Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5].[CH:18](OC)(OC)[O:19]C>>[CH:18]([NH:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)=[O:5])=[O:19]
Reactant: COC(OC)OC
Reactant: COC(=O)COc1ccc(C(=O)CN)cc1
Agent: Cl
Product: COC(=O)COc1ccc(C(=O)CNC=O)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 4-(aminoacetyl)phenoxyacetate hydrochloride (2.6g.) and trimethyl orthoformate (3.18g.) was stirred at 100° C. for 1 hour under reflux. The volatile reaction products were then allowed to distil off. The yellow residual oil thus obtain crystallised on cooling to give methyl 4-[(N-formyl)aminoacetyl]phenoxyacetate as a solid (2.2g.), m.p. 116° C., after recrystallisation from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CN(C=O)C.[NH2:16][C:17]1[C:18]([OH:27])=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][C:17]1[C:18]([OH:27])=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1)=[O:5]
Reactant: O=C(Cl)c1ccncc1Cl
Reactant: Nc1cc(C(F)(F)F)cnc1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)cnc1O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.88 g of 3-chloroisonicotinic acid, 5 ml of thionyl chloride and 20 mg of DMF was heated to reflux for three hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to give 3-chloroisonicotinic acid chloride. The resultant 3-chloroisonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 1.0 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 1.14 g of triethylamine and 8 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and then stirred while heating at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.87 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[C:8](=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)[CH:2]=C.[CH3:18]CCCCC>[Pd]>[CH:1]([C:4]1[C:17]2[C:8](=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)([CH3:18])[CH3:2]
Reactant: CCCCCC
Reactant: C=CCc1cccc2cc3ccccc3cc12
Agent: [Pd]
Product: CC(C)c1cccc2cc3ccccc3cc12

Procedure:
Into a 500 milliliter hydrogenation bottle was placed 0.2 grams of 5% palladium on carbon, 10 grams of 1-(2-propenyl) anthracene and 200 milliliters of hexane and the bottle flushed three times with hydrogen. Hydrogen was fed into the bottle at an initial pressure of 23 pounds per square inch which after 3 days had a final pressure of 19 pounds per square inch. The mixture was filtered, evaporated to an oil and chromatographed on basic alumina with hexane. The mixture was washed with a 10:1 mixture of hexane and benzene and distilled to recover a fraction of pure isopropyl anthracene having a melting point of 36°-36.5° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:21])[CH3:20]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:21][CH2:19][CH3:20])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CCN
Solvent: O
Product: C=CCNc1nc(NCC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 796 mg (15.52 mmol) of a 70% aqueous ethylamine solution was stirred at room temperature for 3 hours. Water. was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 234 mg (yield: 90.6%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][S:32][C:33]1[N:40]2[C:36]([S:37][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:39]2)=[C:35]([C:54]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)=[O:55])[N:34]=1)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][S:32][C:33]1[N:40]2[C:36]([S:37][C:38]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[CH:39]2)=[C:35]([C:54]([C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)=[O:55])[N:34]=1)=[N+:28]=[N-:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(SCCN=[N+]=[N-])nc(C(=O)c3cccnc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(SCCN=[N+]=[N-])nc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Yield: 50.3 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[5-(2-azidoethyl)thio-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (853 mg) was prepared in the same manner as in step a) of Example 1, except that 910 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.59 g of 5-(2-azidoethyl)thio-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH3:26][O:27][C:28](=[O:36])[C@H:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[NH2:30].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH:29]([NH:30][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:23])([F:22])[F:24])[CH:4]=1)[C:28]([O:27][CH3:26])=[O:36]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: C([O:8][C:9]([CH:11]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH:45]([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[O:12][C:13]1[CH:37]=[CH:36][C:16]([C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:20]=2)=[O:18])=[CH:15][CH:14]=1)=[O:10])C1C=CC=CC=1>O1CCOCC1.C(O)C.[Pd]>[C:9]([CH:11]([C:38]1[CH:39]=[CH:40][C:41]([CH2:44][CH:45]([CH3:46])[CH3:47])=[CH:42][CH:43]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:20]=2)=[O:18])=[CH:36][CH:37]=1)([OH:10])=[O:8]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(C(=O)OCc3ccccc3)c3ccc(CC(C)C)cc3)cc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(C(=O)O)c3ccc(CC(C)C)cc3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
Ethyl 4-[3-[4-[(benzyloxycarbonyl)(4-isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyrate (0.36 g) was dissolved in a mixture of 1,4-dioxane (10 ml) and ethanol (10 ml), and 10% palladium on carbon (0.2 g) was added. The mixture was stirred under hydrogen atmosphere at 25° C. for 2 hours. Removal of the catalyst and evaporation of the solvent gave ethyl 4-[3-[4-[(carboxy)(4-isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyrate (0.23 g) as powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:7][C:3]1[C:2]([CH2:8][C:16](=[O:18])[CH3:17])=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1cccnc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1ncccc1C
Temperature: 0 °C

Procedure:
To a stirred solution of 2,3-lutidine (3.21 g) in tetrahydrofuran (20 ml) was added a solution of n-butyllithium in n-hexane (1.56M, 23.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (3.63 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:2) to give 1-(3-methylpyridin-2-yl)propan-2-one (3.70 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([O:39]CC)=[O:38])=[CH:33][CH:32]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([OH:39])=[O:38])=[CH:35][CH:36]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH:28]([CH3:29])[CH3:30])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCNC(C)C)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCCNC(C)C)cc1C(C)(C)C
Yield: 25 %

Procedure:
In a manner similar to that of Example 3, by reacting 190 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate (0.3 mmol) with 0.5 mL of 1N sodium hydroxide solution, 45 mg of 3″-tert-butyl-4″-diethylamino-4′-(4-isopropylaminobutog)-[1,1′;3′,1″]terphenyl-4-carboxylic acid are obtained (yield=25%) in the form of a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[N+:8]([O-])([O-:10])=[O:9].[K+]>S(=O)(=O)(O)O>[N+:8]([C:4]1[CH:3]=[C:2]([CH:6]=[O:7])[S:1][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1cccs1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc([N+](=O)[O-])cs1

Procedure:
As shown in Scheme 3, 5-Nitro-2-thiophenecarboxaldehyde and 5-nitro-3-thiophene-carboxaldehyde, carboxaldehyde, each of which are commercially available, can be reacted with tris(trimethylsilyl)phosphite to give XII. Thiophene-2-carboxaldehyde is nitrated in sulfuric acid with potassium nitrate to give 4-nitrothiophene-2-carboxaldehyde which in turn is reacted with diethylphosphite on basic alumina and allowed to stand for 2-20 hours. Extraction of the product with methylene chloride gives XV. Treatment of XV with 5-8 equivalents of bromotrimethylsilane in methylene chloride (50-100 mL) gives compound XVI.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=O)=O.C([Li])CCC.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]23[CH2:31][N:28]([CH2:29][CH2:30]2)[CH2:27][CH2:26][CH2:25]3)=[CH:20][N:19]=1.[OH-].[Na+]>O1CCCC1.CCCCCC.[Cl-].[Zn+2].[Cl-].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.C(Cl)(Cl)Cl>[NH:8]1[CH:9]=[CH:10][N:6]=[C:7]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]23[CH2:31][N:28]([CH2:29][CH2:30]2)[CH2:27][CH2:26][CH2:25]3)=[CH:20][N:19]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: Brc1ccc(C23CCCN(CC2)C3)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1c[nH]c(-c2ccc(C34CCCN(CC3)C4)cn2)n1
Temperature: -78 °C

Procedure:
1 g (5.7 mmol) of 1-(dimethylaminosulfonyl)imidazole dissolved in 9 ml of tetrahydrofuran is introduced into a 25 ml three-necked flask. The reaction medium is cooled to −78° C. and 4 ml of a 1.6M solution of n-butyllithium in hexane is added dropwise over 20 minutes. 0.73 g (5.4 mmol) of zinc chloride dissolved in 4 ml of tetrahydrofuran is then added. The mixture is stirred while allowing the temperature to return to 20° C., and 1.5 g (11.1 mmol) of zinc chloride, 0.1 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium and 0.56 g (2.1 mmol) of (−)-5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane (prepared according to the method described in step 1.2 of Example 1), dissolved in 5 ml of tetrahydrofuran, are then successively added. The mixture is then refluxed for 24 hours and then cooled to room temperature. 30 ml of aqueous 30% sodium hydroxide solution and 50 ml of chloroform are added. The aqueous phase is extracted with chloroform and the combined organic phases are then washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions and is used in the following step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[NH2:23].[OH-].[Na+]>O1CCCC1>[NH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[O:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:24])=[O:2]
Reactant: COC(=O)c1ccc(OC)cc1Oc1ccc(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(Oc2ccc(C(F)(F)F)cc2N)c1

Procedure:
Methyl-2-(2-amino-4-trifluoromethylphenoxy)-4-methoxybenzoate (13.0 g, 0.038 mol) was mixed in tetrahydrofuran and saponified with 1N sodium hydroxide. The solvent was evaporated and the residue mixed in water and acidified with 3N hydrochloric acid, bringing the pH to 4.0. The aqueous phase was extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residue was flash chromatographed (silica gel, ethyl acetate/hexane/formic acid) to yield the title compound. 1H NMR (250 MHz, methanol d) δ8.00 (d, 1H), 7.10 (d, 1H), 6.88 (dd, 1H), 6.73-6.81 (m, 2H), 6.45 (d, 1H), 3.79 (s, 3H).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:2]1=2.Cl[C:16]1[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=2)[N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([C:16]3[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=4)[N:17]=3)[CH:10]=[CH:11][C:2]1=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc2c(c1)OCCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCCCO4)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (200.0 mg, 1.03 mmol in dioxane (5.0 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 150.0 mg, 0.52 mmol), K3PO4 (325.9 mg, 1.54 mmol) and Pd(PPh3)4 (29.7 mg, 0.03 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (140.0 mg, 63%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[S:19](=[O:21])(=[O:20])[N:18]([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:28])[CH2:16]2)=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1.C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].Cl>C(Cl)Cl>[CH2:30]([O:29][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][C:17](=[O:28])[N:18]([CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[S:19]1(=[O:21])=[O:20])[CH2:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3N)cc2OCc2ccccc2)S1(=O)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3NS(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-[4-((1S*,2R*)-2-aminocyclohexylmethyl)-2-benzyloxy-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (153 mg, 0.238 mmol) and diisopropylethylamine (92 mg, 0.712 mmol) in methylene chloride (5 mL) is added methanesulfonyl chloride (30 mg, 0.258 mmol) and the mixture is stirred at RT for 14 h. The mixture is poured into 1N HCl and extracted with EtOAc and the organic phase is washed with saturated NaHCO3. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=O)[CH2:4][C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C1C=CC=CC=1.[CH3:21][C:22]([N:25]1[C:29]([NH2:30])=[CH:28][C:27]([CH3:31])=[N:26]1)([CH3:24])[CH3:23]>C(O)(=O)C>[CH3:24][C:22]([N:25]1[C:29]2[N:30]=[C:3]([C:2]([CH3:14])([CH3:13])[CH3:1])[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:28]=2[C:27]([CH3:31])=[N:26]1)([CH3:21])[CH3:23]
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C(C)(C)C)nc2c1c(C)nn2C(C)(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 5,5-dimethyl-2,4-dioxohexanoate (392 mg, 1.958 mmol), benzene (10 mL), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (300 mg, 1.958 mmol), and acetic acid (2 mL). The crude product was purified by column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 530 mg (85%) of product. LCMS E-S (M+H)=318.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.52 (m, 12 H), 1.84 (s, 9 H), 2.67 (s, 3 H), 4.50 (q, J=7.07 Hz, 2 H), 7.59 (s, 1 H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COCCCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: c1ccc(CCCOC[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of tert-butyl 3(R)-[(3-phenylpropoxy)methyl]pyrrolidine-1-carboxylate (600 mg, 1.88 mmol) in CH2Cl2 (15 mL) was added a mixture of CF3COOH (4.62 g, 40.5 mmol, 21.6 equiv.) and water (0.3 mL) at 0° C. under N2. The solution was stirred overnight at room temperature. After concentration in vacuo, water was added, and the solution was washed with hexane. The water phase was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic phases were dried and concentrated to obtain the product (220 mg, 53%) as a yellow oil. LC-MS (ESI) m/z 220 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:5]=2[CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].CCN(CC)CC.COC1C(OC)=CC2SC(C(Cl)=O)=CC=2C=1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([NH:23][C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28][CH3:29])=[O:27])=[O:12])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C(=O)O)sc2cc1OC
Reactant: COC(=O)c1ccccc1N
Agent: COc1cc2cc(C(=O)Cl)sc2cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)c1cc2cc(OC)c(OC)cc2s1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a stirred solution of 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (714 mg, 3 mmol) and DMF (20 μl) in anhydrous DCM (20 mL) was added oxalyl chloride (0.5 mL, 6 mmol) dropwise at 0° C. The mixture was then allowed to warm to room temperature and stirring was continued until the acid was consumed completely (about 1 h). The solvent was removed under reduced pressure and the crude 5,6-dimethoxybenzo[b]thiophene-2-carbonyl chloride was used directly in the next step. To a stirred solution of methyl 2-aminobenzoate (500 mg, 3.3 mmol) and Et3N (1.25 mL, 9 mmol) in anhydrous DCM (20 mL) was added 5,6-dimethoxybenzo[b]thiophene-2-carbonyl chloride in anhydrous DCM (2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The organic extract was dried over sodium sulfate, the solvent was removed under reduced pressure and the crude product was purified by re-crystallization from EtOH to give methyl 2-(5,6-dimethoxybenzo[b]thiophene-2-carboxamido)benzoate as a white solid (650 mg, 55%). LC-MS (ES-API); rt 9.38 min; m/z calculated for C19H17NO5S [M+H]+ 372.1, found 372.1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC#N>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Oc1ccccc1I
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1I
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 2-iodophenol (1 g, 4.55 mmol) in CH3CN (20 mL) was added K2CO3 (0.93 g, 6.83 mmol) and ethyl 2-bromoacetate (0.835 g, 5.0 mmol). The reaction mixture was stirred at reflux for 2 h, cooled to room temperature, extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. (1.1 g, yield 79%) MS (ESI+) e/z: 307.1 [M+1]+.