Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([N:11]1[C:16](=[O:17])[CH:15]2[CH2:18][CH:12]1[CH:13]=[CH:14]2)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>CO>[CH3:1][O:2][C:16]([C:15]1[CH2:18][C@@H:12]([NH:11][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:13][CH:14]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C=CC1C2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Sodium methoxide (8.23 ml of a 25% wt solution in methanol, 0.05 mol eq) was added dropwise to a stirred solution of (−)-N-Boc 2-azabicyclo[2.2.1]hept-5-en-3-one (150 g, 0.72 mol) in methanol (750 ml) at 0° C. After 30 minutes, the reaction was warmed to room temperature. After 60 h, the reaction was quenched with acetic acid and concentrated to dryness. The residue was redissolved in dichloromethane (700 ml) and washed with water (300 ml), saturated sodium hydrogen carbonate (300 ml) and brine (300 ml). The combined aqueous washings were then back extracted with dichloromethane (300 ml), the organic extracts combined and dried over magnesium sulfate. Filtration and concentration under reduced pressure gave a white solid which was recrystallized from ethyl acetate/heptane to give the title compound as white crystals (130 g, 75%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([C:35]3([NH:39]C(OC(C)(C)C)=O)[CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:7][CH:6]=1.Cl.O1CCOCC1>CO>[NH2:39][C:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:28]3[N:14]4[C:15]5[CH:27]=[CH:26][CH:25]=[N:24][C:16]=5[NH:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:13]4=[N:12][C:11]=3[C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:3](=[O:47])[O:2][CH3:1])=[CH:10][CH:9]=3)=[CH:30][CH:31]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 132.4 %

Procedure:
Methyl{4-[3-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl]phenyl}carbamate (41 mg, 0.050 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 24 hours. The mixture was concentrated to afford the desired product (35 mg, 83%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 9.79 (s, 1H), 8.79-8.73 (m, 3H), 8.14 (dd, J=4.0 Hz and 1.7 Hz, 1H), 7.96 (dd, J=8.0 Hz and 1.1 Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.44-7.40 (m, 4H), 7.34-7.30 (m, 3H), 7.17 (t, J=7.2 Hz, 1H), 6.91 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.78 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.66 (s, 3H), 2.57 (t, J=7.7 Hz, 4H), 2.24-2.16 (m, 1H), 1.85-1.78 (m, 1H). LCMS: 529 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.O1[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.[CH2:23](OCC)C>>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=2)=[C:18]2[CH:23]=[CH:21][CH:20]=[CH:19]2)=[CH:9][CH:10]=1
Reactant: CCOCC
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: C1CCOC1
Agent: Cl
Product: Cc1ccc(C(=C2C=CC=C2)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 74.5 %

Procedure:
To a 200-ml two-neck flask equipped with a magnetic stirrer, a three-way cock, 6.72 g (31.9 mmol) of 4,4′-dimethylbenzophenone, and 30 ml of tetrahydrofuran were charged under nitrogen atmosphere. 19 ml (38 mmol) of a 2.0 mol/l sodium cyclopentadienyl/tetrahydrofuran solution was gradually added thereto, while cooling it in an ice water bath, and the mixture was stirred at room temperature for 6 days. 100 ml of 1 N hydrochloric acid was gradually added thereto, while cooling it in an ice water bath and 100 ml of diethyl ether was added. The organic layer was separated, and washed twice with 100 ml of water, and once with 100 ml of saturated solution of salt. After the solution was dried over magnesium sulfate, the solvent was distilled off, and the obtained product was purified by column chromatography. The production quantity was 6.15 g, and the yield was 74.5%. Identification was performed by 1H NMR spectrum. The measurement result is shown as follows.
Reaction SMILES: C(O[C:4](=[O:15])[CH:5](P(OCC)(OCC)=O)[CH3:6])C.C([Li])CCC.[CH:21]1([NH:26][C:27]2[C:32]([CH:33]=O)=[CH:31][N:30]=[C:29]([S:35][CH3:36])[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH:21]1([N:26]2[C:27]3[N:28]=[C:29]([S:35][CH3:36])[N:30]=[CH:31][C:32]=3[CH:33]=[C:5]([CH3:6])[C:4]2=[O:15])[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ncc2cc(C)c(=O)n(C3CCCC3)c2n1
Temperature: -40 °C
Yield: 36.5 %

Procedure:
2-(Diethoxy-phosphoryl)-propionic acid ethyl ester (15.24 g, 64 mmol) was dissolved in tetrahydrofuran (100 mL) to which n-butyl lithium (47.7 mL, 119 mmol, 2.5 M in hexanes) was slowly added at −70° C. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (15 g, 63 mmol) was dissolved in tetrahydrofuran (70 mL) then added to the reaction mixture allowing the reaction to warm to −40° C. After 3 hours the reaction was warmed to room temperature, poured into cold 1 N citric acid and extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a yellow oil which was purified by silica gel chromatography. The resulting oil was dissolved to 1,8-diazabicyclo[5.4.0]undec-7-ene (75 mL) and heated to 150° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (350 mL), washed with 5% HCl and brine, dried over MgSO4, then filtered and concentrated in vacuo The remaining residue was diluted with diethyl ether and the precipitated solid was filtered off to give 8-cyclopentyl-6-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (6.33 g, 31.3%). 1H NMR δ (400 MHz, CDCl3) 8.52 (s, 1H), 7.39 (d, J=1.2 Hz, 1H), 5.96 (m, 1H), 2.59 (s, 3H), 2.30 (m, 2H), 2.19 (d, J =1.2 Hz, 3H), 2.07 (m, 2H), 1.86 (m, 2H), 1.67 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][C@H:17]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:12]([C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9][CH:10]=2)=[O:14])[C@H:17]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][N:25]=1
Reactant: O=C(O)c1ccnn1-c1ccccc1
Reactant: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Product: C[C@H]1CCCN(C(=O)c2ccnn2-c2ccccc2)[C@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 1-phenyl-1H-pyrazole-5-carboxylic acid and rac-cis-N-((3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 444, [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[N:11]([O-:13])=[O:12].[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2c(c1)CCO2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(c([N+](=O)[O-])c1)OCC2
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A mixture of 5-methyl-2,3-dihydrobenzofuran (1b) (2.7 g, 20 mmol) in TFA (50 mL) was cooled to 0° C., NaNO2 (2.5 g, 36 mmol) was added thereto. Then it was warmed up to ambient temperature and stirred for 12 h. The mixture was concentrated, poured into water (50 mL), extracted with EtOAc (150 mL), washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1) to give the title compound (1c).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:3].[Br:16][CH2:17][CH2:18][CH2:19][Cl:20].CO>COC(C)(C)C>[Br-:16].[Cl:20][CH2:19][CH2:18][CH2:17][N+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:1])[CH3:3]
Reactant: ClCCCBr
Reactant: CCCCCCCCCCCCN(C)C
Solvent: COC(C)(C)C
Solvent: CO
Product: CCCCCCCCCCCC[N+](C)(C)CCCCl
Product: [Br-]
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A 2 L 3-neck round-bottom flask equipped with an air condenser and a magnetic stirrer was charged with N,N-dimethyldodecylamine (297.24 g), 1-bromo-3-chloropropane (220.44 g) and methanol (250 mL). The reaction was maintained at 65° C. for 24 hours. Methanol was removed by rotary evaporation under reduced pressure to yield a brown sludge. To the sludge was added methyl-tert-butylether (2 liters) causing a white solid to form. The mixture was stirred for two hours and a semi-crystalline, white particulate was collected by vacuum filtration. The particulate was dried in a vacuum oven at 35° C. for 24 hours. Yield 228.2 grams (0.61 moles, 44%). (4-Chlorobutyl)dodecyldimethylammonium bromide and (6-chlorohexyl)dodecyldimethylammonium bromide can be prepared by a similar process using the appropriate bromochloroalkane and dodecyldimethylamine.
Reaction SMILES: S(=O)(=O)=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C.[Cl-].[Na+]>CS(C)=O.ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH2:13][CH2:14][CH:15]=[O:16]
Reactant: OCCCc1c(F)cccc1Cl
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCCc1c(F)cccc1Cl
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of pyridine complex with sulfur trioxide (40.35 g, 0.225 mol) in dimethylsulfoxide (50 mL) was slowly added to a solution of 3-(2-chloro-6-fluoro-phenyl)-propan-1-ol (20.6 g, 0.109 mol) and triethylamine (25.8 g, 0.225 mol) in dichloromethane (250 mL) at 0° C. The reaction was allowed to stir for 30 minutes, and then it was poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The combined organic layers were washed twice with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to afford 3-(2-Chloro-6-fluoro-phenyl)-propionaldehyde (15 g, 80 mmol, 74%), 1H NMR (CDCl3): δ 9.83 (s, 1H), 7.24-7.00 (m, 2H), 6.99-6.94 (m, 1H), 3.13-3.09 (m, 2H), 2.75-2.71 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[S:19][C:13]2[N:14]=[CH:15][NH:16][C:17](=O)[C:12]=2[C:11]=1[CH3:20])(=[O:9])=[O:8].P(Cl)(Cl)([Cl:24])=O>>[ClH:24].[Cl:24][C:17]1[C:12]2[C:11]([CH3:20])=[C:10]([S:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])(=[O:9])=[O:8])[S:19][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: Cc1c(S(=O)(=O)NCCCN(C)C)sc2nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(S(=O)(=O)NCCCN(C)C)sc2ncnc(Cl)c12
Product: Cl
Temperature: 25 °C

Procedure:
To N-(3-(dimethylamino)propyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-sulfonamide (0.6 g, 1.8 mmol) was added phosphorus oxychloride (5.0 mL, 36 mmol) and the suspension heated at reflux for 1.5 hours. The reaction was cooled to ambient temperature and the excess phosphorus oxychloride removed under vacuum. The residue was co-evaporated several times with chloroform. Drying under vacuum gave a hydroscopic cream solid that was used without further purification (0.65 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N([CH2:27][CH3:28])CC)C.C(Cl)Cl.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:32]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:21][CH2:2][CH2:3][CH2:4][CH2:27][CH3:28]
Reactant: CCN(CC)CC
Reactant: OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (2.0 g, 6.84 mmol), triethylamine (1,0 g, 10 mmol) in DCM (70 ml) decanoyl chloride (1.7 g, 8.9 mmol) was added dropwise at room temperature. The mixture was stirred for 1 hour, then was concentrated to a crude solid. The solid was extracted into ethyl acetate, and the insoluble salts were filtered. The solvents were removed. The crude product was purified by flash chromatography (Sorbsil C-30, 30 g, eluted with a mixture of MeOH in DCM). The oil thus obtained (2.5 g, 81%) was converted to a fumarate salt with fumaric acid (650 mg, 1.0 eq) in ethanol. Crystals were collected: 1.48 g, m.p.=109°-110° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[C:9]#[CH:10])[CH:5]=[CH:4][CH:3]=1.[CH3:12][Mg]Cl>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:11])([C:9]#[CH:10])[CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)c1cccc(Br)n1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cccc(Br)n1
Temperature: -78 °C

Procedure:
1-(6-Bromopyridin-2-yl)prop-2-yn-1-one (840 mg, 4.00 mmol) was dissolved in THF (20 mL) and cooled to −78° C. Methylmagnesium chloride (3.0 M in THF, 1.60 mL, 4.80 mmol) was added dropwise. The mixture was allowed to warm to room temperature, quenched with saturated NH4Cl, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-50% EtOAc/hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:22][S:23][CH2:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1>CS(C)=O>[F:1][C:2]1[C:20]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][S:23][CH3:22])[CH:26]=3)[CH2:36][CH2:35]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CSCc1cccc(N2CCNCC2)c1
Solvent: CS(C)=O
Product: CSCc1cccc(N2CCN(c3cc4nc5c(cc4cc3F)c(=O)c(C(=O)O)cn5C)CC2)c1
Yield: 79.9 %

Procedure:
7-Fluoro-1-methyl-8-[4-[3-(methylsulphanylmethyl)phenyl]piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 1, but from 0.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 0.66 g of [3-(methylsulphanylmethyl)phenyl]piperazine in 15 cm3 of dimethyl sulphoxide. After washing 2 times with 15 cm3 of ethanol, 0.61 g of 7-fluoro-1-methyl-8-[4-[3-(methylsulphanylmethyl)phenyl]piperazin-1-yl]-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid was obtained in the form of a yellow solid melting at about 240-5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23]O)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:50]1[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:50]4[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]4)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)C1CNC1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)nc3)no2)cc1Cl
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(Cl)c4)n3)cn2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 23 (23g) using {5-[5-(3-chloro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methanol (0.18 g, 0.54 mmol) that was obtained in Example 26 (26a), carbon tetrabromide (0.36 g, 1.1 mmol), triphenylphosphine (0.28 g, 1.1 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.81 mmol), and N,N-diisopropylethylamine (0.28 mL, 1.6 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:1 to 3:1) as the eluent to afford the title compound (0.15 g) in a yield of 61% as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([NH:8][OH:9])=[O:7].N1C=CC=CC=1.[CH2:21]([C:23]([CH2:30][CH3:31])([C:27](Cl)=[O:28])[C:24](Cl)=[O:25])[CH3:22]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([N:8]1[C:24](=[O:25])[C:23]([CH2:30][CH3:31])([CH2:21][CH3:22])[C:27](=[O:28])[O:9]1)=[O:7]
Reactant: CCC(CC)(C(=O)Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)NO)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1(CC)C(=O)ON(C(=O)c2ccc(OC)c(OC)c2)C1=O
Yield: 73.4 %

Procedure:
A mixture consisting of 1.97 g (0.0100 mol) of 3,4-dimethoxybenzohydroxamic acid, mp 170-173° C. (dec.) (lit, mp 167-168° C., F. Aljundi, E. Hannig, and K. Bohm, Pharmazie, 28, 362 (1973)), 5 ml of pyridine, and 100 ml of methylene chloride was prepared in a 250 ml round bottom flask. The mixture was cooled in an ice bath, and 1.977 g (0.0100 mol) of diethylmalonyl chloride was added dropwise over a 15 minute period with stirring. The reaction mixture was stirred for 1 hour at room temperature after which time all the hydroxamic acid has dissolved. The solution was extracted three times with 50 ml portions of water, four times with 50 ml portions of 5% hydrochloric acid, and two times with 50 ml portions of 5% sodium carbonate. The methylene chloride was dried (MgSO4) and evaporated to dryness under reduced pressure to give 2.36 g (73.5%) of crude 2-(3,4-dimethoxybenzoyl)-4,4-diethylisoxazolidine-3,5dione as a solid residue. Recrystallization of the solid from absolute ethanol gave pure 2-(3,4-dimethoxybenzoyl)-4,4-diethylisoxazolidine-3 5dione as a white solid: mp 108-109° C. IR (Nujol) 1805 (s, C=0), 1752 (s, C=0), 1693 cm-1 (s, C=0); 1H NMR (400 MHz, CDCl3) δ7.40-7.54 (m, 2H), 6.94-6.96 (d, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 1.97 (q, 4H), 1.02 (t, 6H); High resolution MS, calc'd for: C16H19NO6 : 321.1212. Found: 321.1208. Anal. Calc'd for: C16H19NO6 : C, 59.80; H, 5.96; N, 4.36. Found: C, 60.04; H, 6.05; N, 4.44.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][C:9]#[CH:10])[CH:2]=1.Cl[CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[N-:28]=[N+:29]=[N-:30].[Na+].C(O)(C)(C)C>O.ClCCl.[NH4+].[OH-]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][C:9]2[N:28]=[N:29][N:30]([CH2:18][C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:10]=2)[CH:2]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: C#CCC(c1cccnc1)c1cccnc1
Reactant: [N-]=[N+]=[N-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClCCl
Product: c1cncc(C(Cc2cn(Cc3nc4ccccc4[nH]3)nn2)c2cccnc2)c1
Temperature: 125 °C

Procedure:
In a 0.5-2.0 mL microwave vial equipped with a spin vane were placed 3-(1-(pyridin-3-yl)but-3-ynyl)pyridine (0.030 g, 0.14 mmol), 2-chloromethylbenzimidazole (0.023 g, 0.14 mmol), NaN3 (0.0089 g, 0.14 mmol), CuSO4 pentahydrate (0.007 g, 0.03 mmol), and Cu powder (0.007 g, 0.11 mmol), tert-butanol (0.5 mL), and water (0.5 mL). The vial was sealed and warmed to 125° C. for 10 min using microwave heating. After cooling, the reaction mixture was diluted with water (1 mL), dichloromethane (2 mL) and NH4OH (two drops). The dichloromethane layer was removed and filtered, then concentrated and dried. Reverse phase chromatography yielded 0.012 g (2.3%) as a TFA salt. Analytical LCMS: single peak (214 nm), 2.209 min. HRMS m/z 382.1772 (C22H19N7+H+ requires 382.1775).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:9][N+:10]([O-])=O.[H][H]>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:9][NH2:10]
Reactant: O=[N+]([O-])CC(c1ccccc1F)c1c[nH]c2cc(N3CCOCC3)ccc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: NCC(c1ccccc1F)c1c[nH]c2cc(N3CCOCC3)ccc12
Yield: 83.8 %

Procedure:
A mixture of 4-(3-(1-(2-fluorophenyl)-2-nitroethyl)-1H-indol-6-yl)morpholine (0.235 g, 0.636 mmol) and Raney Ni (a small spatula) in MeOH (30 mL) was treated with hydrogen at 55 psi in a Parr shaker apparatus for 3 hr. The catalyst was removed by suction filtration. The filtrate was concentrated under vacuum, diluted with CH2Cl2 (100 mL), washed with brine (25 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.181 g, 0.533 mmol, 84% yield) as an off-white solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(Cl)=[O:24].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH2:27]([N:29]([CH2:30][CH3:31])[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)[CH2:18][CH2:19]1)=[O:24])[CH3:28]
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: O=C(Cl)Cl
Reactant: CCNCC
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN(CC)C(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (1.5 g, 5 mmol) dissolved in toluene (40 ml) was added slowly to a 20% phosgene in toluene solution (12.5 ml, 25 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours and concentrated in vacuo to afford a crude residue (1.91 g). The crude product (300 mg, 0.75 mmol) was then added to a stirred slurry of diethylamine (207 μL, 2 mmol) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.41 g, 4.5 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 16 hours, filtered and concentrated in vacuo. The crude residue was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E61). MS (ES+) m/e 400 [M+H]+.