Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 7.9 %

Procedure:
Pd(PPh3)2Cl2 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-methoxyphenylboronic acid (16 mg, 0.104 mmol). The mixture was heated under 120° C. under Ar using microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 2′-amino-6-(3-methoxyphenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (1.69 mg, 8%). 1H-NMR (MeOD): 2.05 (m, 1H), 2.21 (m, 1H), 3.06 (m, 3H), 3.72 (s, 3H), 5.19 (m, 0.3H), 5.81 (m, 0.7H), 6.76 (m, 1H), 6.91 (m, 2H), 6.97 (m, 1H), 7.08 (m, 1H), 7.21 (m, 1H), 7.26 (m, 1H), 7.33 (m, 2H), 7.39 (m, 2H), 7.57 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:13]2[C:8](=[N:9][C:10]([N:24](C(OC(C)(C)C)=O)[NH:25][C:26](OC(C)(C)C)=O)=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[CH3:40]C(O)=O>>[CH3:40][C:26]1[N:9]2[C:8]3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:14]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:16])=[O:17])[C:13]=3[CH:12]=[CH:11][C:10]2=[N:24][N:25]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccccc1
Product: CCOC(=O)c1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Temperature: 180 °C
Yield: 74 %

Procedure:
A solution of di-tert-butyl 1-[2-(ethoxycarbonyl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (2.5 g, 4.4 mmol, from Step 2) in AcOH (40 mL) was split into 5 batches and each was heated in the microwave to a temperature of 180° C. for 3 minutes. The reaction contents were pooled and AcOH was removed in vacuo. The residue was dissolved in EtOAc and washed with sat′d NaHCO3 solution, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-100% EtOAc in hexanes, followed by 10% MeOH in DCM as mobile phase afforded solid product (1.27 g, 74%).
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:20])=[CH:11][C:12](=[O:19])[N:13]2[CH2:16][CH:17]=O)=[CH:8][CH:7]=1.[C:21]([O:25][C:26](=[O:45])[N:27]([CH2:34][C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.O.C(O)(=O)C>[C:21]([O:25][C:26](=[O:45])[N:27]([CH2:34][C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1)[CH:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][N:13]2[C:14]3[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH3:4])[CH:15]=3)[C:10]([CH3:20])=[CH:11][C:12]2=[O:19])[CH2:30][CH2:29]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To 5 mL of a dichloromethane solution containing 64 mg of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.11 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 16 μl of acetic acid were added and stirred for 1 hour. To the reaction mixture, 89 mg of sodium triacetoxyborohydride was added and stirred for 1 hour. Water and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform] to give 98 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
According to the new process, the 4-nitrobenzoic acid chloride is condensed with aniline and the 4-nitro-benzanilide formed is extracted and nitrated.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1.[I:21]I>C1COCC1>[F:13][C:14]1[C:19]([I:21])=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1
Reactant: Cc1ccc(F)nc1
Reactant: II
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cnc(F)c(I)c1
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
A solution of diisopropylamine (7.0 mL, 50.0 mmol) in THF (100 mL) at −78° C. was treated with 2.5M n-butyllithium in hexanes (20 mL, 50.0 mmol), stirred for 15 minutes, treated dropwise with a solution of 2-fluoro-5-methylpyridine (5.55 g, 50.0 mmol) in THF (20.0 mL), stirred for 4 hours, treated slowly with a solution of iodine (12.7 g. 50.0 mmol) in THF (50 mL), quenched with water, and extracted with diethyl ether. The combined extracts were washed sequentially with Na2S2O3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/diethyl ether to provide 7.24 g (61%) of 2-fluoro-3-iodo-5-methylpyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([C:20](=[O:22])[CH3:21])=[C:15]([CH3:23])[CH:14]=1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu](I)I.O>[CH:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([O:12][C:13]2[CH:14]=[C:15]([CH3:23])[C:16]([C:20](=[O:22])[CH3:21])=[C:17]([CH3:19])[CH:18]=2)=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(Br)cc1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1c(C)cc(Oc2ccc(OC(C)C)cc2)cc1C
Temperature: 90 °C
Yield: 49.6 %

Procedure:
A mixture of 1-bromo-4-isopropoxybenzene (16-3, 3.02 g, 14.0 mmol), 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 3.54 g, 21.6 mmol), N,N-dimethylglycine HCl salt (0.50 g, 3.5 mmol), copper iodide (0.34 g, 1.8 mmol), and cesium carbonate (9.08 g, 27.9 mmol) in dioxane (30 mL) was heated at 90° C. for 48 h. The reaction mixture was cooled to room temperature, added with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by column chromatography on silica gel (EtOAc:hexanes=1:20 as eluant) to give 1-(4-(4-isopropoxyphenoxy)-2,6-dimethylphenyl)ethanone (16-4, 2.07 g) as white solids in 79% yield: 1H NMR (500 MHz, CDCl3) δ 6.94 (m, 2 H), 6.87 (m, 2 H), 6.58 (s, 2 H), 4.50 (t, J=6.1 Hz, 1 H), 2.46 (s, 3 H), 2.21 (s, 6 H), 1.34 (s, 6 H), 1.26 (m, 3 H), 0.87 (m, 3 H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([CH:23]([O:47][SiH](C)C)[C:24]1[C:25]([CH:44]([CH3:46])[CH3:45])=[N:26][C:27]([CH:41]([CH3:43])[CH3:42])=[C:28]([CH:37]=[N:38][O:39][CH3:40])[C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)(C)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:44]([C:25]1[C:24]([CH2:23][OH:47])=[C:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:28]([CH:37]=[N:38][O:39][CH3:40])=[C:27]([CH:41]([CH3:43])[CH3:42])[N:26]=1)([CH3:46])[CH3:45]
Reactant: CON=Cc1c(C(C)C)nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c1-c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CON=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
3.3 ml (3.3 mmol) of 1 M tetrabutylammonium fluoride solution in tetrahydrofuran is added to a solution of 1.5 g (3.3 mmol) of the compound from Example 1 in 15 ml of absolute tetrahydrofuran and the mixture is stirred at room temperature for 1 hour Saturated sodium hydrogencarbonate solution is then added to the reaction solution and it is extracted several times with methylene chloride. The combined organic phases are dried (MgSO4), concentrated and then filtered through silica gel.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: OCCc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: OCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was added 13.8 grams of 2-(4-hydroxyphenyl)ethanol, 14.5 grams of anhydrous potassium carbonate, 33.0 grams of tetrabutylammonium bromide, 12 mL of benzyl chloride and 200 mL of acetone. The reaction mixture was heated at reflux for 3 days, and then cooled to room temperature and filtered. The filtrate was concentrated in vacuo, diluted with 500 mL of dichloromethane, and washed with 2% aqueous sodium hydroxide and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was purified by chromatography on silica gel, eluting with dichloromethane, to yield 20.0 grams of the desired product as a white solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1>O.CN(C)C=O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([S:2][CH3:1])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of sodium methanethiolate (2.25 g, 70.1 mmol) in water (50 mL) was added dropwise to a solution of 4-bromo-2-fluoro-1-nitrobenzene (6.42 g, 29.2 mmol) in N,N-dimethylformamide (150 mL) at 0° C. and the mixture was stirred for 1 hour. The mixture was filtered and the solid washed with water (3×150 mL) to give the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=2)[CH2:31][CH2:32]1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3C)CC2)n(-c2ccccc2)n1

Procedure:
146 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-(2,3-dimethylphenyl)piperazine (79 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])=[CH:12][CH:11]=1)[C:14]([OH:16])=[O:15])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CCOc1ccc(C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: Cc1ccccc1
Product: CC(C)CCOc1ccc(C(CC(=O)OCc2ccccc2)C(=O)O)cc1
Yield: 81.2 %

Procedure:
A suspension of 4-benzyl 1-tert-butyl 2-[4-(isopentyloxy)phenyl]succinate (2.00 g, 4.69 mmol) and silica gel (23.4 g) in toluene (150 mL) was heated at reflux for 3 h. The crude mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane/methanol (8:2; 2×100 mL) then the organic filtrates were combined and evaporated to dryness to give the title compound as white solid (1.41 g, 82%). LC/MS: 3.74 min; z/e 388, calcd (M+1) 388. The enantiomers were separated using a Chiralpak AD column (20% EtOH: Heptane: 0.1% TFA), Flow 20 mL/min, λ=215 nM Ent-1=12.5 min, Ent-2=15.0 min.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25]([OH:27])=O)=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.C([O:41][C:42](=[O:46])[CH2:43][NH:44][CH3:45])C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:33])([CH3:1])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25]([N:44]([CH2:43][C:42]([OH:46])=[O:41])[CH3:45])=[O:27])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)N(C)CC(=O)O)cc2c1
Yield: 73.1 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid (720 mg, 1.60 mmol) in CH2Cl2 (10 mL) and DMAP (586 mg, 4.80 mmol) and EDC (460 mg, 2.40 mmol) are reacted with sarcosine ethyl ester hydrochloride (368 mg, 2.40 mmol) and the intermediate ester is hydrolyzed analogous to Example 7 to yield title compound (610 mg, 73%). MS (ES) m/e: 520.3 (M−1), 522.3 (M+1)
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[NH:22][CH:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)[CH2:5][CH2:4]1>[Pd].CO>[F:1][C:2]([F:30])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[NH:22][CH:23]2[CH2:24][C:25]([F:27])([F:28])[CH2:26]2)[CH2:5][CH2:4]1
Reactant: CNc1cc(NC2CC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1cc(NC2CC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reaction time: 6 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3,3-difluoro-cyclobutylamino]-4-methylamino-5-nitro-benzoic acid amide (crude product from the reaction above), Pd/C (50 mg) and MeOH (10 ml) is stirred under 3 bar H2-atmosphere for 6 h. The mixture is filtered, and the filtrate is concentrated and directly used in the next step.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH:7]2[CH:8]=[CH:9][CH:4]1[NH:5][CH2:6]2>[Pd].CO>[BrH:1].[Cl:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH:4]2[CH2:9][CH2:8][CH:7]([CH2:6][NH:5]2)[CH2:10]1
Reactant: COC(=O)C1(Cl)CC2C=CC1NC2
Agent: [Pd]
Agent: Br
Solvent: CO
Product: COC(=O)C1(Cl)CC2CCC1NC2
Reaction time: 8 h

Procedure:
8.5 g. (0.03 moles) of 7-chloro-7-methoxycarbonyl-2-azabicyclo[2.2.2]oct-5-ene hydrobromide are dissolved in 85 ml. of methanol. 0.85 g. of a 10% palladium-on-charcoal catalyst are prehydrogenated in 15 ml. of methanol, and a clear solution of the starting material to be hydrogenated is added in a closed system. Hydrogenation is carried out in a closed system, the progress of the reaction is monitored by measuring the hydrogen consumption. When the calculated amount of hydrogen is used up, the reaction is terminated. When the reaction is not terminated timely, the reaction proceeds further and the chlorine is replaced by hydrogen. The catalyst is filtered off, the solution is evaporated. A crystalline material is obtained, which is triturated in about 20 ml. of acetone, and allowed to stand overnight in a refrigerator. The precipitate is filtered off on the next day, pulpified with two 5-ml. portions of cold acetone, and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])NC2CCN(C(C)C)CC2)=[O:10])=[N:6][CH:7]=1.CNCC[OH:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[C:13]2[C:24]([OH:40])=[O:35])=[O:10])=[N:6][CH:7]=1
Reactant: CNCCO
Reactant: CC(C)N1CCC(NC(=O)c2nc3cc(C(=O)O)ccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: O=C(Cn1c(C(=O)O)nc2cc(C(=O)O)ccc21)Nc1ccc(Cl)cn1

Procedure:
5-[(2-hydroxy-ethyl)-methyl-amide]2-[(1-isopropyl-piperidin-4-yl)-amide]1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-methyl-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid and 8.3 mg (0.11 mmol) N-methyl-2-aminoethanol. The title compound was obtained as its formiate in form of a white amorphous solid. Yield: 23 mg MS (ES+): m/e=556, chloro pattern.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[N:18]=[C:19]([NH:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:20]2[N:21]([C:23]([CH3:26])=[N:24][N:25]=2)[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34]CN(C(C)C)C(C)C.C=O>C1COCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[N:18]=[C:19]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[C:20]2[N:21]([C:23]([CH3:26])=[N:24][N:25]=2)[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2c(NC3CCNCC3)nc(-c3nc4ccccc4n3Cc3ccccc3)cn12
Agent: C=O
Solvent: C1CCOC1
Product: Cc1nnc2c(NC3CCN(C)CC3)nc(-c3nc4ccccc4n3Cc3ccccc3)cn12
Reaction time: 2 h

Procedure:
N-[6-(1-benzyl-1H-1,3-benzodiazol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]piperidin-4-amine (93 mg; 0.21 mmol) is dissolved in 300 μl THF, treated with DIPEA (62 μl; 0.29 mmol) and formaldehyde (62 μl; 0.83 mmol). To this reaction mixture STAB (62 mg; 0.29 mmol) is added and the reaction mixture is stirred for 2 hours. The crude reaction mixture is purified by reversed phase chromatograph (Method: prep. HPLC1).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)[CH:2]=C.C1C[O:17]CC1.O=[O+][O-].[BH4-].[Na+]>CO>[OH:17][CH2:2][CH2:1][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: C1CCOC1
Reactant: C=CCc1ccc2c(c1)COC2=O
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1OCc2cc(CCO)ccc21
Temperature: 25 °C

Procedure:
5-allyl-2-benzofuran-1(3H)-one (1.53 g, 8.78 mmol) was dissolved in methanol (30 mL). THF was added to solubilize the starting material. The resulting mixture was cooled in a dry ice acetone bath (−78° C.) and ozone was bubbled into the reaction until the color of the mixture changed to orange. Nitrogen was bubbled into the reaction for one minute to remove the excess ozone. Sodium borohydride (0.65 g, 2.9 mmol) was added at −78° C., and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was concentrated part way and then taken up in ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.8 %

Procedure:
To a solution of (4-fluoro-phenyl)-(4-nitrophenyl)-methanone (2.0 g, 8.2 mmol) in dichloromethane (16 mL) at, 0° C. was added trifluromethanesulfonic acid (1.4 mL, 16 mmol) in dichloromethane (16 mL). A solution of triethylsilane (2 mL, 12 mmol) in dichloromethane (16 mL) was subsequently added dropwise, resulting in an exotherm. After 5 min, additional trifluoromethanesulfonic acid (1.4 mL, 16 mmol) was added, followed by triethylsilane (2.0 mL, 12 mmol). The reaction mixture was stirred at rt for 2 h, then poured into cold saturated sodium bicarbonate and extracted several times with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography eluting with 0-10% ethyl acetate in hexanes, gave the desired product as a white solid (260 mg, 14%). 1H NMR (CHCl3-d) δ 8.14 (m, 2H), 7.31 (m, 2H), 7.12 (m, 2H), 7.01 (m, 2H), 4.06 (s, 2H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Product: CN(C(=O)Oc1ccc(Cc2ccccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-benzyl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (56%, white crystals). HPLC-MS m/z=318.1 (M+l), Rt: 5.05 min.