Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([CH:47]=O)=[CH:41]2>C1COCC1>[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([CH:47]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:41]2
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2cc(Cl)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To the cold suspension of hexyl-triphenyl-phosphonium bromide in THF was added LiHMDS in THF and the mixture was stirred for 30 minutes and then the solution of 5-chloro-1H-indole-2-carbaldehyde was added to the reaction mixture and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-chloro-2-hept-1-enyl-1H-indole was purified by column chromatography.
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH2:9][CH2:10][CH2:11][Cl:12]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH3:5]
Reactant: CNC(C)C
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)N(C)CCCCl
Yield: 57.3 %

Procedure:
Isopropylmethylamine (4 g, 56 mmol), acetone (12 ml, 3 vol), 5M NaOH solution (13.44 ml, 1.2 eq.) and 1-bromo-3-chloropropane (13.22 g, 84 mmol, 1.5 eq.) were reacted together according to general procedure A to give the title compound (4.8 g, 66%) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[CH:6][CH:5]=1)([O-])=O.[O:18]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]1=[O:25]>O1CCCC1>[O:17]=[C:12]([CH2:13][C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:23]([CH2:22][CH2:21][CH2:20][C:19]([OH:25])=[O:18])=[O:24])=[CH:5][CH:6]=1
Reactant: CC(=O)CC(=O)CCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)CCc1ccc(NC(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.7 %

Procedure:
200 mL tetrahydrofuran, 6-(4-nitro-phenyl)-hexane-2,4-dione (8.0 g, 34.0 mmol) and dihydro-pyran-2,6-dione (3.88 g, 34.0 mmol) were added to a reaction vessel. The reaction vessel was purged three times with argon. Approximately 200 mg palladium (10 wt % on activated carbon) was added. The reaction vessel was purged again with argon and excess hydrogen introduced via a balloon. Solution stirred 16 hours at room temperature. Hydrogen removed under reduced pressure and catalyst removed by filtration through celite. Tetrahydrofuran removed under reduced pressure to afford title compound (10.5 g, 97%, yellow solid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH3:13])[C:7]2=[O:14].P(Cl)(Cl)([Cl:17])=O.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:17])[N:8]([CH3:13])[C:7]2=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2c(Br)cccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(Cl)nc2c(Br)cccc2c1=O
Yield: 84.3 %

Procedure:
A slurry of 8-bromo-3-methylquinazoline-2,4(1H,3H)-dione (722b, 1.14 g, 4.47 mmol), phosphoryl trichloride (4.09 mL, 44.7 mmol), and N-ethyl-N-isopropylpropan-2-amine (3.11 mL, 17.88 mmol) was stirred at reflux for 19 h. The reaction mixture was concentrated, diluted with ice, basicified with 10 N NaOH to ˜pH 10, filtered, and washed with water to give brown solid. The solid was transferred to an Erlenmeyer flask and dissolved in DCM when a small aqueous layer formed; this was partitioned in a separatory funnel. The organic layer was partially concentrated, loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-40% EtOAc in hexanes to give 8-bromo-2-chloro-3-methylquinazolin-4(3H)-one (722) (1.03 g, 3.77 mmol, 84% yield) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.77 (s, 3H) 7.35 (t, J=7.92 Hz, 1H) 8.02 (dd, J=7.82, 1.37 Hz, 1H) 8.21 (dd, J=8.02, 1.37 Hz, 1H). MS (ESI, pos. ion) m/z: 273.9/275.9 (M+1).
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:40])[F:41])=[CH:39][CH:38]=3)=[O:36])[CH2:20][CH2:21]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]1(CN2CCN(C(=O)c3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
(S)-2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (2.36 mg, 0.882 mmol) was suspended in methylene chloride (10 ml). To the suspension, triethylamine (1 ml, 7.17 mmol) was added. To the solution, 4-(trifluoromethyl)benzoyl chloride (193 mg, 0.926 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution, water and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-(4-trifluoromethylphenyl)methanone (264 mg, yield 68%) as a white powder.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:38])=[O:37])=[CH:34][CH:35]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 61 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-methoxybenzenesulfonyl chloride under the conditions used in example 2 giving 61% of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([NH:36][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[S:38])=[O:35]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (63 mg, yield 80%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][Br:20])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: Cc1ccnc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccnc(-c2ccccc2)c1

Procedure:
To a solution of 100 mg of 2-phenyl-4-methylpyridine in 2 mL of carbon tetrachloride was added 300 mg of sodium carbonate and 100 mg of bromine. The reaction mixture was stirred and irradiated with a 500 W lamp for 1 h, filtered and the solvent removed by evaporation under reduced pressure to yield 2-phenyl-4-bromomethylpyridine which was used in the next step without further purification or characterization.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[N:7][C:8](O)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[N:7]=[CH:6][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cnc1O
Product: O=C(O)c1cc(S(=O)(=O)Cl)cnc1Cl
Temperature: 130 °C

Procedure:
5-(Chlorosulfonyl)-2-hydroxynicotinic acid (500 mg, 2.10 mmol) vas suspended in 5 ml of POCl3 in a sealed tube and heated to 130° C. until all solid had dissolved. The reaction was cooled to 0° C. and poured onto ice and stirred until a solid formed. The filtered white solid was dried to afford 2-chloro-5-(chlorosulfonyl)nicotinic acid. 1H NMR (400 MHz, Acetone-d6) δ ppm 8.9 (d, J=2.6 Hz, 10H), 9.3 (d, J=2.6 Hz, 10H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.I[CH3:16].O>O1CCCC1>[CH3:16][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1CN(C(=O)OC(C)(C)C)C1
Yield: 33.3 %

Procedure:
A suspension of sodium hydride (2.89 g) in tetrahydrofuran (50 ml) was stirred with cooling in an ice bath. A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.00 g) in tetrahydrofuran (50 ml) was gradually added, followed by stirring at the same temperature for 30 minutes. Then, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred with cooling in an ice bath again for 15 minutes. Iodomethane (3.09 ml) was added dropwise to the reaction mixture, followed by stirring for 2 hours. Water was gradually added to the reaction mixture. When bubbling stopped, the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:1, 2:1, 1:1, then ethyl acetate). The fractions containing the target compound were concentrated to give the title compound (1.80 g, 33.3%) as a colorless oil. The fractions containing the starting material were concentrated and collected (2.10 g, 42.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.N1C=CC=CC=1.[CH3:38][C:39]1[S:40][CH:41]=[C:42]([C:44](Cl)=[O:45])[N:43]=1>C(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]3[C:3]([CH:4]=[N:5][NH:6]3)=[C:2]([NH:1][C:44]([C:42]3[N:43]=[C:39]([CH3:38])[S:40][CH:41]=3)=[O:45])[CH:10]=2)=[CH:12][C:13]=1[NH:18][S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methane sulfonamide (100 mg) was dissolved in DCM (5 ml) and pyridine (0.02 ml) was added. 2-Methyl-1,3-thiazole-4-carbonyl chloride (41 mg) was added and the reaction stirred at RT for 1 h. The reaction was evaporated to dryness and the residue was stirred in MeOH:2M NaOH (aq) (5 ml, 1:1, v/v) for 15 min. The reaction was neutralised with 2M HCl and evaporated to dryness. The residue was dissolved in DMSO (1 ml), filtered and purified by MDAP (method E). The pure fraction was evaporated to dryness to give title compound (33 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:40][CH:37]2[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCc1ccc(F)cc1C(=O)c1cnc(S(=O)CC)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(2-ethyl-5-fluoro-phenyl)-methanone (Example 202) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C19H25N5O3SF [(M+H)+] 422.1660, observed 422.1657.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13][CH2:14]C)=[O:12].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1.O>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:4][C:3]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1sc2ncccc2c1N
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1sc2ncccc2c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.8 %

Procedure:
To a solution of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate (0.3 g; 1.35 mmol) in pyridine (10 mL) was added 4-tert-butylbenzenesulfonyl chloride (0.48 g; 2.03 mol). The reaction was stirred at room temperature for 18 hours and then diluted with water and extracted with ethyl acetate. The organic layer was separated and successively washed with aqueous hydrochloric acid (2N) and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate to yield the title compound as a white solid (0.070 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C@@H:14](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:15])[CH:6]=1.[C:28]1([C@H:34]([CH3:37])[CH2:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C@H:14]([NH:36][CH2:35][C@H:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:37])[CH3:15])[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCC[C@H](C)OS(=O)(=O)c2ccc(C)cc2)c1
Reactant: C[C@H](CN)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCC[C@@H](C)NC[C@@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 66.2 %

Procedure:
A solution of {3-[(S)-3-(Toluene-4-sulfonyloxy)-butoxy]-phenyl}-acetic acid methyl ester (0.2 g, 0.51 mmol) and (S)-2-Phenyl-propylamine (0.19, 0.77 mmol) in acetonitrile (30 ml) was treated with solid potassium carbonate (0.149, 1.02 mmol). The reaction was heated to reflux and stirred for six days. Upon cooling to room temperature, the reaction was filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (0.12 g, 40%). MS m/e 356.6 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN1CCCC1=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)Nc1ccccc1
Reaction time: 18 h
Yield: 17.5 %

Procedure:
A solution of the compound of Example 45, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.411 g, 4.95 mmol) in 40 mL of 1-methyl-2-pyrrolidinone was treated with triethylamine (1.38 mL, 9.89 mmol). With vigorous stirring, the solution was treated with phenyl isocyanate (0.538, 4.95 mmol). After 18 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 9:1 CH2Cl2:MeOH) gave 351 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylurea as a white powder.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[C:10]([CH3:13])[NH:9][C:8]=2[C:7](=[O:14])[NH:6][C:5]1=[O:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CO>[CH2:16]([N:9]1[C:8]2[C:7](=[O:14])[NH:6][C:5](=[O:15])[N:4]([CH3:3])[C:12]=2[N:11]=[C:10]1[CH3:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (400 mg) in water (5 ml) was added to a suspension of 3,8-dimethylxanthine (1.80 g) in methanol (10 ml). After stirring for 1 hour at 70° C., benzyl bromide (1.2 ml) was added. After stirring for 5 hours at 70-80° C., the solvent was evaporated under reduced pressure. The residue was treated with saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over magnesium sulfate and concentrated under reduced pressure. The solid was purified by recrystallization from ethanol to provide 7-benzyl-3,8-dimethylxanthine (1.06 g).
Reaction SMILES: Cl.[C:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]1)([O:4][CH3:5])=[O:3].C(N(CC)CC)C.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][C:2]([O:4][CH3:5])=[O:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CC1CCCCN1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCCCN1Cc1ccccc1
Reaction time: 5 h

Procedure:
In 13 ml of acetonitrile was dissolved 1.0 g (5.16 mol) of 2-carbomethoxymethylpiperidine hydrochloride, and 1.77 ml (12.72 mmol) of triethylamine and 0.76 ml (6.36 mmol) of benzyl bromide were added to the solution at room temperature, and the resulting mixture was reacted at the same temperature under stirring for 5 hours. After completion of the reaction, the obtained reaction mixture was filtered and then concentrated under reduced pressure, then, 25 ml of ethyl acetate and 15 ml of a saturated aqueous sodium hydrogen carbonate solution were added to the residue and the organic layer was extracted. The obtained organic layer was washed with 15 ml of a saturated aqueous sodium hydrogen carbonate solution, and saturated saline solution, dried over anhydrous magnesium sulfate, then, filtered and the filtrate was concentrated under reduced pressure to obtain 0.97 g of an oily substance. The resulting oily substance was purified by silica gel column chromatography (WAKOGEL C-200 (trade name), n-hexane/ethyl acetate=4/1(volume ratio)) to obtain 0.75 g (Isolated yield based on 2-carbomethoxymethylpiperidine hydrochloride=59%) of N-benzyl-2-carbomethoxymethylpiperidine.
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([F:19])=[CH:16][C:17]=2[F:18])=[CH:10][C:9]([C:20]([OH:22])=[O:21])=[C:8]([OH:23])[CH:7]=1.[CH3:24]O>>[F:18][C:17]1[CH:16]=[C:15]([F:19])[CH:14]=[CH:13][C:12]=1[C:11]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([C:20]([O:22][CH3:24])=[O:21])[CH:10]=1
Reactant: CO
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Yield: 85 %

Procedure:
H2SO4 (9.6 mL, 179.12 mmol) was added to a solution of diflunisal (15.0 g, 59.95 mmol) in MeOH (200 mL). The reaction mixture was refluxed for 12 h and it was allowed to reach r.t. Solids were collected by filtration and washed with cold MeOH (20 mL) to furnish 13.42 g of methyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 85%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[C:11]([OH:17])=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1>N1C=CC=CC=1>[Cl:9][C:10]1[C:11]([O:17][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1ccco1
Yield: 34 %

Procedure:
A 2.15 g quantity of 2-furoyl chloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 100 ml of pyridine. The same subsequent procedure as in Example 39 was conducted, thereby producing 1.13 g of the title compound in a yield of 34%.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)[CH:2]=[CH2:3].CC(C)([O-])C.[K+].O>O1CCOCC1>[CH:1]([O:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[CH:2][CH3:3]
Reactant: C=CCOCC1CNCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC=COCC1CNCCO1
Yield: 101.8 %

Procedure:
2-(Allyloxymethyl)morpholine (39.5 g, 0.25 mol) was dissolved in 1,4-dioxane (500 ml), and potassium tert-butoxide (28.2 g, 0.25 mol) was added to the solution at room temperature, followed by heating under reflux for 3 hours. After completion of the reaction, water was added to the reaction mixture at room temperature, and the reaction mixture was extracted with chloroform (3×1000 ml). The extract was washed with a saturated aqueous solution of sodium chloride (1000 ml) and dried over magnesium sulfate. The solvent was evaporated to give crude 2-(1-propenyloxymethyl)morpholine (40.0 g) as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[CH:24][C:23]([B:26]([OH:28])[OH:27])=[CH:22][N:21]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][N:12]([C:20]2[N:25]=[CH:24][C:23]([B:26]([OH:28])[OH:27])=[CH:22][N:21]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncc(B(O)O)cn2)CC1

Procedure:
The title compound was synthesised from methyl 4-(tert-butoxycarbonylamino)-piperidine-4-carboxylate and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1Cc2ccccc2C1

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.132 g, 0.50 mmol) and 2,3-dihydro-1H-isoindole (0.114 mL, 1.0 mmol) gives the title compound.