Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])=[O:5])=[CH2:3].[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17].[OH:18][S:19]([OH:22])(=[O:21])=[O:20]>O>[S:19]([O-:22])([O-:21])(=[O:20])=[O:18].[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N+:10]([CH3:12])([CH3:11])[CH2:13][CH:14]([OH:15])[CH2:16][OH:17])(=[O:5])[C:2]([CH3:3])=[CH2:1].[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N+:10]([CH2:13][CH:14]([OH:15])[CH2:16][OH:17])([CH3:12])[CH3:11])(=[O:5])[C:2]([CH3:1])=[CH2:3]
Reactant: OCC1CO1
Reactant: C=C(C)C(=O)NCCCN(C)C
Reactant: O=S(=O)(O)O
Solvent: O
Product: C=C(C)C(=O)NCCC[N+](C)(C)CC(O)CO
Product: O=S(=O)([O-])[O-]
Temperature: 40 °C

Procedure:
To a 1-liter glass beaker containing a magnetic stirrer is added 170.26 g (1 mole) of DMAPMA and 170.26 of deionized water while stirring. Initial pH and temperature are 11.2 and 23.1° C., respectively. Two addition funnels are suspended above the beaker; one contains 75.6 g (1 mole) of glycidol and the other contains 98.2 g of 50% H2SO4. The pH and temperature are monitored continuously during the drop-wise addition of glycidol. Temperature is maintained between 19.5° and 27.5° C. by placing the beaker in an ice bath. The pH is maintained between 10.6 and 11.2 by adding 50% H2SO4 as needed. All of the glycidol is added within 1 hour and 4 minutes. An additional 75.6 g of water is added to the reaction mixture; a portion is flowed through the addition funnel which contained the glycidol and the remainder is added to the addition funnel containing the remaining H2SO4. The ice bath surrounding the reaction vessel is removed and replaced with a warm water bath in order to raise the reaction temperature to 40° C. The remaining acid and water mixture is added to the reaction vessel over a period of 2 hours and 41 minutes. During this stepwise addition the temperature is held at about 40° C. and the pH is maintained between 11.3 and 10.1 until the last portion of acid is added. The final pH is 4.55. The reaction mixture is then placed in a sealed brown bottle and submerged in a 42° C. bath. The reaction mixture is removed at 16 hours. The final pH of the product is 5.2 at room temperature.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:24]=2[C:25]([NH:27][CH2:28][C:29]#[CH:30])=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]>ClCCl.[Au](Cl)(Cl)Cl>[C:1]([C:4]1[CH:5]([C:23]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:24]=2[C:25]2[O:26][C:29]([CH3:30])=[CH:28][N:27]=2)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: C#CCNC(=O)c1cc(C#N)ccc1C1C(C(C)=O)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Agent: Cl[Au](Cl)Cl
Solvent: ClCCl
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1-c1ncc(C)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-N-prop-2-ynyl-benzamide (intermediate 12) (48 mg, 0.097 mmol) is suspended in dichloromethane (2 mL) and degassed with a stream of argon. gold(III)-chloride (1.2 mg, 0.004 mmol) is added and the reaction is shaken at room temperature for 2 h. The solvent is evaporated and the residue is purified by reversed phase HPLC. Yield: 17 mg; ESI mass spectrum [M+H]+=495; Retention time HPLC: 1.09 min (HPLC method Z011_S03).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]2[CH2:11][O:12][CH3:13]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(N)c2n1COC
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(Cl)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a mixture of ethyl 7-amino-4-chloro-1-(methoxymethyl)-1H-indole-2-carboxylate (0.91 g) and pyridine (10 mL) was added thiophene-2-sulfonyl chloride (0.50 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (1.14 g, yield 83%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Temperature: 0 °C
Yield: 14.4 %

Procedure:
Cytidine (100 g, 0.41 mol) was dissolved in warm dimethylformamide (65° C., 1125 mL). The solution was cooled with stirring to 0° C. A slow, steady stream of nitrogen gas was delivered throughout the reaction. Sodium hydride (60% in oil, washed thrice with hexanes, 18 g, 0.45 mol) was added and the mixture was stirred at 0° C. for 45 min. A solution of methyl iodide (92.25 g, 40.5 mL, 0.65 mol) in dimethylformamide (400 mL) was added in portions over 4 h at 0° C. The mixture was stirred for 7 h at 25° C. and then filtered. The filtrate was concentrated to dryness under reduced pressure followed by coevaporation with methanol (2×200 mL). The residue was dissolved in methanol (350 mL). The solution was adsorbed on silica gel (175 g) and evaporated to dryness. The mixture was slurried in dichloromethane (500 mL) and applied on top of a silica gel column (1 kg). The column was eluted with a gradient of dichloromethane-methanol (10:1®2:1). The less polar 2′,3′-dimethyl side product was removed and the coeluting 2′ and 3′-O-methyl product containing fractions were combined and evaporated under reduced pressure to a syrup. The syrup was dissolved in a minimum of hot ethanol (ca. 150 mL) and allowed to cool to 25° C. The resulting precipitate (2′ less soluble) was collected, washed with ethanol (2×25 ml) and dried to give 15.2 g of pure 2′-O-methylcytidine; mp 252-254° C. (lit. mp 252-254° C.); TLC homogenous (Rf 0.50, dichloromethane-methanol 3:1, (Rf of 3′ isomer is 0.50 and the dimethyl product is 0.80). The filtrate was evaporated to give 18 g of a mixture of isomers and sodium iodide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[NH:23][C:22](=O)[C:21]=2[CH:31]=1>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[N:23]=[C:22]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:21]=2[CH:31]=1
Reactant: O=C1Nc2cscc2Nc2ccc(F)cc21
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3cscc3Nc3ccc(F)cc32)CC1

Procedure:
To a stirred mixture of 14.0 g. of N-methylpiperazine, 3.4 ml. of titanium tetrachloride and 6 ml. of anisole in 60 ml. of toluene is added a mixture of 6.7 g. of N-methylpiperazine and 5.6 g. of 7-fluoro-4H-thieno[3,4-b][1,4]benzodiazepin-9(10H)-one in 6 ml. of toluene. The mixture is treated as described in Example 1, giving the desired product as a tan solid, m.p. 224°-227° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].[CH:29]12[CH2:36][CH2:35][CH:32]([CH2:33][CH2:34]1)[CH2:31][NH:30]2>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:20]([N:30]3[CH2:31][CH:32]4[CH2:35][CH2:36][CH:29]3[CH2:34][CH2:33]4)=[O:21])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: C1CC2CCC1CN2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)N3CC4CCC3CC4)nc12

Procedure:
Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine, phenyl chloroformate and 2-aza-bicyclo[2.2.2]octane, the title compound was prepared as off-white crystals (53% yield). MS: m/e=402(M+H+), mp 237-239° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][CH2:23][C:24](Cl)=[O:25].CCCCCCC>C1COCC1>[Cl:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH3:14])=[O:12])=[O:25]
Reactant: O=C(Cl)CCCl
Reactant: CNC(=O)c1c(N)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CNC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Reaction time: 0.08 h
Yield: 43.8 %

Procedure:
2-Amino-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (2.82 g, 13.41 mmol) was completely dissolved in THF (90 mL). Potassium carbonate (2.22 g, 16.09 mmol) was then added and the reaction stirred for 5 min. 3-chloropropanoyl chloride (2.04 g, 1.536 mL, 16.09 mmol) was added and the reaction mixture stirred at RT for 30 min. THF was removed in vacuo. Water was added and the reaction mixture extracted into EtOAc (×3). The combined EtOAc layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. Purification by flash column chromatography-silica gel and elution with 0-60% EtOAc:heptane gave the desired product (1.76 g, 5.87 mmol, 44%).
Reaction SMILES: O[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9]CN=C=NCCCN(C)C.[C:20]([CH2:23][N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]([NH:34][C:35]([C:37]2[NH:38][C:39]3[C:44]([CH:45]=2)=[CH:43][C:42](Cl)=[CH:41][CH:40]=3)=[O:36])[C:25]1=[O:47])([OH:22])=[O:21]>C(Cl)Cl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:22][C:20](=[O:21])[CH2:23][N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]([NH:34][C:35]([C:37]2[NH:38][C:39]3[C:44]([CH:45]=2)=[CH:43][C:42]([CH3:9])=[CH:41][CH:40]=3)=[O:36])[C:25]1=[O:47]
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reactant: O=C1CCC(=O)N1O
Reactant: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Cc1ccc2[nH]c(C(=O)NC3Cc4ccccc4N(CC(=O)ON4C(=O)CCC4=O)C3=O)cc2c1
Reaction time: 18 h
Yield: 101.7 %

Procedure:
N-Hydroxysuccinimide (496 mg, 4.31 mmol) and EDCI (1.04 g, 5.38 mmol) were added to a suspension of N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-5-chloroindole-2-carboxamide (Example 2, 1.71 g, 4.31 mmol)) in DCM (50 mL) and stirred for 18 hours. The suspension was evaporated and the residue partitioned between EtOAc:THF (4:1)(200 mL) and H2O. The organic was dried (Na2SO4), filtered and evaporated. The solid was triturated with refluxing Et2O (25 mL), filtered, washed with Et2O (25 mL) then hexane (25 mL) to afford the title compound (2.08 g, 98%) as a pale brown powder.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[C:20]([O:26][CH2:27][CH2:28][OH:29])=[CH:19][C:18]=1[F:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[NH:16])[NH:14][OH:15])=[CH:9][CH:8]=1)C.[OH-].[Na+:33].[ClH:34]>C1COCC1>[Cl-:34].[Na+:33].[CH2:24]([O:23][C:21]1[C:20]([O:26][CH2:27][CH2:28][OH:29])=[CH:19][C:18]([F:30])=[C:17]([CH:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13](=[NH:16])[NH:14][OH:15])=[CH:11][CH:12]=2)[C:4]([OH:31])=[O:3])[CH:22]=1)[CH3:25]
Reactant: Cl
Reactant: CCOC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(OCC)c(OCCO)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(Nc2ccc(C(=N)NO)cc2)C(=O)O)c(F)cc1OCCO
Product: [Cl-]
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The (RS)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester (44 mg) described in example 1.8 was suspended in THF (0.9 ml). A 1 M solution of NaOH (0.101 ml) was added and the mixture was stirred for 30 min at 0° C. and for 2.5 h at room temperature. The mixture was neutralized with 1 M HCl and concentrated to give 42 mg of (RS)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid sodiumchloride as a colorless solid. MS: 408 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[C:8]([NH:21][CH2:22][CH2:23][OH:24])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:32][Si:33]([CH3:36])([CH3:35])Cl>O1CCCC1>[CH3:32][Si:33]([CH3:36])([CH3:35])[O:24][CH2:23][CH2:22][NH:21][C:8]1[C:9]2[C:10](=[O:20])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17](=[O:19])[C:18]=2[C:5]([NH:4][CH2:3][CH2:2][O:1][Si:33]([CH3:36])([CH3:35])[CH3:32])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NCCO)ccc(NCCO)c21
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCCNc1ccc(NCCO[Si](C)(C)C)c2c1C(=O)c1ccccc1C2=O
Yield: 86 %

Procedure:
In a flame dried 250 ml, three-necked flask equipped with magnetic stirring bar, reflux condenser with nitrogen inlet and rubber septum on one side neck, are placed 1.63 g (5.0 mmol) 1,4-bis(2-hydroxyethylamino)anthraquinone (C.I. Disperse Blue 23, available as Disperse Blue NSP from Inmont Corporation), 4 ml triethylamine and 50 ml tetrahydrofurane (THF) (Aldrich, freshly opened). The mixture is purged with nitrogen and stirred until the dye is at least partially dissolved and 1.55 ml (12 mmol) trimethylchlorosilane is added to the mixture during a two minute period by means of a syringe having its needle through the septum. A mild exothermic reaction occurs and a precipitate forms immediately. The color of the mixture remains deep blue throughout the reaction. After stirring overnight, the reaction mixture is filtered and the whitish solid (triethylamine hydrochloride) washed with fresh THF until it remains white. The filtrate is evaporated on a rotary evaporator and the residue recrystallized from hot hexane. 1,4-Bis(2-trimethylsilyloxyethylamino)anthraquinone is obtained in two crops of blue needles in 86% yield, m.p. 123°-126° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH:18]([CH3:21])[CH:19]=[CH2:20]>CN(C)C=O.O.C1(C)C=CC=CC=1>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([O:1][CH:19]([CH3:20])[CH:18]=[CH2:21])=[CH:3][CH:4]=1)=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: C=CC(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(C)Oc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 45 °C
Yield: 60.2 %

Procedure:
A solution of 1,1-dimethylethyl 4-hydroxybenzoate (5.0 g, 25.7 mmol) in N,N-dimethylformamide (35 ml) was treated with a solution of sodium hydroxide (1.14 g, 35.1 mmol) in water (2 mL). Then 3-chloro-1-butene (3.06 g, 33.8 mmol) was added and the resulting mixture was heated at 45° C. for 5 hours. The cooled mixture was diluted with toluene, washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution toluene-hexane, 1:1) gave 3.84 g (60%) of the title material as a clear oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][C@H:17]([OH:19])[C@H:16]([OH:20])[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1(C)[C@]2(CS(O)(=O)=O)C(C[C@H:23]1CC2)=O.COC(OC)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][C@H:16]3[O:20][C:22]([CH3:23])([CH3:21])[O:19][C@H:17]3[CH2:18]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@@H]1O
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Solvent: CN(C)C=O
Product: CC1(C)O[C@H]2CN(c3cccc(Cc4ccccc4)n3)C[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 2.5 g of 2-benzyl-6-(cis-3,4-dihydroxypyrrolidine-1-yl)pyridine, 2.3 g of dl-10-camphorsulfonic acid, 20 ml of 2,2-dimethoxypropane and 5.0 ml of N,N-dimethylformamide was stirred at room temperature overnight. Aqueous saturated sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, and the solvent was removed. Then, the residue was subjected to filtration through silica gel and eluted with ethyl acetate, to give 2.87 g of the target compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[F:31]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1.[Cl-].[Na+].O>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([F:31])[C:13]([O:16][CH2:17][O:18][CH3:19])=[CH:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COCOc1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cnc(CO[Si](C)(C)C(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of 2-(((tert-butyl(dimethyl)silyl)oxy)methyl)-5-(methoxymethoxy)pyridine (13.5 g) in THF (100 mL) was added 1.6 M n-butyllithium hexane solution (38.6 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (19.5 g) at −78° C., and the mixture was allowed to warm to room temperature, and stirred for 30 min. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (7.49 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:2]1.[NH2:16][C@H:17]([C:23]([O-:25])=[O:24])[CH2:18]CC([O-])=O>>[CH:6]1[CH:5]=[C:4]2[C:3]([CH2:10][C@@:11]([OH:15])([C:12]([OH:14])=[O:13])[CH2:18][C@H:17]([NH2:16])[C:23]([OH:25])=[O:24])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: O=C([O-])C(=O)Cc1c[nH]c2ccccc12
Reactant: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
The KHG aldolases from B. subtilis, E. coli, and S. meliloti were also used with the E. coli L-aspartate aminotransferase to produce monatin enzymatically. The following reaction conditions were used: 50 mM NH4—OAc pH 8.3, 2 mM MgCl2, 200 mM pyruvate, 5 mM glutamate, 0.05 mM pyridoxal phosphate, deaerated water to achieve a final volume of 0.5 mL after the addition of the enzymes, 3 mM potassium phosphate, 20 μg/mL of recombinant B. subtilis KHG aldolase (purified), ca. 400 μg/mL of E. coli L-aspartate aminotransferase (AspC) unpurified from cell extract, and 12 mM indole-3-pyruvate. The reactions were incubated at 30° C. for 30 minutes with shaking. The amount of monatin produced using the B. subtilis enzyme was 80 ng/mL, and increased with increasing amounts of aldolase. If indole-3-pyruvate and glutamate were replaced by saturating amounts of tryptophan and 5 mM alpha-ketoglutarate, the production of monatin was increased to 360 ng/mL. Reactions were repeated with 30 μg/mL of each of the three KHG enzymes in 50 mM Tris pH 8.3, with saturating amounts of tryptophan, and were allowed to proceed for an hour in order to increase detection. The Bacillus enzyme had the highest activity as in Example 7, producing approximately 4000 ng/mL monatin. The E. coli KHG produced 3000 ng/mL monatin, and the S. meliloti enzyme produced 2300 ng/mL.
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].[O:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)[O:31][N:30]=2)[CH2:25][CH2:24]1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=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:35]([NH:34][C:32]2[O:31][N:30]=[C:29]([CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:33]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1cc(C2CCOCC2)no1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCOCC5)no4)c3)c2cc1OC
Yield: 46.1 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) was reacted with phenyl 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate (104 mg, 0.36 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)urea as a cream solid (68 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 10.25 (brs, 1H), 9.07 (s, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.39-7.44 (m, 2H), 7.31 (m, 1H), 6.99 (m, 1H), 6.01 (s, 1H), 3.99-4.00 (2×s, 6H), 3.86-3.90 (m, 2H), 3.40-3.46 (m, 2H), 2.90 (m, 1H), 1.69-1.76 (m, 2H), 1.60-1.69 (m, 2H); LC-MS (ESI) m/z 492 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][C:6]1[CH:27]=[CH:26][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])=[CH:8][CH:7]=1.[Cl:32][CH2:33][CH2:34][CH2:35]Br.[O-]CCCC.[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][C:6]1[CH:27]=[CH:26][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:35][CH2:34][CH2:33][Cl:32])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])=[CH:8][CH:7]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1O
Agent: CCCC[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1OCCCCl
Reaction time: 18 h
Yield: 77.2 %

Procedure:
The product of step 2 (206.5 mg, 0.5 mmole) and 1-chloro-3-bromopropane (95 mg, 0.6 mmole) was dissolved in dimethylsulphoxide (5 ml) in the presence of potassium butoxide (0.55 ml, 1.0M in THF, 0.55 mmole) in and the mixture held at room temperature for 18 hours. Water was added and the mixture extracted with ethyl acetate. The combined extracts were washed with water and brine then dried (MgSO4) and evaporated to give 4-(4-(2-methoxyphenoxy)-anilino)-3-cyano-6-methoxy-7-(3-chloropropoxy)quinoline (189 mg, 77%) as a yellow gum.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH:3]=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 63.5 %

Procedure:
Methyl 5-chloro-2-nitrobenzoate (73 g, 0.34 mol), 2,4-difluorophenol (51.1 g, 0.39 mol) and potassium carbonate (73 g, 0.53 mol) in NMP (200 mL) were stirred at 160° C. for 2 h. The reaction mixture was cooled to room temperature poured into water (250 mL) and extracted into EtOAc (2×100 mL). The organic layer was washed several times with water, dried over sodium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography eluting with hexane: EtOAc (95:5) to yield 66.8 g of 5-(2,4-difluoro-phenoxy)-2-nitro-benzoic acid methyl ester (1A).