Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[OH:34][C:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:43][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([C:35]([OH:34])([CH3:36])[CH3:37])=[CH:39][CH:40]=1)=[O:9]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Oc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
5-Chloro-2-(4-fluoro-phenoxy)-nicotinic acid (1.37 g) was dissolved in anhydrous dichloromethane (15 mL). 4-Methylmorpholine (0.80 mL) was added and the solution cooled in a dry ice/acetone bath. Isobutyl chloroformate (0.85 mL) was added and the solution stirred for 15 minutes. 4-(1-Hydroxy-1-methyl-ethyl)-benzyl amine (0.946 g) was added and the solution warmed to ambient temperature overnight. The solution was then poured into a separatory funnel and water (15 mL) was added. The solution was shaken, and the organics were removed. The remaining aqueous portion was extracted with dichloromethane (6×20 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated to dryness in vacuo to yield the crude product (2.65 g). Purification of the crude material by silica gel chromatography (ethyl acetate:hexanes 1:3) yielded pure title compound (1.61 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7](Br)(Br)[C:8](=[O:15])[NH:9][C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4]>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8](=[O:15])[NH:9][C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)cc2c1C(Br)(Br)C(=O)N2
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc2c1CC(=O)N2

Procedure:
3,3,6-Tribromo-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid methyl ester (5.90 g, 16.9 mmol) is suspended in glacial acetic acid (153 mL) and zinc dust (10 μM Mesh, 11.5 g, 169 mmol) is added over 5 minutes. The reaction is monitored by TLC and when complete (30 min) the reaction is filtered through celite and the filtrate washed with ethyl acetate. The combined filtrate and washings are evaporated in vacuo to yield an oil that is taken up in ethyl acetate (500 mL), washed with water (100 mL) and brine (100 mL). The organic layer is dried filtered and evaporated in vacuo to give the title compound that is recrystalized from ethyl acetate (2.2 g, 11.5 mmol 68%). LCMS (ESMS): m/z 271.3 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].[CH2:14]([OH:17])[CH2:15][OH:16].[H-].[Na+].O>O1CCCC1>[OH:16][CH2:15][CH2:14][O:17][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: OCCO
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1OCCO

Procedure:
To solution of 34.4 grams of pentachlorobenzonitrile in tetrahydrofuran was added a mixture of 8.0 grams ethylene glycol, 8.0 grams of a 50% sodium hydride-mineral oil dispersion and 250 ml tetrahydrofuran. The resulting reaction mixture was heated at reflux for one hour and then poured into a large volume of water. Filtration afforded an almost colorless solid which was dissolved in tetrahydrofuran. Treatment with magnesium sulfate followed by filtration and removal of the solvent gave rise to beta-hydroxyethoxy-tetrachlorobenzonitrile. This material is identical basis both nmr and infrared spectral data to the product formed from the reaction of tetrachlorocyanophenol with ethylene oxide as set forth below.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([OH:44])[CH3:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([OH:44])[CH3:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C(C)O)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 66 %

Procedure:
Prepared in 66% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-(1-hydroxyethyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.22 (dd, J=9.4, 2.6 Hz, 1H), 7.19-7.14 (m, 2H), 6.15 (br. s., 1H), 5.78 (br. s., 1H), 5.46 (br. s., 1H), 4.62 (br. s., 1H), 3.90-3.79 (m, 1H), 3.62-3.52 (m, 1H), 3.50-3.40 (m, 3H), 2.66 (d, J=9.0 Hz, 1H), 2.40 (s, 3H), 1.95-1.52 (m, 10H), 1.49 (d, J=6.8 Hz, 3H), 1.20 (s, 3H), 1.14 (s, 9H), 1.08 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 688.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][C:7](=[O:22])[C:6]=2[CH:23]=1.[BH4-].[Na+].O>CO.C(Cl)Cl>[NH3:11].[OH:22][CH:7]1[C:6]2[CH:23]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:15](=[C:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8]1
Reactant: O=C1Cc2cccnc2C(=C2CCNCC2)c2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: N
Product: OC1Cc2cccnc2C(=C2CCNCC2)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
Mix the title compound of Example 1, (0.29 g, 0.893 mmol) in CH3OH (14 mL) at 0° C. under an argon atmosphere. Add NaBH4 (165 mg, 4.36 mmol) in 3 portions. After 30 minutes, pour the mixture into water and extract (3X) with CH2Cl2. Combine the organic portions, wash once with brine, dry over sodium sulfate, filter and concentrate in vacuo to give a crude product. Purifiy via flash chromatography [5-10% CH3OH saturated with NH3 in CH2Cl2 ] to give the title compound, which can be triturated with isopropyl ether/pentane to give an off-white solid (249 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:27])=[C:5]([CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([O:23]C)=[O:22])[C:6]=1[CH2:7][CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH3:1][C:2]1[S:3][C:4]([CH3:27])=[C:5]([CH2:17][CH2:18][C:19]([CH3:25])([CH3:26])[CH2:20][C:21]([OH:23])=[O:22])[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CC(C)(C)CCc1c(C)sc(C)c1CCC(=O)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: Cc1sc(C)c(CCC(C)(C)CC(=O)O)c1CCCc1ccccc1
Temperature: 210 °C
Yield: 75.6 %

Procedure:
6.4 g (0.0166 mol) of 2,5-dimethyl-3-(3-oxo-3-phenylpropyl)-4-(4-methoxycarbonyl-3,3-dimethylbutyl)thiophene and 100 ml of triethylene glycol are placed in a 250 ml three-necked flask fitted with a mechanical stirrer, a condenser and a thermometer. The temperature is brought to 60° C., 1.86 g (0.0580 mol) of 80% hydrazine hydrate are added to the reaction mixture and then, at 90° C., 2.84 g (0.050 mol) of potassium hydroxide are added. The reaction mixture is then brought to a vigorous reflux and, after the removal of water by distillation, the temperature is maintained at 210° C. for 45 minutes. After cooling, the mixture is hydrolysed with a mixture of water/ice/concentrated HCl (200 g/100 g/17 ml) and then extracted with ether. The combined organic phases are washed with dilute HCl, H2O, and then dried over MgSO4, rendered colourless with carbon black and concentrated to yield 4.5 g of 2,5-dimethyl-3-(3-phenylpropyl)-4-(4-carboxy-3,3-dimethylbutyl)thiophene in the form of a pale yellow oil, yield: 75%.
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]1[C:6]([C:40]([O:42]C)=[O:41])=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]3[C:32]4[C:31](=[O:33])[CH2:30][C:29]([CH3:35])([CH3:34])[CH2:28][C:27]=4[O:26][C:25]4[CH2:24][C:23]([CH3:37])([CH3:36])[CH2:22][C:21](=[O:38])[C:20]3=4)[C:12]=2[CH3:39])=[CH:9][CH:10]=1>C1COCC1.O>[OH:4][C:5]1[C:6]([C:40]([OH:42])=[O:41])=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]3[C:20]4[C:21](=[O:38])[CH2:22][C:23]([CH3:36])([CH3:37])[CH2:24][C:25]=4[O:26][C:27]4[CH2:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](=[O:33])[C:32]3=4)[C:12]=2[CH3:39])=[CH:9][CH:10]=1
Reactant: COC(=O)c1nc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)ccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(O)c(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 21 h
Yield: 39.1 %

Procedure:
Lithium hydroxide monohydrate (84.6 mg, 2.02 mmol) was added to a solution of the methyl 3-hydroxy-6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylate produced in Example 11-3 (250 mg, 0.46 mmol) in THF (5 ml) and water (2.5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 21 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then washed with diethyl ether. A 1 N aqueous solution of hydrochloric acid (2.02 ml) was added to the water layer, and the solution thus mixed was then extracted with dichloromethane seven times. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=3:97 to 6:94, v/v). The fraction thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (95.6 mg, yield: 39%).
Reaction SMILES: [Si](O[CH:9]1[CH:22](O[Si](C(C)(C)C)(C)C)[C:21]2[C:20](=[O:31])[C:19](=[O:32])[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C>[C:20]1(=[O:31])[C:21]2[CH:22]=[CH:9][C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][C:19]1=[O:32]
Reactant: CC(C)(C)[Si](C)(C)OC1C2=C(C=CC(=O)C2=O)c2ccccc2C1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1C=Cc2c(ccc3ccccc23)C1=O
Temperature: 25 °C
Yield: 105.2 %

Procedure:
In a 20 mL volume glass container, 187 mg of the above-prepared 9,10-bis(t-butyldimethylsilyloxy)-9,10-dihydrophenanthrenequinone trimer, 20 mL of tetrahydrofuran, 64 μL of acetic acid, and 2.3 mL of tetrabutylammonium fluoride were placed and stirred at room temperature in air. The resultant reaction mixture was allowed to stand. Thereafter, the precipitate was collected by filtration and washed, thereby to give 87 mg of a phenanthrenequinone compound represented by the following chemical structural formula (1b-2) (hereinafter referred to as a “phenanthrenequinone compound (1b-2)”) (yield 75%), as a reddish brown-colored solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]([C:17](=O)[CH3:18])=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[CH:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:27]OC(OC)N(C)C.[CH3:35][NH:36][C:37]([NH2:39])=[NH:38].Cl.CC[O-].[Na+]>C(O)CC.O.Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:16]([C:17]3[CH:18]=[CH:35][N:36]=[C:37]([NH:39][CH3:27])[N:38]=3)=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[CH:13]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2C(C)=O)CC1
Reactant: COC(OC)N(C)C
Reactant: CNC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: CCOC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(NC)n2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of the ketoimidazole prepared in Example 2 above (2.1 g,5.85 mmol) in 10.5 mL of 1-propanol was added N,N-dimethylformamide dimethyl acetal (1.32 mL, 1.18 g, 9.94 mmol) and the solution was heated at 100° C. for 6 h. At this time, TLC indicated no starting material and N-methylguanidine·HCl (0.96 g, 8.77 mmol) and NaOEt (21% w/w solution, 3.50 mL, 3.05 g, 9.35 mmol) were added. After 18 hours, the solution was cooled to room temperature, diluted with 40 mL of water, 50 mL of 3N HCl and 50 mL of EtOAC. The layers were separated and the organic layer wash washed again with 20 mL of 3N HCl. The combined aqueous layers were basified with solid K2CO3 until bubbling ceased. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were washed with 3×100 mL of water, concentrated and the residue was recrystallized from EtOAc to give 1.24 g (50%) of the title compound: mp=205-206° C.; IR (KBr) 3242, 3110, 1695, 1588, 1568, 1532, 1507 cm-1 ; 1H NMR (CDCl3) δ8.15 (1H, d, J=5.0 Hz), 7.71 (1H, s), 7.44 (2H, m), 6.97 (2H, t, J=8.7 Hz), 6.40 (1H, d, J=5.0 Hz), 5.18 (1H, m), 4.83 (1H, m), 4.34 (2H, m),4.15 (2H, q, J=7.1 Hz), 3.02 (3H, d, J=5.0 Hz), 2.81 (2H, m), 2.19 (2H, m), 1.87 (2H, dq, J=4.4, 12.5 Hz), 1.27 (3H, t, J=7.1 Hz); 13C NMR (CDCl3) δ164.00, 163.03, 160.73, 158.51, 158.32, 155.31, 141.96, 135.57, 130.52, 130.07, 129.97, 125.01, 115.39, 115.11, 111.73, 61.61, 53.80, 43.42, 33.43, 28.43, 14.63; Anal. Cald for C22H25N6O2F; C, 62.2; H, 5.9; N, 19.8; Found C, 61.9, H, 6.0; N, 19.4.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]([CH3:46])([CH3:45])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:21][C:20]=1[C:38]1[N:39]([CH3:44])[N:40]=[CH:41][C:42]=1[Cl:43].[CH:47](=O)[CH2:48][CH3:49].C(Cl)(=O)C>C1COCC1.CO>[Cl:43][C:42]1[CH:41]=[N:40][N:39]([CH3:44])[C:38]=1[C:20]1[CH:21]=[C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[CH:23]=[CH:24][C:19]=1[O:18][CH2:17][C:16]([CH3:46])([NH:15][CH2:47][CH2:48][CH3:49])[CH3:45]
Reactant: CCC=O
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CCCNC(C)(C)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.3 %

Procedure:
Sodium triacetoxyborohydride (34 mg, 161 μmol) was added to a solution of N-(4-(2-amino-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide (53.8 mg, 115 μmol) and propionaldehyde (6.7 mg, 115 μmol) in THF (0.5 mL), and the mixture was stirred at room temperature. After 4 hours, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The extract was evaporated to dryness, the residue was redissolved in methanol, and the products were isolated by preparative HPLC. Product containing fractions were combined and concentrated in a vacuum centrifuge to one fourth of the original volume. The solution was made alkaline with saturated sodium bicarbonate, the product was extracted with dichloromethane, and the extract was evaporated to dryness. The residue was dissolved in a solution of acetyl chloride (16 μl, 230 μmol) in methanol (1 mL) and evaporated to dryness. The residue was dissolved in water and lyophilized to give the title compound (30 mg, 48%) as the hydrochloride salt. LCMS m/z (%)=511.4 (M+H, 37Cl 60.5), 509.3 (M+H, 35Cl 100.0%). 1H NMR (400 MHz, DMSO-d6) δ 0.87 (t, J=7.45 Hz, 3H) 1.26 (s, 6H) 1.46-1.58 (m, 2H) 2.53-2.64 (m, 2H) 3.65 (s, 3H) 4.06 (d, J=10.36 Hz, 1H) 4.16 (d, J=10.36 Hz, 1H) 7.33 (d, J=9.09 Hz, 1H) 7.69 (s, 1H) 7.73 (d, J=2.78 Hz, 1H) 7.80 (t, J=7.83 Hz, 1H) 7.94-8.02 (m, 2H) 8.28 (d, J=8.34 Hz, 1H) 8.31 (s, 1H) 8.65 (s, 2H) 10.59 (s, 1H).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([N:11]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[N:9][CH:10]=1)([F:4])[CH3:3].O.Cl.C1COCC1>CCOC(C)=O>[F:1][C:2]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[N:9][CH:10]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(F)(F)c1cncc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
Add 5-(1,1-difluoroethyl)-N-(diphenylmethylene)pyridin-3-amine (296 mg, 0.92 mmol), water (1 mL) and hydrochloric acid (1N, 4 mL) to THF (10 mL), stir at room temperature for 3 hrs. TLC (PE:EtOAc=2:1) shows the reaction is complete. Extract the mixture with ethyl acetate, wash the organic layer with saturated sodium bicarbonate solution and brine sequentially, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to give the crude product. Purification by flash chromatography (silica gel, EtOAc:PE=1:1) yields the title compound (140 mg, 96.5%). MS: (M+1): 159.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:41])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35]C(OCC)=O)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][C:10]=1[O:42][CH3:43])#[N:2].[CH3:44][Mg]Br.C([O:50][CH2:51][CH3:52])(=O)C>O1CCCC1>[OH:50][C:51]([CH3:52])([CH3:44])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:41])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[C:10]([O:42][CH3:43])[CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(OC)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reactant: CCOC(C)=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(OC)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of ethyl [(trans-4-{6-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (0.13 g) in tetrahydrofuran (1.5 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.88 mL) at 0° C., and the mixture was stirred for 3 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.085 g, 68%).
Reaction SMILES: CO[C:3](=[O:38])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[C:22]([O:28][CH2:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[C:21]=1[F:35])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.Cl.[NH:40]([C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([OH:46])=[O:45])[NH2:41].COC(=O)N=C(SC)C(=NC1C=CC(C#N)=CC=1)C1C=C(OC)C=C(OC)C=1F>>[CH3:32][N:31]([CH3:33])[C:30]([CH2:29][O:28][C:22]1[C:21]([F:35])=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:38])[N:40]([C:42]3[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=3[C:44]([OH:46])=[O:45])[N:41]=2)[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=1)=[O:34]
Reactant: CCc1cc(OCC(=O)N(C)C)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Reactant: NNc1ccccc1C(=O)O
Agent: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OC)c1F
Agent: Cl
Product: CCc1cc(OCC(=O)N(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)c1
Yield: 60.2 %

Procedure:
The same procedure was carried out as in Example (2f), except that 0.409 g of {2-(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and 0.160 g of 2-hydrazinobenzoic acid hydrochloride were used instead of respectively the [2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester and (1-oxypyridin-2-yl)hydrazine, to give the title compound (0.280 g) as a white solid.
Reaction SMILES: [C:1]([C@H:4]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=1)[CH3:5])([OH:3])=O.F[C:22]1C(O)=C(F)C(F)=C(F)C=1F.Cl.[CH:34]1([NH:38][C:39]([C@@H:41]2[CH2:45][CH2:44][CH2:43][NH:42]2)=[O:40])[CH2:37][CH2:36][CH2:35]1.C(N1CCOCC1)C>C(Cl)Cl.O.C(Cl)CCl>[CH3:22][O:20][C:18]([C:9]1[CH:8]=[C:7]([O:6][C@H:4]([CH3:5])[C:1]([N:42]2[CH2:43][CH2:44][CH2:45][C@H:41]2[C:39](=[O:40])[NH:38][CH:34]2[CH2:37][CH2:36][CH2:35]2)=[O:3])[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1)=[O:19]
Reactant: Cc1ccc2c(O[C@H](C)C(=O)O)cc(C(=O)O)nc2c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(O[C@H](C)C(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccc(C)cc2n1

Procedure:
To a solution of 1.30 g 4-((R)-1-Carboxy-ethoxy)-7-methyl-quinoline-2-carboxylic acid in 10 ml DCM, 1.24 g pentafluorophenol and 1.29 g EDC were added. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide hydrochloride (1.10 g) was mixed with 1.1 ml N-ethylmorpholine and 5 ml DCM and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with water and extracted with DCM. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 1.40 g.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:21].Cl.[N:23]1([C@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][N:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:21])=[C:2]([N:30]4[CH2:31][CH2:32][C@H:28]([N:23]5[CH:27]=[CH:26][N:25]=[N:24]5)[CH2:29]4)[N:11]=3)[C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1cn([C@H]2CCNC2)nn1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CC[C@H](n4ccnn4)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 24.2 %

Procedure:
Ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (250 mg, 0.8 mmol) was reacted with 350 mg (2 mmol) of 3(S)-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride in 8 ml of pyridine in the presence of 305 mg (2 mmol) of DBU at 80°-90° C. for 6 h. The reaction was then stirred at r.t. for 4 days. The solvent was then evaporated under reduced pressure and to the residue, water was added and extracted with chloroform. The organic layer was dried and evaporated to dryness. The residue was then chromatographed over alumina (neutral, activity III) using chloroform as solvent to yield 80 mg (24%) of the desired product. 1H NMR (CDCl3) δ: 8.48 (s, 1H), 8.05 (d, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 5.46-5.32 (m, 1H), 4.46-4.26 (m, 4H), 4.15-4.0 (m, 2H), 3.56-3.42 (m, 1H), 2.71-2.57 (m, 2H), 1.4 (t, 3H), 1.26-0.95 (m, 4H).