Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:13][O-].[Na+].O>C(O)(=O)C>[C:1]([C:4]1[C:8]([Cl:13])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)n[nH]1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1[nH]nc(C(C)=O)c1Cl
Temperature: 25 °C
Yield: 23 %

Procedure:
Into a flask containing methyl 3-acetyl-1H-pyrazole-5-carboxylate (4.0 g, 0.0238 mol) in acetic acid (60 ml), 5% sodium hypochlorite (284 ml, 0.190 mol) was added dropwise at 10-12° C. The mixture was stirred at RT over three nights adding more 5% sodium hypochlorite (177 ml, 0.119 mol in total) during the second and third day. Water was added to the reaction mixture and the product was extracted with ethyl acetate. Organic layer was dried with anhydrous Na2SO4 and concentrated. The crude product was recrystallized twice from n-hexane. Yield 23%. LC-MS: [M+1]=203.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1
Reactant: COCCOCCO
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: COCCOCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-(2-methoxyethoxyl)ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([Cl:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[ClH:24].[Cl:24][C:4]1[CH:3]=[C:2]([N:27]2[C@H:26]([CH3:25])[CH2:30][O:29][C:28]2=[O:31])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3Cl)CC2)c(C)c1
Product: Cl
Yield: 30.9 %

Procedure:
By reaction and treatment in the same manner as in Example 79 and using (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.7 g) described in Preparation Example 69 and (R)-4-methyloxazolidin-2-one (510 mg) described in Preparation Example 25, the title compound (299 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])=[O:4].CI.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:25][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[C:3](=[O:4])[C:2]([F:1])([F:21])[F:22]
Reactant: N#Cc1ccccc1Sc1ccccc1NC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccccc1Sc1ccccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 2.8 g of 2-[2-(trifluoroacetylamino)phenylthio]benzonitrile followed by addition of 2.4 g of methyl iodide and 2.4 g of potassium carbonate, and the mixture was stirred at room temperature for 2 hours, at the end of which time the reaction mixture was diluted with water. The crystals separated out therefrom were collected by filtration, washed with water and aqueous ethanol to give 2.8 g of the title compound as white crystals.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][CH:6]=[CH:7][N:8]=1.[Cl:9][C:10]1[CH:11]=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][C:15]=1F.O>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[S:3][C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[NH2:17]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Sc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2nccs2)c(Cl)c1
Reaction time: 4 h

Procedure:
To a suspension of 3.8 g sodium hydride (60% in mineral oil) in 100 ml of dimethylformamide was added slowly a solution of 10.0 g of 2-mercapto thiazole in 100 ml of dimethylformamide. After 15 min a solution of 15.0 g 3-chloro-4-fluoro nitrobenzene in 50 ml of dimethylformamide was added. After 4 hrs, the mixture was poured into water. The resulting solid was collected, washed with water, and dried in vacuum. This material was mechanically stirred at reflux in a mixture of 830 ml of methanol, 230 ml of water, 37.0 g of ammonium chloride, and 30.1 g of iron powder for 4 hrs. The boiling mixture was filtered. The solvent was removed from the filtrate and the residue was extracted with hot ethyl acetate. The ethyl acetate solution was filtered through a short silica gel column. The solvent was removed and the residue was recrystallized from ether hexane giving 17.7 g of an off white solid.: mass spectrum electrospray, m/e): M+H 243.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]1([C:26]#[C:27][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([C:9]([F:12])([F:11])[F:10])[CH:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: C#Cc1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1ccc(C#Cc2ccccc2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 66.7 %

Procedure:
A multinecked flask as described in Example 1 was charged with 10.0 g (0.042 mol) of 2-amino-5-bromobenzotrifluoride, 100 ml of dried, degassed triethylamine, 5.32 g (0.052 mol) of phenylacetylene, 0.48 g (0.41 mmol) of tetrakis(triphenylphosphine)palladium(O), 0.1 g (0.38 mmol) of triphenylphosphine, and 0.05 g (0.26 mmol) of cuprous iodide. The reaction mixture was heated at 70° C. for 48 hours at which point thin layer chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 50 ml of toluene. Filtration of the triethylamine hydrobromide salt by-product followed by concentration of the filtrate under reduced pressure gave the crude product as a yellow oil. Fractionation under reduced pressure (bp 146°-150° C./1.2 mm Hg) gave 7.22 g (0.028 mol, 66% yield) of the product as a viscous yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=1)=[O:4].[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH2:29][CH2:28][C:27]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:26]=2[CH2:25][CH2:24]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:34][C:31]2[CH:32]=[CH:33][C:26]3[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:29][CH2:28][C:27]=3[CH:30]=2)[N:12]=1)=[O:4]
Reactant: CNC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Temperature: 120 °C
Yield: 52.9 %

Procedure:
cis-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentanecarboxylic acid methylamide (60 mg, 0.208 mmol), 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (46 mg, 0.208 mmol) and camphorsulfonic acid (72 mg, 0.312 mmol) were combined in 2 mL isopropanol and heated at 120° C. in microwave for a total of 75 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on an ISCO flash column from 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 52 mg (53%) of a white foam. Compound 2: mp 176° C.; MS (ES+ calculated—472; found—473 M+H). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 7.03 (d, J=8 Hz, 1H), 6.21 (d, J=7, 1H), 5.52 (br s, 1H), 4.58 (t, J=7 Hz, 1H), 3.55 (t, J=5, 2H), 3.34 (s, 3H), 2.91 (br s, 6H), 2.75 (m, 4H), 2.72 (m, 4H), 2.15 (m, 2H), 1.96 (m, 4H), 1.64 (m, 1H) ppm.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9]1.OS(O)(=O)=O.[CH3:20]O>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:12]([O:14][CH3:20])=[O:13])[CH2:9][CH2:10][CH2:11]1
Reactant: CO
Reactant: O=C(O)C1(c2ccccc2I)CCC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1(c2ccccc2I)CCC1

Procedure:
A solution of 1-(2-iodophenyl)cyclobutanecarboxylic acid A52 (425 mg, 1.41 mmol) in MeOH (25 mL) and conc. H2SO4 (1.0 mL) was stirred at 60° C. overnight. The volatiles were removed in vacuo and the resulting residue diluted in EtOAc (50 mL) and sat. soln. Na2CO3 (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL), the combined organic fractions were dried (MgSO4) and the volatiles removed in vacuo to give the title compound A53 as a clear oil (361 mg, 81%). LCMS-A: rt 7.020 min; m/z 317 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7]([CH2:9][S:10][CH3:11])=[O:8].Br[CH2:13][CH:14]([CH2:23]Br)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.C1COCC1.ClCCl>[CH3:6][S:7]([C:9]1([S:10][CH3:11])[CH2:13][CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23]1)=[O:8]
Reactant: CSCS(C)=O
Reactant: BrCC(CBr)OCc1ccccc1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC1(S(C)=O)CC(OCc2ccccc2)C1
Reaction time: 3 h
Yield: 55.5 %

Procedure:
2.5 M of n-butyllithium in hexane (19 mL) was added to a solution of (methylsulfinyl)(methylthio)methane (5.0 g, 0.040 mol) in THF (10 mL) dropwise at −10° C. and the mixture was stirred for 3 h. To the resultant solution was added dropwise [2-bromo-1-(bromomethyl)ethoxy]methylbenzene (4.9 g, 0.016 mol) at −70° C. over 30 min. The mixture was stirred at this temperature for 3 h and then at rt over night. The reaction was diluted with dichloromethane and washed with water. The aqueous phases were extracted with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-55% EtOAc/Hex) to give the desired product (2.4 g, 56%) as brown oil. LCMS (M+Na) 293.3. 1H NMR (400 MHz, CDCl3): δ 7.30 (5H, m), 4.45 (2H, s), 4.33 (1H, m), 2.75 (2H, m), 2.65 (2H, m), 2.41 (3H, s), 2.12 (3H, s) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23](C)=O>>[CH2:22]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH3:23]
Reactant: Cc1nnnn1-c1ccccc1C(=O)O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccccc1-n1nnnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (3.2 L) and 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid (228 g) were combined then stirred at ambient temperature for 15 minutes. Potassium carbonate (228 g) was added to the reaction mixture in a single portion. lodoethane (366.9 g) was added dropwise to the reaction mixture producing a slight exotherm. The reaction mixture was heated at reflux for about 4 hours then stirred overnight while cooling to ambient temperature. The precipitated salts were removed by filtration then rinsed with acetone. The combined riltrates were evaporated under vacuum. The residue was dissolved in dichloromethane (1.5 L). The dichloromethane solution was washed with water (1.5 L), dried over magnesium sulfate then concentrated under vacuum to provide 227 g of ethyl-2-(5-methyl-1H-tetrazol-1-yl)benzoate as a white solid m. p. 98-100° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.[OH2:21]>C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:21])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Product: N#Cc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 62 %

Procedure:
39.6 g of p-cyanobenzylamine, 42.1 g of hexamethylenetetramine, 200 ml of water and 200 ml of acetic acid were mixed and reacted at 100° C. for 2 hours while stirring. The reaction solution was allowed to stand overnight and as a result, scale-like crystals were precipitated. The crystals precipitated were collected by filtration, washed with water and dried to obtain 24.7 g (yield: 62%) of p-cyanobenzaldehyde. The purity was 99.8% or more.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:19][CH2:20][CH2:21][OH:22])=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCCO
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (590 mg, 2.12 mmol) in 2-propanol (20 mL) was added 2-aminoethanol (142 mg, 2.33 mmol) followed by triethylamine (235 mg, 2.33 mmol). The reaction mixture was stirred at reflux for 16 hours and the solvent was then removed under reduced pressure. The residue was washed with 2-propanol (1 mL) and dried by evaporation to afford 2-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol. (Yield 0.7 g, crude). LC-MS: [M+H]+ 304.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:19][CH:17]([N:14]1[C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)=[CH:3][CH:4]=3)[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]=2[CH:16]=[N:15]1)[CH3:18]
Reactant: CCOC(=O)c1cc(-c2ccc(Br)cc2)nc2c1cnn2C(C)C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(-c4cn[nH]c4)cc3)nc21
Yield: 34.9 %

Procedure:
To a 5-mL microwave vial were added ethyl 6-(4-bromophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (80 mg, 0.206 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56.0 mg, 0.288 mmol), 1,4-dioxane (2 mL) and sodium carbonate (0.206 mL, 0.412 mmol), and the mixture was degassed with nitrogen for 10 min. Next added PdP(Ph3)4 (19.05 mg, 0.016 mmol) and the vial was sealed. The reaction mixture was irradiated (microwave) at 120° C. overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified using reverse-phase HPLC to give 25 mg (35%) of product. LCMS E-S (M+H)=348.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.8 Hz, 6H), 5.38 (quin, J=6.6 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 8.14-8.30 (m, 4H), 8.36 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:12][C:13]1[N:18]=[C:17]([F:19])[C:16]([F:20])=[C:15](F)[C:14]=1[F:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([O:5][C:3]([CH:2]([O:1][C:15]1[C:14]([F:22])=[C:13]([F:12])[N:18]=[C:17]([F:19])[C:16]=1[F:20])[CH2:8][CH:9]([CH3:10])[CH3:11])=[O:4])[CH3:7]
Reactant: CCOC(=O)C(O)CC(C)C
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)Oc1c(F)c(F)nc(F)c1F
Reaction time: 240 h
Yield: 112.5 %

Procedure:
To a solution of ethyl 2-hydroxy-4-methylvalerate (0.50 g, 2.5 mmol) in dry DMF (25 mL) was added pentafluoropyridine (0.31 mL, 0.47 g, 2.8 mmol) and cesium carbonate (1.1 g, 3.3 mmol). The resultant mixture was heated to 45° C. and stirred at that temperature for 10 days, then poured into 100 mL of water and 100 mL of ethyl acetate. The aqueous layer was separated and extracted with another 500 mL of ethyl acetate. The combined organic extracts were shed with water (100 mL) then brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 0.87 g (99% yield) of 4-(1-ethoxycarbonyl-3-methylbutyl)oxy-2,3,5,6-tetrafluoropyridine as a clear, yellow liquid: NMR (CDCl3) 5.2 (d, 1), 4.3-4.1 (m, 3), 2.0 (m, 1), 1.8 (m, 1), 1.3 (m, 3), 1.0 (m, 6) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][NH:24][OH:25])[CH:17]=3)[C:12]2=[O:26])=[CH:4][CH:3]=1.C[Si]([N:31]=[C:32]=[O:33])(C)C.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([C:32]([NH2:31])=[O:33])[OH:25])[CH:17]=3)[C:12]2=[O:26])=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(OCCNO)cc2CCN1CCCc1ccc(F)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-hydroxyamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (3.0 g, 8.4 mmol) in dioxane (100 mL) is added trimethylsilyl isocyanate (1.06 g, 9.2 mmol). The reaction is stirred at room temperature for 24 hours and subsequently poured into H2O (350 mL). The resulting suspension is extracted with EtOAc (1×500 mL) and the organic phase washed with 2M HCl (1×250 mL), H2O (5×500 mL), saturated NaCl solution (2×500 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is triturated with hexanes, and recrystallized from EtOAc to give 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-aminocarbonyl-N-hydroxyamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 138°-140°.
Reaction SMILES: C(OC(=O)CCCNC(NC1SC(C2C=CC(S(C)(=O)=O)=C(F)C=2)=C(C)N=1)=O)C.[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[S:44][C:43]([NH2:45])=[N:42][C:41]=2[CH3:46])=[CH:36][C:35]=1[C:47]([F:50])([F:49])[F:48])(=[O:33])=[O:32].[CH2:51]([O:53][C:54](=[O:60])[CH2:55][CH2:56][N:57]=[C:58]=[O:59])[CH3:52]>>[CH2:51]([O:53][C:54](=[O:60])[CH2:55][CH2:56][NH:57][C:58]([NH:45][C:43]1[S:44][C:40]([C:37]2[CH:38]=[CH:39][C:34]([S:31]([CH3:30])(=[O:32])=[O:33])=[C:35]([C:47]([F:50])([F:49])[F:48])[CH:36]=2)=[C:41]([CH3:46])[N:42]=1)=[O:59])[CH3:52]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Reactant: CCOC(=O)CCN=C=O
Agent: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (158a) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)Cl.O>[C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:12]([NH:14][NH:15][C:26]([O:28][CH3:29])=[O:27])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: NNC(=O)c1[nH]ccc1-c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NNC(=O)c1[nH]ccc1-c1ccccc1
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
To a stirred solution of 3-phenyl-1H-pyrrole-2-carbohydrazide (3.80 g, 19.0 mmol) in DCM (60 mL) was added DIPEA (9.89 mL, 56.7 mmol) followed by methyl chloroformate (2.19 mL, 28.3 mmol) at room temperature. The above mixture was stirred for 15 min and was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CombiFlash (REDISEP®, silica gel, 80 g, 50% EtOAc/hexanes) as an eluent to yield methyl 2-(3-phenyl-1H-pyrrole-2-carbonyl)hydrazinecarboxylate (4.00 g, 75.0%) as an off-white solid. LCMS method B-2: retention time 1.75 min, [M+1]=260.2. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.61 (s, 3H), 6.27 (d, J=2.8 Hz, 1H), 6.95 (d, J=2.8 Hz, 1H), 7.20-7.34 (m, 3H), 7.51-7.52 (m, 2H), 9.14 (br s, 2H), 11.51 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH:27](/B(O)O)=[CH:28]/[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.O>C(OCC)(=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>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:27]=[CH:28][CH3:29])[CH:10]=2)[CH2:6][N:7]1[C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:26])[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:16][CH:17]=1
Reactant: C/C=C\B(O)O
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccc(Br)cc3C2=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: [Cs+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC=Cc1ccc2c(c1)C(=O)N(c1ccc(C(C)C(=O)OC(C)(C)C)cc1)C2
Temperature: 120 °C
Yield: 79.5 %

Procedure:
A mixture of tert-butyl 2-(4-(6-bromo-1-oxoisoindolin-2-yl)phenyl)propanoate (0.200 g, 0.48 mmol), cis-1-propene-1-boronic acid (0.413 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.554 g, 0.48 mmol), and cesium carbonate (0.470 g, 1.44 mmol) in 5:2 DME/water (7 mL) was heated in a microwave reactor for 20 min at 120° C. The mixture was cooled to room temperature, then diluted with ethyl acetate (8 mL). The reaction mixture was concentrated and purified by flash chromatography (silica, gradient 1-20%, ethyl acetate/hexanes) afforded tert-butyl 2-(4-(1-oxo-6-(prop-1-enyl)isoindolin-2-yl)phenyl)propanoate (0.144 g, 77%) as a yellow solid: mp 125-130° C.; 1H NMR (500 MHz, CDCl3) δ 7.96-7.80 (m, 2H), 7.75-7.65 (m, 1H), 7.54-7.34 (m, 4H), 6.53-6.33 (m, 1H), 5.93-5.87 (m, 1H), 4.84-4.80 (m, 2H), 3.66-3.60 (m, 1H), 1.94-1.91 (m, 3H), 1.47-1.45 (m, 3H), 1.41 (s, 9H) [6:4 mixture of olefin isomers determined by NMR]; ESI MS m/z 378 [M+H]+.