Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: C1CCNCC1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CCO
Product: N#Cc1c(-c2ccco2)nc(N)nc1N1CCCCC1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and piperidine in ethanol. EI-MS m/e (%): 269 (M+, 36), 268 ([M—H]+, 100), 240 (38).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:7])[C:4](Cl)=[O:5].[NH:8]([C:10]1[C:18]2[O:17][CH:16]([CH3:19])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[NH2:9].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:19][CH:16]1[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:8][NH:9][C:4]([N:3]([O:2][CH3:1])[CH3:7])=[O:5])[C:18]=2[O:17]1
Reactant: CC1Cc2cccc(NN)c2O1
Reactant: CON(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)NNc1cccc2c1OC(C)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.9 g of N-methoxy-N-methylcarbamic chloride was added drop-by-drop (over 5 minutes) to a mixture of 6.6 g of 1D, 125 ml of THF and 5.2 g of N,N-diisopropyl-N-ethylamine, at -10° C. The mixture was stirred for 1 hour at 0° C., and then mixed with ice water. The resulting mixture was extracted with ether, the extract was dried (MgSO4) and the solvent was evaporated, to give 1-(2,3-dihydro-2-methylbenzofuran-7-yl)-4-methoxy-4-methylsemicarbazide (1E), as an amber syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([CH3:17])=[C:10]([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:18][CH2:17]/[C:9](/[C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]1)=[C:10](/[F:16])\[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)=C(C)C1(C(=O)OCC)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C(\CBr)C1(C(=O)OCC)CC1
Yield: 49.8 %

Procedure:
To a solution of ethyl 3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate (152.78 g, 0.625 mol) in chloroform (1500 ml) were added N-bromosuccinimide (111.33 g, 0.625 mol) and a catalytic amount of 2,2′-azobis(isobutyronitrile) and then the resultant mixture was heated under reflux for 16 hours. Then, the liquid reaction mixture was cooled and concentrated under reduced pressure. After adding benzene (300 ml), insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1) to obtain 100.5 g (49.7%) of the title compound as a yellow oily substance. On the other hand, 75 g (37.1%) of (Z)-ethyl 4-bromo-3-(1-ethoxycarbonylcyclopropyl)-2-fluoro-2-butenoate (the geometrical isomer of the title compound) was obtained as a yellow oily substance with the use of another eluent (n-hexane:ethyl acetate=2:1).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Cl[C:16]1[N:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1>>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:21][CH:20]=1)[CH3:23]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(C#Cc2c(-c3ccccc3)noc2C)nc1
Yield: 28 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloro-5-ethylpyrimidine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 40 mg, 28%) which was obtained as a brown oil. MS: m/e=290.1 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH2:3]1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=3)[CH2:3]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(N)C2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Br)cc1)C2

Procedure:
3.4 g of methyl 6-(2-aminoindan-5-yl)-6-(3-pyridyl)hex-5-enoate is placed in 40 ml of chloroform together with 3.3 g of 4-bromobenzenesulphonic acid chloride and 1.8 g of triethylamine are added in batches at ambient temperature. After 30 minutes the solution is washed with water, dried and rotary evaporated. The yellow oil is then chromatographed over a silica gel column using cyclohexane/ethyl acetate (1:2).
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]([O:16][C:17]([CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])=[O:18])[CH3:15]>C(O)C>[CH2:1]([N:7]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:25]([OH:26])=[C:19]([C:17]([O:16][CH2:14][CH3:15])=[O:18])[C:20]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCCCCCn1c(=O)c(C(=O)OCC)c(O)c2ccccc21

Procedure:
In a round-bottomed flask equipped with a condenser, N-hexylaniline (355 mg, 2 mmol) is added to a solution of methanetricarboxylic acid triethyl ester (1.35 ml, 6.4 mmol). The resulting reaction mixture is placed in a CEM Discovery microwave oven and irradiated in the open round-bottomed flask, and then the ethanol formed is distilled off (the parameters are the following: power=250 W, temperature=225° C., execution time=5 min, hold time=15 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Yield: 99 %

Procedure:
4.27 g (12.77 mmol) of the product prepared in step 4.2 in 130 mL of an ethyl acetate/ethanol mixture (v/v=1/1) are placed in a hydrogenation autoclave, and 0.54 g of 10% palladium-on-charcoal is added, under an inert atmosphere. The mixture is stirred under a hydrogen pressure of 3 bar at room temperature. After filtration through thin glass fibre paper and evaporation under reduced pressure, 3.87 g of the expected product are obtained in the form of a pink solid, which is used as obtained in the following step. Yield=99%.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH2:16][NH2:17])[CH:13]=[CH:14][CH:15]=1>CS(C)=O>[Cl:8][C:4]1[N:3]=[C:2]([NH:17][CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: NCc1cccc(F)c1
Reactant: Clc1cncc(Cl)n1
Solvent: CS(C)=O
Product: Fc1cccc(CNc2cncc(Cl)n2)c1
Temperature: 90 °C
Yield: 57.3 %

Procedure:
To 2,6-dichloropyrazine (175 mg, 1.175 mmol) was added DMSO (1.5 ml), TEA (0.196 ml, 1.410 mmol) and (3-fluorophenyl)methanamine (368 mg, 2.94 mmol) l. The reaction mixture then was stirred at 90° C. until completion as indicated by LCMS, about 1 hour. To the reaction mixture was added 3 ml of DMSO, filtered and the residue was purified by prep LC. After lyphilization, 160 mg of the title compound was obtained as a TFA. LCMS (m/z): 238.1 (MH+), retention time=0.96 min.
Reaction SMILES: [Na+].Br[CH2:3][CH2:4][CH2:5][S:6]([O-:9])(=[O:8])=[O:7].C[O-].[Na+].[CH2:13]([SH:16])[CH2:14][SH:15].Cl>CCO.O>[CH2:13]([S:16][CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=[O:8])=[O:7])[CH2:14][S:15][CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=[O:8])=[O:7]
Reactant: SCCS
Reactant: O=S(=O)([O-])CCCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)CCCSCCSCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromopropane sulfonic acid sodium salt (24.7 g, 110 mmol) and sodium methoxide (7.06 g, 131 mmol) in EtOH (300 mL) at ambient temperature was added, dropwise, 1,2-ethanedithiol (4.4 mL, 52.3 mmol) in ethanol (25 mL). Allowed to stir at room temperature for one hour, and then heated to reflux overnight. Cooled to room temperature and acidified with 2 N HCl to pH 1-2. The resulting suspension was heated to 75° C. and water was slowly added in small portions until a clear solution was obtained. Cooled to room temperature, and then to 5° C. The resulting white precipitate was filtered off, washed with cold EtOH and dried, giving 11.9 g (67.4%) as a white powder. 1H NMR (400 MHz, D2O) δ 3.10 (t, J=7.2 Hz, 4H), 2.92 (s, 4H), 2.82 (t, J=7.2 Hz, 4H), 2.11 (m, 4H). 13C NMR (101 MHz, D2O) δ 52.26, 33.38, 32.27, 26.80.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[O:7]
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Reactant: NCCCO
Product: O=C(NCCCO)c1cc(Br)ncc1Nc1ccc(I)cc1F

Procedure:
2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-hydroxy-propyl)-isonicotinamide was synthesized according to General method 3, starting with 145 mg (0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid and 62 mg (0.82 mmol) of 3-Amino-propan-1-ol. LC/MS: [9.15 min, 494, 496]
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1.[Li+].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:24])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate (Step B, 4 g, 13.6 mmol) in dry THF (30 ml) at −68° C. under a dry argon atmosphere was added LiHMDS drop wise (1 M solution in THF, 17.45 ml, 17.4 mmol), and the resulting orange solution was stirred at low temperature for 30 minutes before CH3I (5.71 g, 40.26 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 15 hours. The reaction was quenched with ice, and the product was extracted with EtOAc (2×), the organic phase washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ether 5:1) to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: Clc1ccc2nccc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2nccc(N3CCNCC3)c2c1
Yield: 59.4 %

Procedure:
4,6-Dichloroquinoline (De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315) (0.34 g, 1.7 mmol) and 1-tert-butoxycarbonylpiperazine (1.58 g, 8.5 mmol) are reacted according to method A. The Boc group is cleaved with trifluoroacetic acid (5 mL) in CH2Cl2 (5 mL) giving 0.25 g of the product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
138 g. (1 mole) of 4-hydroxybenzoic acid was dissolved in 1 liter of 95% ethanol and 500 ml. of 2N sodium hydroxide solution. To this solution was added 346 ml. (3 mole) of benzyl chloride and the mixture was boiled under reflux. 1 liter of 5N sodium hydroxide was added dropwise over a period of 2 hours and the mixture heated a further hour with stirring. The solvent was distilled to half its volume, 2 liters of water added, the warm aqueous solution acidified with hydrochloric acid and the precipitated product recrystallised from 80% ethanol, m.p. 188° C.
Reaction SMILES: C(S[C:9](=[O:49])[CH:10]([CH:18]1[CH:25]=[CH:24][CH2:23][CH:22]([CH:26]([NH:39]C(OC(C)(C)C)=O)[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34]C(C)(C)C)=[CH:30][CH:29]=2)[O:21][Si](C)(C)[O:19]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.N1C=CC=CC=1.[Li+].[OH-:57].OO>C1COCC1>[NH2:39][CH:26]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[CH:22]([OH:21])[CH2:23]/[CH:24]=[CH:25]\[CH:18]([OH:19])[CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:57])=[O:49]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C1CC=CC(C(Cc2ccccc2)C(=O)SCc2ccccc2)O[Si](C)(C)O1
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NC(Cc1ccc(O)cc1)C(O)C/C=C\C(O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compounds 8 were silyl deprotected in parallel with HF/pyridine in THF at 0° C. for 30 minutes according to the reported procedure. The products were purified by flash chromatography (4:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) to give the desilylated products in the following yields: (S,S,S,R) 83%, (S,S,R,R) 67%, (S,R,R,R) 85%, (S,R,S,R) 81%. To hydrolyze the thioester to the free acid, these products were dissolved in THF (40 ml/mmole) in parallel, and a 1:1 mixture of 0.2 N LiOH (aq, 4 eq.) and 30% H2O2 (aq) was added to each. The reactions were stirred at room temperature for 3 hours, then cooled to 0° C. and quenched with 2N NaHSO3 (aq, 5 mL per ml 30% H2O2). The reactions were extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to give clean 15 in the following yields: (S,S,S,R)-15 100%, (S,S,R,R)-15 96%, (S,R,R,R)-15 100%, (S,R,S,R)-15 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[CH3:11][O:12][C:13]([CH:15]1[CH2:19][CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]1)=[O:14]>C1COCC1>[CH3:11][O:12][C:13]([CH:15]1[CH2:19][CH2:18][CH:17]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:16]1)=[O:14]
Reactant: COC(=O)C1CCC(OS(C)(=O)=O)C1
Reactant: Sc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCC(Sc2ccccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chlorothiophenol (0.19 g, 1.5 eq) in THF (6.0 mL) was treated with NaH (60% dispersion in mineral oil, 0.05 g, 1.5 eq). The resulting solution was stirred at RT for 30 min. A solution of 3-methanesulfonyloxy-cyclopentanecarboxylic acid methyl ester (0.20 g, 1.0 eq) in THF (2.0 mL) was then added dropwise. The mixture was warmed at 50° C. and stirred for 3 h. The mixture was partitioned between 1N sodium bicarbonate and ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. The title compound was obtained as a colorless oil (0.24 g, 98%) and was used without further purification in the next step. MS (ESI): m/z=271.2 [M+H]+.
Reaction SMILES: C([C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([NH:19][CH:20](C)C)=[O:18])(=O)C1C=CC=CC=1.Cl.N[OH:25]>C(O)C>[NH:16]1[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:20]=[N+:19]([O-:25])[C:17]1=[O:18]
Reactant: CC(C)NC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccccc2c[n+]1[O-]

Procedure:
A stirred mixture of 6.34 g (0.02 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-isopropylurea and 4.17 g (0.06 mole) of hydroxylamine hydrochloride in 100 ml of ethanol was refluxed for 48 hr, and then cooled. The suspended crystals were collected on a filter, washed with alcohol, and then dried in air to give 4.60 g (84%) of 6-chloro-4-phenyl-(2(1H)-quinazolinone 3-oxide as yellow crystals, mp 267°-269° (dec.).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C@@H:7]([OH:21])[C@@H:8]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][C@@H:9]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.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>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[S:6][C:5]([C@@H:7]([OH:21])[C@@H:8]3[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][C@@H:9]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2ccc(F)c(Cl)c2)s1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a solution of (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenylpyrrolidin-2-one (300 mg, 0.82 mmol) in 1,2-dimethoxyethane (2.8 mL) was added 3-chloro-4-fluorobenzeneboronic acid (85.9 mg, 1.07 mmol), followed by a 1M Na2CO3 solution (2.2 mL). A catalytic amount of Pd(PPh3)4 was added and the reaction mixture was heated at the reflux temperature for 3 h, then allowed to cool to room temperature and poured onto a mixture of ice and CH2Cl2. The resulting mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated under reduced pressure. The crude product was triturated (Et2O/ cyclohexane) to give (±)-(4R*,5R*)-5-{(1S*)[5-(3-chloro-4-fluorophenyl)(2-thienyl)]hydroxymethyl}-1-methyl-4-phenylpyrrolidin-2-one (235 mg, 69%): mp 194° C.; TLC (EtOAc) Rf 0.47
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:13]2[CH:14]=[C:15]([NH2:16])[CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cccc(N)c2)cn1
Temperature: 25 °C
Yield: 76 %

Procedure:
2-methoxypyridine-5-boronic acid (0.133 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.091 g in 76% yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]([F:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]([F:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 75.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.030 g, 0.634 mmol) obtained in step 2 and methanesulfonamide (0.064 g, 0.676 mmol), the title compound (0.263 g, 75%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (74.1 mg, 65%).
Reaction SMILES: ClCCCC(C1C=CC2[N:11]([CH2:26][CH3:27])[C:12]3[C:17]([C:18]=2C=1)=CC(C(=O)CCCCl)=CC=3)=O.Cl[CH2:29][CH2:30][CH:31]([CH3:56])[C:32]([C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH2:54][CH3:55])[C:39]3[C:44]([C:45]=2[CH:46]=1)=[CH:43][C:42]([C:47](=[O:53])[CH:48]([CH3:52])[CH2:49][CH2:50]Cl)=[CH:41][CH:40]=3)=[O:33]>>[CH2:54]([N:38]1[C:37]2[CH:36]=[CH:35][C:34]([C:32](=[O:33])[CH:31]([CH3:56])[CH2:30][CH2:29][N:11]3[CH2:26][CH2:27][CH2:18][CH2:17][CH2:12]3)=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[C:42]([C:47](=[O:53])[CH:48]([CH3:52])[CH2:49][CH2:50][N:11]1[CH2:12][CH2:17][CH2:18][CH2:27][CH2:26]1)[CH:43]=2)[CH3:55]
Reactant: CCn1c2ccc(C(=O)CCCCl)cc2c2cc(C(=O)CCCCl)ccc21
Reactant: CCn1c2ccc(C(=O)C(C)CCCl)cc2c2cc(C(=O)C(C)CCCl)ccc21
Product: CCn1c2ccc(C(=O)C(C)CCN3CCCCC3)cc2c2cc(C(=O)C(C)CCN3CCCCC3)ccc21

Procedure:
Following the procedure of Example 6, only substituting for 3,6-bis(4-chlorobutyryl)-N-ethylcarbazole the appropriate molar equivalent amount of 3,6-bis(4-chloro-2-methylbutyryl)-N-ethylcarbazole, the desired product is obtained.