Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:20]=[CH:19][C:8]([NH:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[C:21]([CH2:23][C:24](OCC)=[O:25])#[N:22].C([O-])(=O)C.[NH4+]>>[NH4+:9].[C:21]([C:23]1[C:24](=[O:25])[N:9]([C:8]2[CH:19]=[CH:20][C:5]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:6][CH:7]=2)[CH2:10][C:11]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:22]
Reactant: O=C(CNc1ccc(S(=O)(=O)O)cc1)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#CC1=C(c2ccccc2)CN(c2ccc(S(=O)(=O)O)cc2)C1=O
Temperature: 130 °C
Reaction time: 0.42 h
Yield: 104 %

Procedure:
A mixture of 14.5 grams (50 mmol) of 2-(4-sulfoanilino)acetophenone, 45.2 grams (0.4 mol) of ethyl cyanoacetate and 12.2 grams (0.2 mol) of ammonium acetate in a reaction flask fitted with distillation head was stirred and placed in an oil bath pre-heated to 130° C. At an internal temperature of 60° C. the reaction mixture became easily stirrable. Distillate began to collect at 95° C. and the reaction was brought to an internal temperature of 115° C. After 25 minutes the product mixture had become a thick slurry. The product mixture was then cooled, diluted with 100 mL of ethanol and stirred. The tan-yellow product was collected by filtration and washed with ethanol, acetone and ligroin to give a crude weight of product of 10.1 grams. The product was recrystallized from glacial acetic acid to give 9.35 grams (26 mmol, 52% yield) of product as a yellow powder, m. p.=275°-300° C. (decomposes). Elemental Analysis: Calculated: C=57.13, H=4.23, N =11.76, S=8.97; Found: C=57.07, H=4.31, N=11.66, S=8.40.
Reaction SMILES: [CH2:1]=[O:2].[CH2:3]([O:7][P:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])[CH:4]([CH3:6])[CH3:5]>O>[CH2:3]([O:7][P:8]([CH2:1][OH:2])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[CH:4]([CH3:6])[CH3:5]
Reactant: C=O
Reactant: CC(C)COP(O)c1ccccc1
Solvent: O
Product: CC(C)COP(=O)(CO)c1ccccc1
Reaction time: 1 h

Procedure:
15 g of para-formaldehyde are added, at 70°C and with vigorous agitation, to 100 g (0.505 mole) of benzenephosphonous acid isobutyl ester. Agitation is continued for 1 hour at 75°-90°C. The reaction mixture is then cooled, stirred with water, and the organic phase is separated. The aqueous phase is extracted 2 times with chloroform, and the extract is added to the organic phase. After drying with sodium sulfate, distillation is carried out in a water jet vacuum at an interior temperature of up to 80°C. The residue is distilled in a thin layer evaporator at 0.1 torr and a distillation temperature of 190°C. Subsequently, the distillate is again distilled in a normal distillation apparatus. It is pure hydroxymethyl-phenylphosphinic acid isobutyl ester having a boiling point of 155°C at 0.3 torr.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[C:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[C:10]2[CH:16]=[N:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]2=[N:12][CH:13]=1)(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[CH2:17]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([NH:7][CH3:6])[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[C:10]2[CH:16]=[N:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(F)ccc1-c1c(NC(=O)OC(C)(C)C)cnc2c1cnn2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1cnc2c(cnn2Cc2ccccc2)c1-c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.6 %

Procedure:
To a solution of [1-benzyl-4-(4-fluoro-2-methyl-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-carbamic acid tert-butyl ester (2.6 g, 6.01 mmol) in DMF (50 mL) at 0° C. was added NaH (0.462 g, 50% purity, 9.62 mmol). After 20 minutes, iodomethane (1.54 g, 10.8 mmol) was added and the temperature raised to RT. The reaction was quenched by addition of H2O and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, and concentrated under vacuo to give a crude intermediate which was used directly in the next step without further purification. This residue as dissolved in CH2Cl2 (50 mL) and TFA (15 mL) was added. The reaction mixture was heated at 30° C. for 2 hours, diluted with CH2Cl2 (100 mL) and aqueous NaOH (1N) was added until pH reached 8. The organic phase was dried over Na2SO4, concentrated under vacuo to give the title product 2.24 g (97%) with high purity (no further purification needed) as a light yellow solid. ES-MS m/e: 347.3 (M+H+).
Reaction SMILES: [O:1]=[O+][O-].[Si:4]([O:11][CH:12]([C:14]1[O:15][C:16](=[O:26])[C:17]2[C:22]([C:23]=1[CH:24]=C)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O=O.C(Cl)Cl>[Si:4]([O:11][CH:12]([C:14]1[O:15][C:16](=[O:26])[C:17]2[C:22]([C:23]=1[CH:24]=[O:1])=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])([C:7]([CH3:10])([CH3:8])[CH3:9])([CH3:6])[CH3:5]
Reactant: O=[O+][O-]
Reactant: C=Cc1c(C(C)O[Si](C)(C)C(C)(C)C)oc(=O)c2ccccc12
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1C=O
Reaction time: 8 h

Procedure:
A slow stream of O3 in O2 was passed through a −78° C. cooled solution of 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-vinyl-1H-isochromen-1-one (intermediate B59.1, 2.967 g of crude) in DCM (100 ml) for 1.5 hrs. The excess of 03 was purged by N2 bubbling, then a solution of PPh3 (2.316 g, 8.83 mmol) in DCM (20 ml) was added. The solution was allowed to reach 25° C. and it was stirred overnight. The solvent was removed in vacuo and the crude material was purified by flash chromatography on Biotage silica gel cartridge (cyclohexane to cyclohexane:EtOAc=90:10) to afford 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-1H-isochromene-4-carbaldehyde (Intermediate B59.2, 1.453 g, 4.38 mmol).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:26]12([C:36](Cl)=[O:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[C:26]12([C:36]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[NH:25][C:11]5[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]6[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=6)=[O:18])=[CH:15][C:10]=5[N:9]=4)=[CH:6][CH:7]=3)=[O:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2
Reactant: Nc1ccc(-c2nc3cc(NC(=O)c4ccccn4)ncc3[nH]2)cc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2cn1)c1ccccn1
Yield: 41.5 %

Procedure:
A solution of 22 (0.065 g, 0.197 mmol), adamantane carbonyl chloride (0.060 g, 0.30 mmol) in dry Pyridine (5 ml) was stirred at 80° C. for 2 h. After usual work-up the solid was treated with 10% K2CO3 for 1 h. The solid was filtered and passed through SiO2 gel, eluting with EtOAc affording diamide 24 (0.039 g, 40%). M.p. 305° C.; 1H NMR (DMSO-d6, 500 MHz): δ 13.19 (1H, brs, NH), 10.47 (1H, brs, NH), 9.39 (1H, brs), 8.765 (1H, d, J=4.5 Hz), 8.73 (1H, brs), 8.45 (1H, brs), 8.24 (1H, d, J=8.0 Hz), 8.14-8.09 (2H, m), 7.89 (2H, d, J=8.5 Hz), 7.72 (1H, dt, J=5.0 and 7.5 Hz), 2.0 (3H, brs), 1.92 (6H, brs), 1.72 (6H, brs); EIMS m/z: 493.5 (M+1); Anal (C29H28N6O2×1.23 H2O) C, H, N.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([C:20]1[N:21]=[CH:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]>C(O)(=O)C.[C].[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
1-(6-Acetoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (0.25 g) was dissolved in acetic acid (20 ml). To the mixture was added 10% palladium carbon (0.1 g). The mixture was stirred at 50° C. for 2 h under hydrogen atmosphere. The catalyst was filtered off, and filtrate was concentrated. The residue was purified by silica gel chromatography (eluent; dichloromethane-methanol=10:1) to give the titled compound (0.1 g) as a colorless solid.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=N1>O1CCOCC1.[Pd]>[NH2:3][C:4]1[C:5]([SH:1])=[C:6]([CH:7]=[CH:8][CH:9]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cccc2nnsc12
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(N)c1S

Procedure:
A solution of 1 g of methyl benzo-1,2,3-thiadiazole-7-carboxylate in 40 ml of dioxane is hydrogenated over 0.5 g of palladium-on-charcoal (5%) at 160° C. under an initial pressure of 150 bar. After the starting substance has reacted completely, the catalyst is filtered off and rinsed with dioxane, the filtrate is evaporated, avoiding contact with air, and the residue is purified over silica gel (hexane/ethyl acetate (6:4)). The title compound of melting point 174-175° C. is obtained by this procedure.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:12].[H-].[Na+].[CH3:15]I>CN(C=O)C>[CH3:15][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:12]
Reactant: O=C1CCNc2ccccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCNc2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one (2.0 g, 12.3 mmol) in DMF (30 ml), at −10° C., was added sodium hydride (0.54 g, 60% dispersion, 13.6 mmol). The mixture was stirred at −10° C. for 15 min, then methyl iodide (0.77 ml, 12.3 mmol) was added. The mixture was stirred at −100° C. for a further 1 h and then concentrated in vacuo. The residue was taken up in EtOAc and washed with brine (3 times), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 1.70 g (78%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([N+:32]([O-:34])=[O:33])[CH:23]=1.C(O)(=O)C>O1CCCC1.O>[OH:27][CH:26]([C:25]1[CH:28]=[C:29]([O:30][CH3:31])[C:22]([O:21][CH3:20])=[CH:23][C:24]=1[N+:32]([O-:34])=[O:33])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C#CC(O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 117.2 %

Procedure:
1.5N butyllithium (26.8 ml, 40.2 mmole) was added under the argon atmosphere to a solution of diisopropylamine (6.0 ml, 42.8 mmole) in tetrahydrofuran (75 ml) at -78° C., and the mixture was stirred for 1 hour. Next, ethyl propiolate (3.4 ml, 33.5 mmole) and a solution of 4,5-dimethoxy-2-nitrobenzaldehyde (5.0 g, 23.7 mmole) in tetrahydrofuran (50 ml) were added in this sequence, and the reaction mixture was stirred at -78° C. for further 1.5 hours. After a solution of acetic acid (7.0 ml, 122 mmole) in tetrahydrofuran (20 ml) followed by water were added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(4,5-dimethoxy-2-nitrophenyl)-2-butynoate as an oil (8.59 g).Ethyl 4-hydroxy-4-(4,5-dimethoxy-2-nitrophenyl)-2-butynoate thus obtained was dissolved in toluene (80 ml), 4-methoxybenzylazide (11.6 g, 71.1 mmole) was added, and the mixture was stirred under heating at 100° C. overnight. After the reaction mixture was cooled to room temperature, it was purified by silica gel column chromatography (hexane:ethyl acetate=2:1).
Reaction SMILES: [CH2:1]([N:4]([CH2:17][C:18]([O:20]CC)=[O:19])[NH:5][C:6](=[O:16])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[CH:2]=[CH2:3].O.[OH-].[Li+]>>[CH2:1]([N:4]([CH2:17][C:18]([OH:20])=[O:19])[NH:5][C:6](=[O:16])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)OCC)NC(=O)N[C@@H](C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C=CCN(CC(=O)O)NC(=O)N[C@@H](C)c1ccccc1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-2 with the modification that the reaction was carried out for 2 hours, (S)-ethyl 2-(1-allyl-2-(1-phenylethylcarbamoyl)hydrazinyl)acetate (Compound V-4) 183 mg (0.6 mmol) was reacted with lithium hydroxide monohydrate 30 mg (0.72 mmol) to obtain the title compound 157 mg (94%).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][S:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][C:22]([C:28]([O:30]CC)=[O:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][C:22]([C:28]([OH:30])=[O:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2[nH]cc(CSCCN3CC=C(c4ccccc4)CC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(CSCCN3CC=C(c4ccccc4)CC3)c[nH]c2cc1C(=O)O

Procedure:
4.5 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-methoxy-6-ethoxycarbonylindole are boiled with 20 ml of water and 100 ml of 2N ethanolic KOH for 30 minutes, and the mixture is worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-5-methoxyindole-6-carboxylic acid, m.p. 168°-171°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2
Reactant: C1CCNCC1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(N3CCCCC3)nncc2c1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 108.5 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.1 g, 0.41 mmol), piperidine (0.081 mL, 0.82 mmol) and potassium carbonate (0.056 g, 0.41 mmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. After about 20 min., all starting material was converted to product (M+1=292, 294). The mixture was concentrated under vacuum and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give (0.13 g) 6-bromo-1-(piperidin-1-yl)phthalazine as yellow solid. Found MS (ES+): 292, 294(M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[CH3:21][N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:24]([Sn](CCCC)(CCCC)CCCC)=[N:23]1>CN(C=O)C.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.[Cu]I>[CH3:21][N:22]1[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:24]([C:2]2[N:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]3=[N:6][CH:7]=2)=[N:23]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCC2
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c1CCCC2
Temperature: 90 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (406 mg, 1.14 mmol) and 1-methyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole (485 mg, 1.14 mmol) were dissolved in DMF (3.00 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (65.9 mg, 57.0 μmol) and CuI (43.4 mg, 228 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 18 h. The reaction mixture was concentrated under high vacuum and the dark yellow solid residue was purified by chromatography (80 g column, 50 μm from SiliCycle) gradient 0-50% EtOAc in hexanes over 30 min) to give 2-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (265 mg, 644 μmol, 56.5%) as a light yellow solid. MS (M+H)+=412; 1H NMR (CDCl3) δ: 10.50 (s, 1H), 9.07 (s, 1H), 8.29 (s, 1H), 5.77 (s, 2H), 3.89 (s, 3H), 3.57-3.72 (m, 2H), 3.05 (t, J=6.0 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 1.80-2.02 (m, 4H), 0.92-1.09 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7](Br)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>[Cu](I)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.C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:7]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1ccc(Br)c(Br)c1
Agent: I[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
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)c(C#C[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-tert-butyl-1,2-dibromobenzene (5.0 g, 17 mmol), copper iodide (0.17 g, 0.9 mmol), tetrakis(triphenylphosphine)palladium (1.04 g, 0.9 mmol), ethynyltrimethylsilane (4.2 g, 43 mmol), and triethylamine (25 ml) were heated to 20° C. and stirred for 4 hours. The reaction mixture was then heated to 80° C. for 44 hours. Additional ethynyltrimethylsilane (2.5 g, 25 mmol) was added and the reaction mixture was stirred at 47° C. for 60 hours. Column chromatography (silica) was performed to remove metals and salts, using heptane as eluent. The crude product mixture was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N+:11]([O-])=O)=[C:6]([CH3:14])[N:5]=1>CCO.C(O)(=O)C.[Fe]>[F:15][CH:2]([F:1])[O:3][C:4]1[N:5]=[C:6]([CH3:14])[C:7]([NH2:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)nc1OC(F)F
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(N)c(C)nc1OC(F)F
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 89.8 %

Procedure:
Alternate route. To a solution of 2-(difluoromethoxy)-3,6-dimethyl-5-nitropyridine (1.00 g, 4.58 mmol) in EtOH (40 mL) and acetic acid (4 mL) was added iron powder (1.26 g, 22.9 mmol). The reaction mixture was heated at a vigorous reflux with the aid of a heating mantle in a flask without a stir bar. After 1.75 h, the reaction mixture was cooled to room temperature and the iron powder was removed by filtration through a pad of Celite. The filtrate was concentrated and the residue was transferred to a separatory funnel containing saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by MPLC on silica gel (20%→50% ethyl acetate in hexanes) to afford 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine (774 mg, 90% yield) as a pale yellow solid identical to that prepared by Method A: mp 38.4-39.4° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J=74.5 Hz, 1H), 6.82 (s, 1H), 2.26 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.6, 137.4, 137.1, 127.4, 119.0, 115.0 (J=251.3 Hz), 19.3, 14.8; LRMS (ESI) m/e 189.0 [(M+H)+, calcd for C8H11N2OF2 189.1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[C:18]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:53])[C@@H:33]([C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)[CH2:34][N:35]([CH:43]([CH3:45])[CH3:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:28][CH2:27]2)=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1>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:52][C:49]1[CH:48]=[CH:47][C:46]([C@H:33]([C:32](=[O:53])[N:29]2[CH2:30][CH2:31][N:26]([C:18]3[C:17]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:22][N:21]=[C:20]4[NH:23][CH:24]=[CH:25][C:19]=34)[CH2:27][CH2:28]2)[CH2:34][N:35]([CH:43]([CH3:45])[CH3:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:51][CH:50]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
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+]
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cccnc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 160 °C
Yield: 63.9 %

Procedure:
Pyridin-3-ylboronic acid (20 mg, 0.17 mmol), PS-tetrakis (41 mg, 0.0041 mmol) and sodium carbonate (18 mg, 0.17 mmol, 2N aqueous solution) were added to (S)-tert-butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (50 mg, 0.083 mmol, see Example 4) in degassed (Ar) dioxane (1 mL). The reaction was heated to 160° C. for 1 hour under microwave irradiation. After cooling down, the reaction was diluted with DCM, filtered, dried over MgSO4 and concentrated to dryness. The resulting residue was purified by reverse phase column chromatography (water:ACN 4:1 to 1:9) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate (32 mg, 64% yield) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O)[CH3:13].Cl.O>CO>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH3:13]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1OC
Temperature: 25 °C
Yield: 47.6 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-ethoxy-4-methoxybenzaldehyde 1.33 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and water 150 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.99 g.