Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][C:4]=1[CH:16]=[CH2:17].C12BC(CCC1)CCC2.[OH:27]O.[OH-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][C:4]=1[CH2:16][CH2:17][OH:27]
Reactant: OO
Reactant: C=Cc1ccc(OCOCCOC)cc1OC
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1ccc(CCO)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
3.9 g (16.4 mmol) of 2-methoxy-4-(2-methoxy-ethoxymethoxy)-1-vinyl-benzene diluted in 30 ml of tetrahydrofuran is added dropwise to a solution at room temperature of 4 g (16.4 mmol) of the dimer of 9-borabicyclo[3.3.1]nonane diluted in 10 ml of tetrahydrofuran. After stirring at room temperature for 20 hours, the above reaction mixture is cooled to 0° C. and 10 ml of water is added dropwise. The reaction mixture is stirred at room temperature for 1 hour and then cooled again to 0° C. and 10 ml of hydrogen peroxide is added. After stirring for 2 hours at room temperature, the reaction mixture is treated by adding 3 ml of an aqueous solution of sodium hydroxide of concentration 3M and stirred for 30 minutes. The reaction mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 60/40 to give 3.3 g (78%) of 2-[2-methoxy-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethanol in the form of a light yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[N:9]([CH3:17])[C:8]1=[O:18])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]#[C:29][CH3:30]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][N:12]([CH2:27][C:28]#[C:29][CH3:30])[C:11]=2[C:10](=[O:16])[N:9]([CH3:17])[C:8]1=[O:18])=[O:4]
Reactant: Cn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1cnc2c1c(=O)n(C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.871 g of [1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate was dissolved in 30 ml of N,N-dimethylformamide, and 1.5 g of potassium carbonate and 0.7 ml of 2-butynyl bromide were added thereto. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. Thus, 2.12 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH2:25][CH3:26])=[CH:4][C:3]=1[F:18]
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O

Procedure:
A 59.7 g portion of the above ester was suspended in 425 ml of dimethylformamide, 76.6 g of potassium carbonate was added and this mixture was stirred in an oil bath at 80°-90° C. An 89 ml portion of ethyl iodide was added, the mixture was stirred at 80°-90° C. for 18 hours and then evaporated. The residue was dissolved in water and then extracted with dichloromethane. The extract was washed with water, dried, filtered through hydrous magnesium silicate and evaporated in vacuo. The solid was recrystallized from ethanol, giving 38 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=O)[C:2]1=2.[CH2:15]([CH:17]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][Mg]Br)[CH3:16].Cl[Sn]Cl>C1COCC1.Cl>[CH2:15]([CH:17]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][C:6]1[C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([CH2:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH2:12][CH2:11][CH3:7])=[C:2]2[S:1][CH:5]=[CH:4][C:3]=12)[CH3:16]
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Reactant: CCCCC(CC)C[Mg]Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1c2ccsc2c(CC(CC)CCCC)c2ccsc12
Temperature: 60 °C
Yield: 13 %

Procedure:
To a suspension of benzo[1,2-b:4,5-b′]dithiophene-4,8-dione (25) (Beimling, P.; Koβmehl, G. Chem. Ber. 1986, 119, 3198) (4.9 g, 22.2 mmol) in 100 mL of THF was added 2-ethylhexyl magnesium bromide (111 mL, 1M in diethyl ether). The mixture was then heated at 60° C. for 24 h., and cooled to r.t. following by adding SnCl2 (13.47 g, 71.04 mmol) in 190 mL of 10% HCl. The mixture was heated at 60° C. for 24 h. THF was removed under reduced pressure. The residure was dissolved in ether, washed with water, sat. NaHCO3, brine and water. The organic layer was dried over MgSO4 and then concentrated. Column chromatography with hexane gave 1.2 g (13%) of desired product 26. 1H-NMR (400 MHz, CDCl3): ppm 7.46 (d, 2H, J=5.6 Hz), 7.42 (d, 2H, J=5.6 Hz), 3.18-3.06 (m, 4H), 1.97 (hep, 2H, J=6.4 Hz), 1.43-1.18 (m, 16H), 0.91-0.81 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.[N+:26]([C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[O:32][CH2:33][C:34](O)=[O:35])([O-:28])=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][CH:39]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(O)COc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(C(=O)COc3cccc([N+](=O)[O-])c3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.5 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) and 3-nitrophenoxyacetic acid (0.23 mmol) in DMF (2 ml) was added TBTU (0.21 mmol) followed by diisopropylethylamine (0.21 mmol, 35 μL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 0.5% CH3OH in CH2Cl2), yielding the pure title compound (41 mg) which was characterized by its mass spectrum: MS m/z (%): 538 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>C(OCC)(=O)C>[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:16]=[S:17]
Reactant: NCc1ccccc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: S=C=NCc1ccccc1

Procedure:
Benzylamine (1.5 g) and triethyl amine (2.9 g) were dissolved in anhydrous ethyl acetate (50 ml) and stirred under ice cooling. Thiophosgene (4.9 g) dissolved in ethyl acetate (50 ml) was slowly added to the stirred solution. The solution was heated at reflux for 2 hr and filtered. Evaporation of the solvent afforded (isothiocyanatomethyl)-benzene which was used in the next step without purification. 1H NMR, CDCl3, 4.72 (2H, s), 7.30-7.40 (5H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][O:25][C@H:24]1[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:24]1[C@H:23]([O:22][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:28][CH2:27][CH2:26][O:25]1)(=[O:4])=[O:3]
Reactant: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.51 ml of methanesulfonyl chloride dissolved in 5 ml of benzene was added dropwise to a solution of 2.067 g of dl-7-(trans-3-hexadecyloxytetrahydropyran-2-ylmethoxy)-1-heptanol (prepared as described in Preparation 55) and 1.83 ml of triethylamine dissolved in 15 ml of benzene, whilst ice-cooling. The reaction mixture was stirred at room temperature for 15 minutes, after which it was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 2.406 g of crude dl-7-(trans-3-hexadecyloxytetrahydropyran-2-ylmethoxy)heptyl methanesulfonate as a viscous oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1>CCOC(C)=O.CO.[Pd]>[N:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=[CH:12]3)=[N:7][CH:2]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc2cc(Oc3ccncn3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(2-chloropyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide (0.075 g, 0.17 mmol) in EtOAc (3 mL) and methanol (0.5 mL) was added 10% Pd/C (20 mg). The flask was capped with a septum, and H2 gas was introduced through a balloon/needle. Positive H2 pressure was continued as the reaction was stirred vigorously overnight at RT. The reaction was filtered through Celite, concentrated, and purified by chromatography on silica to afford the desired product as a white solid. MS (ESI, pos. ion) m/z: 410.1 (M+1). Mass Calc'd for C22H14F3N3O2: 409.36.
Reaction SMILES: C([C:3]1[C:4](=[O:11])[NH:5][CH:6]=[CH:7][C:8]=1[O:9]C)#N.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>O>[OH:11][C:4]1[C:3]([N+:16]([O-:18])=[O:17])=[C:8]([OH:9])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc[nH]c(=O)c1C#N
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)ccnc1O
Temperature: 177.5 °C
Reaction time: 2 h

Procedure:
86% phosporic acid (90 mL, 151.3 g) and 3-cyano-4-methoxy-2(1H)-pyridinone (Compound X) (30.0 g, 0.20 mole) are combined under argon in a 500 mL flask equipped with a mechanical stirrer, reflux condensor. The mixture is heated in an oil bath at 175-180° C. for 23 hours. The reaction mixture is cooled to 71° C. and glacial acetic acid (90 mL, 94.5 g) added and the mixture heated at 90° C. for about 90 minutes. Fuming nitric acid (density=1.52) (12.6 g, 8.3 ml) is then added carefully over a period of 15 minutes (giving a mild exotherm), and the mixture heated at 90-95° D. for 2 hours. Water (90 mL) is then added to the mixture and heating at 90° C. continued for 1 hour. The mixture is then cooled slowly with stirring to room temperature, filtered through a sintered glass funnel and the residue washed with water to give Compound XII, m.p. 268° C.; NMR (DMSO) δ7.44 (1H, d); 6.0 (1H, d); 3.5 (2H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Br[CH2:7]/[CH:8]=[CH:9]/[CH2:10]Br>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7]/[CH:8]=[CH:9]/[CH2:10][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:2]
Reactant: CCNCC
Reactant: BrC/C=C/CBr
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C/C=C/CN(CC)CC
Yield: 82.7 %

Procedure:
The synthesis of the free base was carried out by the general procedure of J. J. Roberts and W. C. J. Ross (J. Chem. Soc., 1952, 4288). Diethylamine (3.285 g, 0.045 mol) was added during 15 min to a cooled solution (0° C.) of (E)-1,4-dibromobut-2-ene (1.07 g, 0.005 mol) (1) in benzene (5 ml). The product was diluted with chloroform (25 ml) and the organic layer was washed with water (4×25 ml). The chloroform layer was dried, filtered, and concentrated in vacuo to give (E)-N,N,N',N'-tetra-ethyl-1,4-diaminobut-2-ene as an oil (0.82 g, 82%). δH (90 MHz, CDCl3) 1.10 (12H, t), 2.60 (8H, q), 3.20 (4H, m) and 5.75 (2H, m).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([O:1][C:2]2[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C#N)c(O)c1OC
Product: COc1ccc(C#N)c(OC2CCCC2)c1OC
Yield: 95 %

Procedure:
The subtitle compound was prepared from 2-hydroxy-3,4-dimethoxybenzonitrile and freshly distilled cyclopentyl bromide following the procedure described in Example 10(d). The crude product was purified on silica gel eluting with dichloromethane to give the subtitle compound as a colourless oil (95%). Rf 0.50 (dichloromethane). MS m/z 265 (MNH4)+.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)(CC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: [OH-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CCC(C)O
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 73.2 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and sec-butanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (4 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 10.7 g of p-cyanobenzamide (yield 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[O:10][N:9]=2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[CH:18][CH:17]=1.C=O.[C:35]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:15][C:11]1([CH3:14])[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:35])=[C:3]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])=[CH:20][CH:21]=3)[CH:4]=2)[C:12]1=[O:13]
Reactant: [BH3-]C#N
Reactant: CC1(C)ON=C(c2ccc(N)c(-c3ccc(NC(=O)c4c(F)cccc4F)cc3)c2)C1=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1ccc(C2=NOC(C)(C)C2=O)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
To a 0° C. solution of Example 134 (50 mg, 0.11 mmol, 1.0 eq) in methanol (5 mL) was added formaldehyde (37% aqueous solution) (10 μL, 0.12 mmol, 1.1 eq). After stirring for 30 min at room temperature, sodium cyanoborohydride (8 mg, 0.14 mmol, 1.2 eq) was added to the above reaction mixture followed by a catalytic amount of acetic acid. The resulting mixture was stirred at room temperature for 12 h. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate (10 mL) and washed with water (5 mL), brine (5 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum and the crude product was purified by column chromatography (silica gel, DCM:MeOH as eluent) to afford 8 mg of title compound 1HNMR (400 MHz, CDCl3) δ 8.07 (dd, J=8.5, 2.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.45-7.09 (m, 3H), 7.46-7.43 (m, 3H), 7.04 (t, J=8.0 Hz, 2H), 6.72 (d, J=8.5 Hz, 1H), 4.33 (s, 1H, D2O exchangeable), 2.86 (s, 3H), 1.45 (s, 6H); ESI-MS (m/z) 450 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([Cl:19])[C:13]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCOCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([CH3:18])=[CH:15][C:14]=2[Cl:19])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Reactant: OCCc1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(Cl)c(OCCc2ccc(Br)cc2)c(Cl)c1
Temperature: 80 °C

Procedure:
2-(4-Bromophenyl)ethanol (1 eq.) and 2,6-dichloro-4-methylphenol (1.5 eq.) were taken up in freshly deoxygenated toluene (0.1 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.) and finally tributylphosphine (1.2 eq.). The resulting yellow solution was heated at 80° C. for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→10:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][C@@H:13]1[CH2:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:15][C@H:14]1[N:23]1[C:27]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=2[N:25]=[CH:24]1)(=[O:11])[CH3:10]>CN(C)C=O>[C:9]([O:12][C@@H:13]1[CH2:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:15][C@H:14]1[N:23]1[C:27]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=2[N:25]=[C:24]1[Br:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC[C@H]1C[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1C[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)C1
Temperature: 70 °C

Procedure:
N-Bromosuccinimide (4.54 g, 25.5 mmol) was added to a solution of (±)-(1R*,2R*,4S*)-4-(acetoxymethyl)-2-(5,6-dichloro-1H-benzimidazol-1-yl)cyclopentyl acetate (8.95 g, 23.2 mmol) in dry N,N-dimethylformamide (46 mL). The solution was maintained at ca. 70° C. (oil bath) for 5 hours. Volatiles were removed in vacuo and the residual orange syrup chromatographed on silica gel. Title compound was eluted with chloroform as a pale yellow solid (5.14 g, 48%), m.p. 122°-125° C.; 1H-NMR (DMSO-d6) δ: 8.16 (s, 1, benzimidazole H7), 7.95 (s, 1, benzimidazole H4), 5.60-5.55 (m, 1, OCH), 5.12-5.03 (m, 1, NCH), 4.15 (d, J=6.3 Hz, 2, OCH2), 2.66-2.60 (m, 1, CHCH2), 2.29-2.14 (m, 3, CH), 2.06 (s, 3, CH3CO), 1.93 (s, overlapped by m, 4, CH3CO+CH); mass spectrum (CI): 469 (5.8), 467 (37.5), 465 (95), 463 (54, M+1), 199 (100, M-B).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C.CN(C)C1C=CN=CC=1>[F:23][C:20]([F:21])([F:22])[C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:24]=[C:2]([NH:1][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH:3]=[CH:4][C:5]=2[OH:25])[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=1
Reactant: Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 40.5 %

Procedure:
5-Amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide (100.2 mg, 0.28 mmol) was dissolved in acetonitrile (4 ml). 4-Dimethylaminopyridine (3 mg) and phenylisocyanate (30 μl, 0.28 mmol) were added, and the mixture was stirred at 60° C. for 5 minutes. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to give the title compound (54.8 mg, 41.2%) as a light brown solid.
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)C.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.OS(O)(=O)=O>C1COCC1>[CH2:10]([C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC1=CC(=O)CC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1C=C(Cc2ccccc2)CC1
Reaction time: 6 h
Yield: 35 %

Procedure:
A solution of 3-ethoxy-2-cyclopenten-1-one (5 g, 0.89 mol) in THF (70 mL) was added at room temperature to a solution of 2M benzyl magnesium chloride (800 mL) under N2 and stirred for 6 h. The resulting mixture was poured into a solution of 30% H2SO4 and stirred for 5 h. The resulting organic layer was separated, and the aqueous layer was extracted with several portions of ether. The combined organic layer was dried (MgSO4), and concentrated in vacuo to give the title compound (3.1 g, 35%) as a colorless oil.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1)=[O:26])=[CH:19]2
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1
Reaction time: 24 h

Procedure:
tert-Butyl 1,4-diazepane-1-carboxylate (2.0 g, 10 mmol, Aldrich), 5-fluoro-1H-indole-2-carboxylic acid (1.79 g, 10 mmol, Aldrich), and EDCI (1.92 g, 10 mmol) were combined in CH2Cl2 (30 mL) at room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 1.46 (s, 9H), 1.86–2.14 (m, 2H), 3.40–3.58 (m, 2H), 3.62–3.72 (m, 2H), 3.75–4.05 (m, 4H), 6.78 (s, 1H), 6.99–7.09 (m, 1H), 7.28–7.35 (m, 2H); MS (DCI/NH3) m/z 362 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][OH:19])=[NH:17])=[CH:12][N:11]3[CH:20]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][O:19][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[NH:17])=[CH:12][N:11]3[CH:20]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: N=C(NO)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)ONC(=N)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
2-(4-Fluoro-phenyl)-N-hydroxy-imidazo[1,2-a]pyridine-6-carboxamidine (example 56; 85.1 mg, 0.315 mmol) was dissolved in 5 ml DMF. The mixture was heated to 80° C. after addition of triethylamine (87.8 μl, 0.63 mmol) and ethyl chloroformate (33 μl, 0.34 mmol) for 2.5 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 48 mg (45%) of the desired product. MS: M+H+=343.05.