Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2([CH3:32])[CH2:17][CH2:16][C:15]3[C:18]([CH3:31])=[C:19]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=3[O:13]2)=[S:11])[CH:3]=1.[OH-].[Na+].C(O)(=O)C>C(O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2([CH3:32])[CH2:17][CH2:16][C:15]3[C:18]([CH3:31])=[C:19]([O:24][CH2:25][C:26]([OH:28])=[O:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=3[O:13]2)=[S:11])[CH:3]=1
Reactant: CCOC(=O)COc1c(C)c(C)c2c(c1C)CCC(C)(C(=S)Nc1cc(C)cc(C)n1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)nc(NC(=S)C2(C)CCc3c(C)c(OCC(=O)O)c(C)c(C)c3O2)c1
Reaction time: 2 h

Procedure:
1.77 grams (4 mmol) of the compound of Example 67 are dissolved in 40 cm3 of ethanol. 4 cm3 of 2N sodium hydroxide are added dropwise. The mixture is stirred for 2 hours, then the reaction mixture is diluted with 60 cm3 of water and acidified with acetic acid. The mixture is filtered, washed with water and then dried to obtain the title product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4]C=1.C([C@@H]1COC(=O)[N:39]1C(=O)[C@H](CS(N1CCN(C2N=CC(C3C=NC=CC=3)=CN=2)CC1)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH3:30][CH:28]([CH3:29])[C@@H:24]([CH2:23][S:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:39][CH:2]=[CH:7][CH:6]=3)=[CH:9][N:10]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[C:25]([OH:27])=[O:26]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3cccnc3)cn2)CC1)C(=O)O
Yield: 61 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-{3-methyl-2-(R)-[4-(5-pyridin-3-ylpyrimidin-2-yl)piperazine-1-sulfonylmethyl]butyryl}oxazolidin-2-one (0.353 g), to give the title compound as a white solid (0.157 g, 61%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH:14]=[C:13]1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.O.NN>C(O)C>[NH2:3][CH:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH:14]=[C:13]1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N)C1
Yield: 21.7 %

Procedure:
To an ethanol solution (5.0 mL) of tert-butyl 5-(1,3-dioxoisoindolin-2-yl)-4-(4-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (500 mg, 2.36 mmol) synthesized in Reference Synthesis Example 201, hydrazine monohydrate (177 mg, 7.08 mmol) was added and the resultant mixture was stirred under reflux by heating for 5 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. Chloroform was added to the obtained residue and the resultant mixture was filtered again, followed by concentrating the resultant filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (150 mg, yield 22%).
Reaction SMILES: [CH:1]1([CH:4]([CH:12]2[CH2:14][CH2:13]2)[NH:5][C:6]([NH:8][CH2:9][CH2:10]Cl)=[O:7])[CH2:3][CH2:2]1>O>[CH:1]1([CH:4]([NH:5][C:6]2[O:7][CH2:10][CH2:9][N:8]=2)[CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1
Reactant: O=C(NCCCl)NC(C1CC1)C1CC1
Solvent: O
Product: C1COC(NC(C2CC2)C2CC2)=N1

Procedure:
25 g of raw urea obtained by step (a) are suspended in 150 ml of water and heated under reflux for 2 hours. After allowing the temperature of the mixture to return to room temperature, the aqueous solution is extracted with ether. The aqueous phase is separated and made alkaline by adding concentrated ammonia. The resulting precipitate is separated by suction, washed with water and dried. 11.8 g of 2-(dicyclopropylmethylamino) oxazoline are thus recovered, melting at 105°-106° C. A mixture of the latter with N-(dicyclopropylmethyl) N'-(β-chloroethyl) urea gives a decrease of the melting point.
Reaction SMILES: FC(F)(F)[C:3]1C=C[C:6]([C:9]2([OH:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3=[N:18][CH2:19][CH2:20][CH2:21][N:10]23)=[CH:5][CH:4]=1.FC(F)(F)C1C=CC=CC=1C1([OH:46])C2C(=CC=CC=2)C2=NCCCN12>>[O:46]1[CH:3]=[CH:4][CH:5]=[C:6]1[C:9]1([OH:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2=[N:18][CH2:19][CH2:20][CH2:21][N:10]12
Reactant: OC1(c2ccc(C(F)(F)F)cc2)c2ccccc2C2=NCCCN21
Reactant: OC1(c2ccccc2C(F)(F)F)c2ccccc2C2=NCCCN21
Product: OC1(c2ccco2)c2ccccc2C2=NCCCN21

Procedure:
In a similar manner, 6-(4-trifluoromethylphenyl)-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol; 6-(2-trifluoromethylphenyl)-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol; and 6-furyl-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol are produced.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:33])([CH2:31][OH:32])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:19][CH:18]=2)[C:13]1=[O:30])[CH3:11].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(OCC)(=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:33])([CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:21][CH:22]=2)[C:13]1=[O:30])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (0.5 g) was dissolved in 20 ml of ethyl acetate, to which 0.12 ml of methanesulfonyl chloride and 0.22 ml of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the reaction solution was washed with water (10 ml×2) and 10 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=1:1). The desired fraction was concentrated to give 0.58 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH2:19])=O)=[CH:10][CH:9]=1>CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:19])=[CH:12][CH:13]=1
Reactant: NC(=O)CCCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 12.6 g. (0.33 mole) of lithium aluminum hydride in 340 ml. of dry ether was added dropwise at room temperature 16.4 g. (0.083 mole) of 4-(p-chlorophenyl)-butyramide. The reaction mixture was stirred at room temperature for 4 hours, cooled and cautiously quenched with 13 ml. of water, 10 ml. of 20% sodium hydroxide and 45 ml. of water. The organic layer was separated and the emulsion was extracted with ether. The combined organic and ether extract was dried over sodium hydroxide and concentrated to obtain 4-(p-chlorophenyl)butylamine; m.p. of hydrochloride salt 162°-164° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([C@H:27]3[CH2:26][CH2:25][C@H:24]([OH:23])[CH2:29][CH2:28]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CN([C@H]2CC[C@H](O)CC2)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN([C@H]4CC[C@H](O)CC4)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(trans-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=522.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:17]4C=C[N:19]=[CH:18]4)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH:25]1(C(=NO)N)[CH2:27][CH2:26]1>CN(C)C=O>[CH:25]1([C:18]2[N:17]=[C:15]([C:14]3[N:13]=[CH:12][N:11]4[C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=5[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=34)[O:16][N:19]=2)[CH2:27][CH2:26]1
Reactant: NC(=NO)C1CC1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nc(C4CC4)no3)ncn2-c2ccc(F)cc2C1=O

Procedure:
6.5 g (20 mmol) of 1-[(8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)carbonyl]imidazole are stirred at 100° for 1 hour together with 2.2 g (22 mmol) of cyclopropanecarboxamidoxime in 25 ml of N,N-dimethylformamide. The mixture is then evaporated to dryness, 50 ml of glacial acetic acid are added to the residue and the mixture is heated to reflux for 1 hour. The mixture is again evaporated to dryness in vacuo and the residue is dissolved in methylene chloride. The methylene chloride solution is washed twice with sodium bicarbonate solution, subsequently dried with magnesium sulphate and evaporated. By recrystallization from methylene chloride/ethyl acetate there is obtained 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 216°-217°.
Reaction SMILES: [NH2:1][CH:2]([CH:4]([NH2:6])[CH3:5])[CH3:3].[CH:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[C:11]=2[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[NH2:1][CH:2]([CH3:3])[CH:4]([NH:6][S:17]([C:12]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:19])[CH3:5]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(N)C(C)N
Solvent: ClC(Cl)Cl
Product: CC(N)C(C)NS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 79.9 %

Procedure:
In 100 ml of chloroform was dissolved 12.9 g of 2,3-diaminobutane and to the solution was added dropwise 10 ml of a chloroform solution containing 4.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and the reaction mixture solution was washed with water and dried with anhydrous sodium carbonate. The chloroform was distilled therefrom under reduced pressure, and the residue thus obtained was subjected to a column chromatography [silica gel: 160 g; solvent: chloroform] to give 3.92 g of N-(2-amino-1-methylpropyl)-5-isoquinolinesulfonamide in a yield of 80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[CH:21][CH:20]=2)[CH:6]=[CH:7][CH:8]=1.Cl>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10]=2[O:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2sc3ccccc3c2Oc2ccc(OCc3ccccc3)cc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc(-c2sc3ccccc3c2Oc2ccc(O)cc2)c1
Reaction time: 0.33 h
Yield: 37.6 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-3-(4-benzyloxyphenoxy)benzo[b]thiophene (8.30 g, 29.0 mmol) in 1:1 (100 mL) EtOH/EtOAc in a Paar bottle was added 10% Pd/C (4.0 g). To this suspension was added 2.0 mL of con. HCl. The resulting mixture was hydrogenated at 40 psi for 20 min. The reaction was filtered through Celite®, and the filtrate was concentrated in vacuo to an oil. The crude product was partitioned between CHCl3 and sat. NaHCO3 solution. The layers were separated, and the organic was dried (Na2SO4) and concentrated in vacuo to give 3.8 g (61%) of 2-(3-methoxyphenyl)-3-(4-hydroxyphenoxy)benzo[b]thiophene as an amber brown foam. 1H NMR (CDCl3) d 7.80 (d, J=8.1 Hz, 1H), 7.46-7.27 (m, 6H), 6.88-6.84 (m, 3H), 6.71-6.74 (m, 2H), 4.57 (s, 1H), 3.77 (s, 3H). FD mass spec: 348. Anal. Calcd. for C21H16O3S: C, 72.39; H, 4.63. Found: C, 72.10; H, 4.63.
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[CH3:25][C:26](=[CH:28][CH2:29][CH2:30][C:31](=[CH:33][CH:34]=[O:35])C)C.O>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:34]([OH:35])[CH:33]=[CH:31][CH2:30][CH2:29][CH:28]=[CH:26][CH3:25])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: Clc1cccc(Cn2ccnc2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC=CCCC=CC(O)C(c1cccc(Cl)c1)n1ccnc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
26 ml (40 mmol) of 1.55 molar n-butyllithium/hexane solution were added dropwise to a solution of 7.70 g (40 mmol) of N-(3-chlorobenzyl)-imidazole in 100 ml of absolute THF at -70° C. in the course of 15 minutes. The mixture was stirred for 30 minutes at -70° C., after which a solution of 6.10 g (40 mmol) of citral (cis/trans mixture) in 50 ml of absolute THF was added dropwise at -70° C., stirring was continued for 45 minutes at about -70° C., the mixture was allowed to warm up to room temperature in the course of about 2 hours, 300 ml of water were added, while cooling, and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated down in vacuo. The residue (13.2 g) from the extract was chromatographed over a silica gel S/n-hexane column (diameter 2.5 cm, height 56 cm), with elution with hexane/ethanol mixtures having an increasing ethanol content (up to a maximum of 20% of ethanol). The course of the elution was monitored by means of thin layer chromatography. This showed that the desired compound was present in the form of 4 stereoisomers in similar amounts. Fractions which were shown to be pure by thin layer chromatography were combined and evaporated down in vacuo until the weight remained constant. In this way, 1.2 g of virtually pure stereoisomer (a), having the highest Rf value, were obtained. In addition, 8.2 g of a mixture of the stereoisomers (b), (c)≥(a), (d) were obtained. Finally, 2.6 g were eluted, which were found by thin layer chromatography to contain a high concentration of the stereoisomer (d) (lowest Rf value). This product was subjected to a second chromatography by the same procedure, over a silica S/hexane column (diameter 2 cm, height 22 cm). 1.2 g of a stereoisomer (d) which was shown to be virtually completely pure by thin layer chromatography was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[O:38]1[CH2:43][CH2:42][CH:41]([C:44](=[S:46])[NH2:45])[CH2:40][CH2:39]1.O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:46][C:44]([CH:41]3[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[N:45][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)C1CCOCC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a solution of N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (5.00 g, 11.3 mmol) in DMA (47.2 mL) was added NBS (2.115 g, 11.88 mmol). The reaction stirred 30 min at rt and then tetrahydro-2H-pyran-4-carbothioamide (2.137 g, 14.71 mmol) was added. The reaction stirred 16 h at rt. The reaction mixture was poured into water (500 mL), causing precipitation of a solid. The solid was collected by vacuum filtration, re-dissolved in EtOAc (200 mL), and concentrated onto silica gel. Purification by ISCO chromatography (20 to 100% EtOAc:hexanes) afforded the title compound (3.58 g, 5.87 mmol, 51.9% yield) as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.55 (d, J=5.3 Hz, 1H), 7.58-7.79 (m, 1H), 7.38-7.52 (m, 2H), 7.33 (t, J=7.9 Hz, 1H), 7.24 (t, J=9.1 Hz, 2H), 6.87 (d, J=5.1 Hz, 1H), 3.84-4.00 (m, 2H), 3.41-3.54 (m, 2H), 3.31-3.39 (m, 1H), 1.92-2.13 (m, 2H), 1.66-1.91 (m, 2H); m/z (ESI): 567.03 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[Br:15]Br>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
In a 5-liter three-necked round-bottomed flask equipped with a reflux condenser, overhead stirrer, addition funnel and nitrogen inlet, was placed 220 g of methyl 3-methyl-4-nitrobenzoate, 2 l of anhydrous carbon tetrachloride and 4 g of benzoyl peroxide. To the resulting solution, irradiated with a 275 watt UV light, was added 198 g of bromine dropwise over a period of 2 hours at reflux. After the addition was complete the reaction mixture was refluxed for an additional 60 hours. The reaction mixture was cooled to room temperature. The solid which formed was separated by suction filtration. This solid (159.1 g) consisted of the expected methyl 3-bromomethyl-4-nitrobenzoate with minor amounts of the starting material. The mother liquors together with another 220 g of methyl 3-methyl-4-nitrobenzoate and 4 g of benzoyl peroxide were returned to the flask and treated with 198 g of bromine as described above. After the addition was complete the reaction mixture was refluxed another 96 hours, cooled to room temperature and the resulting solid separated by filtration yielding another 252 g of methyl 3-bromomethyl-4-nitrobenzoate. The solids were combined yielding a total of 411.1 g of methyl 3-bromomethyl-4-nitrobenzoate with minor amounts of the starting methyl 3-methyl-4-nitrobenzoate and methyl 3-dibromomethyl-4-nitrobenzoate. This solid was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([CH3:44])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[C:39]([CH3:44])[N:40]=[C:41]([CH3:43])[CH:42]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acid tert-butyl ester (Example J34) (227 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (199 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:31]([NH2:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:3]=1[C:4]([O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:5].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].C(OCC)C>O1CCCC1>[Cl:33][C:29]1[CH:28]=[C:3]([C:4]([O:6][CH2:7][C:8]2([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[O:5])[C:2]2[NH:1][C:34](=[O:35])[NH:32][C:31]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc(N)c2N)(c2ccc(F)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc3[nH]c(=O)[nH]c23)(c2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((2,3-diamino-5-chlorobenzoyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (714 mg, 1.5 mmol) in tetrahydrofuran (10 mL) at 0° C. was added carbonyldiimidazole (242 mg, 1.5 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was treated with a second portion of carbonyldiimidazole (242 mg, 1.5 mmol) and stirred for 1 h at room temperature. The solution was transferred to a microwave vial and heated at 70° C. for 1 h via microwave. The reaction was poured into diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→100 ethyl acetate/n-hexane) gave 0.52 g (69%) as a brown solid. 1H-NMR (CDCl3, 500 MHz) δ 9.69 (bs, 1H), 9.05 (bs, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.38 (dd, J=8.6, 5.2 Hz, 2H), 7.19 (d, J=1.5 Hz, 1H), 7.11 (dd, J=8.6, 8.5 Hz, 2H), 4.32 (s, 2H), 3.81 (m, 2H), 3.09 (m, 2H), 2.24 (m, 2H), 1.89 (m, 2H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 164.6, 162.6, 160.6, 157.4, 155.1, 136.5, 131.1, 128.8 (d, J=7.7 Hz), 126.0, 121.1, 115.7 (d, J=21 Hz), 114.7, 111.8, 79.8, 73.1, 40.6, 39.9, 31.8, 28.6. Mass spec.: 525.87 (MNa)+.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[CH:7][C:6]=1[N:13]1[C:17](=[O:18])[C:16](=[C:19]([CH2:21][CH3:22])[CH3:20])[O:15][C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CCOCC>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:37])=[CH:7][C:6]=1[N:13]1[C:17](=[O:18])[C:16](=[C:19]([CH2:21][CH3:22])[CH3:20])[O:15][C:14]1=[O:23]
Reactant: CCOC(=O)C(C)Br
Reactant: CCC(C)=C1OC(=O)N(c2cc(O)c(Cl)cc2Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)C(C)Oc1cc(N2C(=O)OC(=C(C)CC)C2=O)c(Cl)cc1Cl
Yield: 73 %

Procedure:
To an acetonitrile solution (30 ml) of a mixture of 3-(2',4'-dichloro-5'-hydroxyphenyl)-5-(sec-butylidene)-1,3-oxazolidine-2,4-dione (1.58 g, 5 mmol) was added potassium carbonate (0.69 g), and the mixture was heated at reflux for 2 hours. After the addition of ethyl 2-bromopropionate (0.93 g, 5.1 mmol), the reaction mixture was further refluxed for 1 hour. Ether was added to the reaction mixture and the solution was washed with 1N hydrochloric acid and extracted with ether. The ethereal extracts combined were dried and then evaporated as small a volume as possible. The resulting residue was purified by silica gel column chromatography to give 3-{2',4'-dichloro-5'-(1"-ethoxycarbonylethyloxy)phenyl}-5-(sec-butylidene)-1,3-oxazolidine-2,4-dione. (1.51 g, 73% yield)