Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClC[CH2:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)C>[C:20]([CH2:21][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)(=[O:22])[CH3:19]
Reactant: CC(=O)CCCl
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of benzyl 1-piperazinecarboxylate (4.1 ml), chloromethyl acetone (1.8 ml) and potassium carbonate (8.8 g) in acetonitrile (40 ml) was stirred overnight at ambient temperature. The reaction mixture was diluted in diethyl ether and the solution was partitioned between diethyl ether and water. The water phase was extracted with diethyl ether, the organic phases were combined and washed with water, brine, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography using dichloromethane/methanol saturated with ammonia (3.5 M) (98/2). Evaporation of the solvent gave benzyl 4-(acetylmethyl)-1-piperazinecarboxylate (3.7 g, 63%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[C:12]#[C:13][C:14]([CH3:21])([O:16][Si](C)(C)C)[CH3:15])=[CH:7][C:4]=1[C:5]#[N:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:16][C:14]([CH3:21])([CH3:15])[C:13]#[C:12][C:11]([C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[C:5]#[N:6])=[O:22]
Reactant: COc1ccc(C(=O)C#CC(C)(C)O[Si](C)(C)C)cc1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)C#CC(C)(C)O)cc1C#N
Reaction time: 0.5 h
Yield: 122.9 %

Procedure:
To a stirred solution of 2-methoxy-5-(4-methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (1.2 g, 3.01 mmol) in DCM (20 mL) was added PTSA (1.08 g, 5.60 mmol) at RT. The reaction mixture was stirred for 30 minutes and diluted with water (5 mL). The combined organic layers were then washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 5-(4-hydroxy-4-methylpent-2-ynoyl)-2-methoxybenzonitrile (0.9 g, 97%) as a semi-solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([CH:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:18]2)=[C:4]([CH:56]=[CH2:57])[C:3]=1[OH:58].[CH2:59](Br)[CH:60]=[CH2:61].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:61]([O:58][C:3]1[C:4]([CH:56]=[CH2:57])=[C:5]([CH:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[O:18]2)[CH:6]=[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)[C:2]=1[Cl:1])[CH:60]=[CH2:59]
Reactant: C=Cc1c(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccc(CC)cc2)c(Cl)c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(Cl)c(Cc2ccc(CC)cc2)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1C=C
Reaction time: 18 h
Yield: 38.9 %

Procedure:
A mixture of compound 82 (320 mg, 0.4 mmol) and allyl bromide (0.05 mL, 0.6 mmol) and K2CO3 (110 mg, 0.8 mmol) in acetone (2.0 mL) was stirred for 18 hours under reflux. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 83 (130 mg, 37%) as colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:4].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(O)(=O)C>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[CH:10][CH:9]=1)[CH3:4]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)OCC)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To 0.325 g (8.1 mmol) of a 60% oil dispersion of NaH suspended in 15 ml of anhydrous DMF and stirred under an argon atmosphere at room temperature was added 1.5 g (7.73 mmol) of 4-hydroxyalpha-oxobenzeneacetic acid ethyl ester. The reaction mixture was stirred at room temperature for 20 minutes and a solution of 3.2 g (9.66 mmol) of 1-bromooctadecane in 20 ml of anhydrous DMF was added dropwise over 15 minutes. After stirring at reflux for 16 hours, 5 ml of acetic acid was added and the solvent was removed at reduced pressure. Water was added to the residue and the product was extracted with methylene chloride. The dried extract was concentrated at reduced pressure and the solid residue was purified by HPLC using 50% methylene chloride-hexane to give 2.9 g (84% yield, mp 46°-48°) of 4-(octadecyloxy)-alpha-oxobenzeneacetic acid ethyl ester.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:2]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(CBr)c1

Procedure:
Compound XIII is prepared by the following series of reactions: (1) ethyl m-toluate is brominated with N-bromosuccinimide in CCl4 to give ethyl 3-bromomethylbenzoate; (2) the bromo compound is treated with sodio bis-tert-butyl malonate and the product heated in toluene with a catalystic amount of a strong acid (preferably p-toluene-sulfonic acid) to effect elimination and decarboxylation and afford m-ethoxycarbonylhydrocinnamic acid; (3) the latter compound is made to react with thionyl chloride and the resulting acid chloride is reduced with potassium or sodium borohydride to yield ethyl 3-(3-hydroxypropyl)-benzoate; (4) the hydroxy ester is treated with phosphorus tribromide is ether to give reagent XIII.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[K+].[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21](Br)[CH2:20]1)[CH3:15]>C(O)C>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([S:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=2)[CH2:20]1)[CH3:15]
Reactant: CCOC(=O)CC1CCC(=O)C(Br)C1
Reactant: CC(C)Cc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CCC(=O)C(Sc2ccc(CC(C)C)cc2)C1
Temperature: 25 °C

Procedure:
31.4 G. of 4-i-butylthiophenol and a solution of 10.6 g. of 85% potassium hydroxide in 300 ml. of ethanol were each placed in a 3 liter three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 49.5 g. of 3-bromo-4-ketocyclohexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotary evaporator), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. A yield of 42.5 g. of 3-(4-i-butylphenylthio)-4-ketocyclohexane acetic acid ethyl ester was obtained, b.p. 205-220/2.0 mm.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16]>C1COCC1>[O:16]=[C:11]1[CH2:12][CH2:13][C:14](=[O:15])[N:10]1[O:9][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C1CCCC(=O)O1
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C(O)CCCC(=O)ON1C(=O)CCC1=O
Yield: 46.1 %

Procedure:
A solution of 10.0 g (0.088 mol) of glutaric anhydride in 50 mL of dry THF under argon was treated with 10.0 g (0.087 mol) of N-hydroxysuccinimide and heated to reflux for 3.5 hours The reaction was concentrated at reduced pressure to an oil. The oil was crystallized from 50 mL of ethyl acetate to yield 9.2 g (46%) of 5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxo-pentanoic acid which was treated with 16 mL of thionyl chloride and heated at 45° C. for 3 hours under argon. The reaction mixture was concentrated at reduced pressure to a white solid which was triturated with a small amount of ether and collected by suction filtration. The product was dried overnight at high vacuum to yield 8.7 g (88%) of 18 as a white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)=O.Cl>O>[C:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4]
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Oc1ccccc1)c1ccccc1S
Reaction time: 0.5 h

Procedure:
In a 250 ml three-necked flask a mixture of 69.4 g (0.45 mol) of thiosalicylic acid and 42.3 g (0.45 mol) of phenol is melted at 135° C. with stirring. Then, at 125°-130° C., 24.5 g (0.16 mol) of phosphorus oxychloride are added dropwise, HCl being liberated. When the addition is complete (about 15 min.) stirring is carried out for 30 minutes. The resulting dark-brown clear solution is stirred into 500 ml of water, a brown oil separating. This oil is taken up in ethyl acetate. The organic phase is extracted three times by shaking with soda solution, washed with water, dried and concentrated to a residue. The residue, which still contains phenol, is purified by distillation. The crude product is recrystallised from 250 ml of absolute methanol in the presence of activated carbon. The product is obtained in the form of colourless crystals having a melting point of 89° C. The yield is 36.0 g (=35% of the theoretical amount).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]2[CH2:27][OH:28])[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1.C(OC([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43]([O:28][CH2:27][C@H:22]1[N:21]([CH2:20][C:13]2[NH:12][C:11]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:26][CH2:25][O:24][CH2:23]1)=[O:44]
Reactant: CCOC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2COC(=O)[C@@H](N)C(C)C)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 35.9 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-6-(((S)-3-(hydroxymethyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 1.96 mmol) was reacted with (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.83 g, 3.8 mmol) according to the procedure as described in Example 49 to give the title compound as a yellow solid (0.43 g, 36%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:50])=[CH:4][C:5]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([S:31](=[O:48])(=[O:47])[N:32]([C:42]4[CH:46]=[CH:45][O:44][N:43]=4)CC4C=CC(OC)=CC=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:49])=[C:6]([CH:20]=1)[O:7][CH:8]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:50])=[CH:4][C:5]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([S:31]([NH:32][C:42]4[CH:46]=[CH:45][O:44][N:43]=4)(=[O:47])=[O:48])=[CH:28][CH:29]=3)[CH:24]=[CH:23][C:22]2=[O:49])=[C:6]([O:7][CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:20]=1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3OC3CCN(C(=O)OC(C)(C)C)C3)c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1cc(F)c(Br)cc1OC1CCNC1
Reaction time: 8 h
Yield: 10.3 %

Procedure:
To a solution of tert-butyl 3-(5-bromo-4-fluoro-2-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)phenoxy)pyrrolidine-1-carboxy late (74.7 mg, 0.097 mmol) in DCM (970 μl) at RT was added trifluoromethanesulfonic acid (25.8 μl, 0.291 mmol). The resulting solution was stirred overnight. LCMS indicated that the reaction was not complete. 0.012 mL of triflic acid was added and the solution stirred 16 hr. LCMS indicated that product was generated but there was a significant amount of PMB protected material. Another equivalent of triflic acid was added and the resulting solution was stirred for 48 hr. The reaction mixture was concentrated by sending a stream of N2 gas into the uncapped reaction vial. The residue was then dissolved in 1 ml of DMSO and 0.050 mL of saturated NaHCO3 was added and the mixture stirred for 5 minutes. The solution was then passed through a 0.20 micron filter. An additional 0.5 ml was used to sinse the reaction vial and the solution was passed through the same filter. The DMSO solution was purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 5 to 30% MeCN in water (containing 0.1% ammonium hydroxide as an additive), flow rate 40 mL/min to yield 1-(4-bromo-5-fluoro-2-(pyrrolidin-3-yloxy)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (5.5 mgs, 10% yield for two steps). 1H NMR (500 MHz, DMSO-d6) δ=ppm 1.22-1.36 (m, 1 H) 1.82-2.01 (m, 2 H) 2.61-2.81 (m, 1 H) 2.84-3.06 (m, 2 H) 3.30 (br. s., 7 H) 5.13 (br. s., 1 H) 6.09 (d, J=11.67 Hz, 1 H) 6.61-6.71 (m, 2 H) 7.60 (t, J=8.19 Hz, 1 H) 7.71 (t, J=8.01 Hz, 1 H) 7.78 (t, J=7.13 Hz, 1 H) 8.07-8.18 (m, 3H). m/z (ESI) 548.8.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N+:13]([O-])=O)=[CH:5][CH:4]=1.[CH2:16]([O:18][P:19]([O:23]CC)[O:20][CH2:21][CH3:22])[CH3:17]>>[NH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH2:2][P:19](=[O:23])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17])=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CBr)c2ccccc12
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(N)c2ccccc12)OCC

Procedure:
1-Bromomethyl-4-nitronaphthalene and triethylphosphite ((C2H5 O)3P) were treated in the same manner as in Reference Example 43 to yield diethyl (4-amino-1-naphthyl)methylphosphonate, which was then recrystallized from ethyl acetate-hexane to yield yellow prisms having a melting point of 73°-74° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].CN(C=O)C.[O:43]([C:45]1[CH:50]=[CH:49][C:48]([N:51]=[C:52]=[S:53])=[CH:47][CH:46]=1)[CH3:44]>CC#N>[CH3:44][O:43][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([N:22]2[CH2:21][CH2:20][N:19]([C:17]3[S:18][C:14](=[CH:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]5[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:33])[F:34])=[CH:31][C:3]=5[C:2]([F:36])([F:1])[F:37])=[C:8]([O:26][CH3:27])[CH:9]=4)[C:15](=[O:25])[N:16]=3)[CH2:24][CH2:23]2)=[S:53])=[CH:47][CH:46]=1
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: COc1ccc(N=C=S)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(NC(=S)N2CCN(C3=NC(=O)C(=Cc4ccc(OCc5ccc(C(F)(F)F)cc5C(F)(F)F)c(OC)c4)S3)CC2)cc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 15.3 %

Procedure:
To a N2 purged flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (120 mg, 220 μmol) from Example 23, DMF (8 mL) and MeCN (8 mL). To the reaction solution was added 4-methoxylphenyl isothiocyanate (55 mg, 330 μmol). The reaction was stirred at 55° C. for 20 h and LC analysis should product was formed. The reaction solution was concentrated under reduced pressure and then taken into EtOAc (100 mL), washed with aq. NH4Cl (70 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed using reverse phase preparative HPLC, H2O/MeCN gradient 90:10 to 10:90) to provide the title compound as a white solid (24 mg, 13% yield). 1H NMR (DMSO-d6) δ 8.17 (1H, d, J=8.1 Hz), 8.11 (1H, s), 8.02 (1H, d, J=8.1 Hz), 7.64 (1H, s), 7.15-7.23 (5H, m), 6.88 (2H, d, J=8.9 Hz), 5.42 (2H, s), 4.16 (2H, br s), 4.09 (2H, m), 4.03 (2H, m), 3.86 (3H, s), 3.80 (2H, m), 3.74 (3H, s); MS (ESI) 711 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].P([O-])([O-])([O-])=O>CN(C=O)C>[Si:32]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: CC(C)(C)[Si](C)(C)OCCOCCCCCCBr
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO[Si](C)(C)C(C)(C)C)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.83 g) in DMF (20 ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.20 g) and the mixture stirred under nitrogen at 20° C. for 30 min. A solution of {2-[(6-bromohexyl)oxy]ethoxy}(tert-butyl)dimethylsilane (1.47 g) in DMF (4 ml) was added and the mixture stirred at 20° C. for 90 min. Phosphate buffer (20 ml, pH6.5) was added, before partitioning between EtOAc (50 ml) and water (50 ml). The layers were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic layer was washed with water (3×50 ml) and dried over Na2SO4 before filtering. Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (1:1) followed by solvent evaporation in vacuo gave the title compound (0.84 g). LCMS RT=4.11 min, ES+ve 507 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[N:22]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: CN(C)CC(=O)O
Reactant: COc1cc(OC[C@@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@@H]2C[C@H](O)CN2C(=O)CN(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 83 %

Procedure:
The procedure described in Example 30 was repeated using (3S,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (157 mg) with N,N-dimethylglycine (43 mg) to give the title compound as a white solid in 83% yield; NMR spectrum (DMSO-d6) 10.03 (s, 1H), 8.46 (s, 1H), 8.19 (dd, 1H), 7.76-7.71 (m, 1H), 7.43 (t, 1H), 6.83 (d, 1H), 6.75 (d, 1H), 5.27-5.26 (m, 1H), 4.72-4.67 (m, 1H), 4.61-4.56 (m, 1H), 4.41-4.40 (m, 1H), 4.34-4.29 (m, 1H), 3.93 (s, 3H), 3.78 (dd, 1H), 3.52 (br d, 1H), 3.14 (d, 1H), 2.99 (d, 1H), 2.26-2.17 (m, 7H), 1.95-1.90 (m, 1H); Mass spectrum MH+ 50
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28]SC3C=CC=CC=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.[C:39]1(C)[CH:44]=[CH:43][C:42]([S:45]([OH:48])(=[O:47])=O)=[CH:41][CH:40]=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:45]([C:42]3[CH:41]=[CH:40][CH:39]=[CH:44][CH:43]=3)(=[O:47])=[O:48])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CSc2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CS(=O)(=O)c2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl]-1,4-dihydro-3-quinolinecarboxamide (0.08 gm) from Example No. 76 in dichloromethane (4 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.03 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.06 gm). The mixture is stirred for 1 hr. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by recrystallization from acetonitrile to afford 0.07 gm of the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:31]=[CH:30][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:18][CH:19]=3)=[O:13])=[CH:30][CH:31]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(F)cc3)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)C3CC3)cc2)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A solution of cyclopropanecarbonyl chloride (Aldrich, 448 mg, 4.31 mmol) in 5 mL of methylene chloride was slowly added over 5 minutes to N-(4-(4-aminobenzoyl)phenyl)-4-fluorobenzamide (1.2 g, 3.59 mmol) in 20 mL of methylene chloride containing 3 mL of pyridine. The reaction was stirred at room temperature for 12 h then quenched with 40 mL of water. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were washed with 0.5 N HCl (100 mL), brine (100 mL), dried over sodium sulphate, and filtered. Concentration of the organics provided N-(4-(4-(cyclopropanecarboxamido)benzoyl)phenyl)-4-fluorobenzamide (1.3 g, 3.23 mmol) as a tan solid which was used without further purification.