Azzindani/Open_Reaction_Data huggingface dataset:
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: O
Solvent: CCOC(C)=O
Solvent: ClCCl
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: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[F:19][C:20]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:21]=1[CH2:22][OH:23]>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:23][CH2:22][C:21]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=1[F:19])=[O:3]
Reactant: COc1ccc(F)c(CO)c1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: COc1ccc(F)c(COC(=O)N2[C@H](C)CNC[C@@H]2C)c1
Product: Cl

Procedure:
2-Fluoro-5-methoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2-fluoro-5-methoxybenzyl alcohol according to the methods described for Examples 54 to give the product as white crystals (0.2714 g, 82% overall); (Found: C, 53.95; H, 6.7; N, 8.3%. C15H21FN2O3.HCl requires C, 54.1; H, 6.7; N, 8.4%); δH (400 MHz, DMSO-d6) 9.84 (2H, br), 7.16 (1H, t, J 9.2 Hz), 6.99 (1H, m), 6.94 (1H, m), 5.13 (2H, s), 4.31 (2H, m, J 6 Hz), 3.73 (3H, s), 3.14 (2H, d, J 13 Hz), 3.06 (2H, dd, J 5.2 and 13 Hz), and 1.31 (6H, d, J 7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[Cl:11].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>CC(O)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cccc2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-amino-2-chlorobenzoic acid methyl ester (0.46 g) and 2,5-dimethoxytetrahydrofuran (0.33 mL) in AcOH (16 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The extract was washed with satd. NaHCO3 and brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 5/1) to yield 0.48 g of 2-chloro-4-(1-pyrrolyl)benzoic acid methyl ester. ESMS: m/z 236 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]=[CH:9][NH:8][C:7]=1[CH2:11][OH:12])([CH3:5])[CH:3]=[CH2:4]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:5][C:2]([C:6]1[N:10]=[CH:9][NH:8][C:7]=1[CH:11]=[O:12])([CH3:1])[CH:3]=[CH2:4]
Reactant: C=CC(C)(C)c1nc[nH]c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: C=CC(C)(C)c1nc[nH]c1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
Manganese dioxide (20 g, 0.23 mol) was added to a solution of [5-(1,1-dimethyl-allyl)-3H-imidazol-4-yl]-methanol (2.56 g, 0.02 mol) in acetone (300 ml) and the resulting mixture was stirred at room temperature for 5 h. The mixture was filtered through filter paper and the residue was washed with acetone. The filtrate and washings were combined and evaporated to afford 5-(1,1-dimethyl-allyl)-3H-imidazole-4-carbaldehyde (1.82 g, 51%). (Hayashi et al., J. Org. Chem., 65:8402–8405 (2000)).
Reaction SMILES: Cl.[C:2]1([C:8](=[NH:10])[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:12]N.[CH:14]1([C:19]([NH:21][CH:22]([CH2:30][CH3:31])[C:23](=O)[C:24](OCC)=[O:25])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[O:25]=[C:24]1[C:23]([CH:22]([NH:21][C:19]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:20])[CH2:30][CH3:31])=[N:12][N:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:10]1
Reactant: CCOC(=O)C(=O)C(CC)NC(=O)C1CCCC1
Reactant: NN
Reactant: N=C(N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCC(NC(=O)C1CCCC1)c1nnc(-c2ccccc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 g (22.3 mmol, 1 equiv.) benzenecarboximidamide hydrochloride are suspended in 10 ml of ethanol and 1.37 g (26.8 mmol, 1.2 equiv.) hydrazine hydrate are added. After stirring at room temperature for 1 hour, 6.28 g (24.6 mmol, 1.1 equiv) of ethyl 3-[(cyclopentylcarbonyl)amino]-2-oxopentanoate (Example 99A), dissolved in 40 ml of ethanol, are added. The reaction mixture is stirred at 70° C. (bath temperature) for 4 hours. The mixture is evaporated to dryness in vacuo and the product is purified by chromatography (flash or column chromatography or preparative HPLC).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH2:28][CH:29]1[CH2:46][C:32]2[C:33]3[NH:34][C:35](=[O:45])[C:36](=[O:44])[NH:37][C:38]=3[CH:39]=[C:40]([N+:41]([O-:43])=[O:42])[C:31]=2[CH2:30]1>C1COCC1.CN(C=O)C>[N+:41]([C:40]1[C:31]2[CH2:30][CH:29]([NH:28][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[O:8])[CH2:46][C:32]=2[C:33]2[NH:34][C:35](=[O:45])[C:36](=[O:44])[NH:37][C:38]=2[CH:39]=1)([O-:43])=[O:42]
Reactant: O=C(O)c1ccoc1
Reactant: NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1)c1ccoc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of furan-3-carboxylic acid (1 mmol) in anhydrous THF was treated with carbonyldiimidazole (1.2 mmol) and triethyl amine (1 mL) and heated at 60° C. for 30 min. After cooling to room temperature a solution of 8-amino-6-nitro-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione (1 mmol) in DMF was added. The reaction mixture as stirred at room temperature for 2 h, then heated at 70° C. for 2 h. The solvent was evaporated and the residue triturated with acetone. The solid was collected by filtration, washed with diethyl ether and dried in vacuo. Calc'd for C16H12N4O6.H2O: C, 51.34; H, 3.77; N, 14.97; found: C, 50.97; H, 3.18; N, 14.89. MS M+1 (357).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])O[C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[C:25](C(Cl)=O)=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[N:22]1.[CH:33]([NH2:36])([CH3:35])[CH3:34].O>C(#N)C.N1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[C:25]([C:9]([NH:10][C:11]2[C:6]([C:7]([NH:36][CH:33]([CH3:35])[CH3:34])=[O:13])=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])=[O:12])=[CH:24][C:23]([C:29]([F:30])([F:31])[F:32])=[N:22]1
Reactant: CC(C)N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: Cc1cccc2c(=O)oc(=O)[nH]c12
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 95 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a sample of the title compound of Example 1, Step C (22.3 g, 0.126 mole), suspended in acetonitrile (100 mL) was added crude 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride (43 g). The mixture was diluted with 350 mL of pyridine and heated to approximately 95° C. for a period of 2 hours. The mixture was cooled to 29° C., then was treated with isopropylamine (32.2 mL, 0.38 mole). The reaction mass self-heated to 60° C. and was maintained at about 50° C. for one hour, then stirred overnight. The reaction mixture was poured into 1 L of water and stirred. The resulting solid was collected by filtration and washed with water. The wet cake was taken up in a mixture of dichloromethane and methanol, the water removed, and the organic phase was dried with molecular sieves and filtered. Volatiles were removed on a rotary evaporator. The crude product was triturated with 1:1 ether/hexane, collected by filtration and washed with hexanes to yield 42.6 g of a light tan solid melting at 230-231° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:50]1[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)(Cl)Cl.O>[CH2:43]([N:50]1[CH2:55][CH2:54][CH:53]([NH:56][C:35]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([F:23])[CH:18]=2)=[O:41])[CH2:52][CH2:51]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5)CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (142 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzyl-4-piperidineamine (91 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (47 mg, yield 28%).
Reaction SMILES: [CH:1]1[C:17]2[CH:16]=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([I:22])[CH2:19][CH2:20][CH3:21]>>[IH:22].[CH2:18]([NH+:6]1[C:7]2[C:15]([N:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:16][C:17]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH2:19][CH2:20][CH3:21]
Reactant: c1ccc2[nH]c3c4ccccc4nc-3cc2c1
Reactant: CCCCI
Product: CCCC[NH+]1C2=c3ccccc3=NC2=Cc2ccccc21
Product: I
Temperature: 140 °C

Procedure:
A suspension of quindoline (1 g, 4.6 mmol) from Example 2 and butyl iodide (3 ml, 26.4 mmol) was heated in a bomb at 140° C. for 16 hours and then cooled. The solid was filtered, washed thoroughly with ether, washed with 10% EtOH in ethyl ether and then dried to afford 5-butylquindolinium hydroiodide, 1.82 g (100%) as a brown solid. Recrystallization from water gave bright yellow crystals of 5-butylquindolinium hydroiodide, mp 252°-253° C.; 1H NMR (DMSO-d6) δ 12.96 (s, 1H, NH), 9.34 (s, 1H, H11), 8.77 (d, J=9.2, 1H, H4), 8.61 (d, J=8.4, 1H, H6), 8.54 (d, J=8.4, 1H, H1) , 8.19 (t, J=8.4, 1H, H3), 7.96 (t, J=8.4, J=7.2, 2H, H2 and H8), 7.88 (d, J=8.4, 1H, H9), 7.58 (t, J=7.2, 1H, H7), 5.51 (t, J=7.2, 2H, N-CH2), 2.09 (m, 2H), 1.69 (m, 2H), 1.00 (t, J=7.2, 3H, CH3); 13C NMR (DMSO-d6) δ 145.78, 137.07, 134.64, 133.93, 133.52, 132.71, 130.07, 127.11, 126.40, 125.38, 125.29, 121.88, 117.55, 113.47,112.89, 51.29, 30.11, 19.22, 13.83; MS (EI, m/z) 275 (M+) .
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.O1CCCC1>[CH3:19][O:18][C:13]([C:14]([CH3:16])([CH3:15])[CH2:25][C:24]1[CH:27]=[CH:28][C:21]([Br:20])=[CH:22][CH:23]=1)=[O:17]
Reactant: COC(=O)C(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C(C)(C)Cc1ccc(Br)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A 1.25M solution of n-butyl lithium in hexane (32 ml) was cooled to 0° C. under an argon atmosphere and diisopropylamine (4.05 g; 5.24 ml) was added slowly. The resulting mixture was cooled to -70° C. and stirred while methyl isobutyrate (4.08 g; 4.58 ml) was added dropwise while maintaining the temperature at <-60° C. After a further 30 minutes at -70° C., a solution of 4-bromobenzyl bromide (10.0 g) in anhydrous tetrahydrofuran (20 ml) was added and the temperature was maintained at -70° C. for a further 1.5 hours. The reaction mixture was allowed to attain ambient temperature then heated to reflux for 18 hours. On cooling, the mixture was acidified with 8% aqueous citric acid and extracted with ethyl acetate (3×75 ml). Insoluble material at the interface was removed by filtration and the combined organic phase was washed with brine (20 ml), dried (Mg SO4) and evaporated. The residue was subjected to vacuum flash chromatography on silica eluting with a gradient of 0-10% ethyl acetate in hexane to give 4-(2-methoxycarbonyl-2-methylpropyl)bromobenzene (7.79 g); 1H NMR (d6 -DMSO): 1.13 (s, 6H); 2.79 (s, 2H), 3.60 (s, 3H), 7.04 (m, 2H), 7.46 (d of t, 2H); mass spectrum (CI+): 272 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])CCC.[C:36](=[O:38])=[O:37]>C1COCC1.O>[F:1][C:2]1[C:10]2[O:9][C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:36]([OH:38])=[O:37]
Reactant: Fc1cccc2c1OC(c1ccccc1)(c1ccccc1)O2
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1F)OC(c1ccccc1)(c1ccccc1)O2
Temperature: -78 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
4-Fluoro-2,2-diphenyl-benzo[1,3]dioxole (5.8 g, 20 mmol) were dissolved in THF (40 ml). The reaction was cooled to −78° C. under argon. TMEDA (2.9 ml, 20 mmol) was added followed by n-butyl lithium (12.5 ml, 1.6 N in hexane) dropwise. The reaction was stirred at −78° C. for 2 hours. Carbon dioxide (20 g) was added at that temperature. The reaction was allowed to warm to 0° C. and poured into water (80 ml). The reaction was extracted twice with ethyl acetate. The aqueous layer was neutralized with 1N aqueous HCl solution, extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue suspended in n-hexane, stirred for 10 minutes and the product was filtered off to yield the acid as a white solid (4.0 g, 60%). m.p.: 189-191° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=O)=[CH:20]2)[CH3:12].N1CCCCC1>C(O)C>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])=[CH:20]2)[CH3:29]
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4ccccc43)cc2c1
Temperature: 95 °C
Yield: 18.3 %

Procedure:
A mixture of oxindole (26 mg, 0.19 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 13 mg (18%) of the title compound as an orange crystalline solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](O)=[O:28]>>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:28]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccccc1Br)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-bromophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.90-7.93 (m, 1H), 7.64 (dd, J=7.9, 1.2 Hz, 1H), 7.53 (dd, J=7.6, 1.7 Hz, 1H), 7.39 (td, J=7.5, 1.3 Hz, 1H), 7.23-7.28 (m, 1H), 3.82-3.87 (m, 5H), 3.49-3.62 (m, 1H), 3.09-3.14 (m, 4H); MS (ESI+) M/Z 443 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.B(F)(F)F.[CH3:17][CH2:18][O:19]CC.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:17][CH2:18][OH:19])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COCCO)cc1
Temperature: -5 °C
Reaction time: 0.58 h
Yield: 60329.8 %

Procedure:
To a flame-dried 2-neck flask was added a solution of methyl-4-(hydroxymethyl)benzoate (2.5 g, 15 mmol) in dichloromethane (30 mL). The reaction was purged with nitrogen and brought to −5° C. A dewar condenser (also flame-dried) containing a dry ice/acetone bath (−78° C.) was affixed to the flask and ethylene oxide-tetradeuterate was added (˜55 drops). Then BF3.Et2O (510 μL, 0.0041 mmol) was added dropwise and the reaction stirred at −5° C. for 35 minutes under nitrogen atmosphere. Monitoring by TLC (100% ethyl acetate) showed complete consumption of the starting material. The reaction was warmed to room temperature and vented to remove any excess ethylene oxide gas. The reaction was then diluted with brine and extracted with dichloromethane (2 times). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude oil. Purification by flash column chromatography (4:1 pentane:ethyl acetate) provided the product as a clear oil (520 mg, 16% yield). 1H NMR (600 MHz, CDCl3) δ 8.02 (d, 2H, J=8.2 Hz), 7.41 (d, 2H, J=8.1 Hz), 4.62 (s, 2H), 3.92 (s, 3H); 13C NMR (150 MHz, CDCl3167.1, 143.5, 130.8) δ 129.9, 127.5, 72.8, 52.4.
Reaction SMILES: OC1C2N=N[NH:7][C:6]=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[O:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=O)[C:27]=2[O:26][CH:25]=[CH:24]1.CN>CN(C=O)C.C1C=CC=CC=1.ClCCl>[CH3:6][NH:7][C:36](=[O:38])[CH2:35][CH2:34][CH2:33][C:32]1[C:27]2[O:26][CH:25]=[CH:24][O:23][C:28]=2[CH:29]=[CH:30][CH:31]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCc1cccc2c1OC=CO2
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)CCCc1cccc2c1OC=CO2

Procedure:
0.1 g (0.75 mmol) of hydroxybenzotriazole (HOBt) and 0.14 g (0.75 mmol) of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) are introduced at 0° C. into a reaction mixture comprising 0.15 g (0.68 mmol) of the acid obtained in Step F dissolved in 3 ml of anhydrous DMF. After the addition of 1.02 mmol of a 10% solution of methylamine in benzene, stirring is maintained for 24 hours and then the solvent is evaporated off in vacuo. The residue obtained is taken up in dichloromethane and then washed with water. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. Chromatography over silica gel (eluant:AcOEt/PE:70/30) allows isolation of the title amide in the form of a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[CH3:42][N:43]([CH3:48])[CH2:44][CH2:45][CH2:46]O>>[CH3:42][N:43]([CH3:48])[CH2:44][CH2:45][CH2:46][O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CN(C)CCCO
Reactant: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CN(C)CCCOc1ccc2c(c1)C(=O)C(c1cccnc1)=C2c1ccccc1
Reaction time: 96 h
Yield: 30 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 6-hydroxy-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 55 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 3-(dimethylamino)propanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 4 d, and being recrystallized with EtOAc to obtain the title compound (30%).
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>[NH2:8][C:7]1[N:9]=[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[NH:5][N:6]=1
Reactant: N=C(N)NN
Reactant: CCCCCCCCCCCC(=O)O
Agent: O=C(O)O
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: O
Product: CCCCCCCCCCCc1nc(N)n[nH]1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A slurry of aminoguanidine bicarbonate (8.0 g, 59 mmol), dodecanoic acid (11.8 g, 59 mmol), and N,N-dimethylaniline (0.1 mL, 0.8 mmol) in toluene (100 mL) was heated under reflux with the azeotropic removal of water (72 hours). The resulting slurry was cooled (25° C.) and concentrated in vacuo. The residue was partitioned between ethyl acetate (300 mL) and saturated sodium bicarbonate (300 mL). The aqueous layer was back extracted with ethyl acetate, and the combined organics were washed with brine (1×250 mL), then dried (MgSO4), and concentrated in vacuo. The resulting solid was dissolved in hot chloroform and chromatographed on silica (first ethyl acetate, then 90:10 chloroform:methanol). The product containing fractions were combined and concentrated in vacuo to yield 6.9 g (49.1%) of 3-amino 5-undecyl-1H-1,2,4-triazole as an off-white powder, m.p. 128.5°-132.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]S(=O)(=O)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.C(O)(C)(C)C.O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=[O:13])[CH2:10][CH:9]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: O=C1CCS(=O)(=O)C(c2ccccc2F)c2cc(Cl)ccc2N1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: O=C1CC=C(c2ccccc2F)c2cc(Cl)ccc2N1
Temperature: 35 °C
Reaction time: 0.58 h

Procedure:
67.0 g of 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine 5,5-dioxide are suspended in a mixture of 670 ml of carbon tetrachloride, 670 ml of t-butanol and 31.5 ml of water. The suspension is pre-warmed to 35° C. There are then rapidly added thereto while cooling four 51.5 g portions of potassium t-butylate (the temperature amounts to 45°-50°). The mixture is stirred for a further 35 minutes, the temperature dropping to about 35°. The mixture is poured on to ice, whereupon it is extracted with methylene chloride. The organic phase is evaporated and the residue is triturated with ether. The crystalline product is filtered off. There is obtained 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one of melting point 214°-215°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:9][C:6]1[N:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)nc1[N+](=O)[O-]

Procedure:
A mixture of 3-methoxy-6-methyl-2-nitropyridine (10.08 g, 60 mmol), NBS (9.79 g, 55 mmol), and benzoyl peroxide (2 g, 6 mmol) in CCl4 (250 mL) was refluxed for 56 hours under nitrogen atmosphere. The reaction mixture was added 100 mL 1M NaOH aq. and extracted using ethyl acetate (3×300 mL). The combined organic layer was dried over Mg2SO4 and filtered. The solvent was evaporated to yield a brown oily. 1H-NMR (CDCl3): δ 3.99 (s, 3H, OCH3), 4.51 (s, 2H, CH2), 7.55 (d, 1H, J=8.8 Hz, Py-H), 7.70 (d, 1H, J=8.4 Hz, Py-H). HR-MS (ESI+) m/z 246.9600 [M+1]+ C7H7BrN2O3 requires 245.9640.