Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8](Br)[CH:7]=1)[CH3:2].[CH2:15]([O:22][C:23](=[O:47])[N:24]([CH2:45][CH3:46])[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:7]=[C:8]([C:27]2[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:26]=2[CH2:25][N:24]([C:23]([O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:47])[CH2:45][CH3:46])[C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Product: CCOC(=O)Cc1ccc(O)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester and ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][Br:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1-c1cccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1cccc2ccccc12
Yield: 91.2 %

Procedure:
114 g (0.52 mol) of 18 and 103 g (0.58 mol) of N-bromo-succinimide were dissolved in 2000 cm3 of tetrachloro-methane at room temperature, 3 g of azobisisobutyronitrile were added, and the mixture was refluxed for 4 hours. The succinimide which precipitated was filtered off, the solvent was removed in vacuo, and the residue was purified by filtration through 1000 g of silica gel (hexane/methylene chloride 9:1), giving 141 g (82%) of 19 as a colorless lachrymatory oil.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:15]([OH:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH2:19](O)[CH3:20]>>[F:6][C:7]1[C:15]([OH:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:8]=1[C:9]([O:11][CH2:19][CH3:20])=[O:10]
Reactant: CCO
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)c(F)c(O)c1F

Procedure:
5 ml of concentrated sulfuric acid were added to a solution of 20.0 g (0.104 moles) of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X=X'=F] (prepared as described in Preparation 13) in 500 ml of ethanol, and the mixture was heated under reflux for 4 hours. The ethanol was then removed by distillation under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure, to give 16.9 g of ethyl 2,4,5-trifluoro-3-hydroxybenzoate as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.Cl.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 mmol of 2-(4-((6-fluoro-2-quinolinyl)oxy)phenoxy)propionyl chloride in 5 milliliters (ml) of methylene chloride was slowly added to an ice-cooled solution comprising 1.17 grams (g) (5.5 mmol) of 4-(trifluoromethoxy)aniline hydrochloride and 1.21 g (12 mmol) of triethylamine in 40 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 30 minutes then at room temperature for 3 hours. The mixture was poured into a dilute aqueous HCl solution. The organic layer was separated, washed with water, then washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was taken up in methylene chloride and filtered through a short column of silica gel, eluting with additional methylene chloride. After removal of the solvent, the residue was recrystallized from methylcyclohexane to give 1.0 g (41 percent of theoretical) of the above-named product as colorless crystals. The product melted at 134°-136° C. and its structure was confirmed by its infrared (IR) and its nuclear magnetic resonance (NMR) spectrum. (Compound 3)
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(N(CC)C(C)C)(C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>O1CCCC1>[CH:39]1([S:42]([N:23]2[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]3[CH:20]=[C:16]([C:15]4[C:10]5[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=5[N:12]=[CH:13][N:14]=4)[CH:17]=[N:18]3)[CH2:24]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C5CC5)C4)c3)ncnc21
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To a oven dried 2 L round bottom flask equipped with the overhead stirring, a nitrogen inlet, a septa and a thermocouple was charged anhydrous tetrahydrofuran (THF, 800 mL), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (16, 38.6 g, 94.2 mmol) and N,N-diisopropylethylamine (DIEA, 22.0 mL, 126 mmol, 1.34 equiv) at room temperature. The resulting solution was then cooled to 0-5° C. before being charged with cyclopropanesulfonyl chloride (14.3 mL, 134 mmol, 1.42 equiv) portion wise over eight minutes via syringe at 0-5° C. After 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm gradually to room temperature. When HPLC showed that the reaction was complete after 22 h, the reaction mixture was concentrated under reduced pressure to remove about 400 mL of solvent. The residue was treated with ethyl acetate (EtOAc, 500 mL) and the resulting solution was washed with 20% aqueous sodium chloride solution (NaCl, 300 mL). The aqueous layer was back extracted with ethyl acetate (EtOAc, 150 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to yield the crude product (25) as an amber oil. The crude product was then purified by flash column chromatography (SiO2, 50% to 70% ethyl acetate/hexane gradient elution) to afford {1-(cyclopropylsulfonyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25, 39.4 g, 48.4 g theoretical, 81.4% yield) as a light yellow oil, which solidified upon standing at room temperature in vacuum. For 25: 1H NMR (DMSO-d6, 300 MHz) δ 8.98 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.81 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 4.66 (d, 2H, J=9.5 Hz), 4.28 (d, 2H, J=9.3 Hz), 3.69 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 2.84 (m, 1H), 1.01 (m, 4H), 0.82 (t, 2H, J=8.4 Hz), −0.12 (s, 9H) ppm; C23H31N7O3SSi (MW, 513.69), LCMS (EI) m/e 514 (M++H) and 536 (M++Na).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:6]=1[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:17])(=[O:10])=[O:9].[H-].[Na+].[CH3:27]I>CN(C)C=O>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:6]=1[CH:7]([S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:17])(=[O:9])=[O:10])[CH3:27]
Reactant: CI
Reactant: O=S(=O)(Cc1cc(Cl)ccc1OCC(F)(F)F)c1cccc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1cc(Cl)ccc1OCC(F)(F)F)S(=O)(=O)c1cccc[n+]1[O-]

Procedure:
In the same manner as Example 1, 2.00 g of 2-[2-(2,2,2-trifluoroethoxy)-5-chlorobenzylsulfonyl]pyridine-N-oxide, 230 mg of 55% sodium hydride and 740 mg of methyl iodide were mixed with 50 ml of dimethylformamide and the mixture was reacted, followed by the same after-treatment as in Example 1, whereby 1.43 g of Compound No. 27 of the present invention was obtained. The product was white crystals having a melting point of from 119° to 121° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[N:21]1([S:18]([C:15]2[CH:16]=[CH:17][C:8]([O:7][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])(=[O:20])=[O:19])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCOCC2)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
K2CO3 (138 mg, 1.00 mmol) was added to a stirred solution of methyl 2-hydroxy-5-(4-morpholinylsulfonyl)benzoate (may be prepared as described in Description 64; 300 mg, 1.00 mmol) in acetone (20 ml), followed by the addition of (bromomethyl)benzene (170 mg, 1.00 mmol). The mixture was heated to reflux for 16 h, and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated to yield the title compound as a colourless oil. 380 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]#[N:22])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.[OH-].[K+].[CH3:25]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]([CH3:25])[C:21]#[N:22])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CC#N)c3o2)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)C#N)c3o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of acetonitrile 18 (0.200 g, 0.682 mmole) in 10 mL dimethylformamide was added pulverized potassium hydroxide (0.046 g, 0.818 mmole) and methyl iodide (0.161 g, 0.818 mmole). After stirring at rt for 2 hours, the orange reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 95:5) to afford 0.087 g (42%) of propionitrile 19 as a white solid. Used as is for conversion to 21, infra.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:48](=[O:49])[N:13]3[C:14]([C:32]([O:34][CH:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])=[C:15]([CH2:18][O:19][C:20](=[O:31])[CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>CO>[NH2:10][CH:11]1[C:48](=[O:49])[N:13]2[C:14]([C:32]([O:34][CH:35]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])=[C:15]([CH2:18][O:19][C:20](=[O:31])[CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH2:16][S:17][C@H:12]12
Reactant: COc1ccc(OCC(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(OCC(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)cc1
Yield: 92.8 %

Procedure:
Benzhydryl 7-(2-phenylacetamido)-3-[2-(4-methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate (6.0 g.), phosphorus pentachloride (5.65 g.), pyridine (2.2 g.) and methanol (7.3 ml.) were reacted according to a similar manner to that of Preparation 30 (4) to give benzhydryl 7-amino-3-[2-(4-methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate (4.6 g.).
Reaction SMILES: [C:1]([C:3]([N:8]1[C:12](=[O:13])[CH:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=O)[C:9]1=[O:23])([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH:4]([C:3]([CH3:7])([N:8]1[C:12](=[O:13])[C:11]2[C:10](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:21]=2)[C:9]1=[O:23])[C:1]#[N:2])([CH3:6])[CH3:5]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2ccccc2C=O)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC(C)C(C)(C#N)N1C(=O)c2cc3ccccc3nc2C1=O
Yield: 81 %

Procedure:
A solution of N-(1-cyano-1,2-dimethylpropyl)-2-(o-formylanilino) maleimide (7.19 g, 0.023 mol) in xylene (300 ml) containing p-toluenesulfonic acid (0.3 g, 0.0016 mol) is heated at reflux for 4 hours using a Dean-Stark trap to collect the eliminated water. The reaction is cooled, evaporated under reduced pressure and dissolved in hot ethyl acetate which is passed through a 3 inch silica gel column. The ethyl acetate fractions eluted are combined to give a solid, mp 195°-195.5° C., 5.51 g, (81%) of 1,3-dihydro-α-isopropyl-α-methyl-1,3-dioxo-2-H-pyrrolo [3,4-b] quinoline-2-acetonitrile.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[NH:7][N:8]=[N:9][C:5]=2[CH:4]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1ccc2[nH]nnc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2[nH]nnc2c1
Reaction time: 16 h

Procedure:
To a solution of 5-chloromethyl-1,2,3-benzotriazole (2.2 g, 12.2 mmol, Katritzky et al. Synth. Commun. 1993, 23, 2019) dissolved in DMF (25 mL) was added sodium azide (2.4 g, 36.5 mmol). The resulting mixture was stirred under Ar for 16 h and the precipitated product was filtered and air dried to afford the title compound:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH:8]=[C:7]([F:19])[C:3]=1[C:4](O)=O.ClCCCl.S(Cl)(Cl)=O.[N:28]1C=CC=CC=1>>[F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH:8]=[C:7]([F:19])[C:3]=1[C:4]#[N:28]
Reactant: C=C[C@H]1CC[C@H](c2cc(F)c(C(=O)O)c(F)c2)CC1
Reactant: c1ccncc1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: C=C[C@H]1CC[C@H](c2cc(F)c(C#N)c(F)c2)CC1
Temperature: 25 °C

Procedure:
To 20 g of 2,6-difluoro-4-(trans-4-vinylcyclohexyl) benzoic acid were then added 120 ml of 1,2-dichloroethane, 16 g of thionyl chloride and few drops of pyridine. The reaction mixture was then heated under reflux for 6 hours. The reaction mixture was then allowed to cool to room temperature. The solvents and excess thionyl chloride were distilled off under reduced pressure. To the residue was then added 150 ml of dichloromethane. The residue solution was then cooled to a temperature of 10° C. or lower. Ammonia was then introduced into the solution with stirring at a rate such that the liquid temperature was kept at 20° C. or lower. When heat generation was terminated, the solvents were then distilled off under reduced pressure. To the residue was then added 150 ml of N,N-dimethylformamide. The residue solution was then cooled to a temperature of 10° C. or lower. To the solution was then added dropwise 26.5 g of phosphorus oxychloride at a rate such that the liquid temperature was kept at 10° C. or lower. The temperature of the reaction solution was then returned to room temperature. The solution was then poured onto crushed ice. The resulting crystal was then filtered. The crystal thus obtained was washed with water, and then dried under reduced pressure. The crystal was then purified through silica gel column chromatography (solvent: toluene) to obtain 2,6-difluoro-4-(trans-4-vinylcyclohexyl)benzonitrile. The product was then recrystallized from ethanol to obtain 12.1 g of a purified product. The compound thus obtained had a melting point of 39° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc([N+](=O)[O-])ccc1OC
Yield: 94 %

Procedure:
A mixture of 2-methoxy-5-nitrophenol (5.3 g, 31.3 mmol), iodoethane (14.6 g, 93.9 mmol), and potassium carbonate (43.2 g, 310 mmol) in acetone (100 mL) was heated to reflux for 4 hours. The reaction mixture was cooled, and the solvent was evaporated in vacuo. The residue was dissolved in water (250 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL) and dried (MgSO4), and the solvent was evaporated under vacuum, providing 5.8 g of the product, in 99% yield: 1H NMR (CDCl3) δ 1.51 (t, J=7.0 Hz, 3H), 3.97 (s, 3H), 4.18 (q, J=7.0 Hz, 2H), 6.22 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.31 (d, J=2.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:17])[CH2:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[CH:12]=[CH:13][CH:14]=1
Reactant: C=C(C)C(=O)OC
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CC(C(=O)c1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 16 °C
Reaction time: 60 h

Procedure:
Methyl methacrylate (82 mL, 773 mmol) was added to a solution of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (195.2 g, 736 mmol; Example 1, Step A) in anhydrous THF (1.5 L) under an atmosphere of nitrogen. A suspension of potassium t-butoxide (8.26 g, 73.6 mmol) in anhydrous THF (340 mL) (sonicated to break up the solids) was then prepared and cannulated into the solution containing the 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone. The solution was cooled to ˜16° C. and the orange colored solution was left to stir at ambient temperature for 2.5 d. (After 2 d TLC shows the absence of the starting material). The mixture was concentrated under vacuum. The residual reddish brown oil was diluted with ethyl acetate (900 mL) and washed with water (4×190 mL) and then sat. aq. NaCl solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as a racemic mixture of diastereomers.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.C(OCC)(=O)C>O1CCOCC1.[OH-].[Na+]>[CH2:1]([S:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCS(=O)(=O)NCCCCCC(=O)O
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A solution of ethanesulfonyl chloride (3.9 ml, 41.1 mmol) in dioxane (10 ml) was added to a solution of 6-aminohexanoic acid (2 g, 15.2 mmol) in 1N NaOH (56 ml) and dioxane (10 ml), while stirring at 0° C.-5° C. The pH of the reaction mixture was adjusted to 8-9 by addition of 25% sodium hydroxide solution. The mixture was allowed to warm to room temperature and stirred for 30 minutes. Further 25% NaOH solution was added to adjust the pH to about 11. After 3.5 h 1N hydrochloric acid (15 ml) and ethyl acetate (60 ml) were added. The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with a mixture of diethyl ether (5 ml) and hexane (15 ml). The solid was collected by filtration and dried affording 1.3 g of the title compound (40% yield).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH:15]=O)[C:10]([O:12]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24](=[NH:26])[NH2:25])[CH:21]=[CH:20][N:19]=1>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([OH:12])=[N:25][C:24]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:17])[CH:23]=2)=[N:26][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C=O)OCc1ccccc1
Reactant: N=C(N)c1ccnc(Cl)c1
Solvent: CCO
Product: Oc1nc(-c2ccnc(Cl)c2)ncc1OCc1ccccc1
Yield: 66 %

Procedure:
A mixture of crude ethyl 2-(benzyloxy)-3-oxopropanoate (all from previous step), 2-chloropyridine-4-carboximidamide (9.57 g, 50 mmol) and 100 mL of anhydrous ethanol was refluxed for 4 h under nitrogen. The mixture was then cooled and the volatile solvents were removed by rotary-evaporator. The residue was re-dissolved in water and filtered. The filtrate was acidified by HCl (4N aq) in an ice bath and the white precipitate was filtered, washed with water, and dried to give 5-(benzyloxy)-2-(2-chloropyridin-4-yl)pyrimidin-4-ol (10.4 g, 66%). 1H NMR δ (400 MHz, d6-DMSO): 13.12 (s, 1H), 8.58 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J=5.2 Hz, 1H), 7.94 (s, 1H), 7.51-7.34 (m, 5H), 5.20 (s, 2H); MS (ESI) m/z (M++H)+ 314.
Reaction SMILES: FC(F)(F)C(O)=O.Cl.Cl.C([NH:17][C:18]1[CH:46]=[CH:45][C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[CH:20][CH:19]=1)(OC(C)(C)C)=O>ClCCl>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[CH:45][CH:46]=1
Reactant: COc1cc2c(Nc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(N)cc3)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
Trifluoroacetic acid (1.00 ml, 13.1 mmol) was added to a suspension of 4-(4-(N-Boc-amino)anilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline dihydrochloride (100 mg, 0.172 mmol) in dichloromethane (2.0 ml) and the reaction stirred for 1 hour at ambient temperature. The solvents were removed in vacuo, the residue was suspended in water (2.0 ml) and saturated aqueous sodium bicarbonate solution (4.0 ml) was added. The aqueous phase was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with brine (25 ml) and evaporated in vacuo. Drying of the solid in vacuo yielded 4-(4-aminoanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (53 mg, 75% yield) as a white 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].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=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:32]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:30][CH:29]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)c2cc1OC
Yield: 83.3 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and 4-(trifluoromethyl)phenyl isocyanate (42 uL, 0.3 mmol) using the procedure in Example 182 to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea (119 mg, 0.25 mmol, 82%). 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.03 (s, 1H), 8.57 (s, 1H), 7.68-7.62 (m, 4H), 7.61-7.55 (m, 2H), 7.44-7.37 (m, 2H), 7.28 (d, 1H), 6.95 (d, 1H), 3.99 (s, 6H); LC-MS (ESI) m/z 485 (M+H)+.