Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH2:25]>ClCCl>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH:25][NH:24][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:9])=[N:4][CH:3]=1
Reactant: Cc1cnc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cnc(C(=O)NNC(=O)OC(C)(C)C)s1
Reaction time: 0.25 h

Procedure:
A solution of 5-methyl-1,3-thiazole-2-carboxylic acid (500 mg, 3.49 mmol) in dry dichloromethane (DCM) (17.500 ml) was stirred at room temperature under an atmosphere of argon. EDC (803 mg, 4.19 mmol) and HOBT (267 mg, 1.746 mmol) were added to the stirred solution. After 15 minutes, 1,1-dimethylethyl hydrazinecarboxylate (554 mg, 4.19 mmol) was added to the stirred solution. The resulting solution was stirred for 18 hours. After this time, the solution was diluted with DCM (approx. 50 ml) and washed with water (2× approx. 20 ml). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oil of desired product in 451 mg.
Reaction SMILES: B(O)(O)O.S(=O)(=O)(O)O.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.[C:20]1([CH:27]=[CH:26][C:24](O)=[CH:23][CH:22]=1)[OH:21].B(O)(O)O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC=CC=1>[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][C:24]2[CH:26]=[CH:27][C:20]([OH:21])=[CH:22][CH:23]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Oc1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 3.75 h
Yield: 98.5 %

Procedure:
To carry out the process according to a preferred embodiment the catalysts e.g. 0.01 to 3, preferably 0.1 to 1.5% by weight of boric acid and 0.01 to 3, preferably 0.1 to 1.5% by weight of concentrated sulphuric acid are added to the starting components 4-hydroxybenzoic acid and hydroquinone in an inert solvent, preferably an aromatic hydrocarbon, for example toluene or xylene, and the mixture is esterified under reflux and with removal of the water of condensation, for example through a water separator). Preferably used is a boric acid/sulphuric acid mixture containing 25 to 70 parts by weight of boric acid and 75 to 30 parts by weight of sulphuric acid, in particular about 40 to 60 parts by weight of boric acid and 60 to 40 parts by weight of concentrated sulphuric acid. The esterification reaction in the heterogeneous mixture (when using xylene as solvent) is completely after 3.5 to 4 hours. In the case of lower-boiling solvents such as toluene, the esterification time is extended until virtually complete water separation has occurred. The batch is allowed to cool, and the well-crystallized crude product is rapidly filtered off under suction, and washed with an inert solvent, preferably xylene or toluene, then with dilute sodium hydrogen carbonate solution and subsequently with water. After drying, 4-hydroxyphenyl 4-hydroxy-benzoate is obtained in a yield of 98.5% of theory; melting point 242°-245° C. (when using xylene as solvent). In another preferred embodiment the combination sulforic acid/boric acid is replaced by p-toluene sulfonic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([I:21])[CH:20]=1.CO>O1CCCC1>[Cl:22][C:18]1[N:17]=[CH:16][C:15]([CH2:14][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)=[CH:20][C:19]=1[I:21]
Reactant: O=C1C=C(NC2CC2)CO1
Reactant: Clc1ncc(CBr)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=C(N(Cc2cnc(Cl)c(I)c2)C2CC2)CO1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
200 mg (1.44 mmol) of 4-(cyclopropylamino)furan-2(5H)-one (VI-1) and 86 mg (2.17 mmol) of a 60% strength dispersion of sodium hydride in mineral oil in 100 ml of tetrahydrofuran are heated under reflux for 1 hour. After cooling to room temperature, 478 mg (1.44 mmol) of 3-bromomethyl-6-chloro-5-iodopyridine (VII-3) are added, and the mixture is heated under reflux for a further 6 hours. After cooling of the reaction mixture to room temperature and addition of methanol, the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (3:1) gives 149 mg (26% of theory) of 4-[[(6-chloro-5-iodopyridin-3-yl)methyl](cyclopropyl)amino]furan-2(5H)-one.
Reaction SMILES: [H-].[Na+].BrC[CH2:5][CH2:6][CH2:7][N:8]([CH2:21][CH2:22]C)[S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:11])=[O:10].[C:24]1([CH3:79])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32]([N:35]([CH2:60][CH2:61]CN(S(C1C(C)=CC(C)=CC=1C)(=O)=O)CCC)[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:34])=[O:33].C1(C)C=CC=CC=1.CCOC(C)=O>CN(C=O)C>[C:24]1([CH3:79])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32]([N:35]([CH2:60][CH2:61][CH2:22][CH2:21][N:8]([S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:10])=[O:11])[CH2:7][CH2:6][CH3:5])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:33])=[O:34]
Reactant: CCCN(CCCN(CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CCCN(CCCCBr)S(=O)(=O)c1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCN(CCCCN(CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 85 %

Procedure:
NaH (60%, 0.12 g, 2.90 mmol), 71 (1.24 g, 2.42 mmol) in DMF (30 mL), and 67 (0.91 g, 2.42 mmol) in DMF (10 mL) were reacted and worked up following the method of 72. Column chromatography (25:1 toluene/EtOAc) gave 1.67 g (85%) of 74 as an oil: NMR δ 0.74 (t, 3 H, J=7), 1.35-1.45 (m, 11 H), 2.00 (t, 2 H, J=7), 2.25 (s, 3 H), 2.28 (s, 3 H), 2.55 (s, 6 H), 2.56 (s, 6 H), 2.98-3.08 (m, 8 H), 6.90 (s, 2 H), 6.91 (s, 2 H), 7.15-7.44 (m, 15 H). Anal. (C48H61N3O4S2) C, H, N.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=2[OH:14])[NH:7][CH:6]([CH3:23])[CH2:5]1.C=O.[C:26]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[OH:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=2[OH:14])[N:7]([CH3:26])[CH:6]([CH3:23])[CH2:5]1
Reactant: [BH3-]C#N
Reactant: CCCCSCCCc1cc(O)c2c(c1)NC(C)CC2CCO
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCCSCCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO

Procedure:
To a stirred solution of dl-4-(2-hydroxyethyl)-5-hydroxy-2-methyl-7-(4-thiaoctyl)-1,2,3,4-tetrahydroquinoline (337 mg, 1.0 mmole) in 5 ml acetonitrile cooled to 15° C. is added 0.5 ml aqueous formaldehyde and 100 mg sodium cyanoborohydride. Acetic acid is added to maintain a neutral pH until the reaction is complete. The reaction mixture is partitioned between water and ethyl ether, the organic phase dried (MgSO4) and evaporated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](Br)=[C:11]([C:14]#[N:15])[N:10]([CH3:16])[C:9]2=[O:17])=[CH:4][CH:3]=1.[F-:18].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([F:18])=[C:11]([C:14]#[N:15])[N:10]([CH3:16])[C:9]2=[O:17])=[CH:4][CH:3]=1
Reactant: Cn1c(C#N)c(Br)n(-c2ccc(Cl)cc2)c1=O
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(C#N)c(F)n(-c2ccc(Cl)cc2)c1=O

Procedure:
A solution of the product of Example 66, 1-(4-chlorophenyl)-5-bromo-4-cyano-3-methyl-1,3-dihydro-2H-imidazol-2-one (0.4 g, 1.3 mmol) and potassium fluoride (0.14 g, 2.66 mmol) in 100 mL of dry dimethyl sulfoxide was heated to 130° C. for two hours, then cooled and poured into 100 mL of water. The product was extracted into ethyl acetate, washed with saturated brine solution, dried, and concentrated to an oil. The oil was chromatographed through silica gel (25:75 ethyl acetate:petroleum ether). Collection of the appropriate fractions furnished 0.14 g of 1-(4-chlorophenyl)-4-cyano-5-fluoro-3-methyl-1,3-dihydro-2H-imidazol-2-one (m.p. 105° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C@@H:40]([OH:44])[C@H:39]2[OH:45])[C:34]([F:46])=[CH:33][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C@@H:40]([OH:44])[C@H:39]4[OH:45])[C:34]([F:46])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: O[C@@H]1[C@H](O)CCC[C@@H]1Nc1nc(Cl)ncc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](O)[C@H]4O)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
To a deoxygenated solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.22 g, 0.51 mmol) and (1R,2S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol, 31b, (0.08 g, 0.24 mmol) in acetonitrile (6 ml) was added 2M sodium carbonate (0.45 mL of 2 M solution, 0.894 mmol) and Pd(PPh3)4 (34.5 mg, 0.030 mmol). The reaction was sealed and heated to 120° C. for 15 minutes in the microwave. The rxn was diluted with EtOAc and filtered thru florisil. The solution was concentrated to crude and purified via silica gel chromatography (DCM to 20% MeOH/DCM) to give compound 31c (0.11 g) as a pink solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([CH2:36]Cl)[CH:30]=[CH:29]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)C=O>O>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([CH2:36][N:12]1[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]1)[CH:30]=[CH:29]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Reactant: ClCc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Sodium hydride (60%, oily, 0.36 g) was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (1.81 g), 6-benzyloxy-2-chloromethylnaphthalene (2.54 g) and N,N-dimethylformamide (35 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and methyl 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carboxylate (3.20 g, yield: 80%) was obtained as colorless crystals from the fraction eluted with tetrahydrofuran-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 109–110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](N(OC)C)=[O:11])=[C:7]([CH3:16])[C:6]=2[CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: CON(C)C(=O)c1oc2ccc(Cl)cc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C=O)oc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution (40 mL) of 5-chloro-N-methoxy-N,3-dimethyl-1-benzofuran-2-carboxamide (2.15 g) synthesized above in tetrahydrofuran was added lithium aluminum hydride (322 mg) at 0° C., and the mixture was stirred for 1 hr. Water (320 μL) was added to quench the reaction, 1N aqueous sodium hydroxide solution (320 μL) was added, and the mixture was stirred at room temperature for 1 hr. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (tetrahydrofuran) to give a pale-yellow solid. The obtained solid was washed with diisopropyl ether to give the title object compound (1.21 g, 73%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[Cl:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCc1nc2ccccc2s1
Reactant: Clc1cccc(Cl)n1
Product: Clc1cccc(C#CCCc2nc3ccccc3s2)n1
Yield: 18.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2,6-dichloro-pyridine (395 mg, 2.67 mmol) and 2-but-3-ynyl-benzo[d]thiazole (100 mg, 0.53 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 31 mg (0.10 mmol, 19%) of 2-(4-(6-chloropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:20]=3)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH2:31](I)[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:31]([O:30][C:9]1[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:11][C:10]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[CH:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1)[CH3:32]
Reactant: CCS(=O)(=O)c1ccc(O)c(-c2cn(C)c(=O)c3ccc(-c4cnn(C)c4)cc23)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(S(=O)(=O)CC)cc1-c1cn(C)c(=O)c2ccc(-c3cnn(C)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
A mixture of the title compound of Example 80 (25.0 mg, 0.059 mmol), ethyl iodide (27.7 mg, 0.177 mmol), and K2CO3 (24.5 mg, 0.177 mmol) in acetone (2 mL) was stirred at room temperature for 18 h. After CH2Cl2 extractive work up, purification by preparative TLC (PE:EA=2:1) gave the title compound (15.8 mg, 60%) as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.48 (d, J=8.4 Hz, 1H), 7.97 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.61 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.17 (d, J=1.2 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.08 (s, 1H), 4.3 (q, J=7.2 Hz, 2H), 3.94 (s, 3H), 3.66 (s, 3H), 3.17 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H). LCMS: 452.1 (M+H)+
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].C(Cl)Cl.CO>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1)=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1nc(SC)ncc1C
Solvent: CO
Solvent: ClCCl
Product: CNc1nc(S(C)=O)ncc1C

Procedure:
Prepared from 2-methylsulphenyl-4-methylamino-5-methyl-pyrimidine by reacting with 3-chloro-peroxybenzoic acid in methylene chloride, Rf value: 0.23 (silica gel; methylene chloride/methanol/ conc. aqueous ammonia=20:1:0.1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:43]=[CH:42][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:39]([OH:41])=O)[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:45][C@@H:46]([C:54]([O:56]C(C)(C)C)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][C@H:33]([C:39]([NH:45][C@@H:46]([C:54]([OH:56])=[O:55])[CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:41])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:31])=[CH:42][CH:43]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Reactant: NC(=O)CC[C@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: NC(=O)CC[C@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine (15 mg, 0.0244 mmol), tert-butyl D-phenylalaninate hydrochloride (8 mg, 0.0310 mmol) and N-methylmorpholine (10 mg, 0.099 mmol) were dissolved in methylene chloride (0.5 ml). TBTU (10 mg, 0.0313 mmol) was added and the mixture was stirred for 1 h at room temperature. The solvent was evaporated and the residue was dissolved in formic acid (0.5 ml). The mixture was heated to 45-50° C. and stirred at this temperature for 6 h. The reaction mixture was evaporated under reduced pressure. Methanol (5 ml) was added and evaporated. The residue was dissolved in methanol (1 ml). Two drops of TEA was added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC using acetonitrile/ammonium acetate buffer (40:60) as eluent. After freeze-drying 12 mg (64%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 1.55-1.97 (m, 4H), 2.77-3.10 (m, 4H), 4.20-4.38 (m, 3H), 4.49 (s, 2H), 4.66-4.78 (m, 1H), 4.99-5.07 (m, 1H), 6.70 (s, 1H), 6.88-7.40 (m, 19H), 8.00-8.20 (m, 2H).
Reaction SMILES: [H-].[Na+].C(S)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:26]=[C:27]([Cl:31])[C:28]=1[O:29]C)[C:10]([N:13]1[CH2:17][C:16]([CH3:18])=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:25])([CH3:12])[CH3:11].Cl>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:26]=[C:27]([Cl:31])[C:28]=1[OH:29])[C:10]([N:13]1[CH2:17][C:16]([CH3:18])=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:25])([CH3:12])[CH3:11]
Reactant: COc1c(Cl)cc(C(C)(C)N2CC(C)=C(c3ccccc3)C2=O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)c(O)c(Cl)c2)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A DMF suspension of 2.2 g (0.05 mol) of sodium hydride (about 60% in oil) was cooled with ice water, and 5.1 g (0.05 mol) of ethyl mercaptan was dropwise added thereto at a temperature not higher than 10° C. under stirring. The reaction mixture was returned to room temperature and left to stand for about 30 minutes. Then, a DMF solution of 15.7 g (0.04 mol) of 1-(3,5- dichloro-4-methoxy-α,α-dimethylbenzyl)-4-methyl-3-phenyl- 3-pyrrolin-2-one (Compound No. 143) prepared in Example 2, was added thereto. The solution was heated at about 80° C. and reacted for three hours. After completion of the reaction, the reaction solution was poured into a large amount of ice water, acidified with a 10% hydrochloric acid aqueous solution and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The solid thereby obtained was washed with isopropyl ether to obtain 11.0 g (yield: 73.3%) of the desired compound as colorless crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[CH:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH:25]([CH2:26][OH:27])[CH2:28][OH:29])[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1C(CO)CO
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1C(CO)CO
Temperature: 100 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yl)indolin-5-yl)cyclopropanecarboxamide (40.3 mg, 0.0711 mmol as the trifluoracetic acid salt) was dissolved in toluene (1 mL). To the resulting solution was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (35 mg, 0.14 mmol). The resulting suspension was heated at 100° C. in an oil bath for 10 minutes. The crude product was then evaporated to dryness, dissolved in a 1 mL of N,N-dimethylformamide and purified by purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 450.2. found 451.5 (M+1)+. Retention time of 1.59 minutes.
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].C(O[C:20]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)(C)(C)C>[OH-].[K+].C(O)C>[C:26]([O:25][C:23]([O:22][C:20]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 28 °C
Yield: 63 %

Procedure:
A solution comprising 0.49 grams potassium hydroxide, 40 grams of 4-acetoxystyrene, and 100 grams of absolute ethanol was refluxed for 4 hours. The reaction solution was cooled to 28° C. and 13 grams of potassium hydroxide pellets were added over a period of 10 minutes. After an additional 30 minutes of reaction, 64 grams di-tertiary-butyl-dicarbonate was charged portionwise over 20 minutes and the reaction was stirred for an additional hour at 28° C. After aqueous washing, the reaction product was extracted with ethyl acetate. The ethyl acetate was stripped from the extraction mixture on a rotary evaporator and the residual oil was charged with 0.07 grams phenothiazine. Distillation at 0.1 Mm Hg gave 34.2 grams (64%) 4-tertiary-butoxycarbonyloxystyrene.