Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)([OH:24])N.[O-]Cl=O.[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:24])=[O:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Reactant: NS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
An alternative method for preparing this intermediate is as follows. 4-(2-Formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.50 g, 1.72 mmol) is dissolved in 80 mL of dioxane and 20 mL of H2O. The mixture is cooled to 4° C. To this is added sulfamic acid (1.36 g, 14.00 mmol) in one portion. The mixture is stirred for an additional 30 min. To this is added 3 mL of a solution of NaClO2 (0.343 g, 3.80 mmol) in a dropwise manner. The reaction is quenched reaction with addition of 50 mL of H2O and 50 mL of brine. The mixture is extracted with 3×100 mL of CH2Cl2. The organic phase is washed with 2×50 mL of brine, dried (MgSO4), filtered and concentrated to give 500 mg of 4-(2-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, 95% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].[H-].[Na+]>CN(C)C=O>[CH3:12][C:4]1[N:3]=[C:2]([N:22]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)[CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N(C)c2ccc([N+](=O)[O-])cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 4-chloro-2-methylquinazoline (1.4 g, 7.84 mmol) and (4-nitro-phenyl)-methylamine (1.09 g, 7.16 mmol) in 20 mL of dimethylformamide cooled to 0° C. was added sodium hydride (0.6 g, 60 oil suspension, 15 mmol). The reaction mixture was stirred at 0° C. for 1 h and quenched by adding 200 uL of water. It was diluted with 150 mL of ethyl acetate, washed with water (100 mL×3), saturated NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography (30% ethyl acetate/hexanes) to give the title compound (1.41 g, 4.78 mmol, 67%). 1H NMR (CDCl3): 8.14 (m, 2H), 7.91 (m, 1H), 7.71 (ddd, J=8.4, 6.6, 1.8, 1H), 7.19-7.32 (m, 2H), 7.05 (m, 2H), 3.76 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][C:15](=[O:18])[CH2:16][Cl:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][C:15]2([CH2:16][Cl:17])[O:21][CH2:20][CH2:19][O:18]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CC(=O)CCl)c1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC1(CCl)OCCO1)c1ccc(Br)cc1

Procedure:
To a solution of ethyl 2-(4-bromophenyl)-5-chloro-4-oxopentanoate (1-2) (35 g, 105 mmol) and ethylene glycol (19.5 g, 315 mmol) in toluene (300 mL) was added para-toluenesulfonic acid (100 mg) and the reaction was heated to reflux with a dean stark trap for 6 hours. The reaction mixture was concentrated was purified by column chromatography eluting with 0-50% EtOAc/Hexane. The appropriate fractions were combined, concentrated, and the resulting solid was recrystallized from EtOAc and hexane to give ethyl 2-(4-bromophenyl)-3-[2-(chloromethyl)-1,3-dioxolan-2-yl]propanoate (1-3) as a white solid MS (M+H)+: 378.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:16]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:10][N:11]=2)[CH2:16][NH:3]1
Reactant: CN(N)C(=O)Nc1nnc(C2CCC2)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1NCN(c2nnc(C3CCC3)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-Methyl-4-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-methyl-4-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: I[C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].C(N(CC)CC)C.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]#[CH:43])=[CH:38][CH:37]=1)#[N:35]>CN(C=O)C.[Cu]I>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]#[C:43][C:2]2[NH:16][C:15]3[C:17]4[C:3]=2[CH2:4][C@@H:5]2[C@@H:10]([C:11]=4[CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]2[CH3:26])=[CH:38][CH:37]=1)#[N:35]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(I)c(c34)C[C@H]2N(C)C1
Reactant: C#Cc1ccc(C#N)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#Cc5ccc(C#N)cc5)c(c34)C[C@H]2N(C)C1
Yield: 43.6 %

Procedure:
Under argon, 200 mg of 3-(2-iodo-6-methyl-8α-ergolinyl)-1,1-diethylurea is heated to 80°-90° C. in 4 ml of DMF with 4 ml of triethylamine, 4 mg of copper(I) iodide, 8 mg of palladium(O) tetrakis(triphenylphosphine) and 112 mg of 4-cyanophenylacetylene for 2 hours. After evaporation, the mixture is distributed in ethyl acetate and saturated sodium bicarbonate solution, and the organic phase is washed with saturated sodium chloride solution. After chromatography over silica gel with methylene chloride:ethanol=10:1, 87 mg of 3-[2-(4-cyanophenylethynyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea is obtained, mp 150°-151° C., [α]D =+139.5° (c=0.2; pyridine).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[NH2:20])[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:25]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:16][CH2:15]2)(=[O:27])[CH3:26]
Reactant: Nc1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2-Penylchroman-6-yloxy)-aniline (0.093 g) was dissolved in 1 ml of dry pyridine under nitrogen. DMAP (10 mol-%) and acetic acid anhydride (0.1 ml) were added and the solution was stirred for 4 hours at room temperature followed with quenching with 0.5 ml of H2O. The solution was evaporated to dryness and toluene was added and evaporated again. Toluene evaporation was repeated. Product was purified by column chromatography (CH2Cl2:i-PrOH/98:2 as the eluant) and recrystallized from 0.5 ml of heated absolute ethanol by cooling and adding 0.5 ml of 1H-NMR (400 MHz; d6-DMSO): δ 9.43 (s, 1H), 7.96 (m, 1H), 7.48-7.30 (m, 5H), 7.08-6.99 (m, 2H), 6.89-6.74 (m, 4H), 5.10 (dd, 1H, J=9.9, J=2.0), 3.03-2.88 (m, 1H), 2.76-2.65 (m, 1H), 2.21-2.11 (m, 1H), 2.10-1.91 (m, 1H), 2.06 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:21])([C:14]([NH:16][CH2:17][CH:18]([OH:20])[CH3:19])=[O:15])[CH2:6][CH2:5]2.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:23][C:7]([CH3:21])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:22])[C:14]([NH:16][CH2:17][CH:18]([OH:20])[CH3:19])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC(C)O)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCC(C)O)=C(C)C1=O
Yield: 93.5 %

Procedure:
Oxidation as described in protocol B, using 505 mg (1.64 mmol) of 6-hydroxy-N-(2-hydroxypropyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 1.99 mg CAN (3.62 mmol) yielded 496 mg of 2-hydroxy-N-(2-hydroxypropyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:16][C:6]1[C:7]([CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(Cc1c(Cl)ncnc1Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(Cc1c(Cl)ncnc1-c1ccccc1)OCC
Temperature: 100 °C
Yield: 63.6 %

Procedure:
The 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (1.1 g), phenyl boronic acid (500 mg) and potassium carbonate (556 mg) were dissolved in toluene (15 mL) and water (1.5 mL). The reaction mixture was degassed with nitrogen for 30 minute and then Pd(PPh3)4 (230 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes before heated to 100° C. for 3 hours in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using EtOAc/hexane (0.5:9.5) as eluent to afford 4-chloro-5-(2,2-diethoxyethyl)-6-phenylpyrimidine (800 mg) as colorless viscous liquid. 1H NMR (DMSO-d6): δ 1.07-1.10 (t, 6H), 3.21-3.23 (d, 2H), 3.32-3.36 (q, 2H), 3.37-4.00 (q, 2H), 4.79-4.81 (t, 1H), 7.47-7.49 (m, 3H), 7.63-7.66 (m, 2H), 8.91 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>C1COCC1.[NH4+].[Cl-]>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 1-(4-Bromo-phenyl)-4-methyl-piperazine (8.05 g, 31.54 mmol, CAS 130307-08-3) in dry THF (500 ml) are added dropwise 28 ml of a solution of n-BuLi (2.5M in hexanes, 69 mmol). After 1 h, of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.1 ml, 63.1 mmol) in solution in dry THF (20 ml) are introduced. After complete addition, the reaction mixture is allowed to slowly warm up to RT. The reaction mixture is then diluted with 200 ml of a saturated solution of NH4Cl and most of the THF is removed by evaporation. The residue is diluted with EtOAc and the phases are separated. The aqueous phase is re-extracted three times with EtOAc and the combined organic extracts are washed twice with de-ionized water, once with saturated brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography (silicagel, CH2Cl2/EtOH 9:1) to afford the title compound as a colorless solid, Rt=0.851 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 303 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:25]=[CH:24][C:23](=[O:26])[N:14]3[C:13]4[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=4[NH:11][C:10]=23)=[O:19])=[CH:4][CH:3]=1
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1ccc(Br)cc1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 500 mg (1.57 mmol) of 1-(4-Bromophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXVI), 169.2 mg (3.13 mmol) of sodium methylate and 131.7 mg (1.57 mmol) methyl propiolate.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[CH:6][CH:5]=1.O[NH:31][C:32]([CH:34]1[CH2:36][CH2:35]1)=[NH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:34]1([C:32]2[N:33]=[C:26]([CH:12]3[CH2:11][CH:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=4)[CH2:15][N:14]([C:16]([N:18]4[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]4)=[O:17])[CH2:13]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: N=C(NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)(=O)CC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCS(=O)(=O)CC1)N1CC(c2ccc(OC(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 mg (0.23 mmol) of the compound from Example 37A and 46 mg (0.46 mmol) of N-hydroxycyclopropanecarboximidamide were initially charged in 0.8 ml of DMF and reacted with 132 mg (0.35 mmol) of HATU and 0.12 ml (90 mg, 0.69 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred at RT for 15 minutes and then partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 3.0 ml of DMF and converted in a microwave at 180° C. for 2 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 46 mg (37% of theory)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1Cl)=[CH:16][CH:15]=[CH:14][CH:13]=2)=O.Cl.C([O:28][NH2:29])C1C=CC=CC=1>C(O)(C)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:29]([OH:28])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: NOCc1ccccc1
Reactant: O=C(CCCCCl)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CC(C)O
Product: On1c(CCCCCl)nc2cnc3ccccc3c21
Temperature: 82 °C
Yield: 44.2 %

Procedure:
A mixture of 5-chloro-N-(4-chloroquinolin-3-yl)pentanamide (1.0 g, 3.365 mmol) and O-benzylhydroxylamine hydrochloride (0.59 g, 3.70 mmol) in 10 mL of isopropanol was heated to 82° C. under an atmosphere of N2. After 2 days the mixture was cooled, solids were filtered off and rinsed with hexane and then ether. The brown solid was dried to give 0.4105 g of 2-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-1-ol.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([F:28])[CH:23]=[C:24]([F:27])[CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:29])[CH2:11][C@H:10]1[O:30][CH3:31])C1C=CC=CC=1>CO.C(#N)C.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([F:28])[CH:23]=[C:24]([F:27])[CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:29])[CH2:11][C@H:10]1[O:30][CH3:31]
Reactant: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1N
Reaction time: 4 h
Yield: 90.2 %

Procedure:
Cis(±)1-{2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one (Intermediate 168, 240 mg, 0.46 mmol) was hydrogenated in methanol/acetonitrile (10 mL, 9:1) over palladium hydroxide on carbon (20%, 120 mg) at room temperature and normal pressure for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness under reduced pressure to give 140 mg (90%) of crude product. This was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(CS(C)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CS(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(methylsulfinylmethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: B#B.[Cl:3][C:4]1[CH:15]=[CH:14][C:7](OC(C)C(O)=O)=[CH:6][CH:5]=1.[O:16]1C[CH2:19][CH2:18][CH2:17]1>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:18]([CH3:19])[CH2:17][OH:16])=[CH:14][CH:15]=1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)O
Reactant: C1CCOC1
Agent: B#B
Product: CC(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 833 ml. of a chilled solution (0° C.) of 1M diborane in tetrahydrofuran is added dropwise a solution of 96 g. of 2-(p-chlorophenoxy)propionic acid in 500 ml. of tetrahydrofuran. The reaction mixture is stirred for 2 days at room temperature and then poured onto 2 kg. of ice/water. The resulting mixture is extracted with diethyl ether and the extract is washed with water and dried over MgSO4. The solvent is removed under vacuum and the residual liquid is distilled to give 83 g. (b.p. 116°-120° C./0.1 mm.) of product.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:3]=1
Reactant: CCOC(=O)CSc1nccc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)CSc1nccc(Cl)n1

Procedure:
A stirred mixture of 32.1 g of (4-hydroxy-2-pyrimidinylthio)acetic acid, ethyl ester and 22.4 g of N,N-diethylaniline in 400 ml. of phosphorus oxychloride were heated under reflux for 5 hr. The phosphorus oxychloride was removed in a rotary evaporator in vacuo. The residue was poured onto ice and the mixture was extracted with 1 liter of ether. The ether solution was dried over MgSO4 and then filtered. The filtrate was taken to dryness in a rotary evaporator yielding 22.9 g of (4-chloro-2-pyrimidinylthio)acetic acid, ethyl ester (an oil). This material was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:17][CH2:18][C:19]([OH:21])=[O:20].Cl>CN(C=O)C.C(O)(C)C>[ClH:17].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:18][C:19]([OH:21])=[O:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCl
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: O=C(O)COC1CCN(Cc2ccccc2)CC1
Reaction time: 4 h
Yield: 20.1 %

Procedure:
1-Benzyl-4-hydroxypiperidine (10 g) in dry DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (5 g, 50% dispersion in mineral oil) in dry DMF (50 ml) at 20° under an atmosphere of nitrogen. The suspension was stirred at 20° for 4 hours, then 2-chloroacetic acid (4.95 g) in DMF (50 ml) was added slowly in two equal portions with a 2 hour interval between each. The resulting thick slurry was stirred at 20° for 24 hours. Isopropanol (75 ml) was added and the slurry was acidified to pH 6 with 2 N hydrochloric acid then concentrated in vacuo. The aqueous residue was adjusted to pH 10 with sodium hydroxide solution and extracted with chloroform (3×100 ml). The aqueous layer was separated, acidified to pH 3 with 2 N hydrochloric acid and extracted with chloroform (3×100 ml). The organic extracts were again discarded and the aqueous phase was concentrated to half volume, filtered and the filtrate evaporated in vacuo to give 2-(1-benzylpiperidin-4-oxy)acetic acid, hydrochloride (3 g), characterised by n.m.r.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7]([NH:9]CC1C=CC(OC)=CC=1)[CH3:8]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7]([NH2:9])[CH3:8]
Reactant: COc1ccc(CNC(C)C2COCCO2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(N)C1COCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 1-(1,4-dioxan-2-yl)ethanone (12 g, 92.2 mmol) in 1,2-dichloroethane (100 mL) was added (4-methoxyphenyl)methanamine (25 g, 184.4 mmol) at room temperature. The mixture was allowed to stir for 3 hours, and then sodium triacetoxyborohydride (39 g, 184.4 mmol) was added. The resulting mixture was allowed to stir for 48 hours at room temperature. The reaction mixture was quenched by adding water, extracted with dichloromethane (100 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel (elute: dichloromethane/methanol 100:1→50:1→20:1) to give 1-(1,4-dioxan-2-yl)-N-(4-methoxybenzyl)ethanamine (16.4 g, 71%) as a yellow solid. LCMS (M+H+) m/z: calcd. 251.15. found 251.9. To a solution of 1-(1,4-dioxan-2-yl)-N-(4-methoxybenzyl)ethanamine (5 g, 19.9 mmol) in anhydrous methanol (100 mL) was added palladium 10% on carbon (240 mg, 2 mmol), then purged with hydrogen (30 psi), the mixture was allowed to stir overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to afford the title compound (2.5 g, 96%) as a brown solid.