Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[CH:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:19])[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(Cl)c4)cc3CCC12
Yield: 74.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-chlorophenylboronic acid (122 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 1.5 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 164 mg (74%) of the title compound as an amorphous foam. mp 158°-65°. FDMS: m/e=339. α[D]589 =+74.90 (c=1.00, methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
A mixture of 3,4-difluorobenzaldehyde (2.00 g, 14.8 mmol), 6-chloropyridin-3-ol (1.82 g, 14.1 mmol) and potassium carbonate (2.14 g, 15.5 mmol) in N,N-dimethylformamide (DMF) (25 mL) was stirred at 110° C. for 12 h, diluted with ethyl acetate (50 mL), washed with water (50 mL×2). The organic part was separated, dried over anhydrous Na2SO4, filtered and concentrated. Purification via silica gel (3% ethyl acetate in petroleum ether) afforded the title product (2.8 g)
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].I[C:12]1[N:21]=[CH:20][C:19]2[CH2:18][CH2:17][C:16]3[C:22]([C:26]([NH2:28])=[O:27])=[N:23][N:24]([CH3:25])[C:15]=3[C:14]=2[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:12]1[N:21]=[CH:20][C:19]2[CH2:18][CH2:17][C:16]3[C:22]([C:26]([NH2:28])=[O:27])=[N:23][N:24]([CH3:25])[C:15]=3[C:14]=2[N:13]=1)(=[O:3])[CH3:2]
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(I)ncc1CC2
Reactant: CC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1Nc1ncc2c(n1)-c1c(c(C(N)=O)nn1C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Palladium acetate Pd(OAc)2 (20 mg, 0.09 mmol), (±)-BINAP (55 mg, 0.09 mmol) and dimethylformamide (5 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. The mixture was stirred under argon for 30 minutes and added to a mixture of 2-acetylaniline (0.162 ml, 1.35 mmol), 8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (319 mg, 0.9 mmol), potassium carbonate (1.24 g, 9 mmol) in dimethylformamide (10 mL). The resulting mixture was stirred at 80° C. for 4 hours under argon. After cooling to room temperature, the reaction mixture was filtered on a pad of celite. The solvent was concentrated, the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 153 mg (47% yield) of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][N:24]=[C:25]1[C:29]2([CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]2)[CH2:28][NH:27][CH2:26]1.C(#N)C.C(N(CC)CC)C>CN(C)C=O>[C:36]([O:35][C:33]([N:31]1[CH2:32][C:29]2([C:25](=[N:24][O:23][CH3:22])[CH2:26][N:27]([C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]4[CH:1]4[CH2:2][CH2:3]4)=[C:9]([NH2:17])[C:10]=3[F:16])[CH2:28]2)[CH2:30]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 30.9 %

Procedure:
1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid, 1.05 g of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 4 g of AmberliteR IRA-420 were added to 20 ml of acetonitrile and thereto 2 ml of triethylamine was added by dropping. The mixture was refluxed for 5 days and then 2 ml of dimethylformamide was added thereto. The resulting mixture was stirred for 1 hour and thus precipitated solid was filtered off. The filtrate was concentrated under the reduced pressure and then to the resulting residue 10 ml of acetonitrile was added and stirred for 1 hour. The precipitated solid was filtered and dried to give 420 mg of the titled compound (yield: 30.9%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C)C=O>[C:16]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[NH:5][C:6](=[O:15])[CH2:7][CH2:8]2)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CCc2ccccc2N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)c3ccccc3)ccc2N1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
To a stirred amount of 45.3 parts of aluminiumtrichloride were added drop wise 6.9 parts of N,N-dimethylformamide. After stirring for 5 min. at 70° C., there were added portionwise 5 parts of 3,4-dihydroquinolin-2(1H)-one and, after another 5 min., 4.7 parts of benzoylchloride. Stirring at 70° C. was continued for 2 hours and then the reaction mixture was carefully poured into ice-water. There were added 50 ml of HCl 12N and the whole was stirred for 15 min. The precipitate was filtered off and boiled in 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 6.3 parts (73.8%) of 6-benzoyl-3,4-dihydro-2(1H)-quinolinone; mp. 211.0° C. (interm. 18).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[CH3:24])[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:27]=3)[CH2:20][CH:19]2[CH3:24])[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Clc1nc(-c2ccccc2)no1
Reactant: CC1CNCCC1N(C(=O)c1ccc(-c2cnco2)cc1)C1CC1
Solvent: CN1CCCC1=O
Product: CC1CN(c2nc(-c3ccccc3)no2)CCC1N(C(=O)c1ccc(-c2cnco2)cc1)C1CC1

Procedure:
The title compound is prepared from N-cyclopropyl-N-(3-methyl-piperidin-4-yl)-4-oxazol-5-yl-benzamide and 5-chloro-3-phenyl-[1,2,4]oxadiazole following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 3): tR=2.01 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1OS(C(F)(F)F)(=O)=O.[CH2:22]([NH:29][C:30](=[O:48])[N:31]([CH3:47])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Cl-].[NH4+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([N:31]([CH3:47])[C:30]([NH:29][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:48])[CH:37]=1
Reactant: COC(=O)/C=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2F)c1
Temperature: 92.5 °C
Yield: 7.3 %

Procedure:
85 mg (0.38 mmol, 0.05 eq) of palladium acetate are added to a mixture of 2.50 g (7.6 mmol, 1 eq) of methyl (E)-3-(3-fluoro-4-trifluoromethanesulfonyloxyphenyl)acrylate, 3.71 g (9.9 mmol, 1.3 eq) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea (prepared as in Example 1e), 272 mg (0.78 mmol, 0.1 eq) of 2-(dicyclohexylphosphino)biphenyl and 5.5 mL of 2M potassium phosphate solution in 28 ml of dimethylformamide. The reaction mixture is heated at 90-95° C. overnight. The reaction medium is hydrolyzed in saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and the brown paste obtained (4.16 g) is chromatographed on silica gel (120 g CombiFlash column) eluted with 80/20 heptane/ethyl acetate. 706 mg (22%) of a “cis/trans” mixture are obtained. This solid is washed in an ethyl ether/heptane mixture, filtered and dried. 238 mg of methyl (E)-3-[2-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in the form of a white solid are obtained. Yield=7%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Br[C:12]1C=CC=C2C=1N(C)C=C2.BrC1C=CC=C2C=1NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: Cn1ccc2cccc(Br)c21
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Brc1cccc2cc[nH]c12
Product: Cn1ccc2cc(Br)ccc21

Procedure:
5-Bromo-1-methylindole was prepared from 5-bromoindole as described for the preparation of 7-bromo-1-methylindole from 7-bromoindole. Purification by chromatography using EtOAc:petroleum ether 1:10
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]>CN1C(=O)CCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:2]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:4][C:3]=2[C:19]([F:22])([F:21])[F:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(COCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(COCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)cc1
Temperature: 120 °C

Procedure:
To a mixture of 1-chloro-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene (1.5 g, 4.5 mmol) and cyclohexylzinc bromide THF solution (0.5 M, 27 mL) in NMP (30 mL) is added bis(tri-t-butylphosphine)palladium(0) (115 mg, 0.225 mmol). The mixture is purged with N2 for 5 min, followed by heating at 120° C. 12 h under N2. After cooling to room temperature, the reaction is quenched by the addition of H2O (100 mL) and aqueous HCl (1N, 20 mL). The mixture is extracted with EtOAc (3×40 mL). The combined organic phases are washed with saturated aqueous NaHCO3, saturated aqueous NaCl, and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (5% EtOAc in hexanes) to give 1-cyclohexyl-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:33][C:32]1=[O:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:33][C:32]1([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:3]=1)[OH:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-vinylbenzyl)benzene (intermediate AM) (215 mg) in toluene:THF (2:1) (3 mL) at −78° C. was added n-BuLi (0.34 mL, 2.5 M in hexane) dropwise. After 45 min, the above mixture was added dropwise into a pre-cooled (−78° C.) solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxylmethyl)tetrahydro-2H-pyran-2-one (453 mg) in toluene (3 mL). After being stirred for 2.5 h at −78° C., the reaction mixture was quenched by saturated NH4Cl and diluted with ethyl acetate. The organic layer was separated, washed with brine and dried over Na2SO4. Concentration gave the crude product which was purified by chromatography to provide intermediate AN (712 mg) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.[CH3:24][C:25]1(C)[C:29](C)(C)OB(C(C)=C)O1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]([CH3:29])=[CH2:24])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: O=[N+]([O-])c1cc(F)ccc1Cl
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 78.7 %

Procedure:
To 1-chloro-4-fluoro-2-nitrobenzene (1.03 g, 5.87 mmol) in a 100 mL round-bottomed flask equipped with a stir bar and nitrogen was added sodium carbonate (0.746 g, 7.04 mmol), dioxane (23.47 ml) and water (5.87 ml). To this was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.323 ml, 7.04 mmol) followed by bis(triphenylphosphine)palladium(II)chloride (0.329 g, 0.469 mmol). The reaction mixture was evacuated and backfilled with nitrogen (3×). The reaction was heated to 80° C. overnight. The reaction was determined to be complete by TLC (10% EtOAc/Hex). The reaction was cooled, filtered through Celite, washed with EtOAc and concentrated. The residue was taken up in dichloromethane, poured through a phase separator and concentrated. Purification by flash column chromatography provided the title compound 4-fluoro-2-nitro-1-(prop-1-en-2-yl)benzene (0.837 g, 75%) as a yellow oil: IR (thin film) 3091 (w), 2979 (w), 2918 (w), 1642 (w), 1530 (s), 1350 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=8.2, 2.5 Hz, 1H), 7.37-7.21 (m, 2H), 5.19 (p, J=1.5 Hz, 1H), 4.97-4.89 (m, 1H), 2.11-2.04 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 160.96 (d, JCF=250.8 Hz), 148.46, 141.88, 135.18 (d, JCF=4.1 Hz), 132.09 (d, JCF=7.8 Hz), 119.98 (d, JCF=20.9 Hz), 115.99, 111.63 (d, JCF=26.4 Hz), 23.35.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([Cl:40])[C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1)[NH2:24]>>[Cl:40][C:26]1[CH:25]=[C:23]([NH:24][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]=2[CH3:1])=[O:18])[CH:22]=[C:21]([Cl:20])[C:27]=1[N:28]1[CH2:29][CH2:30][CH:31]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH2:32][CH2:33]1
Reactant: Nc1cc(Cl)c(N2CCC(N3CCOCC3)CC2)c(Cl)c1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(C(=O)Nc2cc(Cl)c(N3CCC(N4CCOCC4)CC3)c(Cl)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 68.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.87 g) and 3,5-dichloro-4-(4-morpholinopiperidin-1-yl)aniline (1.0 g), the title compound (1.2 g) was obtained, melting point: 252–254° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24].O.ON1C2C=CC=CC=2N=N1.Cl.[Cl-].C(N=C=N)C.Cl>CN(C)C=O.O.C(OCC)C>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[O:6][C:5]1[CH:16]=[CH:17][CH:18]=[C:3]([N:2]([CH3:1])[CH3:19])[CH:4]=1
Reactant: NCc1ccccc1Cl
Reactant: CN(C)c1cccc(Oc2ncccc2C(=O)O)c1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)c1cccc(Oc2ncccc2C(=O)NCc2ccccc2Cl)c1

Procedure:
To a stirred solution 2-(3-Dimethylamino-phenoxy)-nicotinic acid (0.200 grams, 0.775 mmole), 2-Chloro-benzylamine (0.120 grams, 0.85 mmole), and 1-hydroxybenzotriazole hydrate (0.126 grams, 0.93 mmole) in dry dimethylformamide (4 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide chloride hydrochloride (0.193 grams, 1.00 mmole) and stirred over night. The mixture was diluted with 50 ml water and extracted with ethyl acetate. The combined organics were washed with 1N NaOH, water and brine, dried over Na2SO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel. Recrystalization from ethyl acetate/hexane gave an oil. The product was dissolved in diethyl ether and hydrochloric acid (g) was used to precipitate the salt, which was filtered, dissolved in methylene chloride and concentrated to a solid (0.075 g). M.P. 85-87° C.; Anal. calcd. for C21H20N3O2Cl.HCl: C, 60.30; H, 5.06; N, 10.04. Found: C, 60.58; H, 5.60; N, 9.28.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:15]([NH:17][NH:18][C:19]([CH:21]2[CH2:24][N:23]([C:25]([O:27][CH2:28][CH:29]3[C:41]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:35]4[C:30]3=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH2:22]2)=[O:20])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:15]2[O:20][C:19]([CH:21]3[CH2:22][N:23]([C:25]([O:27][CH2:28][CH:29]4[C:41]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[C:35]5[C:30]4=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:26])[CH2:24]3)=[N:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NNC(=O)C2CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)c2ccccc2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnc(C3CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)o2)CC1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of 4-[1-phenyl-1-(2-(N-(9-fluorenylmethoxycarbonyl)-3-azetidinecarbonyl)-hydrazinocarbonyl)-methylene]-piperidine-1-carboxylic acid tert-butyl ester(0.411 g, 0.645 mmol), iPr2NEt (0.775 mL, 4.448 mmol) and PPh3 (0.693 g, 2.643 mmol) in CH3CN (8 mL) was added hexachloroethane (0.351 mg, 1.483 mmol). The mixture was allowed to stir for 1 h and then it was worked up as in Method A above and the crude product purified by flash chromatography (SiO2/EtOAc-hexane, 1:1) to give the title compound (0.299 g, 75%) as a colorless solid:
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH2:8]([C:10]1[NH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)c1ccc[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(CCc2ccc[nH]2)cc1

Procedure:
A solution of 6.00 g (0.032 mole) of the 2-phenylacetylpyrrole (III) in 200 ml of anhydrous tetrahydrofuran was added to a suspension of 600 g (0.153 mole) of lithium aluminum hydride in dry tetrahydrofuran. The mixture was stirred at reflux temperature for 48 h. The mixture was cooled to 0°, ethyl acetate was cautiously added to destroy the excess hydride and then saturated aqueous sodium sulfate was added. The organic phase was decanted, dried over sodium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on neutral alumina (Fluka, Act II). 4.800 g (88%) of 2-[phenethyl]pyrrole (IV) was eluted with hexane-ethyl acetate and crystallized, m.p. 40°-42° (hexane). (Step 2).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[N:7][C:8](Cl)=[N:9]2)=[C:4]([Cl:15])[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1>C(O)(C)C>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:21][CH:22]=3)=[N:9]2)=[C:4]([Cl:15])[CH:3]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: COc1c(Br)cc(Cl)c2cnc(Cl)nc12
Solvent: CC(C)O
Product: COc1c(Br)cc(Cl)c2cnc(Nc3ccc(C(=O)N4CCOCC4)cc3)nc12
Temperature: 90 °C

Procedure:
To 7-bromo-2,5-dichloro-8-methoxyquinazoline (1 eq) was added (4-aminophenyl) (morpholino)methanone (1 eq) in isopropanol and the mixture was heated to 90° C. for 16 h. The solid formed was filtered to give (4-(7-bromo-5-chloro-8-methoxyquinazolin-2-ylamino)phenyl) (morpholino)methanone and was confirmed by LC/MS. ES/MS m/z 478 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.[NH2:8][C:9]1([C:15](O)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1COCC1>[NH2:8][C:9]1([CH2:15][OH:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: NC1(C(=O)O)CCOCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NC1(CO)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4-Amino-tetrahydropyran-4-yl)-methanol is prepared by adding LAH (99%, 1.2 g), portionwise, to a stirred mixture of 4-aminotetrahydropyran-4-carboxylic acid hydrochloride (2.0 g, 11.0 mmol) in THF (30 mL) at 0° C. Upon completion of addition, the reaction mixture is warmed to room temperature and stirred for 1 hour. The reaction mixture is cooled to 0° C. and cautiously quenched by the portionwise addition of Na2SO4.10H2O (4 g). The reaction mixture is diluted with ethyl acetate, warmed to room temperature, and filtered through Celite to give the desired product.
Reaction SMILES: [OH:1][C@@H:2]1[O:10][C@@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].O[C@H]1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O.O[C@@H]1O[C@@H]([C@H](CO)O)[C@@H](O)[C@@H]1O.O[C@H]1O[C@@H]([C@H](CO)O)[C@@H](O)[C@@H]1O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@H]1O
Agent: OC[C@@H]1O[C@H](O)[C@@H](O)[C@H](O)[C@H]1O
Agent: OC[C@H](O)[C@@H]1O[C@@H](O)[C@@H](O)[C@@H]1O
Agent: OC[C@H](O)[C@@H]1O[C@H](O)[C@@H](O)[C@@H]1O
Product: O=C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
α-L-glucopyranose; β-L-glucopyranose; α-L-glucofuranose; β-L-glucofuranose