Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[CH:26]([C:28]1[NH:32][N:31]=[N:30][N:29]=1)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:26][C:28]1[NH:32][N:31]=[N:30][N:29]=1
Reactant: O=Cc1nnn[nH]1
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Product: CC1=C(CCON=Cc2nnn[nH]2)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 5-formyltetrazole by the method of Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH:7]([CH:10]([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])([CH3:9])[CH3:8].C(N(CCCC)CCCC)CCC>[OH-].[Na+]>[OH:12][C:11]1[C:10]([CH:7]([CH3:9])[CH3:8])=[C:16]([OH:17])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)c1c(O)nc2ncnn2c1O
Temperature: 180 °C
Reaction time: 6 h
Yield: 82.4 %

Procedure:
A mixture of 14 g (0.17 mol) of 3-amino-1,2,4-triazole, 34.3 g (0.17 mol) of diethyl 2-isopropylmalonate and 50 ml of tributylamine were stirred at 180° C. for 6 h. The reaction mixture was then cooled to 70° C., an aqueous solution of sodium hydroxide (21 g/200 ml of water) was added and the mixture was stirred for 30 min. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The aqueous phase was then acidified using conc. hydrochloric acid and the resulting precipitate was collected by filtration. Drying gave 27 g (0.14 mol) of the title compound.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:4]1.N.C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27]([NH2:32])=[O:28])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:4]1
Reactant: CO[C@@H]1CCC[C@H](Oc2ncccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CO[C@@H]1CCC[C@H](Oc2ncccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 0.1 g racemic 4-[2-((cis)-3-methoxycyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (7 M in methanol) using TBTU instead of HATU in DMF as solvent.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[CH:8][C:7]=1[CH3:29].[OH-].[Na+].[CH2:33]1COCC1>CO>[CH3:29][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=3)=[CH:17][C:18]=2[CH3:33])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:2])=[O:30]
Reactant: C1CCOC1
Reactant: COC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)cc2C)ccc1CCC(=O)O

Procedure:
3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionic acid methyl ester (0.043 g, 0.0959 mmole) is treated with a mixture of NaOH(aq) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight. The organic solvents are removed on rota-vapor. The residue is diluted with water (10 mL), acidified to pH=2 with 6N HCl(aq). The precipitate is collected through filtration, washed with cold water (30 mL) and dried to provide the titled compound as a white solid. MS (ES): 433 (M+H); the structure is also confirmed by proton NMR. A substantially similar process is used to make the following compound and the Compound of Example 45, below.
Reaction SMILES: [NH2:1][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(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=2)[NH:7]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Yield: 90 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (2 g, 13.5 mmol, prepared according to U.S. Pat. No. 6,114,371) in 30 ml of dichloromethane was added with triethylamine (1.9 ml). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with methanesulfonyl chloride (1 ml, 13.5 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated at 45° C. for 1 hour until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-methanesulfonamide (2.7 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH:28]([CH2:31]OS(C3C=CC=CC=3)(=O)=O)[CH2:27]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH:28]([CH2:31][N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[CH:3]=4)[C:8]3=[O:13])[CH2:27]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: Cc1cc2c(cc1C)C(=O)NCC2
Reactant: COc1ccc(CCN2CCC(COS(=O)(=O)c3ccccc3)C2)cc1OC
Product: COc1ccc(CCN2CCC(CN3CCc4cc(C)c(C)cc4C3=O)C2)cc1OC

Procedure:
Prepared from 6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline and N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-benzenesulphonyloxymethyl-pyrrolidine analogously to Example 2.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C([O-])([O-])=O.[K+].[K+].CS(C)=O.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[CH:26]1([CH2:25][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:28][CH2:27]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
55 g of 4-(difluoromethoxy)-3-hydroxybenzaldehyde, 42.42 g of K2CO3 (1.05 eq), 4.86 g of KI (0.1 eq) and 220 mL of dimethylsulphoxide (DMSO) were loaded in a reactor. The mixture was heated at 70° C. and kept for 1 h. A mixture previously prepared of 42.65 g of bromomethyl cyclopropane (1.08 eq) and 110 mL of DMSO was added for 1 hour. The reaction was kept for 3 h at 70° C., and then cooled at room temperature. Once the temperature was reached, 375 mL of toluene was added. The suspension was filtered to remove the remaining K2CO3, and then it was cooled at 0-5° C., and 375 mL of deionised water were loaded. The phases were separated and the organic phase was washed twice with 55 mL of deionised water. The solvent was removed at reduced pressure, obtaining 70 g (yield 99%) of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde as a viscous yellowish fluid.
Reaction SMILES: [OH:1][CH:2]([C:25]([O:27][CH3:28])=[O:26])[C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].CS([C:39]1[N:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([CH3:47])[N:40]=1)(=O)=O>CN(C=O)C.O>[CH3:28][O:27][C:25]([CH:2]([O:1][C:39]1[N:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([CH3:47])[N:40]=1)[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[O:26]
Reactant: COC(=O)C(O)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(C)cc(OC)n1)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
10 g (25.9 mmol) of methyl 3-(2-hydroxy-2-methoxycarbonyl-1,1-di-phenylethoxy)-2,2-dimethylpropionate were dissolved in 40 ml of DMF under N2, 1.78 g (13 mmol) of K2CO3 and 5.2 g (25.9 mmol) of 2-methanesulfonyl-4-methoxy-6-methylpyrimidine were added, and the mixture was stirred at 80° C. for 2 h. It was subsequently diluted with 40 ml of H2O and extracted twice with 30 ml of diethyl ether, the organic phase was dried over MgSO4 and concentrated, and the residue was purified by chromatography on silica gel with ethyl acetate/cyclohexane mixtures. Crystallization from diethyl ether/hexane resulted in 11.8 g (90%) of the product as colorless crystals.
Reaction SMILES: [C:1]([CH:4]([CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])(=[O:3])[CH3:2]
Reactant: C=CCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(OC)c(OC)c2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(OC)c3)nn12

Procedure:
Analogously to Example 1, 160 mg (0.36 mmol) of 2-acetyl-N-{1-[3-(3,4-di-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-6-heptenamide (Example 30A) and 0.06 g (0.36 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetyl-5-hexenyl)-2-(3,4-dimethoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([CH:6]([CH2:10][CH2:11][CH2:12][C@H:13]1[C@@H:21]2[C@@H:16]([NH:17][C:18]([NH:20]2)=[O:19])[CH2:15][S:14]1)[C:7](=[O:9])[OH:8])=[O:5].[CH3:22]O>>[CH3:1][N:2]([CH3:22])[CH2:3][C:4]([CH:6]([CH2:10][CH2:11][CH2:12][C@H:13]1[C@@H:21]2[C@@H:16]([NH:17][C:18]([NH:20]2)=[O:19])[CH2:15][S:14]1)[C:7](=[O:8])[OH:9])=[O:5]
Reactant: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Reactant: CO
Product: CN(C)CC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O

Procedure:
N-methyl-glycyl-biotin is esterified in refluxing methanol containing gaseous HCl to give the methylester, methyl-(N-methyl)glycyl-biotin. This methyl ester is dissolved in ethylene diamine and stirred at 23° C. for 14 hours to afford biotinyl-N-methyl-glycyl-ethylene diamine monoamide. The solvent (ethylene diamine) is evaporated under vacuum. The amino group of biotinyl-N-methyl-glycyl-ethylene diamine monoamide is acylated with N-hydroxysuccinimidyl iodoacetate (prepared from iodoacetic acid available from Aldrich Chemical Co., N-hydroxysuccinimide and dicyclohexylcarbodiimide (DCC)) in DMF with triethylamine to form an acylated iodinated biotin derivative. Troc-NH-palytoxin prepared as set forth above is deprotonated with 1.0 equivalents of sodium hydride and O-alkylated with the iodo-biotin derivative, N-(iodoacetyl)-ethylene-diamine-N′-(N-methyl)glycylbiotin, to afford the ether, N-(trichloroethoxycarbonyl)-palytoxin-mono-oxo-N-acetamido-ethylenediamine-N′-(N-methyl)glycylbiotin. The trichloro-carbamate group of the ether is cleaved with zinc in aqueous THF, pH 5.5-7.2, to afford the final product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13]
Reactant: CCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
A mixture of 2.15 g of 6,7-dichloro-2-ethyl-5-methoxybenzo[b]thiophene and 15 g of pyridine hydrochloride is stirred at 170°-180° for 90 min. The mixture is cooled, triturated with water and extracted three times with dichloromethane. The combined organic extracts are washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to an oily residue. Purification by column chromatography (silica gel-ether-pentane 50:50) affords 1.5 g of 6,7-dichloro-2-ethyl-5-hydroxybenzo[b]thiophene as off-white crystals, mp 69°-70°.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21][CH3:22])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=1.[C:25]([O:33]C(=O)C1C=CC=CC=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[C:25]([O:33][CH2:22][S:21][C:15]1[C@:16]2([CH2:18][C@H:19]([OH:20])[C@@:2]3([F:1])[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:24])[CH:4]=[CH:5][C:6](=[O:23])[CH:7]=4)[C@@H:12]2[CH2:13][CH:14]=1)[CH3:17])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(SCOC(=O)c4ccccc4)[C@@]3(C)C[C@H](O)[C@@]12F

Procedure:
A solution of 9-fluoro-11β-hydroxy-17-(methylthio)androsta-1,4,16-trien-3-one (100 mg, see Example 1B) in 30 ml of xylene containing 4.0 g of benzoic anhydride and 300 mg of sodium methoxide is stirred at 130° C for 48 hours. The product is then isolated and chromatographed over silica gel to yield 80 mg of the title compound, melting point 220°-222° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].[H-].[Na+].[CH:28](OCC)=[O:29]>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:28][OH:29])=[O:25])[CH3:2]
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CO)c1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl 2-[2-(ethyloxy)-2-oxoethyl]-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrole-3-carboxylate (6.1 g) in dry tetrahydrofuran (100 ml) was stirred at room temperature under argon. Sodium hydride (60% dispersion in mineral oil, 23.0 g) was added portionwise and stirring continued for 20 minutes after complete addition. Ethyl formate (3 ml) was added to the reaction mixture and stirred for 45 minutes after which time an exotherm was observed and controlled by cooling the reaction mixture to room temperature with an ice bath. The reaction mixture was stirred for a further 90 minutes then ethyl formate (3 ml) was added and the mixture stirred overnight. The reaction mixture was cooled in an ice bath and quenched by addition of the minimum amount of ethanol then evaporated. The residue was partitioned between ethyl acetate and saturated ammonium chloride, the aqueous layer was removed and acidified to pH 1 with a 2M solution of aqueous hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated to afford an oil consisting of two layers. The top layer was discarded and the lower layer isolated to afford the title compound as a brown oil (6.59 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:9]=1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]([NH:14][C:12]1[N:13]=[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[N:9]=[C:10]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:11]=1)=[O:5]
Reactant: Nc1nc(N)nc(NC2CC2)n1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc(NC(=O)COC)nc(NC2CC2)n1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
7.2 g of methoxyacetyl chloride are slowly added dropwise to a suspension of 5.0 g of 2,4-diamino-6-cyclopropylamino-1,3,5-triazine in 50 ml of pyridine. The reaction mixture is subsequently stirred for 1 hour at 55° C. and then for 16 hours at room temperature. After filtration of the reaction mixture, washing of the filter residue with water and finally drying, the product is obtained as white crystalline powder having a melting point of 175°-180° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1COCC1>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[O:10]1
Reactant: CN1CCNCC1
Reactant: CC1(C)OB(c2cccc(CBr)c2)OC1(C)C
Solvent: C1CCOC1
Product: CN1CCN(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1

Procedure:
1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-methylpiperazine was prepared by reacting 2-(3-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.35 mmol) with methyl piperazine (196 μl, 1.76 mmol) in THF at room temperature for 2 hours. The intermediate product was purified by flash chromatography to afford 68 mg of colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])[S:5][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1>[CH2:37]([NH:44][C:7]([C:6]1[S:5][C:4]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])=[N:3][C:2]=1[CH3:1])=[O:9])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(c3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylic acid (0.30 g, 1.00 mmol) and 4-methylmorpholine (0.15 mL, 1.10 mmol) in tetrahydrofuran (50 mL) was added isobutyl chloroformate (0.15 mL, 1.3 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours and benzylamine (0.20 mL, 1.80 mmol) was added. The reaction mixture was kept stirring for 17 hours at ambient temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a white powder in 7% yield (0.030 g): mp 234-236° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J=5.7 Hz, 1H), 7.60 (d, =7.8 Hz, 2H), 7.39-7.12 (m, 8H), 4.35 (d, J=5.7 Hz, 2H), 4.14-3.92 (m, 4H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.6, 156.7, 152.7, 150.7, 139.5, 138.9, 128.8, 128.1, 127.1, 126.6, 123.3, 118.3, 117.8, 42.4, 42.3, 41.2, 17.0; MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([S:5][C:6]1[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:4].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:18][N:19]([CH3:23])[C:20]([N:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=[C:6]1[S:5][C:3](=[O:4])[N:2]([CH3:17])[CH3:1])=[O:21]
Reactant: CN(C)C(=O)Sc1nc(-c2ccccc2)c[nH]1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Sc1nc(-c2ccccc2)cn1C(=O)N(C)C
Temperature: 120 °C
Yield: 99.5 %

Procedure:
In 5 ml of pyridine was dissolved 0.70 g (2.84 millimoles) of 2-(N,N-dimethylcarbamoylthio)-4-phenylimidazole, and 0.26 ml (2.84 millimoles) of N,N-dimethylcarbamoyl chloride was added to the solution and the mixture was heated at 120° C. for 5 hours. The mixture was concentrated under reduced pressure and 20 ml of water and 20 ml of chloroform were added to the concentrate to effect extraction. The chloroform layer was dried and concentrated under reduced pressure to obtain 0.9 g (yield=100%) of intended 1-(N,N-dimethylcarbamoyl)-2-(N,N-dimethylcarbamoylthio)-4-phenylimidazole (compound No. 30) in the form of a light brown oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[C:28]4[NH:27][C:26](=[O:29])[O:25][C:24]([CH3:31])([CH3:30])[C:23]=4[CH:22]=[CH:21][CH:20]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:32]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[C:28]4[NH:27][C:26](=[O:29])[O:25][C:24]([CH3:31])([CH3:30])[C:23]=4[CH:22]=[CH:21][CH:20]=3)=[O:32])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2c(OCCCCSc3ccc(C4CCCCC4)cc3)cccc21
Product: CC1(C)OC(=O)Nc2c(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cccc21

Procedure:
Prepared analogously to Example 2 from 8-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].O.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>[OH-].[Na+].[Rh]>[CH2:18]([O:17][C:15]([N:1]1[CH:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]1[C:7]([OH:9])=[O:8])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)c1cccc(C(=O)O)n1
Agent: [Rh]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCC(C(=O)O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 83.1 %

Procedure:
2,6-Pyridine dicarboxylic acid (25 g, 0.15 mol) was dissolved in 2.0M NaOH (154 mL) and H2O (30 mL) at room temperature, and placed in a 500-mL Parr bottle. Rhodium on alumina powder (5%, 1.87 g) was added and the mixture was purged with argon for 15 minutes. The reaction mixture was shaken under 55 psi of hydrogen for 48 hours. The suspension was filtered through compacted Celite, and the clear filtrate was cooled to 0° C. Benzyl chloroformate (30.62 g, 0.18 mol) was added from the top to the cooled filtrate in three portions during a period of 30 minutes, and the solution was allowed to reach room temperature and stirred for additional 5 hours. The remaining benzyl chloroformate was extracted from the mixture with diethyl ether. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (EtOAc). The EtOAc was passed over a short plug of Na2SO4 and evaporated. The residue was triturated with EtOAc (20 mL), and the resulting white solid was collected by vacuum filtration, washed with EtOAc (3×20 mL), and air-dried to give Compound 1 (38.3 g, 83% yield). Rf=0.06 (10% MeOH/CHCl3); 1H NMR: δ 1.49-1.73 (m, 4H), 1.96-2.03 (m, 2H), 4.48-4.65 (m, 2H), 5.10 (s, 2H), 7.26-7.35 (m, 5H).
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#N)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.[OH:26]S(O)(=O)=O>C(Cl)Cl>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][C:12]([CH:13]=[O:26])=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2coc(C3CC3)n2)cc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1ccc(-c2coc(C3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a 0C solution of 4-(2-cyclopropyl-1,3-oxazol-4-yl)benzonitrile (0.984 g, 4.68 mmol) in anhydrous CH2Cl2 (3 ml) was added dropwise a 1M solution of DIBAL in CH2Cl2 (5.60 ml, 1.22 mmol). Upon completion of addition, the solution was warmed to 45C for 3 h. The solution was cooled and 10% aqueous H2SO4 was slowly added until pH<4. The mixture was stirred overnight at rt. The aqueous phase was extracted with CH2Cl2 (3×40 ml). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/hexanes, 1:4) to yield the title compound as a yellow solid (0.92 g, 92%).