Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:35][CH3:36])=[C:25]([NH:28][C:29](=[O:34])[CH:30]=[CH:31][CH2:32]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16].CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:35][CH3:36])=[C:25]([NH:28][C:29](=[O:34])[CH:30]=[CH:31][CH2:32][N:6]4[CH2:7][CH2:8][CH:3]([F:2])[CH2:4][CH2:5]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCCl
Reactant: FC1CCNCC1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC(F)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
131 mg of 4-Fluoro-piperidine hydrobromide was added to 300 mg of 4-Chloro-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide and 0.37 ml of DIEA were dissolved in 5 ml THF stirred at 70° C. overnight. The mixture was then diluted with ethyl acetate, washed with water and brine and dried over Na2SO4. The resulting solids were flash chromatographed with 0-4% methanol in chloroform to give 189.4 mg of 4-(4-Fluoro-piperidin-1-yl)-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH2:14][N:15]([CH3:24])[C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[O:31]=[C:26]1[NH:27][C:28](=[O:30])[C:29](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([CH2:14][N:15]([CH3:24])[C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:12][CH:13]=3)=[CH:5][CH:4]=2)[S:25]1
Reactant: O=C1CSC(=O)N1
Reactant: CN(Cc1cc(-c2ccc(C=O)cc2)cs1)C(=O)c1ccccc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(Cc1cc(-c2ccc(C=C3SC(=O)NC3=O)cc2)cs1)C(=O)c1ccccc1
Yield: 76.7 %

Procedure:
A solution of 4 g (9 mmol) of N-[4-(4-formylphenyl)thiophen-2-ylmethyl]-N-methylbenzamide, 1.1 g (9 mmol) of 2,4-thiazolidinedione and 0.3 g (1.8 mmol) of piperidinium acetate in 40 ml of toluene is refluxed for 2 hours in a Dean-Stark system. The reaction medium is cooled and the precipitate is filtered off under vacuum. 3 g (78%) of N-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]thiophen-2-ylmethyl}-N-methylbenzamide are obtained.
Reaction SMILES: Br[C:2]1[C:6]([CH2:7][CH3:8])=[CH:5][S:4][CH:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C>C(OCC)C>[CH2:7]([C:6]1[C:2]([CH:17]=[O:18])=[CH:3][S:4][CH:5]=1)[CH3:8]
Reactant: CN(C)C=O
Reactant: CCc1cscc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1cscc1C=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromo-4-ethylthiophene, B9, (3.4 g, 0.018 mol) in 40 mL of diethyl ether was cooled to -78° C., and a solution of n-BuLi (12.0 mL, 1.6M) in hexanes was added dropwise. The solution was allowed to warm to -20° C., and DMF (1.46 g, 0.020 mol) was added. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction was quenched with aqueous ammonium chloride solution and extracted twice with diethyl ether. The organic extracts were combined, washed with twice with water and then brine and dried (MgSO4). The solution was filtered and concentrated to provide 4-ethylthiophene-3-carboxaldehyde, C9, which was used directly in the next step. ##STR65##
Reaction SMILES: COC1C2OCCC=2C=C2C=CC(OC=12)=O.[Cl:17][C:18]1[C:19](=[O:30])[C:20]([C:28]#[N:29])=[C:21]([C:26]#[N:27])[C:22](=[O:25])[C:23]=1[Cl:24].C1(C)C=CC=CC=1>ClC1C=CC=CC=1>[Cl:17][C:18]1[C:23]([Cl:24])=[C:22]([OH:25])[C:21]([C:26]#[N:27])=[C:20]([C:28]#[N:29])[C:19]=1[OH:30]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: COc1c2c(cc3ccc(=O)oc13)CCO2
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N

Procedure:
The 2,3-dihydroxanthotoxin thus obtained is then dehydrogenated. This advantageously is effected by heating the 2,3-dihydroxanthotoxin with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a substantially inert solvent, for example, toluene or chlorobenzene, advantageously at reflux, until substantial dehydrogenation is obtained. The 2,3-dichloro-5,6-dicyano-hydroquinone formed and any residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are removed and the product taken up in chloroform and recovered therefrom. If substantial amounts of the residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are present, it is desirable to convert this to the corresponding hydroquinone with sodium dithionite, dissolve the hydroquinone in aqueous sodium bicarbonate, and extract the sodium bicarbonate solution with chloroform to recover the 8-methoxypsoralen which can be recovered by drying over sodium sulphate and concentrating to dryness. The resulting product can then be recrystallized from benzene or any suitable inert solvent in which 8-methoxypsoralen has limited solubility. If there is little residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, the reaction mixture can be cooled and the precipitated hydroquinone filtered off and the reaction mixture, i.e., the filtrate, then extracted with chloroform. If desired, the filter cake can be extracted with benzene or like solvents such as chlorobenzene, toluene, and the like, for example, by refluxing the filter cake in the solvent and then adding the extract to the reaction mixture filtrate prior to the chloroform extraction. The chloroform solution is then washed successively with dilute sodium bisulfite solution, dilute sodium bicarbonate solution, and water and dried over sodium sulfate. The resulting chloroform solution is then concentrated by distillation until the product precipitates and an inert non-solvent such as hexane or like aliphatic or cycloaliphatic hydrocarbon is added to cause further precipitation of the product and the product is filtered. If desired, the product can be further purified by redissolving it in chloroform, or chloroform containing a minor amount of ethyl acetate, passing the solution over an alumina column concentrating the effluent until crystallization takes place, adding hexane or like solvent further to cause precipitation of the product, and filtering the solution.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C>CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)[CH:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(Cn2ccc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(C(=O)O)cc3)ccc2c1
Reaction time: 0.67 h

Procedure:
To a slurry of the product of step i) (1 g) in methanol (15 mL) at reflux was added sodium hydroxide solution (1N, 2.4 mL). The reaction mixture was then stirred at reflux for 90 minutes. Additional sodium hydroxide solution (1N, 0.5 mL) was added and heating continued for a further 40 minutes. Acetic acid (0.16 mL) was added and the reaction was stirred at room temperature for 17 hours.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]3[S:32][C:31](=N)[NH:30][C:29]3=[O:34])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=O)C.Cl.[OH2:38]>COCCO>[C:15]([C:14]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10]([CH2:20][CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:38])[NH:30][C:29]4=[O:34])=[CH:25][CH:24]=3)([CH3:19])[O:11]2)=[CH:6][C:5]=1[OH:4])([CH3:16])([CH3:18])[CH3:17]
Reactant: O
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(CCOc1ccc(CC3SC(=N)NC3=O)cc1)CC2
Agent: Cl
Solvent: COCCO
Product: CC1(CCOc2ccc(CC3SC(=O)NC3=O)cc2)CCc2cc(O)c(C(C)(C)C)cc2O1

Procedure:
75 mg of 5-{4-[2-(6-acetoxy-7-t-butyl-2-methylchroman-2-yl)ethoxy]benzyl}-2-iminothiazolidin-4-one (prepared as described in Example 6) were added to a mixture of 0.5 ml of concentrated hydrochloric acid, 2 ml of water and 2 ml of ethylene glycol monomethyl ether, and the mixture was heated under reflux for 4 hours. The mixture was then processed and purified by the procedures described in Example 1(a), except that the crude product, in the form of an oil, was purified by column chromatography through silica gel, eluted with a 5:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[NH:11][C:10]([CH3:20])=[C:9]2[C:21]([O:23]CC)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.N12CCCC=C1CCCCN2.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([C:13]1[CH:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[O:1][C:21](=[O:23])[C:9]2=[C:10]([CH3:20])[NH:11][C:12]=1[CH3:19])=[O:15])[CH3:18]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ncccc1O
Agent: C1=C2CCCCNN2CCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(C)=C2C(=O)Oc3cccnc3C12
Temperature: 140 °C
Yield: 55.3 %

Procedure:
Diethyl 1,4-dihydro-4-(3-hydroxypyridyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (17.3 grams; 0.05 mole) was nearly dissolved in 250 ml toluene heated at 140° C. Diazabicyclo(5.4.0) undec-7-ene (8.3 grams; 8.2 ml; 0.05 mole) dissolved in 20 ml toluene was added and the reaction mixture refluxed for a period of 22 hours at 180° C. (bath temperature). The black solution was cooled and concentrated to afford 23.3 grams of a black paste. High pressure liquid chromatography (HPLC) using ethyl acetate yielded 8.3 grams of a yellow solid, m.p. 100°-150° C. Two recrystallizations from 2-propanol gave 4.5 grams (30%) of fluorescent yellow material, m.p. 150°-160° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:41])[CH2:37][CH2:38][O:39][CH3:40]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:41]=[C:36]([CH2:37][CH2:38][O:39][CH3:40])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COCCC(N)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70 mmol) and the solution was stirred at room temperature for 1 hour. N′-hydroxy-3-methoxypropanimidamide (J.Amer.Chem.Soc.; 80; 1958; 3769-3771) (201 mg, 1.70 mmol) was then added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as a colourless oil (410 mg).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]=[C:6]1[O:12][CH:11]2[N:8]([C:9](=[O:13])[CH2:10]2)[CH:7]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[CH2:1]([S:3]([CH2:4][CH:5]=[C:6]1[O:12][CH:11]2[N:8]([C:9](=[O:13])[CH2:10]2)[CH:7]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])=[O:32])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSCC=C1OC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCS(=O)CC=C1OC2CC(=O)N2C1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl 3-(2-ethylthioethylidene)-7-oxo-4-oxa-1-azabicyclo[3,2,0]heptane-2-carboxylate (704 mg) was dissolved in methylene chloride (40 ml) and treated with m-chloroperbenzoic acid (370 mg). The solution was stirred at 0° C. for 1.0 hour and washed with a dilute bicarbonate solution (×2). The extract was dried over MgSO4 and evaporated. Chromatography over silica gel yielded the title product as a mixture of R and S sulphoxides (295 mg);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][C:20](=[CH2:22])[CH3:21].OS(O)(=O)=O>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([C:16]([O:18][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of N-[(4-fluorophenyl)-sulfonyl]-D-valine from Example 1a (8.00 g, 29.1 mmol) in CH2Cl2 /dioxane was treated with isobutylene in the presence of H2SO4 at room temperature at a pressure of 18 psi. The reaction was quenched by adding the solution to a mixture of NaHCO3 (20 g) in water (300 mL) cooled in an ice bath. The mixture was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with H2O and brine, dried over MgSO4, and concentrated to a solid. Recrystallization from diethyl ether/hexane afforded N-[(4-fluorophenyl)-sulfonyl]-D-valine, 1,1-dimethylethyl ester, as a white solid (6.99 g, 73%): MS MH+ calc'd for Cl5H22NO4SF: 332, found: 332. Anal. calc'd for Cl5H22NO4SF: C, 54.36; H, 6.69; N, 4.23. Found: C, 54.21; H, 6.86; N, 4.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=1.[NH2:12][C:13]1[C:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=[C:15]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH2:28]2)[N:14]=1.N1C=CC=CC=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:11])[C:8]([NH:12][C:13]2[C:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=[C:15]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[O:34])[CH2:28]3)[N:14]=2)=[O:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: C[C@H](C(=O)O)n1cc(Cl)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)OC(C)(C)C)n1cc(Cl)cn1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
(R)-2-(4-Chloro-1H-pyrazol-1-yl)propanoic acid (105 mg, 0.60 mmol) and (R)-tert-butyl 2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-ylcarbamate (195 mg, 0.50 mmol) were dissolved in ethyl acetate (0.5 mL) with pyridine (0.20 mL, 2.5 mmol) at room temperature. The mixture was cooled to 0° C. 1-Propanephosphonic acid cyclic anhydride (0.375 mL, 50% solution in ethyl acetate, 1.25 mmol) was added while stirring at 0° C. The resulting mixture was stirred for 15 min, and then warmed to room temperature. After stirring for 1.5 h at room temperature, the mixture was quenched with an aqueous solution of hydrochloric acid (0.5 M, 1 mL). The mixture was partitioned between ethyl acetate (10 mL) and water (5 mL). The organic layer was washed sequentially with water (5 mL), a saturated aqueous solution of sodium bicarbonate (5 mL), and brine (5 mL). The organics were dried over magnesium sulfate, filtered, and concentrated. The residue was dried under reduced pressure to afford tert-butyl 2-((R)-2-(4-chloro-1H-pyrazol-1-yl)propanamido)-6-((R)-3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-ylcarbamate (268 mg, 98% yield). 1H NMR (500 MHz, CDCl3) δ 1.48 (s, 9H), 1.48-1.55 (m, 1H), 1.73-1.76 (m, 1H), 1.80-2.05 (m, 6H), 1.86 (d, 3H), 2.53-2.59 (m, 1H), 2.84-2.90 (m, 1H), 2.96-3.01 (m, 1H), 3.43-3.51 (m, 3H), 3.55-3.60 (m, 1H), 4.12 (br d, 1H), 4.33 (br d, 1H), 5.10 (br s, 1H), 6.56 (d, 1H), 7.30 (br s, 1H), 7.57 (s, 1H), 7.61 (s, 1H), 7.76 (br s, 1H), 8.58 (br s, 1H); MS (ES+) (M+H) 546.3; Chiral HPLC retention time 4.61 min (Method: Chiralpak AS-H 0.46×25 cm; Mobile Phase: CO2/methanol; Flow: 2.5 mL/min); 97.1% de.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([S:8][CH2:9][C:10]([NH2:12])=[O:11])=[O:7].[C:13](OC(=O)C)(=[O:15])[CH3:14].C(Cl)(=O)C>>[C:13]([NH:12][C:10](=[O:11])[CH2:9][S:8][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)CSC(=O)c1ccco1
Solvent: CC(=O)Cl
Product: CC(=O)NC(=O)CSC(=O)c1ccco1
Temperature: 0 °C

Procedure:
A reaction mixture comprising 2.8 g. of the product of Step A above, 30 ml. of acetic anhydride and 2 ml. of acetyl chloride, was heated on a steambath for 6 hours. The reaction mixture was then cooled and poured into ice water, giving a gummy solid after about 15 minutes. The product was filtered and air dried to yield 1.1 g. This was recrystallized from toluene to yield 0.65 g., m.p. 103°-105° C.
Reaction SMILES: C1(C2C[CH2:11][N:10]([C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[O:26][C:25]([N:27]5[C:36]6[C:31](=[CH:32]C=CC=6)[CH2:30][CH2:29][CH2:28]5)=[N:24][C:23]=4[C:37]([F:40])([F:39])[F:38])=[O:21])=[CH:15][CH:14]=3)[CH2:9]C2)C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.ON1[C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:72][N:73]([CH:75]=[O:76])[CH3:74]>O>[O:76]=[C:75]1[N:73]([CH2:74][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:72][CH2:11][N:10]([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[O:26][C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH:31]([CH3:32])[CH2:36]4)=[N:24][C:23]=3[C:37]([F:39])([F:40])[F:38])=[O:21])=[CH:15][CH:14]=2)[CH2:9]1
Reactant: O=C(Nc1ccc(N2CCC(c3ccccc3)CC2)nc1)c1oc(N2CCCc3ccccc32)nc1C(F)(F)F
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCN(Cc5ccccc5)C(=O)C4)nc3)o2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
To a solution of intermediate B-15 (170 mg, 0.6 mmol) and intermediate A-10 (185 mg, 0.67 mmol) in DMF (8 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (173 mg, 0.9 mmol, EDCI), 1-hydroxybenzotriazole (122 mg, 0.9 mmol, HOBT), and N,N-diisopropylethylamine (200 μL, 1.2 mmol). The reaction mixture was stirred at RT for 17 h. The mixture was poured into water (150 mL). The precipitate was filtered, dissolved in DMF and purified by chromatography on a C-18 reverse phase column (eluant: acetonitrile/water gradient) to give 2-(3-methyl-1-piperidinyl)-N-[6-[3-oxo-4-(phenylmethyl)-1-piperazinyl]-3-pyridinyl]-4-(trifluoromethyl)-5-oxazolecarboxamide (31) (169 mg, 52% yield) 1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 8.04 (d, 1H, J=9 Hz), 7.61 (s, 1H), 7.4-7.3 (m, 5H), 6.64 (d, 1H, J=9 Hz), 4.73 (s, 2H), 4.23 (s, 2H), 4.15 (bt, 2H), 3.88 (t, 2H, J=5.5 Hz), 3.43 (t, 2H, J=5.5 Hz), 3.08 (dt, 1H), 2.75 (t, 1H, J=12 Hz), 1.97-1.74 (m, 3H), 1.31 (bs, 1H), 1.28-1.16 (m, 2H), 1.03 (d, 3H, J=6.5 Hz). LCMS (ESI) Rt=3.83 min, 543.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1[C:15]([NH:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:16].[OH-].[Na+].ClCCl.O>C1COCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5](=[O:14])[C:4]=1[C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16]
Reactant: COC(=O)CNC(=O)c1c(OC)c2ccccc2n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(=O)NCC(=O)O)c(=O)n(C)c2ccccc12
Reaction time: 1.5 h

Procedure:
Methyl 2-(4-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.150 g, 0.5 mmol) was dissolved in THF in a 25 mL round bottom flask. NaOH was added and the mixture was stirred for 1.5 hours. Dichloromethane and water were added to the reaction and the layers were separated. The aqueous layer was washed two more times with dichloromethane. To the aqueous phase, IN HCL was added until the pH was approximately 1. The aqueous phase was then extracted with 25% IPA/CHCl3, dried with MgSO4 and concentrated on a roto-evaporator. The compound was then purified by HPLC to give the desired product as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[NH:8][N:7]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2>ClCCCl.O>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[C:22]2[C:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[NH:8][N:7]=1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: O=S1(=O)NN=C(Cl)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
AlCl3 (1.2 g, 10.5 mmol) was added to a solution of 4-chloro-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (1.5 g, 7.0 mmol) and 5-fluoro-2-methyl indole (1.0 g, 7.0 mmol) in DCE (35 mL), and stirred overnight at 70° C. The reaction solution was diluted with H2O, and the product was extracted with a solution of CH2Cl2/EtOH (9/1, v/v). The extracted product was concentrated and purified via silica gel chromatography eluting with a gradient of 0 to 70% EtOAc in hexanes to afford 0.44 g (19%) of the sub-title compound. MS calculated for C16H12FN3O2S—H: 328, observed: 328.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[CH:31]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([C:35]([CH:31]3[CH2:34][CH2:33][CH2:32]3)=[O:36])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: O=C(Cl)C1CCC1
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CN(C(=O)C4CCC4)CCC3C(C)(C)OC2=C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and cyclobutanecarbonyl chloride (1 mole) with triethylamine (1 mole) in dimethylformamide, stirring 16 hours at 25°C gave the desired product.