Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([Si:19]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[I:9])([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cl)cc1I
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 4-chloro-2-iodophenol (1.587 g, 6.238 mmol) in dichloromethane (10 ml) was added 1H-imidazole (1.01 g, 14.3 mmol) followed by a solution of tert-butyl(chloro)dimethylsilane (2.63 ml, 13.7 mmol) in dichloromethane (10 ml) dropwise. The resulting white suspension was stirred for 16 hours at room temperature before concentrating in vacuo. The residue was diluted with ethyl acetate (20 ml) and water (20 ml). The aqueous phase was acidified with hydrochloric acid (2 M aqueous solution) and extracted with ethyl acetate. The combined organic layers were washed with hydrochloric acid (2 M aqueous solution), saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel column) eluting with ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) to afford the title compound as pale yellow oil, 2.2 g, 95% yield.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][OH:11].CCN(CC)CC>C(Cl)Cl>[CH:1]1([CH:7]=[N:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ON=CC1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of cyclohexanecarbaldehyde (4 ml, 33.02 mmol) in CH2Cl2 (100 ml) at room temperature was added hydroxylamine hydrochloride (2.76 g, 39.62 mmol) followed by Et3N (5.52 ml, 39.62 mmol) and the reaction was stirred overnight. The resulting mixture was partitioned between CH2Cl2 and H2O and the layers were separated. The organic layer was dried over Na2SO4, concentrated in vacuo and used directly for the next step. 1H NMR (CDCl3) δ 1.0-2.0 (m, 10H), 3.0 (m, 1H), 6.6 (d, 0.5H), 7.4 (d, 0.5H), 8.2 (bs, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][CH:3]=1.[Br-].[Si:10]([O:17][CH2:18][C:19]1[S:23][C:22]([Zn+])=[N:21][CH:20]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Si:10]([O:17][CH2:18][C:19]1[S:23][C:22]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][CH:3]=2)=[N:21][CH:20]=1)([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc([Zn+])s1
Reactant: Nc1ncc(Br)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cnc(-c2cnc(N)nn2)s1
Temperature: 80 °C

Procedure:
In a separate flask was added 6-bromo-1,2,4-triazin-3-amine (10.0 g, 57.5 mmol), (PPh3)4Pd (12.1 g, 11.5 mmol), and THF (200 mL). The mixture was heated to 80° C., followed by the dropwise addition (1 h) of (5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)zinc(II) bromide prepared in the step above. The reaction was then cooled to rt, filtered through a silica pad, concentrated, and then purified using silica gel chromatography to afford 6.7 g the title compound as a light yellow solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:15]([C:17]1[N:22]=[C:21]([C:23]2[S:24][C:25]3[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=3[C:27](=[O:29])[N:28]=2)[CH:20]=[CH:19][CH:18]=1)=[O:16])[CH2:13][CH3:14]>C(OCC)(=O)C>[CH2:12]([S:15]([C:17]1[N:22]=[C:21]([C:23]2[S:24][C:25]3[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=3[C:27](=[O:29])[N:28]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:9])=[O:16])[CH2:13][CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 40.6 %

Procedure:
A solution of 3-chloroperbenzoic acid (ca. 50%, 0.44 g, 1.2 mmol) in ethyl acetate (10 ml) was added dropwise to a solution of 2-(6-propylsulfinyl-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.64 mmol), which was obtained in Example 60, in ethyl acetate (50 ml) with stirring. The reaction mixture was stirred at room temperature for 18 hrs, washed with saturated aqueous sodium hydrogen carbonate solution (50 ml×2) and saturated brine, dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the titled compound (0.09 g, 41%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[O:12][C:10]2=O)=[CH:5][CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(C2CC(=O)OC2=O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(C2CC(=O)N(c3ccncc3)C2=O)cc1
Reaction time: 6.5 h

Procedure:
The starting material is prepared as follows: The mixture of 57.9 g of 2-(p-methoxyphenyl)-succinic anhydride, 26.3 g of 4-aminopyridine and 500 ml of xylene is refluxed on a water separator while stirring for 6.5 hours. The hot solution is decanted off, cooled, filtered and the residue recrystallized from ethanol, to yield the 3-(p-methoxyphenyl)-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 179°-180°; its 3,4-dimethoxy-analog melts at 172°14 174°.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3[S:17][CH:18]=[CH:19][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-:22]S([O-])(=O)=O.[Mg+2].O.[O-][Mn](=O)(=O)=O.[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:22])[C:12]3[S:17][CH:18]=[CH:19][C:11]2=3)=[O:9])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2sccc21
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccsc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of 9.0 g of 4-(4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine in 713 ml of acetone is added 6.74 g of MgSO4 and 351 ml of water followed by 8.2 g of KMnO4 and heating at 70° C. for 18 hours. Another 6.24 g of MgSO4 and 8.2 g of KMnO4 is added and heating continued at 70° C. for 8 hours. An additional 6.24 g of MgSO4 and 8.2 g of KMnO4 is added and heating continued at 70° C. for 18 hours. The reaction mixture is filtered through diatomaceous earth and the cake washed with acetone and 500 ml of methylene chloride. The combined filtrates are evaporated in vacuo to a residue which is washed with water and air dried to give 5.7 g of a solid. The solid is crystallized from ethyl acetate to give 5.1 g of off white solid, m.p. 184°-186° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([CH2:44][CH:45]=O)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:45][CH2:44][CH:41]3[CH2:42][CH2:43][N:38]([C:35]4[CH:34]=[CH:33][C:32]([C:31]([OH:47])=[O:30])=[CH:37][CH:36]=4)[CH2:39][CH2:40]3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)c1ccc(N2CCC(CC=O)CC2)cc1
Product: O=C(O)c1ccc(N2CCC(CCNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)CC2)cc1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-[4-(2-oxo-ethyl)-piperidin-1-yl]-benzoic acid methyl ester. MS (ESI) m/z 610.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([C:23](=O)[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[CH2:28]([O:30][NH2:31])[CH3:29].N1C=CC=CC=1>C(O)C>[CH2:28]([O:30]/[N:31]=[C:23](\[C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)/[CH2:24][CH3:25])[CH3:29]
Reactant: CCON
Reactant: CCC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCO/N=C(/CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 26 h

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-one (250 mg, 0.612 mmol), O-ethylhydroxylamine hydrochloride (179 mg, 1.84 mmol) and pyridine (1.5 mL) in ethanol (6.0 mL) was stirred at 80° C. for 26 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compounds as a colorless crystal respectively (E (Example 123): 111 mg, 0.246 mmol, 40%, Z (Example 124): 31.0 mg, 0.0686 mmol, 11%).
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:34]([C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[CH:39][NH:40]2)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CCCCCC.O>[NH:40]1[C:41]2[C:37](=[C:36]([CH:34]=[CH:5][C:4]3[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=3[OH:2])[CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:39]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccccc1C=Cc1cccc2[nH]ccc12
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Under an inert atmosphere, 31 g of ortho hydroxybenzyltriphenyl-phosphonium bromide were suspensed in 350 ml of tetrahydrofuran and then over a period of one hour, 86 ml of a 1.6 M solution of butyllithium in hexane were added. The mixture stood for 30 minutes with stirring and then over 30 minutes, a solution of 5 g of 4-formyl-indole in 150 ml of tetrahydrofuran was added. The mixture was stirred for 24 hours and then was diluted with 500 ml of water. Potassium carbonate was added to saturation, and the mixture was extracted with ethyl acetate. The fractions with Rf=0.20 were isolated by chromatography on silica (eluent: methylene chloride) and the crystals obtained were triturated in methylene chloride, then filtered and dried under reduced pressure to obtain 7.4 g of 2-[(1H-indol-4-yl)-ethenyl]-phenol melting at 140° C., and after recrystallization from methylene chloride at 142° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:23])[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:23][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[N:18][C:17]([C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:22])=[CH:16][CH:15]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:24])[CH2:6]1
Reactant: C1COCCN1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](N)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
5-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (for a preparation, see Intermediate 55) (510 mg, 1.567 mmol), morpholine (0.149 mL, 1.72 mmol), HATU (656 mg, 1.724 mmol) and DIPEA (0.821 mL, 4.70 mmol) were combined in DMF (5 mL) and the mixture stirred at room temperature overnight. Morpholine (0.149 mL, 1.72 mmol) was added and the reaction stirred at room temperature for a further 3 h. The mixture was concentrated in vacuo before being dissolved in DCM and loaded onto an aminopropyl SPE column (50 g). The column was eluted with 10% MeOH in DCM and the appropriate fractions were combined and concentrated in vacuo to give a residue. This residue was purified by chromatography (50 g column, 2M methanolic ammonia/DCM gradient) to give 1-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (470 mg, 1.19 mmol, 76% yield) as a beige solid. LCMS: (Formate, 2 min), Rt=0.48 mins, MH+=395.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[S-:11][C:12]#[N:13].[NH4+]>O>[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:12]([NH2:13])=[S:11]
Reactant: N#C[S-]
Reactant: NCc1ccccc1Cl
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: NC(=S)NCc1ccccc1Cl
Yield: 59.8 %

Procedure:
A solution of 2-chlorobenzylamine hydrochloride (41 g, 0.23 mol) and ammonium thiocyanate (19.28 g, 0.253 mol) in water (170 mL) was heated on the steam bath for 18 hours. This mixture was concentrated in vacuo, and the residue was taken up in toluene (1 L) and azeotroped with a Dean-Stark head. The residue was triturated with wet diethyl ether to provide 27.6 g (60%) of 1-(2-chlorophenyl)methyl thiourea. The product was recrystallized from ethanol; mp 120°-122° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:34])[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccc(OC(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethoxy-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.077 mmol), β-alanine (682 mg, 7.7 mmol) and NaOMe solution (12 mL, 6.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 21 mg of the title compound as a yellow solid. MS: (+) m/z 528.27 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17](Cl)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(CC)c2cc(N3CCNCC3)c(F)cc2c1=O
Reaction time: 5 h
Yield: 81 %

Procedure:
Anhydrous piperazine (10.3 g) and 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester were added to a mixture of pyridine (9 ml) and toluene (18 ml), and the mixture was refluxed with stirring for 5 hrs. The same procedure as described in Example 1 was followed to give 8.4 g (81% yield) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 178.5°-180° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=1.CC(C)([O-])C.[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.CCCCCC>C1COCC1.C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[C:18](/[CH:19]=[CH:1]/[C:2]2[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1cncc(C)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cncc(/C=C/c2cccc(F)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
2,6-Dimethylpyrazine (5.0 g, 46 mmol) was dissolved in THF (200 mL) and cooled to 0° C. Potassium t-butoxide (46 mL of a 1.0M solution in THf, 46 mmol) was added to afford a dark red solution. The solution was allowed to warm to ambient temperature and stir for 1 hr. The solution was then cooled to 0° C., and 3-fluorobenzaldehyde (4.9 mL, 46 mmol) was added via syringe pump over 2 h. The reaction was then allowed to slowly warm to ambient temperature. After stirring at ambient temperature for 18 h, the reaction mixture was cooled to 0° C. and quenched by the addition of concentrated aqueous HCl (10 mL). The resulting suspension was allowed to warm to ambient temperature for 15 minutes, then cooled to 0° C. and brought to pH=8 by addition of solid NaHCO3. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3.times.200 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 90:10, 85:15, then 80:20 hexane:ethyl acetate to afford 2-[(E)-2-(3-fluorophenyl)ethenyl]-6-methylpyrazine (4.14 g, 42% yield) as a light yellow solid. M.p. 43-44° C. 1H NMR (CDCl3, 300 MHz) Δ8.44 (s, 1H), 8.31 (s, 1H), 7.29 (d, J=16 Hz, 1H), 7.37-7.26 (m, 3H), 7.12 (d, J=16 Hz, 1H), 7.05-6.98 (m, 1H), 2.59 MS (ESI) 214.5 (M+). This material was carried on to the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[C-:14]#[N:15].[Na+]>CS(C)=O>[F:11][C:10]([F:13])([F:12])[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:14]#[N:15])=[CH:4][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(OC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Using analogous conditions and workup as described for the preparation of I-24a above, 1-(bromomethyl)-4-(trifluoromethoxy)benzene (5 g, 19.607 mmol) in DMSO (30 mL) was reacted with NaCN (1.44 g, 35.1864 mmol). The resulting mixture was stirred at 90° C. for 1 hour to afford 3.8 g of the product (95% yield). 1H NMR (300 MHz, CDCl3): 7.45-7.20 (m, 4H), 3.8 (s, 2H)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:8]=[CH:9][CH:10]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CC(C)([O-])C.[K+]>CC(N(C)C)=O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COCOc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCOc1cccc(CCc2ccccc2OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 68.4 %

Procedure:
Following a procedure similar to that described in Example: 40(a), 1.58 g of 2-[2-(3-methoxymethoxyphenyl)ethyl]phenol, 2.34 g of 1-t-butoxycarbonyl-4-[2-(p-toluenesulfonyloxy) ethyl]piperidine and 0.686 g of potassium t-butoxide were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.96 g (yield 68%) of the title compound as a colorless oil.
Reaction SMILES: C(#N)C.[CH2:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[CH2:4]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Yield: 88.7 %

Procedure:
In an acetonitrile (30 mL) solvent, benzyl bromide (1.95 mL, 16.40 mmol) was added to a solution including 4-hydroxybenzaldehyde (2.0 g, 16.38 mmol) and potassium carbonate (3.40 g, 24.60 mmol), and then, the reaction mixture was refluxed for 1.5 hours. After cooling, the reaction mixture was distributed between methylene chloride and water. An organic layer was dried by using MgSO4, and filtered. A filtrate was evaporated, and water was added to the resultant solid. The solid was filtered and washed with water to obtain 4-(benzyloxy)benzaldehyde (3.082 g, 88.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:15]1[NH:16][CH:17]=CN=1)=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([N:16]([CH3:17])[CH3:15])=[O:6]
Reactant: CNc1ccc(C(=O)O)cc1Cl
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNc1ccc(C(=O)N(C)C)cc1Cl
Reaction time: 1 h

Procedure:
To 3-chloro-4-methylamino-benzoic acid (387 mg) in dry N. N-dimethylformamide (10 mL) was added carbonyl diimidazole (440 mg). After one hour, dimethylamine. HCl (221 mg) and triethylamine (0.38 mL) were added. The reaction mixture was stirred overnight, then diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent removed in vacuo. Purification using flash chromatography yielded 3-chloro-N,N-dimethyl-4-methylamino-benzamide.