Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(OCC)(=O)C.[C:12]([Cl:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[ClH:20].[C:12]([O:5][CH2:4][CH2:3][NH:2][CH3:1])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCCO
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CNCCOC(=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a mixture of 2-(methylamino)ethanol (30.04 g) and ethyl acetate (90 mL) was dropwise added a mixture of di-tert-butyl Bicarbonate (87.30 g) and ethyl acetate (10 mL) under ice-cooling. After stirring at room temperature for 1 hr., benzoyl chloride (61.8 g) and pyridine (38.8 mL) were added under ice-cooling. After stirring at room temperature for 1 hr., a solid was filtered off. The solid was washed with ethyl acetate (100 mL) and the filtrate and the washing were combined, which was washed with water (100 mL) and saturated brine (100 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), a 4N hydrogen chloride-ethyl acetate solution (200 mL) was added, and the mixture was stirred at room temperature for 30 min. Diethyl ether (100 mL) was added and a solid was collected by filtration. The solid was washed twice with ethyl acetate (100 mL) and dried under reduced pressure at 60° C. to give the title compound (57.4 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](I)[CH:31]=3)=[CH:24][C:23]=2[C:39]([F:42])([F:41])[F:40])[CH2:17][CH2:16]1>>[OH:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([C:2]#[C:1][C:3]4[N:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:31]=3)=[CH:24][C:23]=2[C:39]([F:42])([F:41])[F:40])[CH2:19][CH2:20]1
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CCO)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and N-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 14. The product was obtained as a solid: 563 m/z (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:12])[C:7]([O:9]CC)=[O:8])=[CH:2]1.[OH-].[Na+].CO>O>[S:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:12])[C:7]([OH:9])=[O:8])=[CH:2]1
Reactant: CCOC(=O)C(=O)c1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccsc1
Reaction time: 1 h

Procedure:
To a mixture of ethyl thien-3-yl-glyoxylate (10 g) and 2 N-sodium hydroxide (50 ml) was added sufficient methanol to produce a homogeneous solution, and the reaction was allowed to stand at room temperature for one hour. The solution was poured into water, extracted with ether, acidified with 2 N-hydrochloric acid and extracted with ether. The combined extracts were dried and evaporated to give an oil which was triturated with benzene-petroleum ether, and the resulting solid filtered and dried (7.5 g; 88%), m.p. 63°, νmax. (Nujol) 3600 and 1702 cm-1 (CO2H), τ (DMSO-d6) values include 1.29, 2.21, 2.38 (thien-3-yl protons).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH:17]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:25]=4)=[O:22])[CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].O.[NH2:35]N.COC(OC)[N:40]([CH3:42])C>O>[C:30]([C:26]1[CH:25]=[C:24]([NH:23][C:21]([CH:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:1]5[CH:2]=[CH:42][NH:40][N:35]=5)[CH:9]=4)=[CH:12][CH:13]=3)[CH2:18]2)=[O:22])[CH:29]=[CH:28][CH:27]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: CC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cccc(C(C)(C)C)c2)CC3)ccn1
Solvent: O
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5cc[nH]n5)c4)cc3C2)c1
Temperature: 115 °C
Reaction time: 12 h
Yield: 34 %

Procedure:
A solution of 7-[(2-acetylpyridin-4-yl)oxy]-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.516 g, 1.16 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (20 mL) was allowed to stir at 115° C. for 12 h. The reaction mixture was concentrated. The residue was dissolved in ethanol (20 mL) and hydrazine hydrate (0.600 mL, 12.3 mmol) was added. The reaction mixture was allowed to stir at 90° C. for 1 h and then diluted with water. The solution was extracted with EtOAc and the combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-{[2-(1H-pyrazol-3-yl)-pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide 1-231 (0.184 g, 0.394 mmol, 34%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 10.02 (s, 1H), 8.63-8.51 (m, 1H), 8.05-7.96 (m, 1H), 7.85-7.77 (m, 1H), 7.68-7.62 (m, 1H), 7.54-7.46 (m, 1H), 7.37-7.03 (m, 7H), 3.06-2.73 (m, 5H), 2.18-2.05 (m, 1H), 1.88-1.74 (m, 1H), and 1.25 (s, 9H). LCMS: (FA) ES+467.8, ES−465.5.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:14]1(/[CH:13]=[CH:12]/[C:4]2[CH:3]=[C:2]([NH:1][C:21](=[O:23])[CH3:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(N)c2ccccc2n1
Product: CC(=O)Nc1cc(/C=C/c2ccccc2)nc2ccccc12
Yield: 64.3 %

Procedure:
A mixture of 4-aminoquinaldine (2-methyl4-quinolinamine) (3.00 g, 19.0 mmol), benzaldehyde (6.05 g, 5.80 mL, 57.0 mmol) and acetic anhydride (5.82 g, 5.38 mL, 57.0 mmol) was stirred at reflux for 5 h. After cooling, the volume was reduced in vacuo to give a brown oil, which was triturated overnight with diethyl ether. A formed solid was collected by filtration and air-dried to provide the title compound as a yellow solid (3.52 g, 64%). MS (API+): M+1: 289 (100%); 1H NMR (300 MHz, DMSO-d6) d 2.30 (s, 3H), 7.32-7.51 (m, 4H), 7.55-7.65 (m, 1H), 7.70-7.80 (m, 4H), 8.00 (d, J=7.7 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.38 (s, 1H), 10.24 (s, 1H, exchangeable).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([OH:21])[C@H:12]([NH:19][CH3:20])[CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:9]=[CH:10][C:2]1=2.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.CCOC(C)=O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C@@H:11]([OH:21])[C@H:12]([N:19]([CH3:20])[C:31](=[O:40])[CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH:9]=[CH:10][C:2]1=2
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CN[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CCc1ccccc1)[C@H](CN1CCCC1)[C@H](O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a 0° C. solution of compound 5 (0.2 g, 0.72 mmol) in THF (4 mL) was added Hunig's Base (0.09 g, 0.72 mmol) followed by hydrocinnamoyl chloride (0.12 g, 0.72 mmol) dropwise. The resulting mixture was allowed to stir overnight at room temperature, diluted with EtOAc and washed with satd. aq. NaHCO3, satd. aq. NaCl and dried over MgSO4. Purification by flash silica chromatography (MeOH/CH2Cl2) gave a yellow oil (0.12 g, 0.29 mmol, 41% yield). HPLC purity 98.4% (tR=5.02 min). NMR (500 MHz, CDCl3) δ 7.2 (s, 1H), 7.1-7.2 (m, 4H), 6.8-6.9 (m, 3H), 4.8 (s, 1H), 4.3 (s, 4H), 2.9 (s, 3H), 2.8-3.2 (m, 4H), 2.5-2.6 (m, 2H), 1.8-2.1 (m, 2H), 1.5-1.8 (m, 4H). ESI-MS m/z 425.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[N:14]=[C:13]([CH3:15])[NH:12][C:10]3=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>C(O)C>[ClH:1].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]4[N:14]=[C:13]([CH3:15])[NH:12][C:10]4=3)[N:5]=[C:4]([CH3:16])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(Cl)c2c(ccc3nc(C)[nH]c32)n1
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: COc1ccc(Nc2cc(C)nc3ccc4nc(C)[nH]c4c23)cc1
Product: Cl
Reaction time: 8 h

Procedure:
A mixture of 18.5 g. (0.08 m.) of 9-chloro-2,7-dimethylimidazo[4,5-f]-quinoline, 9.85 g. (0.08 m.) of p-anisidine and 300 ml. of ethanol is refluxed, with stirring, overnight. The solution is concentrated in vacuo to give 27 g. m.p. 307°-311° C. Recrystallization from 300 ml. of MeOH yields 13 g. m.p. 317°-318° C.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH:15]1([NH:19][C:20](=[O:31])[NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH:15]1([NH:19][C:20](=[O:31])[NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:7]3[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]3[CH3:1])=[O:27])=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)NC1CCC1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccc(NC(=O)NC2CCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.6 %

Procedure:
To a solution of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.10 g, 0.50 mmol) in N,N-dimethylformamide (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uronium hexafluorophosphate (0.190 g, 0.50 mmol, HATU), 4-(3-cyclobutylureido)benzoic acid (0.117 g, 0.50 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature for 20 hours and concentrated under vacuum. The residue was diluted with dichloromethane (15 mL) and washed with saturated ammonium chloride (aqueous) and brine. The organic layer was dried (sodium sulfate), filtered and concentrated under vacuum. The crude material was purified by column chromatography on silica (using a solvent gradient of dichloromethane/methanol) to afford the title compound (0.145 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20](O)=[O:21])=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([NH2:26])=[O:21])=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(N)=O)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) in DMF (2.5 mL) was added 1,1′-carbonyldiimidazole (49 mg, 0.3 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (25%, 385 μL, 2.5 mmol) and stirred for 2 h at room temperature. The reaction mixture was then evaporated. Purification by trituration from water/methanol afforded the title compound (64 mg, 77%) as an off white solid after. MS: m/e=331.0 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1.CN([CH:14]=[O:15])C.O>C1COCC1.C([Li])CCC>[CH:14]([C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1)=[O:15]
Reactant: Brc1cnc2n1CCCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cnc2n1CCCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (2.84 g) in THF (50 ml), n-butyllithium (1.6M hexane solution, 28 ml) was added dropwise at −78° C. The mixture was stirred for 1 hour at −78° C., DMF (5 ml) was added to the mixture, and the mixture was stirred for 0.5 hour at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→ethyl acetate), to give 3-formyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.48 g) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]>Cl.O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C)nc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 33.1 %

Procedure:
A mixture of 4-Chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (30 mg) in 3 mL of 4M HCl in dioxane and 1 mL of water was refluxed for 3 hours. After cooling to rt the mixture was diluted with water and sodium bicarbonate was added until pH was 9. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was further purified via flash column (70% ethyl acetate in hexane) to afford 9.1 mg of title compound as an off white solid. 1H NMR: (400 MHZ, CDCl3) δ 8.97 (m, 1H), 8.35 (m, 1H), 8.16-8.13 (m, 2H), 8.08-8.05 (m, 1H), 7.93-7.91 (m, 1H), 7.59-7.57 (m, 1H), 7.25-7.23 (1H), 2.63 (s, 3H). MS: (M+H)/z=490.0.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:39]2[CH:40]=[C:41]([NH:45][C:46](=[O:48])[CH3:47])[CH:42]=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([C:39]2[CH:40]=[C:41]([NH:45][C:46](=[O:48])[CH3:47])[CH:42]=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2cccc(NC(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2cccc(NC(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.78 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, N-{3-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]phenyl}acetamide (0.38 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (4 mL), N,N′-carbonyldiimidazole (0.20 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.26 g, 62%).
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C([C@:20]([C@:24](CC1C=CC=CC=1)([C@@:26](CC1C=CC=CC=1)([C@@H:28]([CH:30](CC1C=CC=CC=1)[OH:31])[OH:29])[OH:27])[OH:25])([OH:23])[CH:21]=[O:22])C1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([C:21]([C@@H:20]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])[OH:23])=[O:22])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: O=C[C@@](O)(Cc1ccccc1)[C@](O)(Cc1ccccc1)[C@@](O)(Cc1ccccc1)[C@H](O)C(O)Cc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)ccc1O

Procedure:
Vanillic acid having a benzyl-protected hydroxyl group at the 4 position and 2,3,4,6-tetrabenzyl glucose having benzyl-protected hydroxyl groups at positions other than the 1 position (Sigma-Aldrich) were condensed in a DMF solvent (at a reaction temperature of 60° C.) using the following condensing agents: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, Kokusaikagaku Co., Ltd.), 4-dimethylaminopyridine (DMAP, Tokyo Kasei Kogyo), and triethylamine (Et3N, Wako Pure Chemical Industries, Ltd.). The obtained condensate was a mixture comprising a anomer and β anomer at a ratio of 1:2. The condensate was purified using an open column (at different concentration ratios of hexane:ethyl acetate=6:1 and 5:1). A unreacted starting material was removed. The yield was found to be 84%: Molecular MS [M+Na]+ m/z 803.14, 1H NMR (300 MHz, CDCl3): δ7.60 (1H, dd, H-6), 7.59 (1H, d, H-2), 7.45-7.26 (60H, m, H-benzylic CH2), 6.90 (1H, d, H-5), 6.55 (1H, d, H-Glc1α, J=3.21), 5.84 (1H, d, H-Glc1β, J=7.65), 5.25 (10H, s, H-benzylic CH2), 4.96-3.56 (94H, m, CH3, H-Glc).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].ClC1C=C(C2C=CC=C(Cl)C=2)C=CC=1.Cl[C:32]1[CH:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:46]=3)[CH:39]=2)[CH:35]=[CH:36][CH:37]=1>CCOCC.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:36]1[CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:46]=3)[CH:39]=2)[CH:33]=[CH:32][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: Clc1cccc(-c2cccc(Cl)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc(Oc2cccc(Oc3cccc(-c4cccc(Oc5cccc(Oc6ccccc6)c5)c4)c3)c2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A 500 ml. four-necked flask equipped with stirrer, thermometer, and Dean-Stark strap surmounted by a Friedrichs condenser, was charged with 93.5 g. (0.505 mole) of m-phenoxyphenol, and 30.8 g. (0.50 mole) of potassium hydroxide was added in increments with stirring at 100°C. After the initial exothermic reaction had subsided, 80 ml. of toluene was added and water azeotroped from the reaction mixture until the theoretical amount had been collected, including that from the potassium hydroxide. The toluene was distilled from the reaction mixture until the pot temperature reached 230°C. After cooling to 150°C., 100 ml. of diglyme was added together with 7 g. of cuprous chloride and 2 g. of copper powder. The reaction mixture was then heated with stirring to 170°C. and 129.3 g. (0.57 mole) of 3,3'-dichlorobiphenyl was added over a 1 hr. period. Diglyme was distilled from the reaction mixture until the pot temperature reached 235°C. when reaction was continuted for 18 hours. On cooling, the reaction mixture was diluted with an equal volume of ether, and filtered to remove copper and potassium salts. The ethereal solution was washed three times with 150 ml. portions of 20% potassium hydroxide followed by water washing until nuetral. The water and potassium hydroxide layers were extracted with additional ether, the ether solutions combined and dried over anhydrous magnesium sulfate. After filtration, the ether was removed under vacuum and a dark red-brown oil was distilled to yield 71.4 g. of the intermediate compound 3-chloro-3'-(m-phenoxyphenoxy)biphenyl, bp 220°-222°C/0.04 mm. and 17.2 g. of the desired product, bp 312°C./0.05 mm. Final purification of the desired product was effected by dissolving in ethyl ether, treating with 1.0 g. of activated charcoal, followed by filtration through filter aid and removal of ethyl ether under vacuum.
Reaction SMILES: O[CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[S:5](=[O:12])(=[O:11])[C:4]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:3]1=2.[OH:20]S(O)(=O)=O.[C:25](#[N:27])[CH3:26]>>[C:25]([NH:27][CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[S:5](=[O:12])(=[O:11])[C:4]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:3]1=2)(=[O:20])[CH3:26]
Reactant: O=S(=O)(O)O
Reactant: CC#N
Reactant: CCCC1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Product: CCCC1CC(NC(C)=O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Reaction time: 8 h

Procedure:
A suspenison of 6 (47.41 g, 0.146 mol) in acetonitrile (500 ml) was chilled to -10° C. The cold stirring suspension was treated with 95% H2SO4 (165.5 ml, 3.11 mol) at a rate sufficient to maintain the temperature below 0° C. After equilibrating to room temperature overnight, the resulting solution was poured over ice and was stirred for 4.0 hours. The resulting aqueous suspension was partitioned between 1000 ml and 250 ml of ethyl acetate. The aqueous phase was collected, buffered to pH 8, and partitioned with an additional 50 ml of ethyl acetate. All organic phases were combined and washed with 250 ml of saturated aqueous sodium bicarbonate followed by washing with 250 ml of saturated aqueous sodium chloride. The dried (Na2SO4) organic phase was filtered and concentrated to give 55.27 g (quantitative) of 7 as an orange foam.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([CH2:14][N:15]2[N:43]=[C:19]3[CH2:20][C:21](=O)[C:22]4[CH2:23][S:24][N:25]=[C:26]([N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:17]([C:18]=43)=[N:16]2)[C:8]=1[CH3:44].CO.[CH:47]1([NH2:50])[CH2:49][CH2:48]1>C(O)(=O)C.O1CCCC1>[CH:47]1([NH:50][CH:21]2[C:22]3[CH2:23][S:24][N:25]=[C:26]([N:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[C:17]4=[N:16][N:15]([CH2:14][C:9]5[C:8]([CH3:44])=[C:7]([O:6][CH3:5])[C:12]([CH3:13])=[CH:11][N:10]=5)[N:43]=[C:19]([C:18]=34)[CH2:20]2)[CH2:49][CH2:48]1
Reactant: NC1CC1
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(C)cnc(CN2N=C3CC(NC4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
Sodium cyanoborohydride (1.89 g) was added to a mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (5.71 g), methanol (50 mL), tetrahydrofuran (25 mL), cyclopropylamine (1.04 mL) and acetic acid (1.72 mL) under cooling in an ice bath, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate, and the solution was washed with a saturated sodium bicarbonate solution and then with brine. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure to obtain the title compound (5.91 g, 97%) as an oil.