Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH2:27])[CH:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH:27][S:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)(=[O:11])=[O:10])[CH:18]([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:26])[F:24])[CH3:14]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(NS(=O)(=O)c1cc(F)cc(F)c1)C(C(F)(F)F)C(F)(F)F
Reaction time: 72 h
Yield: 58.7 %

Procedure:
To a solution of 3,5-difluoro-benzenesulfonyl chloride (252 mg, 1.19 mmol) and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (300 mg, 1.19 mmol) in CH2Cl2 (7 mL) was added anhydrous pyridine (144 μL, 1.77 mmol, 1.50 equiv.) and the vial capped and shaken for 72 h. The reaction solution was transferred to a separatory funnel with CH2Cl2 (100 mL), washed with 1M citric acid solution (100 mL), water (50 mL×4), brine (100 mL), dried (MgSO4), filtered and evaporated to give a white solid (300 mg, 59%). Mass Spectrum (−ESI): 427.8 [M−H]−
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23]>C(O)CC>[OH:23][CH2:22][CH2:21][CH2:20][NH:19][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Reactant: NCCCO
Solvent: CCCO
Product: CCCOc1ccccc1-c1nc(NCCCO)cc(=O)[nH]1

Procedure:
A stirred solution of 4-chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.66 g) and 3-amino-1-propanol (0.56 g) in n-propanol was heated under reflux for 16 hours. The cooled reaction mixture was evaporated under reduced pressure to yield an oil which was partitioned between chloroform (20 ml) and water (20 ml). The chloroform layer was separated from the aqueous layer which was extracted with chloroform (2×10 ml) and the combined chloroform layers were washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from isopropanol:diethyl ether to yield the title compound, 0.54 g, m.p. 147.5-148.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9]Cl>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: ClI
Reactant: Nc1cc(Cl)ncn1
Solvent: CN(C)C=O
Product: Nc1ncnc(Cl)c1I
Temperature: 45 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 3.03 g (23.39 mmol) of 6-chloropyrimidin-4-amine in 60 mL of dimethylformamide was added dropwise a solution of iodine monochloride (2.34 mL, 46.70 mmol) in 40 mL of dimethylformamide. Then the mixture was stirred at 45° C. overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and a 4% aqueous solution of sodium bicarbonate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by flash chromatography (0% to 20%, methanol-dichloromethane) to obtain 4.28 g (72% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([O:7]CC)=O.C(OCC)(=O)[C:13]([O:15]CC)=[O:14].[O-]CC.[Na+]>C(O)C.Cl>[F:11][C:2]([F:1])([F:10])[CH2:3][CH2:4][C:5](=[O:7])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CCC(F)(F)F
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)CCC(F)(F)F
Reaction time: 0.5 h

Procedure:
Ethyl 4,4,4-trifluorobutyrate (1 g, 5.88 mmol) and diethyl oxalate (3.87 g, 26.5 mmol) was dissolved in ethanol. Sodium ethoxide (21% in ethanol, 2.09 g) was added to the solution, and the reaction mixture stirred for 0.5 hrs. Solvent was distilled, and the residue extracted with EtOAc/water. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed to give a clear liquid. MS (ESI): m/z 269.1 (M−1). The liquid was then dissolved in 3N HCl (20 mL), and the reaction mixture refluxed for 4 hrs. After cooling down, the reaction mixture was extracted with EtOAc. The organic layers were collected and dried over sodium sulfate. After filtration, solvent was removed, and the residue used directly in the next step. MS (ESI): m/z 169.7 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cu](C#N)[C:16]#[N:17]>CN(C)C=O>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[N:17])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To 5.39 g (24.44 mmol) of 2-chloro-5-fluoro-1,3-dinitro-benzene dissolved in 20 mL dimethylformamide was added 2.63 g (1.2 eq., 29.27 mmol) copper cyanide. The mixture was stirred at 140° C. for 2 hours, cooled and partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography, eluting with ethyl acetate/hexanes, provided 1.44 g of 4-fluoro-2,6-dinitrobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C@@H:10]2[O:17][C@@H:16]3[C@@H:12]([O:13][C:14]([CH3:19])([CH3:18])[O:15]3)[C@@H:11]2[OH:20])=[O:9])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:9])[C@@H:10]2[O:17][C@@H:16]3[C@@H:12]([O:13][C:14]([CH3:18])([CH3:19])[O:15]3)[C@@H:11]2[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)c3ccc(Cl)c(Cc4ccc5c(c4)OCCO5)c3)[C@@H](O)[C@@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)O[C@@H]2O[C@@H]([C@@H](O)c3ccc(Cl)c(Cc4ccc5c(c4)OCCO5)c3)[C@@H](O)[C@@H]2O1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of compound 135 (0.77 g, 1.7 mmol) in CH3OH was added CeCl3−7H2O and the mixture was stirred at room temperature until all solids were dissolved. The mixture was then cooled to −78° C. and NaBH4 was added in portions. The mixture was stirred for 1 h at −78° C., slowly warmed to 0° C. and quenched with saturated NH4Cl solution. The mixture was concentrated under reduced pressure to remove CH3OH and then extracted with EtOAc and washed with saturated NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired alcohol (0.67 g, 87%) as a white solid. The obtained product was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][C:12]=2[F:27])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].S(=O)(=O)(O)O.[CH3:38]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][CH3:38])=[O:23])[CH:17]=3)=[CH:13][C:12]=2[F:27])=[CH:4][C:3]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CO
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)ccn1
Yield: 80 %

Procedure:
4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)picolinic acid (1 g, 2.13 mmol) was suspended in methanol (20 mL). Concentrated sulfuric acid (5 mL) was added at room temperature. The resulted mixture was refluxed for 3 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=10:1) to give methyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)picolinate B8 (0.83 g, purity 97%, yield 80%) as a white solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[S:12][C:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:15]=1>CCOCC>[C:1]1([NH:7][C:8]([NH:10][C:11]2[S:12][C:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)Cc1sc(N)nc1-c1ccc(Cl)cc1
Solvent: CCOCC
Product: CCOC(=O)Cc1sc(NC(=O)Nc2ccccc2)nc1-c1ccc(Cl)cc1

Procedure:
2 Grams of phenylisocyanate in 50 c.c. ether are added to a suspension of 5 g. of ethyl (2-amino-4-p-chlorophenyl-thiazol-5-yl)-acetate in 200 c.c. of anhydrous ether. After 24 hours the precipitated solid is filtered off, m.p. 192°-93°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([NH:9][C:10](=[O:12])[CH3:11])[CH:8]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([NH:9][C:10](=[O:12])[CH3:11])=[C:6]([CH3:13])[CH:5]=1
Reactant: COc1ccc(C)c(NC(C)=O)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)c(C)cc1Br
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of N-(5-methoxy-2-methylphenyl)acetamide in acetic acid (40 mL) was added Br2 (3 g, 19 mmol) slowly. The mixture was capped and stirred at 50° C. for 5 hours. The reaction was cooled to room temperature, then quenched with sodium sulfite aqueous solution, and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over Na2SO4 and concentrated to give crude N-(4-bromo-5-methoxy-2-methylphenyl)acetamide as a brown oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].C1C(=O)N([Br:27])C(=O)C1>CC#N.C(Cl)Cl>[Br:27][C:17]1[CH:18]=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
To a solution of 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2-amine (7.49 g, 24.87 mmol) in CH3CN/DCM (100/30 mL) was added NBS (4.43 g, 24.87 mmol) in portions at 0° C. The reaction solution was stirred at 0° C. for 10 min. The precipitate was removed by filtration. The black filtrate was concentrated to give a black residue which was purified by CombiFlash (80 g silica gel column, EtOAc/Hexane) to afford 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (7.8 g, 82%) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>>[C:1]([NH:4][C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Acetamido-tetralone (15 g) was added in small portions to a cold solution of nitric acid (46 ml) at -30° C. After the addition was complete (2-3 hours), the reaction mixture was stirred at the same temperature for 1 hour, warmed to 0° C. and stirred for 4 hours. The reaction was poured on ice, basified with aqueous sodium hydroxide and extracted with ethyl acetate several times. The organic layer was separated, dried and evaporated. The desired 5-nitro-isomer was separated using flash chromatography (ethyl acetate-methylene chloride) to afford 8.73 g (48%).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]([CH2:32][CH3:33])[C:21]3[C:26]([C:27]=2[C:28]#[N:29])=[CH:25][CH:24]=[C:23]([O:30][CH3:31])[CH:22]=3)[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O>[C:28]([C:27]1[C:26]2[C:21](=[CH:22][C:23]([O:30][CH3:31])=[CH:24][CH:25]=2)[N:20]([CH2:32][CH3:33])[C:19]=1[C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=[CH:17][CH:16]=1)#[N:29]
Reactant: CCn1c(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c(C#N)c2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(-c2cccc(NC(N)=S)c2)c(C#N)c2ccc(OC)cc21
Temperature: 50 °C
Yield: 96.4 %

Procedure:
A suspension of 1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (241 mg, 0.530 mmol) in methyl alcohol (2.0 ml) and water (0.5 mL) was stirred at room temperature as sodium hydroxide (31 mg, 0.78 mmol) was added. The reaction mixture was heated to 50° C. for 17 h. The reaction mixture was concentrated to remove methyl alcohol. Water was added to the mixture and the solid was filtered, washed with water and dried to give 179 mg of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea, compound 767 (96% yield) as a white solid.
Reaction SMILES: [C:1]([O:9][CH2:10]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:12].[Na+]>C(#N)C.O>[C:1]([O:9][CH2:10][I:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(OCI)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
Chloromethyl benzoate (2.87 g, 16.82 mmol) was dissolved in acetonitrile (20 mL) and treated portionwise with sodium iodide (5.04 g, 33.6 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (3.15 g);
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:27]=[C:26]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:25]=2)=[CH:20][CH:19]=1>CN(C=O)C>[Si:6]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:27]=[C:26]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:25]=2)=[CH:22][CH:23]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1cc(-c2ccc(OCCO)cc2)n(-c2ccc(OC)cc2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Imidazole (680 mg) and t-butyldimethylsilyl chloride (903 mg) was added successively to a solution of ethyl 5-[4-{2-(hydroxy)ethoxy}phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1.91 g) in DMF (15 ml) under cooling in an ice bath. After stirring at ambient temperature for 2 hours, the mixture was partitioned between AcOEt and H2O. The oreganic layer was washed with H2O, saturated aqueous sodium chloride solution, dried over MgSO4, concentrated in vacuo. The residual crystals were collected and washed with n-hexane to give ethyl 5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (2.34 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[CH:8]=2)=[O:4]>CO.C(OC(=O)C)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH2:14])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-Nitro-1H-indole-2-carboxylic acid methyl ester 108 200 mg (0.91 mmole) in a mixture of methanol/ethylacetate (1:1) 10% Pd/C (40 mg) was added. The flask was rinsed 3 times with hydrogen and filled with hydrogen at 30 to 35 psi. The suspension was stirred vigorously at room temperature for 30 minutes. The catalyst was filtered off, the filtrate was evaporated in vacuo to dryness. The resulted 6-amino-1H-indole-2-carboxylic acid methyl ester gave a single spot on TLC (Silica, toluene-ethylacetate 7:3, Rf: 0.31) and was used for the next step without purification
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(C=O)cc1
Yield: 71.5 %

Procedure:
By the method of Example 1, Step H, 10.0 g (0.0819 mole) of 4-hydroxybenzaldehyde and 16.4 g (0.0983 mole) of methyl 2-bromopropionate were reacted in the presence of 13.6 g (0.0983 mole) of anhydrous potassium carbonate in N,N-dimethylformamide, yielding 12.2 g of methyl 2-(4-formylphenoxy)propionate as a yellow liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:15][NH2:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][N:19]=1>>[NH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:16][CH2:15][C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: NCc1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: Nc1nccc(C(=O)NCc2cnc(OCC(F)(F)F)c(Cl)c2)n1
Yield: 17 %

Procedure:
The title compound is prepared in 17% yield (43 mg, pale yellow oil) from (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (199 mg, 0.72 mmol, Amine-19) and 2-aminopyrimidine-4-carboxylic acid (100 mg, 0.72 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:3][CH:2]=1.[H-].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24]Br>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccncc1)OCc1ccccc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [K+]
Product: O=C(OCc1ccccc1)C1(c2ccncc2)CCCC1

Procedure:
Benzyl 4-pyridylacetate (Step B, 0.80 g, 3.5 mmol) was reacted with potassium hydride and 1,4-dibromobutane according to the procedures described in Example 33, Step A to afford the title compound. 1H NMR (400 MHz, CD3OD): 8.42 (d, 2H), 7.39 (d, 2H), 7.28 (m, 3 H), 7.19 (m, 2H), 5.06 (s, 2H), 2.62 (m, 2H), 1.97 (m, 2H), 1.74 (m, 4H). LC-MS: m/e 282 (M+H)+ (2.2 min).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][C:17]=1[O:24][CH3:25].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Br:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][C:17]=1[O:24][CH3:25]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1ccc(C=O)nc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC)c(Br)n3)nc2c1
Temperature: 120 °C
Yield: 269.8 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (1.23 g, 6.25 mmol) in N,N-dimethylacetamide (100 mL) was added 6-bromo-5-methoxypicolinaldehyde (1.35 g, 1.2 mmol) followed by NaHSO3 (0.98 g, 9.38 mmol) and p-toluenesulfonic acid monohydrate (1.19 g, 6.25 mmol). The resulting mixture was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with saturated Na2CO3. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol) followed by trituration with ethyl acetate to give 2-(6-bromo-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.27 g, 52%) as a white solid: 1H NMR (400 MHz, DMSO-d6): δ 11.03 (br s, 1H), 8.32 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]3[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccc3c(c2)CCC3=O)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a stirred solution of 5-bromo-1-indanone (0.40 g, 1.90 mmol) and 4-cyanophenyl boronic acid (0.36 g, 2.47 mmol) in glyme (17 mL) was added a solution of sodium carbonate (0.60 g, 5.70 mmol) in water (3 mL) and tetrakis(triphenylphosphine)palladium (0) (0.11 g, 0.10 mmol). The resulting solution was heated to reflux for 2.5 hours. The solution was cooled to room temperature and partitioned between a saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 4-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile as a white solid (0.35 g, 79%). MS (ESI) m/z 234.0936; HRMS: calcd for C16H11NO+H+, 234.09134; found (ESI, [M+H]+), 234.0936.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH2:6][CH2:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH2:6][CH2:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1CCn1nccc1-2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CCn1nccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of methyl 8-amino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 22, 0.060 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.081 g) in pyridine (2 mL) and DCM (4 mL) was stirred at room temperature overnight. A further amount of 2-bromo-4-fluoro-benzenesulfonyl chloride (0.010 g) was added and the reaction mixture was stirred at room temperature for 2 hours. The resultant mixture was concentrated in vacuo and the residue was dissolved in DCM and washed with 1M hydrochloric acid, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl 8-(2-bromo-4-fluorobenzenesulfonylamino)-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (0.088 g) as a glass.