Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]([CH:18]=1)=[N:16][C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]=2[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(O)C.C(OCC)(=O)C.[Zn]>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:9]([C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:10]3[C:15]([NH:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COc1ccc2c(C(=O)Oc3ccccc3)c3ccccc3nc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)Nc1ccccc1C2C(=O)Oc1ccccc1
Reaction time: 2 h

Procedure:
Ammonium chloride (3.45 g, 64 mmol) and 4.2 g of zinc (64 mmol) were added to an Ar-purged suspension of 0.85 g (2.5 mmol) of the ester from step (c) in 50 mL of ethanol. The mixture was stirred for 2 h, filtered and the solids washed with CH2Cl2. The combined solutions were evaporated to dryness producing a white solid which was dissolved in ethyl acetate and washed with 3×25 mL of water. The product was used without further purification. 1H NMR (CDCl3) δ 3.76 (s, 3H), 5.29 (s, 1H), 6.47-7.36 (m, 12H), 8.21 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:11](=[O:15])[CH:12](Cl)[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH3:25])[C:21]([OH:24])=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:11](=[O:15])[CH:12]([O:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=1[CH3:25])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Cl
Reactant: Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Cl)cc1C
Yield: 78.8 %

Procedure:
25.1 g of diethyl-2-chloro-propionyl-malonate and 14.2 g of 4-chloro-o-cresol are dissolved in 100 ml dimethyl formamide. The mixture is stirred at 60° C. for 48 hours in the presence of 13.8 g of potassium carbonate. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in 100 ml of benzene and washed successively with 100 ml of a saturated aqueous sodium bicarbonate solution and 100 ml of water. The benzene phase is evaporated to yield 28 g of the desired compound, yield 80%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: OB(O)c1ccc(F)cc1
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: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 90 °C
Reaction time: 17 h
Yield: 65.2 %

Procedure:
Step 1 A mixture of 6-bromo-1H-indole (0.25 g, 1.275 mmol), 4-fluorophenylboronic acid (0.178 g, 1.275 mmol), and 2 M aqueous sodium carbonate (2.0 mL, 4.00 mmol) in toluene (10 mL) and ethanol (2.500 mL) was purged with argon and treated with tetrakis(triphenylphosphine)palladium (0.074 g, 0.064 mmol). The mixture was heated at 90° C. After 17 h, the mixture was cooled to rt and partitioned between water and EtOAc. The organic phase was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 60:40 hexane-EtOAc) to provide 6-(4-fluorophenyl)-1H-indole as a white solid (175.5 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 11.17 (1H, br. s.), 7.65-7.71 (2H, m), 7.56-7.62 (2H, m), 7.37 (1H, t, J=2.9 Hz), 7.22-7.31 (3H, m), 6.44 (1H, t, J=2.0 Hz). Mass spectrum m/z 212.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[C:4]([C:15]([Cl:18])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].ClCCl.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>>[Cl:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([F:19])[C:2]([N:1]([S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])[S:26]([CH2:23][CH2:24][CH3:25])(=[O:28])=[O:27])=[CH:17][CH:16]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(Cl)c(C(=O)OCc2ccccc2)c1F)S(=O)(=O)CCC
Temperature: 0 °C
Yield: 72.7 %

Procedure:
Benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 15.37 mmol) was dissolved in dry dichloromethane (270 mL) Triethylamine (5.36 mL, 2.5 eq.) was added, and the mixture was chilled to 0° C. Propane-1-sulfonyl chloride (3.63 mL, 32.3 mmol, 2.1 eq.) was then added via syringe, and a precipitate resulted. Once the addition was complete, the mixture was allowed to warm to room temperature, and the starting material was consumed as determined by TLC (3:1 hexane:ethyl acetate). The mixture was then diluted with dichloromethane (200 mL), washed with 2M aqueous HCl (2×100 mL), saturated Na2HCO3 solution, dried over sodium sulfate and concentrated. The resulting residue was purified on a 65 Biotage chromatography system (40% ethyl acetate/hexane) to produce benzyl 6-chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (5.5 g, 72%) as an oil that slowly solidified upon standing. NMR (CDCl3, 400 MHz) δ 7.28-7.45 (m, 7H), 5.42 (s, 2H), 3.58-3.66 (m, 2H), 3.43-3.52 (m, 2H), 1.08 (t, 6H, J=8).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.[CH2:28]([OH:32])[CH2:29][CH:30]=[CH2:31]>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21](/[CH:31]=[CH:30]/[CH2:29][CH2:28][OH:32])=[CH:22][CH:23]=1
Reactant: C=CCCO
Reactant: Clc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCC/C=C/c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 52 %

Procedure:
To a suspension of triphenyl phosphine (2.1 g, 8.0 mmole) in 300 ml of triethylamine and 30 ml of acetonitrile under nitrogen is added successively palladium (II) acetate (0.45 g, 2.0 mmole), 1-bromo-4-chlorobenzene (19.1 g, 110 mmole) and 3-buten-1-ol (7.21 g, 100 mmole) in a pressure tube. The tube is sealed and heated in an oil bath to 100° C. for 24 hr. The tube is opened under nitrogen, charged with additional palladium (II) acetate, resealed and heated 20 hr longer at 100°-120° C. The mixture is cooled, vented to nitrogen and partitioned between 300 ml of 2N hydrochloric acid and ether. The layers are separated and the aqueous layer is extracted with two additional volumes of ether. The combined ether extracts are washed with 2×100 ml portions of 2N hydrochloric acid and then dried over sodium sulfate. The filtered ether extract is concentrated under vacuum to give 12.7 g of crude product which is purified by chromatography on silica gel using toluene eluent. There is obtained 9.5 g of the title compound. Rf =0.77 (silica gel, toluene).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)(=[O:8])=[O:7].[NH2:16][C:17]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[CH3:18].CCN(CC)CC>CC#N>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([C:17]([NH:16][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)(=[O:8])=[O:7])([C:19]2[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=2)[CH3:18])=[CH:26][C:27]=1[F:33])#[N:30]
Reactant: O=S(=O)(NCCCBr)c1cccc(O)c1
Reactant: Cn1cncc1C(C)(N)c1ccc(C#N)c(F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1cncc1C(C)(NCCCNS(=O)(=O)c1cccc(O)c1)c1ccc(C#N)c(F)c1

Procedure:
N-(3-Bromo-propyl)-3-hydroxy-benzenesulfonamide (0.23 g, 0.782 mmol), (+)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrile (Example 1, Step I) (0.191 g, 0.78 mmol), and Et3N (0.218 mL, 1.56 mmol) were dissolved in CH3CN (5 mL) and heated at reflux for 16 h. The reaction mixture was concentrated in vacuo, azeotroped with toluene, and dried to give the title compound. MS (M+1) 458.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1cccc(F)c1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1c(F)cccc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,6-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].Cl.[CH3:12]O>O1CCOCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([O:10][CH3:12])=[O:9]
Reactant: CO
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCCC[C@@H]1N

Procedure:
To a solution of (1R,2S)-2-aminocyclohexanecarboxylic acid (0.13 g, 0.91 mmol) in methanol (5 mL) was added 4N HCl in dioxane (1 mL) and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to afford an oil which was used directly for the next step.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1([CH2:34][CH2:35][O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[S:12][C:11]2[CH:13]=[C:14]3[S:18][C:17]([CH2:26][CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH2:19][CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16][C:15]3=[CH:33][C:10]=2[S:9]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[I:46]I.S(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1>[C:29]([O:28][CH2:27][CH2:26][C:17]1([CH2:19][CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:18][C:14]2[C:13]([I:46])=[C:11]3[S:12][C:8]([CH2:34][CH2:35][O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([CH2:7][CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[S:9][C:10]3=[CH:33][C:15]=2[S:16]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OCCC1(CCOC(C)(C)C)Sc2cc3c(cc2S1)SC(CCOC(C)(C)C)(CCOC(C)(C)C)S3
Reactant: II
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OCCC1(CCOC(C)(C)C)Sc2cc3c(c(I)c2S1)SC(CCOC(C)(C)C)(CCOC(C)(C)C)S3
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A dry flask under argon was charged with 2,2,6,6-tetra(t-butoxyethyl)benzo[1,2-d:4,5-d']bis(1,3)dithiole (60.0 g, 95.08 mmol) and dry tetrahydrofuran (2000 ml). The mixture was cooled to -20° C. and n-Butyl lithium (76 ml of a 2.5M solution in hexane, 0.19 mol) was added over 3 minutes. The mixture was stirred for 20 minutes at -20° C. and then a solution of iodine (120 g, 0.475 mol) in tetrahydrofuran (500 ml) was added. The reaction mixture was poured into an aqueous sodium bisulphite solution and extracted with diethyl ether. The organic phase was washed once with an aqueous solution of sodium bisulphite and once with brine, dried (MgSO4) and evaporated. The product was purified by chromatography on silica gel using a mixture of CH2Cl2 and ethyl acetate as the eluent. Yield: 36.7 g (51 i).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)[CH3:2].Br[C:17]1[CH:22]=[CH:21][N:20]=[N:19][CH:18]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[N:19]1[CH:18]=[CH:17][C:22]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:7][CH:8]=2)=[CH:21][N:20]=1
Reactant: CCOC(=O)Cc1ccc(B(O)O)cc1
Reactant: Brc1ccnnc1
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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccnnc2)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 4-(2-ethoxy-2-oxoethyl)phenylboronic acid 37-2 (310 mg, 1.5 mmol), 4-bromopyridazine 37-1 (158 mg, 1 mmol), Pd(PPh3)4 (70 mg, 0.1 mmol), toluene (4 mL), ethanol (1 mL) and 2M Na2CO3 (1.5 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooled down to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution and brine. The organic phase was dried over Na2SO4 and then concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give ethyl 2-(4-(pyridazin-4-yl)phenyl)acetate 37-3 as pale yellow solid. MS m/z 243.1 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=3.C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:84]1[CH2:89][CH2:88][O:87][CH2:86][CH2:85]1>>[O:87]1[CH2:88][CH2:89][N:84]([C:2]2[CH:3]=[C:4]([F:24])[C:5]3[N:6]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:7]4[C:12]([S:13][C:14]=3[CH:15]=2)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=4)[CH2:85][CH2:86]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1c2ccc(Br)cc2Sc2cc(Br)cc(F)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1c2ccc(Br)cc2Sc2cc(N3CCOCC3)cc(F)c21

Procedure:
To a stirred solution of 3,7-dibromo-1-fluoro-10-Boc-phenothiazine (8) (290 mg, 0.6 mmol) in toluene (10 mL) Pd(dba)2 (17.3 mg, 0.03 mmol), BINAP (13.5 mg, 0.02 mmol), Cs2CO3 (390 mg, 1.2 mmol) and morpholine (70 mg, 0.8 mmol) were added. The mixture was refluxed for 24 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:25])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(CCc1ccccc1)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-phenylpropanamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and hydrocinnamoyl chloride in a similar manner as described above to give a white solid (53% yield). 1H-NMR (CDCl3): δ 8.43 (s, 1H), 7.58 (m, 1H), 7.28-7.21 (m, 5H), 7.20-7.15 (m, 2H), 5.51 (d, 1H), 5.05 (m, 1H), 3.00 (t, 2H), 2.62 (m, 2H), 2.58-2.43 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.67 (m, 1H); MS m/z 397 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: O=C(Cc1ccc(F)cc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 23.1 %

Procedure:
Example 4 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (4-fluorophenyl)acetic acid (0.031 g) to give thetitle compound (0.019 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH2:18]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH2:17][CH:16]([O:19][CH3:20])[O:15][CH3:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COC(CN)OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(CNc1ccc(Br)cn1)OC

Procedure:
After 50 g of 2,5-dibromopyridine and 50 mL aminoacetaldehyde dimethyl acetal were heated at 130° C. for 8 hours, an aqueous saturated sodium bicarbonate solution was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane), to give 23.53 g of the title compound (pale yellow oil).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[CH2:37]([O:36][C:34]([CH:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:35])[CH3:38]
Reactant: O=C(OCc1ccccc1)n1ccc2c(O)cccc21
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1cccc2c1ccn2C(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
The indole 11 (10.69 g, 40 mmol) was added to a suspension of anhydrous potassium carbonate (8.29 g, 60 mmol) in acetone (400 mL) and the mixture was stirred at room temperature for 15 min. Diethyl bromomalonate (11.47 g, 48 mmol) was added and the mixture was heated under reflux for 17 h. The solid was filtered off and washed with acetone and the combined filtrates were evaporated. The residue was dissolved in diethyl ether (150 mL), washed with 0.5 M aq. sodium hydroxide and brine, dried and evaporated to a brown viscous oil (16.87 g). After trituration with diethyl ether, the precipitated white solid was filtered off and the filtrate was evaporated. The residue was flash chromatographed [ethyl acetate-hexanes (15:85)] to give more solid and the combined solids were recrystallised to give 12 as white crystals (13.83 g, 81%), mp 77-78° C. (from ethyl acetate-hexanes); 1H NMR (500 MHz) δ 7.86-7.92 (br d, 1H), 7.57 (d, J=3.7 Hz, 1H), 7.47-7.49 (m, 2H), 7.36-7.43 (m, 3H), 7.20 (t, J=8.1 Hz, 1H), 6.86 (d, J=3.9 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 5.45 (s, 2H), 5.30 (s, 1H), 4.29-4.37 (m, 4H), 1.30 (t, J=7.1 Hz, 6H). Anal. Calcd for C23H23NO7: C, 64.93; H, 5.45; N, 3.29. Found: C, 65.06; H, 5.64; N, 3.21.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:43]1([C:49](=[O:57])[CH2:50][N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:54]3[CH2:53][CH2:52][N:51]([CH2:50][C:49]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[O:57])[CH2:56][CH2:55]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (7.967 g, 15.03 mmol, example 11) in methylene chloride (60 mL) cooled to 0° C. were added triethylamine (4.19 mL) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (3.366 g, 15.78 mmol, Oakwood Products), respectively. The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min. The reaction was monitored by thin layer chromatography (silica gel, 20% ethyl acetate in hexane). The reaction mixture was concentrated to dryness, and the crude residue was purified by flash column chromatography (silica gel, eluting with 0.1% triethylamine in ethyl acetate) to give 2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone as white foam. The white foam was taken in 100 ml of ethyl acetate then filtered. Hydrogen chloride (18.04 mL, 1 M solution in diethyl ether) was added dropwise to the filtrate. The white solids formed were filtered off and dried in vacuo to give 2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride (9.3 g). HR-MS (ES, m/z) calculated for C38H46N5O4Cl2 [(M+H)+] 706.2922, observed 706.2917.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]=1>C(O)C>[ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: COC1=NCCCCC1
Agent: Cl
Solvent: CCO
Product: c1ccc([C@H]2CCC[C@H]2N=C2CCCCCN2)cc1
Reaction time: 144 h

Procedure:
A mixture of 4.0 g of cis-2-phenylcyclopentylamine hydrochloride, M.P. 205°-206° C and 5.0 ml of O-methylcaprolactim is allowed to stand at room temperature for 6 days with occasional stirring. A few drops of ethanol are added to maintain a stirrable slurry, after which the mixture is cooled. The resulting solid is washed with ether and recrystallized from acetone/methanol to give the desired product, M.P. 181.5°-183.5° C (dec.).
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=O)/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1(/[CH:11]=[CH:10]/[CH:9]=[N+:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O-:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: ONc1ccccc1
Solvent: CCO
Product: [O-][N+](=C/C=C/c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 9 h
Yield: 77.2 %

Procedure:
According to the literature procedure (Utzinger et al. Helv. Chim. Acta 1954, 37, 1892; incorporated herein by reference) N-phenyl-hydroxylamine (188.7 mg, 1.7 mmol, 1.0 equiv) was added to a solution of (E)-cinnamaldehyde (218 μL, 1.73 mmol, 1 equiv) in ethanol (1.5 mL, absolute). The bright yellow solution was stirred for 9 h at 23° C. in the dark, and then was cooled in an ice bath. The cooled, heterogeneous solution was filtered and the filter cake was washed once with hexanes (10 mL). The filter cake was dried in vacuo overnight, furnishing α-(trans-2-phenyl-ethenyl)-N-phenylnitrone (293 mg, 76%, yellow solid) mp=150-152° C. (lit. 150-151° C.). 1H NMR data were in accord with that previously reported.