Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:42])[NH:6][C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[C:21]([C:23]5[N:28]=[CH:27][C:26]([CH2:29][N:30]([CH2:38][CH2:39][O:40][CH3:41])C(=O)OC(C)(C)C)=[CH:25][CH:24]=5)[S:22][C:15]=34)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[C:21]([C:23]5[CH:24]=[CH:25][C:26]([CH2:29][NH:30][CH2:38][CH2:39][O:40][CH3:41])=[CH:27][N:28]=5)[S:22][C:15]=34)=[CH:11][N:12]=2)=[O:42])[CH2:2][CH2:3]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)nc4)c3s2)nc1
Yield: 57.8 %

Procedure:
A solution of 28 (754 mg, 1.27 mmol) and TFA (5 mL) in DCM (25 mL) was stirred at RT for 5.5 hr. The TFA was removed by co-evaporation with DCM, dissolved in a minimum of methanol, diluted with water, and the pH was adjusted to around 13 with 1N NaOH. The resulting sticky suspension was extracted with DCM in the presence of traces of methanol. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by Biotage (SiliaSep 40 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 1/99 to 10/90 over 20 CV) to produce a material that upon trituration with MeOH afforded the title compound 29 (360 mg, 0.734 mmol, 67% yield over 2 steps) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.23 (bs, 1H), 8.56 (d, J=1.6 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.27-8.20 (m, 2H), 7.89 (dd, J=8.2, 2.2 Hz, 1H), 7.79-7.72 (m, 2H), 7.66 (bd, J=9.0 Hz, 1H), 6.69 (d, J=5.5 Hz, 1H), 3.78 (s, 2H), 3.41 (t, J=5.9 Hz, 2H), 3.24 (s, 3H), 2.68-2.57 (m, 3H), 0.74-0.60 (m, 2H), 0.52-0.39 (m, 2H), one NH is missing. MS (m/z): 491.6 (M±H).
Reaction SMILES: [CH2:1]([CH:3]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH2:1]([CH:3]([CH:6]1[CH2:7][C:8](=[O:13])[CH:9]([C:25](=[O:26])[NH:24][S:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[C:10](=[O:12])[CH2:11]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)C1CC(=O)CC(=O)C1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CCC(CC)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-(1-ethylpropyl)-1,3-cyclohexanedione with p-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-(1-ETHYLPROPYL)-2-(N-p-CHLOROBENZENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 121°-122° C. (corr.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:22]([C:24]1[N:29]=[C:28]2[CH2:30][O:31][C:32](=O)[C:27]2=[CH:26][CH:25]=1)=C.Cl>C1COCC1>[CH2:6]([N:7]([CH2:22][C:24]1[N:29]=[C:28]2[CH2:30][O:31][C:32](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:27]2=[CH:26][CH:25]=1)[CH2:8][CH3:4])[CH3:5]
Reactant: C=Cc1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (3.38 g, 22.4 mmol.) in THF (100 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (45 mL of a 1 M solution in THF, 45 mmol) dropwise. The resulting solution is stirred at room temperature for 15 min and then treated with 2-vinyl-7H-furo[3,4-b]pyridin-5-one (1.2 g, 7.45 mmol) in one portion. The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is poured into a cold aqueous 2 N HCl solution (200 mL). The ice bath is removed and the reaction mixture is heated at 50° C. for 2 h and then stirred at room temperature overnight. The reaction mixture is treated with 100 mL ice water and stirred for 30 min. The yellow solid is collected by filtration and dried. The solid is purified by chromatography (silica gel, MeOH-Chloroform) and the product containing fractions concentrated. The residue is triturated with MeOH and the solid is collected by filtration and dried to give 5-Fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (Example 6) as an orange solid (0.82 g, 37%). The filtrate is absorbed to silica gel and subjected to chromatography (silica gel, EtOAc-hexane) to afford (Example 28) as a yellow solid (50 mg, 1.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH3:19])=[C:5]2[CH2:20][C:21]([NH2:23])=[O:22].[H-].[Na+].[CH3:26][O:27][P:28]([CH2:32][CH2:33][CH2:34]Br)(=[O:31])[O:29][CH3:30].CO.CCOC(C)=O>O>[CH3:26][O:27][P:28]([CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH3:19])=[C:5]2[CH2:20][C:21]([NH2:23])=[O:22])(=[O:31])[O:29][CH3:30]
Reactant: CCc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: COP(=O)(CCCBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
5-Hydroxy-2-ethyl-1-(phenylmethyl)-1H-indole-3-acetamide (308 mg, 1.0 mmol) was added to 40 mg (1.0 mmol) of NaH/mineral oil washed with hexanes) in 4 mL of DMF, stirred 0.5 hours, 196 mg (0.85 mmol) of (3-bromopropyl)phosphonic acid dimethyl ester added and stirring maintained for 6.5 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel eluting with EtOAc, 5% MeOH/EtOAc, then 10% MeOH/EtOAc to give 269 mg (59% yield) of [3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester.
Reaction SMILES: Cl.[N:2]1([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([NH:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])=[N:19][N:18]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>O1CCOCC1>[N:2]1([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([NH:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])=[N:19][N:18]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2nnc(C(=O)Nc3ccc(N4CCOCC4)nc3)o2)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Nc2nnc(C(=O)Nc3ccc(N4CCOCC4)nc3)o2)c1
Reaction time: 18 h
Yield: 98.9 %

Procedure:
4M HCl in 1,4-dioxane (70 mL) was added to tert-butyl 3-[(5-{[(6-morpholin-4-ylpyridin-3-yl)amino]carbonyl}-1,3,4-oxadiazol-2-yl)amino]benzoate (3.22 g, 6.90 mmol) and the suspension stirred for 18 hours. All volatiles were removed in vacuo and the residue triturated with Et2O (20 mL), the solid filtered, washed with Et2O (2×10 mL), hexane (2×10 mL) to give the title compound (2.80 g, 99%) as a cream powder; MS m/e (MH)+ 411
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]([O:15][CH:16]([O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:17])=[O:14])[N:8]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[N:41](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:40]=[N:39][N:38]=4)=[CH:27][CH:26]=3)[N:6]2[N:7]=1)[CH3:2].CO>C(O)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]([O:15][CH:16]([O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:17])=[O:14])[N:8]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][N:40]=[N:39][N:38]=4)=[CH:27][CH:26]=3)[N:6]2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)OC(C)OC(=O)c1c(CC)c2nc(CC)nn2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)OC(C)OC(=O)c1c(CC)c2nc(CC)nn2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 95.6 %

Procedure:
A mixture consisting of 5.64 g of 1-ethoxycarbonyloxyethyl 2,7-diethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylate, 230 ml of methanol and 12 ml of acetic acid was heated under reflux for 3 hours. After removing the solvent by distillation under a reduced pressure, the resulting residue was subjected to silica gel column chromatography. Elution was conducted with a methanol-chloroform (1:19, v/v) mixed solvent to give 3.76 g of 1-ethoxycarbonyloxyethyl 2,7-diethyl-5-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole-6-carboxylate in the form of amorphous foamy material.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[N:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:7][CH:6]=1
Reactant: NC1CC1
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1cc(CNC2CC2)ccn1
Temperature: 90 °C
Reaction time: 24 h
Yield: 126.1 %

Procedure:
Cyclopropylamine (69 μL, 0.99 mmol) in ethanol (1 mL) was mixed with 4-pyridinecarbaldehyde (86 μL, 0.99 mmol) at room temperature and refluxed at 90° C. for 2 hours. After completion of the reaction, the ethanol was evaporated azeotropically. The resulting reaction product in methanol (1 mL) was mixed with sodium borohydride (204 mg, 5.40 mmol) under cooling with ice and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (185 mg, quant.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH3:18]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:18])=[O:11]
Reactant: CO
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 77 %

Procedure:
Indole-2-carboxylic acid (47.0 g, 292 mmol) was dissolved in 200 ml of methanol. To this solution was added 6 ml of concentrated sulfuric acid. The resulting mixture was heated to reflux and maintained at this temperature for about 16 hours. The reaction mixture was then cooled to room temperature and the solids were removed by filtration and then washed with 200 ml of methanol. The crystals were dried in a vacuum oven, yielding 39.5 grams (77%) of the desired title product as white needles. Analytical data obtained was consistent with the proposed title structure.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])=[O:5].[OH:18]S(O)(=O)=O>>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1)[NH:6][C:4](=[O:5])[C:3]2=[O:18]
Reactant: COc1ccc(NC(=O)C=NO)c([N+](=O)[O-])c1
Reactant: O=S(=O)(O)O
Product: COc1cc2c(c([N+](=O)[O-])c1)NC(=O)C2=O
Temperature: 80 °C

Procedure:
2-Hydroxyimino-N-(4-methoxy-2-nitro-phenyl)-acetamide (5 g, 22 mmol) was added portion wise to a hot solution of conc. H2SO4 (20 mL, 4 vol) at 60° C. After completion of the addition, temperature was raised to 80° C. and maintained the same for one hour. After completion of the reaction, the reaction mixture was poured on to the crushed ice and the resulting precipitate separated was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as brick red colored solid which was used directly for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]=1[OH:26])([CH3:15])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([C:20]1[CH:19]=[C:18]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:17]([OH:26])=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:21]=1)=[O:5]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Cc1ccc(C(=O)Cl)c(Cl)n1
Product: Cc1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Yield: 82.8 %

Procedure:
The similar procedure in reference example 1 by using 19 g of 2-chloro-6-methylnicotinoyl chloride, 24.7 g of 2,6-di-tertiary butylphenol and 31.3 g of anhydrous stannic chloride is performed and the obtained crude product is recrystallized from hexane to give 29.8 g of 4-(2-chloro-6-methylnicotinoyl)-2,6-di-tertiary butylphenol as pale yellow crystals, melting at 116°-117° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15])([CH3:11])[CH3:10]>>[CH3:8][Si:9]([O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:10])[CH3:11]
Reactant: C[Si](C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)C(=O)Cl
Agent: Cl
Product: CC(=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O[Si](C)(C)C

Procedure:
A method of synthesizing pyruvyl-phenylalanine according to the invention comprises the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting pyruvyl chloride with a suspension of phenylalanine trimethylsilyl ester hydrochloride to yield pyruvyl-phenylalanine trimethylsilyl ester and then subjecting the pyruvyl-phenylalanine trimethylsilyl ester to hydrolysis to yield pyruvyl-phenylalanine. The pyruvyl-phenylalanine synthesized via the route set forth above serves as a pyruvyl-amino acid pyruvate precursor.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:37])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:18][CH:17]2[C:16](=[O:19])[NH:15][C:14]3=[O:20])=[CH:9][CH:8]=1.CN(C1C=CC=CN=1)C.Cl>C(Cl)Cl.O.N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:18][CH:17]2[C:16](=[O:19])[NH:15][C:14]3=[O:20])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C23CC2C(=O)NC3=O)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C23CC2C(=O)NC3=O)cc1
Reaction time: 16 h

Procedure:
A solution of 1.2 ml of methanesulfonyl chloride in 10 ml of methylene chloride is stirred dropwise at room temperature into a mixture of 3 g of 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione, 90 mg of dimethylaminopyridine and 37 ml of pyridine. After it has been stirred for 16 hours, the reaction mixture is freed from solvent in vacuo. The residue is dissolved in 100 ml of water and the solution is adjusted to pH 1 with hydrochloric acid. After further stirring, the crystals are isolated by filtration and recrystallised from methanol. The title compound is obtained in the form of whitish orange crystals with a melting point of 208°-209° C. and with Rf=0.32 on thin-layer silica gel plates in the system methylene chloride/methanol (10:1).
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].C[N+](C)(C)C.[C:19]([O:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(OC(C)(C)C)=O.OC1C=CC(C=C)=CC=1>>[C:30]([O:29][C:27]([O:26][C:19]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C=Cc1ccc(O)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 87 %

Procedure:
10.00 gs (6.17×10-2 moles) of 4-acetoxystyrene was added to a 25 wt % solution of tetramethylammonium hydroxide (52 mL, 15% mole excess). After stirring for 15 minutes, a clear yellowish solution was obtained. To this solution was added with stirring to mix the phases 13.46 gs (6.17×10-2 moles) of di-tert-butyl dicarbonate. Slow formation of product was observed during 1 to 2 hours and the reaction essentially reached completion after 5 hours. A slight amount of residual 4-hydroxystyrene was detected by thin layer chromotography. The reaction mixture was extracted with two (15 mL) portion of ethyl ether. The ethyl ether extract was washed with 10 mL of 25% tetramethylammonium hydroxide(TMAH) and distilled water to remove base. The organic layer was dried over MgSO4 filtered and the solvent removed under vacuum yielding 11.87 gs (87% yield) of pure 4-tert-butyloxycarbonyloxystyrene. Analysis of the product indicated: IR(cm-1): 2950, 1755, 1275, 1150; 1H NMR(CDCl3, ppm): 1.54(s, 9H), 5.20(d(11 Hz), 1H), 5.67(d(18 Hz), 1H), 6.67(d of d(11, 18 Hz), 1H), 7.11(d(8 Hz), 2H); 7.38(d(8Hz), 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:10]1([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1ccc(Br)cc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Clc1ccc(-c2ccccc2)cc1Cl
Temperature: 120 °C
Yield: 30.4 %

Procedure:
A mixture was prepared of 1-Bromo-3,4-dichlorobenzene (20.0 g, 88.5 mmol), phenylboronic acid (13.5 g, 110.6 mmol), triphenylphosphine (2.32 g, 8.85 mmol), potassium carbonate (30.58 g, 221.25 mmol), 150 mL xylenes, and 150 mL water. The mixture was stirred and nitrogen bubbled into it for 20 minutes. Palladium acetate was added (0.99 g, 4.425 mmol) and the mixture was heated at 120° C. under nitrogen overnight. Cooled to room temperature and diluted with water and dichloromethane. The mixture was filtered through Celite and the Celite was washed with water and dichloromethane. The layers were separated and the aqueous layer extracted with dichloromethane. The organic layers were dried over magnesium sulfate, filtered, and evaporated to yield a brown oil. The crude material was purified by column chromatography eluting with hexanes. The cleanest fractions containing product were collected. Obtained 6 g (30%) of clean product.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][C:9]1([CH3:18])[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:24]O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][C:9]1([CH3:18])[C:15]([O:17][CH3:24])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC1(C(=O)O)COCC(=O)N1Cc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)C1(C)COCC(=O)N1Cc1ccccc1
Temperature: 50 °C

Procedure:
Dissolve 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylic acid (1 eq) in MeOH (10 volumes) and stir. Add sulfuric acid (3 eq) dropwise. Heat at 50° C. for 24 hours. Cool to room temperature and concentrate. Add EtOAc (25 volumes) wash with water (7 volumes), followed by saturated aqueous NaHCO3 (5 volumes), and then water (7 volumes). Dry the EtOAc layer and concentrated to give methyl 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=O>>[CH3:45][N:44]([CH3:46])[CH2:42][CH2:41][O:39][C:38]1[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:34])[CH3:35])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[C@@H:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[CH:3][C:2]=1[F:1]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: CN(C)C(=O)CCl
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN(C)C)c(F)c2)C(C)C)c1
Yield: 50.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N,N-dimethylacetamide (9.4 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (10 mg) was obtained.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[NH2:7][C:8]1[N:13]=[C:12]([CH2:14]Cl)[CH:11]=[C:10]([O:16][CH3:17])[N:9]=1>CO.O>[NH2:7][C:8]1[N:9]=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([CH2:14][S:1][C:2]2[S:3][CH2:4][CH2:5][N:6]=2)[N:13]=1
Reactant: SC1=NCCS1
Reactant: COc1cc(CCl)nc(N)n1
Solvent: O
Solvent: CO
Product: COc1cc(CSC2=NCCS2)nc(N)n1
Reaction time: 1 h

Procedure:
11.9 g of 4,5-dihydro-2-mercapto-thiazole are suspended in 100 ml of methanol, and to the suspension are added 18.0 g of 30% methanolic sodium methylene solution. To the formed clear solution are subsequently added 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine, and refluxing is carried out for 1 hour. After the solution has cooled, it is diluted with about 1 liter of water, and the product which precipitates is separated and dried. The yield is 22.5 g (88% of theory) of 2-amino-4-methoxy-6-(4,5-dihydrothiazol-2-yl-thiomethyl)-pyrimidine, m.p. 122°-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH:17](O)=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:17]=[O:18]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=CNc1ccccc1-c1cc2ccccc2[nH]1

Procedure:
To a solution prepared from 20 g of 2-(2-aminophenyl)indole, 12.7 ml of formic acid and 500 ml of THF was added 26 g of dicyclohexyl carbodiimide at room temperature under N2. The resultant solution was stirred overnight at room temperature. The mixture was then filtered and the filtrate washed with aqueous NaHCO3 (2x), H2O and saturated NaCl solution and dried (MgSO4). Concentration gave a red oil which was purified by HPLC, using 1% EtOAc/CH2Cl2 as an eluent, to afford 11.45 g of solid, m.p. 147°-149° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1)CC)[C:2]1C=CC=CC=1>C(O)C.[Pd]>[CH2:1]([NH:8][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCNCCc1ccc(NS(C)(=O)=O)cc1

Procedure:
N-Benzyl-N-ethyl-4-methanesulphonamidophenethylamine (4.3 g, 12.9 mmole) was stirred under a hydrogen atmosphere (50 p.s.i. =344.7 kPa) in ethanol (50 ml) containing 10% Pd/C (0.5 g) for 5 hours. The mixture was then filtered, evaporated and the residue triturated with ether to give the title compound, yield 2.6 g, m.p. 125°-128°.