Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[CH2:16][CH2:17][F:18].[H-].[Na+]>CN(C=O)C.CCOC(C)=O.O>[F:18][CH2:17][CH2:16][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CCF)CC1
Temperature: 50 °C
Yield: 85.3 %

Procedure:
To a stirred mixture of tert-butyl piperidin-4-ylcarbamate (1.00 g, 5.0 mmol) and 1-bromo-2-fluoroethane (0.952 g, 7.50 mmol) in DMF (10 mL) was added NaH (0.180 g, 7.50 mmol) at ambient temperature. The mixture was heated to 50° C. for 18 hours under N2. After cooling to ambient temperature, the mixture was diluted with EtOAc and water. The phases were separated, and the organic phase was washed with water, brine, dried (Na2SO4), filtered, and concentrated. The product was obtained as a waxy solid (1.05 g, 84%).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccncc2N)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1N1CCNCC1
Yield: 25 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid and tert-butyl 4-(3-aminopyridin-4-yl)piperazine-1-carboxylate. Obtained the desired product as a white solid (27.0 mg, 25%). prepared 1H NMR (400 MHz, DMSO) δ 9.29 (d, J=11.1, 1H), 8.86 (s, 1H), 8.31 (d, J=5.6, 1H), 7.71 (s, 2H), 7.64-7.52 (m, 1H), 7.30 (t, J=8.8, 3H), 3.26 (s, 8H). ESIMS m/z=417.4 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].O>CS(C)=O>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][N:1]=[N+:2]=[N-:3]
Reactant: COC(=O)CCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Add sodium azide (12.5 g, 193 mmol) to a rapidly stirred solution of methyl 5-bromovalerate (25.08 g, 129 mmol) in DMSO (200 mL, anhydrous). Stir at room temperature overnight under N2. Add water (400 mL) and stir for 30 minutes. Extract with Et2O (×3) and wash combined Et2O layers with brine (×3). Dry organic layer over MgSO4 and concentrate to give the title compound (20.3 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.C1(C)C(C)=CC=CC=1.P.[OH-].[Na+]>Cl[Pd]Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: Cl[Pd]Cl
Agent: P
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Nc1cc(Cl)ccc1O

Procedure:
A degassed solution of 10 mmol of 5-chloro-2-hydroxynitrobenzene (starting material) and 40 ml of xylene are placed in an autoclave (volume: 200 ml).0.125 mmol of BINAS (in the form of 0.72 g of an aqueous solution containing 0.173 mol of BINAS/kg of solution) as phosphine and 0.6 g (15 mmol) of NaOH, 41 ml of H2O and 0.25 mmol of PdCl2 are added. The pH is from 10 to 11.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]([C:19](=O)[CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=O)=[CH:7][CH:6]=1.O>C(O)C>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:19]([CH3:20])=[N:2][NH:3][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: COC(=O)Cc1c(C)n[nH]c1-c1ccc(Cl)cc1

Procedure:
2.236 g (45 mmol) of hydrazine hydrate were added to a solution of 10 g (37 mmol) of methyl 3-[(4-chlorophenyl)carbonyl]-4-oxopentanoate in ethanol (100 ml). The mixture was heated under reflux for 6 hours and then added to water and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and concentrated. This gave 6.9 g of product (63% of theory).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([CH2:15][CH3:16])[C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4].O[Li].O>C1COCC1.O>[Br:14][C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[N:8][N:9]([CH2:15][CH3:16])[C:10]=2[CH:11]=1
Reactant: CCn1ncc2c(C(=O)OC)cc(Br)cc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a stirred solution of 6-bromo-1-ethyl-1H-indazole-4-carboxylic acid methyl ester (700 mg, 2.47 mmol) in THF (35 mL) was added a solution of LiOH.H2O (312 mg, 7.42 mmol) in water (15 mL) and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and washed with EtOAc (2×25 mL). The aqueous layer was acidified (pH ˜5) with 1N HCl. The precipitated solid was collected by filtration and dried to furnish 6-bromo-1-ethyl-1H-indazole-4-carboxylic acid as a white solid (450 mg, 68%).
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:17]([O:10][CH:7]1[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4][C:3]([CH2:1][CH3:2])([CH3:14])[CH:8]1[CH3:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1(C)CC(OCc2ccccc2)C(C)C(C)(CC)N1
Yield: 48.3 %

Procedure:
To a solution of 3.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidinol (Compound 1) in 30 ml of dry toluene was added, at 0°-5° C., 0.65 g of sodium hydride (purity 52.9%). The mixture was refluxed by heating for 6 hours. After cooling the mixture, 1.9 g of benzyl chloride were added dropwise at 0°-5° C. and the resulting mixture was refluxed by heating for 4 hours. The reaction mixture was then washed with water and dried over anhydrous magnesium sulphate; the solvent was then distilled off. The residue was purified by column chromatography on silica gel using benzene as eluent, followed by distillation under reduced pressure. There were obtained 2.1 g of Compound 95 as a pale yellow oil (bp 120°-124° C./0.2 mmHg).
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:34]=[C:33]([CH3:35])[C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([OH:32])=[C:22]([CH:31]=2)[C:23]([N:25]([CH:27]2[CH2:30][CH2:29][CH2:28]2)[CH3:26])=[O:24])=[C:15]([CH3:36])[CH:14]=1)=[O:11])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH:27]1([N:25]([CH3:26])[C:23](=[O:24])[C:22]2[CH:31]=[C:18]([O:17][C:16]3[C:15]([CH3:36])=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][OH:8])=[CH:34][C:33]=3[CH3:35])[CH:19]=[CH:20][C:21]=2[OH:32])[CH2:30][CH2:29][CH2:28]1
Reactant: Cc1cc(NC(=O)COCc2ccccc2)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)CO)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Reaction time: 2 h

Procedure:
To a solution of 5-[4-(2-benzyloxy-acetylamino)-2,6-dimethyl-phenoxy]-N-cyclobutyl-2-hydroxy-N-methyl -benzamide (50 mg) in EtOAc (2.0 mL) was added catalyst 10% Pd/C (10 mg). The reaction mixture was hydrogenated under 50 psi at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated to give the title compound of Step B and Example 9 (40 mg) as a white solid. MS (APCl−) Calc.: 398.2, Found: 397.2 (M−1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[C:11]2=[O:28])[CH:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([N:12]2[C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[N:10]([CH2:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH:2][C:33]4[CH:32]=[N:31][C:30]([Cl:29])=[CH:35][CH:34]=4)[CH:8]=3)[C:11]2=[O:28])=[CH:23][CH:22]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Clc1ccc(I)cn1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)c3)C(C)(C)C2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4ccc(Cl)nc4)c3)C(C)(C)C2=O)cc1
Temperature: 90 °C

Procedure:
To a solution of 0.5 g of 1-[(2-aminopyridin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione hydrochloride obtained in stage c) of Example 7 in 35 mL of dioxane are successively added under argon 0.39 g of 2-chloro-5-iodopyridine, 1.8 g of caesium carbonate, 947 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (xantphos) and 30 mg of palladium diacetate. The reaction mixture is heated at 90° C. for 3 hours and then filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of cyclohexane and ethyl acetate (62/38 by volume) to give 0.368 g of 3-(4-tert-butylphenyl)-1-({2-[(6-chloropyridin-3-yl)amino]pyridin-4-yl}methyl)-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:37]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[CH:36][C:35]([F:52])=[CH:34][C:33]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].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.C(Cl)Cl.CO>[C:27]([O:30][CH2:31][C:32]1[C:37]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[CH:36][C:35]([F:52])=[CH:34][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
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: CO
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 130 °C
Yield: 69.1 %

Procedure:
Following Example 121b, 264c (210 mg, 0.5 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (242 mg, 0.5 mmol), 1M sodium carbonate solution (2 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and 1,2-dimethoxyethane (5 mL) were heated at 130° C. for 15 minutes in the microwave reactor. Work-up and flash column chromatography (silica, 9:1 methylene chloride/methanol) gave a 69% yield (240 mg) of 265a as brown oil: MS (ESI+) m/z 695.5 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[C:14]1([C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 27 %

Procedure:
A solution of glutaryl chloride (10 mmol, 1.3 mL) dissolved in anhydrous dichloromethane (20 mL) is introduced into a 100 mL two-necked round-bottomed flask under an inert atmosphere. Aluminum chloride (30 mmol, 4.00 g) is added to the mixture, which immediately turns orange-yellow. A solution of benzene (20 mmol, 1.8 mL) dissolved in anhydrous dichloromethane (10 mL) is added dropwise at room temperature. The solution becomes bright red. The mixture is then refluxed for 24 hours, and turns brown-black. The mixture is then cooled to room temperature and poured into a crystallizing basin containing 20 mL of 10% acidified water, with stirring. A black solid forms, and is filtered off on a Büchner funnel. The yellow organic phase is then extracted with ethyl acetate, dried over MgSO4, filtered, concentrated on a rotary evaporator and recrystallized from 20 mL of methanol. The product obtained is a white solid in a mass of 680 mg. The reaction yield is 27%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]1[CH3:37]>C(#N)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:24][CH2:25][N:26]4[C:35](=[O:36])[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][CH:27]4[CH3:37])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2ccccc2c(=O)n1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1Nc2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2 mmol), K2CO3 (3.76 g, 27.2 mmol) and 3-(2-chloroethyl)-2-methyl-3H-4-quinazolinone (6.0 g, 27 mmol) in acetonitrile (300 ml) was heated at reflux for 16 hours. The reaction was complete as judged by TLC. The solids were filtered and the solvent was evaporated. The residue was purified over a flash chromatography column (SiO2, 75 gm, eluted with dichloromethane and MeOH in dichloromethane). The pure product thus obtained weighed 6.5 gm. Recrystallization from ethanol yielded white crystals, 3.94 gm (53%), m.p. 164°-165° C. This material appeared pure by TLC over silica gel plates.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N>C(N(CC)CC)C.[Cu]I>[C:11]1([C:17]#[C:18][C:2]2[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: N#CCc1ccc(C#Cc2ccccc2)cc1

Procedure:
A mixture of 49 g (0.25 mol) 4-bromobenzylcyanide, 30 g (0.3 mol) phenylacetylene, 0.1 g di(triphenylphosphine)-palladium(II-dichloride, 0.1 g copper(I)iodide and 0.2 g triphenylphosphine in 300 ml triethylamine are heated for 20 hours under a blanket of N2 and vigorously stirred. The mixture is then evaporated under water jet vacuum, the residue heated in hexane and the undissolved solid sucked off and dried. The thus obtained title compound is employed as such in the following reaction step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[C:11]([CH3:12])=[CH:10][S:9][C:4]=2[CH:3]=1
Reactant: CC(=O)CSc1ccc(F)c(Br)c1
Solvent: Cc1ccccc1
Product: Cc1csc2cc(Br)c(F)cc12
Yield: 71.3 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 24 for the preparation of I-24b above, 1-(3-bromo-4-fluoro-phenylsulfanyl)-propan-2-one (I-29a: 2.1 g, 8.015 mmol) in toluene (10 mL) was cyclized with polyphosphoric acid (8 g) to yield crude product which was purified by column chromatography on silica gel (100% hexane) to afford 1.4 g of product (72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:16].C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11](=[CH:22][N:23]([CH3:25])[CH3:24])[C:10]1=[O:16]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCCC1c1cc(Cl)ccc1Cl
Product: CN(C)C=C1CCCCC(c2cc(Cl)ccc2Cl)C1=O

Procedure:
2-(2,5-Dichloro-phenyl)-cycloheptanone (157 mg, 0.61 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (197 mg) as a red solid which was used directly in the next step. MS ISP (m/e): 312.0 [(M+H)+].
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[F:13])[NH2:9].C([O:16][C:17]([C:19]1[N:20]=[C:21]([Br:37])[N:22]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[C:23]=1[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[OH:25])=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[Cl:5][C:6]1[CH:7]=[C:8]([NH:9][C:17]([C:19]2[N:20]=[C:21]([Br:37])[N:22]([CH:33]3[CH2:34][CH2:35][CH2:36]3)[C:23]=2[CH:24]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[OH:25])=[O:16])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1nc(Br)n(C2CCC2)c1C(O)c1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nc(Br)n(C2CCC2)c1C(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirred solution of trimethylaluminium (2M in toluene) (0.87 ml, 1.74 mmol) was added drop wise the solution of 3-chloro-4-fluoroaniline (0.267 g, 1.80 mmol) and toluene (2.0 ml) at 0° C. and then the temperature was raised to rt. The mixture was concentrated. 2-bromo-5[(4-chloro-phenyl)-hydroxyl-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester (step AK2; 0.502 g, 1.20 mol) in toluene (6.0 ml) was added and the mixture was stirred for 3 h at 80° C., then cooled to rt. The reaction mixture was taken up in Teac (40 ml), poured onto “Rochelle Salt-Solution” (1M in water) and stirred for 15 min at rt. The organic phase was washed with brine and dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (EtOAc/hexane, 1:4), then triturated in hexane to afford the title compound. tR: 1.46 min (LC-MS 2); ESI-MS: 514.1 [M+H]+ (LC-MS 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Mg].[CH:13]1[C:34]2[C:17](=[CH:18][C:19]3[C:20](=O)[C:21]4[C:30](C(=O)[C:32]=3[CH:33]=2)=[CH:29]C2[C:23](=[CH:24][CH:25]=CC=2)[CH:22]=4)[CH:16]=[CH:15][CH:14]=1.[I-].[K+]>O1CCCC1.C(O)(=O)C>[CH2:25]([C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:7]3[C:2](=[CH:3][C:4]4[C:5]([CH:6]=3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:13]([C:34]3[CH:33]=[CH:32][C:19]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:17]=3)=[C:18]3[C:19]=2[CH:32]=[C:33]2[C:34](=[CH:17]3)[CH:13]=[CH:14][CH:15]=[CH:16]2)=[CH:30][CH:29]=1)[CH2:16][CH2:15][CH3:14]
Reactant: CCCCc1ccc(Br)cc1
Reactant: O=C1c2cc3ccccc3cc2C(=O)c2cc3ccccc3cc21
Agent: [I-]
Agent: [K+]
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2c3cc4ccccc4cc3c(-c3ccc(CCCC)cc3)c3cc4ccccc4cc23)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
6,13-bis(4-butylphenyl)pentacene was synthesized as follows. A solution of 1-bromo-4-butylbenzene (about 5.09 grams, about 32.40 mmol) in about 20 milliliters of anhydrous tetrahydrofuran (THF) was added over a period of about 1 hour to a stirred suspension of magnesium turnings (about 0.79 grams, about 32.40 mmol) in about 10 milliliters of THF in a 250 milliliter round-bottomed flask under an inert argon atmosphere. The resultant mixture was stirred at about 60° C. for about 2 hours. A solution of 6,13-pentacenequinone (about 1.0 grams, about 3.24 mmol) in about 20 milliliters of THF was added and the resulting mixture was stirred at about 60° C. for about 2 hours. Subsequently, the reaction mixture was cooled to about 22° C. to about 25° C. and quenched with ice. The reaction mixture was extracted with toluene and the organic layer was separated and dried with anhydrous magnesium sulfate (MgSO4). The solvent was removed and a solution of potassium iodide (KI) (about 2.00 grams, about 12.0 mmol) in about 50 milliliters acetic acid (AcOH) was added to the solid residue. The resultant mixture was then refluxed for about 1 hour and then cooled to about 22° C. to about 25° C. A purple precipitate, obtained after filtration, was washed with water and methanol, yielding about 0.83 grams of 6,13-bis(4-butylphenyl)pentacene as a dark purple solid (about 47% yield). Further purification was conducted by sublimation. An overview of this process is set forth below in Scheme 1.
Reaction SMILES: [OH-].[Na+:2].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].[CH3:16]I.Cl>CO>[O:14]=[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:16])[C:11]([O-:13])=[O:12].[Na+:2]
Reactant: CI
Reactant: O=C([O-])C(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)C(=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 2N aqueous solution of sodium hydroxide (10 ml, 20 mmoles) and 30 ml of methanol were added to 3.92 g (20 mmoles) of sodium phenylpyruvate to form a solution. Then, 1.25 ml of methyl iodide was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with 150 ml of ether. The ether layer was dried over magnesium sulfate, and concentrated under reduced pressure to give a pale yellowish white oil. A 3N aqueous solution of sodium hydroxide (6.5 ml) was added, and the mixture was concentrated. Ether was added to the resulting semi-solid mixture, and the precipitated sodium 2-oxo-3-phenylbutanoate was isolated by filtration as a white solid (1.62 g, yield 85 %).
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:12]=1)[CH:10]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:10]=[CH:14][C:15](=[O:16])[CH3:17])[CH:12]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(Cl)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(Cl)ccc1C
Reaction time: 1 h

Procedure:
To a mixture of acetone (80 ml), sodium hydroxide (1.2 g) and water (80 ml) was added dropwise at 0° C. a solution of 5-chloro-2-methylbenzaldehyde (4.1 g) in acetone (10 ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(5-chloro-2-methylphenyl)-3-buten-2-one (5.5 g) as oil.