Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.[OH-].[NH4+].CCOCC>O1CCCC1.CN(C)C1C=CN=CC=1>[C:1]1(=[O:24])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][C:8]([NH2:27])=[O:9])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)CC(c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h
Yield: 35.6 %

Procedure:
To a stirred solution of 3-phthalimido-3-(3,4-dichlorophenyl)propionic acid (1.10 g, 3.02 mmol) in 20 mL of tetrahydrofuran at room temperature under nitrogen was added carbonyldiimidazole (0.51 g, 3.17 mmol) and a catalytic amount of 4-dimethylaminopyridine The mixture was stirred for 45 in and then concentrated ammonium hydroxide (0.21 mL, 3.2 mmol) was added. The reaction mixture was stirred for 10 minutes and then the tetrahydrofuran was removed under reduced pressure. To the resulting mixture was added 20 mL of water, a light yellow oil was formed. To the mixture was added 3 mL of ether, the mixture was stirred at room temperature for 1 hour. The resulting slurry was filtered, the solid was washed with water and air-dried to afford 0.73 g of the crude product as a white solid. The crude product was purified by flash chromatography (silica gel, hexane/methylene chloride, 220% (v/v)) to afford 0.39 g (36%) of 3-phthalimido-3-(3,4-dichlorophenyl)propionamide as a white powder: 1H NMR (DMSO-d6, 250 MHz) δ7.83 (m, 4H, Ar), 7.35-7.75 (m, 4H), 6.93 (br s, 1H), 5.72 (t, 1H, J=8 Hz), 3.23 (dd, 1H, J1 =8 Hz, J2 =15 Hz), 3.14 (dd, 1H, J1 =8 Hz, J2 =15 Hz); 13C NMR (DMSO-d6) δ170.8, 167.6, 140.2, 134.6, 131.2, 131.0, 130.7, 130.3, 129.2, 127.7, 123.2, 49.3, 36.5. Anal. Calcd for C17H12 N2O3Cl2. Theoretical C, 54.69; H, 3.54; N, 7.53. Found C, 54.69; H, 3.38; N, 7.15.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:11][CH:12]=[N:13][CH:14]=1.[Br:21][C:22]1[C:30]2[N:29]=[C:28](Cl)[NH:27][C:26]=2[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1.C(N(CC)C(C)C)(C)C>>[Br:21][C:22]1[C:30]2[N:29]=[C:28]([N:18]3[CH2:17][CH2:16][N:15]([C:10]4[C:9]([Cl:8])=[CH:14][N:13]=[CH:12][N:11]=4)[CH2:20][CH2:19]3)[NH:27][C:26]=2[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1
Reactant: Clc1cncnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncncc4Cl)CC3)[nH]c2c1

Procedure:
The reaction of 1-(5-chloropyrimidin-4-yl)piperazine trifluoroacetic acid salt (0.414 g, 0.97 mmol, Example 33d), 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.29 g, 0.97 mmol, Example 9b) and N,N-diisopropylethylamine (0.5 mL, 2.91 mmol, Aldrich) under the conditions of Example 1d gave the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.C([O-])(=O)C.[NH4+:30]>C(O)(=O)C>[C:20]1([C:2]2[N:30]=[C:10]3[C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=4[NH:7][C:6]4[N:16]=[CH:17][CH:18]=[CH:19][C:5]=4[N:4]3[CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CN1C(=O)c2ccccc2Nc2ncccc21)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: c1ccc(-c2cn3c(n2)-c2ccccc2Nc2ncccc2-3)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
To a solution of 5-(2-oxo-2-phenylethyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.5 g, 1 eq.) in acetic acid (5 mL) was added ammonium acetate (4.6 g, 13 eq.). The reaction was stirred at 120° C. for 3 hours. The reaction was poured onto water (100 mL) and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with sodium bicarbonate solution (3×100 mL), water (1×100 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ethyl acetate and ether to give 2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.9 g, 63%). 1H NMR (DMSO-d6) 400 MHz δ 8.51 (s, 1H), 8.19 (dd, JA=5.2 Hz, JB=1.6 Hz, 1H), 8.14 (s, 1H), 7.96-7.87 (m, 4H), 7.45 (t, J=8 Hz, 2H), 7.36-7.28 (m, 2H), 7.22-7.15 (m, 2H), 7.12-7.07 (m, 1H); LCMS: 311 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH2:29])[CH3:22].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]2[CH2:21][CH3:22])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCC1CCCCC1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1CCCCC1Nc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a solution of 0.48 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 1.5 ml of abs. DMF was added 1.00 g of potassium carbonate, followed by 0.31 g of 2-ethylcyclohexylamine. After 16 h at rt, the mixture was poured into water, the pH was adjusted to 4 by the addition of 2 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 0.44 g (60%) of 4-(2-Ethyl-cyclohexylamino)-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:14](=[O:17])[CH2:15][CH3:16].C(O)C>[C].[Pd].O1CCCC1>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[NH:4][C:3]([C:14](=[O:17])[CH2:15][CH3:16])=[C:2]2[CH3:1]
Reactant: CCC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(=O)c1[nH]c2c(N)cccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 1-(3-methyl-7-nitro-1H-indol-2-yl)propan-1-one (0.29 g), 10% palladium-carbon (50% containing water, 0.03 g), ethanol (4 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight under a hydrogen atmosphere. Palladium-carbon was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.17 g, yield 70%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). melting point>194° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][CH:15]=[N:16][C:10]=2[CH:9]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]2=[O:40])=[N:31][CH:32]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][N:16]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]4=[O:40])=[N:31][CH:32]=3)[C:10]=2[CH:9]1[C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1ccc(Cl)cn1-c1ccc(CBr)cn1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ncn(Cc3ccc(-n4cc(Cl)ccc4=O)nc3)c2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(4-Cyano-phenyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (0.16 g, 0.50 mmol) and 5'-bromomethyl-5-chloro-[1,2']bipyridinyl-2-one (Example 10, Step 2)(0.15 g, 0.50 mmol) were dissolved in DMF (6 mL). NaH (0.02 g, 0.60 mmol) was added and stirred at RT under Ar for 1.5 h. The reaction was concentrated in vacuo and partitioned between EtOAc and satd NaHCO3 soln, washed with H2O, brine, dried (MgSO4), filtered and concentrated to give the title compound as a mixture of racemic regioisomers.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:35][CH2:36]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(C)cc4C)CC3)nn2-c2ccccc2)cc1

Procedure:
113 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(2,4-dimethylphenyl)piperazine (53 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[N:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][C:5]2[N:13]=[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][N:7]3[N:6]=2)[CH2:24][CH2:23]1
Reactant: ClCCCc1nc2ccccn2n1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCc2nc3ccccn3n2)CC1
Yield: 60 %

Procedure:
A solution of 3.9 g of 2-(3-chloropropyl)-s-triazolo[1,5-a]pyridine, 3.8 g of 1-o-methoxyphenylpiperazine and 2.8 g of potassium carbonate in 150 ml of dimethylformamide was refluxed for 8 hours. Then the reaction mixture was proceeded by the same manner as described in Example 2. The compound was recrystallized from cyclohexane to give colorless prisms, mp 55°-55.5° C. Yield was 60%. Anal. Calcd. for C20H25ON5 : C, 68.35; H, 7.17; N, 19.53. Found: C, 68.20; H, 6.94; N, 20.21.
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N:15]2[C:19]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)=[CH:18][NH:17][C:16]2=[O:30])=[CH:7]1)=O)C.CN>C1COCC1>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N:15]2[C:19]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)=[CH:18][NH:17][C:16]2=[O:30])=[CH:7]1
Reactant: CCOC(=O)n1cc(-n2c(-c3cn(C)c4ccccc34)c[nH]c2=O)c2ccccc21
Agent: CN
Solvent: C1CCOC1
Product: Cn1cc(-c2c[nH]c(=O)n2-c2c[nH]c3ccccc23)c2ccccc21
Yield: 94 %

Procedure:
The sub-title product of step c) (0.17 g, 0.44 mmol) was dissolved in THF (3 ml) and aqueous methyl amine (40%, 3 ml) and stirred for 30 minutes. The solvent was removed and the product precipitated from diethyl ether to give the title compound (0.14 g, 94%) as a slightly brown solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9]
Reactant: CC(C)(C)O
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccccc1
Temperature: 50 °C

Procedure:
Phenylisocyanate (500 g) and tert-butanol (500 mL) are mixed in toluene (500 mL) in a 2 L round bottom flask. The solution is stirred over night in a 50° C. water bath. The N-Boc aniline is collected by filtration to give the white solid (702 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O[CH2:13][CH:14]([CH2:16]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]2[C:8]=1[CH:13]=[CH:14][CH:16]=[N:7]2
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c2ncccc12
Temperature: 105 °C
Yield: 76.8 %

Procedure:
5-methyl-2-nitroaniline (1.0 g, 6.57 mmol), glycerol (1.88 g, 20.4 mmol), 3-nitrobenzenesulfonic acid sodium salt (1.92 g, 8.54 mmol) were added to H2SO4/H2O (6 ml, 7:5) solution and heated at 105° C. for 48 h. After completion of the reaction (monitored by LCMS), the mixture was cooled to 45° C. and poured slowly onto ice water (50 ml) and the mixture was extracted with DCM. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give the title compound (950 mg, 77%) which was used in the next step without purification.
Reaction SMILES: CC(OC([NH:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:11]=2[N:10]=1)=O)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30].CN(C)C=O.FC(F)(F)C(O)=O>ClCCl.O>[NH2:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]([NH:18][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:22]=3)=[O:28])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(N)cc2s1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-aminobenzothiazol-2-yl tert-butyl carbamate (Intermediate 4, 0.796 g, 3.0 mmol), 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.731 g, 3.3 mmol) and dimethylformamide (80 mL) was stirred overnight at r.t. Water was added, the resulting precipitate was filtered off, washed thoroughly with water and dried. The so obtained material was suspended in dichloromethane (15 mL) and trifluoroacetic acid (15 mL) was added. After stirring for 1.5 h at r.t., the volatiles were removed in vacuo and dimethylformamide (20 mL) was added to the residue. The solution was neutralised by adding saturated sodium hydrogencarbonate solution. Water was added and the resulting precipitate was filtered off, washed with water and dried (grey solid, 0.999 g, 2.58 mmol, 86%). LC/ESI-MS: m/z=387 [M(35Cl)+H]+; m/z=385 [M(35Cl)−H]−; Rt=3.54 min.
Reaction SMILES: [CH3:1][O:2][CH:3](C)[C:4]([CH3:11])=[CH:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].[CH:13]([Mg]Cl)=[CH2:14].O>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]([CH3:11])=[CH:5][CH2:6][CH2:7][C:8]([CH3:9])([OH:10])[CH:13]=[CH2:14]
Reactant: C=C[Mg]Cl
Reactant: COC(C)C(C)=CCCC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)(O)CCC=C(C)COC
Yield: 85 %

Procedure:
141 g (0.9 mole) of 7-methoxy-6-methyl-oct-5-en-2-one are added to 1 mole of a 1.5 normal solution of vinyl-magnesium chloride in tetrahydrofuran, at below 20° C, in the course of one hour. After a further 2 hours' reaction, hydrolysis is carried out with 100 ml of water, whilst cooling with ice. After a homogeneous salt suspension has formed, the salt and the tetrahydrofuran solution are separated by filtering or centrifuging. The tetrahydrofuran is distilled off under reduced pressure and the reaction product which remains is purified by fractional distillation. 164 g of 8-methoxy-3,7-dimethyl-octa-1,6-dien-3-ol (yield 85%) are obtained. Boiling point 73°-75° C/0.01 bar; nD25 = 1.4676.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1>C1COCC1>[C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
1-Boc-isonipecotic acid (10.0 g, 214 mmol) was dissolved in THF (400 mL) and cooled to 0° C. A solution of BH3.THF (180 mL, 1 N in THF, 180 mmol) was added slowly. The mixture stirred for 1 h at 0° C. and was allowed to warm to room temperature for 12 h. The mixture was carefully quenched with water and diluted with ethyl acetate. The water layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated to provide 1-Boc-piperidine-4-methanol (7.98 g, 85%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([N:12]3[CH2:17][CH2:16][C:15]4([C:29]5[CH:28]=[N:27][N:26]([CH3:30])[C:25]=5[C:24]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:18]4)[CH2:14][CH2:13]3)=[O:11])[C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH3:33]I>C1COCC1.CO>[CH3:33][N:3]1[C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][C:15]4([C:29]5[CH:28]=[N:27][N:26]([CH3:30])[C:25]=5[C:24]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:18]4)[CH2:14][CH2:13]3)=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[CH:2]1
Reactant: CI
Reactant: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2cccc3[nH]cnc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2cccc3ncn(C)c23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1H-benzo[d]imidazol-4-yl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (21 mg, 0.052 mmol) in dry THF (0.2 mL) under N2 was added NaH (1.9 mg, 0.079 mmol) at 0° C. After 30 min, MeI (3.3 μL, 0.052 mmol) was added and the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with water and the solvent removed under vacuum to yield a crude residue that was taken up in methanol and purified by reverse phase HPLC to give (3-methylbenzoimidazol-4-yl)-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 413.5. found 414.5 (M+1)+. Retention time: 1.13 minutes (3 min run).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]2[C:25]3[N:26]=[C:27]([CH2:29][O:30][CH2:31][CH2:32][OH:33])[NH:28][C:24]=3[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[C:8]1([CH2:14][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]2[C:25]3[N:26]=[C:27]([CH2:29][O:30][CH2:31][CH2:32][O:33][S:42]([CH3:41])(=[O:44])=[O:43])[NH:28][C:24]=3[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
Triethylamine (0.17 mL, 1.25 mmole) was added to a solution of N,N-bis(phenylmethyl)-2-(2-hydroxyethoxy)methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.14 mmole) in methylene chloride (20 mL). Methanesulfonyl chloride (0.09 mL, 1.14 mmole) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide 0.6 g of N,N-bis(phenylmethyl)-2-(2-methylsulfonyloxyethoxy)methyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([NH2:28])(=[O:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:16][C:15]([CH3:18])([S:13]([NH:12][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:28][C:25](=[O:27])[CH3:26])=[CH:3][CH:4]=2)[CH2:11][O:10][CH2:9]1)=[O:14])[CH3:17]
Reactant: CC(C)(C)S(=O)NC1(c2ccc(Br)cc2)COC1
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C2(NS(=O)C(C)(C)C)COC2)cc1
Temperature: 100 °C

Procedure:
To a 5 mL microwave tube was added N-(3-(4-bromophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (436 mg, 1.312 mmol), cesium carbonate (1283 mg, 3.94 mmol), and acetamide (116 mg, 1.968 mmol) in dioxane (6.5 ml). Xantphos (76 mg, 0.131 mmol) and tris(dibenzylideneacetone)dipalladium(O) (60.1 mg, 0.066 mmol) were added; the tube was flushed with nitrogen and capped. The mixture was heated at 100° C. for 45 minutes. Aqueous work up with dichloromethane extraction gave an organic layer that was dried with sodium sulfate, filtered and concentrated under vacuum. Regular phase chromatography provided the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.N[C@H](C([C:19]1([NH2:34])[C:25](=[O:26])[N:24]([CH3:27])[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[N:21]([CH3:32])[C:20]1=[O:33])=O)C>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:34][C@H:19]([C:25]([NH:34][CH:19]2[C:20](=[O:33])[N:21]([CH3:32])[C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=3[N:24]([CH3:27])[C:25]2=[O:26])=[O:26])[CH3:20])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(C)c2ccccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2 ,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-R), the title compound was prepared as a white solid (melting point=206-207° C.). Purification was by flash chromatography eluting with straight EtOAc gradient to EtOAc/Acetone (95:5). Rf=0.32 (EtOAc).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1.[OH:19][CH:20]([CH2:27][OH:28])[CH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.[H-].[Na+]>>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][CH:20]([OH:19])[CH2:27][OH:28])[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ICCCc1cccc(OCc2ccccc2)c1
Reactant: OCC(O)Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCc1cccc(OCc2ccccc2)c1
Yield: 63.6 %

Procedure:
Using benzyl 3-(3-iodopropyl)phenyl ether (1.98 g), 2-(2,3-dihydroxypropyl)imidazole (1.0 g) and 65% oily sodium hydride (0.259 g), the same reaction as Reference Example 11-(iv) was carried out to yield the titled compound (1.31 g) as a colorless oily substance.