Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[CH:12]=[C:11]2[NH:13][S:14]([C:17]3=[CH:18][CH:19]=[CH:20][C:9](=[C:10]23)[CH:8]=1)(=O)=O>CCOCC.O1CCCC1>[NH2:13][C:11]1[CH:12]=[CH:7][CH:8]=[C:9]2[C:10]=1[C:17]([SH:14])=[CH:18][CH:19]=[CH:20]2
Reactant: O=S1(=O)Nc2cccc3cccc1c23
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cccc2cccc(S)c12
Yield: 79 %

Procedure:
To a mixture of 3.0 g of lithium aluminum hydride in 150 mL of anhydrous ether was added dropwise a solution of 4.0 g of 1,8-naphthosultam in 15 mL of anhydrous tetrahydrofuran over a period of 45 minutes while maintaining a gentle reflux. After completion of the addition, the yellow mixture was refluxed for another hour. The mixture was cooled in an ice-bath and the excess of lithium aluminum hydride was destroyed by dropwise addition of 10 mL of water. The resulting mixture was acidified with 200 mL of 4N sulfuric acid and extracted with ether (3×100 mL). The ether extracts were washed with water (75 mL) and dried (magnesium sulfate). Removal of the solvent gave 2.7 g (79%) of 8-amino-1-naphthalenethiol, mp. 68°-70°. This compound is sensitive to air, and therefore was used immediately.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)[C:13]([C:28]#[N:29])=[C:12]([O:30][CH2:31][C:32]2[N:33]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[O:35][CH:36]=2)[N:11]=1.[ClH:44]>C(#N)C.[Cu](Cl)Cl>[Cl:44][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:23]=2)[C:13]([C:28]#[N:29])=[C:12]([O:30][CH2:31][C:32]2[N:33]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[O:35][CH:36]=2)[N:11]=1
Reactant: N#Cc1c(N)nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(OCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
78 mg (0.67 mmol) of isopentyl nitrite and 90 mg (0.67 mmol) of copper(II) chloride were initially charged in 8.5 ml of acetonitrile, and 72 mg (0.64 mmol) of the compound from Example 49A were added. The reaction mixture was stirred at 60° C. for 3 h. 8.5 ml of 1N hydrochloric acid were added to the reaction solution. The aqueous phase was extracted twice with in each case 20 ml of ethyl acetate, and the combined organic phases were dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the residue was dried under reduced pressure and used without further purification for the subsequent reaction.
Reaction SMILES: [CH2:1]([C:8]1[CH:24]=[CH:23][C:11]([C:12](=[O:22])[CH2:13][C:14]2[CH:15]=C([CH:19]=[CH:20][CH:21]=2)C#N)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:25]([OH:28])(=[O:27])[CH3:26]>S(=O)(=O)(O)O.O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:22])[CH2:13][C:14]2[CH:15]=[C:26]([CH:19]=[CH:20][CH:21]=2)[C:25]([OH:28])=[O:27])=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCc1ccc(C(=O)Cc2cccc(C(=O)O)c2)cc1
Yield: 1.5 %

Procedure:
A mixture of 3-cyanophenylacetic acid (13 g, 0.08 mole) and thionyl chloride (100 ml) is heated under reflux for 90 minutes. The excess thionyl chloride is removed by evaporation under reduced pressure. The residue is dissolved in methylene chloride (20 ml) and the resulting solution added to aluminum chloride (16.2 g, 0.12 mole) in methylene chloride (200 ml) with vigorous stirring. A solution of 1-phenylheptane (14.3 g, 0.12 mole) in methylene chloride (50 ml) is then added over 20 minutes. The reaction mixture is heated under reflux (1 hour) and then poured into ice water (1 liter) with vigorous stirring. The mixture is extracted twice with ether (600 ml and 100 ml). The extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel (hexane/ether) to give 3-(4-n-heptylphenacyl)benzonitrile (7.6 g) as a White crystalline solid, m.p. 68° C. Then, 3-(4-n-heptylphenacyl)benzonitrile (1.5 g, 4.7 mole) is heated under reflux (1 hour) in a mixture of 75% aqueous sulfuric acid (12 g) and acetic acid (12 g). The reaction mixture is diluted with water (100 ml) and extracted with ether (2×75 ml). The ether extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting yellow solid is chromatographed on silica gel (hexane:ether:acetic acid; 60:40:1) and recrystallized from heptane to give 3-(4-n-heptylphenacyl)benzoic acid (1 g) as a pale yellow crystalline solid, 128°-133°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:49])[C:32]([C:47]#[N:48])=[CH:33][C:34]([N:37]([CH2:45][CH3:46])C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:33][C:34]([NH:37][CH2:45][CH3:46])([CH3:35])[CH3:36])[C:47]#[N:48])=[O:49])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(C)(C)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate (60 mg, 0.089 mmol) in DCM (10 mL) was added 2.5 mL of CF3COOH. The mixture was stirred for 2 h at room temperature. The volatile phase was removed under reduced pressure and the residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm Sum; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted 12 mg (16%) of the title compound as a white solid and bis TFA salt. LC-MS: m/z 569 (M+H+). H-NMR (400 MHz, CD3OD, ppm): 8.37 (s, 1H), 7.72 (s, 1H), 7.57 (t, J=8.4 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 7.28 (t, J=7.2 Hz, 1H), 7.17 (d, 8.0 Hz, 2H), 6.97 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.91 (dd, J=11.6 Hz, 2.0 Hz, 1H), 4.95-4.82 (m, 2H), 4.70-4.65 (m, 1H), 3.71-3.65 (m, 3H), 3.59-3.55 (m, 1H), 2.15-2.11 (m, 1H), 2.02-1.93 (m, 2H), 1.81-1.79 (m, 1H), 1.53 (s, 3H), 1.47 (s, 3H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([S:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][S:11]([C:4]2[C:5](=[O:10])[N:6]([CH2:8][CH3:9])[CH:7]=[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:3]=2)(=[O:13])=[O:12])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: CCn1cc(Br)nc(S(=O)(=O)Cc2ccc(Cl)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1cc(-c2ccccc2)nc(S(=O)(=O)Cc2ccc(Cl)cc2)c1=O
Yield: 26.2 %

Procedure:
200 mg (0.51 mM) of 5-bromo-3-[(4-chlorobenzyl)sulfonyl]-1-ethylpyrazin-2(1H)-one and 20 mg of tetrakis Pd(PPh3) in 4 ml of toluene were stirred for 10 min at room temperature under nitrogen atmosphere. 93.4 mg (0.77 mM) of phenyl boronic acid and 1.5 ml of a 2M cesium carbonate aqueous solution were added and the reaction mixture was refluxed under stirring for 1 h30. 10 ml of water and 10 ml of toluene were added, the organic layer was separated. The aqueous layer was extracted with toluene and the combined organic layer was separated and washed with water, dried on anhydrous sodium sulfate and concentrated under vacuum. The residue was further purified by silica gel column chromatography, using dichloromethane/dimethylketone (95/5) as eluant, to give 52 mg of 3-[(4-chlorobenzyl)sulfonyl]-1-ethyl-5-phenylpyrazin-2(1H)-one as a solid. Yield: 26%.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19](CC5C=NC=CC=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[CH:19]=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3
Reactant: COc1cc2c3c(c1)c(=O)c(Cc1cccnc1)cn3-c1cc(Br)ccc1S2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc2c3c(c1)c(=O)ccn3-c1cc(Br)ccc1S2
Yield: 88.3 %

Procedure:
The compound (2 g) obtained in Example 36 <step 2> was suspended in dioxane (110 mL) and to the suspension was added DDQ (1.88 g). The mixture was heated under reflux for 3 hours. After allowing to cool, to the mixture were added 1N-sodium hydroxide (20 mL) and ethyl acetate(50 mL) . The precipitate crystals were collected by filtration and washed with water and ethanol in turns to obtain the title compound (1.41 g; 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[CH:13]([C:16]1[C:17]([Cl:24])=[N:18][C:19](Cl)=[N:20][C:21]=1Cl)([CH3:15])[CH3:14]>CN(C=O)C>[Cl:24][C:17]1[C:16]([CH:13]([CH3:15])[CH3:14])=[C:21]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:20]=[C:19]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:18]=1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2nc(Cl)c(C(C)C)c(OCc3ccc(OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a stirred solution of p-methoxybenzyl alcohol (110 ml) in anhydrous DMF (50 ml) in a water bath under nitrogen atmosphere, was portionwise added 60% sodium hydride (4 g, 100 mmol). After complete reaction of sodium hydride, the mixture was cooled in an ice-water bath and 5-isopropyl-2,4,6-trichloropyrimidine (11.275 g, 50 mmol) was added. After 1 hr., the mixture was stirred for overnight at room temperature. The excess p-methoxybenzyl alcohol and DMF were distilled off in high vacuo and the residue was partitioned between ether and water. The ether layer was taken, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a colorless syrup. The crude product was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 17 g (79%) of a white solid. m.p. 69-70° C.; 1H NMR (200 MHz, CDCl3) δ 1.23 (6H, d, J=7.0 Hz), 3.42 (1H, m), 3.81 (3H, s), 3.82 (3H, s), 5.31 (2H, s), 5.35 (2H, s), 6.87-6.92 (4H, m), 7.30-7.43 (4H, m).
Reaction SMILES: [OH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:33])[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:7][CH:6]=1.C>C(O)C>[OH:1][C@H:2]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:7][CH:6]=1
Reactant: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1OCc1ccccc1
Solvent: CCO
Product: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
Intermediate 6 (2.5 g, 4.8 mmol) was dissolved in 8.0 mL of ethanol and treated with activated charcoal, Darco G-60 (1.25 g). The suspension was stirred at 50° C. for 20 min and then filtered to remove the Darco. To the filtrate was added 10% palladium on activated carbon (250 mg) and the suspension placed on a Parr shaker. The reaction was shaken for 10 h under 30 psi hydrogen gas. The reaction was filtered through celite and concentrated under vacuum to afford compound 1 as a brown gelatinous solid (1.9 g, 4.3 mmol, 91%). 1HNMR (300 MHz, DMSO-d6) δ 2.40-2.68 (m, 6H), 2.92-3.18 (m, 2H), 4.35-4.45 (m, 1H), 4.60-4.69 (m, 1H), 5.22-5.30 (m, 1H), 6.82 (s, 1H), 6.85 (s, 1H), 6.68-6.86 (m, 4H), 7.12-7.36 (m, 5H), 7.95 (d, 1H, J=1.4 Hz), 8.19 (s, 1H), 9.49 (br s, 1H). m/z: [M+H+] calcd for C25H29N3O4 436.2. Found 436.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+].O>C(O)C>[CH2:15]([NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(CNCCCN2CCN(CCCNCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and benzaldehyde (0.532 mL, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]>CS(C)=O.C(OCC)(=O)C>[Cl:16][C:17]1[C:18]([O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:19][C:20]([F:33])=[C:21]([CH:32]=1)[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:23]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(Cl)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
3,4-Dichlorophenol (110 mg, 0.67 mmol) and potassium carbonate (20 mg, 1.42 mmol) were stirred in dimethylsulfoxide (20 mL). After 5 minutes, 4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 10, 200 mg, 0.71 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with a 1M aqueous solution of sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo to give a white solid. The solid was purified by silica gel column chromatography (50% ethyl acetate in heptane elution) to afford the title compound as a white solid (286 mg, 95%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(F)cc1NCc1ccccc1
Temperature: 90 °C
Yield: 66 %

Procedure:
A mixture of benzyl-(5-fluoro-2-nitrophenyl)amine (3.8 g, 15.2 mmol), iron powder (3.42 g, 60.8 mmol) and ammonium chloride (4.7 g, 91.2 mmol) in methanol (40 mL) and water (10 mL) was heated to 90° C. for 2 h, under an atmosphere of nitrogen. The resultant mixture was diluted with methanol (20 mL) and filtered through Celite®. The Celite® was washed with DCM, methanol and EtOAc (4×) and the filtrate concentrated in vacuo. The residue was partitioned between water (25 mL) and EtOAc (40 mL) and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic fractions were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a dark brown gum (2.17 g, 66%). The crude material was used without purification in the next step. 1H NMR (CDCl3, 400 MHz): δ 7.41-7.25 (5H, m), 6.67-6.59 (1H, m), 6.40-6.28 (2H, m), 4.28 (2H, s)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:28]>COCCOC>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][Br:28])[CH:7]=1)[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CO)c1
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(2-hydroxymethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (15.14 g, 41.9 mmol) in DME was added phosphorus tribromide (5.92 mL, 62.8 mmol), and the reaction was stirred at room temperature overnight. After cooling to 0° C., the mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31](OC2C=CC([N+]([O-])=O)=CC=2)=[O:32])=[CH:5][CH:4]=1)#[N:2].[CH3:43][S:44]([C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=1)(=[O:46])=[O:45]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:54][CH2:53][C:50]2[CH:49]=[CH:48][C:47]([S:44]([CH3:43])(=[O:46])=[O:45])=[CH:52][CH:51]=2)=[O:32])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(CNC(=O)N2C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C2c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 200 mg, 0.347 mmol) and (4-(methylsulfonyl)phenyl)methanamine (193 mg, 1.04 mmol in acetonitrile (5 mL) is stirred at room temperature for 1 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 92 mg; ESI mass spectrum [M+H]+=623; Retention time HPLC: 0.66 min (X012_S01).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[C@H:12]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14](=[O:22])[C@@H:13]1[CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)C=C.N1CCOCC1>O1CCCC1.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>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([C@H:12]2[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[C@@H:13]2[CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:36])[CH3:35])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[C:5]([OH:4])[CH:10]=1
Reactant: C=CCOc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(Br)cc1O)c1ccc(F)cc1
Yield: 82.7 %

Procedure:
(3R,4S)-4-[2-(Allyloxy)-4-bromophenyl]-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.34 g, 2.15 mmol) was dissolved in deoxygenated tetrahydrofuran (20 mL). Morpholine (1.8 mL, 1.8 g, 20.6 mmol) was added with additional deoxygenated tetrahydrofuran (5 mL). The reaction was purged with nitrogen and tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19 mmol) was added. The reaction was purged with nitrogen again. After 1.5 h at room temperature the reaction was diluted with ethyl acetate, washed twice with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and filtered. The solution was treated with activated charcoal, filtered, concentrated and purified by chromatography (40 g silica gel, 6% to 80% ethyl acetate-hexane) to afford (3R,4S)-4-(4-bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (1.04 g, 83% yield); Rf 0.38 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.28-7.18 (m, 6H), 7.09-6.92 (m, 6H), 5.91 (s, 1H), 4.93 (d, J=2.3 Hz, 1H), 4.65 (t, J=5.4 Hz, 1H), 3.06 (ddd, J=4.8, 2.3, 2.3 Hz, 1H), 1.98-1.77 (m, 4H), 0.86 (s, 9H), 0.006 (s, 3H), −0.16 (s, 3H) ppm; MS [M−H]+581.7.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=O)[O:3]1.C1COCC1.[CH3:20][NH2:21]>CC(O)=O>[CH3:20][N:21]1[C:4](=[O:3])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=2)[C:2]1=[O:1]
Reactant: CN
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1C(=O)c2ccc(C(=O)O)cc2C1=O
Reaction time: 12 h

Procedure:
To a microwave vial was added 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (200 mg, 1.041 mmol), THF (2 mL) and methylamine (2.0M THF, 2.0 mL). The flask was irradiated in a microwave at 100° C. for 5 min. At this time, AcOH (glacial, 0.4 mL) and an additional portion of methylamine (2.0M THF, 2.0 mL) were added, and the flask was placed in a the microwave at 100° C. for 2 h. The flask was allowed to cool and then azeotropically dried (toluene, 3×5 mL). The flask was placed under a high vacuum for 12 h to provide 2-methyl-1,3-dioxoisoindoline-5-carboxylic acid which was used directly in the amide coupling reaction without further purification.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(#N)C.CCOC(C)=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([F:13])[CH:15]=2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(O)C(Br)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)C(Nc1cccc(F)c1)c1ccc(F)cc1
Temperature: 100 °C
Yield: 90.1 %

Procedure:
A mixture of 2-bromo-2-(4-fluorophenyl)acetic acid (500 mg, 2.15 mmol) and 3-fluoroaniline (477 mg, 4.29 mmol) in acetonitrile (8 ml) was heated under microwave irradiation at 100° C. for 50 minutes. Then 3-fluoroaniline (238 mg, 2.15 mmol) was added again, and the reaction mixture was heated at 120° C. for 45 minutes in a microwave oven (UPLC-MS monitoring: complete conversion). The organic solution was diluted with EtOAc and was washed with 2N HCl and then with brine. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated to give 2-(4-fluorophenyl)-2-(3-fluorophenylamino)acetic acid (510 mg, 90% yield).