Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].[CH3:9][CH:10]([CH3:45])[CH2:11][C@H:12]([NH:34][C:35]([C@H:37]1[O:39][C@@H:38]1[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:36])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[C:23]=2[O:32][CH3:33])[CH2:17][CH2:16]1)=[O:14]>CC(C)=O>[C:3]([O-:8])(=[O:7])[C:4]([O-:6])=[O:5].[CH3:9][CH:10]([CH3:45])[CH2:11][C@H:12]([NH:34][C:35]([C@H:37]1[O:39][C@@H:38]1[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:36])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[C:23]=2[O:32][CH3:33])[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(O)C(=O)O
Agent: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(Cc2ccc(OC)c(OC)c2OC)CC1
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])C(=O)[O-]
Yield: 590.1 %

Procedure:
An acetone solution (2 ml) of oxalic acid dihydrate (0.25 g) was added to an acetone solution (6 ml) of ethyl (2S,3S)-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate (1.04 g), and the crystal which had precipitated was collected by filtration and dried to yield 1.03 g of an oxalate of ethyl (2S,3S)-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate as a colorless crystal (yield: 84%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.O>COCCOC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: FC(F)(F)c1ccnc(Cl)c1
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1ccnc(-c2ccccc2Cl)c1
Temperature: 110 °C
Yield: 89.1 %

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyridine (4 g, 22.0 mmol), 2-chlorophenylboronic acid (5.04 g, 24.2 mmol), Ba(OH)2 (12.5 g, 66.1 mmol) and Pd(PPh2)2Cl2 (464 mg, 0.66 mmol) in DME (140 mL)/water (35 mL) was heated at 110° C. for 1 h. The solids were filtered off and the mother liquor were concentrated to around 80 mL and extracted with EtOAc. The organic layer was washed with brine, then water, dried (MgSO4), filtered and concentrated. Purification by column chromatography (1/1 Petroleum ether/EtOAc) gave the Suzuki adduct (5.05 g, 89%) as a colourless oil.
Reaction SMILES: [NH2:1][C@H:2]1[C@@:7]([OH:9])([CH3:8])[C:6]([CH3:11])([CH3:10])[O:5][C:4]2[CH:12]=[CH:13][C:14]([C:16]3[N:20]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:19]=[N:18][N:17]=3)=[CH:15][C:3]1=2.Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH2:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][N:20]1[C:16]([C:14]2[CH:13]=[CH:12][C:4]3[O:5][C:6]([CH3:10])([CH3:11])[C@:7]([OH:9])([CH3:8])[C@H:2]([NH:1][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([S:36][CH3:37])[N:31]=4)[C:3]=3[CH:15]=2)=[N:17][N:18]=[N:19]1)=[O:25])[CH3:28]
Reactant: CSc1nccc(Cl)n1
Reactant: CCOC(=O)CCCn1nnnc1-c1ccc2c(c1)[C@@H](N)[C@](C)(O)C(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CCCn1nnnc1-c1ccc2c(c1)[C@@H](Nc1ccnc(SC)n1)[C@](C)(O)C(C)(C)O2
Temperature: 120 °C

Procedure:
A mixture containing (3S,4R)-4-amino-3,4-dihydro-6-(1-[3-ethoxycarbonylprop-1-yl]-1H-tetrazol-5-yl)-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (see Preparation 55) (0.6 g), 4-chloro-2-methylthiopyrimidine (0.5 g), anhydrous potassium carbonate (0.7 g) and anhydrous dimethylacetamide (5 ml) was heated at 120° C. for 24 hours. On cooling to room temperature water (10 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The extracts were combined and washed with water (50 ml) then concentrated in vacuo to give an oil which was purified by chromatography on silica eluting with dichloromethane containing ethyl acetate (40%). The product-containing fractions were combined and concentrated in vacuo to give a foam which was further purified by chromatography on silica eluting with dichloromethane containing isopropanol (3.3%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was triturated with hexane to give the title compound as a foam, 0.077 g, m.p. 115°-130° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[C:9]([N:16]1[CH:20]=[CH:19]N=[CH:17]1)(N1C=CN=C1)=[O:10].[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH:29]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1>O1CCCC1.C(Cl)Cl>[OH2:10].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:9]([N:16]1[CH2:17][CH2:31][CH:30]([CH:29]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[NH:28][C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[CH2:19][CH2:20]1)=[O:10])[CH3:2].[CH2:1]([N:3]([CH2:4][CH2:5][NH:6][C:9]([N:33]1[CH2:34][CH2:35][CH:30]([CH:29]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH2:31][CH2:32]1)=[O:10])[CH2:7][CH3:8])[CH3:2]
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: CCN(CC)CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)N1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: O
Temperature: 25 °C
Yield: 124.1 %

Procedure:
A solution of N,N-diethylethylenediamine (1.63 g, 0.014 mol) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mol) in 100 mL of tetrahydrofuran was stirred at room temperature under nitrogen for 2 h. A solution of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine (3.76 g, 0.01245 mol) was added. The resulting solution was heated at reflux 16 h under nitrogen. The solution was cooled to room temperature and concentrated to dryness. The brown residue obtained was dissolved in methylene chloride. The methylene chloride layer was extracted with water, dried (Na2SO4), and filtered. The methylene chloride was removed with a rotary evaporator to give a dark brown oil (5.63 g). This material was dissolved in methylene chloride and placed on a silica gel column for flash chromatography. The column was eluted with 20% methanol-ethyl acetate, 50% methanol-ethyl acetate, and methanol. Fractions of similar purity were combined and solvents removed to give a dark brown oil. This material was dried for 16 h at 100° C. in the presence of phosphorus pentoxide. The procedure provided 4.21 g (74.2%) of a dark brown glass.
Reaction SMILES: N(C([O:8][CH2:9][CH3:10])=O)=NC([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:30]1C=CC=[C:31]1CC(O)=O.OC[CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][C:49]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:50][C:45]=2[S:44][C:43]1=[N:56][C:57]([O:59][CH:60]=[CH2:61])=[O:58]>O1CCCC1.CO>[C:9]([S:30][CH2:31][CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][C:49]([O:51][C:52]([F:54])([F:53])[F:55])=[CH:50][C:45]=2[S:44][C:43]1=[N:56][C:57]([O:59][CH:60]=[CH2:61])=[O:58])(=[O:8])[CH3:10]
Reactant: C=COC(=O)N=c1sc2cc(OC(F)(F)F)ccc2n1CCO
Reactant: CCOC(=O)N=NC(=O)[O-]
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: C=COC(=O)N=c1sc2cc(OC(F)(F)F)ccc2n1CCSC(C)=O
Reaction time: 0.5 h

Procedure:
3-(2-Acetylthioethyl)-2-vinyloxycarbonylimino-6-trifluoromethoxybenzothiazoline may be obtained in the following manner: ethyl azodicarboxylate (10.5 cc) is added dropwise to triphenylphosphine (17.6 g) dissolved in tetrahydrofuran (150 cc) at 0° C. Stirring is continued for 30 minutes at this temperature. A solution of thiolacetic acid (4.8 cc) and 3-(2-hydroxyethyl)-2-vinyloxycarbonylimino-6-trifluoromethoxybenzothiazoline (11.7 g) in tetrahydrofuran (75 cc) is then added gradually. The reaction is continued for 1 hour at 0° C. and then 1 hour at a temperature in the region of 20° C. After concentration to dryness under reduced pressure (20 mm Hg; 2.7 kPa), the residue obtained is taken up in methanol (50 cc), then filtered and washed once with methanol (50 cc). 3-(2-Acetylthioethyl)-2-vinyloxycarbonylimino-6-trifluoromethoxybenzothiazoline (10.4 g), m.p. 173° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:36][C:37](=[O:40])[CH2:38]Br)([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:1]([O:5][C:6](=[O:24])[CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(Cc1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
15.1 g (46.1 mmol) of N-benzyl-tyrosine-tert-butyl ester (Example a) is dissolved in 50 ml of tetrahydrofuran and mixed with 5 ml of water and 9.54 9 (69 mmol) of potassium carbonate. After instillation of 9.89 g (51 mmol) of bromoacetic acid-tert-butyl ester, it is stirred for two days at 65° C. After cooling, it is filtered, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O.Cl.[OH-].[Na+]>C(O)C.O.C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CC(C#N)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C#N)c1ccc(O)c(N)c1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
2-(3-Nitro-4-hydroxyphenyl) propionitrile (123.8 g., 0.64 mole.) was suspended in absolute ethanol (950 ml.) and added during 20 minutes, with cooling, to a solution of stannous chloride dihydrate (437.8 g., 1.94 mole.) in concentrated hydrochloric acid (591 ml., 7 mole.). The addition was made at such a rate that the temperature of the reaction mixture did not exceed 20°C. Stirring of the mixture was continued for a further 19 hours at room temperature. The resulting solution, together with ice (1.75 kg.) was added during one hour to a cooled solution of sodium hydroxide (650 g.) in water (600 ml.). The temperature of the reaction mixture was maintained at 15°-20°C during the addition. The mixture was stirred for a further 1 hour, and the pH then adjusted to 6 by the addition of concentrated hydrochloric acid. The resulting suspension was filtered and the filtrate saturated with sodium chloride, then extracted with ether (x6). The combined ether extracts were dried (Na2SO4) and evaporated to leave a solid (69.15 g.) which was suspended in chloroform and extracted with 2N-hydrochloric acid (x6). The combined acid extracts were neutralised to pH 7-8 by the addition of sodium bicarbonate. The resulting suspension was extracted with ether (x4). The combined ether extracts were washed twice with water, dried (Na2SO4), and evaporated to yield 2-(3-amino-4-hydroxyphenyl) propionitrile as a light brown solid (62.85 g.), m.p. 110° -112°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[N:7]([CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]1)=[O:21])[CH2:6][CH2:5]2.[CH2:32]([O:36]C=C)[CH2:33]CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:32]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[N:7]([CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]1)=[O:21])[CH2:6][CH2:5]2)(=[O:36])[CH3:33]
Reactant: O=C(CN1CCc2cc(Br)ccc2C1c1ccccc1Cl)N1CCN(C2CCC2)CC1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2c(c1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2c1ccccc1Cl
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To a solution of 2-[6-bromo-1-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-1-(4-cyclobutyl-piperazin-1-yl)-ethanone (310 mg, 0.62 mmol) in dry DMF (5.0 ml) is added n-butylvinyl ether (310 mg, 3.98 mmol, 5.0 eq.), TEA (75 mg, 0.74 mmol, 1.2 eq.), 1,3-bis(diphenylphosphino)propane (7 mg, 0.0017 mmol, 0.0276 eq.), and palladium acetate (3.5 mg, 0.015 mmol, 0.025 eq.) under nitrogen. The resulting mixture is stirred at 80° C. for 7 hr. Water (20 ml) is added to quench the reaction, and the mixture is extracted with EtOAc (10 ml×3). The combined organic phase is washed with water, and treated with concentrated HCl (1.0 ml). The mixture is stirred at rt for 2 hr, and then basified with saturated sodium carbonate solution. The organic phase is collected, and the aqueous phase is extracted with EtOAc (10 ml×2). The combined organic phase is dried over sodium sulfate, and concentrated. The residue is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.74 (1H, s), 7.59 (1H, dd), 7.41 (1H, dd), 7.10˜7.25 (3H, m), 6.72 (1H, d), 5.22 (1H, s), 3.81 (1H, m), 3.04˜3.52 (7H, m), 2.78˜2.98 (2H, m), 2.67 (1H, m), 2.55 (3H, s), 2.41 (1H, m), 2.27 (1H, m), 1.96˜2.14 (4H), 1.60˜1.92 (4H); MS (+VE) m/z 466.00 (M+).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][OH:12])[O:10][C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>N1C=CC=CC=1>[C:14]([O:12][CH2:11][CH:9]1[CH2:8][C:7]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]([F:13])[C:6]=2[O:10]1)(=[O:16])[CH3:15]
Reactant: OCC1Cc2c(F)ccc(F)c2O1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC1Cc2c(F)ccc(F)c2O1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
4,7-Difluoro-2,3-dihydro-2-hydroxymethylbenzofuran (1.2 g) was dissolved in 6 ml pyridine, then 0.73 ml acetic anhydride was added thereto at 0° C. in a nitrogen stream, and the mixture was stirred at room temperature for 17 hours. The reaction solution was poured into 10% aqueous hydrogen chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was subjected to silica gel chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 750 mg 2-acetoxymethyl-4,7-difluoro-2,3-dihydrobenzofuran as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(O[Cl:16])(C)(C)C>C1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[OH:10].[Cl:16][C:9]1[CH:8]=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(O)c1
Reactant: CC(C)(C)OCl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(O)ccc1Cl
Product: CC(C)c1ccc(Cl)c(O)c1
Temperature: 25 °C
Yield: 104.4 %

Procedure:
A solution of 3-isopropyl phenol (10.0 g, 73.4 mmol) in 350 mL 9:1 benzene/CHCl3 was cooled to 0° C. Hypochlorous acid tert-butyl ester (8.77 g, 80.8 mmol) was added drop-wise over 5 min and the mixture was allowed to warm to rt. After 16 h the mixture was concentrated in vacuo to give a crude oil. Purification via flash chromatography afforded 2-chloro-5-isopropyl-phenol and 4-chloro-3-isopropyl-phenol (6.540 g, 52%) as a 7:3 inseparable mixture of isomers in the form of a pale yellow oil. The combined regioisomers were used together in the following step.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[CH3:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-methylbenzylamine (0.125 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 136 mg. To a solution of tert-butyl 4-((3-methylphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((3-methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((3-Methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 48 mg; 13C-NMR (CD3OD, rotamers): δ 20.4, 26.8, 28.3, 40.2, 43.9, 44.1, 44.5, 51.8, 54.2, 54.57, 54.61, 114.0, 114.1, 123.2, 123.7, 126.7, 127.0, 127.1, 127.3, 128.0, 128.1, 128.7, 129.8, 129.9, 137.9, 138.6, 138.9, 159.0, 159.1, 173.1, 173.7.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:11]=2[C:10]=1[OH:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:24].C(OC(C)C)(C)C.C(OCC)(=O)C>>[NH2:24]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:19])[C:11]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: Cc1cccc2sc(C(=O)c3ccccc3)c(O)c12
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc2c1C(=O)/C(=C(\N)c1ccccc1)S2
Yield: 50 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-4-methyl-benzo[b]thiophen-3-ol and ammonium acetate with a yield of 50% of theory. M.p. 198°-200° C. (diisopropyl ether/ethyl acetate 2:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:26]=3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)c1ccc2ccccc2n1

Procedure:
According to the general method of Example 61, 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-2-carbonyl chloride were combined to provide N2-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-quinolinecarboxamide as an off white crystalline solid, m.p. 81.1-83.9° C. 1H NMR (300 MHz, DMSO-d6) δ 8.90 (t, J=6.0 Hz, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.12-8.07 (m, 4H), 7.90-7.84 (m, 1H), 7.75-7.54 (m, 7H), 7.36 (t, J=7.5 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.70 (broad s, 2H), 4.61 (m, 2H), 3.23 (m, 2H), 1.88 (m, 2H), 1.49 (m, 2H); MS (CI) m/e 487 (M+H).
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:12]1[CH:16]=[C:15]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]=[CH:13]1.[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>C1(C)C=CC=CC=1.C(O)(C)C>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH2:1]([NH:9][C:10]([N:20]1[CH2:19][CH2:18][CH:17]([C:15]2[N:14]=[CH:13][NH:12][CH:16]=2)[CH2:22][CH2:21]1)=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=C=NCCc1ccccc1
Reactant: c1nc(C2CCNCC2)c[nH]1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: S=C(NCCc1ccccc1)N1CCC(c2c[nH]cn2)CC1
Temperature: 80 °C

Procedure:
A solution of 1.63 g (0.01 mol) of phenethyl isothiocyanate in 60 ml of toluene and 1.51 g (0.01 mol) of 4-(4-imidazolyl)piperidine is heated to reflux for 1h 30 min. After cooling, the solution is evaporated under reduced pressure and the residual oil obtained is dissolved in 60 ml of isopropanol in the presence of 1.2 equivalents of oxalic acid. After 30 minutes of heating at 80° C., the white precipitate formed is drained, washed with ether and recrystallised in acetonitrile.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][N:6]2[C:10]3=[N:11][CH:12]=[N:13][C:14]([NH2:15])=[C:9]3[C:8]([C:16]#[C:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)=[N:7]2)[CH2:2]1.NC1N=CN=C2N(CC3[CH2:54][N:53]([C:55](=O)[CH:56]=[CH2:57])[CH2:52]3)N=C(C#CC3C=C(OC)C=C(OC)C=3)C=12.[CH3:59][O:60]C1C=C(C#CC2C3C(=NC=NC=3N)N([C@H]3CCNC3)N=2)C=C(OC)C=1>>[NH2:15][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[N:6]([CH2:5][CH:3]3[CH2:4][N:1]([C:59](=[O:60])[CH:57]=[CH:56][CH2:55][N:53]([CH3:52])[CH3:54])[CH2:2]3)[N:7]=[C:8]([C:16]#[C:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[C:9]=12
Reactant: COc1cc(C#Cc2nn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Reactant: C=CC(=O)N1CC(Cn2nc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)C1
Reactant: COc1cc(C#Cc2nn(CC3CNC3)c3ncnc(N)c23)cc(OC)c1
Product: COc1cc(C#Cc2nn(CC3CN(C(=O)C=CCN(C)C)C3)c3ncnc(N)c23)cc(OC)c1

Procedure:
In accordance with Example 4, except that 1-(azetidin-3-ylmethyl)-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (i.e., an intermediate obtained in Example 29) was used in place of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, the title compound was obtained as a light-yellow, amorphous substance. Table 1 shows the physical properties thereof.