Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2(O)[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH2:31]2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].FC(F)(F)C(O)=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH2:35][CH2:34][C:33]([CH3:36])([CH3:37])[CH2:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C2(O)CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Reaction time: 1.5 h

Procedure:
To a solution of 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(1-hydroxy-4,4-dimethyl-cyclohexyl)-thiophene-2-carbo-xylic acid methyl ester (14.4 g, previous step) in dry toluene (50 mL) at room temperature was added trifluoroacetic acid (50 mL). The reaction mixture was stirred for 90 min. Water (1.28 g, 71.1 mmol) was added to the mixture and stirred for 90 min. The reaction mixture was evaporated to dryness, extracted with EtOAc and washed with saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and evaporated to obtain crude 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (13.3 g) which was used for the next step without any purification.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCOCC4)cc2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (prepared below, 30 mg, 0.072 mmol) and THF (1 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (19.3 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature, concentrated in vacuo and redissolved in EtOAc. Hexanes were added to the reaction mixture. The solid precipitate that formed was filtered and washed with ˜1 mL of ice cold THF yielding 36% (15 mg, 0.026 mmol) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])[C:4]=2[CH2:3][CH2:2]1.[I:19]I>C(O)(=O)C.C(Cl)Cl>[I:19][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[C:9]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: II
Reactant: CCC(=O)NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(=O)NC[C@@H]1C[C@H]1c1c(I)ccc2c1CCO2
Reaction time: 1.5 h
Yield: 26.9 %

Procedure:
To a solution of 0.12 g (0.6 mmol) (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl]methyl]propanamide and 0.27 g (0.6 mmol) of lead IV tetraacetate in 1 mL acetic acid was added 0.075 g (0.25 mmol) iodine. The solution was allowed to stir for 1.5 h and was diluted with methylene chloride. The resulting solution was washed with water and saturated sodium bicarbonate solution and dried. The solution was concentrated in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate-hexane, 3:7 containing 0.2% methanol to give the product (25 mg, 11%, mp 148-149° C.).
Reaction SMILES: C[O:2][C:3](=[O:38])[C@@H:4]([N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)[N:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Li+].CO>O>[CH2:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C:14]2([N:13]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:12][N:11]([C@@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]([OH:38])=[O:2])[C:15]2=[O:16])[CH2:21][CH2:20]1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (S)-benzyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.16 g, 4.21 mmol, 1 equiv.) and lithium hydroxide (353 mg, 8.41 mmol, 2 equiv) in a 4:1 mixture of methanol and water (20 ml t/v) was stirred at ambient temperature for 16 hrs. The reaction was concentrated in vacuo and the mixture was partitioned between ethyl acetate and 10% citric acid. The organic layer was further washed with water and brine, dried over MgSO4, filtered and concentrated. The resulting residue was dried thoroughly to afford (S)-2-(8-(benzyloxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetic acid as a white solid (2.05 g, quant); 1H NMR (400 MHz, DMSO-d6): δ 1.67 (t, 2H, J=12.4 and 10.4 Hz); 2.25-2.33 (m, 2H); 3.56 (m, 2H); 3.98-4.05 (m, 2H); 4.14 (d, 1H, J=4.4 Hz); 4.86 (d, 1H, J=5.2 Hz); 5.14 (m, 2H); 5.81 (s, 1H); 6.67 (d, 2H, J=7.6 Hz); 6.81 (t, 1H, J=6.8 and 7.6 Hz); 7.17 (dd, 2H, J=7.6 and 7.2 Hz); 7.32-7.45 (m, 10H); 13.5 (s, 1H); MS for C29H29N3O5 m/z 500.21 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([C:12](O)=[O:13])=[CH:10][N:9]=[C:8]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:7]=12)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:22])=O>>[CH2:1]([NH:5][C:6]1[C:11]([C:12]([Cl:22])=[O:13])=[CH:10][N:9]=[C:8]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:7]=12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1c(C(=O)O)cnc2c1cnn2CC
Reactant: O=S(Cl)Cl
Product: CCCCNc1c(C(=O)Cl)cnc2c1cnn2CC

Procedure:
26.2 g of 4-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.1 mol) and 100 ml of thionyl chloride are refluxed for 4 hours. The thionyl chloride is removed by means of a water aspirator. The residue, containing the crude 4-butyl-amino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl chloride, is recrystallized from benzene, and has a melting point of 142°-145°. Yield 23.5 g = 84% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[C:10]([O:16]CC)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].O.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[C:10]([OH:16])[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(C=O)cc(O)c1C(=O)OC
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 58.7 %

Procedure:
A mixture of methyl 2,6-diethoxy-4-formylbenzoate (950 mg, 3.8 mmol) and AlCl3 (1.0 g, 7.6 mmol) in anhydrous DCM (30 mL) was stirred at 10° C. for 5 minutes. The resulting mixture was poured into water (100 mL) followed by a standard aqueous/EtOAc workup. The residue was purified by column chromatography on silica gel (PE:EtOAc=10:1) to give Intermediate 8 as off-white solid (500 mg, yield 59%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([C:29]([OH:31])=[O:30])=[CH:16][N:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[C:17]([C:29]([OH:31])=[O:30])=[CH:16][N:15]=[C:14]([C:12]4[S:13][C:9]([S:6](=[O:8])(=[O:7])[NH2:5])=[CH:10][CH:11]=4)[N:19]=3)[CH:25]=2)[CH2:27][CH2:28]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(C(=O)O)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2ncc(C(=O)O)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reaction time: 3 h

Procedure:
To a solution of 2-(5-(N-tert-butylsulfamoyl)thiophen-2-yl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylic acid (80 mg, 0.17 mmol, 1.0 eq) in CH2Cl2 (20 mL) was added 1N BCl3 (3.4 mL, 3.4 mmol, 20.0 eq) at rt. The mixture was stirred for 3 h and concentrated. The residue was purified by recrystallization with methanol and isopropylether to 4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-(5-sulfamoylthiophen-2-yl)pyrimidine-5-carboxylic acid (Compound 179) (30 mg, 44%). LC-MS (m/z)=407.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.77-0.80 (m, 2H), 0.98-1.03 (m, 2H), 1.95-2.00 (m, 1H), 6.60 (s, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.92 (s, 2H), 7.95 (d, J=4.0 Hz, 1H), 8.92 (s, 1H), 10.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[C:22]3[N:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=4[CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[NH:19][C:18]=3[C:17]([O:38]C)=[CH:16][CH:15]=2)=[O:13])[C:6]=1[Cl:7].B(Br)(Br)Br>O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[C:22]3[N:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=4[CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[NH:19][C:18]=3[C:17]([OH:38])=[CH:16][CH:15]=2)=[O:13])[C:6]=1[Cl:7]
Reactant: COc1ccc(C(=O)NCCCn2cnc(Cl)c2Cl)c2nc(-c3ccc(N)cc3CCN3CCOCC3)[nH]c12
Agent: BrB(Br)Br
Solvent: O
Product: Nc1ccc(-c2nc3c(C(=O)NCCCn4cnc(Cl)c4Cl)ccc(O)c3[nH]2)c(CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.3 %

Procedure:
2-[(2-morpholinoethyl)-4-amino-phenyl]-7-methoxy-1H-benzoimidazole-4-carboxylic acid-[3-(4,5-dichloro-imidazol-1-yl)-propyl]-amide (15 mg, 0.03 mmol) obtained in step 5 was dissolved in MC, BBr3 (1.0M solution in MC, 0.3 mL, 0.3 mmol) was added thereto and stirred at room temperature for 48 hours. The reaction was stopped by adding water thereto and the resulting solution was extracted with MC/MeOH (7:1). The extract was concentrated under a reduced pressure and purified by silica gel chromatography to obtain the title compound (5.9 mg, 0.01 mmol) in a yield of 40%.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:23]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:32]([OH:34])=O)[CH2:13][CH2:12]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:26][CH:27]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:32]([NH:11][C:17]2[CH:18]=[CH:19][C:20]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:30][CH2:29][O:28][CH2:25][CH2:24]3)=[CH:21][CH:16]=2)=[O:34])[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(2-methoxybenzyl)-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (340 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (267 mg) was added thereto at 0° C., the temperature was returned to room temperature, and the mixture was stirred for 1 hour under nitrogen atmosphere. The solvent and excess thionyl chloride were evaporated under reduced pressure, and the resulting residue was suspended in tetrahydrofuran (30 ml), which was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (197 mg) and triethylamine (906 mg) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred at room temperature for 1 hour under nitrogen atmosphere, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(2-methoxybenzyl)-N-[4-[[N-methyl N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (337 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:14][N:30]2[CH2:31][CH2:32][CH:27]([C:23]3[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=3)[CH2:28][CH2:29]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccsc1Sc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccsc3Sc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-[(4- chlorophenyl)sulfanyl]-3-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.0 (M+H)+.
Reaction SMILES: O1CCOCC1.O.[C:8]12([NH:18][S:19]([C:22]3[CH:23]=[C:24]([C:32](O)=[O:33])[C:25]4[O:30][CH2:29][CH2:28][O:27][C:26]=4[CH:31]=3)(=[O:21])=[O:20])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.[CH2:35]([NH2:39])[CH2:36][CH2:37][CH3:38]>C(N(CC)CC)C>[CH2:35]([NH:39][C:32]([C:24]1[C:25]2[O:30][CH2:29][CH2:28][O:27][C:26]=2[CH:31]=[C:22]([S:19](=[O:21])(=[O:20])[NH:18][C:8]23[CH2:15][CH:14]4[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]4)[CH2:9]2)[CH2:17]3)[CH:23]=1)=[O:33])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN
Reactant: O=C(O)c1cc(S(=O)(=O)NC23CC4CC(CC(C4)C2)C3)cc2c1OCCO2
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCNC(=O)c1cc(S(=O)(=O)NC23CC4CC(CC(C4)C2)C3)cc2c1OCCO2
Temperature: 25 °C
Yield: 46.5 %

Procedure:
500 ml of dioxane, 50 ml of water, 49 g of 7-[(1-adamantyl)-sulfamoyl]-1,4-benzodioxane-5-carboxylic acid and 12.5 g of triethylamine were introduced into a 2-liter balloon flask provided with an agitator and a thermometer. The solution was agitated at ambient temperature and then 17 g of isobutyl chloroformiate was added. The mixture was agitated and then 10 g of butylamine was introduced. After agitation of the mixture dioxane was removed. The residue was dissolved in 200 ml of hot water. The crystals formed by cooling were washed with water, dried and redissolved in 250 ml of acetone by boiling temperature. The solution was filtered hot. The crystals formed by cooling were dried off, washed and dried. 26 g of N-(butyl)-7-[(1-adamantyl)sulfamoyl]-1,4-benzodioxane-5-carboxamide was produced (M.P. 147° C.; yield: 46.4%).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Br:11][C:12]1[CH:13]=[C:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([NH:18][C:19]([NH2:21])=[S:20])=[N:16][CH:17]=1.C(N(CC)CC)C>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]([NH:18][C:19]2[S:20][CH:2]=[C:3]([CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[N:21]=2)=[N:16][CH:17]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Reactant: COC(=O)CCC(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A mixture of methyl 5-bromo-4-oxopentanoate (2.51 g, 12.0 mmol), 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (3.00 g, 9.25 mmol), triethylamine (2.19 mL, 15.7 mmol), and ethanol (60 mL) was refluxed for 3 hours and then stirred at ambient temperature overnight. The solvent was removed to about one third original volume and partitioned between CH2Cl2 and water. The organics were concentrated and purified on silica gel eluting with 40% EtOAc/Hexanes to give the title compound (3.22 g, 80.1% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1F>>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2cccc(Cl)c2Cl)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Br-:12].[Br-:13].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])([O-])=O.[Ca+2].Cl>C(Cl)Cl.CO>[Br:12][C:3]1[C:2]([CH3:1])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[C:5]([Br:13])[C:4]=1[OH:11]
Reactant: [Br-]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])cc(Br)c(O)c1Br
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
3-Methyl-4-nitrophenol (1.50 g, 9.75 mmol) was dissolved in a mixture of CH2Cl2 (30 mL) and methanol (30 mL) and cooled to 4° C. While stirring, benzyltrimethylammoniumtribromide (7.6 g, 19.5 mmol) and CaCO3 (1.95 g, 19.5 mmol) was added and the reaction was allowed to warm to room temperature. After 30 minutes, 1N HCl (45 mL) was added and reaction mixture left for 16 hours at 4° C. The organic phase was removed in vacuo and the resulting precipitate was collected by filtration and washed by water. The damp solid was co-evaporated with toluene and Et2O to yield 2.8 g (93%) of 2,6-dibromo-3-methyl-4-nitrophenol as a white solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[C:9]2[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[OH:4].C.C(=O)(O)[O-].[Na+:36].O1CCOCC1>[Pd].O>[F:30][C:2]([F:1])([F:29])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[C:9]2[C:13]([O-:15])=[O:14])[OH:4].[Na+:36]
Reactant: O=C(OCc1ccccc1)C1=C(N2CCOCC2)CC2C(C(O)C(F)(F)F)C(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])C1=C(N2CCOCC2)CC2C(C(O)C(F)(F)F)C(=O)N12
Reaction time: 0.5 h

Procedure:
A mixture of benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (25 mg), 10% palladium on powdered charcoal (25 mg), sodium bicarbonate (5 mg), dioxane (2 ml), and water (1 ml) is hydrogenated at 40 psi for 30 mins. The mixture is filtered to remove the catalyst which is washed with water (3×2 ml). The combined filtrate is extracted with ethyl acetate (2×2 ml), concentrated in vacuo, and lyophilized to give sodium 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-morpholino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29].C(N(C(C)C)C(C)C)C.[O:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:46][CH:43]4[CH2:44][CH2:45][O:40][CH2:41][CH2:42]4)=[O:22])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: NC1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a mixture of 0.08 g (0.19 mmole) of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292), 0.13 mL (0.76 mmole) of ethyldiisopropyl amine and 0.021 g (0.21 mmole) of tetrahydro-pyran-4-ylamine in 2.0 mL of dimethylformamide was added 0.082 g (0.21 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.086 g of give 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-297) as a white solid.
Reaction SMILES: CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.[CH3:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47](=[O:52])[C:48]([NH:50][CH3:51])=[O:49].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.P([O-])([O-])([O-])=O>C(OCC)(=O)C>[CH3:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH:47]([OH:52])[C:48]([NH:50][CH3:51])=[O:49]
Reactant: CNC(=O)C(=O)c1ccccc1C
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Solvent: CCOC(C)=O
Product: CNC(=O)C(O)c1ccccc1C
Yield: 74.2 %

Procedure:
Using the plasmid pTrcGSRs, E. coli HB101 was transformed. The resulting transformant was inoculated in a sterilized LB medium (100 ml) containing 0.1 mM of IPTG and 50 μg/ml of ampicillin, and was shaking-cultured (37° C., 15 hours). The resulting culture was centrifuged to obtain 0.5 g of wet bacterial cells. To a reaction tube were added 30 mg of 2-(2-methyl-phenyl)-N-methyl-2-oxo-acetamide, 0.5 g of the wet bacterial cells, 30 mg of NADP+, 45 mg of glucose, and 5 ml of a 100 mM phosphate buffer solution (pH 7), and these were reacted at a stirring rate of 1000 rpm at 30° C. for 24 hours. After the completion of the reaction, 5 ml of ethyl acetate was added to the reaction solution, and this was centrifuged (1000×g, 5 minutes) to recover an organic layer. The organic layer was distilled off to obtain 22.5 mg of oily 2-(2-methyl-phenyl)-N-methyl-2-hydroxy-acetamide. 1H-NMR analysis result of the resulting 2-(2-methyl-phenyl)-N-methyl-2-hydroxy-acetamide is shown below.