Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.Cl.[CH3:29][C:30]1([OH:34])[CH2:33][NH:32][CH2:31]1.Cl>O1CCCC1>[OH:34][C:30]1([CH3:29])[CH2:33][N:32]([S:2]([C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]3=[O:15])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:31]1
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Reactant: CC1(O)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(O)CN(S(=O)(=O)c2ccc3c(C(=O)O)c[nH]c(=O)c3c2)C1

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g), diisopropylethylamine (3 ml) and 3-methylazetidin-3-ol hydrochloride (0.8 g) in tetrahydrofuran (8 ml) were heated at 55° C. for 3 days. The mixture was acidified with hydrochloric acid and then filtered to yield 7-[(3-hydroxy-3-methylazetidin-1-yl)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a pale pink solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([CH:38]([CH2:40][CH3:41])[CH3:39])[N:18]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([CH:38]([CH2:40][CH3:41])[CH3:39])[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nn(C(C)CC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nn(C(C)CC)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.93 g), sodium hydrogen carbonate (1.33 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(3-butyl-1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (0.61 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.10 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.14 g, 20%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH2:35][OH:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH2:35][OH:36])[C:23](=[O:24])[CH2:22][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: OCCNCc1ccccc1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:22][C:23]1[CH:35]=[CH:34][C:26]([NH:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:31]2[CH2:30][CH2:29][CH:28]([NH:27][C:26]3[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:33][CH2:32]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: Fc1ccc(NC2CCNCC2)cc1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCC(Nc5ccc(F)cc5)CC4)cc3nc21
Yield: 68.1 %

Procedure:
7-Fluoro-8-[4-(4-fluoroanilino)piperidino]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 1.6 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 3.7 g of 4-(4-fluoroanilino)-piperidine in 16 cm3 of pyridine. After recrystallizing from 10 cm3 of dimethylformamide, 1.65 g of 7-fluoro-8-[4-(4-fluoroanilino)piperidino]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 280° C.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)[O-])=[C:23]([O:31][CH3:32])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([C@H:33]3[CH2:38][CH2:37][C@@H:36]([N:39]4[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]4)[CH2:35][CH2:34]3)[N:19]=2)=[CH:22][C:23]=1[O:31][CH3:32]
Reactant: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 200 mL) was added to a solution of N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate(10.85 g, 20.24 mmol) in dichloromethane (100 mL) at 0° C. 2 hours later, the ice-bath was removed and the solvents were evaporated and the residue was dissolved in dichloromethane. Sodium hydroxide (1.0N) was added to adjust the pH to about 10. The solid formed upon removal of organic solvent was collect by filtration to give cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (8.84 g, 100%). 1H NMR (CDCl3) δ 1.65 (m, 2H), 1.83 (m, 2H), 2.18 (m, 2H), 2.31 (s, 3H), 2.35-2.60 (m, 11H), 3.90 (s, 3H), 4.00 (bs, 2H), 4.89 (m, 1H), 5.61 (bs, 2H), 6.83 (d, J=7.78 Hz, 1H), 7.12 (m, 2H), 8.35 (s, 1H).
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([O:24]CC)=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.O>O1CCCC1.CO.O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([OH:24])=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3)nc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(C(=O)O)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
0.63 g (1.80 mmol) of ethyl 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were dissolved in 100 mL of a mixture tetrahydrofuran/methanol/water 8/1/1 and 0.19 g (4,53 mmol) of lithium hydroxide hydrate were added. The solution was stirred at 60° C. for 1.5 hours. The mixture was then cooled to room temperature and 1 N HCl added until neutral pH. Water was added and the resulting precipitate collected by filtration (87% yield).
Reaction SMILES: [Si]([O:8][C@H:9]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([CH2:44][OH:45])[CH:38]=1)[CH2:10][NH:11][C@H:12]([CH3:36])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1)(C(C)(C)C)(C)C>CCOCC>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][C@H:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([CH2:44][OH:45])[CH:38]=3)[CH3:36])[CH:15]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc(CCNC(=O)Cc2cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)c2)cc1OC
Solvent: CCOCC
Product: COc1ccc(CCNC(=O)Cc2cccc(C[C@@H](C)NC[C@H](O)c3ccc(O)c(CO)c3)c2)cc1OC

Procedure:
Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide (Preparation 27) according to the method for example 3 to give the title compound as a white foam after trituration with ether.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][O:16]C(=O)C)[CH:11]=2)[O:8][C@@H:7]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([Cl:30])=[N:24][C:25]=3Cl)[C@@H:6]1[O:31]C(=O)C)(=O)C.[NH2:35][CH2:36][CH:37]([C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1)[C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1>>[OH:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([C:45]2[CH:46]=[CH:47][C:48]([OH:51])=[CH:49][CH:50]=2)[CH2:36][NH:35][C:25]2[N:24]=[C:23]([Cl:30])[N:22]=[C:21]3[C:26]=2[N:27]=[CH:28][N:20]3[C@H:7]2[C@H:6]([OH:31])[C@H:5]([OH:4])[C@@H:9]([C:10]3[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=3)[O:8]2)=[CH:39][CH:40]=1
Reactant: NCC(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(=O)OCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Product: OCc1cc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)on1

Procedure:
The title compound is prepared from acetic acid (2R,3R,4R,5S)-4-acetoxy-5-(3-acetoxymethyl-isoxazol-5-yl)-2-(2,6-dichloro-purin-9-yl)-tetrahydro-furan-3-yl ester (WO 99/38877) analogously to (2R,3R,4S,5S)-2-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(3-hydroxymethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol (Intermediate CG) by replacing 2,2-diphenylethylamine with 4,4′-(2-aminoethylidene)bisphenol (Intermediate A).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=O)([O-:3])=[O:2].Cl.[O:15]([NH2:17])[CH3:16].C(N(CC)CC)C.CCOCC>CO>[CH3:16][O:15][N:17]=[C:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCc2c1cccc2[N+](=O)[O-]
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CON=C1CCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a solution of 4-nitroindane-1-one (4.75 g, 26.81 mmol) in MeOH was added methoxyl amine hydrochloride (4.50 g, 53.88 mmol) and triethyl amine (7.50 mL, 53.81 mmol). After refluxing overnight, the reaction mixture was cooled to room temperature and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with H2O (3×200 mL), brine (1×200 mL), dried over MgSO4 and concentrated. Purification by column chromatography using hex: Et2O (4:1) as eluant afforded 5.31 g (97% yield) of the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ (1st isomer) 2.92-2.98 (m, 2H), 3.50-3.56 (m, 2H), 4.01 (s, 3H), 7.45 (t, J=7.62 Hz, 1H), 8.00 (d, J=7.33 Hz, 1H), 8.20 (d, J=7.92 Hz, 1H). 2nd isomer: 2.90-2.98 (m, 2H), 3.49-3.58 (m, 2H), 4.02 (s, 3H), 7.45 (t, J=8.21 Hz, 1H), 8.19 (d, J=8.21 Hz, 1H), 8.66 (d, J=7.92 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:24])[CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].CC(C)([O-])C.[K+].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([CH3:40])[CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([O:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH2:18][C:17]([NH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[O:24])=[CH:33][C:34]=1[CH3:40])#[N:37]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCO)ccc21
Reactant: Cc1cc(F)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCOc3ccc(C#N)c(C)c3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
To a solution of N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxy-3-methylpentanamide (0.34 g, 1.05 mmol) in DMF (8.0 mL) was added potassium-t-butoxide (0.258 g, 2.31 mmol) under argon atmosphere. The mixture was stirred at room temperature for 15 min, and 4-fluoro-2-methylbenzonitrile (0.212 g, 1.57 mmol) was added thereto. The reaction solution was stirred at room temperature for 14 hr, and ethyl acetate (80 mL) was added thereto. The organic layer was washed with cold water (2×20 mL) and saturated brine (2×20 mL), and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20 to 30% ethyl acetate/hexane) to give the title compound (0.16 g, 35%) as a white powder.
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6](OC(=O)C)(=[O:8])[CH3:7].[NH2:13][CH:14](/[CH:18]=[CH:19]/[CH2:20][P:21]([OH:24])([OH:23])=[O:22])[C:15]([OH:17])=[O:16]>O1CCOCC1.O>[NH:13]([CH:14](/[CH:18]=[CH:19]/[CH2:20][P:21]([OH:24])([OH:23])=[O:22])[C:15]([OH:17])=[O:16])[C:6]([CH3:7])=[O:8]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NC(/C=C/CP(=O)(O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
At 0°, 170 mg of sodium hydrogen carbonate and, within a period of 5minutes, 50 microliters of acetic anhydride are added to a solution of 100 mg of E-2-amino-5-phosphono-3-pentenoic acid in 6 ml of dioxan/water (1:1). The whole is stirred for 30 minutes at 0°, approximately 2 ml of Dowex 50 H+ are added and filtration is carried out. The filtrate is concentrated by evaporation and purified by ion exchange chromatography (Dowex 50 H+). Lyophilisation of the pure fractions yields 110 mg of E-2-acetamino-5-phosphono-3-pentenoic acid, m.p. 155°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@@H:5]([OH:7])[CH:4]=[CH:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][C@H:2]1[CH:3]=[CH:4][C@H:5]([OH:7])[CH2:6]1
Reactant: C1=COCCC1
Reactant: O[C@H]1C=C[C@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O[C@H]1C=C[C@H](OC2CCCCO2)C1
Yield: 62.8 %

Procedure:
Ten milligrams of (R)-trans-3,5-dihydroxycyclopent-1-ene and 8 milligrams of dihydropyran were stirred at room temperature for 24 hours in 1.0 milliliter of methylene chloride in the presence of 0.1 milligram of p-toluenesulfonic acid. The organic solution was first washed with an aqueous sodium bicarbonate solution and then with an aqueous sodium chloride solution followed by drying with magnesium sulfate and thereafter distilling off the solvent under reduced pressure to obtain a crude product. This product was purified by thin-layer chromatography (n-hexane:ethyl acetate = 6:4), and 11 milligrams (60%) of (R)-trans-5-tetrahydropyranyloxycyclopent-1-en-3-ol was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2=[O:21])[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:35][C:31]1[CH:32]=[N:33][CH:34]=[C:29]([N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:30]=1)=[C:3]([CH3:22])[C:4]([N:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]1=[O:21])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CC(C)(C)CC2=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CC(C)(C)CC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4,4-dimethylpyrrolidin-2-one (150 mg, 0.46 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-4,4-dimethylpyrrolidin-2-one. 1H NMR (CDCl3) δ ppm 8.11 (1H, d, J=1.8 Hz), 8.02 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=2.2 Hz), 7.45 (1H, dd, J=9.3, 1.1 Hz), 7.02 (1H, ddd, J=13.3, 8.6, 2.5 Hz), 6.82 (1H, t, J=2.2 Hz), 3.91 (2H, br. s.), 3.71-3.85 (4H, m), 3.25-3.39 (4H, m), 2.44 (2H, s), 2.09 (3H, s), 1.34 (6H, s). Mass Spectrum (ESI) m/e=468.3 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][S:9]([C:11]2[S:12][C:13]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[O:24][CH2:25][C:26]([O:28]CC)=[O:27])[C:14]=3[N:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.CO>[C:31]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][S:9]([C:11]2[S:12][C:13]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[O:24][CH2:25][C:26]([OH:28])=[O:27])[C:14]=3[N:15]=2)=[O:10])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S(=O)CC(c3ccccc3)c3ccccc3)nc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1cccc2c1CCc1sc(S(=O)CC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of ethyl [(2-(2,2-diphenylethylsulfinyl)-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (0.50 g, 0.965 mmol) in a mixture of tetrahydrofuran (16 mL) and methanol (4 mL) was added 1N-aqueous sodium hydroxide (2 mL) dropwise, and the mixture was stirred at room temperature for 20 minutes. After the solvent was distilled off under reduced pressure, 1N-hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 0.36 g of the title compound as amorphous solid. Yield 76%.
Reaction SMILES: C[C:2]1([C:8](O)=O)[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=C>CC(C)=O>[CH2:8]([CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7])[CH:17]=[CH2:18]
Reactant: C=CCBr
Reactant: CC1(C(=O)O)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCC1CCCC1=O
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A stirred solution of methyl 2-carboxycyclopentanone (35.5 g, 250 mmol) in acetone (500 mL) was treated with anhydrous potassium carbonate (138 g, 1.0 mol) and allyl bromide (100 mL, 1.15 mol) and refluxed for 5 h. The mixture was cooled and filtered through Celite® (rinse filter cake with acetone), and the filtrate was concentrated in vacuo. The residual oil was dissolved in methanol (450 mL), treated with 6 N HCl (250 mL), and refluxed for 40 h. The solution was cooled to room temperature, concentrated in vacuo to remove most methanol, and diluted with water (200 mL). The aqueous solution was extracted with dichloromethane (3×250 mL), and the combined organic solution was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride (200 mL each), dried (Na2SO4), and gently (volatile product) concentrated in vacuo to 75 mL volume. This solution was loaded onto a silica gel column (˜500 cc) and eluted with dichloromethane to afford (after gentle concentration of fractions) 2-allylcyclopentanone (27.3 g, 88%) as a colorless oil. NMR (CDCl3): δ 5.65-5.75 (m, 1 H), 4.90-5.05 (m, 2 H), 2.40-2.50 (m, 1 H), 2.20-2.30 (m, 1 H), 1.85-2.15 (m, 5 H), 1.65-1.75 (m, 1 H), 1.45-1.55 (m, 1 H).
Reaction SMILES: Br[C:2]1[N:18]=[C:5]2[CH:6]=[C:7]([NH:10]C(=O)OC(C)(C)C)[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(OCC)(=O)C.O.[ClH:31].C(OCC)(=O)C>>[ClH:31].[N:19]1([C:2]2[N:18]=[C:5]3[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][N:4]3[N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(Br)nc2c1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 150 °C

Procedure:
The tert-butyl (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (75 mg) obtained in (Example 3.15) <Step 4> and pyrrolidine (1 ml) were stirred under microwave heating at 150° C. for 1 hour. Thereafter, ethyl acetate (10 ml) and water (3 ml) were added to the reaction solution. An organic layer was separated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Thereafter, potassium hydroxide (134 mg) was added to an ethanol (2 ml) solution of the obtained residue, and the obtained mixture was then heated to reflux for 16 hours. Thereafter, the solvent was distilled away under reduced pressure, and potassium hydroxide (134 mg) was added to an ethylene glycol (2 ml) solution of the obtained residue, followed by heating the obtained mixture at 155° C. for 2 hours. The solvent was distilled away under reduced pressure, and ethyl acetate (10 ml) and water (3 ml) were then added to the obtained residue. An organic layer was separated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=50:50-0:100) to obtain a crude product. The obtained crude product was dissolved in 4 N hydrochloric acid-ethyl acetate (1 ml), and the precipitated solid was then collected by filtration, so as to obtain the title compound (16 mg) in the form of a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].S(Cl)(Cl)=O.[C:12](=O)([O-])O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CO.O>[CH2:21]([O:20][C:18]([NH:1][C@@H:2]([C:5]([O:7][CH3:12])=[O:6])[CH2:3][OH:4])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])O
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H](CO)C(=O)O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of D-serine (10.5 g) in methanol (100 mL) was added thionyl chloride (8.76 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 4 hr, and to the reaction mixture were added sodium hydrogen carbonate (25.2 g) and benzyl chloroformate (17.1 mL). The reaction mixture was stirred at room temperature overnight, the reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.3 g).