Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[O:17]C)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[OH:17])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(Cl)cc1-n1c(=O)[nH]c2cc(Cl)ccc21
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)ccc2n1-c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-Chloro-1-(5-chloro-2-methoxy-phenyl)-1,3-dihydro-benzimidazol-2-one (4 g, 13 mmol) in dichloromethane was cooled to −10° C., and boron tribromide (14.6 ml 1 M solution in dichloromethane 14.6 mmol) was added. The reaction mixture is stirred at room temperature for 6 hours, poured into water (app. 200 ml), and stirred for 15 minutes and filtrated. The title compound was crystallized from toluene/heptane. M.p. 256-257° C.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=O)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[O:10]1[C:9]2=[N:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:4]2[CH:1]=[CH:2]1
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2ccoc2nc1C(=O)OCC

Procedure:
A xylene solution of the hydroxy-furo compound obtained in Example 23, (3.7 g) containing para-toluene sulfonic acid (0.01 g) is heated at reflux for two hours. The solution is cooled and the xylene solution decanted off. The residue is extracted with ether and the extracts combined with the xylene. Distillation of the solvents gives a yellow solid which is crystallized from a cyclohexane-toluene mixture to give pure diethyl furo[2,3-b]pyridine-5,6-dicarboxylate mp 66°-77° C.
Reaction SMILES: C([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=2)=[C:11]([Cl:24])[CH:10]=1)CCC.[OH-].[Na+]>CO>[Cl:24][C:11]1[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:25])=[O:5])[CH:14]=[C:13]([CH3:15])[C:12]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=1
Reactant: CCCCOC(=O)/C=C/c1cc(C)c(Oc2ccc(O)cn2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(/C=C/C(=O)O)cc(Cl)c1Oc1ccc(O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a MeOH (10 mL) solution of the ester (4.73 g) was added 5 M NaOH (2 mL), and stirred for 1 hour at 50° C., then MeOH was evaporated. The residue was dissolved in water, and acidified with 6 M HCl. The resulting precipitate was collected by filtration and dried to afford (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methylphenyl}prop-2-enoic acid as a pale yellow powder (3.77 g).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:16]([C:28]1[O:32][CH:31]=[N:30][CH:29]=1)=[CH:15]2.[Cl:33]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:33][C:31]1[O:32][C:28]([C:16]2[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)=[CH:29][N:30]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnco2)cc2cc(F)ccc21
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
LiHMDS (1.06 M in THF, 3.44 mL, 3.43 mmol) was added to a solution of tert-butyl 5-fluoro-2-(oxazol-5-yl)-1H-indole-1-carboxylate 49 (0.865 g, 2.86 mmol) in THF (20 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (1.01 g, 4.29 mmol) in THF (5 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC:H2O (50 mL:15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-chlorooxazol-5-yl)-5-fluoro-1H-indole-1-carboxylate 50 (0.74 g, 77% yield) as white solid. MS (ES) m/z 337 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[NH:8][C:9]=1[CH3:10])[CH2:2][CH2:3][CH3:4].[C:21](O)(=[O:24])[C:22]#[CH:23].N1(C(N2C=CN=C2)=O)C=CN=C1>>[CH2:1]([C:5]1[NH:6][C:7]2[N:8]([C:9]=1[CH3:10])[C:21](=[O:24])[CH:22]=[CH:23][C:11]=2[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC(=O)c2ccc(F)cc2)[nH]c1C
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCCc1[nH]c2c(C(=O)c3ccc(F)cc3)ccc(=O)n2c1C

Procedure:
The compounds are prepared as described in example 10 with 200 mg (0.73 mmol) of 2-(4-butyl-5-methyl-1H-imidazo-2-yl)-1-(4-fluorophenyl)ethanone (example XXVI), 77 mg (1.09 mmol) of propiolic acid and 212 mg (1.31 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole.
Reaction SMILES: C([O:8][C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=[C:11]2[O:19][C@H:20]3[CH2:45][N:23]([C:24](=[O:44])[C@H:25]([C:40]([CH3:43])([CH3:42])[CH3:41])[NH:26][C:27](=[O:39])[O:28][C@@H:29]4[CH2:38][CH2:37][CH2:36][C@H:30]4[CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][C:10]=12)[C@H:22]([C:46]([O:48][CH3:49])=[O:47])[CH2:21]3)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[C:40]([C@H:25]1[C:24](=[O:44])[N:23]2[CH2:45][C@@H:20]([CH2:21][C@H:22]2[C:46]([O:48][CH3:49])=[O:47])[O:19][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]([OH:8])=[C:10]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]2[CH2:36][CH2:37][CH2:38][C@H:29]2[O:28][C:27](=[O:39])[NH:26]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCc1ccccc1)O2
Agent: [Pd]
Agent: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCc1ccccc1)O2
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of methyl (3aR,7S,10S,12R,21E,24aS)-19-(benzyloxy)-7-tert-butyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxylate (synthesized as in Example 1 with intermediates B6 and C3) (1.16 g) in THF (8.7 ml) and methanol (8.7 mL) was added 10% Pd/C (92 mg) and the mixture was stirred for 18 hours under hydrogen atmosphere. The atmosphere was changed to nitrogen and the reaction was carefully filtered through celite to give 0.88 g of the desired product. LRMS (ES+) m/z 582.40 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12](=[O:32])[CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:23]#[N:24])[CH3:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:26]1([C:13]2[N:14]=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[C:23]#[N:24])[O:32][C:12]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C#N)CCCCCC(=O)NC(C(=O)c1ccccc1)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C#N)CCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
7.3 g of phosphorus oxychloride are added to a solution of 5.75 g of (RS)-1,2-diphenyl-2-(7-cyanooctanamido)ethanone in 30 cm3 of toluene, and the mixture is heated to 80° C. for 6 hours. After treatment, the product obtained is chromatographed on a column 2 cm in diameter containing 60 g of silica gel (50 to 200μ). The column is eluted with 0.6 liter of diisopropyl ether, collecting 50 cm3 fractions. The fractions emerging at between 0.1 liter and 0.6 liter are concentrated under reduced pressure (0.2 kPa). 4.2 g (76%) of (RS)-7-(4,5-diphenyl-2-oxazolyl)-2-methylheptanenitrile are obtained in the form of an oil, which is used directly in the subsequent reaction.
Reaction SMILES: [N:1]1([CH:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[Na]>>[N:1]1([CH:6]2[CH:15]3[CH:10]([CH2:11][CH2:12][CH2:13][NH:14]3)[CH2:9][CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cnc2c(c1)CCCC2N1CCCC1
Agent: [Na]
Solvent: CCO
Product: C1CNC2C(C1)CCCC2N1CCCC1

Procedure:
This product is obtained mixed with other diastereoisomers by reduction of the product obtained in Step B either by catalytic hydrogenation or by a sodium-ethanol mixture. The description of these two reductions is given at the end of Example 4.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18]C(=O)OC(C)(C)C)[CH2:13]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.O1CCOCC1>CO>[NH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:10]2[CH:9]=[CH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[N:11]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc3ncnc(N)c3n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncnc2ccc(N3CCC[C@H](N)C3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.5 %

Procedure:
To a 40 mL screw-cap vial was added tert-butyl N-[(3S)-1-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-3-piperidyl]carbamate 43 (2.53 g, 7.35 mmol) followed by methanol (7 mL), then HCl in dioxane (4 mol/L, 7.5 equiv., 55.1 mmol, 13.8 mL). The reaction was stirred at room temperature for 2 hours. Resulting precipitate was collected by filtration, and washed 2× with ethyl acetate, yielding 1.93 g of product as an orange solid, 3×HCl salt. 25 mg was purified by reverse phase HPLC, yielding 5 mg of neutralized product. 1H NMR (400 MHz, DMSO) δ 8.17-8.13 (s, 1H), 7.77-7.73 (d, J=9.3 Hz, 1H), 7.46-7.39 (d, J=9.4 Hz, 1H), 7.39-7.07 (s, 2H), 4.48-4.26 (m, 2H), 3.03-2.90 (m, 1H), 2.73-2.62 (m, 2H), 1.93-1.82 (m, 1H), 1.82-1.67 (m, 1H), 1.52-1.36 (m, 1H), 1.34-1.16 (m, 1H). LCMS M?Z (M+H)=245.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>>[Cl:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:15]1[CH2:16][CH2:17][O:18][CH:13]([CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:14]1
Reactant: Clc1cccc(CBr)c1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: O=C(NCC1CN(Cc2cccc(Cl)c2)CCO1)Nc1ccc(Cl)cc1

Procedure:
Example 26 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 1-(bromomethyl)-3-chlorobenzene (5.4 μl) to give the title compound (0.0023 g). LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 394 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH:27]=[O:28])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[O-:29][Mn](=O)(=O)=O.[K+].[OH-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[C:27]([OH:29])=[O:28])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 55 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (1.4 g) in THF (20 mL) was added KMnO4 (1.1 g) and aqueous KOH (10 mL). The reaction mixture was stirred at 55° C. overnight. After cooled to room temperature, the mixture was diluted with THF (30 mL), and filtered. The filtrate was concentrated and the aqueous suspension was acidified with aqueous HCl (2 M) to pH 5-6. The resulting white solid was collected, washed with water, dried in vacuo to give the crude compound, which was purified by column chromatography (10% ethyl acetate in hexane) to afford 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carboxylic acid (D95) as a white solid (1.3 g). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.74 (3H, s), 4.88 (1H, m), 7.35 (1H, dd), 7.45 (1H, d), 7.53 (1H, dd), 8.12 (1H, d), 8.14 (1H, d), 8.20 (1H, d), 8.32 (1H, dd), 12.15 (1H, s). MS (ES): C21H18ClN3O4 requires 411. found 412.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[I:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.O>C1COCC1>[I:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:21][NH:20][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([CH:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)=[CH:23][CH:22]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: CC1CCC(N2CCN(c3ccc(C(=O)NN)cc3)CC2)CC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC1CCC(N2CCN(c3ccc(C(=O)NNC(=O)c4ccc(I)cc4)cc3)CC2)CC1
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a suspension of 4-[4-(4-methylcyclohexyl)-1-piperazinyl]benzohydrazide (12.48 g) and pyridine (11.7 ml) in THF (374 ml) was added 4-iodobenzoyl chloride (11 g) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added water (3700 ml). The resulting precipitate was collected by filtration and dried to give N′-(4-iodobenzoyl)-4-[4-(4-methylcyclohexyl)-1-piperazinyl]benzohydrazide (22.45 g).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[CH3:7].[Cl:15][C:16]1[C:24]2[O:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:21][C:20]=2[CH:19]=[C:18]([CH:30]=[O:31])[C:17]=1[Cl:32].[Cl-].[NH4+]>CCCCCC.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[Cl:15][C:16]1[C:24]2[O:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:21][C:20]=2[CH:19]=[C:18]([CH:30]([C:14]2[N:10]([CH2:9][O:8][CH2:6][CH3:7])[N:11]=[CH:12][CH:13]=2)[OH:31])[C:17]=1[Cl:32]
Reactant: CCOC(=O)C1Oc2cc(C=O)c(Cl)c(Cl)c2O1
Reactant: CCOCn1cccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOCn1nccc1C(O)c1cc2c(c(Cl)c1Cl)OC(C(=O)OCC)O2
Reaction time: 1 h
Yield: 28.8 %

Procedure:
1.25 ml of 1.6M n-butyl lithium in n-hexane is added dropwise to a solution of 252 mg of 1-ethoxymethyl-pyrazole in 5 ml of tetrahydrofuran at -60° to -50° C. 0.4 ml of hexamethylphosphoric triamide is added to the mixture and the mixture is stirred at the same temperature for 1 hour. The mixture is added to a solution of 582 mg of ethyl 4,5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylate in 10 ml of tetrahydrofuran at -60° to -50° C. and the mixture is stirred at the same temperature for 5 minutes. An aqueous saturated ammonium chloride solution is added to the mixture and the mixture is extracted with ethyl acetate. The extract is washed, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform-acetone-ethanol) to give 240 mg of ethyl 4,5-dichloro-6-((1-ethoxymethyl-pyrazol-5-yl)-hydroxymethyl)-1,3-benzodioxole-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29]C(=O)OCCCC)=[CH:25][CH:24]=3)[C:18]2=[O:37])[S:5][C:6]=1[C:7](=[O:16])[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]2[CH2:20][CH2:21][N:17]([C:4]3[S:5][C:6]([C:7]([NH:8][CH2:9][C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[O:16])=[C:2]([CH3:1])[CH:3]=3)[C:18]2=[O:37])=[CH:28][CH:27]=1
Reactant: CCCCOC(=O)Nc1ccc(CN2CCN(c3cc(C)c(C(=O)NCc4cccnc4)s3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N2CCN(Cc3ccc(N)cc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of tent-butyl 4-((3-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)-thiophen-2-yl)-2-oxoimidazolidin-1-yl)methyl)phenylcarbamate (0.18 g, 0.34 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (2 mL) was stirred at ambient temperature for 2 h and concentrated. The residue was taken up in saturated aqueous sodium bicarbonate solution (25 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-10% methanol in dichloromethane to afford the title compound as a cream solid in 46% yield (0.07 g): mp 118-120° C.: 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.44 (s, 1H), 8.30 (t, J=5.9 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.52 (d, J=8.4 Hz, 2H), 6.18 (s, 1H), 5.09 (br s, 2H), 4.38 (d, J=5.9 Hz, 2H), 4.18 (s, 2H), 3.80-3.72 (m, 2H), 3.40-3.32 (m, 2H), 2.36 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 162.9, 155.3, 148.8, 148.0, 147.8, 142.7, 139.1, 135.4, 135.0, 128.9, 123.4, 123.0, 119.7, 113.8, 111.8, 46.8, 42.4, 40.9, 15.7; MS (ES+) m/z 422.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[CH3:27])(O)O>>[CH3:27][C:19]1[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:25]=[CH:26][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3C)c(C)c2)o1

Procedure:
The title compound was prepared from 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 A1) and 4-borono-3-methylbenzoic acid (D33) using a similar procedure to Description 11 as a white solid (31%).
Reaction SMILES: [CH3:1][C:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:29])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:3][CH2:4][C:5]1[C:10]([OH:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[OH:13].C(O[C:34](=[O:36])[CH3:35])(=O)C>N1C=CC=CC=1>[CH3:1][C:2]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:29])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:3][CH2:4][C:5]1[C:6]([O:13][C:10](=[O:11])[CH3:9])=[CH:7][C:8]([O:12][C:8](=[O:12])[CH3:7])=[CH:9][C:10]=1[O:11][C:34](=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=CCc1c(O)cc(O)cc1O)CCCC(C)CCCC(C)CCCC(C)C
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(OC(C)=O)c(CC=C(C)CCCC(C)CCCC(C)CCCC(C)C)c(OC(C)=O)c1
Reaction time: 4 h
Yield: 59 %

Procedure:
2-(3,7,11,15-Tetramethyl-2-hexadecenyl)-1,3,5-benzenetriol (1.00 g;2.47 mmole) was dissolved in 10 ml of pyridine and 833 mg (8.16 mmole) of acetic anhydride was added thereto with ice-cooling, followed by bringing it back to room temperature, stirring for 4 hours, removing the solvent by distillation and subjecting the resulting residue to silica gel column chromatography to thereby recover 0.77 g of the title compound from the fractions eluted with hexane-ethyl acetate (5:1). Yield=59%.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:40])(=[O:39])[NH:34]C(C)(C)C)=[CH:23][CH:22]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33](=[O:39])(=[O:40])[NH2:34])=[CH:23][CH:22]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 94 %

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-2-(3-nitrophenyl)-3H-1,2,4-triazol-3-one (from Step B) according to the procedure of Example 13, Step B, and was obtained in 94% yield as a pale yellow solid after flash chromatography, mp 73°-76° C., homogenous by TLC (19:1 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 508 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CC2CC2)CC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 121.3 %

Procedure:
Treat a solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.50 g, 1.58 mmol, Preparation 9) and dimethylformamide (10 mL) with sodium hydride (0.083 g, 2.08 mmol, 60% dispersion in oil) at room temperature. After 15 minutes, add (bromomethyl)cyclopropane (0.21 mL, 2.17 mmol, Aldrich Chemical Company) and heat two hours at 80° C. Cool the reaction and partition between dichloromethane (150 mL) and NaHCO3 solution (40 mL). Wash the organic phase with brine (40 mL), dry (MgSO4), filter and concentrate the filtrate to afford 4-(1-cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.71 g, Rf=0.87, silica gel, 95:5:0.5 dichloromethane:methanol:ammonium hydroxide).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[OH:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1.O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:37]4[CH2:38][CH2:39][C@@H:35]([OH:34])[CH2:36]4)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: O[C@@H]1CCNC1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC[C@@H](O)C3)oc21
Temperature: 90 °C

Procedure:
N,N-Diisopropylethylamine (0.48 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.500 g) were added to a solution of (R)-3-hydroxypyrrolidine (0.22 mL) in DMF (30 mL). The reaction mixture was heated to 90° C. for 2 h. The mixture was allowed to cool to room temperature, poured into water (60 mL), and extracted with ethyl acetate (4×50 mL) then CH2Cl2 (2×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 98/2, 97/3, 95/5) followed by recrystallization from ethyl acetate to yield 0.360 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 189-190° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.64, 8.54, 7.41-7.32, 6.85, 4.73, 4.55, 4.22-4.16, 3.93, 3.68, 2.78-2.74, 2.68-2.62, 2.52-2.47, 2.41-2.37, 2.02-1:94, 1.58-1.50; MS (ESI+) m/z 416 (M+H)+; [α]25D=−3 (CH2Cl2).