Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=[C:4]2[CH:3]=1.C[OH:16]>ClCCl>[F:13][C:11]([F:14])([F:12])[C:8]1[N:5]2[N:6]=[CH:7][C:2]([CH:1]=[O:16])=[CH:3][C:4]2=[N:10][N:9]=1
Reactant: Cc1cnn2c(C(F)(F)F)nnc2c1
Reactant: CO
Solvent: ClCCl
Product: O=Cc1cnn2c(C(F)(F)F)nnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A finely-ground powder of NaI4 is added to a solution of 7-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine x233 (0.52 g, 2.0 mmol) in absolute methanol (42 ml). The reaction mixture is stirred at room temperature for 1.5 h and diluted with an equal volume of dichloromethane. The mixture is filtered through the Celite layer, and the solvents are removed under reduced pressure. The residue (0.5 g) is purified by chromatography on silicagel (hexane/ethyl acetate 3/2) to yield 0.34 g of 3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine-7-carbaldehyde x235 as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([O:12][CH:13]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][NH2:15])(=[O:11])[CH3:10].[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](N)=[NH:27].CN(C)C=O>O>[ClH:24].[C:9]([O:12][CH:13]([CH2:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][NH:15][C:26](=[NH:27])[C:25]([Cl:30])([Cl:29])[Cl:24])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(CN)COc1ccccc1
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OC(CNC(=N)C(Cl)(Cl)Cl)COc1ccccc1
Temperature: 60 °C

Procedure:
Triethylamine (0.50 g., 5.0 mmoles) is added in small portions over 10 minutes to a well stirred mixture of 1.23 g. (5.0 mmoles) of 2-acetoxy-3-phenoxy-propylamine hydrochloride and 1.61 g. (10 mmoles) of trichloroacetamidine in 5 ml. of dimethylformamide. The reaction mixture is heated at 60° C. for 2 hours, diluted with water and extracted with benzene. The benzene extract is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is dissolved in benzene and treated with an excess of ethanolic hydrogen chloride. Concentration to dryness affords N-(2-acetoxy-3-phenoxypropyl) trichloroacetamidine hydrochloride with a m.p. of 70° to 77° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=2[O:25]C)=[N:5]1)[CH:2]=[CH2:3].C1CCCCC=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[OH:25])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: O
Solvent: ClCCl
Product: C=CCn1nc(-c2ccc(O)cc2O)c2cccc(C(F)(F)F)c21
Temperature: 25 °C

Procedure:
1-allyl-3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.065 g, 0.18 mmol) in CH2Cl2 containing 1.0 mL of cyclohexene at −78° C. was treated with boron tribromide (0.136 mL, 1.4 mmol) and slowly allowed to warm to ambient temperature. The reaction was quenched by dropwise edition of CH3OH to the cooled reaction. The solvent was removed in vacuo and the residue partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo afforded the crude product. Pure product was obtained by crystallization or flash chromatography through water deactivated silica gel. A sample of 0.066 g was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 100 °C
Yield: 90 %

Procedure:
A stirred mixture of 2-chloro-5-nitropyridine (3.16 g, 20.0 mmol), 1-methyl-piperazine (2.00 g, 2.00 mmol) and potassium carbonate (2.76 g, 20.0 mmol) in DMF is heated at 100° C. for 24 h, cooled, poured into water and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 2% ammonia in 10:90 ethanol:ethyl acetate as eluent) affords the title compound as an off-white solid, 4.0 g (90% yield), identified by NMR analysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=[O:25])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH2:64]([O:71][NH2:72])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:25])[NH:72][O:71][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NOCc1ccccc1
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)NOCc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
The acid compound 6 (4.8 g, 10.5 mmol) was dissolved in dry DMF and cooled to 0-5° C. 1-Hydroxybenzotriazole (1.56 g, 11.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 2.0 g, 10.5 mmol), and triethylamine (4.4 mL, 31.6 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (1.85 g, 11.5 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (100 mL). The organic layer was extracted with 2.0 M HCl (1×20 mL), saturated NaHCO3 (1×20 mL), and brine (1×50 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography (30-70% ethyl acetate in hexane containing 1% acetic acid) yielded the desired benzyl hydroxamate 7 (4.7 g, 78%). 1H NMR (400 MHz, DMSO-d6): 10.96 (s, 1H), 7.32-7.38 (m, 5H), 7.23 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 7.06 (d, J=8.0 Hz, 1H), 6.86 (overlapped d, J=8.4 Hz, 4H), 4.72 (s, 2H), 4.53 (m, 1H), 2.90 (s, 3H), 2.69-2.86 (m, 7H), 2.25 (t, J=7.6 Hz, 2H), 1.30 (s, 9H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH:6]1[CH2:23][CH2:22][C:9]2([CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.[N-:24]=[N+:25]=[N-:26].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C1C=CC=CC=1.C(OCC)(=O)C>[N:24]([CH:2]([CH2:3][OH:1])[CH2:4][O:5][CH:6]1[CH2:23][CH2:22][C:9]2([CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: c1cc(CCC2CCC3(CC2)CCC(OCC2CO2)CC3)co1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: [N-]=[N+]=NC(CO)COC1CCC2(CCC(CCc3ccoc3)CC2)CC1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of 0.12 g of 9-(oxiranylmethoxy)-3-(2-(3-furyl)ethyl)-spiro[5.5]-undecane (prepared as intermediate in Ex. 21), 0.130 g of sodium azide and 0.030 g of tetrabutylammonium hydrogen sulfate in 1.5 ml of water and 1.5 ml of benzene was vigorously stirred at reflux temperature for 48 hrs. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, the organic phase washed with water several times, dried on sodium sulfate and evaporated to dryness. The residue was purified by chromatography (SiO2 ; n-hexane/diethylether 50/50), to give 0.110 g of 9-(2-azido-3-hydroxypropoxy)-3-(2-(3-furyl)ethyl)-spiro[5.5]-undecane as brown foam. [TLC: Rf=0.48 (SiO2 plates, diethylether/n-hexane 70/30). PG,28 1H-NMR (300 MHz, CDCl3, ppm from TMS): 7.35 (1H, m), 7.20 (1H, m), 6.23 (1H, m), 4.00-3.80 (1H, m), 3.55-3.20 (5H, m), 2.42 (2H, t), 1.90-0.80 (19H, m)].
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[O:36][C:37]1[C:38]([F:44])=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([O:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[C:38]=2[F:44])=[O:21])[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 42.3 %

Procedure:
A mixture of phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (prepared as described in Example 162A steps 1 and 2) (211 mg, 0.714 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared as described in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 36 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (104 mg, 42%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) 89.96 (brs, 1H), 8.87 (brs, 1H), 8.58 (s, 1H), 8.08 (m, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.27 (m, 1H), 7.15 (m, 1H), 6.81 (s, 1H), 4.66 (d, J=47 Hz, 4H), 4.01 (s, 6H), 1.34 (s, 3H); LC-MS (ESI) m/z 518 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[N+:19]([O-])=O)=[CH:7][CH:6]=1)=[O:4].C(OCC)(=O)C>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[NH2:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OC)cc2N)cc1
Reaction time: 18 h
Yield: 98.3 %

Procedure:
To 4′-Methoxy-2′-nitro-biphenyl-4-carboxylic acid methyl ester (4.00 g) suspended in ethanol (150 mL) and ethyl acetate (150 mL) is added 5% palladium on carbon (0.300 g). The reaction mixture is placed under an atmosphere of hydrogen (50 psi) and is shaken on a Parr apparatus. After 18 h, the reaction mixture is degassed with nitrogen and is filtered through a plug of silica gel, eluting with 700 mL ethyl acetate and 600 mL methylene chloride. The filtrate is evaporated to afford the title compound (3.52 g, >99%) as a white solid.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C[OH:10].OO.[OH-].[Na+]>CCOCC>[CH:7]12[O:8][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]2=[O:10]
Reactant: CO
Reactant: O=C1C=CCCCC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C1CCCCC2OC12
Reaction time: 1 h
Yield: 80 %

Procedure:
To a 0° C. solution of 50.0 g. (0.454 mmole) of cyclohept-2-en-1-one in 800 ml. of methanol was added 85 ml. of 30% hydrogen peroxide (0.75 mole) followed by the dropwise addition of 15 ml. of 6N sodium hydroxide (0.09 mole). The reaction was stirred for one hour and then added to 400 ml. ether-500 ml. petroleum ether. The ether extract was removed and the aqueous methanol phase extracted with four 500 ml. portions of petroleum ether and three 300 ml. portions of dichloromethane. The combined organic extracts were washed with three 800 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure to an oil (53 g.). The crude oil was purified via vacuum distillation to yield 45.9 g. (80%) of the title compound as an oil. Caution: several forceful detonations have occurred during distillation of the crude product. (In general, however, the crude product is pure enough for further synthetic manipulations and distillation can be avoided.)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C)(C)C.Cl[CH2:16][CH:17]([OH:21])[CH2:18][CH2:19][Cl:20].[OH-].[Na+]>O>[Cl:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: OC(CCl)CCCl
Reactant: Cc1cc(O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(OCC(O)CCCl)ccc1Cl
Temperature: 40 °C
Reaction time: 10 h
Yield: 22.3 %

Procedure:
To a mixture of 286 g (2 mole) of 3-methyl-4-chlorophenol, 700 ml of tertiary butanol, 700 ml of water and 3.0 mole of 1,4-dichloro-2-butanol, sodium hydroxide (2.9 moles, 230 g in 700 ml of water) was added with stirring at 40° C. to maintain a pH of 9.5-10.0 as the reaction progressed. The addition was 10 hr; the reaction was stirred at 40° C. for 48 hr. The resulting reaction mixture was extracted with chloroform sodium hydroxide at 25° C. The chloroform extract was washed with sodium sulfate. The dried chloroform solution was concentrated and the residue was distilled under reduced pressure to give 110.9 g of the product which distilled at 135°-143° C./0.007 mm and melted at 87°-89° C. after recrystallization with isopropanol and petroleum ether (30°-60° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C.CCCCCC>[C:10]1([CH2:9][CH2:8][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(CCNc2ccccc2)cc1
Yield: 78 %

Procedure:
According to GWM, 0.011 mol (=1.00 ml) of aniline and 0.011 mol (=1.25 ml) of styrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:3) as eluent, the product N-phenylethylaniline being obtained as a yellow liquid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.CCCCCC.[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[C:24]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[Cl:36][C:37]1[CH:54]=[CH:53][C:40]([O:41][C:42]2[CH:49]=[CH:48][C:45]([CH:46]=[O:47])=[C:44]([CH2:50][CH2:51][CH3:52])[CH:43]=2)=[CH:39][CH:38]=1.[Cl-].[NH4+]>C1COCC1>[Cl:31][C:25]1[C:26]([O:29][CH3:30])=[CH:27][C:28]([CH:46]([C:45]2[CH:48]=[CH:49][C:42]([O:41][C:40]3[CH:53]=[CH:54][C:37]([Cl:36])=[CH:38][CH:39]=3)=[CH:43][C:44]=2[CH2:50][CH2:51][CH3:52])[OH:47])=[C:23]([F:22])[C:24]=1[Si:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C=O
Reactant: COc1ccc(F)c([Si](C)(C)C)c1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(O)c1cc(OC)c(Cl)c([Si](C)(C)C)c1F
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (2.75 g, 10 mmol) in THF (50 mL) cooled at −75° C. was added a solution of n-butyllithium in hexane (1.6 M, 6.3 mL, 10 mmol). After 15 min, 4-fluoro-2-chloro-3-(trimethylsilyl)anisole (2.3 g, 10 mmol) was added and the solution was warmed gradually to −40° C. over a 2 h period. The solution was recooled to −75° C. and a solution of the aldehyde from Step 1 of Example 3 (1.4 g, 5.0 mmol) in THF (3 mL) was added quickly. The reaction mixture was stirred for 15 min., poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After removal of the solvent, the residue was purified by chromatography on silica gel to give the title product.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C@H:13]3[CH2:17][O:16]C(C)(C)[O:14]3)[C:7](=[O:20])[C:6]3([CH3:25])[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1.[CH3:26][NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[OH:14][C@H:13]([CH2:17][OH:16])[CH2:12][N:8]1[C:7](=[O:20])[C:6]2([CH3:25])[CH2:21][O:22][CH2:23][CH2:24][N:5]2[C:4]2[N:3]=[C:2]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28]([NH:27][CH3:26])=[O:29])=[CH:36][CH:35]=3)[N:11]=[CH:10][C:9]1=2
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC1(C)OC[C@H](CN2C(=O)C3(C)COCCN3c3nc(Cl)ncc32)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2(C)C(=O)N3C[C@H](O)CO)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 11.6 %

Procedure:
Combined 2-chloro-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (0.201 g, 0.545 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.166 g, 0.599 mmol), PdCl2(dppf) (0.080 g, 0.109 mmol), sodium carbonate (saturated in water) (1.5 ml, 0.545 mmol) and dioxane (3 ml). The suspension was heated by microwave irradiation at 100° C. for 45 minutes. The reaction mixture was filtered via syringe filter and purified the title compound was purified by preparative HPLC (eluting with 20-30% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column. Product containing fractions were concentrated in vacuo to remove about ½ of the total volume and allowed t and let sit at room temperate. After 3 days, the sample was concentrated and purified by HPLC (15-25% of AcCN [containing 0.035% TFA] in water [containing 0.05% TFA], Phenomenex Gemini 5 μm C18, 75×30 mm column) and the product containing fractions were combined, concentrated in vacuo and lyophilized, affording the title compound (27.9 mg, 11.5% yield) as a pale green solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.46 (m, 3H) 2.66 (s, 3H) 3.23-3.36 (m, 1H) 3.36-3.46 (m, 1H) 3.59 (t, J=12.00 Hz, 1H) 3.66-3.74 (m, 1H) 3.74-3.87 (m, 2H) 3.88-4.66 (m, 7H) 6.12 (br. s., 1H) 7.44-7.58 (m, 2H) 8.09-8.23 (m, 2H) 8.28-8.45 (m, 1H) 8.73-8.87 (m, 1 H). MS [M+H] found 443.4.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:27])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:37]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:28])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:27])=[O:8])=[CH:29][CH:30]=1)(=[S:37])[NH2:2]
Reactant: S
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1NC(=O)NC(=O)c1ccc(C#N)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1NC(=O)NC(=O)c1ccc(C(N)=S)cc1

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (611 mg), pyridine (70 ml), triethylamine (10 ml) and H2S gas were reacted to give t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-3-methylphenoxyacetate (660 mg) as a yellow solid: NMR Spectrum (DMSO-d6) 1.44 (9H, s), 2.27 (3H, s), 4.61 (2H, s), 6.76 (1H, dd), 6.83 (1H, d), 7.76 (1H, d), 7.95 (2H, d), 8.05 (2H, d), 9.67 (1H, br s), 10.06 (1H, br s), 10.55 (1H, s), 11.12 (1H, s); Mass Spectrum m/Z 466 (M+Na)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[Cl:26])=[CH:14][N:13]([CH2:27][C:28]2[C:33]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:31]=[CH:30][C:29]=2[F:38])[C:12]1=[O:39]
Reactant: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c3ccccc3)c2=O)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 95.6 %

Procedure:
Compound 3g (2.7 g, 4.2 mmol) was dissolved in dichloromethane (10 mL), TFA (14 mL, 175 mmol) was added, and the mixture was stirred at room temperature for 4.5 hours. After concentration, the residue was taken up in DCM and sat'd aq. NaHCO3 was added. The aq. layer was extracted with DCM. Combined organic extracts were dried over Na2SO4 and concentrated to give compound 3h (2.2 g, 96%). MS (CI) m/z 548.0, 550.0 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][C:8]=1[C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C1Cc2cc(C(=O)CCl)c(Br)cc2N1
Temperature: 50 °C
Reaction time: 17 h
Yield: 97.8 %

Procedure:
Chloroacetyl chloride (0.65 mL, 8.2 mmol) was added to a cooled (0° C.) suspension of 6-bromooxindol (0.825 g, 3.9 mmol) and aluminium chloride (1.82 g, 13.6 mmol) in 1,2-dichloroethane (8 mL). The resulting mixture was stirred at 0° C. for 20 min and at 50° C. for 17 h. The mixture was cooled to room temperature and was then poured on ice. The formed solid was filtered off, washed with water, and dried in vacuo to give 1.10 g (99% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 7.69 (s, 1H), 7.09 (s, 1H), 4.97 (s, 2H), 3.52 (s, 2H).
Reaction SMILES: N[C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[I:15]CI.N(OCCC(C)C)=O.C(OCC)(=O)C>C1COCC1.[Cu]I.O>[C:13]([C:3]1[C:2]([I:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=1)#[N:14]
Reactant: ICI
Reactant: COC(=O)c1cc(N)c(C#N)cc1F
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(I)c(C#N)cc1F
Temperature: 25 °C
Yield: 42.3 %

Procedure:
To a solution of methyl 5-amino-4-cyano-2-fluorobenzoate (437 mg, 2.2 mmol) in THF (13 mL) was added copper(I) iodide (419 mg, 2.2 mmol), diiodomethane (890 uL, 11 mmol), and isoamyl nitrite (890 uL, 6.6 mmol). The solution was heated to reflux for 4 h and was then allowed to cool to room temperature. After dilution with ethyl acetate, water was added and the mixture was filtered through celite. The biphasic filtrate was partitioned. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was then subject to column chromatography to provide impure methyl 4-cyano-2-fluoro-5-iodobenzoate (452 mg, ˜63% purity, ˜0.93 mmol). The remainder of the material consisted primarily of methyl 4-cyano-2-fluorobenzoate and was carried forward into the subsequent reaction without further purification. 1H NMR (400 MHz, CDCl3): 8.44 (d, 1H), 7.43 (d, 1H), 3.97 (s, 3H); MS (EI) for C9H5FINO2: 305 (M+).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:19]>>[CH2:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1)[CH3:19]
Reactant: Clc1nccnc1OCCOc1ccccc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nccnc2OCCOc2ccccc2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) and N-ethylpiperazine (250 mg, 2.19 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 127 mg (64%) of the title product. Anal. (C18H24N4O2) C, H, N.