Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:17])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[CH:18](O)=[O:19]>CCCCCC>[CH:18]([NH:11][C:10]1[C:9](=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:17])=[O:16])=[O:19]
Reactant: O=CO
Reactant: Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=CNc1ccccc1C(=O)O

Procedure:
A toluene (1100 ml) solution of anthranilic acid (205.5 g) and formic acid (170 ml) was heated under reflux for 4.5 hours. After the solution was allowed to cool, hexane was added to crystals deposited. The crystals were collected by filtration and washed with hexane. The resulting crystals were dried at 110° C. under reduced pressure to obtain N-formyl-anthranilic acid (244.0 g, crude product) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])([CH3:9])[CH3:8].[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>>[S:21]([NH:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])([CH3:8])[CH3:9])(=[O:24])(=[O:23])[NH2:22]
Reactant: CCNC(=O)NC(C)(C)COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CCNC(=O)NC(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from 1-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)-3-ethylurea (Example 230b) and sulfamoyl chloride in 100% yield. MS 356 (MB).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:22][C:23]1[N:28]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=3)=[C:27]2[N:26]=[C:25]([CH:42]2[CH2:48][CH:47]3[NH:49][CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[C:24]=1I.[CH3:51][S:52]([O-:54])=[O:53].[Na+].CS(C)=O>[Cu]I>[NH2:22][C:23]1[N:28]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=3)=[C:27]2[N:26]=[C:25]([CH:42]2[CH2:48][CH:47]3[NH:49][CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[C:24]=1[S:52]([CH3:51])(=[O:54])=[O:53]
Reactant: CS(=O)[O-]
Reactant: CC(C)(O)c1ccc(-c2cnn3c(N)c(I)c(C4CC5CCC(C4)N5)nc23)cn1
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1ccc(-c2cnn3c(N)c(S(C)(=O)=O)c(C4CC5CCC(C4)N5)nc23)cn1
Yield: 82.1 %

Procedure:
2-{5-[7-amino-5-(8-azabicyclo[3.2.1]oct-3-yl)-6-iodopyrazolo[1,5-a]pyrimidin-3-yl]pyridin-2-yl}propan-2-ol tris(trifluoroacetate) (salt) (0.720 g, 0.851 mmol), sodium methanesulfinate (306 mg, 2.55 mmol), and Copper(I) iodide (486 mg, 2.55 mmol) were dissolved/suspended in dry dimethyl sulfoxide (18 mL, 250 mmol) under a nitrogen atmosphere. The reaction was placed in an oil bath at 90° C. After mixing 15 min, HPLC showed the starting material to have been consumed and a mixture of the desired material:des-iodo material was observed. The reaction mixture was poured into a 7:3 mixture of sat'd NH4Cl:20% NH4OH (200 ml) and extracted 3×75 ml with 10% IPA in DCM. The combined organics were washed with brine, dried, filtered and evaporated to provide a yellow oil, which was purified by silica gel chromatography, eluted with 0-15% (10% NH4OH in MeOH) in chloroform to provide the desired material as a yellow solid (319 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4cccc(C=O)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 obtained in Example 120-(1) and 3-formylphenylboronic acid were used and treated in a manner similar to Example 120-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 640 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-formylphenyl)-2-thienylmethyl)-4-methylbenzene (100 mg) was dissolved in dichloromethane (2 ml), and added thereto was (diethylamino) sulfur trifluoride (0.30 ml). The mixture was stirred at room temperature overnight. Water was added to the mixture and the mixture was extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate, and then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene (82 mg). APCI-Mass m/Z 662 (M+NH4). (3) The above obtained 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene was used and treated in a manner similar to Example 120-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)-4-methylbenzene as colorless powder. APCI-Mass m/Z 494 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][OH:33])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(Cl)Cl.C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([CH:32]=[O:33])[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OCc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.4 %

Procedure:
To a solution of the product of example 274(1.0 g) in methylene chloride (200 ml) was added manganese(IV)oxide (3.0 g), and the suspension was stirred at ambient temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was evaporated under reduced pressure to give the titled compound (930 mg).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26]3)=[N:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)nc1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(c2ccc(C(=O)NCCc3ccc(Cl)cc3)cn2)CC1

Procedure:
In analogy to example 21.b 6-chloro-N-[2-(4-chloro-phenyl)-ethyl]-nicotinamide was reacted with 1-(2-methoxyethyl)piperazine. Light yellow solid. MS (ISP): 403.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([OH:17])(=[O:16])[C:10]([CH2:12][C:13](O)=[O:14])=[CH2:11]>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:13](=[O:14])[CH2:12][CH:10]([C:9]([OH:17])=[O:16])[CH2:11]2)=[CH:3][CH:4]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(O)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(O)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of 2.355 mol of 4-aminophenol and 2.32 mol of itaconic acid was heated gradually: At 60° C., the powder started to become viscous, at 110–120° C. it became liquid and the colour turned to dark brown while the rest of solid material was also dissolved. The exothermic reaction started under boiling, and the temperature rose to 150° C. The sandy product was left to cool down to RT within 1–2 hours. The obtained crude (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid was engaged in the next step without further purification or characterisation.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[O:10])=[O:7].[C:11]([CH:13]1[CH2:15][NH:14]1)#[N:12]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]([N:14]1[CH2:15][CH:13]1[C:11]#[N:12])=[O:10])=[O:7]
Reactant: O=C=NC(=O)c1cccs1
Reactant: N#CC1CN1
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)c1cccs1
Reaction time: 1 h

Procedure:
2.76 g. Thiophene-2-carbonyl isocyanate are dissolved in 45 ml. anhydrous toluene and mixed dropwise, while stirring, at 20° to 30° C. with a solution of 1.22 g. 2-cyanoaziridine in 30 ml. toluene. Stirring is continued for 1 hour at ambient temperature and the precipitate obtained is filtered off with suction, washed with toluene and subsequently triturated with diethyl ether. There are thus obtained 3.4 g. 1-(N-2-thiophene-carbonyl-carbamoyl)-2-cyanoaziridine; m.p. 156°-160° C., which still contains a little thiophene-2-carboxylic acid amide.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH:15]([C:21]1[S:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][N:25]=1)[CH2:16][O:17][CH2:18][O:19][CH3:20]>CC(C)=O>[CH3:20][O:19][CH2:18][O:17][CH2:16][C:15]([C:21]1[S:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][N:25]=1)=[O:14]
Reactant: COCOCC(O)c1ncc(S(N)(=O)=O)s1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COCOCC(=O)c1ncc(S(N)(=O)=O)s1
Reaction time: 0.25 h
Yield: 5.6 %

Procedure:
Jones' reagent (0.14 mL, 0.39 mmol, 2.67M) was added dropwise to a 0° C. solution of 2-(1-hydroxy-2-(methoxymethoxy)ethyl)-5-thiazole sulfonamide (0.086 g, 0.32 mmol) in acetone (1 mL). The ice bath was removed and the solution stirred for 15 min. The reaction was incomplete an additional 0.07 mL of Jones' reagent was added and the reaction stirred for 15 more minutes. The reaction was quenched with a few drops of isopropanol and the acetone removed in vacuo. The residue was taken up in water and extracted with EtOAc. The combined extracts were dried (MgSO4), concentrated and purified by flash chromatography using 55% EtOAc/hexane to give 4.8 mg (5.3%) of 2-(2-(methoxymethoxy)ethanoyl)-5-thiazole sulfonamide.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:23][CH:24]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.7 %

Procedure:
Trifluoroacetic acid (6 mL) was added to a solution of N-tert-butoxycarbonyl-4-(4-benzyloxyphenoxy)piperidine (B, 473 mg) in dichloromethane (12 mL) at room temperature. After stirring at room temperature for 20 hr, the reaction was quenched with saturated sodium hydrogen carbonate. The resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the titled compound (345 mg) as a yellow brown solid, which was used in the next reaction without further purification.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>[Pd]>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Product: CC(C)(C)OC[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 83.4 %

Procedure:
2.5 g. of palladium-on-carbon are added to the solution of 17.2 g. (32 mmoles) of Z-30-31-OtBu in 350 ml. of methanol, and gaseous hydrogen is bubbled into the mixture for 1 hour. The catalyst is removed by filtration, the filtrate is evaporated to dryness under reduced pressure, the solid residue is mixed with petroleum ether, and the mixture is filtered. 10.97 g. (83.4 %) of H-Glu(OtBu)-Ser(tBu)-OtBu are obtained. M.p.: 78°-82° C, Rf11 = 0.4.
Reaction SMILES: CO[C:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C:5](=[O:11])[CH:4]=1.[NH3:12]>>[NH2:12][C:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C:5](=[O:11])[CH:4]=1
Reactant: COC1=CC(=O)CCC1(C)C
Reactant: N
Product: CC1(C)CCC(=O)C=C1N
Temperature: 100 °C

Procedure:
3-Methoxy-4,4-dimethyl-2-cyclohexen-I -one in condensed anhydrous ammonia (50 mL) was heated at 100 ° C. (850 psi) for 34 hours. Ammonia was removed by evaporation, the residue dissolved in ethyl acetate (5 mL) and filtered through Florisil to provide 1,14 g of the title compound as a pale tan oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([NH:26][C:27]([C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[C:31]([OH:33])=O)=[O:28])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39]>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([N:26]3[C:27](=[O:28])[C:29]4[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:31]3=[O:33])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39]
Reactant: Nc1nc(NCCNc2ncc(NC(=O)c3ccccc3C(=O)O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1nc(NCCNc2ncc(N3C(=O)c4ccccc4C3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
1 mmol of 2-{N-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]carbamoyl}benzoic acid was heated to 120° C. in acetic acid for four hours and then concentrated in vacuo to obtain 2-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl ]isoindoline-1,3-dione.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[CH2:14]([C:8]1[CH:9]=[CH:10][C:11]([B:19]([OH:24])[OH:20])=[C:12]([F:13])[C:7]=1[F:6])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCc1cccc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(B(O)O)c(F)c1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
n-Butyllithium (10 cm3, 10M in hexanes, 0.1 mol) was added dropwise to a stirred, cooled (-78° C.) solution of the compound from Example 22 (17.3 g, 94 m mol) in dry THF (250 cm3) under an atmosphere of dry nitrogen. The reaction mixture was stirred (2.5 h) then a previously cooled (-78° C.) solution of triisopropyl borate (35.7 g, 0.19 mol) in dry THF (70 cm3) added dropwise at -78° C. The reaction mixture was allowed to warm to room temperature overnight then stirred (1h) with hydrochloric acid (10%, 100 cm3). The product was extracted into diethyl ether (2×100 cm3), and the combined extracts washed with water and dried (MgSO4). The solvent was removed in vacuo to yield colourless crystals.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: C([N:8]([CH3:33])[CH:9]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]([OH:31])=[C:25]([C:27](OC)=[O:28])[N:26]=[C:10]12)C1C=CC=CC=1.Cl.[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[CH3:44])[CH2:39][NH2:40]>CO.[Pd]>[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[CH3:44])[CH2:39][NH:40][C:27]([C:25]1[N:26]=[C:10]2[CH:9]([NH:8][CH3:33])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13][CH2:12][N:11]2[C:23](=[O:32])[C:24]=1[OH:31])=[O:28]
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C(=O)OC(C)(C)C)CC2N(C)Cc1ccccc1
Reactant: Cc1ccc(CN)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1CN(C(=O)OC(C)(C)C)CCn2c1nc(C(=O)NCc1ccc(C)c(Cl)c1)c(O)c2=O
Temperature: 25 °C

Procedure:
8-tert-butyl 2-methyl 10-[benzyl(methyl)amino]-3-hydroxy-4-oxo-6,7,9,10-tetrahydropyrimido[1,2-d][1,4]diazepine-2,8(4H)-dicarboxylate (see Example 11, Steps 1-4) was dissolved in MeOH, treated with 1 N HCl (1 eq.) and stirred overnight under an H2 atmosphere in the presence of 10% Pd/C. The catalyst was then filtered off through celite, and the filtrate was concentrated under reduced pressure. MS (ES) C16H24N4O6 requires 368. Found: 369 (M+H+). The crude organic product was taken in methanol and treated with 1.2 eq. of 3-chloro-4-methyl-benzylamine and resulting mixture was refluxed overnight. After cooling to room temperature, evaporation of volatiles under reduced pressure yielded title product which was directly taken in the next step. MS (ES) C23H30ClN5O5 requires 491. Found: 492 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C([O-])(O)=O.[Na+]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[CH3:12])=[O:6]
Reactant: CNc1ccccc1O
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Reaction time: 1 h
Yield: 56.3 %

Procedure:
3-Bromo-4-chloro-benzoyl chloride (Step 2A, 106.9 mmol) in acetonitrile (300 mL) was added dropwise over 30 minutes to a vigorously stirring solution of 2-methylamino-phenol (15.1 g, 122.9 mmol) and NaHCO3 (18.0 g, 213.7 mmol) in acetonitrile (200 mL) and water (200 mL). The mixture was stirred for additional 1 h and then concentrated to remove acetonitrile. The solid was filtered, washed with HCl (1N, 600 mL) and water (500 mL), and dried. The solid was dissolved in dichloromethane (500 mL) and n-butylamine (20 mL) was added. The mixture was stirred at rt for 16 hrs and concentrated. The residue was partially purified via silica gel flash chromatography (eluting with 20% to 35% ethyl acetate in hexane) and then crystallized from hexane/ethyl acetate (75/25) to give 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (20.5 g) as a white solid. MS [M+H]+: 339.7/341.8; tR=2.19 min. (method 1)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[O:12][CH2:13][CH:14]([O:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:15]>C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[O:12][CH2:13][CH:14]([O:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)OC(C)COc2c([N+](=O)[O-])ccc(F)c2F)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC(C)COc2c(N)ccc(F)c2F)cc1
Reaction time: 1 h

Procedure:
To a solution of 2.32 g of the compound obtained in Example 8 in 50 ml of ethanol was added 1 g of 5% palladium on charcoal, and the catalytic reduction was carried out under atmospheric pressure at room temperature for about 1 hour. The catalyst was removed by filtration, and the solvent was removed under reduced pressure to yield the titled compound. This product was used in the following reaction without purification.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:40][CH2:39][CH2:38][O:37][CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCN
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: COCCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Yield: 91.7 %

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and 2-methoxyethylamine (225 mg, 2.97 mmol) as starting materials to afford the title compound as a colourless oil (372 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:10])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NCCc1ccccc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NCCc2ccccc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
1-Amino-2-(2-chlorophenyl)ethane (44.5 g) was dissolved in 140 ml of pyridine, and with stirring under cooling, 44.5 g of p-toluoyl chloride was added dropwise. The reaction was performed at room temperature for 3 hours. The reaction mixture was poured into ice water, and the crystals that precipitated were collected by filtration. The crystals were dissolved in benzene, washed successively with hydrochloric acid, water and saturated aqueous sodium chloride solution, and dried. The solvent was distilled off. The residue was recrystallized from benzene to afford 72 g of 1-(p-toluoylamino)-2-(2-chlorophenyl)ethane as colorless needles having a melting point of 106.0° to 108.5° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5](Br)=[C:6]([CH3:8])[N:7]=1.[SH:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:2][C:3]1[S:4][C:5]([S:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(N)sc1Br
Reactant: Sc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)sc1Sc1ncccn1
Temperature: 90 °C
Yield: 57.8 %

Procedure:
A mixture of 2-amino-5-bromo-4-methylthiazole hydrochloride (1.15 g), 2-mercaptopyrimidine (0.6 g) and potassium carbonate (1.7 g) in N,N-dimethylformamide (20 ml) was heated at 90° C. for 3.5 hours with stirring. The reaction mixture was poured into ice water. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-methyl-5-(2-pyrimidinylthio)thiazole (0.65 g, yield: 58.0%).