Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([C:34]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:34]([C:36]2[CH:37]=[CH:38][C:39]([NH:40]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:41][CH:42]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccc(C(=O)N2CCCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(C(=O)N3CCCCC3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(piperidin-1-yl-carbonyl)-aniline
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=1>CN(C=O)C>[C:1]12([CH2:11][O:12][C:16]3[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [O-][n+]1ccc(OCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of adamantanemethanol (1.2 g, 7.4 mmol) in DMF (8 mL) was added NaH (0.3 g, 7.4 mmol) in a single portion. After gas evolution subsided, 4-chloropyridine N-oxide (0.8 g, 6.17 mmol) was added. The reaction mixture was stirred at room temperature under Ar until the reaction was complete. The mixture was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) gave 4-(adamantylmethoxy)pyridine N-oxide (1.55 g, 97%) as a yellow solid. This material was suspended in Ac2O (5 mL), heated to 140° C. and stirred at 140° C. for 4 h. After cooling, the mixture was diluted with CH3OH and H2O (10 mL, 1:1 mixture) and stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give 4-(adamantylmethoxy)pyridin-2(1H)-one (1.08 g, 70%) as a brown solid. Following the procedure of Example 62 (step f), but substituting 5-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazole for 4-(2-(5-iodo-1H-indazol-1-yl)ethyl)morpholine, 4-(adamantylmethoxy)pyridin-2(1H)-one for 4-phenethylpyridin-2(1H)-one, and 1,2-trans-cyclohexyldiamine for 8-hydroxyquinoline, the title compound (142 mg, 79%) was obtained as a yellow powder: mp 252-254° C.; 1H NMR (500 MHz, CD3OD) δ 8.24 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.46 (dd, J=9.0, 2.0 Hz, 1H), 6.29 (dd, J=7.5, 3.0 Hz, 1H), 6.04 (d, J=2.5 Hz, 1H), 4.87 (t, J=6.5 Hz, 2H), 3.86 (t, J=5.5 Hz, 2H), 3.69-3.72 (m, 2H), 3.63 (s, 2H), 3.16-3.20 (m, 2H), 2.16-2.19 (m, 2H), 2.00-2.03 (m, 3H), 1.71-1.84 (m, 12H), 1.24-1.31 (m, 2H); ESI MS m/z 473 [M+H]+; HPLC (Method D) 98.9% (AUC), tR=15.4 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15])[CH:3]=1
Reactant: OCc1cc(Br)ccn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a stirring solution of (4-bromopyridin-2-yl)methanol (1.50 g, 8.0 mmol) in DCM (4 mL) was added tert-butylchlorodimethylsilane (1.20 g, 8.0 mmol) following by TEA (1.60 g, 12.0 mmol). The reaction mixture was stirred at room temperature for 12 h then washed with brine and EA. The combined organic layers were dried over MgSO4, filtered, and concentrated to yield an amber liquid. The crude product was purified by chromatography (EA/Hexanes) to produce 1.67 g (70%) of 4-bromo-2-((tert-butyldimethylsilyloxy)methyl)pyridine INT-70 as a light yellow liquid. LCMS-ESI (m/z) calculated for C12H20BrNOSi: 302.3; found 303.0 [M+H]+, tR=4.87 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=5.3, 1H), 7.68 (dd, J=1.9, 0.7, 1H), 7.35-7.24 (m, 1H), 4.80 (s, 2H), 0.99-0.86 (m, 9H), 0.16-0.06 (m, 6H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH3:29])[CH:9]=[C:10]2[C:15]=1[N:14](C(OCC(C)C)=O)[CH:13]=[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]2=[O:28])(=O)C.BrN1C(=O)CCC1=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O)C>ClCCl>[CH:5]([C:6]1[CH:7]=[C:8]([CH2:29][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]2[OH:28])=[O:4]
Reactant: CCOC(=O)c1cn(C(=O)OCC(C)C)c2c(COC(C)=O)cc(C)cc2c1=O
Reactant: C1COCCN1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnc2c(C=O)cc(CN3CCOCC3)cc2c1O
Reaction time: 0.17 h

Procedure:
A stirred solution of 3-ethyl 1-isobutyl 8-((acetyloxy)methyl)-6-methyl-4-oxo-1,3-(4H)-quinolinedicarboxylate (Preparation 26, 3.0 g) and N-bromosuccinimide (3.0 g) in dichloromethane (300 mL) is irradiated with a 650 watt sun lamp for 20 min. Morpholine (15 mL) is added to the solution. After 10 min, ethanol (20 mL) is added, and the solvents are removed at 50° C./20 mm. The reaction is repeated on the same scale. The reaction mixtures are combined and partitioned between chloroform (250 mL) and water (150 mL). The chloroform layer is washed twice with water, and the chloroform is evaporated. The residual oil is chromatographed on silica gel (1% methanol/chloroform) to give 2.15 g of the title compound. Physical characteristics: M.p. 202-204° C.; 1H NMR (CDCl3) δ1.43, 2.50, 3.69, 3.74, 4.42, 8.19, 8.59, 8.67, 10.18, 11.8. Anal. Found: C, 62.42; H, 5.92; N, 8.03.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1>C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(Br)c3cc([N+](=O)[O-])ccc32)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2nc(Br)c3cc(N)ccc32)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
SnCl2 dihydrate (0.85 g, 3.79 mmol) was added to a suspension of 3-bromo-5-nitro-1-tosyl-1H-indazole (0.300 g, 0.76 mmol) in ethyl acetate (25 mL), and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and quenched with saturated NaHCO3 (25 mL). The resulting suspension was filtered through a pad of celite, and the filter cake was washed with ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:1) to give 3-bromo-1-tosyl-1H-indazol-5-amine (0.256 g, 92%) as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[N:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5](=[O:18])[CH:4]=1.[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1.O>[OH:2][C:3]1[CH:8]=[N:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5](=[O:18])[CH:4]=1
Reactant: COc1ccc(Cn2ncc(OC)cc2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2ncc(O)cc2=O)cc1
Temperature: 80 °C
Yield: 87 %

Procedure:
To a stirring solution of 5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one (117 mg, 0.47 mmol) in THF (3 mL) at room temperature under argon was added 1M NaOH (2.0 mL, 2.0 mmol). The resulting reaction mixture was heated at 80° C. under argon for a day and monitored by LCMS until the reaction was completed. EtOAc (20 mL), 1 M HCl (2 mL), and water (10 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 95 mg (77%) of 5-hydroxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one was obtained as a gum. MS (ESI) 233 (M+H).
Reaction SMILES: [BrH:1].Cl[C:3]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[N:4]=1>BrCBr>[Br:1][C:3]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[N:4]=1
Reactant: CCOC(=O)C1CC(Cl)=NN1c1ncccc1Cl
Reactant: Br
Solvent: BrCBr
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Yield: 99 %

Procedure:
Hydrogen bromide was passed through a solution of ethyl 3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (i.e. product of Step B) (8.45 g, 29.3 mmol) in dibromomethane (85 mL). After 90 minutes the gas flow was terminated, and the reaction mixture was washed with aqueous sodium bicarbonate solution (100 mL). The organic phase was dried and evaporated under reduced pressure to give the title product as an oil (9.7 g, 99% yield), which crystallized on standing.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23](I)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH2:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]=[O:37])[CH3:30]>C(Cl)Cl.C(OCC)C.ClCl>[CH2:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1[CH:36]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[OH:37])[CH3:30]
Reactant: CCc1sccc1C=O
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[Mg+]
Agent: ClCl
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1sccc1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of N-trityl-4-iodo-imidazole (4.1 g, 0.0095 mol) in dry CH2Cl2 (75 mL) was added a solution of MeMgBr (4.0 mL, 3.0M) in diethyl ether and the solution was stirred for 3 hrs. Then a solution of 2-ethylthiophene-3-carboxaldehyde, B7, (1.66 g, 0.0087 mol) in CH2 Cl2 (20 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with a second portion of CH2Cl2. The extracts were combined and washed with a small portion of water, dried (Na2 SO4), and filtered. The solvent was evaporated in vacuo, and the residue was triturated with Et2O to give (2-ethylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, C7, as a beige solid which was taken on to the next step directly. ##STR56##
Reaction SMILES: [O:1]=[C:2]1[C:11]2=[N:12][N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([CH2:15][C:16](O)=[O:17])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:1]=[C:2]1[C:11]2=[N:12][N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([CH2:15][C:16]([N:35]3[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]3)=[O:17])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1
Reactant: O=C(O)Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2c3c(nn2-c2ccccc2)c(=O)[nH]c2ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of (4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)acetic acid (1.50 g, 4.70 mmol), N-Boc piperazine (0.96 g, 5.17 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.35 g, 7.05 mmol), 1-hydroxybenzotriazole (0.95 g, 7.05 mmol) and 20 mL of DMF was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure. The residue was triturated with acetonitrile, isolated by filtration, and dried to afford 1.96 g of tert-butyl 4-[(4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)acetyl]piperazine-1-carboxylate as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[N:7]([CH2:39][CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:8]1[S:9][C@H:10]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C@H:13]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C@H:11]2[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:50]C1(C)N([O])C(C)(C)CCC1.C1C(=O)N(Br)C(=O)C1.C[Mg+].[Br-]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].ClCCl.O.C1COCC1>[CH2:42]([O:41][CH2:40][CH2:39][N:7]([C:8]1[S:9][C@H:10]2[O:16][C@H:15]([C@@H:17]([OH:18])[CH3:50])[C@@H:14]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C@H:13]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[C@H:11]2[N:12]=1)[C:6](=[O:49])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(CCOCc4ccccc4)C(=O)OC(C)(C)C)S[C@H]3O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Mg+]
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CO[C@H]2[C@H](OCc3ccc(OC)cc3)[C@H]3N=C(N(CCOCc4ccccc4)C(=O)OC(C)(C)C)S[C@H]3O[C@@H]2[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 134 (1.5 g, 2.2 mmol), KHCO3 (970 mg, 9.7 mmol), TBAB (70 mg, 0.2 mmol), TEMPO (31 mg, 0.2 mmol) in dichloromethane (50 mL) and H2O (10 mL) was added NBS (423 mg, 2.4 mmol) at 0° C. After stirred for 30 minutes at room temperature, the reaction was diluted with water (50 mL) and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic layers was dried over anhydrous sodium sulfate, and concentrated under vacuum to give crude 135, which was dissolved into THF (20 mL). To the solution of 135 in THF was added MeMgBr (3 mL, 6 mmol, 2M in THF) at room temperature. After 1 hr, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and extracted with ethyl acetate (4×20 mL). The combined organic layer was washed with brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was purified by a silica gel column, eluted with 10%-20% ethyl acetate in petroleum ether to afford 136 (0.95 g, 63%, two epimers, the ratio was 1:4 determined by 1H NMR) as a light yellow syrup. (ES, m/z) [M+H]+ 709.0; 1H NMR (300 MHz, CDCl3) δ 7.15-7.38 (m, 9H), 6.79-6.92 (m, 4H), 6.11 (m, 1H), 4.50-4.55 (m, 4H), 4.49 (s, 2H), 4.31-4.33 (m, 1H), 4.05-4.06 (m, 1H), 3.83-3.90 (m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.54-3.66 (m, 2H), 3.31-3.52 (m, 3H), 3.11-3.15 (m, 1H) 1.54 (s, 9H), 1.12 (d, J=1.8 Hz, 3H).
Reaction SMILES: O/[N:2]=[CH:3]\[C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:3]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc2cc(/C=N\O)oc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2cc(C#N)oc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
E/Z-Methyl 2-[(hydroxyimino)methyl]-1-benzofuran-6-carboxylate (438 mg, 2.0 mmol) is suspended in CH2Cl2 (8 ml) in a dry flask under nitrogen. Pyridine (0.65 ml, 8.0 mmol) is added via syringe, and the mixture is cooled to 0° C. Trifluoroacetic anhydride (0.56 ml, 4.0 mmol) is added drop-wise, and the reaction is stirred overnight, allowing the ice bath to expire. The reaction is carefully quenched with saturated NaHCO3 (10 ml). The layers are separated and the organic layer is dried (K2CO3), filtered, and concentrated to a pink solid. The crude material is chromatographed over 25 g slurry-packed silica gel, eluting with 25% EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 315 mg (78%) of methyl 2-cyano-1-benzofuran-6-carboxylate as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:16][N:17]([CH3:21])[C:18]([N:7]1[C:8]([S:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:19]
Reactant: CC(C)(C)c1n[nH]c(SCS(C)(=O)=O)n1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCS(C)(=O)=O
Yield: 54.6 %

Procedure:
2 g (8.0 mmole) of 3-t-butyl-5-(methylsulfonylmethylthio)-1H-1,2,4-triazole, 0.8 ml (8.8 mmole) of dimethylcarbamoyl chloride, 1.25 ml (9.0 mmole) of triethylamine and 0.1 g (0.8 mmole) of 4-dimethylaminopyridine were dissolved in 20 ml of tetrahydrofuran and refluxed for 4 hours. After removal of the solvent the mixture was partitioned between ether and water, dried over magnesium sulfate and concentrated under vaccum. After chromatography on silica gel, trituration with ether afforded 1.4 g of 1-dimethylcarbamoyl-3-t-butyl-5-(methylsulfonylmethylthio)-1H-1,2,4-triazole. m.p. 109°-110° C.
Reaction SMILES: ClCCl.Cl.[NH2:5][CH2:6][CH:7]([OH:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Br:24][CH2:25][C:26](Br)=[O:27]>O>[Br:24][CH2:25][C:26]([NH:5][CH2:6][CH:7]([OH:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:27]
Reactant: O=C(Br)CBr
Reactant: NCC(O)Cc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)NCC(O)Cc1ccc(F)cc1
Yield: 97.5 %

Procedure:
To a dichloromethane suspension (16 mL) of 1-amino-3-(4-fluorophenyl)propan-2-ol hydrochloride (0.75 g, 3.64 mmol) synthesized in Reference Synthesis Example 41, triethylamine (0.92 g, 9.10 mmol) and bromoacetyl bromide (0.88 g, 4.37 mmol) were added at 0° C. and the resultant solution was stirred for 0.5 hours. After completion of the reaction, water was added thereto and extraction with chloroform from the resultant mixture was performed. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (1.03 g, yield 97%).
Reaction SMILES: N#N.Br[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])O1.C([O-])(O)=O.[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]
Reactant: Brc1cccs1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])O
Solvent: COCCOC
Product: Nc1ccccc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
AB427 (The following reaction is carried out in an N2 atmosphere.) Dissolve Tetrakis-(triphenylphosphine)-palladium(0) (297 mg, 0.26 mmol) and 2-Bromo-thiophene (837 mg, 5.13 mmol) in DME (42 mL), degas the reaction mixture carefully (5 times) and flush with N2. After 10 min stirring add 2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.24 g, 5.64 mmol) and a 1M aqueous NaHCO3 solution (15.4 mL, 15.4 mmol), degas the reaction mixture again carefully (5 times) and flush with N2. Stir the mixture for 3 h at 95° C. Cool mixture to rt, remove solvent under reduced pressure and partition the residue between EtOAc and water. Extract the separated aqueous layer with EtOAc (3 times). Wash combined organic layer with brine and dry it with Na2SO4. Purify the crude product by flash chromatography (silica gel 60, CyH/EtOAc 15+1] to obtain 2-Thiophene-2-yl-phenylamine (55) as a brown solid (825 mg, 92%). 1H NMR (400 MHz, CDCl3): 4.40-6.00 (m, 2 H); 6.88 (td, 1 H, J1=7.6 Hz, J2=1.0 Hz); 6.93 (dd, 1 H, J=8.0 Hz, J2=1.0 Hz); 7.07 (dd, 1 H, J=5.3 Hz, J2=3.5 Hz); 7.17 (td, 1 H, J1=8.0 Hz, J2=1.5 Hz) 7.22 (dd, 1 H, J=3.5 Hz, J2=1.3 Hz); 7.30 (dd, 1 H, J1=7.6 Hz, J2=1.5 Hz); 7.33 (dd, 1 H, J=5.3 Hz, J2=1.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1.ClC1C=CC2N=CCN=C(C3C=CC=CC=3)C=2C=1.C(O)(=O)C.[SH:41][CH2:42][CH2:43][OH:44]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([S:41][CH2:42][CH2:43][OH:44])[CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1
Reactant: OCCS
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCCN2
Agent: Clc1ccc2c(c1)C(c1ccccc1)=NCC=N2
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCCSC1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine (10 g) was oxidized to 7-chloro-5-phenyl-3H-1,4-benzodiazepine as described in Example 1 with the addition of 0.1 ml of acetic acid. The crude oxidation product was taken up in THF (60 ml), treated with 2-mercaptoethanol (10 ml ) and heated under reflux overnight. The resulting solution was concentrated under reduced pressure until the product began to crystallize and then diluted with 100 ml of ether. The product was collected and washed with ether to give the above-named product as colorless crystals, mp 135°-140° (dec).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.O>CN(C=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:18][CH:19]=1
Reactant: O=c1cc(O)cc[nH]1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of potassium carbonate (12.44 g, 90 mmol), 4-hydroxypyridin-2(1H)-one (10 g, 90 mmol) in DMF (500 mL) was stirred at 140° C. for 60 min prior to addition of a solution of 1-(chloromethyl)-4-fluorobenzene (13.01 g, 90 mmol) in DMF (5.0 mL). After stirring at 140° C. for 60 min, the reaction was cooled to RT prior to dilution with water (1.0 L). The resulting suspension was stirred at RT for 60 min prior to collection of precipitate by filtration. The filter cake was washed with water (250 mL), suspended with stirring in ethyl ether (500 mL) for 15 min and collected by filtration. After air-drying, 4-(4-fluorobenzyloxy)pyridin-2(1H)-one 17A was obtained as a white solid (6.67 g, 28.9 mmol, 32.1% yield). 1H NMR (400 MHz, MeOD) δ ppm 7.42-7.56 (2H, m), 7.34 (1H, d, J=7.26 Hz), 7.03-7.25 (2H, m), 6.12-6.24 (1H, m), 6.01 (1H, br. s.), 5.10 (2H, s).
Reaction SMILES: C(O[C:4](=[O:13])[CH2:5][C:6]([C:8]1[O:12][N:11]=[CH:10][CH:9]=1)=O)C.[NH:14]([C:16]1[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([CH3:31])[C:25]([CH3:33])([CH3:32])[CH2:24]2)=[O:21])=[CH:18][CH:17]=1)[NH2:15].C(O)C>C(O)(=O)C>[O:12]1[C:8]([C:6]2[NH:15][N:14]([C:16]3[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH:23]4[CH2:24][C:25]([CH3:32])([CH3:33])[N:26]([CH3:31])[C:27]([CH3:30])([CH3:29])[CH2:28]4)=[O:21])=[CH:18][CH:17]=3)[C:4](=[O:13])[CH:5]=2)=[CH:9][CH:10]=[N:11]1
Reactant: CCOC(=O)CC(=O)c1ccno1
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-n3[nH]c(-c4ccno4)cc3=O)cc2)CC1(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
3-Isoxazol-5-yl-3-oxo-propionic acid ethyl ester (49 mg) and 4-Hydrazino-N-(1,2, 2,6,6-pentamethyl-piperidin-4-yl)-benzamide (93 mg) were dissolved into ethanol (2.5 ml) and acetic acid (0.3 ml) and the solution stirred at 65° C. for 2 h. Concentration in vacuo and purification by HPLC gave the expected product. LC/MS: main peak is product (m/z: 424.3)