Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][C:16]([CH3:20])=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=3)[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: Cc1nc(Br)ccc1C(=O)O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)nc1C
Yield: 57.6 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (745 mg) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (744 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (801 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][S:11][NH:10][C@@H:9]2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:28]([CH3:30])[CH3:29]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][S:11][N:10]([CH:28]([CH3:30])[CH3:29])[C@@H:9]2[C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: Clc1ccc([C@H]2NSCC[C@@H]2c2cccc(Cl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1SCC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 85 °C

Procedure:
To a solution of 1.21 g (3.40 mmol) of (3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,2-thiazinan (Example 117, Step C) in DMF (8.5 mL) was added cesium carbonate (4.31 g, 13.23 mmol), followed by 2-iodopropane (2.9 mL, 29.0 mmol). The resulting mixture was heated at 85° C. for 23 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by flash chromatography on silica gel (0 to 2% MeOH in DCM gradient) provided the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH:12]=[C:13](C(C)(C)C)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH:12]=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
Methyl 3,5-di-tert-butyl-2-hydroxybenzoate (28.66 g, 108.4 mmol) was dissolved with stirring in 430 mL glacial acetic acid and the resulting mixture was treated drop wise with fuming nitric acid (90%, 179.26 mL). When the addition was complete, the resulting mixture was stirred for 2.5 h. The reaction mixture was poured into a 2.0 L of crushed ice and allowed to stand 30 min. Afterwards, 1.0 L of water was added and the ice water mixture was allowed to melt. The mixture was then filtered, washed with water and dried to provide the title compound (24.57 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:26]#[C:27]Br>C(O)C>[NH2:26][C:27]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([Cl:25])[C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)c(Cl)nc2ccccc12
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCn1c(N)nc2c(Cl)nc3ccccc3c21
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl 4-[(3-amino-2-chloroquinolin-4-yl)amino]butylcarbamate (Nanba et al, U.S. Pat. No. 6,069,149, Example 14, 9.5 g, 26 mmol) in ethanol (100 mL) was heated to 110° C.; cyanogen bromide (2.98 g, 28.6 mmol) was added. The reaction was stirred for three hours at 110° C., and an analysis by LC/MS indicated the presence of starting material. Additional cyanogen bromide (0.55 equivalent) was added, and the reaction was stirred for three days at 110° C. and allowed to cool to room temperature. Most of the solvent was removed under reduced pressure, and 2 N aqueous sodium hydroxide (500 mL) was added. The mixture was stirred for 30 minutes, and ethyl acetate (400 mL) was added. A precipitate formed and was isolated by filtration to provide 7.188 g of tert-butyl 4-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate as a cream-colored solid.
Reaction SMILES: [Li].C1(S([C:11]2([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:14][CH2:13][CH2:12]2)(=O)=O)C=CC=CC=1.[Br:24][CH2:25][CH2:26][CH2:27]Br>O1CCCC1>[Br:24][CH2:25][CH2:26][CH2:27][C:11]1([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:12][CH2:13][CH2:14]1
Reactant: BrCCCBr
Reactant: O=S(=O)(c1ccccc1)C1(S(=O)(=O)c2ccccc2)CCC1
Agent: [Li]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)C1(CCCBr)CCC1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
A solution of lithium napthtalenide in tetrahydrofuran (4.3M, 60 ml) was added to a stirred solution of 1,1-bis(phenylsulfonyl)cyclobutane (4.15 g, 12.35 mmol) at −78° C. over 20 min. The mixture was stirred for 15 min. and 1,3-dibromopropane (10 ml) was added in one portion. The cold bath was removed and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was treated with saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel to give the title product (2.55 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[CH2:7][OH:8].C(N(CC)CC)C.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1>[C:22]([O:8][CH2:7][C:6]1[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][O:3][C:2]=1[CH3:1])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Cc1occ(-c2ccccc2)c1CO
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCc1c(-c2ccccc2)coc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-methyl-4-phenyl-3-furanmethanol (Compound 59, 48 mg, 0.26 mmol) and triethylamine (39 mg. 0.38 mmol) in tetrahydrofuran (3 ml) at 0 degrees under argon was added lauroyl chloride (73 mg. 0.33 mmol). This solution was warmed gradually to room temperature and stirred for 4 1/2 hours. The organics were extracted into ethyl ether and washed with a 5% aqueous sodium bicarbonate solution, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 3% ether/hexanes to give the title compound.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([Sn:7](Br)(Br)[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].C([Sn](Br)(Br)Br)CCC.O>C1CCCCC1>[CH2:3]([Sn:7](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6]
Reactant: CCCC[Sn](Br)(Br)CCCC
Reactant: [OH-]
Agent: CCCC[Sn](Br)(Br)Br
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: CCCC[Sn](=O)CCCC
Temperature: 70 °C

Procedure:
The same apparatus as used in Example 1 was employed. To the flask were continuously fed 1,075 g of 30% aqueous sodium hydroxide solution and 1,500 g of a cyclohexane solution which had been prepared by dissolving, in 750 g of cyclohexane, 750 g of di-n-butyltin dibromide containing 1.8% tri-n-butyltin bromide and 1.5% mono-n-butyltin tribromide. The above feeding was performed with stirring and heating at 70° C., to conduct hydrolysis for 45 minutes. To the resulting reaction mixture overflowed was added 3,600 g of water, and the mixture was then allowed to stand, whereby it split into three distinct phases. The specific gravities of the upper, intermediate and lower phases were 0.6, 1.1 and 1.3 respectively. The lower phase was separated out, washed with water, and then dried under reduced pressure, thereby obtaining 445 g of a white substance of di-n-butyltin oxide. Acid titration revealed that its purity was 99.8%, and the oxide had an average particle diameter of 50 μm.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([NH:23][CH:24]([CH3:26])[CH3:25])[C:21]([CH2:27][O:28][CH2:29][CH3:30])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CO.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:27][O:28][CH2:29][CH3:30])[N:22]([NH:23][CH:24]([CH3:26])[CH3:25])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1NC(C)C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
A solution of 7-benzyloxy-2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.67 g, 4.12 mmol) in 25 mL of toluene and 25 mL of methanol was treated with palladium on carbon (0.44 g, 0.42 mmol, 10% w/w). The mixture was shaken under an atmosphere of hydrogen (3.8×105 Pa). After 16 h, the reaction was filtered through a pad of CELITE filter agent and rinsed with solvent until the filtrate ran clear. The filtrate was concentrated under reduced pressure to provide a white solid. Purification by chromatography (SiO2, 3:1 CHCl3:(80:18:2 CHCl3:MeOH:NH4OH) gradient to 1:1) gave 0.50 g of 4-amino-2-ethoxymethyl-1-isopropylamino-1H-imidazo[4,5-c]quinolin-7-ol as a white solid. MS (APCI) m/z 316 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]2[CH:36]=[CH:35][C:26]3[CH:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)[CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]4[CH:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][O:29][C:25]=4[CH:24]=3)[CH:16]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)CC1COc2cc(OCc3cccc(-c4ccc(OC5CCCCO5)cc4C)c3)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CC1COc2cc(OCc3cccc(-c4ccc(O)cc4C)c3)ccc21
Yield: 86.4 %

Procedure:
A solution of methyl (6-{[2′-methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetate (4.49 g, 9.19 mmol) and p-toluenesulfonic acid monohydrate (0.175 g, 0.919 mmol) in methanol (50 mL) was stirred at room temperature for 30 hr. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (3.21 g, yield 86%) as a colorless viscous oil.
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[CH2:4][O:5][N:6]=[C:7]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1)[CH2:8][NH2:9].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[Cl:16][C:15]1[C:10]([C:7](=[N:6][O:5][CH2:4][C:3]([F:18])([F:2])[F:19])[CH2:8][NH:9][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[C:21]([F:20])([F:31])[F:32])=[N:11][CH:12]=[C:13]([Cl:17])[CH:14]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 92.8 %

Procedure:
To 2.0 g of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone-O-(2,2,2-trifluoroethyl)oxime hydrochloride in 12.0 ml of water, 1.4 g of 2-(trifluoromethyl)benzoyl chloride in 12.0 ml of dichloromethane and 2.4 g of potassium carbonate were added at room temperature with stirring, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the resulting organic layer was collected and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 2.6 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB(/[CH:43]=[CH:44]/[CH2:45][CH2:46][OH:47])O1>CC(N(C)C)=O>[NH2:28][C:18]1[N:17]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2](/[CH:43]=[CH:44]/[CH2:45][CH2:46][OH:47])[CH:7]=3)=[CH:10][CH:11]=2)[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=1
Reactant: CC1(C)OB(/C=C/CCO)OC1(C)C
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc(/C=C/CCO)c3)cc2)cc(-c2ccccc2)n1
Temperature: 150 °C
Yield: 14.5 %

Procedure:
N4-{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine (0.10 g, 0.26 mmol, Example 48), K2CO3 (0.089 g, 0.64 mmol), and DMA (2.5 mL) were placed into a small microwave vial. The mixture was degassed for 10 min before (3E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (0.10 g, 0.33 mmol) and Pd(dppf)Cl2 CH2Cl2 complex (0.012 g, 0.020 mmol) were added. The mixture was heated at 150° C. for 20 min in a microwave reactor. The mixture was cooled, filtered, and purified by prep-HPLC. Concentration of the desired fractions gave 0.016 g of the title compound (10%). MS ES: 426 (M+H)+, calcd 426, RT=1.90 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.N1C=CC=CC=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
10 g (70.4 mmol) of 3,4-di-fluoro-benzaldehyde, 14.65 g (2 eq.) of malonic acid, and 0.59 g (0.1 eq.) of piperidine were added to 16.7 g (3 eq.) of pyridine and stirred at room temperature for about 1 hour. After heating it to 80° C., the mixture was stirred for 12 hours. After the reaction, the resulting solution cooled down to room temperature and was slowly added with 1M HCl until it was titrated to about pH 4. The resulting powder was filtered and washed with water, and then dried in a vacuum oven. (Yield: 95%)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[Cl:16][C:17]1[C:18](=[O:23])[CH:19]=[CH:20]/[C:21](=[N:1]/[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:22]=1
Reactant: Oc1ccccc1Cl
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(/N=C2/C=CC(=O)C(Cl)=C2)c(=O)n(-c2ccccc2)n1C

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of 2-chlorophenol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC3(CCc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 98.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.06 g, 0.13 mmol) obtained in step 4 and ethanesulfonamide (0.066 g, 0.62 mmol), the title compound (0.073 g, 100%) was obtained. ESI-MS m/z: 573 (M+H)+; 1H-NMR (CDCl3,δ):1.46 (t, J=7.3 Hz, 3H), 1.46-1.53 (m, 2H), 1.57-1.70 (m, 2H), 1.98 (t, J=7.3 Hz, 2H), 2.43 (s, 3H), 2.92 (t, J=7.1 Hz, 2H), 3.61 (q, J=7.5 Hz, 2H), 3.70-4.06 (m, 4H), 7.09-7.23 (m, 4H), 7.29-7.42 (m, 4H), 8.35 (s, 1H), 8.35 (s, 1H), 8.63 (s, 1H), 10.54 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH2:10])[CH:4]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>C(Cl)Cl.O=C=O.C([Rh]CCCCCCC)CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH:13]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cccc(OC)c1
Agent: CCCCCCC[Rh]CCCCCCC
Agent: O=C=O
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To a mixture of 1-methoxy-3-vinylbenzene (3.10 g, 23.1 mmol) and dioxomethane-diheptylrhodium (4:2) (0.090 g, 0.12 mmol) in DCM (100 mL) under an atmosphere of argon at rt was added a solution of ethyl diazoacetate (1.22 mL, 11.6 mmol) in DCM (6 mL) dropwise via syringe. The reaction mixture as allowed to stir at rt for 2 h and then concentrated. The residue was purified by column chromatography to give the desired product (1.63 g) as a mixture of cis and trans isomers, along with recovered starting material (1.50 g). LCMS: (FA) ES+ 221.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][C:10]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[N:22])[CH:17]=3)[C:11]=2[N:12]=1.BrNC(=O)CCC(N)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][C:10]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[N:22])[CH:17]=3)[C:11]=2[N:12]=1
Reactant: CC1(C)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: NC(=O)CCC(=O)NBr
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)COC(=O)N1c1nc2c(ccc3cc(C#N)ccc32)s1
Yield: 54.1 %

Procedure:
2-(4,4-Dimethyl-2-oxo-1,3-oxazolidin-3-yl)-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile (0.65 g, 2.0 mmol), prepared in step 5 of Example 6, N-bromosuccinamide (0.39 g, 2.2 mmol) and a catalytic amount of 2,2′-azobis(2-methylproprionitrile) were stirred in carbontetrachloride (68 mL) at reflux for 4 h. The reaction was diluted with ethyl acetate and washed with 10% sodium thiosulfate. The layers were separated and the organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 0.64 g of crude product. Purification of the crude product on silica gel using a stepwise gradient of 6:1 to 1:1 hexane:ethyl acetate as the eluent gave 0.35 g of product that contained an impurity. Recrystallization from ethyl acetate afforded the title compound (0.02 g, 3%), mp>230° C.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:16][C:17]1[C:18]([CH3:30])=[N:19][C:20]2[C:25]([N:26]=1)=[C:24]([C:27](=O)[CH3:28])[CH:23]=[CH:22][CH:21]=2>C(Cl)Cl>[Si:1]([O:8][C:27]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[N:26]=[C:17]([F:16])[C:18]([CH3:30])=[N:19]2)=[CH2:28])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(F)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
TBSOTf (2.92 mL, 12.73 mmol) was added (dropwise, over 3 min) to a mixture 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (2.00 g, 9.79 mmol) and TEA (2.05 mL, 14.7 mmol) in DCM (100 mL) at 0° C., and the resulting solution was stirred at 0° C. for 30 min. The mixture was diluted with DCM (50 mL), washed with saturated aq. NaHCO3 (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide 5-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-fluoro-2-methylquinoxaline (3.451 g) as an orange-brown oil. This oil was taken up in THF (100 mL) and cooled to 0° C., water (2.82 mL, 157 mmol) and NBS (1.743 g, 9.79 mmol) were sequentially added, and the resulting solution was stirred at 0° C. for 2 min. The mixture was diluted with Et2O (100 mL) and sequentially washed with water (80 mL), saturated aq. NaHCO3 (80 mL), water (80 mL), and brine (80 mL). The resulting solution was dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-20% EtOAc/hexanes) provided 2-bromo-1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (2.77 g, 9.78 mmol, 100% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (1H, d, J=5.3 Hz), 8.25 (1H, d, J=4.3 Hz), 7.82 (1H, t, J=7.8 Hz), 5.02 (2H, s), 2.80 (3H, d, J=1.4 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −69.34 (1F, s). m/z (ESI, +ve) 283.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1CS(N)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:8][S:25]([CH3:28])(=[O:27])=[O:26])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 43.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.148 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfon amide (Intermediate 17) (58 mg, 0.178 mmol) using sodium carbonate (47 mg, 0.444 mmol) and Pd(PPh3)2Cl2 (5 mg, 0.0074 mmol) in DME/water (10/1 ml). This afforded 27 mg (43.8% yield) after purification by column (Silica gel 60/120) using 30% ethyl acetate in hexane as eluent.