Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[O:20][CH:21]=[CH:22][N:23]=2)[CH:16]=[CH:15][C:14]=1[C:24]1[C:25]([S:30]([N:33]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[C:41]=2[CH3:46])COCCOC)(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.Cl[Si](C)(C)C.[I-].[Na+]>C(Cl)Cl.O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[O:20][CH:21]=[CH:22][N:23]=2)[CH:16]=[CH:15][C:14]=1[C:24]1[C:25]([S:30]([NH:33][C:40]2[O:44][N:43]=[C:42]([CH3:45])[C:41]=2[CH3:46])(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CN1C(=O)c2ccccc2C1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN2C(=O)c3ccccc3C2=O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of the title compound of Step (A) (0.05 g, 0.087 mmol) in 10 mL of CH2Cl2, chlorotrimethylsilane (0.019 g, 0.17 mmol) and sodium iodide (0.026 g, 0.17 mmol) were added the mixture stirred at room temperature for 2 hr. Additional portions of chlorotrimethylsilane (0.019 g, 0.17 mmol) and sodium iodide (0.026 g, 0.17 mmol) were added and the mixture stirred for an additional 1 hr. The mixture was diluted with 15 mL of water and extracted with 3×15 mL of CH2Cl2. The combined organic extracts were then washed once with water and dried and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 75% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 25% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.026 g (54%) of the title compound of this Example as a white solid. m.p 120°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-(3-fluoro-4-methoxylphenyl)-2-naphthol (1 g, 3.73 mmol) and NCS (748 mg, 5.60 mmol) in THF (35 mL) according to method A to yield 780 mg (69%) of brown solid: mp 137–139° C.; 1H NMR (DMDO-d6): δ 3.89 (3H, s), 7.26–7.33 (2H, m), 7.61 (1H, d, J=8.63 Hz), 7.71 (1H, dd, J=13.08 Hz, J=2.16 Hz), 7.84 (1H, d, J=8.93 Hz), 7.92 (1H, dd, J=8.92 Hz, J=1.80 Hz), 8.06 (1H, d, J=8.86 Hz), 8.19 (1H, d, J=1.55 Hz), 10.52 (1H, s); MS (ESI) m/z 301/303(M−H)−.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1)=[O:23]>>[CH2:1]([C:5]1[N:6]([CH2:36][C:33]2[CH:34]=[CH:35][C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:22]([O:21][CH3:20])=[O:23])=[CH:31][CH:32]=2)[CH:7]=[C:8]([CH2:10][CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCNC(=O)OC(C)(C)C)c[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nc(CCNC(=O)OC(C)(C)C)cn1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 8 h

Procedure:
2-n-Butyl-4-{2-(t-butoxycarbonylamino)ethyl}-imidazole and 2'-(methoxycarbonyl)biphenyl-4-ylmethyl bromide are treated in the same manner as in Reference Example 1-(6) except that the reaction is carried out overnight to give 2-n-butyl-4-{2-(t-butoxycarbonylamino)-ethyl}-1-{2'-(methoxycarbonyl)biphenyl-4-yl}methylimidazole.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[CH2:15]([N:19]([C:22]1[C:27]([CH3:28])=[C:26](Cl)[N:25]=[C:24]([CH3:30])[N:23]=1)[CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18]>CS(C)=O>[CH2:15]([N:19]([CH2:20][CH3:21])[C:22]1[N:23]=[C:24]([CH3:30])[N:25]=[C:26]([CH:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:12])[C:10]#[N:11])[C:27]=1[CH3:28])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc(C(C#N)c2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.1 %

Procedure:
A solution of mesitylacetonitrile (66 mg, 0.41 mmol) in 1 ml of DMSO was treated with NaH (60% in oil, 20 mg 0.50 mmol) and stirred at room temperature for 20 minutes, butyl-(6-chloro-2,5-dimethylpyrimidin-4-yl)-ethylamine (100 mg, 0.414 mmol) was added and the resulting mixture was heated at 130° C. for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 160 mg of brown oil. The oil was purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 6.83 (s, 2H), 5.49 (s, 1H), 3.2-3.4 (m, 2H), 3.0-3.2 (m, 2H), 2.51 (s, 3H), 2.24 (s, 3H), 2.21 (s, 6H), 1.66 (s, 3H), 1.35-1.50 (m, 2H), 1.1-1.3 (m, 2H), 1.05 (t, 3H), 0.84 (t, 3H) ppm.
Reaction SMILES: F[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.[CH3:20][NH2:21]>O.C1COCC1>[CH3:9][O:8][C:7]1[C:2]([NH:21][CH3:20])=[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=[N:5][CH:6]=1
Reactant: CN
Reactant: COc1cnnc(-c2cccc(C(F)(F)F)c2)c1F
Solvent: O
Solvent: C1CCOC1
Product: CNc1c(OC)cnnc1-c1cccc(C(F)(F)F)c1
Yield: 95 %

Procedure:
4-Fluoro-5-methoxy-3-[3-(trifluoromethyl)phenyl]pyridazine (0.6 g, 0.0022 mole, Compound No. 46) and methylamine (1.54 g of a 40% solution in water, 0.0194 mole) were stirred at RT in THF (20 mL) under N2 for 24 h. The mixture was poured into water and extracted 3×50 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated in vacuo. The crude solid was recrystallized from cyclohexane/ethyl acetate to give 5-methoxy-N-methyl-3-[3-(trifluoromethyl)phenyl]-4-pyridazinamine (0.59 g, 95% yield, Compound No. 86) as an off white solid.
Reaction SMILES: [C:1]1([S:17]([O-:20])(=O)=[O:18])[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na+].O=P(Cl)(Cl)[Cl:24].S1(CCCC1)(=O)=O>C(#N)C>[Cl:24][S:17]([C:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:20])=[O:18]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Product: O=C1c2ccccc2C(=O)c2c1cccc2S(=O)(=O)Cl
Temperature: 110 °C

Procedure:
Sodium anthraquinone-1-sulfonate (50.0 g) was combined with POCl3 (31 mL) and a 1:2 (v/v) mixture of sulfolane (100 mL) and acetonitrile (200 mL). The mixture was stirred and heated to 110° C. under a nitrogen atmosphere for 44 hours. The mixture was allowed to cool to room temperature and was then further cooled in a refrigerator. The mixture was filtered and the filtrate was poured onto ice in a beaker and this mixture was stirred for 1 hour. The brown precipitate was filtered, washed with deionized water, dried in air and then further dried overnight in a vacuum oven at 45° C. and less than lmmHg pressure to give 12.08 g of the product as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(CC)C(C)C)(C)C.[CH3:32][O:33][CH2:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([NH:47][C:48](=O)[O:49]C2C=CC=CC=2)[CH:40]=[CH:41][C:42]=1[C:43]([F:46])([F:45])[F:44]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:48]([NH:47][C:39]2[CH:40]=[CH:41][C:42]([C:43]([F:45])([F:46])[F:44])=[C:37]([O:36][CH2:35][CH2:34][O:33][CH3:32])[CH:38]=2)=[O:49])[CH:20]=[CH:21][CH:22]=1
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ccc1C(F)(F)F
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)ccc1C(F)(F)F
Temperature: 50 °C
Yield: 65.4 %

Procedure:
As described in Example 113C, 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol) in THF (5 mL) was treated with N,N-diisopropylethylamine (78 μl, 0.45 mmol), 4-(dimethylamino)pyridine (4 mg, 0.03 mmol) and phenyl 3-(2-methoxyethoxy)-4-(trifluoromethyl)phenylcarbamate (161 mg, 0.45 mmol). The reaction mixture was heated to 50° C. for 3 h. After removal of the solvent, the crude material was purified by silica gel chromatography (ethyl acetate/dichloromethane 1:1) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)urea (109.5 mg, 65%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 9.02 (s, 1H), 8.57 (s, 1H), 7.59 (d, 2H), 7.50-7.38 (m, 2H), 7.43-7.38 (m, 2H), 7.27 (d, 1H), 7.04 (d, 1H), 6.96 (d, 1H), 4.17-4.14 (m, 2H), 4.04 (s, 6H), 3.69-3.67 (m, 2H), 3.34 (s, 3H); LC-MS (ESI) m/z 559 (M+H)+.
Reaction SMILES: [OH-].[K+].[C:3]([NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28](=[N:34][O:35][CH:36]=[CH2:37])[C:29]([O:31]CC)=[O:30])[N:27]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[K]>C(O)C.O1CCOCC1>[C:3]([NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28](=[N:34][O:35][CH:36]=[CH2:37])[C:29]([OH:31])=[O:30])[N:27]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: C=CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C

Procedure:
20 ml of a solution of 0.5 M of potassium hydroxide in absolute ethanol and 12 ml of absolute ethanol were added at room temperature to a mixture of 3.227 g of the product of Step D in 3.2 ml of dioxane and the mixture was stirred at 50° C. under argon for 1 hour during which a potassium salt crystallized. The mixture cooled to 20° C. and was vacuum filtered and the recovered product was rinsed with ethanol and was taken up in a mixture of 50 ml of ethyl acetate and 50 ml of distilled water. The mixture was acidified with 6 ml of 2 N hydrochloric acid and was stirred until 2 homogeous phases were obtained. The organic phase was decanted and was washed 3 times with 20 ml of distilled water. The wash waters were extracted with ethyl acetate and the combined organic phases were dried and vacuum filtered. The filter was rinsed with ethyl acetate and the filtrate was concentrated to a volume of 15 ml and was iced at 0° to 5° C. The mixture was vacuum filtered and the recovered product was rinsed with ethyl acetate and dried to obtain 2.53 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-vinyloxyiminoacetic acid which was used as is for the next step. A sample after crystallization melted at 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,5-Dichloro-4-(3'-isopropyl-4'-methoxyphenoxy)-nitrobenzene (10.63 g) in 100 ml. dichloromethane is cooled in a dry ice/acetone bath and 60 ml of 1M boron tribromide in dichloromethane is added at less than -40°. After addition is completed, the mixture is stirred 18 hours at room temperature, poured into ice, and extracted twice with ethyl acetate. The combined organic layers are dried, filtered, and stripped to yield 3,5-dichloro-4-(3'-isopropyl-4'-hydroxyphenoxy)-nitrobenzene. NMR(CDCl3): δ 1.2 (6H,d), 3.3 (1H,m), 6.5 (1H, d of d), 6.7 (1H,d), 6.8 (1H,d), 8.3 (2H,s).
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[BrH:15].BrBr.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)(=O)C.C(O)C>[BrH:15].[BrH:15].[NH2:21][C:19]1[S:20][C:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][CH2:2][CH3:3])[CH2:9][C:10]=2[N:18]=1
Reactant: NC(N)=S
Reactant: CCCN1CCC[C@@H]2CC(=O)CC[C@H]21
Agent: Br
Agent: BrBr
Solvent: CCO
Solvent: CC(=O)O
Product: CCCN1CCC[C@H]2Cc3nc(N)sc3C[C@@H]21
Temperature: 0 °C

Procedure:
Five grams of trans-(±)-1-n-propyl-6-oxodecahydroquinoline were dissolved in 30 ml. of glacial acetic acid. Five and eight tenths milliliters of 37% by weight hydrogen bromide in glacial acetic acid were added followed by the dropwise additions of 1.5 ml. of bromine dissolved in glacial acetic acid. The reaction mixture was illuminated with ultraviolet radiation using a commercially available sunlamp. The illuminated reaction mixture was stirred for one-half hour after all the reactants had been added. Volatile constituents were removed from the reaction mixture in vacuo yielding, as a residue, trans-(±)-1-n-propyl-6-oxo-7-bromodecahydroquinoline hydrobromide. One hundredth mole of this salt was dissolved in 50 ml. of ethanol. Eighty-four hundredths grams of thiourea were added thereto. The resulting mixture was refluxed for about 18 hours under a nitrogen blanket. A colorless solid began to form after about 20 minutes. The reaction mixture was cooled to about 0° C. and the solid, which had continued to form, was separated by filtration. The filter cake was dried in vacuo. One and fifteen hundredths grams of trans-(±)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline dihydrobromide salt were obtained. The salt melted above 255° C., tlc (9:1 chloroform:methanol plus a trace of ammonium hydroxide) Rf =0.13.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])=[O:6].[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1>CCCCCC.CN(C=O)C>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])[C:5](=[O:6])[C:4]([F:18])([F:19])[F:3])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1ccc(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CN(C(=O)C(F)(F)F)c2ccc(C)cc2[N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A portion of 60% NaH in mineral oil (2.9 g, 71.8 mmol, 1.1 eq) was pre-washed with hexane and suspended in dry DMF under nitrogen. The slurry was cooled in an ice bath and a solution of 2,2,2-trifluoro-N-(4-methyl-2-nitrophenyl)-acetamide (16.2 g, 65.3 mmol, 1.0 eq) in dry DMF was added dropwise over 15 min. The cooling bath was removed and the mixture was stirred for 30 min. The reaction mixture was cooled again and a solution of 4-bromomethylbenzoic acid methyl ester (20 g, 65.3 mmol, 1.0 eq) in dry DMF was added dropwise over 10 min. The reaction mixture was stirred at room temperature for 18 h and evaporated under reduced pressure to give a residue. The residue was partitioned between ethyl acetate and water. The organic layer was washed sequentially with water and brine, dried (Na2SO4) and concentrated to give a yellow solid. The yellow solid was purified by column chromatography. (Silica gel 230-400 mesh: eluent CHCl3 MeOH:0→5%) to give 4-{[(4-methyl-2-nitrophenyl)-(2,2,2-trifluoroacetyl)amino]methyl}benzoic acid methyl ester, yield: 59%. 1H NMR (400 MHz, CDCl3): 7.97 (m, 3H); 7.27 (m, 3H); 6.76 (d, J=8 Hz, 1H); 5.66 & 4.26(2H); 3.92 (s, 3H); 2.46(s, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[CH:11]([S:14](Cl)(=[O:16])=[O:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][S:14]([CH:11]([CH3:13])[CH3:12])(=[O:16])=[O:15]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1cccc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1cccc(Br)c1

Procedure:
In analogy to example 1, step 1, 3-bromobenzylamine hydrochloride was reacted with isopropylsulfonyl chloride and triethylamine in dichloromethane to give propane-2-sulfonic acid 3-bromo-benzylamide as a colorless solid. MS: 290.0 ([M−H]−)
Reaction SMILES: [I:1]I.C([Sn](CCCC)(CCCC)[C:8]1[CH:9]=[C:10](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][F:23])CCC.C(Cl)Cl>C1COCC1>[I:1][C:8]1[CH:9]=[C:10](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:11]=[N:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][F:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(/C=C/c2ccc(N(C)C)cc2)cnc1OCCOCCOCCF
Reactant: II
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)c1ccc(/C=C/c2cnc(OCCOCCOCCF)c(I)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of iodine (I2, 0.063 g, 0.24 mmol) in THF (2 mL) was added dropwise to an ice bath cooled solution of 12a (0.114 g, 0.172 mmol) in THF (3 mL). After the addition, the reaction was stirred at 0° C. for 1 h. Following standard workup with CH2Cl2, the crude product was purified by FC (EtOAc/Hexanes, 25/75) to give a light yellow solid 13a (0.037 g, 48%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:19])/[CH:16]=[CH:17]/[CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[CH3:21][S+](C)(C)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH:16]2[CH2:18][CH:17]2[CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C/C(=O)c1cccc(OCc2ccccc2)c1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CC1C(=O)c1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of 93.C (5.33 g, 21.1 mmol) in ACN (200 mL) were added trimethylsulfoxonium iodide (available from Aldrich) (5.58 g, 25.3 mmol) and DBU (4.11 mL, 27.5 mmol). The mixture was stirred overnight at 60° C. under N2, cooled to room temperature, and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford 93.D (2.04 g, 36% yield) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][C:21]=1[CH3:27]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:17]([OH:28])=[O:16])=[C:21]([CH3:27])[CH:22]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ccc(S)cc1C
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Product: Cc1cc(SCc2cc(-c3ccc(Cl)cc3)on2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and 2C. mp 79-80° C.; MS m/z 404 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[N:10]([CH2:20][C:21]([N:23]([CH3:34])[C:24]3[CH:33]=[CH:32][C:27]4[N:28]=[C:29]([CH3:31])[O:30][C:26]=4[CH:25]=3)=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:41](I)[CH3:42]>CN(C=O)C.O>[CH2:41]([O:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]([CH2:20][C:21]([N:23]([CH3:34])[C:24]3[CH:33]=[CH:32][C:27]4[N:28]=[C:29]([CH3:31])[O:30][C:26]=4[CH:25]=3)=[O:22])[C:11]2=[O:19])=[CH:16][CH:15]=1)[CH3:42]
Reactant: CCI
Reactant: Cc1nc2ccc(N(C)C(=O)Cn3nc(-c4cccc(F)c4)c4ccc(O)cc4c3=O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(-c3cccc(F)c3)nn(CC(=O)N(C)c3ccc4nc(C)oc4c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
2-(4-(3-fluorophenyl)-7-hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (6.5 g, 14.19 mmol) was dissolved in DMF (60 mL), treated with K2CO3 (3.04 g, 21.2 mmol) and stirred at rt for 30 min. After cooling to 0° C., EtI (1.26 mL, 15.59 mmol) was added dropwise and the reaction was warmed to rt for 1 h. It was diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The organics were washed with brine (300 mL), dried over Na2SO4, and concentrated to give crude material which was purified by chromatography (40% EtOAc/hexane) to yield 2-(7-ethoxy-4-(3-fluorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (3.5 g) (487.52 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 1.39-1.42 (t, 3H), 2.62 (s, 3H), 3.24 (s, 3H), 4.22-4.24 (d, J=7.2, 2H), 4.72 (s, 2H), 7.37-7.49 (m, 5H), 7.58-7.65 (m, 3H), 7.71-7.73 (d, J=8.4, 1H), 7.90 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5]([O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:22]=[N:23][C:24]3N[CH2:26][CH2:27][CH2:28][C:29]=3[CH:30]=2)[CH:20]=1)[C:6]1C=CC=CC=1>>[CH2:5]([O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:22]=[N:23][C:24]3[N:1]([C:2](=[O:3])[NH2:4])[CH2:26][CH2:27][CH2:28][C:29]=3[CH:30]=2)[CH:20]=1)[CH3:6]
Reactant: NC(N)=O
Reactant: O=C(Cc1cncc(-c2cnc3c(c2)CCCN3)c1)OCc1ccccc1
Product: CCOC(=O)Cc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1

Procedure:
[5-(8-Carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-acetic acid ethyl ester is synthesized according to the procedure of Urea Formation Method I using [5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-acetic acid benzyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].[Cl:11][C:12]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:13]=1[C:14](C#N)=[O:15].C(N(CC)CC)C.Cl>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:12]=2[Cl:11])[C:3]1=[O:9]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: N#CC(=O)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(=O)C(C(=O)c2ccc(Cl)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione [14.0 grams (g), 0.1 mole], 20.0 g (0.1 mole) 2,4-dichlorobenzoyl cyanide and 13.6 (0.11 mole) anhydrous, powdered zinc chloride were combined in 100 milliliters (ml) methylene chloride. Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was stirred at room temperature for 5 hours and then poured into 2N hydrochloric acid. The aqueous phase was discarded and the organic phase was washed with 150 ml 5% Na2CO3 four times. The aqueous washings were combined and acidified with HCl, extracted with methylene chloride, dried and concentrated to yield 25.3 g of crude product. The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH. This yielded an oil (40% yield). The structure was confirmed by instrumental analysis.