Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19].O>C1COCC1>[Cl:16][CH2:17][C:18]([NH:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)CCl)cn1
Temperature: -60 °C
Yield: 41 %

Procedure:
A mixture of 6-methylpyridin-3-amine (1 g) and triethylamine (2.2 mL) in dry THF (20 mL) was stirred and cooled to −60° C. 2-Chloroacetyl chloride (1.567 g) was added via syringe to the stirred mixture forming a yellow suspension. The mixture was stirred at −60° C. until analysis showed complete disappearance of starting material. The reaction slurry was poured into water and the products extracted with ethyl acetate (2×150 ml). The combined organic extracts were dried over magnesium sulphate and concentrated to dryness. The crude brown solid was recrystallised from ether to afford the subtitled compound (700 mg).
Reaction SMILES: [CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].[OH-].[Na+]>C(O)C>[CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCN(c1ncnc2c1ncn2CCCCCCCCC(=O)OC)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCN(c1ncnc2c1ncn2CCCCCCCCC(=O)O)C1CCCCC1
Yield: 71 %

Procedure:
3.2 g. (7.5 mmole) of the compound of Example 13 are heated under reflux for 5 hours with 50 ml. 5% aqueous sodium hydroxide solution and 40 ml. ethanol. The reaction mixture is evaporated and the residue is taken up in water, washed with diethyl ether and the aqueous phase is adjusted to pH 6, extracted with dichloromethane, dried and evaporated. After trituration of the residue with diethyl ether, there are obtained 2.2 g. of the title compound (71% of theory); m.p. 100°-102° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:35]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH2:40])[CH3:36]>CN(C=O)C>[CH2:35]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:18][CH:17]=1)[CH3:36]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A solution containing about 1.26 g of Compound 39 in about 20 ml anhydrous DMF under nitrogen was cooled in an ice-salt bath. About 0.55 ml of N-methylmorpholin was added to the cooled solution, followed 5 minutes later by about 0.65 ml isobutylchloroformate. After stirring for a period of about 20 minutes, 1.20 g diethyl-L-glutamate hydrochloride was added, followed immediately by about 0.55 ml N-methylmorpholin. The reaction mixture was warmed to room temperature and stirred for 12 hours. At this time, the activation cycle was repeated using ½ the amounts of reagents indicated above, after which the reaction mixture was warmed to room temperature and stirred for an additional 12 hours. The solvents were removed under reduced pressure, and the residue was dissolved in about 100 ml CH2Cl2, washed with about 75 ml water, 50 ml 0.1 NHCl, and about 50 ml saturated NaCl. The organic layers were dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure and the residue was flash chromatographed on silica gel (2.4×24 cm), eluting first with CH2Cl2 and then with 1% methanol in CH2Cl2. Fractions showing a single spot corresponding to the product were pooled and evaporated under reduced pressure to yield about 1.29 g of Compound 34.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:13](O)=[C:14]([CH:19]=[C:20]([C:22]#[N:23])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].BrC1C2OC(C3C=CC(C([O-])=O)=CC=3)=NC=2C=C(C#N)C=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:13]3[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(=O)c1cc(C#N)cc(N)c1O
Agent: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)[O-])cc3)nc2c1
Product: COC(=O)c1cc(C#N)cc2nc(-c3ccc(Br)cc3)oc12

Procedure:
The title compound was prepared from 4-bromobenzoyl chloride and methyl 3-amino-5-cyano-2-hydroxybenzoate (INTERMEDIATE 26) by a procedure analogous to that described in INTERMEDIATE 1, Step C. Mass spectrum (ESI) 358.9 (M+3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH2:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 18 h
Yield: 111.1 %

Procedure:
tert-Butyl 4-(3-methyl-4-nitrophenoxy)piperidine-1-carboxylate (5.2 g, 14.30 mmoles) was dissolved in ethyl acetate (60 ml) and methanol (10 ml). The solution was treated with 500 mg of 10% palladium on carbon (50% water w/w). The slurry was then shaken on a Parr hydrogenator and treated with a 40 psi atmosphere of hydrogen gas, at room temperature. After 18 hours, the slurry was filtered through a plug of Celite, which was subsequently washed with ethyl acetate (50 ml) and methanol (50 ml). The resulting filtrate was then evaporated at reduced pressure and then triturated with hexane to give a solid. This material was filtered off and dried at reduced pressure to give 4.87 g of tert-butyl 4-(3-methyl-4-aminophenoxy)piperidine-1-carboxylate (100% yield). 1H-NMR (400 MHz, DMSO-d6) δ 6.33 (d, 1H), 6.32 (s, 1H), 6.23 (s, 1H), 5.85 (bs, 2H), 3.70 (m, 1H), 3.39 (m, 2H), 3.29 (m, 2H), 2.35 (s, 3H), 2.00 (m, 2H), 1.75 (m, 2H), 1.42 (s, 9H). MS (EI): for C18H28N2O3: 320 (MH+).
Reaction SMILES: Br.[Br:2][CH:3]1[CH2:9][CH:8]([CH3:10])[NH:7][CH2:6][CH2:5][C:4]1=O.Br.[Br:13][CH:14]1[C:20](=O)[CH2:19][CH2:18][CH:17]([CH3:22])[NH:16][CH2:15]1.[C:23]([NH2:26])(=[S:25])[CH3:24]>CCO>[BrH:2].[CH3:24][C:23]1[S:25][C:5]2[CH2:6][NH:7][CH:8]([CH3:10])[CH2:9][CH2:3][C:4]=2[N:26]=1.[BrH:13].[CH3:24][C:23]1[S:25][C:19]2[CH2:18][CH:17]([CH3:22])[NH:16][CH2:15][CH2:14][C:20]=2[N:26]=1
Reactant: CC(N)=S
Reactant: CC1CC(Br)C(=O)CCN1
Reactant: CC1CCC(=O)C(Br)CN1
Agent: Br
Solvent: CCO
Product: Cc1nc2c(s1)CC(C)NCC2
Product: Cc1nc2c(s1)CNC(C)CC2

Procedure:
A mixture of 33 g 5-bromo-7-methyl-azepan-4-one hydrobromide and 3-bromo-7-methyl-azepan-4-one hydrobromide and 8.6 g thioacetamide in 400 mL dry EtOH was refluxed overnight. The reaction mixture was concentrated to give 30 g of the desired product, which was used for the next step without further purification. Rf: 0.2 (DCM/MeOH=20/1), (M+H)+=183
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[CH2:7]C(C)=CC[C:3]1=2.C[N+]([O-:19])(C)C.[C:20]([OH:24])([CH3:23])([CH3:22])[CH3:21]>O.CCOCC.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[CH2:7][CH:22]([OH:19])[C:20]([CH3:23])([OH:24])[CH2:21][C:3]1=2
Reactant: CC1=CCC2=C(C1)C(C)CCC2(C)C
Reactant: CC(C)(C)O
Reactant: C[N+](C)(C)[O-]
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOCC
Product: CC1CCC(C)(C)C2=C1CC(O)C(C)(O)C2

Procedure:
24 g of crude 2,2,5,8-tetramethyl-bicyclo[4.4.0]deca-1(6),8-diene (43%) in 120 ml of tert.butanol are treated with a solution of 10.5 g of trimethylamine N-oxide in 43 ml of water in a three-necked sulphonation flask equipped with a stirrer, a reflux condenser, a thermometer and an argon flow with a bubble counter. 50 ml of a 0.05% solution of osmium tetroxide in tert.butanol are added thereto. The resulting emulsion is held at reflux temperature for 96 hours with good stirring. The cooled solution is diluted with ether and washed with a saturated sodium chloride solution, with 2N hydrochloric acid and with ice-water. The aqueous phases are extracted twice with ether. After drying the combined organic phases over magnesium sulphate and concentration on a rotary evaporator, 24 g of crude product was obtained. By recrystallization from hexane there are obtained 6 g of 2,2,5,9-tetramethyl-bicyclo[4.4.0]dec-1(6)-ene-8,9-diol of melting point 121°-123° C.
Reaction SMILES: C1(C2C=CC([N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([OH:39])[CH2:33][C:34]4[N:35]=[N:36][NH:37][N:38]=4)=[CH:28][CH:27]=3)[C:14]([NH:16][C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)=[O:15])=CC=2)CCCCC=1.C(O[C:44](=[O:46])[CH3:45])(=O)C.[CH2:47](O)[CH3:48]>C(Cl)Cl>[C:17]1([C:48]2[CH:47]=[CH:28][C:27]([CH:25]([NH:13][C:14]([NH:16][C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)=[O:15])[C:26]3[CH:31]=[CH:30][C:29]([CH:32]([O:39][C:44](=[O:46])[CH3:45])[CH2:33][C:34]4[N:35]=[N:36][NH:37][N:38]=4)=[CH:28][CH:27]=3)=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCO
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)N(Cc1ccc(C(O)Cc2nn[nH]n2)cc1)c1ccc(C2=CCCCC2)cc1
Solvent: ClCCl
Product: CC(=O)OC(Cc1nn[nH]n1)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)-1-{4-[1-hydroxy-2-(2H-tetrazol-5-yl)ethyl]benzyl}urea (30 mg, 0.05 mmol) was dissolved in DCM (1.5 ml) and acetic acid anhydride (15 μl) was added. The mixture was stirred at room temperature overnight, and then taken to dryness. The residual oil was dissolved in ethanol (2 ml), and heated to reflux for 0.5 min. Then cooled and evaporated to dryness. The residue was stripped twice from acetonitrile to give a quantitative yield of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 175.4 %

Procedure:
To a stirred solution of (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5, 10 mg), (3-methylsulfonylphenyl)boronic acid (58 mg), tetrakis-(triphenylphosphine)palladium (0) (30 mg) in 1,2-dimethoxyethane (2 mL) was added potassium carbonate (90 mg). The mixture was stirred at 80° C. overnight. Water was added, the phases were separated and the inorganic one was extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 2:1 to EtOAc) to yield (E)-3-(3′-methanesulfonyl-biphenyl-4-yl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (21 mg, 18%) as a light yellow foam, MS (ESI+): m/z=457.2 ([M+H]+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:16](COCC[Si](C)(C)C)[N:15]=[CH:14][C:13]=2[C:25]#[N:26])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:13]([C:25]#[N:26])=[CH:14][NH:15][N:16]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)CCOCn1ncc(C#N)c1Nc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Nc2n[nH]cc2C#N)cc1

Procedure:
5-{[4-(methylsulfonyl)phenyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (0.82 g, 2.089 mmol) was stirred in ethanol (40 mL)/2 N HCl (40 mL) at 80° C. for 2 hours. Room temperature was attained, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 3-{[4-(methylsulfonyl)phenyl]amino}-1H-pyrazole-4-carbonitrile as a pale yellow solid.
Reaction SMILES: C[Si](O/C(=N/[Si](C)(C)C)/C)(C)C.[F:13][C:14]1[C:15](=[NH:22])[N:16]([CH3:21])[C:17](=[O:20])[NH:18][CH:19]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:27](Cl)=[O:28]>C(#N)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:27]([N:18]1[CH:19]=[C:14]([F:13])[C:15](=[NH:22])[N:16]([CH3:21])[C:17]1=[O:20])=[O:28]
Reactant: Cn1c(=O)[nH]cc(F)c1=N
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC#N
Product: Cn1c(=N)c(F)cn(C(=O)c2cc(Cl)cc(Cl)c2)c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
In a capped vial, (E)-trimethylsilyl-N-(trimethylsilyl)acetimidate (157 mg, 0.774) was added to 5-fluoro-4-imino-3-methyl-3,4-dihydropyrimidin-2(1H)-one (100 mg, 0.704 mmol) and acetonitrile (1.0 mL) and heated at 70° C. for 30 min. The solution was cooled to room temperature and 3,5-dichlorobenzoyl chloride (133 mg, 0.633 mmol) was added dropwise and the contents were stirred overnight at room temperature. The reaction was concentrated with a stream of nitrogen. Diethyl ether (Et2O; 3 mL) was added and the vial was recapped and shaken briefly. The solids were filtered and washed with a small amount of Et2O and air dried to provide the title compound as a white solid (78 mg, 35%): mp 142-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=5.5 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.49 (d, J=1.8 Hz, 2H), 3.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.97, 136.71, 135.23, 135.12, 132.76, 132.37, 127.95, 126.48, 114.66, 114.27, 29.56, 29.01; ESIMS m/z 317 ([M+H]+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[CH3:13][Mg]Br>O1CCCC1>[OH:12][CH:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)[CH3:13]
Reactant: C[Mg]Br
Reactant: O=Cc1ccc2nccnc2c1
Solvent: C1CCOC1
Product: CC(O)c1ccc2nccnc2c1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
To a mixture of quinoxaline-6-carboxaldehyde (0.10 g, 0.63 mMol) in dry tetrahydrofuran (3 mL) at zero degrees was added methyl magnesium bromide (3M in Et2O, 0.253 mL, 0.76 mMol) drop wise. Upon complete addition the ice bath was removed and the solution allowed to warm to room temperature. The reaction was quenched with methanol and IN hydrochloric acid added until the pH was approximately seven. The neutral solution was partitioned between ethyl acetate and water, the aqueous layer discarded and the organics washed with brine. The organics were dried (MgSO4), filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 10-100% methanol in dichloromethane yielded 62 mg (56% yield) of 6-(1-hydroxyethyl)quinoxaline as a clear oil. 1H NMR (DMSO-d6): δ=8.92 (dd, 2H, J=9.1, 1.9 Hz), 8.06 (d, 1H, J=8.6 Hz), 8.02 (d, 1H, J=1.7 Hz), 7.87 (dd, 1H, J=8.7, 1.9 Hz), 5.51 (br s, 1H), 4.99 (q, 1H, J=6.4 Hz), 1.43 (d, 3H, J=6.4 Hz). LC/MS (Method A), rt=0.56 mins., purity=99%, calculated mass=174, [M+H]+=175.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[S:23][C:24]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[N:21][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (6-{2-[4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[NH:6]1.[H-].[Na+].[CH2:23](I)[CH2:24][CH3:25]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[N:6]1[CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)CC1NC(=O)N(Cc2ccc(C)cc2)C1=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)C(=O)C1CC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
A 0° C. solution of compound [1-(4-methyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester (1.60 g, 5.8 mmol) in DMF (28 mL) is treated with sodium hydride (60% dispersion, 0.25 g, 6.4 mmol) and warmed to room temperature and stirred under N2 for 15 minutes. The resultant mixture is cooled to 0° C. and then treated with 1-propyl iodide (1.08 g, 6.4 mmol) and then warmed to room temperature and stirred for 30 minutes. The reaction is quenched with aqueous 1 N HCl (28 mL) and then worked up extractively with EtOAc and water. The organic layer is dried i and the solvent removed to give crude product that is purified by flash chromatography using a gradient of 10:1 to 1:1 hexanes:EtOAc to afford 1.40 g (76%) [1-(4-methyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-acetic acid methyl ester. 1H NMR. MS (ES+) Calc'd for C17H23N2O4 (M+1) 319. Found m/z 319 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1.[I:19]I.N1C=CN=N1>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([I:19])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Reactant: II
Agent: O=S(=O)(O)O
Agent: c1c[nH]nn1
Product: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Yield: 93 %

Procedure:
To a 250 mL roundbottom flask equipped with a mechanical stirrer and a thermometer was added 100 mL of 20% fuming sulfuric acid (oleum) (% wt/vol. triazole to solvent—28.7%), followed by 28.7 grams (0.104 mole—1.0 equiv.) of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole. The mixture was vigorously stirred at ambient temperature to effect dissolution. The mixture was cooled in an ice-bath, and 26.3 grams (0.104 mole—1.0 equiv.) of iodine crystals were added. The reaction mixture was then warmed to ambient temperature, where it stirred for seven hours. After this time gas chromatographic (GC) and TLC analysis of the reaction mixture indicated that the reaction was almost complete. The reaction mixture was stirred at ambient temperature for an additional 16 hours. At the conclusion of this period a second GC analysis of the reaction mixture indicated 100% conversion of the triazole starting material. The reaction mixture was poured into 300 grams of ice, and the resulting mixture was extracted with two 250 mL portions of methylene chloride. The organic extracts were combined and washed with an aqueous 10% potassium carbonate solution, an aqueous 5% sodium bisulfite solution, and an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding a white solid, which was dried to a constant weight, yielding 38.8 grams of 92% pure 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (92.5% yield). GC analysis of the product indicated the presence of about 4% of an impurity. The 92% pure product was recrystallized from 300 mL of methanol, yielding 29.8 grams of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, m.p. 125-127° C. The mother liquor was concentrated under vacuum to yield a residue, which was recrystallized from 60 mL of methanol, yielding an additional 5.9 grams of 1-(4-chloro2-fluoro-5-iodophenyl)-4-difluoromethyl4,5-dihydro-3-methyl-5-oxo-l H-1,2,4-triazole.
Reaction SMILES: C(Cl)(=O)C.[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=[CH:43][C:42]([C:45](=[O:50])NCCC)=[CH:41]C=1)=O)C2>>[C:45]([N:6]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])[CH:9]=2)[CH2:5]1)(=[O:50])[CH:42]([CH3:43])[CH3:41]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc2c(c1)CNC2)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: CC(C)C(=O)N1Cc2ccc(NC(=O)N3Cc4ccccc4C3)cc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting isobutyryl chloride for acetyl chloride and N-(isoindolin-5-yl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 7.59-7.61 (bs, 1H), 7.46 (ddd, J=10.8, 8.5, 2.1 Hz, 1H), 7.30-7.38 (m, 4H), 7.20-7.24 (m, 1H), 4.82-4.87 (m, 2H), 4.76-4.77 (bs, 4H), 4.55-4.60 (m, 2H), 2.78 (h, J=6.9 Hz, 1H), 1.07 (d, J=6.7 Hz, 6H); MS (ESI(+)) m/e 350 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[N:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Ce+3].C(=O)([O-])[O-].C(=O)([O-])[O-].[Ce+3]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:12][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[C:3]=2[F:13])[N:8]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: Fc1c(Br)ccc2nc(Cl)ncc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(-c2ccc3nc(Cl)ncc3c2F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A mixture of 6-bromo-2-chloro-5-fluoroquinazoline (1.5 g, 5.74 mmol), 3,5-dimethoxyphenylboronic acid (1.15 g, 6.31 mmol), cerium carbonate (1.87 g, 5.74 mmol) and bis(tri-tert-butylphosphine)palladium (148 mg, 0.29 mmol) in THF (30 mL) and water (3 mL) was degassed with nitrogen for three times and stirred at 80° C. overnight. The mixture was cooled to room temperature and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=8:1) to get the title product as a white solid (1.3 g, 70%). MS (ES+) C16H12ClFN2O2 requires: 318, found: 319, 321 [M+H]+.