Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCC[CH2:21]1.O>CCOCC>[CH3:21][C:14]([C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:12]=1)=[O:16]
Reactant: C1CCOC1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 1.5 h

Procedure:
Over a period of 1.5 hours, methyl lithium (531 ml. of a 2 molar solution, 1.06 M) is added under a nitrogen atmosphere to a rapidly stirring solution of 3-benzyloxybenzoic acid (116 g., 0.532 M) in ether (250 ml.) - tetrahydrofuran (1400 ml.) maintained at 15°-20° C. After stirring an additional 0.75 hour at 10°-15° C., water (600 ml.) is slowly added keeping the reaction temperature below 20° C. The aqueous layer is separated and extracted with ether (3 × 250 ml.). The organic phases are combined, washed with saturated sodium chloride solution (4 × 300 ml.), dried over sodium sulfate, and concentrated under vacuum to give the product as an oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]1[N:12]=[C:13]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][OH:33])[CH2:28][CH2:27]2)[C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][S:17][C:15]=2[N:16]=1>CN(C)C=O>[OH:33][CH2:32][CH:29]1[CH2:30][CH2:31][N:26]([C:13]2[C:14]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:18][S:17][C:15]=3[N:16]=[C:11]([CH2:10][N:3]3[CH2:7][CH2:6][CH2:5][C:4]3=[O:8])[N:12]=2)[CH2:27][CH2:28]1
Reactant: O=C1CCCN1
Reactant: OCC1CCN(c2nc(CCl)nc3scc(-c4ccccc4)c23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1nc(N2CCC(CO)CC2)c2c(-c3ccccc3)csc2n1
Reaction time: 0.17 h

Procedure:
Sodium hydride (25 mg, 60% w/w in mineral oil) was added to a solution of 2-pyrrolidinone in dry N,N-dimethylformamide (2 mL) under a nitrogen atmosphere. The mixture was stirred for 10 min then [1-[2-(chloromethyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]-4-piperidyl]methanol (100 mg) was added. The mixture was stirred for 2 hr at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate (10 mL) and water (10 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (1×10 mL), dried (sodium sulfate), filtered and evaporated to give the target compound (96 mg) as a yellow solid. m/z [M+H]+ 424.0. Retention time 3.95 min (LCMS method+ve 6 min). It was used in the next reaction without purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](F)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([NH2:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH2:23])[CH3:22]>C(Cl)CCl>[CH3:22][CH:21]([NH:23][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:13])[F:14])=[CH:5][CH:6]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:24][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=1
Reactant: CC(N)CCCCCCN
Reactant: O=C(F)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCCl
Product: CC(CCCCCCNC(=O)c1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
m.p. 137°-138° C., 15.1 g., was prepared as in Example 20 using 18.7 g. of 4-trifluoromethoxybenzoyl fluoride in 50 ml. of ehtylene dichloride, 6.0 g. of 1,7-octanediamine in 100 ml. of ethylene dichloride, 13.8 g. of anhydrous potassium carbonate, and recrystallization from chloroform.
Reaction SMILES: [Li].[O:2]([CH2:5][CH3:6])CC.IC.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2(C(O)=O)[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1>O>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2([C:5](=[O:2])[CH3:6])[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)=[CH:14][CH:15]=1
Reactant: CCOCC
Reactant: Cc1ccc(NC2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1
Agent: [Li]
Solvent: CI
Solvent: O
Product: CC(=O)C1(Nc2ccc(C)cc2)CCN(CCc2ccccc2)CC1
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
To a stirred solution of 17.4 parts of lithium in 140 parts of dry 1,1'-oxybisethane is added dropwise a small amount of a solution of 193.7 parts of iodomethane in 210 parts of dry 1,1'-oxybisethane. After the reaction is started by heating, there are added 420 parts of dry 1,1'-oxybisethane. The remainder of the solution is added dropwise at reflux temperature. Stirring at reflux is continued for 45 minutes. Then there are added portionwise (quickly) 41.8 parts of 4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylic acid (exothermic reaction: reflux temperature is maintained). Upon completion, stirring at reflux is continued for one hour. The reaction mixture is cooled in an ice-bath and decomposed by the dropwise addition of 1000 parts of water. The organic layer is separated and discarded. The aqueous phase is extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off and recrystallized from 2,2'oxybispropane, yielding 26 parts (62.4%) of 1-{4-[(4-methylphenyl)amino]-1-(2-phenylethyl)-4-piperidinyl}ethanone; mp. 133.7° C.
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:26])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[CH2:19]([C:16]1[C:17](=[O:18])[NH:8][C:9](=[O:26])[N:10]2[CH2:15][CH2:14][CH2:13][S:12][C:11]=12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1c(Cc2ccccc2)c2n(c(=O)n1Cc1ccccc1)CCCS2
Agent: BrB(Br)Br
Solvent: CO
Solvent: Cc1ccccc1
Product: O=c1[nH]c(=O)n2c(c1Cc1ccccc1)SCCC2
Reaction time: 0.5 h

Procedure:
To a solution of 9.11 g (25 mmol) of 7,9-dibenzyl-3,4-dihydro-2H,6H-pyrimido-[6,1-b][1,3]thiazine-6,8(7H)-dione in 200 ml of toluene, 12.5 g (50 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 50 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanol-diethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 4.88 g (71.1%, light white crystal) of the desired product.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[N:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[N:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(F)cc3)oc2C)C2CCCCC2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccc(F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)nc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of 5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridine-2-carboxylic acid (694 mg), ethyl 3-(methylamino)propanoate (223 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), hydroxybenzotriazole monohydrate (260 mg) and triethylamine (237 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give ethyl 3-[{[5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate (263 mg) as an amorphous compound. Ethyl 3-[{[5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (246 mg, 30%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([NH2:12])[CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26](O)=[O:27].CN(C)CCCN=C=NCC>N1C=CC=CC=1>[NH2:12][C:8]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]([NH:11][C:26]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:20]=1)=[O:27])[CH3:10]
Reactant: CC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CC(NC(=O)c1cnccn1)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
1,1-bis(4-fluorophenyl)-1,2-propanediamine (94 mg) and pyrazinecarboxylic acid (53 mg) was dissolved in pyridine (1 mL), and to the solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (103 mg). The mixture was stirred at room temperature for 24 hrs. The reaction mixture was concentrated, and the obtained residue was dissolved in chloroform, followed by washing with saturated sodium hydrogen carbonate aqueous solution. The aqueous layer was extracted with chloroform twice, and the combined chloroform layers were dried over magnesium sulfate. After evaporating the solvent in vacuo, the obtained residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=1:1→1:3) to give N-[2-amino-2,2-bis(4-fluorophenyl)-1-methylethyl]-2-pyrazinecarboxamide (112 mg) as the mixture with pyrazinecarboxylic acid methyl ester. The mixture was dissolved in methanol (1 mL), and to the solution was added 2N sodium hydroxide aqueous solution (0.5 mL), and the solution was stirred at room temperature for one hr. The reaction mixture was diluted with chloroform, followed by washing with water. The aqueous layer was extracted with chloroform twice, and the combined chloroform layers were dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give the pure amide compound (95 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].Br[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Brc1ccc(N(Cc2cccnc2)c2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2cccnc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 74.7 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (1060.0 mg) was reacted with N-(4-bromophenyl)-N-((pyridin-3-yl)methyl)pyrimidin-2-amine (120.0 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyridin-3-ylmethyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (147.8 mg). Column chromatography (silica gel, eluent: chloroform→chloroform/ethyl acetate=1/1) and thin layer chromatography (chloroform/ethyl acetate=1/1) were used for purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH:3]([N:7]1[CH2:10][CH:9]([CH2:11][C:12]2[N:13]([CH3:37])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:27]2[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[C:28]2[CH3:36])[N:15]=3)[CH2:8]1)[C:4]([OH:6])=O.[OH-].[NH4+:40]>>[CH3:1][CH:2]([CH3:38])[CH:3]([N:7]1[CH2:10][CH:9]([CH2:11][C:12]2[N:13]([CH3:37])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:17]=[C:16]([N:27]2[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=[C:28]2[CH3:36])[N:15]=3)[CH2:8]1)[C:4]([NH2:40])=[O:6]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C(=O)O)C(C)C)C3)n(C)c2n1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C(N)=O)C(C)C)C3)n(C)c2n1

Procedure:
Following General Procedure K, 3-methyl-2-(3-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)azetidin-1-yl)butanoic acid and ammonium hydroxide were coupled to give 579. LCMS m/z: 259.7 (2M+H+)
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: CC1(C)CC(CCBr)CCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCOC(C)(C)C1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11][Mg]Br>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ncnc2[nH]ccc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 15.9 %

Procedure:
Into a round bottom flask the catalyst PdCl2(dppf), under an atmosphere of nitrogen, was placed with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene was added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) was added dropwise. The solution turned from orange to yellow, and was slowly heated to 60° C. and stirred for 3 hrs at 60° C. and then overnight at room temperature. The resulting dark orange reaction mixture was quenched with 1 N hydrochloric acid and adjusted to pH ˜5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (42, 202 mg). 1H-NMR(dmso-d6) was consistent with the desired compound. MS(ESI) [M+H+]+=134.3.
Reaction SMILES: C(O)(=O)C.C(=O)([O-])O.[K+].[C:10]([NH:14][C:15]([C@@H:17]1[CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][NH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CS([O:31][C@@H:32]1[C@@H:38]([NH:39][C:40](=[O:52])[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47]C(=O)C)[C:42]=2[CH3:51])[CH2:37]OC(C)(C)O[CH2:33]1)(=O)=O>>[C:10]([NH:14][C:15]([C@@H:17]1[CH2:26][C@H:25]2[C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][N:18]1[CH2:33][C@H:32]([C@@H:38]1[CH2:37][O:52][C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([OH:47])[C:42]=2[CH3:51])=[N:39]1)[OH:31])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: CC(=O)Oc1cccc(C(=O)N[C@H]2COC(C)(C)OC[C@@H]2OS(C)(=O)=O)c1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1c(O)cccc1C1=N[C@H]([C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)CO1
Temperature: 45 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
Production of compound [13] (Step 9) Acetic acid (14.0 ml, 245 mmol) was added to the mixture obtained in Example 8 at not more than 10° C. to make the mixture acidic, and potassium hydrogencarbonate (25.0 g, 250 mmol) and (3S, 4aS, 8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [12], 13.7 g, 57.6 mmol) were successively added. The mixture was stirred at 45° C. for 6 hours to give a pale yellow suspension. The suspension was concentrated to ⅕ and water (340 ml) was added. The suspension was stirred for one hour at room temperature. The resulting crystals were collected by filtration and washed successively with water (200 ml) and butyl acetate (340 ml). The crystals were dried under reduced pressure at 60° C. to give colorless crystals of (3S, 4aS, 8aS)-2-{(2R)-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [13], 17.3 g, yield 46%, from compound [9]), melting point 240° C.
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].[NH2:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11]>C(O)C>[C:1]([NH:5][C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])=[S:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(CO)CO
Reactant: CC(C)(C)N=C=S
Solvent: CCO
Product: CC(C)(C)NC(=S)NC(CO)CO
Temperature: 20 °C
Reaction time: 94 h

Procedure:
30.4 cm3 of tert-butyl isothiocyanate are added to a solution of 14.6 g of 2-amino-1,3-propanediol in 245 cm3 of ethanol, and the mixture is then stirred at a temperature in the region of 20° C. for 94 hours. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and the residue is slurried in a mixture of 160 cm3 of petroleum ether and 26 cm3 of ethanol, and the product is filtered off and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 60° C. 30 g of 1-tert-butyl-3-(2-hydroxy-1-hydroxymethylethyl)thiourea are obtained in the form of a white solid [1H NMR spectrum (250 MHz, (CD3)2SO-d6, δ in ppm): 1.42 (s: 9H); 3.38 (mt: 2H); 3.54 (mt: 2H); 4.17 (unresolved complex: 1H); 4.70 (t, J=5 Hz: 2H); 7.08 (d, J=8 Hz: 1H); 7.38 (s: 1H]).
Reaction SMILES: NCCN1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[NH2:23][CH2:24][C@H:25]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>CO>[CH2:34]([O:33][C:31]([NH:30][CH:25]([CH2:24][N:23]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1)[C:26]([O:28][CH3:29])=[O:27])=[O:32])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(Cn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate A Step 3) (1.342 g, 3.98 mmol), (S)-methyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate (1.207 g, 4.18 mmol) and triethylamine (1.665 ml, 11.94 mmol) were suspended in methanol (20 ml). The mixture was heated to reflux for 16 hours then cooled to room temperature and filtered. The residue was rinsed with methanol (20 ml) to afford the title compound.
Reaction SMILES: [CH2:1]([C:5]1([CH2:33][CH2:34][CH2:35][CH3:36])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][O:26]COC)[C:19]=3[S:18](=[O:31])(=[O:30])[N:17]=2)[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>Cl.O1CCOCC1>[CH2:1]([C:5]1([CH2:33][CH2:34][CH2:35][CH3:36])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][OH:26])[C:19]=3[S:18](=[O:31])(=[O:30])[N:17]=2)[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3c(COCOC)csc3N2)=C(O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
A solution of the product of Example 10F (27 mg, 0.051 mmol) in 4.0 N HCl in dioxane (4 mL) was stirred at 25° C. for 18 hours and concentrated in vacuo. A suspension of the residue in acetonitrile (2 mL) was treated with 1.0 N sodium hydroxide solution (51 μL, 0.051 mmol) and stirred at 25° C. for 1 h. The solution was lyophilized to afford the title compound (28 mg, 100%). 1H NMR (300 MHz, DMSO-d6): δ 16.82 (m, 1 H), 8.04 (d, J=7.35 Hz, 1 H), 7.47 (m, 2 H), 7.32 (t, J=7.35 Hz, 1 H), 6.95 (s, 1 H), 5.32 (t, J=5.70 Hz, 1 H), 4.61 (m, 2 H), 2.09 (m, 2 H), 1.70 (m, 2 H), 1.02 (m, 4 H), 0.84 (m, 2 H), 0.67 (m, 6 H), 0.49 (s, 2 H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:18]=1)=[O:11].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][CH:35]=1)[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:18]=1)=[O:11])(=[O:4])=[O:3]
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N)c3)ccc2C)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(NS(C)(=O)=O)c3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
Methanesulphonyl chloride (0.25 g) was added to a stirred mixture of N-[5-(3-aminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.84 g), pyridine (0.5 ml) and methylene chloride (25 ml) and the mixture was stirred at ambient temperature for 48 hours. The mixture was washed with 2N hydrochloric acid and with water, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether and the resultant white solid was dried under vacuum at 60° C. There was thus obtained the title compound (0.85 g), m.p. >300° C.; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.03 (s, 3H), 3.82 (s, 6H), 7.06 (d, 1H), 7.23 (d, 1H), 7.4 (br d, 1H), 7.47 (t, 1H), 7.55 (br m, 2H), 7.63 (m, 1H), 7.66 (br d, 1H), 7.72 (d, 1H), 7.78 (d, 1H), 9.73 (br s, 1H), 9.91 (br s, 1H), 10.24 (br s, 1H);