Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7]([O:12]C)(=O)[C:8]([CH3:10])=[CH2:9]>[O-2].[Ca+2].[OH-].[Li+].O.COC1C=CC(O)=CC=1>[C:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][C:7](=[O:12])[C:8]([CH3:10])=[CH2:9])(=[O:12])[C:8]([CH3:10])=[CH2:9]
Reactant: OCCCCO
Reactant: C=C(C)C(=O)OC
Agent: COc1ccc(O)cc1
Agent: [Ca+2]
Agent: [Li+]
Solvent: O
Product: C=C(C)C(=O)OCCCCOC(=O)C(=C)C
Temperature: 96 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
788 kg of 1,4-butanediol, 2664 kg of methyl methacrylate (MMA), 0.123 kg of hydroquinone monomethyl ether as inhibitor and a mixture of 5 kg of calcium oxide, 1 kg of lithium hydroxide and 4 kg of water as catalyst are combined in a 6 m3 stirred tank reactor provided with agitator, steam heating, distillation column and condenser and the mixture is stirred while passing in air. To stabilize the column, a total of 151 kg of MMA containing 0.24 kg of hydroquinone monomethyl ether and 0.016 kg of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl in dissolved form are introduced into the column runback during the course of the reaction. The apparatus is heated to a temperature at the bottom of 96° C., with the column initially being operated under total reflux. As soon as the temperature at the top of the column drops to below 70° C., the methanol/MMA mixture is taken off at a reflux ratio of 2.5:1. The MMA stock in the reactor is supplemented by introduction of equal parts of MMA per part of methanol/MMA mixture taken off. Thus, a total of 1267 kg of MMA are introduced over a period of 5 hours. Over a period of 8 hours, the reflux ratio is adapted to the decreasing formation of methanol up to a value of 4.5:1. At a temperature at the bottom of 130° C., the reaction is complete and excess MMA is taken off under reduced pressure, with the pressure being gradually reduced to 100 mbar. When no more MMA distills off, the vacuum is broken. The contents of the tank, comprising the catalyst-containing 1,4-butanediol dimethacrylate, is admixed with 9 kg of bleaching earth and 6 kg of aluminium silicate (Perlite) as filter aid and freed of catalyst by washcoat filtration. The filtrate is fed into a continuous evaporator (area: 2 m2) having a rotating wiper system at a pressure of 15 torr and a vaporizer temperature of 142° C. A total of 1800 kg of 1,4-butanediol dimethacrylate are obtained from the bottom product:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:23]=[C:24]([F:26])[CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: OB(O)c1cc(F)cc(OCc2ccccc2)c1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncnc2[nH]nc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Reaction time: 8 h
Yield: 33.1 %

Procedure:
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6.10 mmol 1.591 g), (3-(benzyloxy)-5-fluorophenyl)boronic acid (4.06 mmol 1.0 g), dppf (0,610 mmol, 338 mg) Potassium phosphate anhydrous (10.16 mmol, 2.157 g) were suspended in dioxane and the mixture was heated at 180 C for 25 min in a Mw reactor then poured in 100 ml of water. The mixture was stirred overnight then filtered on a buchner funnel washing with 30 ml of water. The crude material was purified by chromatography eluting with DCM\ MeOH (80/20) in DCM to give the title compound (450 mg, 1.342 mmol, 33% yield) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][SH:10].[OH-].[K+].Cl[CH:15]([CH3:19])[C:16]([OH:18])=[O:17].Cl>O>[CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][S:10][CH:15]([CH3:19])[C:16]([OH:18])=[O:17]
Reactant: CC1(C)[C@H]2CC[C@@H](CS)[C@@H]1C2
Reactant: CC(Cl)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(SC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C)C(=O)O
Temperature: 100 °C

Procedure:
To a solution of ((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanethiol (Eisen, Moris; et al. Inorg. Chim. Acta 1991, 188, 167-176) (52.0 g, 0.30 mmol) and potassium hydroxide (41.2 g, 0.62 mmol) in water (200 mL) was added α-chloro-propionic acid (33.2 g, 0.306 mmol) drop wise. The mixture was heated at 100° C. for 1 hour. The mixture was cooled and acidified to pH=1 with 6N HCl (100 mL). The product was extracted with ether, dried with magnesium sulfate and concentrated. The residue was distilled at reduced pressure (143-147° C., 0.5 mm of Hg) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][O:18][CH2:19][CH2:20]Br.Cl>CN(C)C=O.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:20][CH2:19][O:18][CH3:17])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(C=O)cc1O
Temperature: 0 °C
Reaction time: 120 h
Yield: 23.1 %

Procedure:
Commercially available 3,4-dihydroxybenzaldehyde (39.3 g, 285 mmol) and sodium carbonate (45.2 g, 427 mmol) were dissolved in N,N-dimethylformamide (400 mL), then commercially available 2-bromoethyl methyl ether (26.7 mL, 285 mmol) was added under nitrogen atmosphere at room temperature, and the mixture was stirred for 5 days. The mixture was cooled to 0° C. and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The aqueous layer was extracted with ethyl acetate, then the combined organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated, dichloromethane was added, the precipitate was separated by filtration, and then the resultant filtrate was purified with silica gel column chromatography (n-heptane:ethyl acetate=17:3-1:1). The target fraction was concentrated under vacuum to obtain the title compound (12.9 g, 23%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]([F:29])([F:28])[C:21]([O:23]C(C)(C)C)=O.[CH3:30][N:31]([CH3:38])[C:32]1[O:36][N:35]=[C:34]([CH3:37])[N:33]=1.Cl>O1CCCC1>[CH3:30][N:31]([CH3:38])[C:32]([NH:33][C:34]1[CH:37]=[C:21]([C:20]([F:19])([F:28])[F:29])[O:23][N:35]=1)=[O:36]
Reactant: Cc1noc(N(C)C)n1
Reactant: CC(C)(C)OC(=O)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1cc(C(F)(F)F)on1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Dry tetrahydrofuran (84.6 ml) was added to diisopropylamine (dried with potassium hydroxide, 9.85 g, 0.0973 mole) nder a nitrogen atmosphere. The solution was cooled to -60° C. and thereto was added a 15% solution of n-butyllithium in n-hexane (58.5 ml, 0.0901 mole). After being stirred at 0° C. for 30 minutes, it was cooled to -75° C. A mixture of t-butyl trifluoroacetate (10.80 g, 0.0635 mole), 5-dimethylamino-3-methyl-1,2,4-oxadiazole (5.72 g, 0.0423 mole) and dry tetrahydrofuran (423 ml) was added dropwise to it at -73--75° C. over 1.5 hours. After being stirred at -75° C. for 1 hour, it was allowed to warm to room temperature over 1 hour. It was further heated to 50° C. and stirred for 30 minutes. 1N hydrochloric acid (190 ml) was then added thereto with ice cooling and tetrahydrofuran and n-hexane were distilled off under reudced pressure in a water bath at 40° C. After being extracted with methylene chloride, the extract was concentrated and purified column chromatrography on silica gel to give the crude title compound (8.91 g, crude yield 94.4%). Repeated recrystallizations from benzene gave colorless fine needles, m.p. 126.0°-126.5° C. The structure of this compound was confirmed by IR, NMR and elemental analysis.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8](F)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([NH:26][C:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]2)=[O:28])=[C:18]([F:35])[CH:17]=1.O>C(#N)C.C(OCC)(=O)C>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([N:26]2[C:27](=[O:28])[CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[CH:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:18]([F:35])[CH:17]=1
Reactant: CCOC(=O)C(F)Br
Reactant: CC(C)Oc1cc(NC(=O)C2CCCCN2)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1N(c2cc(OC(C)C)c(Cl)cc2F)C(=O)C2CCCCN21
Yield: 21.1 %

Procedure:
A mixture of potassium carbonate (724 mg, 5.24 mmol), ethyl bromofluoroacetate (882 mg, 4.76 mmol) and the product of Step A (1.5 g, 4.76 mmol) in acetonitrile (50 mL) was heated at reflux overnight. 100 mL of H2O and 200 mL of ethyl acetate were added to the mixture. The organic layer was separated, dried (MgSO4), filtered, and evaporated under vacuum to dryness. Flash chromatography yielded the title compound of Step B as a white solid (400 mg) m.p. 83°-85° C. 1H NMR δ7.21 (d,1H), 7.18 (d,1H), 4.92 (s,1H), 4.50 (m,1H), 4.16-4.09 (m,2H), 3.29 (m,1H), 2.95 (m,1H), 2.50 (m,1H), 2.10 (m,1H), 1.96 (m,1H), 1.80-1.58 (m,2H), 1.37 (d,6H), 1.35 (t,3H).
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[OH-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:2]([CH3:1])=[CH2:3])[C:5]1=[O:13]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: ClCCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=C(C)n1c(=O)n(CCCCCl)c2ccccc21
Reaction time: 5 h

Procedure:
To a stirred and hot (50° C.) mixture of 28.3 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, 5 parts of N,N,N-triethylbenzenemethanaminium chloride and 225 parts of a sodium hydroxide solution 60% are added dropwise, during a 30 minutes-period, 33.7 parts of 1-bromo-4-chlorobutane. Upon completion, stirring is continued for 5 hours at 60° C. The reaction mixture is cooled, water is added and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 1-(4-chlorobutyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:21].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:24][CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:21]
Reactant: O=S(Cl)Cl
Reactant: O=c1c2ccccc2c(-c2ccccc2)cn1CCCO
Solvent: c1ccccc1
Product: O=c1c2ccccc2c(-c2ccccc2)cn1CCCCl

Procedure:
Then, 23 of 2-(3-hydroxypropyl)-4-phenyl-1-(2H)-isoquinolone was added to a mixture of 60 ml of benzene and 25 ml of thionyl chloride and the mixture was heated at reflux for 1 hour. The solvent was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water and dried, and then the solvent was distilled off. The resulting crystals were recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 23.3 g of 2-(3-chloropropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 138° C. as colorless prisms.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.C(Cl)Cl.[CH3:24][C:25]1[CH:38]=[C:37]2[C:28]([S:29][C:30]3[CH:31]=[C:32]([C:40](Cl)=[O:41])[CH:33]=[CH:34][C:35]=3[C:36]2=[O:39])=[CH:27][CH:26]=1>O>[CH2:1]([O:13][C:40]([C:32]1[CH:33]=[CH:34][C:35]2[C:36](=[O:39])[C:37]3[C:28]([S:29][C:30]=2[CH:31]=1)=[CH:27][CH:26]=[C:25]([CH3:24])[CH:38]=3)=[O:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCO
Reactant: Cc1ccc2sc3cc(C(=O)Cl)ccc3c(=O)c2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(=O)c1ccc2c(=O)c3cc(C)ccc3sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
1.5 g (8.06 mmoles) of dodecan-1-ol and 1.0 g (9.90 mmoles) of triethyl amine are added to a CH2Cl2 solution containing 2.26 g (7.41 mmoles) of 7-methyl 9-oxo-thioxanthene-3-carbonyl chloride. After approximately 1 hour at room temperature under stirring, the mixture is poured in water, the organic phase is separated and washed again with water. The organic phase is then separated, dehydrated and after purification on a flash column (SiO2— eluent: CH2Cl2:AcOEt 8:2) it is dried, obtaining 1.62 g (49.8%) of a yellow solid with the following spectral properties:
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][CH2:19][N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cc2ccc(Cl)o2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Cc2ccc(Cl)o2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a mixture of 4-(5-chloro-furan-2-ylmethyl)-benzaldehyde (270 mg, 1.2 mmol) described in Manufacturing Example 62-1-4 and acetic acid (3 mL) were added nitromethane (500 μL, 9.3 mmol) and ammonium acetate (290 mg, 3.7 mmol) at room temperature, which was stirred for 3 hours at 100° C. The reaction mixture was cooled to room temperature, and extracted by addition of water and ethyl acetate. This organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and was concentrated under a reduced pressure. To a mixture of acetic acid (0.6 mL) and dimethyl sulfoxide (10 mL) was added sodium borohydride (76 mg, 2.0 mmol) at room temperature while cooling appropriately, which was stirred for 10 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride. The organic layer was concentrated under a reduced pressure, and the residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (210 mg, 62%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][C:19]([O:28][CH3:29])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>C(O)C>[CH3:29][O:28][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17][N:16]([C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[CH2:21][CH2:20]1
Reactant: COC1(c2ccccc2)CCN(c2ccc(N3CCN(C(C)=O)CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC1(c2ccccc2)CCN(c2ccc(N3CCNCC3)cc2)CC1
Yield: 97.6 %

Procedure:
A mixture of 1-acetyl-4-[4-(4-methoxy-4-phenylpiperidin-1-yl)phenyl]piperazine (2.5 g) and 10% NaOH aq. (10.2 ml) in ethyl alcohol (50 ml) was refluxed for 23.5 hours. The reaction mixture was evaporated under reduced pressure. The residue was washed with water, and dried to give 1-[4-(4-methoxy-4-phenylpiperidin-1-yl)phenyl]piperazine (2.18 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([CH3:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([CH3:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C)c2)CCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.77 g) was dissolved in ethanol (200 ml), and to the solution, sodium borohydride (0.13 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 7) (0.64 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: C1CCNC1
Solvent: CO
Product: N=C(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1)N1CCCC1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with pyrrolidine (19 IIl, 0.23 mmol) via procedure W to afford 25 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(pyrrolidin-1-yl)methyl)benzamide. MS (Q1) 405 (M)+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10](=[O:12])[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc2[nH]ccc12
Reaction time: 16 h

Procedure:
To a mixture of 1H-indole-4-carboxylic acid (322 mg, 2.00 mmol), tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (554 mg, 2.00 mmol), and diisporopylethylamine (700 μL, 4.00 mmol) in DMF (3 mL) was added HATU (950 mg, 2.50 mmol) and the solutions stirred for 16 h. The solvent was removed and the resulting residue was purified by silica gel chromatography, using a gradient of 70% to 100% EtOAc in hexanes as eluent and the solvent removed. This gave 557 mg (66%) of the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O)([O-:12])=[O:11]>CO.O.C(O)(=O)C.CO.O.CCO.Cl.CC([O-])=O.CC([O-])=O.[Cu+2].O>[CH3:9][C:3]1[C:2]2[NH:1][C:15]([C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N+:10]([O-:12])=[O:11])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Temperature: 25 °C
Yield: 71.1 %

Procedure:
2,3-Diaminotoluene (12.2 g, 0.1 mol) was dissolved in the mixture of MeOH/H2O (500 mL, v/v=1:1), acetic acid (10 mL) was added to the stirring mixture. 2-Nitrobenzaldehyde (21.1 g, 0.14 mol) in MeOH (250 mL) and Cu(OAc)2.H2O (28.0 g, 0.14 mmol) in water (250 mL) were added subsequentially to the mixture. It was then heated to reflux for 3 h under vigously stirring, a pale yellow precipitate was formed. Filtered while it was hot and washed with water to afford a gray-yellow solid. Redissolved the precipitate in EtOH (600 mL) and HCl (75 mL, Conc.), a solution of Na2.S9 H2O (48.0 g, 0.2 mol) in water (300 mL) were added. The mixture was heated to reflux for 1 h resulted in a black slurry. Cooled down to room temperature, it was filtered through a pad of celite to remove of CuS. The filtrate was neutralized with ammonium hydroxide to PH=8-9. Concentration using a rotary evaporator, a green-yellow precipitate was formed. After filtration and dried in vaccum oven, the crude product was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate (1:1) as the eluent to give 4-methyl-2-(2-nitrophenyl)-benzimidazole (18 g, 72%) as a yellow needle crystal. Rf=0.21 (hexane/ethyl acetate=1:1); 1H NMR (250 MHz, CDCl3) δ 2.60 (s, 3H), 7.10 (d, J=8.2 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.41 (bs, 1H), 7.52-7.66(m, 2H), 7.89-7.97 (m, 2H), 10.41 (bs, 1H); HRMS: Calcd for C14H11N3O2 253.0851, found 253.0854.
Reaction SMILES: Br[CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[NH:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1>>[CH2:4]([CH:3]([CH2:6][CH3:7])[CH2:2][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=2[CH:10]=[CH:9]1)[CH3:5]
Reactant: CCC(CC)CBr
Reactant: O=Cc1cccc2[nH]ccc12
Product: CCC(CC)Cn1ccc2c(C=O)cccc21
Yield: 60.8 %

Procedure:
The same procedures used in Example 1 were repeated except for using 4.55 g of 1-bromo-2-ethylbutane and 2.00 g of indole-4-carbaldehyde as a starting material to give 1.92 g of 1-(2-ethylbutyl) indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 61%.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[NH3:15]>[N+](C)([O-])=O>[NH2:15][C:9]1[C:10]([F:11])=[C:2]([F:1])[C:3]([C:4]([OH:6])=[O:5])=[C:7]([F:14])[C:8]=1[F:13]
Reactant: N
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Solvent: C[N+](=O)[O-]
Product: Nc1c(F)c(F)c(C(=O)O)c(F)c1F

Procedure:
A mixture of 10.0 g of 2,3,4,5,6-pentafluorobenzoic acid and 400 ml of nitromethane is saturated with anhydrous ammonia at room temperature and then placed in a bomb and heated at 100° for 20 hrs. The resulting solution is evaporated and the residue crystallized from chloroform-hexane to yield 4-amino-2,3,5,6-tetrafluorobenzoic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]2=[N:4][C:3]=1[CH2:12]Cl.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]2=[N:4][C:3]=1[CH2:12][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19]
Reactant: ClCc1nc2c(Cl)cccn2c1Br
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2c(Cl)cccn2c1Br
Temperature: 80 °C

Procedure:
DMF (4.6 ml) was added to a mixture of 3-bromo-8-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (258 mg, 0.922 mmol), phthalimide (136 mg, 0.922 mmol) and K2CO3 (55.6 μL, 0.922 mmol). The reaction was heated at 80° C. After the reaction was complete, the mixture was initially partitioned between EtOAc and water, but the product did not dissolve readily. The product was collected by filteration of the mixture to give 2-((3-bromo-8-chloroimidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione as a white solid.