Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH2:30][CH2:31]Cl)=[C:26]([O:35][CH3:36])[CH:25]=1)(=[O:23])[CH3:22].[C:37](=[O:40])([OH:39])[O-].[Na+]>CN(C)C=O>[C:7]([OH:8])(=[O:23])[C:37]([OH:39])=[O:40].[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:8])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:33]=[CH:34][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][C:26]=3[O:35][CH3:36])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])O
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Product: O=C(O)C(=O)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 115.2 %

Procedure:
A mixture of 5.2 g (0.0194 mole) of α,α-diphenyl-4-piperidinemethanol, 4.7 g (0.0194 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.6 g (0.0194 mole) of sodium bicarbonate in 60 ml of dimethylformamide was stirred at 100° C. for 3 hrs. After cooling, the reaction mixture was filtered and the dimethylformamide was removed under reduced pressure. The residual oil weighed 8.3 g (90%). Some of the product crystallized upon trituration in anhydrous ether and was collected by filtration. The filtrate was evaporated to dryness and the residue was dissolved in hot benzene-isooctane. Upon cooling, the crystalline product was obtained. A total yield of 6.3 g of solid product was obtained. The solid free base was converted to the oxalate salt. Recrystallization from isobutyl methyl ketone gave the off-white solid melting at 174°-176° C. (See Ex. 15, U.S. Pat. No. 3,956,296).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:21])=[CH:7][N:8]2[S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:22]([NH:24][NH2:25])=[O:23].C1COCC1.[N:31]([CH:34]([CH3:36])[CH3:35])=[C:32]=S.CCN=C=NCCCN(C)C.Cl>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:21])=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=2)(=[O:12])=[O:13])=[CH:4][C:3]=1[C:22]1[O:23][C:32]([NH:31][CH:34]([CH3:36])[CH3:35])=[N:25][N:24]=1
Reactant: CC(C)N=C=S
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)c(F)cc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)C)o4)c(F)cc32)cc1
Temperature: 60 °C
Yield: 40.3 %

Procedure:
In a 250 mL round bottomed flask, 6-fluoro-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (880 mg, 1.86 mmol) was treated with THF (10 mL) and 2-isothiocyanatopropane (0.56 mL, 5.58 mmol) and heated to 60° C. for 1 h. The THF was removed under reduced pressure (rotary evaporator) and replaced with DMF (5.0 mL) and the solution was treated with EDC HCl (Aldrich, St. Louis, Mo., 535 mg, 2.79 mmol) and heated at 90° C. for 30 min. The reaction mixture was cooled to RT and treated with water and extracted with EtOAc (2×50 mL), washed with brine (2×50 mL) and dried over MgSO4, filtered and concentrated. Purification of the crude residue on the ISCO Combiflash Rf (40 g Redisep column, using a gradient of 0-100% EtOAc in hexanes) afforded 5-(6-fluoro-3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (407 mg, 0.75 mmol, 40.5% yield) as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 540.8 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (1H, s), 8.03 (2H, m, J=8.4 Hz), 7.95 (1H, d, J=11.2 Hz), 7.81 (1H, d, J=7.4 Hz), 7.71 (1H, d, J=6.7 Hz), 7.44 (2H, m, J=8.2 Hz), 3.74 (1H, dq, J=13.4, 6.6 Hz), 2.35 (3H, s), 1.21 (6H, d, J=6.5 Hz).
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.[F:48][C:49]([F:59])([F:58])C1C=CC(CN)=CC=1>C(N(CC)CC)C.CN(C)C=O.ClCCl>[O:20]=[C:9]1[C:8]([C:6]([NH:5][CH2:4][C:3]2[CH:21]=[CH:22][C:23]([C:49]([F:59])([F:58])[F:48])=[CH:24][CH:2]=2)=[O:7])=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:11][NH:10]1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.21 cm3 of 4-(trifluoromethyl)benzylamine and 0.19 cm3 of triethylamine, 0.22 g of 3-oxo-6-pyridin-4-yl-N-[4-(trifluoromethyl)benzyl]-2,3-dihydropyridazine-4-carboxamide-was obtained in the form of a cream-colored solid melting at 227° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[CH3:16][C:17]1([CH3:25])[CH2:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]1>CCO.N1CCCCC1>[NH2:14][C:13]1[O:24][C:19]2[CH2:18][C:17]([CH3:25])([CH3:16])[CH2:22][C:21](=[O:23])[C:20]=2[CH:1]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:12]=1[C:11]#[N:15]
Reactant: N#CCC#N
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C2C(C#N)=C(N)OC3=C2C(=O)CC(C)(C)C3)cc1
Yield: 80.1 %

Procedure:
A stirred solution of p-anisaldehyde (1.74 mL, 14.3 mmol) and malononitrile (0.90 mL, 14.28 mmol) in 75 mL of 95% EtOH at RT was treated with a few drops of piperidine and after about 5 min, a yellow precipitate was formed and the mixture was stirred for another 10 min after which 5,5-dimethylcyclohexan-1,3-dione (2.00 g, 14.3 mmol) was added as a solid in one portion. The stirred suspension became a solution after about 5 min. After about 2 h a white precipitate was formed and TLC analysis showed complete reaction. The precipitate was filtered and washed with cold 95% EtOH then dried under vacuum, resulting in 3.71 g (81%) of the title compound as a white solid, mp 197-200° C. 1H NMR (DMSO-d6): 7.04 (d, 2H), 6.96 (bs, 2H), 6.83 (d, 2H), 4.11 (s, 1H), 3.71 (s, 3H), 2.49 (m, 2H), 2.15 (m, 2H), 1.03 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1([C:17]2[C:18]([O:23][CH2:24][CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]1=[O:16].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[S:36](Cl)(=[O:38])=[O:37]>CN(C)C=O>[NH2:3][C:4]1([C:17]2[C:18]([O:23][CH2:24][CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]([S:36]([C:29]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=2[O:27][CH3:26])(=[O:38])=[O:37])[C:5]1=[O:16]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ncccc1C1(N)C(=O)Nc2cc(F)c(C#N)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(C#N)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
80 mg (1.68 mmol) of sodium hydride (60% dispersion in mineral oil) were added in portions to a solution of 350 mg (1.12 mmol) of 3-amino-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 15 ml of anhydrous dimethylformamide under a nitrogen atmosphere and while cooling in an ice bath. The mixture was stirred at 0° C. for 10 min and then 398 mg (1.68 mmol) of 2,4-dimethoxyphenylsulfonyl chloride were added, and the mixture was stirred at room temperature for 15 min. The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 0 to 3% methanol in ethyl acetate). 236 mg of the title compound were obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[C:17]([CH:20]=1)[CH:18]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:18]/[C:17]2[CH:20]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=2[O:21][CH3:22])/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: COc1ccc(Cl)cc1C=O
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Yield: 37.4 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (2.8 g, 16.6 mmol) was reacted with 5-chloro-2-methoxybenzaldehyde (Matrix) (3.4 g, 19.9 mmol), methanolic solution (25 wt %) of sodium methoxide (4.17 mL, 18 mmol) in methanol (100 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-acrylonitrile as a white solid (2.0 g, 37%).
Reaction SMILES: [C:1]1([C:8]2[C:9]([OH:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([OH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C1(=O)[O:19][CH2:18][CH2:17]O1.[I-].[K+].CN(C)C=O.[C:28](OCC)(=[O:30])[CH3:29]>>[OH:30][CH2:28][CH2:29][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:17][CH2:18][OH:19]
Reactant: CCOC(C)=O
Reactant: O=C1OCCO1
Reactant: Oc1ccccc1-c1ccccc1O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccccc1-c1ccccc1OCCO
Temperature: 140 °C
Reaction time: 4 h

Procedure:
To a 12000 ml 3 neck round bottom equipped with an overhead stirrer, heating mantle, temperature probe, and condenser with gas bubbler was added 2421 g. biphenyl-2,2′-diol (XI), 2519 g. ethylene carbonate, 24.2 g. potassium iodide, and 50 g. N,N-dimethlformamide (DMF). The reaction was stirred well and heated to 140° C. The reaction was monitored by the amount of gas released and gas chromatography (GC). After 4 hours the reaction was ˜70% starting material. The temperature was increased to 150° C. After an additional 4 hours the starting material and mono substituted intermediate were reacted. The reaction was cooled to 40° C. and 2000 ml ethyl acetate was added. The reaction mixture was washed 3 times with 500 ml water/sodium chloride (brine). The organic layer was dried over MgSO4, filtered and concentrated under vacuum to recover a dark brown oil. The yield was 3400 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl.[NH2:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:27][CH:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3C2)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-aminoindan hydrochloride.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:41])[NH:5][C:6](=[O:40])[N:7]([CH:39]=1)[C@@H:8]1[O:38][C@H:16]([CH2:17][O:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:10](OS(C)(=O)=O)[CH2:9]1)[CH3:2].[I-:42].[Na+]>COCCOC>[I:42][C@@H:10]1[C@@H:16]([CH2:17][O:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:38][C@@H:8]([N:7]2[CH:39]=[C:3]([CH2:1][CH3:2])[C:4](=[O:41])[NH:5][C:6]2=[O:40])[CH2:9]1
Reactant: CCc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reactant: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cn([C@H]2C[C@H](I)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O

Procedure:
A mixture of 5-ethyl-3'-O-methanesulfonyl-5'-O-trityl-2'-deoxyuridine (3.2 g, 5.6 mmole) and sodium iodide (15.0 g, 100 mmole) in 1,2-dimethoxyethane is refluxed for 18 hr.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[NH:10][CH:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3Cl)[C:6]=2[N:7]=1.O.NN>C(O)C.[Pd]>[NH2:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[NH:10][CH:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Nc1nc2c(Cc3ccccc3Cl)c[nH]c2c(=O)[nH]1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1nc2c(Cc3ccccc3)c[nH]c2c(=O)[nH]1

Procedure:
A solution of 2-amino-3,5-dihydro-7-(2-chlorophenylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one (0.5 g, 1.8 mmol) in hot ethanol (80 mL) is treated with 30% Pd-C (1.0 g) under N2 and then hydrazine monohydrate (1.5 mL) is added dropwise during a period of 10 minutes. The reaction mixture is held at reflux for 16 hours and then filtered hot through Celite. The filtrate is evaporated to dryness, and the residue triturated and sonicated with H2O (3 mL). The product is collected, washed with H2O and dried to yield 2-amino-3,5-dihydro-7-(phenylmethyl)-4H-pyrrolo[3,2-d]-pyrimidin-4-one melting at 269°-270° C. dec.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:15]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a well stirred solution of 5-(benzyloxy carbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine (17.0 g, 44.04 mmol) and 4-dimethylaminopyridine (6.99 g, 57.25 mmol) in CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl chloroformate 11.54 g, 57.25 mmol) at room temperature. The reaction mixture was stirred for 12 hours and then the solvent was removed in vacuo. The residue was purified by chromatography (SiO2, EtOAc/Hexane 10-30%) to get 5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine as a colorless viscous oil(12.6 g, 50%). 1H NMR (CDCl3): δ 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq, δA =5.08, δB =5.20, J=12.3 Hz, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[CH:62][CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48](B2OC(C)(C)C(C)(C)O2)[C:47]([CH3:60])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[CH:62][CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:47]([CH3:60])=[N:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 60 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 39) (250 mg, 0.379 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (220 mg, 0.666 mmol) in sodium carbonate (121 mg, 1.139 mmol), Pd(PPh3)2Cl2 (13.3 mg, 0.0189 mmol), toluene/ethanol/water (25/12.5/6 ml). This afforded 267 g (60% yield) after purification by column (Silica gel 60/120) using 1.5% of methanol in chloroform as eluent. MS: m/z=735.3 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC.C(O)(C(F)(F)F)=O>[Ag]=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[F:12][C:3]1[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6].[F:12][C:3]1[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Br)c1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(-c2ccccn2)c1F
Product: O=C(O)c1cccc(-c2ccccn2)c1F
Yield: 17 %
Yield: 23 %

Procedure:
In a 150 mL round bottom flask was combined methyl 3-bromo-2-fluorobenzoate (1.47 g, 6.3 mmol), DMF (10 mL), silver oxide (0.79 g, 6.4 mmol), 2-(tributylstannyl)pyridine (2.40 ml, 7.2 mmol), and dichlorobis(triphenylphosphine)-palladium (II) (0.23 g, 0.33 mmol) and the mixture was stirred at 100° C. to about 72 h. Monitoring the reaction by LC-MS revealed two products, the ester and the hydrolyzed product. The reaction was cooled, filtered through a pad of celite and the celite was washed with EtOAc. The filtrate was concentrated in vacuo and taken up in a small amount of DMF. The solution was purified by reverse-phase preparative HPLC on a Phenomenex Luna column (10 micron, C18, 100 Å, 150×50 mm) eluting at 45 ml/min with an linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 10 minutes to give 2-fluoro-3-(pyridine-2-yl)benzoic acid (0.24 g, 0.72 mmol, 23% yield) as a light red-colored TFA salt and methyl 2-fluoro-3-(pyridine-2-yl)benzoate (0.19 g, 0.55 mmol, 17% yield) as a golden syrup-colored TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:31][C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)ccc34)cnc21
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)cnc21
Temperature: 100 °C
Yield: 68.2 %

Procedure:
A 5 ml microwave vial was charged with 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (300 mg, 0.73 mmol), 4-(2-chloroacetyl)morpholine (0.19 ml, 1.46 mmol), cesium carbonate (713 mg, 2.19 mmol) and DMF (3.3 ml). The vial was flushed with argon, sealed and heated in a microwave reactor at 100° C. for 2 h. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-70% EtOAc) to afford 268 mg (68%) of 2-[6-fluoro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow powder.
Reaction SMILES: O([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([Cl:17])=[C:11]([CH3:18])[C:10]=1[Cl:19])S(C(F)(F)F)(=O)=O.CCN(CC)CC.C[OH:28].O1C[CH2:33][O:32][CH2:31]C1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:19][C:10]1[C:11]([CH3:18])=[C:12]([Cl:17])[C:13]([O:15][CH3:16])=[CH:14][C:9]=1[C:33]([O:32][CH3:31])=[O:28]
Reactant: CO
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(C)c1Cl
Reactant: C1COCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OC)c(Cl)c(C)c1Cl

Procedure:
2,4-Dichloro-5-methoxy-3-methlphenyl triflate (7.60 g, 22.4 mmol) was dissolved in dioxan (75 mL), 1,3-bis (diphenylphosphino)propane (371 mg, 0.90 mmol) and palladium acetate (202 mg, 0.90 mmol) were added. After flushing with CO, Et3N (6.90 mL, 49.4 mmol) and MeOH (23 mL) were added. Reaction with CO at 70° C. and at atmospheric pressure for 25° C., filtration and evaporation, of the solvent partition of the residue between Et2O (350 mL) and 3M NH3 (150 mL), extraction of the aqueous layer with Et2O (2×150 mL) followed by washing the combined organic phase with brine (150 mL), drying (MgSO4), evaporation of the solvent gave a crude product. Filtration through SiO2 using EtOAc as the eluent gave 5.2 g of a product which was purified by flash column chromatograhy (SiO2,, EtOAc-Hexane 1:3) to yield 4.18 g of the title compound. Mp: 74° C.; 1H NMR (DMSO-d6): δ 7.33 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.45 (s, 3H); 13C NMR (DMSO-d6): δ 165.69, 153.26, 136.09, 130.46, 125.22, 122.95, 110.78, 56.64, 52.72, 17.86; MS (EI, 70 eV): m/z (rel.int.) 250/248 (M+, 53/80), 219/217 (66/100), 191/189 (8/12).
Reaction SMILES: C(#N)C.[Cl:4][CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=O)[C:10]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:9]=2[O:8]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>C1(C)C=CC=CC=1>[Cl:4][CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[S:25])[C:10]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:9]=2[O:8]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ccc(C(F)(F)F)cc2C1=O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc(C(F)(F)F)cc2C1=S

Procedure:
To 30 ml of acetonitrile was added 1.25 g (0.004 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-(trifluoromethyl)-1,4-benzoxazepine-5(4H)-one and 0.92 g (0.002 mole) of phosphorus pentasulfide and the reaction mixture heated to reflux for 4 hr. After cooling, 30-40 ml of toluene was added and the mixture filtered. The filtrate was washed with 3×50 ml of saturated potassium carbonate, charcoaled, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl ether to give 0.65 g (50%) of yellow, analytically pure crystals, m.p., 146°-48° C.