Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][C:9]=2[OH:11])[O:4][C@H:3]([C:13]2[CH:18]=[C:17](O)[C:16]([OH:20])=[C:15]([OH:21])[CH:14]=2)[C@@H:2]1[O:22][C:23]([C:25]1[CH:30]=[C:29]([OH:31])[C:28]([OH:32])=[C:27]([OH:33])[CH:26]=1)=[O:24].OO>CC(C)=O>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][C:9]=2[OH:11])[O:4][C@H:3]([C:13]2[CH:18]=[C:18]3[C:13]([C@@H:3]4[O:4][C:5]5[C:10](=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=5)[CH2:1][C@@H:2]4[O:22][C:23]([C:25]4[CH:26]=[C:27]([OH:33])[C:28]([OH:32])=[C:29]([OH:31])[CH:30]=4)=[O:24])=[CH:14][C:15]([OH:21])=[C:16]([OH:20])[C:17]3=[C:16]([OH:20])[C:15](=[O:21])[CH:14]=2)[C@@H:2]1[OH:22]
Reactant: O=C(O[C@@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1cc(O)c(O)c(O)c1)c1cc(O)c(O)c(O)c1
Agent: OO
Solvent: CC(C)=O
Product: O=C(O[C@H]1Cc2c(O)cc(O)cc2O[C@H]1c1cc(O)c(O)c2c(O)c(=O)cc([C@H]3Oc4cc(O)cc(O)c4C[C@H]3O)cc12)c1cc(O)c(O)c(O)c1
Yield: 28.1 %

Procedure:
EC (1 g) and EGCG (1 g) were dissolved in a mixture of acetone-pH 5.0 phosphate citrate buffer (1:10, v/v, 50 mL), which contained 4 mg horseradish peroxidase. While being stirred, 2.0 ml of 3.13% H2O2 was added four times during 45 minutes. The reaction mixture was extracted by ethyl acetate (50 ml×3). After concentration, the residue was subjected to Sephadex LH 20 column eluted with acetone-water solvent system (45%). 220 mg theaflavin 3-gallate was obtained.
Reaction SMILES: Cl.[CH2:2]([S:4][CH2:5][CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.Cl[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(Cl)(Cl)Cl>[C:20]([O:19][C:17](=[O:18])[CH2:16][NH:7][CH2:6][CH2:5][S:4][CH2:2][CH3:3])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCSCCN
Reactant: CC(C)(C)OC(=O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCSCCNCC(=O)OC(C)(C)C
Yield: 34.2 %

Procedure:
To a solution of 10 g of 2-ethylthioethylamine hydrochloride and 15 g of triethylamine in 20 ml of chloroform was added with stirring 11 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an addition 1 hour. At the end of this period, the chloroform was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 5.3 g (34 percent) of N-(2-ethylthioethyl)glycine tert-butyl ester, B.P. 106°-9° C/1.5 mm Hg.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.C(OC([N:15]1[C@H:19]([CH2:20][C:21]2[S:25][C:24]3=[CH:26][N:27]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:28]([CH3:29])=[N+:23]3[CH:22]=2)[CH2:18][C@H:17]([S:34][C:35]2[C@H:36]([CH3:52])[C@@H:37]3[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:38]3[C:39]=2[C:40]([O:42]CC=C)=[O:41])[CH2:16]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.C(O)C>[CH2:32]1[CH2:33][CH:31]1[CH2:30][N:27]1[CH:26]=[C:24]2[S:25][C:21]([CH2:20][C@H:19]3[NH:15][CH2:16][C@@H:17]([S:34][C:35]4[C@H:36]([CH3:52])[C@@H:37]5[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:38]5[C:39]=4[C:40]([O-:42])=[O:41])[CH2:18]3)=[CH:22][N+:23]2=[C:28]1[CH3:29]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(C)n(CC5CC5)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1n(CC2CC2)cc2sc(C[C@@H]3C[C@H](SC4=C(C(=O)[O-])N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)CN3)c[n+]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
Anhydrous THF (0.7 ml) and 0.7 ml of dry ethanol are added to 47.9 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-(2-cyclopropylmethyl)-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethanesulfonate. Triphenylphosphine (7.8 mg), 0.016 ml of morpholine, and 4.3 mg of tetrakis(triphenylphosphine)palladium(0) are successively added thereto, and the mixture is stirred in an argon atmosphere at room temperature for one hr. THF (10 ml) is added thereto, and the resultant precipitate is further washed twice with 3 ml of THF and dried in vacuo to give a yellow powder which is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 2.0 mg of the title compound as a slightly yellow powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[O-:38][C:39]#[N:40].[K+]>CO.O>[NH:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:29][CH:30]=1)[C:39]([NH2:40])=[O:38]
Reactant: N#C[O-]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN)cc1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CNC(N)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
300 mg of 3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone are dissolved in 15 ml of methanol and 200 ml of triethylamine are added. Then 400 mg of potassium cyanate in 5 ml of water are added. After 2 days of stirring at room temperature the reaction solution is concentrated by rotary evaporation, the residue taken up in methylene chloride and washed once with water and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation. The residue is dried in vacuo at 100° C.
Reaction SMILES: COC1C=CC=CC=1S[CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36][C:37]([F:47])([F:46])[O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[SH:45].C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:26][C:22]([S:21][C:18]1[S:17][C:16]([NH:15][C:14]([N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[CH2:12][CH2:11][CH2:10][S:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[O:38][C:37]([F:36])([F:46])[F:47])=[O:28])=[N:20][CH:19]=1)([CH3:27])[C:23]([OH:25])=[O:24]
Reactant: FC(F)(F)Oc1ccccc1S
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccccc2OC(F)(F)F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-trifluoromethoxy-thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:14])(O)[C:11]#[N:12]>>[CH3:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([CH3:14])[C:11]#[N:12]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(O)C#N
Product: Cc1ccc(NC(C)(C)C#N)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A mixture of p-toluidine (1.07 g, 10 mmol) and acetone cyanohydrin (10 ml) was heated to 80° C. and stirred for 4 h. The medium was concentrated and dried under vacuum to yield 2 -methyl-2-(4-methylphenyl)aminopropanenitrile, 5a (1.72 g, 9.9 mmol, 99%) as brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:44]1[O:45][CH:46]=[CH:47][CH:48]=1)CCC>O1CCOCC1.C(OCC)(=O)C.C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:38])[N:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:7][N:6]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc(-c2c(OCCOc3ncc(-c4ccco4)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 86.7 %

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl)]4-(tert-butyl)benzenesulfonamide (Example 3) (277 mg) in 1,4-dioxane (7.5 ml) at room temperature was added 2-(tributylstannyl)furan (329 mg) and bis(triphenylphosphine)palladium (II) chloride (32 mg) the mixture was stirred and heated to reflux for 16 hrs. The reaction was diluted with ethyl acetate (100 ml) and washed with a 10% solution of potassium fluoride in water (100 ml), the aqueous portion was then extracted with ethyl acetate (100 ml). The organic fractions were separated and combined, washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ethyl acetate:hexane (3:2) to yield an oil which was dissolved in acetonitrile (20 ml) and washed with hexane (6×10 ml). Evaporation of the acetonitrile under reduced pressure yielded the title compound as a white solid (235 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([O:17][CH3:18])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[OH-].[K+].CO>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([O:17][CH3:18])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CCCC#CCC(OC)c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(CC#CCCCC(=O)O)c1ccco1
Yield: 95.8 %

Procedure:
A solution of 1.25 g of methyl 8-(2-furyl)-8-methoxy-5-octynoate, 0.66 g of 85% potassium hydroxide, 15 ml of methanol and 10 ml of water was heated under reflux for one hour. The methanol was evaporated and the residue partitioned with ether and water. The aqueous layer was chilled at 0° to 10° C., acidified with hydrochloric acid and the product extracted with ether. The extract was washed with brine, dried and concentrated, giving 1.13 g of the desired compound as a colorless oil. The identification is established by PMR; δ 3.35 (3H, s, methyl ether).
Reaction SMILES: F[C:2]([F:13])(F)[C:3]([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[F:14][C:15]1[C:20]([F:21])=CC(F)=[C:17]([F:23])[C:16]=1O.B(F)(F)F.CCOCC>>[F:10][C:7]([F:8])([F:9])[C:6]([O:5][C:3]1[C:2]([F:13])=[C:17]([F:23])[CH:16]=[C:15]([F:14])[C:20]=1[F:21])=[O:11]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Yield: 61.4 %

Procedure:
Trifluoroacetic anhydride (28 mL, 0.2 mol) was added dropwise with stirring to 27.1 g (0,163 mol) of 2,3,5,6tetrafluorophenol. Boron trifluoride etherate (0.2 mL) was added and the mixture was refluxed overnight. The residual solution was distilled at atmospheric pressure to remove trifluoroacetic anhydride and trifluoroacetic acid. The desired product 18 (32.2 g; 75% yield) was collected at 45° C. (18mm) as a colorless liquid:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[N+:15]([O-])=O)=[C:4]([N+:18]([O-])=O)[CH:3]=1.CCO.[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[NH2:15])=[C:4]([NH2:18])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(Br)ccc1-c1ccc(Br)cc1N
Temperature: 25 °C
Yield: 67.5 %

Procedure:
4,4′-dibromo-2,2′-dinitrobiphenyl (6.1 g, 15.17 mmol) was stirred in HCl 30 ml/EtOH 75 ml, Sn powder (7.2 g, 60.68 mmol) was added thereto, and then the reaction mixture was refluxed for 24 hours. Next, the reaction mixture was cooled to room temperature, neutralized with 10% NaOH solution, and then recrystallized in ethanol to obtain 4,4′-dibromo-2,2′-diaminobiphenyl (3.5 g, 67%). MS [M+H] 341.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]2[CH2:41][CH2:40][NH:39][C:38](=[O:42])[CH2:37]2)=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[O:42]=[C:38]1[NH:39][CH2:40][CH2:41][N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[F:27])=[CH:14][CH:15]=3)=[O:5])=[N:34][CH:33]=2)[CH2:37]1
Reactant: Nc1ccc(CN2CCNC(=O)C2)cn1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCNC(=O)C4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 4-(6-amino-pyridin-3-ylmethyl)-piperazin-2-one (Step 103.1), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 7 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 535.1 [M+H]+; tR=3.50 min (System 1); TLC: Rf=0.16 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9].C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:24])=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: Nc1ccc(Br)cc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2-Amino-phenyl)-(4-chloro-phenyl)-methanone (9.41 g, 0.04 mmol) dissolved in 150 mL DCM was added NBS (7.25 g, 0.04mol) at 0° C. The mixture is stirred at RT for overnight. The mixture is extracted with DCM, washed with NaHCO3, dried over NaSO4 and concentrated. This provides the desired compound. This is used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:46])[CH:28]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH2:29][CH3:30])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:46])[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:32]=1)[CH2:29][CH3:30])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)C(CC)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(CC)c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butyric acid ethyl ester.
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>CN(C=O)C>[Br:33][C:34]1[CH:40]=[CH:39][C:37]([N:38]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH:6]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:36][CH:35]=1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(Br)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
The product from Example 1C (0.7 g, 1.433 mmol) and 4-bromoaniline (2.54 g, 14.33 mmol) were suspended in DMF (6 mL) and stirred at 50° C. overnight. The resulting mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with 1N HCl (2×50 mL) followed by a brine wash then dried over MgSO4 filtered and concentrated. The crude product was purified by chromatography on silica gel using a solvent gradient of 2-50% ethyl acetate in hexane to give the title compound as a mixture of stereoisomers (74.4 mg, 11% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:32][C@H:33]2[CH2:53][CH2:52][C:35]3([O:39][C@H:38]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C@@H:37]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[O:36]3)[CH2:34]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH2:23][O:24]C3CCCCO3)=[CH:21][N:22]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:58].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:58][C:16]([C:18]3[S:19][C:20]([CH2:23][OH:24])=[CH:21][N:22]=3)=[CH:15][CH:14]=2)[CH2:32][C@H:33]2[CH2:53][CH2:52][C:35]3([O:36][C@H:37]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C@@H:38]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[O:39]3)[CH2:34]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ncc(CO)s3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (416 mg) in acetic acid (2.5 mL) was added ammonium acetate (659 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (151 mg, yield 42%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio). MS: 675 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:37]=[CH:36][C:26]([CH2:27][N:28]2[C:32]([CH2:33][CH2:34][NH2:35])=[CH:31][N:30]=[CH:29]2)=[CH:25][CH:24]=1)#[N:22].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[C:21]([C:23]1[CH:37]=[CH:36][C:26]([CH2:27][N:28]2[C:32]([CH2:33][CH2:34][NH:35][C:18]([C@@H:17]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][N:8]3[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:20])=[CH:31][N:30]=[CH:29]2)=[CH:25][CH:24]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)NCCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 18 h

Procedure:
To a solution of 2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydro-isoquinoline-3(S)-carboxylic acid (0.15 g, 0.54 mmol) and 3-(4-cyanobenzyl) histamine (0.122 g, 0.54 mmol) in DMF (5 mL) was added 1-hydroxybenzotriazole (0.083 g, 0.54 mmol), EDC (0.104 g, 0.54 mmol), and N-methylmorpholine (0.24 mL, 2.16 mmol). After stirring for 18 hr. the mixture was evaporated in vacuo and the residue was partitioned with EtOAc (50 mL) and saturated NaHCO3 (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration was done which gave the title compound.
Reaction SMILES: [NH2-].[Na+].CC1C=CC=CC=1.[C:10]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3(C#N)[CH2:33][CH2:32][C:27]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>CC1C=CC=CC=1C>[C:10]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:33][CH2:32][C:27]4([O:28][CH2:29][CH2:30][O:31]4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC1(c2ccc(OCc3ccccc3)cc2)CCC2(CC1)OCCO2
Agent: [NH2-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: c1ccc(COc2ccc(C3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 24 h
Yield: 87 %

Procedure:
To a stirred and heated (±65° C.) mixture of 60 parts of sodium amide solution 50% in dimethylbenzene and 315 parts of methylbenzene are added portionwise 33.5 parts of 8-[4-(phenylmethoxy)phenyl]-1,4-dioxaspiro[4,5]decane-8-carbonitrile. Upon completion, stirring is continued for 24 hours at reflux. The reaction mixture is cooled, about 16 parts of methanol are added dropwise and the whole is poured onto ice-water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 27 parts (87%) of 8-[4-(phenylmethoxy)phenyl]-1,4-dioxaspiro[4,5]decane as a residue.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([NH:8][C:9]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:12]([Br:19])=[CH:11][N:10]=1)=O)[CH3:2].C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[NH:8][C:9]2[N:10]=[CH:11][C:12]([Br:19])=[CH:13][C:14]=2[S:15](=[O:18])(=[O:17])[N:16]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)Nc1ncc(Br)cc1S(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1=NS(=O)(=O)c2cc(Br)cnc2N1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
In a sealed tube, N-(5-Bromo-3-sulfamoyl-pyridin-2-yl)-malonamic acid ethyl ester (2.2 g, 6.0 mmol) was suspended in toluene (44 mL) and triethylamine (11 mL, 78.9 mmol) was added. The mixture was heated at 110° C. while stirring for 30 min. The solid was completely dissolved, yet an immiscible, oily residue was observed along the bottom of the flask. Upon cooling to 25° C., ethyl acetate (˜50 mL) was added. Everything became miscible. The solution was concentrated in vacuo to afford a golden oil. The oil was dissolved in methanol (˜50 mL) and concentrated in vacuo to afford the crude product, (7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid ethyl ester (2.18 g, >6.0 mmol, 100%, still contained some solvent), as a golden oil. LC-MS (ESI) calcd for C10H10BrN3O4S 346.96, found 348.1 (100%), 349.2 (10%), 350.2 (99%) [M+H+].