Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][NH:23][C:24](=[O:26])[O-:25])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:23][CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([N:15]2[C:7]3=[C:8]4[S:14][CH:13]=[CH:12][C:9]4=[N:10][CH:11]=[C:6]3[N:5]=[C:4]2[C@H:2]([OH:1])[CH3:3])[CH2:17][CH2:18]1.[C:24]([OH:25])([C:28]([F:33])([F:32])[F:27])=[O:26]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNC(=O)[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1

Procedure:
[(trans-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]carbamate (0.21 g, 0.49 mmol) was treated with trifluoroacetic acid (0.7 mL, 9 mmol) in dichloromethane (2 mL) at room temperature for 1 h. The mixture was stripped to dryness to give the desired product as TFA salt (0.35 g, 79%). LCMS calculated for C17H23N4OS (M+H)+: m/z=331.1. Found: 331.0.
Reaction SMILES: [CH:1](O)=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH:19]=1)[NH2:18]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH:19]=1)[NH:18][CH3:1]
Reactant: O=CO
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CNc1cc(OC)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A mixture of formic acid (7.64 g) and acetic anhydride (16.9 g) was stirred at 60° C. for 2 hr then a solution (100 mL) of 5-methoxy-2-nitroaniline (9.30 g) in tetrahydrofuran was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To a solution (200 mL) of the residue in tetrahydrofuran was added a 1.0M solution (140 mL) of borane-tetrahydrofuran complex in tetrahydrofuran at 0° C., and the mixture was stirred with heating under reflux for 2 hr. Methanol was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 30 min. After stirring, 1N hydrochloric acid was added to adjust to pH=2. The reaction mixture was stirred with heating under reflux for 1 hr, and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title object compound (6.30 g, 62%) as a colorless oil.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[CH:38]=[N:39][C:40]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:42]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]3[CH:38]=[N:39][C:40]([CH2:43][N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[CH:41][CH:42]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:22])([CH3:21])[CH3:23]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-c3ccc(CN4CCOCC4)nc3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.CN(C(O[N:38]1N=N[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NC1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:19])=[CH:15][CH:16]=2)[NH:4][N:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1n[nH]c2cccc(-c3ccc(CC(=O)O)cc3)c12
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: Nc1n[nH]c2cccc(-c3ccc(CC(=O)Nc4ccccc4)cc3)c12
Yield: 29.3 %

Procedure:
A mixture of Example 53B (40 mg, 015 mmol), diisopropylethylamine (0.078 mL, 0.45 mmol), TBTU (57 mg, 0.18 mmol), and aniline in THF (1 mL) was stirred for 18 hours at room temperature and concentrated. The residue was purified by preparative HPLC using the conditions described in Example 15H to provide 15 mg of the desired product as the trifluoroacetate salt. MS (ESI(+)) m/e 343 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.74 (s, 2H), 6.84 (dd, J=5.09, 3.05 Hz, 1H), 7.02-7.07 (m, 1H), 7.28-7.33 (m, 4H), 7.43-7.50 (m, 4H), 7.62 (d, J=7.80 Hz, 2H).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([O:19][CH3:20])=[O:18])[N:14]=2)[CH2:7]1)(=O)=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+]>CN(C)C=O>[C:21]([S:23][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([O:19][CH3:20])=[O:18])[N:14]=2)[CH2:9]1)(=[O:24])[CH3:22]
Reactant: CC([O-])=S
Reactant: COC(=O)NCc1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCc1csc(N2CC(SC(C)=O)C2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 105.3 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(methoxycarbonylamino-methyl)-1,3-thiazol-2-yl]azetidine (448 mg, 1.39 mmol) (obtained as described in Reference Example 63(3)) in dimethylformamide (13 ml) was added potassium thioacetate (952 mg, 8.34 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 6 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-acetylthio-1-[4-(methoxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (441 mg, yield 100%) as a pale brown solid.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(O)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Magnesium ribbon (0.11 g) is suspended in absolute ethanol (0.5 ml), and thereto is added carbon tetrachloride (0.05 ml). After 10 minutes, to the mixture is added dropwise a mixture of diethyl malonate (1.5 ml), absolute ethanol (0.9 ml) and anhydrous ether (3.8 ml) at a room temperature. After the addition, the mixture is refluxed for 3 hours. Thereafter, a solution of 2,3,4,5-tetrafluorobenzoyl chloride (2.0 g) in anhydrous ether (0.9 ml) is added dropwise under ice-cooling. After the addition, the mixture is stirred at room temperature for 3 hours, and then allowed to stand overnight. A mixture of ice-water (4 ml) and conc. sulfuric acid (0.24 ml) is added dropwise to the reaction mixture under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. The ether layer is separated, and the remaining reaction mixture is extracted with ether. The ether layers are combined, and are washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give diethyl 2,3,4,5-tetrafluorobenzoylmalonate (3.0 g).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:19][CH:18]=1.O.Cl>O1CCCC1.C(O)C>[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:40][CH:41]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3cccs3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
Lithium hydroxide monohydrate (177 mg) was added to a solution of ethyl E-6-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate (747 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (4.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoic acid (653 mg, yield 92%) as colorless crystals. m.p. 101-102° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]3[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[C:10]2[C:5](=[CH:6][C:7]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:8][CH:9]=2)[N:4]=1.C(OCC)C>ClCCl>[ClH:1].[ClH:1].[CH2:29]([O:28][C:7]1[CH:6]=[C:5]2[C:10]([C:11]3[N:15]4[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:14]4=[N:13][C:12]=3[C:3]([NH2:2])=[N:4]2)=[CH:9][CH:8]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (20 mL of 4 N in 1,4-dioxane) was added to a solution of tert-butyl 6-amino-3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-9(10H)-carboxylate (3.89 g, 8.46 mmol, prepared as described in Part A of Examples 435-450) in dichloromethane (50 mL), and the reaction was stirred at ambient temperature for one hour. Diethyl ether was added, and a precipitate formed. The precipitate was isolated by filtration and dried in a vacuum oven at 65° C. to provide 3.52 g of 3-benzyloxy-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine dihydrochloride.
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4].O.[CH2:15]([NH:22]CC(O)=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:27]1(C)C=CC=CC=1>>[CH2:15]([N:22]1[CH2:4][CH:3]([CH3:27])[CH:2]2[CH:12]1[CH2:11][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:1]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)CNCc1ccccc1
Reactant: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2C(C)CN(Cc3ccccc3)C2C1

Procedure:
18.5 g (0.1 mol) of ethyl N-(2-buten-1-yl)-N-(2-oxoethyl)-carbamate are heated under reflux overnight in a water separator with 16.5 g (0.1 mol) of N-benzylglycine in 300 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[N:17]2[C:18]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=3[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:23])[CH2:22][C:16]2=[N:15][N:14]=1)=O)C1C=CC=CC=1.Br>C(O)(=O)C>[NH2:11][CH2:12][C:13]1[N:17]2[C:18]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=3[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:23])[CH2:22][C:16]2=[N:15][N:14]=1
Reactant: O=C(NCc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NCc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2

Procedure:
4.5 g of 1-[[(benzyloxycarbonyl)amino]-methyl]8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 60 ml acetic acid saturated with hydrogen bromide is stirred at 20° for 1 hour. The reaction mixture is concentrated to one-half its original volume in vacuo and diluted with ether. The precipitate is filtered off, suspended in methylene chloride and shaken with excess 2 N aqueous sodium bicarbonate. The organic phase is separated, washed with water, dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]=[CH:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1C=C(O)[CH:37]=[CH:36][CH:35]=1>>[C:5]([O:4][C:1]1[CH:19]=[CH:20][CH:21]=[C:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH2:32][CH:33]=[CH:34][CH2:35][CH:36]=[CH2:37])[CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC/C=C\C/C=C\CCCCCCCc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCC=CCC=CCCCCCCCc1cccc(OC(C)=O)c1
Reaction time: 0.5 h

Procedure:
A mixture of acetic anhydride (0.1 mol, 15 ml) and p-toluenesulphonic acid (PTSA, 3.15 mol %, 0.6 g) were taken in a two necked RB flask and double distilled cardanol (0.1 mol, 30 g) was added dropwise with stirring over a period of 30 minutes at ambient conditions. The reaction was continued for 8-12 h. The product (AC) was washed free of acetic acid and catalyst with water and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].N[N:13]1[CH:17]=[N:16][N:15]=[CH:14]1.O>C(O)(C)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:15]2[CH:14]=[N:13][CH:17]=[N:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nn1cnnc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Temperature: -2 °C
Reaction time: 0.67 h
Yield: 37.4 %

Procedure:
4-Nitrobenzyl bromide (64.22 g), 4-amino-1,2,4-triazole (26 g) and isopropyl alcohol (586 ml) were stirred together at reflux for 7% hours. The isopropanol solvent was replaced with water by using an azeotropic distillation procedure, in vacuo, on a Buchi rotary evaporator. The volume of the final aqueous slurry was 750 ml. 675 ml of this slurry was cooled to -2° C. and hydrochloric acid (50.8 ml, 12M) added over a few minutes. A solution of sodium nitrite (21.7 g) in water (86 ml) was then added dropwise, and subsurface over a 40 minute period. The temperature of the batch was kept between -2 and -1° C. during the addition and then allowed to warm to 18° C. over 30 minutes. The temperature was then increased to 28° C. and held for 1 hour and the solution treated with charcoal (4.5 g, Fisons) for 15 minutes. The charcoal was removed and the filtrate (750 ml) divided equally in two. One half of the solution was made basic with ammonia solution (22 ml) and the precipitated base collected, washed with water (2x30 ml) and dried (16 hours at 35° C. in vacuo). This gave an 83.3% yield (22.73 g) of 1-(4-nitrobenzyl)-1,2,4-triazole.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([O:7][P:8]([CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1)[OH:9])[CH3:6].[O-]CC.[Na+].C(O)(=O)C>C(O)C>[C:1]([CH2:2][CH2:3][P:8]([CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1)(=[O:9])[O:7][CH2:5][CH3:6])#[N:4]
Reactant: C=CC#N
Reactant: CCOP(O)C1CCCO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOP(=O)(CCC#N)C1CCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.68 g of acrylonitrile and 2.11 g of tetrahydrofuran-2-yl phosphonous acid ethyl ester in 5 ml of absolute ethanol is cooled to 0° under argon and treated, dropwise, with an ethanolic solution of sodium ethoxide (from 0.15 g of sodium metal and 15 ml of absolute ethanol) at such a rate so that the temperature does not exceed 5° (extremely exothermic). After the addition is completed the reaction mixture is stirred at room temperature for 30 minutes and 0.4 g of glacial acetic acid are added. The solvent is removed in vacuo and the residue partitioned between dichloromethane water. The organic layer is dried with anhydrous magnesium sulphate and removed in vacuo to afford ethyl 2-cyanoethyl(tetrahydrofuran-2-yl)-phosphinate; 1H-NMR (CDCl3): δ4.15 (3H, m), 3.90 (2H, m), 2.72 (2H, m, CH2CN), 2.34-1.87 (6H, m), 1.32 (3H, m, CH3).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH3:9][NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:9][N:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)=[O:8]
Reactant: O=C(O)c1cc[nH]c1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(C)C(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
Into a suspension of 3.30 g (30 mmol) of 3-pyrrolecarboxylic acid in 10 ml of dichloromethane, a solution of 5.90 g (45 mmol) of ethyl N-methyl-3-aminopropionate in 50 mt of dichloromethane, a solution of 4.55 g (45 mmol) of triethylamine in 50 ml of dichloromethane, and 8.63 g (45 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were successively added, followed by stirring at room temperature for 3 hours. Dichloromethane was added to the reaction mixture, and the resulting organic layer was washed successively with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure, whereby 5.31 g of the title compound were obtained (yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[C:10](I)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C([Li])CCC.CCCCCC.C1(C)C=CC(S([C:32]#[N:33])(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[C:10]([C:32]#[N:33])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: Clc1nn2ccccc2c1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1c(Cl)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled −78° C. solution of the title compound from Example 1 Step A (0.20 g, 0.718 mmol) in tetrahydrofuran (3.59 ml) was added a solution of n-butyllithium in hexane (1.6 M, 0.494 ml, 0.790 mmol). After 5 minutes, p-toluenesulfonyl cyanide (0.169 g, 0.934 mmol) was added, and the resulting reaction mixture was allowed to warm to room temperature. After 18 hours, the mixture was concentrated under reduced pressure. Purification by column chromatography on silica gel (0-30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 177.91 [M+H]+, 179.86 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=6.9 Hz, 1 H), 7.70 (d, J=9.0 Hz, 1 H), 7.52 (dd, J=8.0, 8.0 Hz, 1 H), 7.26-7.20 (m, 1 H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21](Cl)=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[N:24]2)=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:8]([NH:15][C:21]1[C:20]2[C:25](=[CH:26][C:17]([Br:16])=[CH:18][CH:19]=2)[N:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: NCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (5.24 g, 51.8 mmol) and benzylamine (4.15 mL, 38.0 mmol) were sequentially added to a solution of 7-bromo-4-chloro-3-nitroquinoline (10.0 g, 34.5 mmol, see U.S. Patent Publication Application No. US 2004/0147543 (Hays et al.), Example 1 Parts A through D) in DMF (100 mL). The reaction was stirred at room temperature for three days, poured into water (800 mL), and stirred vigorously for 20 minutes. A precipitate formed and was isolated by filtration, washed with diethyl ether (800 mL), and dried under vacuum for four hours to provide 10.98 g of N-benzyl-7-bromo-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1B(O)O.C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
To a round bottom flask containing 83.26A (1.0938 g, 3.93 mmol) and 2-fluoro-5-methoxyphenylboronic acid (0.7053 g, 4.15 mmol) (commercially available from Aldrich) was added a premixed solution of 1:1 isopropanol (6 mL) and water (6 mL). After stirring at room temperature for 5 minutes, sodium carbonate (0.5526 g, 5.21 mmol) and palladium, 10 wt % on activated carbon (0.0725 g, 0.0681 mmol) were added, and the reaction was then heated to 65° C. After 17 hours, the reaction was cooled to room temperature and then filtered through Celite. The filtrate was concentrated and then saturated aqueous ammonium chloride was added. After extracting three times with EtOAc, the organic solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (0-40% EtOAc/hexane) to afford 83.26B (834.3 mg, 77% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.69 (2H, td, J=7.7, 1.7 Hz), 7.33 (1H, d, J=7.8 Hz), 7.14 (1H, t, J=9.0 Hz), 6.94 (1H, dt, J=9.0, 3.5 Hz), 6.89 (1H, dd, J=5.9, 3.2 Hz), 5.42 (1H, s), 3.94 (3H, s), 3.82 (3H, s).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:13]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CCCCCC.CCOCC>[OH:19][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:18]
Reactant: O=C1CCCCO1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(CCCCO)c1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution prepared by adding 497 ml (1 mole) of 2.01 molar solution of n-butyllithium in hexane into 2 l of ether at -60° C., is added dropwise with stirring under argon at -78° C. a solution of 172 g (1.09 mole) of 3-bromopyridine in 50 ml of ether over a period of 15 min. The mixture is stirred at -78° C. for an additional 30 min and a solution of 100 g(1 mole) of δ-valerolactone in 100 ml of ether is added dropwise over a period of 15 min. The mixture is stirred at -78° C. for 3 h, quenched with 500 ml of concentrated aqueous ammonium chloride, washed with water, dried (MgSO4) and evaporated to give 5-hydroxy-1-(3-pyridyl)pentan-1-one as an oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[NH3:13]>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:8]([NH2:13])=[O:9]
Reactant: N
Reactant: O=C1OC(=O)c2c(F)cccc21
Product: NC(=O)c1c(F)cccc1C(=O)O

Procedure:
reacting the fluorophthalic anhydride with ammonia to form an ammonium salt of a fluorophthalamic acid, and