Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:7]1[CH:8]=[CH:9][C:10]([CH:13](O)[CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[N:11][CH:12]=1)[CH3:6].O>C(Cl)(Cl)Cl>[Br:2][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:5][CH3:6])=[CH:12][N:11]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: BrP(Br)Br
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1ccc(C(Br)COc2ccc(C=O)cc2)nc1
Yield: 89.8 %

Procedure:
2.93 g (0.01 mol) PBr3 was added to a solution of 5 g (0.018 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde dissolved in 50 mL chloroform at 55-60° C. Reaction mixture was refluxed for 1 hr. Progress of the reaction was monitored by TLC and after completion of reaction, subsequent work-up in alkaline water furnished 3 g (50%) of desired product.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH2:23][OH:24])[C:15]1=[O:25].N1C=CC=CC=1>ClCCl>[C:1]([O:24][CH2:23][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH2:13][CH2:12][CH2:11][Cl:10])[C:15]1=[O:25])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: O=c1n(CO)c2ccccc2n1CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCC(=O)OCn1c(=O)n(CCCCl)c2ccccc21
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Heptanoyl chloride (0.64 mL, 4.15 mmol) was added dropwise at 0° C. to 1-(3-chloropropyl)-3-(hydroxymethyl)-1H-benzo[d]imidazol-2(3H)-one (1.00 g, 4.15 mmol) and pyridine (0.50 mL, 6.23 mmol) in dichloromethane (20 mL) and then allowed to warm to room temperature. The mixture was washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (30% ethyl acetate/hexanes) to give product as an oil (1.35 g, 92%); NMR (DMSO-d6); δ0.80 (t, J=6.8 Hz, 3H); 1.15-1.19 (m, 6H); 1.46-1.49 (m, 2H); 2.08-2.12 (m, 2H); 2.30 (t, J=7.2 Hz, 2H); 3.67 (t, J=6.4 Hz, 2H); 3.97 (t, J=6.8 Hz, 2H); 5.88 (s, 2H); 7.10-7.16 (m, 2H); 7.24-7.29 (m, 2H); MS for C18H25ClN2O3 m/z 353 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([N:63]4[CH2:68][CH2:67][O:66][CH2:65][CH2:64]4)=[O:27])=[CH:22][N:21]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: C1COCCN1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)N2CCOCC2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.40 g), 1-hydroxybenzotriazole monohydrate (0.17 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g), morpholine (0.10 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-((2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoyl)morpholine as yellow crystals (0.41 g, yield 91%). Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 180-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[F:8].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:19]=[O:20]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:8])=[CH:4][N:5]=[CH:6][C:7]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Fc1cnccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cncc(F)c1Cl
Temperature: -78 °C
Reaction time: 5 h

Procedure:
4-Chloro-3-fluoropyridine (1 g) was dissolved in tetrahydrofuran (15 ml), and the solution was then cooled to −78° C. Lithium diisopropylamide (1.1 M solution in tetrahydrofuran and n-hexane, 7.6 ml) was added dropwise thereto, and the mixture was stirred at the same temperature as above for 5 hours. Then, N,N-dimethylformamide (1 ml) was added thereto, and the mixture was further stirred for 30 minutes while being heated to room temperature. Saturated saline was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate) to obtain the title compound (521 mg).
Reaction SMILES: [C:1]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].FC(F)(F)S(O)(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH:3]([CH3:4])[CH2:2][C:1]([N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])=[O:5])=[CH:24][CH:23]=1
Reactant: COc1ccc(N)cc1
Reactant: C/C=C/C(=O)N1CCOC1=O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(NC(C)CC(=O)N2CCOC2=O)cc1
Yield: 92 %

Procedure:
In a stream of nitrogen, a solution of 3-crotonoyl-1,3-oxazolidin-2-one (78 mg, 0.5 mmol), anisidine trifluoromethanesulfonate (205 mg, 0.75 mmol) and Pd((R)-binap)(μ-OH)]2(OTf)2 (4.6 mg, 0.0025 mmol) in tetrahydrofuran (0.5 mL) was stirred at room temperatures for 12 hours. When no starting material remained was observed, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective 3-[3-(4-methoxyphenylamino)butyryl]-1,3-oxazolidin-2-one (128 mg, 92% yield). The enantiomeric excess ratio was determined to be 98% e.e. by a liquid chromatography with an optical isomer separating column (column: AD-H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=1.[NH2:34][CH2:35][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[OH:37][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccn3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(2-pyridinyl)benzoic acid, and (1S)-2-amino-1-phenylethanol, the title compound was obtained in 69% purity by HPLC. MS(ESI+): m/z=459.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[C:16]([O:20][CH3:21])(=[O:19])[C:17]#[CH:18].Cl>C1COCC1.O.C(OCC)(=O)C>[CH3:21][O:20][C:16]([C:17]1[NH:7][N:6]=[C:5]([Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:18]=1)=[O:19]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C#CC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([Si](C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.2 %

Procedure:
Place trimethylsilyl-diazomethane (2 M in THF) (25 mL, 50 mmol) in THF (50 mL). Cool the reaction to −78° C. and add lithium diisopropylamide (2 M in THF) (25 mL, 50 mmol) over 30 min. Add methyl propiolate (4.45 mL, 50 mmol) and stir at −78° C. for 2 hours. Warm to room temperature and stir for 18 hours. Add ethyl acetate, water, and 1 N HCl. Separate organic layer and extract aqueous with ethyl acetate (2×25 mL). Combine organic extracts, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 0-60% EtOAc:hexane to yield 3.59 g (36%) of 5-trimethylsilanyl-2H-pyrazole-3-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([CH2:25][NH2:26])=[N:3]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:13]=2)=[N:5][C:4]([CH2:25][NH:26][S:28]([CH3:27])(=[O:30])=[O:29])=[N:3]1
Reactant: Cn1nc(CN)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cn1nc(CNS(C)(=O)=O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 23 %

Procedure:
A solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanamine (0.5 g) and methane sulphonyl chloride (0.16 g) in pyridine (25 ml) was stirred at room temperature for 18 h. The solution was evaporated to give a brown oil which was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80°) to give the title compound (0.14 g) as a white powder, m.p. 117°-118°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[C:22](Br)=[N:21][C:20]([Br:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:12][C:13]1[C:22]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[N:21][C:20]([Br:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: OCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc(CO)cc2)c1N
Yield: 45.7 %

Procedure:
A mixture of 4-(hydroxymethyl)phenylboronic acid (2.35 g, 15.5 mmol), methyl 3-amino-2,6-dibromoisonicotinate (4.0 g, 12.9 mmol), tetrakistriphenylphosphine palladium(0) (0.895 g, 0.774 mmol), sodium carbonate (3.28 g, 31.0 mmol) was flushed with nitrogen and toluene (32.3 mL), and MeOH (10.75 mL) were added. The reaction was heated at reflux under nitrogen for 24 hr. It was partitioned between EtOAc and water. The organic phase was washed with brine, dried with sodium sulfate, and the solvents removed. The organic phase was washed with brine, dried with sodium sulfate and the solvent removed. The residue was chromatographed (step gradient elution with DCM containing 0 to 20% EtOAc afforded methyl 3-amino-6-bromo-2-(4-(hydroxymethyl)phenyl)isonicotinate (1.99 g, 5.90 mmol, 46% yield) as a yellow fluffy solid. MS (ESI) m/z 336.8 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 7.80 (1H, s), 7.61 (2H, d, J=8.24 Hz), 7.48 (2H, d, J=7.93 Hz), 5.94 (2H, br. s.), 4.75 (2H, d, J=5.80 Hz), 3.92 (3H, s), 1.72 (1H, t, J=5.80 Hz).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:20](=[O:21])[O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(O)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A solution of 4-pentylphenol (20.1 g, 0.13 mol) and pyridine (10 ml, 0.13 mol) in 300 ml of methylene chloride was added under nitrogen dropwise over 45 minutes to a solution of 4-nitrophenyl chloroformate (25.28 g, 0.13 mol) in 200 ml of methylene chloride at room temperature. After the addition, the reaction was stirred overnight at room temperature. The reaction was extracted one time with 1N HCl, four times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 36.97 g of a yellow crytstalline solid. Purification of the solid on 450 g of silica gel (230-400 mesh) using 50-60% CH2Cl2 -hexane as the eluent gave 11.58 g (28%) of the title compound as a yellow crystalline solid, mp 67-69° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4](I)[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.CC1(C)C(C)(C)OB(/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])O1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[Cl:1][C:2]1[C:3]([F:18])=[C:4](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: CCOc1c(C2(C)OCCO2)cc(Cl)c(F)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1c(F)c(Cl)cc(C2(C)OCCO2)c1OCC
Temperature: 80 °C
Yield: 96.1 %

Procedure:
A mixture of 2-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)-2-methyl-1,3-dioxolane (22 g, 58 mmol) (from Step 1), ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (16 mL, 70 mmol), and potassium carbonate (24 g, 170 mmol) in 1,4-dioxane (230 mL) and water (110 mL) was degassed with nitrogen for 10 min. The reaction mixture was treated with [1,1′-bis (diphenylphosphino\)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (2.4 g, 2.9 mmol), degassed with nitrogen for another 10 min, and heated at 80° C. for 2 h. The reaction mixture was filtered through Celite and washed with ethyl acetate (300 mL). The filtrate was poured into water (400 mL). The aqueous layer was separated and extracted with additional ethyl acetate (300 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude brown solid. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-30%) to give the desired product (20 g, 96%). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=16.5 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 6.70 (dd, J=16.5, 0.9 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.10-3.99 (m, 2H), 3.91 (q, J=7.0 Hz, 2H), 3.87-3.76 (m, 2H), 1.73 (s, 3H), 1.44 (t, J=7.0 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H). LCMS for C17H21ClFO5(M+H)+: m/z=359.1; Found: 359.1.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]1=[O:10].[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:12]=[O:13].[C:20]1(C)C=CC=CC=1>>[CH2:14]([NH:11][C:12]([N:3]1[C:4]2[CH:5]=[N:6][CH:7]=[C:8]([CH3:20])[C:9]=2[NH:1][C:2]1=[O:10])=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccccc1
Reactant: O=c1[nH]c2ccncc2[nH]1
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)n1c(=O)[nH]c2c(C)cncc21

Procedure:
Analogously to Example 1, 2 g (14.8 mmol) of 1,3-dihydroimidazo[4,5-c]pyridin-2-one and 1-isocyanatohexane (2.26 g, 17.76 mmol) were reacted in toluene. Yield: 43 mg (1%), M+H+: 263.19.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:38][CH:35]3[CH2:37][CH2:36]3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCN(C2CCCC2)CC1
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide give the desired product as a colorless foam (44%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH:10]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=O.CC(O)=O.C[N:34](C)C=O>>[O:25]1[C:22]2[CH:23]=[CH:24][C:19]([C:10]3[CH:11]=[C:12]([C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[N:34]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH:9]=3)=[CH:20][C:21]=2[O:27][CH2:26]1
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccsc1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccsc2)n1

Procedure:
A mixture of 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(thiophen-3-yl)-1,5-pentanedione on Wang resin. (2.0 g, 1.76 mmol), NH4OAc (1.0 g), and AcOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-benzo[1,3]dioxol-5-yl-6-thiophen-3-yl-pyridin-2-yl)-phenol; mp 120-121° C.; 1H NMR (DMSO-d6) d 6.15 (s, 2H), 6.97 (m, 2H) 7.13 (d, J=8.2 Hz, 1H), 7.35 (m, 1H), 7.66 (dd, J=8.2, 1.9 Hz, 1H), 7.80 (m, 3H), 8.16 (d, J=1.4 Hz, 1H), 8.31 (m, 2H), 8.37 (dd, J=2.9, 1.4 Hz, 1H), 14.58 (s, 1H); IR (KBr) 1602 cm−1; MS [M+H]+ m/z=374. Anal. calcd for C22H15NO3S: C, 70.76; H, 4.05; N, 3.75; Found: C, 70.66; H, 4.02; N, 3.59.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH2:15][C:14](=[O:16])[N:13]3[C:9](=[N:10][C:11]4[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=43)[CH2:8]2)=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(C2CC(=O)N3C(=[N:37]C4C=CC(I)=CC=43)C2)=CC=1.N>O1CCOCC1.O>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:8][C:9]2[NH:10][C:11]3[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=3[N:13]=2)[CH2:15][C:14]([NH2:37])=[O:16])=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3cc(I)ccc3n21
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3ccc(I)cc3n21
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc(-c2ccccc2)cc1

Procedure:
The 1:1-mixture of 3-(biphenyl-4-yl)-7-iodo-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one and 3-(biphenyl-4-yl)-8-iodo-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (140 mg) was dissolved in 1,4-dioxane (2 ml) at reflux temperature. A 25% solution of ammonia in water (1 ml) was added and refluxing was continued for 2 h while addition of 25% ammonia solution in 1 ml portions was repeated every half an hour (3 times). Then all volatiles were removed at the water aspirator and the residue was triturated with acetone to leave 3-(biphenyl-4-yl)-4-(5-iodo-2-benzimidazolyl)-butyramide (85 mg) as light colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a stirred solution of 1-chloro-2,5-difluorobenzene (0.770 g, 5.18 mmol) in concd H2SO4 (8.0 mL) at 0° C., KNO3 (0.525 g, 5.19 mmol) was added in one lot. The resulting yellow solution was allowed to warm to room temperature and stirred overnight at room temperature. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum and the residue was dried further under vacuum to afford 0.845 g (85%) of title compound as a yellow liquid; 1H NMR (CDCl3) δ7.43 (dd, 1H, J1 =9.6 Hz, J2 =6.0 Hz), 7.93 (t, 1H, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)=[CH:18]2)(=O)=O)C=CC=CC=1>>[C:2]1([NH:1][C:28]2[N:27]=[C:26]([C:19]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:17][CH:18]=3)[CH:31]=[CH:30][N:29]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: c1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 46.5 %

Procedure:
Using the procedure of example 1, aniline (83 mg) was reacted with compound 1f (100 mg) to provide compound 3 (36 mg, 47%). 1H NMR (400 MHz, CD3OD) δ 8.88 (d, J=7.8 Hz, 1H), 8.29 (t, J=6.0 Hz, 2H), 8.19 (s, 1H), 7.69 (d, J=7.8 Hz, 2H), 7.36 (t, J=7.6 Hz, 2H), 7.21 (m, 1H), 7.08 (t, J=7.8 Hz, 2H). MS (ESI) m/z: 288 (M+H)+.
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Br)c2ccccc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a solution of imidazole (2.3 g, 34 mmole) and 4-bromonaphthol (13, 5.0 g, 22 mmole) in DMF (10 mL) at 0° C. was added t-butyldimethylsilyl chloride (3.7 g, 24.6 mmole) in several portions. The mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was partitioned between Et2O (500 mL) and water (300 mL) and the aqueous layer was back-extracted with Et2O (300 mL). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes) to afford (4-bromonaphthalen-1-yloxy)(tert-butyl)dimethylsilane (14, 6.4 g, 85%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.21-8.14 (m, 2H), 7.61-7.49 (m, 3H), 6.74 (d, J=8.2 Hz, 1H), 1.10 (s, 9H), 0.28 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][O:16][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:11][O:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 1.55 g of 4(S)-(3-hydroxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester [177198-40-2] in 22 ml of methylene chloride at room temperature under argon is added 3.49 ml of triethylamine and 0.855 ml of methanesulfonyl chloride. The mixture is stirred at room temperature for 13 hours. The reaction is quenched by addition of 35 ml of 0.5M HCl. The mixture is extracted with methylene chloride. The organic layer is concentrated, dried over sodium sulphate and concentrated. The crude title compound is obtained as an orange oil. Rf=0.52 (1:1 EtOAc-heptane); Rt=3.64 (gradient I).