([CH2:16][N:10]1[CH:11]=[C:12]2[CH2:13][S:14](=[O:15])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[C:8]2=[N:9]1)([OH:19])=[O:18]
Reactant: CCOC(=O)Cn1cc2c(n1)-c1cc(Cl)ccc1S(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cc2c(n1)-c1cc(Cl)ccc1S(=O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
A mixture of 8-chloro-2-ethoxycarbonylmethyl-2,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole 5-oxide (3 g) and 1N aqueous sodium hydroxide (9.25 ml) in methanol (90 ml) was stirred at ambient temperature for 30 minutes and then evaporated in vacuo. To the residue were added 1N hydrochloric acid and ethyl acetate, the insoluble material was collected by suction, and washed with water. The obtained crude product was recrystallized from a mixture of ethanol and n-hexane to give 2-carboxymethyl-8-chloro-2,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole 5-oxide (0.78 g).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F)([O-:18])=[O:17]>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([S:13][C:20]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(S)cnn(C(C)(C)C)c1=O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(Sc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cnn(C(C)(C)C)c1=O
Temperature: 25 °C

Procedure:
To a solution of 2.0 g (0.01 mol) of the crude product of 2-tert.-butyl-5-mercapto-4-methyl-3(2H)-pyridazinone dissolved in 15 ml of ethanol was added 1.5 ml of 20% sodium hydroxide under stirring at room temperature. After stirring for additional 15 minutes at room temperature, the resulting mixture was added dropwise with a solution of 1.4 g of 2,4-dinitrofluorobenzene dissolved in 5 ml of ethanol and stirred for 10 minutes at room temperature. Crystalline precipitates were collected by filtration, washed with 50 ml of water and 50 ml of ethanol and then recrystallized from 50 ml of benzene to give 2.0 g of 2-tert.-butyl-4-methyl-5-(2',4'-dinitrophenylthio)-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]([CH3:11])[N:4]=1>CO.[Pd]>[NH3:4].[CH3:1][O:2][C:3]1[C:7]([NH2:8])=[CH:6][N:5]([CH3:11])[N:4]=1
Reactant: COc1nn(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1nn(C)cc1N
Product: N
Reaction time: 2.5 h
Yield: 47 %

Procedure:
3-Methoxy-1-methyl-4-nitropyrazole (2.9 g) was dissolved in MeOH (100 ml) at room temperature and Pd/C (0.58 g, 50% wet) was added. The solution was purged with nitrogen for 10 minutes, followed by hydrogen for 2.5 hours. The reaction mixture was filtered through a cake of celite, washed with EtOAc (200 ml) and the volatiles removed under vacuum to give the crude product as a deep red oil. Column chromatography (SiO2; 50:50, EtOAc:heptane), followed by further purification via a ‘catch and release’ method (2 g isolute flash SCX-2, eluting with 100% MeOH then methanolic ammonia (0.5 M to 7 M) furnished 3-methoxy-1-methylpyrazol-4-amine as a deep blue liquid (0.551 g). NMR Spectrum: (CDCl3) 2.35 (m, 2H), 3.62 (s, 3H), 3.94 (s, 3H), 6.83 (s, 1H); Mass spectrum: MH+ 128.
Reaction SMILES: C(O[C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])C.[H-].[Na+].[H][H].[CH3:15][N:16]1C(=O)O[C:19](=[O:20])[C:18]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:17]12.Cl>CC(N(C)C)=O>[OH:20][C:19]1[C:18]2[C:17](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:16]([CH3:15])[C:4](=[O:10])[C:5]=1[S:6]([CH3:9])(=[O:7])=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)c(S(C)(=O)=O)c(O)c2ccccc21
Temperature: 90 °C
Yield: 47.9 %

Procedure:
A solution of ethylmethanesulfonylacetate (3.78 g, 22.74 mmol) was added slowly in a suspension of sodium hydride (60% in mineral oil, 1.07 g, 25 mmol) in dimethylacetamide under N2 atmosphere. The mixture was allowed to stir at room temperature until the evolution of hydrogen gas ceased, then heated to 90° C. for 30 min and cooled to room temperature. A solution of N-methylisatoic anhydride (4.43 g, 25 mmol) in dimethylacetamide was added slowly and heated overnight at 120° C. The mixture was cooled to room temperature, poured into ice water and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to yield 2.76 g (48%) of white solids. Mp 170° C. 1H NMR (DMSO-d6): δ 3.51 (s, 3H), 3.59 (s, 3H), 7.39 (t, J=7.4 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.84 (t, J=7.0 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H). EIMS m/z 254 (M+1), 276 (M+23). Anal. (C11H11NO4S) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:43])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40](=[O:42])[CH3:41])=[CH:36][N:35]=4)[CH2:30][CH2:29]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:44][Mg]I>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:43])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][N:15]([C:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([OH:42])([CH3:44])[CH3:41])=[CH:36][N:35]=4)[CH2:32][CH2:33]3)=[O:27])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)=O)cn3)CC2)C[C@H]1c1ccc(Cl)c(F)c1
Reactant: C[Mg]I
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)(C)O)cn3)CC2)C[C@H]1c1ccc(Cl)c(F)c1
Reaction time: 1.5 h
Yield: 13.2 %

Procedure:
A mixture of 142 mg (0.23 mmol) [(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carbonyl)-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 59) and 0.097 mL (0.29 mmol) methylmagnesium iodide (3M) in 5 mL was stirred from 0° to 15° C. during 90 min and quenched at 0° C. with NH4Cl (aq.). The mixture was extracted with ethyl acetate and the combined organic layers were dried with Na2SO4 and evaporated. The residue was subjected to preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 19 mg (13%) of the title compound as white solid. MS m/e: 627.2 [M+11]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)=[CH:3][C:4]=1[N+:13]([O-:15])=[O:14])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of (4-bromo-2-nitro-phenyl)-tert-butyl-amine (7.2 g, 0.026 mol) in DMF (100 mL) and H2O (10 mL) are added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-ylamine (8.7 g, 0.04 mol), Pd(PPh3)4 (3 g, 0.003 mol) and K2CO3 (7.3 g, 0.053 mol) at room temperature. The solution is heated to 100° C. for 2 hours. The solution is cooled down, washed with H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layer is dried with MgSO4 and filtered. The filtrate is concentrated and the residue is re-crystallized in CH2Cl2 (10 mL) to afford 5-(4-tert-butylamino-3-nitro-phenyl)-pyrimidin-2-ylamine as a scarlet solid (6.3 g, 83%).
Reaction SMILES: [N:1]12CC[N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[I:9][C:10]([I:15])([CH2:13][CH3:14])CC.[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1>>[I-:9].[N:1]12[CH2:6][CH2:5][N:4]([CH2:3][CH2:2]1)[CH2:18][CH:17]2[CH2:16][CH2:20][CH2:14][CH2:13][CH2:10][I:15]
Reactant: C1CN2CCN1CC2
Reactant: C1CCOC1
Reactant: CCC(I)(I)CC
Product: ICCCCCC1CN2CCN1CC2
Product: [I-]

Procedure:
1,4-diazabicyclo[2.2.2]octane is suspended in THF. Diiodopentane is added dropwise and the mixture is refluxed overnight. The reaction mixture is filtered.
Reaction SMILES: CN.[Br:3][C:4]1[C:9](F)=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:5]=1[F:14].C[CH2:16][N:17](C(C)C)C(C)C>C1COCC1>[Br:3][C:4]1[C:5]([F:14])=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[CH2:16][NH2:17]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1CCOC1
Product: NCc1c([N+](=O)[O-])ccc(F)c1Br
Yield: 91.3 %

Procedure:
Methylamine (2M in THF, 19 mL, 38.1 mmol) was added to a solution of 2-bromo-1,3-difluoro-4-nitrobenzene (4.53 g, 19 mmol) and DIPEA (6.8 mL, 38.1 mmol) in THF (70 mL) and the resultant mixture stirred at 60° C. for 3 h. The reaction mixture was concentrated in vacuo and the residue purified by chromatography eluting with (SiO2 0-80% DCM in cyclohexane) to give title compound as an orange/yellow solid (4.32 g, 91%). LCMS (Method C): RT 3.46 min [M+H]+ 249.0, 251.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7]([CH2:15][CH:16](OC)[O:17]C)[CH:6]=[C:5]2[CH3:21].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7]([CH2:15][CH:16]=[O:17])[CH:6]=[C:5]2[CH3:21]
Reactant: COC(=O)c1cc(Cl)cc2c(C)cn(CC(OC)OC)c12
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc2c(C)cn(CC=O)c12
Temperature: 60 °C
Yield: 89.6 %

Procedure:
To a stirred solution of methyl 5-chloro-1-(2,2-dimethoxyethyl)-3-methyl-1H-indole-7-carboxylate (909 mg, 2.9 mmol) from Step C above in THF (20 ml) was added 2N HCl (20 ml). The mixture was heated to 60° C. for 4 h. The solvent was evaporated and the residue purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 5-chloro-3-methyl-1-(2-oxoethyl)-1H-indole-7-carboxylate (690 mg, 89%) as a yellow solid: MS (ESI+) m/z 266 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:43][C:24]4=[N:25][CH:26]=[C:27]([Br:42])[C:28]([N:29]5[CH2:34][CH2:33][N:32]([CH2:35][C:36]6[N:37]=[C:38]([CH3:41])[S:39][CH:40]=6)[CH2:31][CH2:30]5)=[C:23]4[N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:42][C:27]1[C:28]([N:29]2[CH2:30][CH2:31][N:32]([CH2:35][C:36]3[N:37]=[C:38]([CH3:41])[S:39][CH:40]=3)[CH2:33][CH2:34]2)=[C:23]2[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:16][CH:17]=3)[NH:43][C:24]2=[N:25][CH:26]=1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCNCC6)cc5)nc34)CC2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
tert-Butyl-4-(4-(6-bromo-7-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate (0.022 g, 0.033 mmol) was suspended in DCM (2.0 mL) and the mixture cooled in an ice bath. TFA (0.5 mL) was added and the resulting solution was allowed to warm up to room temperature and stirred for 2 h. The mixture was passed through an SCX column (5 g), washed with methanol and then eluted with ammonia (0.2M) in methanol. The filtrate was collected and the solvent removed in vacuo to give the title compound as a off-white solid (0.017 g, 91%); 1H-NMR (500 Mz, DMSO-d6): δ 2.26-2.36 (m, 4H), 2.61-2.75 (m, 11H), 3.50 (s, 2H, NCH2), 3.61-3.70 (m, 6H), 7.32 (s, 1H, thiazole 5-H), 7.45 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.13 (d, J=8.05 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 2.19 min—567/569 [(M+H)+, Br isotopic pattern]; ESI-HRMS: Found: 567.1634, calculated for C26H32N8SBr (M+H)+: 567.1654.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2([CH2:14][C@H:15]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])OCC[O:10]2)=[N:3]1>CC(C)=O.CC#N.CC#N.Cl[Pd]Cl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:10])[CH2:14][C@H:15]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:3]1
Reactant: Cc1ccccc1[C@H](CC1(c2ccc(=O)n(C)n2)OCCO1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl[Pd]Cl
Solvent: CC(C)=O
Solvent: CC#N
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(S(C)(=O)=O)cc1
Yield: 55.4 %

Procedure:
To a solution of (R)-2-methyl-6-(2-(2-(4-(methylsulfonyl)phenyl)-2-o-tolylethyl)-1,3-dioxolan-2-yl)pyridazin-3(2H)-one (10 mg, 22 μmol) in acetone (1 ml) was added bis(acetonitrile)dichloropalladium(II) (1.4 mg, 5 μmol, Eq: 0.25), then after 24 h at room temperature another portion of bis(acetonitrile)dichloropalladium(II) (6 mg, 22 μmol) was added, then after 24 h the reaction mixture was evaporated. Chromatography (SiO2; gradient heptane/ethyl acetate 2:1 to ethyl acetate) afforded the title compound (5 mg, 55%). White solid, MS: 411.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: O=C(Cl)OCCCl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)OCCCl)C1O
Reaction time: 21 h
Yield: 87.3 %

Procedure:
400 mg (1.70 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole, 260 μl (1.87 mmol) of triethylamine and 40 mg of dichloromethane were stirred at room temperature, and 193 μl (1.87 mmol) of 2-chloroethyl chloroformate were added thereto and stirred for 21 hours. The reaction liquid was washed thrice with water and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from chloroform to obtain 507 mg of the intended compound as pale yellow crystals. (yield: 87%)
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][N:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:36])=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CN(C)Cc4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Product: COc1cc(-c2cc3cc(CNCc4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 19 %
Yield: 60 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with N-methylbenzylamine (0.258 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(benzylaminomethyl)indol-2-yl]isoindolinone (22.6 mg, yield 19%) and 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(N-methylbenzylaminomethyl)indol-2-yl]isoindolinone (72.1 mg, yield 60%).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[C:10]([NH2:27])=[N:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:14]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.[Cu]I.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>[CH:24]([S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:9]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[C:10]([NH2:27])=[N:11][CH:12]=2)=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH3:26])[CH3:25]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#C[Si](C)(C)C)n2)cc1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
Triethylamine (47.58 g, 65.54 mL, 470.2 mmol) was added to a stirred suspension of 3-bromo-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (33.5 g, 94.04 mmol) in anhydrous DMF (234.5 mL). Copper(I) iodide (2.148 g, 11.28 mmol) was then added followed by Pd(PPh3)4 (5.433 g, 4.702 mmol). The stirred mixture was cooled to 0° C. in an ice-bath and (trimethylsilyl)acetylene (12.01 g, 17.28 mL, 122.3 mmol) was added dropwise over 10 minutes. The ice bath was then removed and the mixture allowed to warm to ambient temperature over 2 hours. The mixture was poured into EtOAc/water (500 mL/300 mL) and the mixture was filtered through a pad of celite. The organic phase was separated and the aqueous layer extracted with EtOAc. The combined organics were washed with water (×1) and brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 750 g column, eluting with 0 to 15% DCM/EtOAc, dry-loaded) to give the sub-title product as a dark yellow solid (28.0 g, 78% Yield). 1H NMR (400.0 MHz, DMSO) δ 0.15 (s, 9H, 1.03 (d, 6H), 3.29 (sept, 1H), 6.80 (br s, 2H), 7.74 (d, 2H), 8.05 (d, 2H) and 8.60 (s, 1H) ppm; MS (ES+) 375.1.