Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]#[N:10].Cl.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([CH:5]3[CH2:6][CH2:2][N:3]([CH2:8][C:9]#[N:10])[C:4]3=[O:7])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: N#CCN1C(=O)CCC1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC#N)C3=O)CC2)cc1
Yield: 77.3 %

Procedure:
To a solution of 2-(2-bromo-5-oxopyrrolidin-1-yl)acetonitrile (730 mg, 3.6 mmol) and (4-methoxyphenyl)(piperidin-4-yl)methanone hydrochloride (920 mg, 3.6 mmol) in acetonitrile (4 mL) was added triethylamine (1.5 mL, 11 mmol). The mixture was microwave at 130° C. for 12 minutes. The solvent was removed in vacuo and the residue was taken up in methylene chloride and water. The organic layer was purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide slightly yellow oil (950 mg, 74% yield). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 4.22-4.39 (m, 2H), 3.90 (s, 3H), 3.57 (dt, J=22.6, 9.0 Hz, 2H), 3.40-3.51 (m, J=8.5 Hz, 1H), 3.23-3.39 (br s, 1H), 2.93-3.20 (m, 3H), 2.33-2.61 (m, 2H), 2.13-2.31 (m, 1H), 1.83-2.03 (m, 4H). HRMS calculated for C13H23N3O3 342.1818. found (ESI, [M+H]+), 342.1830.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].Cl.[NH2:13][OH:14].[OH-].[Na+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:13][OH:14])=[O:11]
Reactant: NO
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NO)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
A solution of 14.2 g (75 mmol) of 2,4-dichlorophenylisocyanate in 50 mL of toluene was added to a mixture of 8.26 g (120 mmol) of hydroxylamine hydrochloride and 4.8 g (120 mmol) of sodium hydroxide in a two-phase solvent mixture consisting of 50 mL of water and 50 mL of toluene. The resulting mixture was stirred at 25° C. for 30 minutes and filtered. The solid thus obtained was washed with water and then dissolved in 200 mL of ethyl acetate. The solution was dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 12.7 g of the title compound of Step A as a white solid melting at 157-158° C. It was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:8]1[CH2:11][CH2:12][O:13][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: OCCO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2OCCO2)cc1
Reaction time: 5 h

Procedure:
To a solution of 4-cyanobenzaldehyde (5-1) (20.0 g, 152.5 mmol) and ethylene glycol (25.5 mL, 457.5 mmol) in toluene (250 mL) was added p-toluenesulfonic acid (300 mg). The flask was equipped with a Dean-Stark trap and the mixture heated to reflux. After 5 hours, the mixture was concentrated. The residue was taken up in ethyl acetate and washed with saturated NaHCO3, H2O (2×), and brine. The organic layer was dried (Mg504), filtered, and concentrated to give 4-(1,3-dioxolan-2-yl)benzonitrile as a clear oil which solidified under vacuum: 1H-NMR (500 MHz, CDCl3) δ 7.67 (d, J=8.06 Hz, 2H), 7.59 (d, J=8.30 Hz, 2H), 5.85 (s, 1H), 4.13-4.05 (m, 4H).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:35])[C:20]([C:33]#[N:34])=[C:21]4[C:27]=3[O:26][CH:25]([CH3:28])[CH2:24][N:23]([CH:29]3[CH2:32][NH:31][CH2:30]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12.C(N(CC)CC)C.[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1>CN(C)C=O>[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:15]([C:17]3[CH:18]=[C:19]([Cl:35])[C:20]([C:33]#[N:34])=[C:21]4[C:27]=3[O:26][CH:25]([CH3:28])[CH2:24][N:23]([CH:29]3[CH2:32][N:31]([CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH2:30]3)[CH2:22]4)[CH3:16])[N:12]=[C:13]([CH3:14])[C:6]=12
Reactant: CC1(C)CO1
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CNC2)C3)c2ncnc(N)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CN(CC(C)(C)O)C2)C3)c2ncnc(N)c12
Temperature: 85 °C
Reaction time: 4 h

Procedure:
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride (0.015 g, 0.034 mmol) was dissolved in N,N-dimethylformamide (1.0 mL) and triethylamine (0.025 mL, 0.18 mmol), and 2,2-dimethyloxirane (0.050 g) was added. The reaction was heated to 85° C. stirred for 4 h. The reaction was concentrated in vacuo, and the product was purified without workup by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as two diastereomers: Peak #1 (Example 54) (0.002 g, 13%): LCMS calculated for C26H34ClN8O2 (M+H)+: m/z=525.2; found: 525.2; Peak #2 (Example 55) (0.002 g 13%): LCMS calculated for C26H34ClN8O2 (M+H)+: m/z=525.2; found: 525.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH2:33]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1)[CH3:34]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[C@H:35]([CH2:33][CH3:34])[CH2:39][O:38][C:37]5=[O:40])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 85.7 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (519 mg) described in Preparation Example 179 and (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, the title compound (474 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 389.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([O:12]CC)=[O:11])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7]([CH2:9][C:10]([OH:12])=[O:11])=[O:8])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CS(=O)Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CS(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 2-(4-fluorobenzylsulfinyl)acetate (1.60 g, 6.55 mmol) in THF (10.0 mL) and MeOH (20.0 mL) was added 1 N NaOH (20.0 mmol). The mixture was stirred at room temperature for 2 h. After removal of organic solvent under reduced pressure, the remaining aqueous solution was neutralized with 1 N HCl (25.0 mL). It was extracted with EtOAc (3×100 mL) and the combined organic layer was dried over MgSO4. The solution was then filtered and concentrated in vacuo to give 2-(4-fluorobenzylsulfinyl)acetic acid (1.25 g, 88% yield). MS (ESI+): m/z 217.05 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([C:8]([O:10][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ncc(Br)cc1C
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 83.3 %

Procedure:
To a solution 5-bromo-3-methylpyridine-2-carboxylic acid (2.6 g, 12 mmol) in N,N-dimethylformamide (20.0 mL) was added potassium carbonate (4.99 g, 36.1 mmol) and methyl iodide (1.50 mL, 24.1 mmol) and the reaction was stirred 80° C. for 40 min. The reaction mixture was partitioned with EtOAc and water. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2.3 g (83% yield) of the desired product as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:49](Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C>[CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[CH:23][CH:24]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]([CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: BrCc1ccccc1
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a mixture of ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.65 g), potassium carbonate (0.533 g) and dimethylformamide (6 ml) is added benzyl bromide (0.33 g). The mixture is stirred at room temperature for one hour, then diluted with ethyl acetate. The solution is washed with water, dried, and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-5-benzyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.49 g).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[C:37]([CH:38]=O)=[CH:36][NH:35][N:34]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:38][C:37]4[C:33]([CH3:32])=[N:34][NH:35][CH:36]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: Cc1n[nH]cc1C=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]nc4C)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 3-methyl-1H-pyrazole-4-carboxaldehyde (9 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1nc(-c2ccccc2)cs1)c1cc(Br)ccc1O
Yield: 16 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole as the raw materials, the same operation as the example 195(3) gave the title compound.
Reaction SMILES: CS(C1C=C[C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].N1CCCCC1>>[CH3:31][NH:30][S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:14]2[CH2:8][CH2:15][CH2:16][CH2:17][CH2:18]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:33])=[O:32]
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc(N2CCCCC2)c(C(=O)O)c1
Yield: 48 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-methylsulfamoyl-benzoic acid and piperidine and obtained in 48% yield. MS (m/e): 297.4 MH−(100%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:10][CH2:11][CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH3:9].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O>[CH2:8]([O:10][CH2:11][CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[N:22]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH3:9]
Reactant: BrCc1ccccc1
Reactant: CCOCCn1c(NC2CCN(C(=O)OCC)CC2)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(N(Cc2ccccc2)C2CCN(C(=O)OCC)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
A mixture of 2.7 parts of a sodium hydride dispersion 50% and 282 parts of N,N-dimethylformamide was stirred at room temperature under nitrogen atmosphere. 18.8 Parts of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate were added portionwise to the previous mixture. Upon complete addition, stirring for continued for 1 hour at room temperature. 10 Parts of (bromomethyl)benzene were added dropwise and upon completion, stirring was continued for 1 hour. The reaction mixture was decomposed with water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and ethanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 parts (13.6%) of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b] pyridin-2-yl](phenylmethyl)amino]-1-piperidinecarboxylate; mp. 115.0° C. (compound 177).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C[Al](C)C.[CH2:9]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:10][CH3:11]>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:13]1[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=[C:12]1[CH2:9][CH2:10][CH3:11])[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: CCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCNC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Reaction time: 0.05 h

Procedure:
A solution of n-propylamine (3.0 mL, 36 mmol) in dichloromethane (75 mL) was cooled to 0° C.; trimethylaluminum (available as a 2 M solution in toluene, 18 mL, 36 mmol) was added dropwise with stirring over a period of three minutes. The reaction was stirred for one hour at 0° C. and 30 minutes at ambient temperature. A solution of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate (5.80 g, 17.8 mmol, prepared as described in Parts A-D of Example 1) in dichloromethane (30 mL) was added, and the reaction was then heated at reflux for three days. The work-up procedure described in Part E of Example 1 was followed to provide N-propyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide as a brown oil.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1>O1CCCC1>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]([OH:9])[CH3:1])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: [Li]C
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 66 %

Procedure:
A solution of methyl lithium (46 mL, 1.4 M in Et2O), was slowly added under argon, at −78° C., to a stirred solution of 4-chloro-2-nitrobenzaldehyde (10 g, 53.9 mmol) in dry tetrahydrofuran (150 mL). After 20 min. at −78° C., the reaction mixture was quenched with water (400 mL), extracted twice with ethyl acetate (500 mL), dried (Na2SO4), and concentrated to dryness under reduced pressure. Chromatography on silica (EtOAc/CH2Cl2/EtOH, 1:6:1) yielded the title compound (7.2 g, 66%) as yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.56 (d, J=6.4 Hz, 3H, ArH), 2.40 (br s, 1H, OH), 5.42 (q, J=6.4 Hz, 1H, CH), 7.63 (dd, J=8.4 Hz, J=2.0 Hz, 1H, ArH), 7.82 (d, J=8.4 Hz, 1H, ArH), 7.92 (d, J=2.0 Hz, 1H, ArH).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]([NH:14][CH2:15][CH2:16][OH:17])([CH3:13])[CH3:12].C(N(CC)CC)C>O1CCCC1>[CH:11]([N:14]([CH2:15][CH2:16][OH:17])[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)([CH3:13])[CH3:12]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(CCO)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chlorobenzoxazole (23.04 g) was added dropwise to an ice-cooled solution of 2-(isopropylamino)ethanol (15.45 g) and triethylamine (30.3 g) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 30 minutes, then heated at reflux overnight before being cooled and evaporated. The residue was dissolved in dichloromethane (800 ml) and washed with saturated sodium bicarbonate solution (500 ml), water (3×1 l) brine (1 l), dried (MgSO4), filtered and evaporated. The title compound was obtained as an oil following chromatography on silica gel using 1.5% methanol-dichloromethane as solvent.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])C.[CH3:40][Li].[Cl-].[NH4+]>O1CCCC1>[C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:32])=[O:31])[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)(=[O:5])[CH3:40]
Reactant: [Li]C
Reactant: CCOC(=O)c1ncc2c(c1COC)c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1c(C(C)=O)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
3.3 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid ethyl ester is suspended in 25 ml of absolute tetrahydrofuran (THF) and cooled to -60° C. under an N2 atmosphere. To this suspension is added dropwise 5.2 ml of a 1.5-molar ethereal methyllithium solution and the mixture is stirred for another 2 hours at -60° C. After heating to room temperature, the reaction mixture is combined with saturated ammonium chloride solution and extracted with ethyl acetate. The crude product is purified by chromatography on silica gel with toluene+ethyl acetate in a ratio of 95:5.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH:22]1([CH:28]=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][N:9]1[CH2:28][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Reactant: O=CC1CCCCC1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1CC1CCCCC1

Procedure:
L4. (2S,4R)-4-Benzenesulfonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride prepared in analogy to experiment K1 was reductively aminated with cyclohexanecarbaldehyde in analogy to experiment L3 to give (2S,4R)-4-benzenesulfonyl-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a white solid. MS: 390.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]=[CH:4][I:5].N1C=CN=C1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].CCCCCC>CN(C)C=O>[I:5][CH:4]=[CH:3][C:2]([CH3:11])([O:1][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCC(C)(O)C=CI
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCC(C)(C=CI)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a stirred solution of 11.7 g of 3-hydroxy-1-iodo-3-methyl-1octene (Example 184) and 7.4 of imidazole in 45 ml of dry dimethylformamide is added dropwise 5.98 g of trimethylsilylchloride at 0° C under argon atmosphere. After stirring at 0° C for an additional 15 minutes, the solution is stirred at ambient temperature for 18 hours. The reaction mixture is poured into 600 ml of hexane and the resulting solution washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and taken to dryness to furnish 14.7 g of oil. Distillation affords 13.4 g of clear oil; bp 65° C (0.05 mm); λ max 6.21, 8.00, 9.90, 10.51, 11.90, 13.2μ.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([OH:10])=O)[NH:5][N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[Cl:18][C:15]1[CH:14]=[C:13]2[C:12](=[CH:17][CH:16]=1)[NH:11][C:8](=[O:10])[C:7]([C:4]1[NH:5][N:6]=[C:2]([CH3:1])[CH:3]=1)=[C:19]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cc(CC(=O)O)[nH]n1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)[nH]n1
Yield: 23 %

Procedure:
Synthesized from 5-methyl-2H-pyrazol-3-yl-acetic acid and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 23%.