Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:28]([OH:30])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:32]>ClCCl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:28]([Cl:32])=[O:30]
Reactant: O=C(O)c1cnc2cc(OCc3ccccc3)c(OCc3ccccc3)cn2c1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cnc2cc(OCc3ccccc3)c(OCc3ccccc3)cn2c1=O
Reaction time: 1.5 h

Procedure:
To a suspension of 4-oxo-7,8-bis(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (1.21 g, 3.0 mmol) in 30 ml of dichloromethane was added 0.69 g (3.3 mmol) of phosphorous pentachloride at 0° C. After stirring for 90 minutes, the solid was filtered off, washed with dichloromethane and dried in vacuo. Yield: 0.91 g; melting point 152.4° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.Cl.[CH3:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35]>O1CCCC1.CN(C)C=O>[CH3:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][NH:35][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)CCN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
17.2 g of t-butyloxycarbonyl-L-proline were dissolved in 160 ml of tetrahydrofuran, cooled to -20° C and treated with 11.1 ml of triethylamine and 7.7 ml of chloroformic acid ethyl ester. The resulting suspension was stirred at -20° C for a further 5 minutes and treated with a suspension, pre-cooled to -20° C, prepared from 13.4 g of β-alanine methyl ester hydrochloride and 13.4 ml of triethylamine in 160 ml of a mixture of dimethylformamide and tetrahydrofuran (1:1). The mixture was stirred for 1 hour at a temperature below -10° C and for a further hour at room temperature, filtered and the filtrate concentrated in vacuo. The oily residue was dissolved in 200 ml of ethyl acetate and washed three times, each time with 5% potassium hydrogen sulphate solution, water, 5% sodium hydrogen carbonate solution and water, and dried over sodium sulphate. The organic phase was concentrated in vacuo and the oily residue crystallised from ether/petroleum ether. Yield: 19.2 g; melting point 70° C; [α]D25 = -39.2° (c = 1 in dimethylformamide).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:22][O:23][C:24](=[O:27])[CH2:25][CH:8]([C:6]1[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(Br)ccc2[N+](=O)[O-])cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(c1nc(Br)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A mixture of 6-bromo-3-nitro-2-(toluene-4-sulfonylmethyl)-pyridine (3.3 g, 9.0 mmol), bromo-acetic acid methyl ester (2.1 mL, 22.5 mmol) and K2CO3 (8.4 g, 60.8 mmol) were suspended in DMF (18.0 mL) and stirred at 40° C. for 1 hour before pouring into water (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 3-(6-bromo-3-nitro-pyridin-2-yl)-3-(toluene-4-sulfonyl)-propionic acid methyl ester (3.9 g, quant.) as a light yellow solid. MS: 443.1 & 445.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:6][CH2:7]Br.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCNCC1.CCN(CC)CC.I([O-])(=O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:6][CH2:7][N:29]1[CH2:30][CH2:31][N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)C(CCCBr)(c1ccc(Br)cc1)C(C)C
Reactant: c1ccc(N2CCNCC2)cc1
Agent: C1CNCCN1
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(CCCN1CCN(c2ccccc2)CC1)(c1ccc(Br)cc1)C(C)C

Procedure:
After the 5-bromo-2-(4-bromophenyl)-2-isopropylpentanoic acid methyl ester (200 mg, 1 eq) was dissolved in acetonitrile, 4-phenylpiperazine (70 mg, 1 eq) as a piperazine derivative, Et3N (0.06 ml, 1.2 eq), and sodium iodate were added into the solution and heated and refluxed for 3 hours. When the reaction was completed, the precipitate was filtrated and the mixture was vacuum distilled and extracted with ethyl acetate and water. After the organic layer was washed with 1N HCl and saturated NaHCO3, the target compound 2-(4-bromophenyl)-2-isopropyl-5-(4-phenylpiperazine-1-yl)pentanoic acid methyl ester was obtained by drying the mixture with anhydrous sodium sulfate and removing the solvent at low pressures (69 mg, 42%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[S:29][C:30]([CH2:33][N:34]([CH3:36])[CH3:35])=[CH:31][CH:32]=2)=[CH:22][N:21]=1)([O-])=O>>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[S:29][C:30]([CH2:33][N:34]([CH3:35])[CH3:36])=[CH:31][CH:32]=2)=[CH:22][N:21]=1)[CH3:3]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)s1
Product: CN(C)Cc1cccc(OCCCNc2ncc(Cc3ccc(CN(C)C)s3)c(=O)[nH]2)c1

Procedure:
Reaction of 3-(3-dimethylaminomethylphenoxy)propylamine with 2-nitroamino-5-(5-dimethylaminomethyl-2-thienyl methyl)-4-pyrimidone gives 2-[3-(3-dimethylaminomethylphenoxy)propylamino]-5-(5-dimethylaminomethyl-2-thienylmethyl)-4-pyrimidone.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[CH:39]=[C:38]([CH3:40])[N:37]=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[N:36]1)=[O:11]
Reactant: Cc1ccc(-n2cc(C)nn2)c(C(=O)O)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2cc(C)nn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, starting 5-methyl-2-(4-methyl-1H-1,2,3-triazol-1-yl)benzoic acid. ESI-MS (m/z): 328 [M+1]+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.Br[CH2:14][CH2:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18]Br.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:20]1([CH:16]2[CH2:17][CH2:18][N:2]([CH:3]3[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]3)[CH2:14][CH2:15]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCC(CCBr)c1ccccc1
Reactant: COC(=O)C1CCC(N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C1CCC(N2CCC(c3ccccc3)CC2)CC1

Procedure:
A solution of 3.896 g (20.117 mM) of methyl 4-aminocyclohexanecarboxylate hydrochloride, 6.77 g (22.1 mM) of 1,5-dibromo-3-phenylpentane, and 14.0 ml (80.5 mM) of N,N-diisopropylethylamine in 100 ml of acetonitrile was refluxed for one day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])[N:7]([CH2:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].F[C:32](F)(F)S(OC)(=O)=O.[NH4+].[OH-]>C1(C)C=CC=CC=1.O.CC(C)=O>[C:1]([C:5]1[N:6]([CH3:32])[N:7]([CH2:24][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])/[C:8](=[N:10]/[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=2[F:22])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)c1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)n(CCCC(F)(F)F)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1CCCC(F)(F)F
Temperature: 100 °C
Reaction time: 20 h
Yield: 74.4 %

Procedure:
To a solution of Example 135C (1.7 g, 3.9 mmol) in toluene (15 mL) was added methyl trifluoromethanesulfonate (0.64 mL, 5.8 mmol). The mixture was warmed to 100° C. and stirred for 20 hours, cooled to ambient temperature and diluted with water (20 mL) and acetone (50 mL). This solution was allowed to stir for 30 minutes then concentrated NH4OH (10 mL) was added. The mixture was stirred for 30 minutes then partially concentrated under reduced pressure. The mixture was diluted with EtOAc (30 mL) and brine (10 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 80% hexanes/EtOAc to 100% EtOAc to 10% MeOH in EtOAc) afforded the title compound (1.3 g, 2.9 mmol, 74% yield). MS (ESI−) m/z 454 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:12]2=[N:11][C:10]=1[C:23]([O:25]CC)=[O:24])[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH:15]3[CH2:16][CH2:17][N:18]([C:12]2=[N:11][C:10]=1[C:23]([OH:25])=[O:24])[CH2:19][CH2:20]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCN2CC1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCN2CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A mixture of ethyl 3-(benzyloxy)-4-oxo-6,7,8,9-tetrahydro-4H-7,10-ethanopyrimido[1,2-a][1,3]diazepine-2-carboxylate (0.5491 g, 1.486 mmol) and LiOH.H2O (0.071 g, 2.97 mmol) in ethanol (12 mL) and water (3.00 mL) was stirred at room temperature for 6 h. The mixture was acidified with concentrated HCl and the product was extracted with ethyl acetate. The organic phase was washed with brine, then dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (0.4521 g, 89% yield). 1H NMR (500 MHz, CD3OD) δ: 7.53-7.49 (2H, m), 7.42-7.36 (3H, m), 5.27 (2H, d, J=15.3 Hz), 4.11-4.00 (4H, m), 3.96 (2H, d, J=14.0 Hz), 3.17-3.13 (1H, m), 2.45-2.39 (2H, m), 2.10-2.03 (2H, m). LCMS (M+H) calcd for C18H20N3O4: 342.14; found: 342.20.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][C:6]([NH:8][NH:9][C:10]([C:12]1[S:13][C:14]([Cl:17])=[CH:15][CH:16]=1)=O)=[O:7].Cl>[OH-].[Na+].O>[Cl:17][C:14]1[S:13][C:12]([C:10]2[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[C:6](=[O:7])[NH:8][N:9]=2)=[CH:16][CH:15]=1
Reactant: O=C(NCc1ccccc1F)NNC(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]nc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Temperature: 25 °C

Procedure:
6.3 g (19.2 mmol) of the compound from Example 151A are heated overnight under reflux in 38.4 ml of 4 N aqueous sodium hydroxide. After cooling to RT, the mixture is diluted with water and adjusted to pH 10 by addition of 1 N hydrochloric acid. The product is extracted several times with ethyl acetate. The combined organic phases are washed with water to a neutral pH value, then washed with saturated sodium chloride solution and dried over sodium sulphate. After filtration, the solvent is removed on the rotary evaporator. 4.07 g (68% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[N:12]=[C:13]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]3[CH:25]=2)[OH:10])=[CH:5][CH:4]=1)[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[N:12]=[C:13]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]3[CH:25]=2)=[O:10])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(O)c2cn3c(cc(OC)c4ccccc43)n2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCc1ccc(C(=O)c2cn3c(cc(OC)c4ccccc43)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
8 g of activated manganese dioxide were added to a solution of 1.99 g (6 mmol) of the product of Step C in 100 ml of chloroform and the mixture was vigorously stirred at room temperature for 16 hours and was filtered. The filter was washed with chloroform and the filtrate was evaporated to dryness under reduced pressure. The residue was crystallized from ethyl acetate to obtain 1.32 g (67% yield) of (4-ethylphenyl)(5-methoxy-imidazo[1,2-a]quinolin-2-yl)-methanone in the form of a light yellow crystalline solid melting at 147°-148° C. Overall yield based on the starting ester was 29%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](I)[CH3:24]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:23][CH3:24])[CH:12]=1)[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21

Procedure:
The procedure of Referential Example 1(a) was repeated, except that N-tert-butoxycarbonyl-D-tryptophan (462 mg) and ethyl iodide (184 μL) were used, whereby the title compound (456 mg) was yielded.
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12]>C(O)C>[NH2:13][C:10]1[CH2:11][CH2:12][N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: C=CC#N
Reactant: NNc1ccccc1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccccc2)CC1

Procedure:
A 2.0 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 40.0 ml. of phenylhydrazine is added followed by 26.0 ml. of acrylonitrile. The reaction mixture is refluxed for 3 hours with exothermic crystallization of a product. The product is collected by filtration and washed with 95% ethanol. The material is recrystallized from dichloromethane-benzene to give 43.6 g. of the desired product as a solid, m.p. 168°-170.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[N:3]=1.[CH3:18][N:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[C:21]([CH3:34])[C:20]1=[O:35]>>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:23]3[CH:22]=[C:21]([CH3:34])[C:20](=[O:35])[N:19]([CH3:18])[CH:24]=3)=[N:3][C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: CS(=O)(=O)Cc1ncc(OCC2CC2)c(Cl)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Product: Cc1cc(-c2nc(CS(C)(=O)=O)ncc2OCC2CC2)cn(C)c1=O

Procedure:
The title compound of Example 143, step 2 was reacted with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 3.86 (d, J=6.8 Hz, 2H), 3.67 (s, 3H), 3.11 (s, 3H), 2.24 (s, 3H), 1.29-1.27 (m, 1H), 0.72-0.67 (m, 2H), 0.39-0.35 (m, 2H). LCMS: 364.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7]N2C3C=CC=CC=3N=N2)=[C:4]([CH:19]2[CH2:21][O:20]2)[CH:3]=1.[Li+].CC([N-]C(C)C)C>O1CCCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH:7]=[C:19]([CH2:21][OH:20])[C:4]=2[CH:3]=1
Reactant: Clc1ccc(OCn2nnc3ccccc32)c(C2CO2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1coc2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 17 h
Yield: 110.7 %

Procedure:
99 (25.7 g, 85.1 mmol) is dissolved in 300 ml of tetrahydrofurane and cooled to −78° C. A 2M solution of LDA in THF (93.7 ml, 187.4 mmol) is added dropwise within 45 min. The reaction mixture is allow to warmup to room temperature within 17 h. Then the reaction mixture is quenched with saturated aqueous ammonium chloride solution and evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed with water and brine and dried over sodium sulfate. Evaporation gave 17.2 g of an brown resin which is further purified by flash-chromatography (silicagel, ethyl acetate/hexanes 2:8).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1ccc(N/C(=C2\C(=O)Nc3cc(OC)c(OC)cc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and p-anisidine
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][PH:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][PH:15](=[O:20])[O:16][CH:17]([CH3:18])[CH3:19])[CH2:10]1
Reactant: CC(C)O[PH](=O)C[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)O[PH](=O)C[C@H]1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.3 %

Procedure:
To a solution of (±)-cis-isopropyl [3t-butyldimethylsilyloxy)cyclopentanyl]methylphosphinate (5) (3.2 g, 10 mmol) in anhydrous THF (30 cm3) was added tetrabutylammonium fluoride (11 cm3 of a 1 M solution in THF). The reaction mixture was stirred at room temperature for 12 h at which time the solvent was removed in vacuo. The crude product was purified by short column vacuum chromatography on silica gel (15% ethanol/ethyl acetate); earlier fractions contained the trans isomer, later fractions contained the desired cis (6) isomer which was isolated as a colourless oil (1.8 g, 87%): 1H NMR (300 MHz, CDCl3) δ 1.28 and 1.31 (6H, d, J=6.3 and 6.3 Hz, OCHCH3), 1.45 (3H, d, J=113.2 Hz, PCH3), 1.61-2.32 (6H, m, C(1)—H, C(2)—H, C(2)—H′, C(4)—H, C(4)—H′ and C(5)—H), 4.26 (1H, m, C(3)—H), 4.61 (1H, m, OCHCH3), 13C NMR (75.46 MHz, CDCl3) δ 12.15 and 12.76 (PCH3, d, JPC=90.2 and 89.9 Hz), 23.62 (C(5)), 24.20 and 24.24 (POCCH3, 2×d, 3JPOCC=3.3 Hz), 35.24 and 35.29 (C(2, s), 35.81 and 35.89 (C(1), d, JPC=97.9 and 98.5 Hz), 35.98 and 36.01 (C(4), d, 3JPC=7.2 and 7.5 Hz), 69.11 and 69.12 (POCHCH3, d, 2JPOC=6.9 and 6.9 Hz), 72.8 and 73.3 (C(3), d, 3JPC=4.1 and 4.9 Hz), 31 P NMR (121 MHz, CDCl3) δ 59.4, 59.7, (ESI) 207.1154 (MH+-C9H20O3P requires 207.1150).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:35]=[CH:34][C:16]2[NH:17][C:18]([CH2:20][C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][C:29]([C:31]([OH:33])=O)=[CH:30][C:23]=4[N:22]=3)=[N:19][C:15]=2[CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C[N:48](C)[CH2:49][CH2:50][CH2:51][N:52]=C=NCC.NCCCN.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:35]=[CH:34][C:16]2[N:17]=[C:18]([CH2:20][C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][C:29]([C:31]([NH:48][CH2:49][CH2:50][CH2:51][NH2:52])=[O:33])=[CH:30][C:23]=4[N:22]=3)[NH:19][C:15]=2[CH:14]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cn1c(Cc2nc3cc(CN4C(=O)c5ccccc5C4=O)ccc3[nH]2)nc2cc(C(=O)O)ccc21
Agent: Cl
Agent: NCCCN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1c(Cc2nc3ccc(CN4C(=O)c5ccccc5C4=O)cc3[nH]2)nc2cc(C(=O)NCCCN)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.5 %

Procedure:
2-[5-(1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1-methyl-1H-benzoimidazole-5-carboxylic acid (0.05 g, 0.108 mmol), 1-hydroxybenzotriazole (0.016 g, 0.118 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.023 g, 0.12 mmol) and the mono-BOC protected derivative of 1,3-diaminopropane were dissolved at 0° C. in methylene chloride (1 mL) and DMF (minimal amount sufficient to effect a solution). The solution was adjusted to pH-8 with N-methylmorpholine and the mixture was allowed to slowly warm to room temperature and then stirred for 20 hours. The mixture was transferred to a separatory finnel, diluted with methylene chloride, washed with 0.1N HCl solution and then saturated NaHCO3 solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparatory TLC (10% methanol/ethyl acetate) to provide 2-[6-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1-methyl-N-(3-aminopropyl)-1H-benzoimidazole-5-carboxamide (0.02 g, 28% yield); 1H-NMR (300 Mhz, CDCL3): 7.75-7.81 (m, 4H), 7.61-7.68 (m, 3H), 7.33 (br s, 1H), 7.27 (d, 1H, J=8.6 Hz), 7.15 (d, 1H, J=9.3 Hz), 5.10 (br t, 1H), 4.90 (br s, 2H), 4.57 (s, 2H), 3.71 (s, 3H), 3.49 (q, 2H, J=7.2 Hz), 3.24 (q, 2H, J=7.2 Hz), 1.72 (m, 2H), 1.41 (s, 9H);
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[Br:20]C1C=CC=C2C=1NC=C2>>[Br:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: Brc1cccc2cc[nH]c12
Product: CC1(C)OB(c2cc3cccc(Br)c3[nH]2)OC1(C)C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-bromo-1H-indole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:18][CH3:19])[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=1.[CH:20](=O)[CH3:21].[BH3-]C#N.[Na+].C(O)(=O)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:18]([CH2:20][CH3:21])[CH3:19])[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CNc1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(C)c1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
0.34 g (0.001 mol) of [3-bromo-5-(4-nitrophenylsulphanyl)-phenyl]-methylamine was dissolved in 10 ml of acetonitrile, treated with 1.4 ml (0.025 mol) of acetaldehyde, 0.74 g (0.010 mol) of NaBH3CN and 1.76 ml of acetic acid and stirred at room temperature for 1 hr. Thereafter, the solvent was removed, the residue was partitioned in ethyl acetate/water and the organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:19. There was obtained 0.33 g (93%) of [3-bromo-5-(4-nitro-phenylsulphanyl)-phenyl]-ethylmethylamine as an orange-red oil. MS (EI): me/e=368, 366 (C15H15BrN2O2S+).