Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].N1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]([O:21][CH2:20][C:5]2[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=2[O:3][CH2:1][CH3:2])[CH2:8][C:9]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][O:10]2)=[O:37])[CH:32]=[CH:33][CH:34]=1
Reactant: CCOc1ccc(CC2(C(=O)OC)CCCO2)cc1CO
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1ccc(CC2(C(=O)O)CCCO2)cc1COC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 0.012 g of methyl 2-(4-ethoxy-3-hydroxymethylbenzyl)tetrahydro-2-furancarboxylate in 0.2 ml of tetrahydrofuran were added 0.010 ml of pyridine and 0.0066 g of 3-chlorophenylisocyanic acid, and the mixture was stirred at room temperature for 15 hours. 1 ml of ethyl acetate and 0.5 ml of 1 N hydrochloric acid were added, and the organic layer was concentrated. The residue was dissolved in 0.5 ml of tetrahydrofuran, 0.5 ml of ethanol and 0.2 ml of 1 N sodium hydroxide, and the mixture was stirred for 2 hours. 1 ml of ethyl acetate and 0.5 ml of 1 N hydrochloric acid were added, and the organic layer was concentrated. The residue was purified by HPLC using a reverse-phase column and a water-acetonitrile-trifluoroacetic acid elution solvent system, to give the title compound.
Reaction SMILES: C([C@@H]1COC(=O)N1[C@:14]([CH2:47][C:48]([O:50][CH3:51])=[O:49])([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH2:27][N:28]([C:40]([O:42]C(C)(C)C)=O)[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)C(N)=O)C1C=CC=CC=1.OO.O[Li].O.S([O-])([O-])=O.[Na+].[Na+].Cl.C(N(CC)CC)C.C([O-])(O)=O.[Na+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]2[CH2:18][C@@H:14]([CH2:47][C:48]([O:50][CH3:51])=[O:49])[C:40](=[O:42])[N:28]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=3)[CH2:27][C:20]=2[CH:21]=1
Reactant: COC(=O)C[C@@](Cc1ccc(OC)cc1CN(Cc1ccc(C(F)(F)F)cc1)C(=O)OC(C)(C)C)(C(N)=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1Cc2ccc(OC)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a stirred solution of (R)-4-benzyl-2-oxazolidinonyl 3-[2-[N-(tert-butoxycarbonyl)-N-(4-trifluoromethylbenzyl)aminomethyl]-4-methyoxyphenyl]-2(S)-methoxycarbonylmethyl-propionamide (38.0 g, 54 mmol) in THF (300 mL) and water (100 mL) was added dropwise at 0° C. over 30 min a solution of 30% H2O2 (18.9 mL) and LiOH.H2O (2.3 g, 55 mmol) in water (62 mL). The cloudy solution was stirred for an additional 1 h at 0° C. The resulting homogeneous solution was treated slowly with a solution of sodium sulfite (34.3 g, 272 mmol) in water (175 mL) at 0° C., then was acidified with an ice-cold solution of concentrated HCl (35 mL) in water (150 mL). The reaction was extracted with ethyl acetate (2×200 mL), and the combined organic layers were washed with brine (400 mL), dried (MgSO4) and concentrated to dryness. The resulting residue was treated with 4.0 M HCl in dioxane (400 mL) with stirring at RT (slow gas evolution was observed). After 1 h, the reaction was concentrated and reconcentrated from 1:1 CHCl3/toluene (2×), then the residue (37.65 g) was taken up in dry DMF (400 mL). To this solution with stirring under argon at 0° C. in a Dewar flask were added triethylamine (15.3 mL, 109 mmol) and NaHCO3 (22.9 g, 273 mmol), followed by diphenylphosphoryl azide (13 mL, 60 mmol). After stirring for 24 h at 0° C. the reaction was concentrated to dryness. The residue was taken up in ethyl acetate (400 mL), and washed sequentially with water (300 mL) and brine (300 mL). Drying (MgSO4), concentration, and flash chromatography on silica gel (35% ethyl acetate/hexanes) gave the title compound (16.87 g, 74%) as a clear thick oil: TLC (40% EtOAc/hexane) Rf 0.50; MS (ES) m/e 422.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.1, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.02 (d, J=8.5 Hz, 1H), 7.75 (dd, 1H), 6.36 (d, J=2.7 Hz, 1H), 5.18 (d, J=16.5 Hz, 1H), 4.96 (d, J=15.4 Hz, 1H), 4.48 (d, J=15.4 Hz, 1H), 3.87 (m, 1H), 3.74 (d, J=16.5 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.08 (dd, 1H), 3.02 (dd, 1H), 2.95 (dd, 1H), 2.48 (dd, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH:20]2[CH2:22][CH2:21]2)[OH:19])[C:13]=1[CH3:23].C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([CH:20]2[CH2:21][CH2:22]2)=[O:19])[C:13]=1[CH3:23]
Reactant: Cc1c(Cl)ccnc1C(O)C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(Cl)ccnc1C(=O)C1CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 92.5 %

Procedure:
11.22 ml of oxalyl chloride was dissolved in 300 ml of anhydrous dichloromethane, and under cooling at −78° C., 100 ml of anhydrous dichloromethane solution of 9.83 ml of anhydrous dimethylsulfoxide was dropped thereto. The resulting mixture was stirred at −78° C. for 40 minutes, and thereafter, 200 ml of anhydrous dichloromethane solution of 19.55 g of (4-chloro-3-methyl-2-pyridyl)cyclopropylmethane-1-ol (IX) was dropped thereto. The resulting mixture was stirred at −78° C. for 30 minutes, and thereafter, the reaction temperature was elevated to −45° C. and the resulting mixture was stirred at the same temperature for 1 hour, and thereafter, 68.93 ml of triethylamine was dropped thereto and the temperature of the resulting mixture was elevated to a room temperature. Water was added thereto and the resulting mixture was extracted with chloroform, and the resulting organic layer was washed with water and saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=19:1) to obtain 17.89 g of (4-chloro-3-methyl-2-pyridyl)cyclopropylketone (X).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13]C)[C:6]([O:15]C)=[N:5]2.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:3]([N:17]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:15])[NH:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(N(Cc3cccnc3)S(C)(=O)=O)c2nc1OC
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N(Cc1cccnc1)c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Yield: 181.3 %

Procedure:
A mixture of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(3-pyridylmethyl)-methanesulphonamide (130 mg, 0.293 mmol), 2M hydrochloric acid (2 ml) and dioxane (4 ml) was heated at reflux for 2.5 hours, cooled, and concentrated under reduced pressure. The residue was suspended in water (1 ml), filtered off, and washed with water and ether to give the title compound (120 mg, 98%) as a white solid, m.p. 234°-235° C. (dec.).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[CH3:41])[O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([N:29]=[C:30]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[N:31]=2)[CH:28]=1>CN(C)C=O.CN(C)C(=O)C>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:40]([CH3:41])=[C:19]([NH:18][C:6]([CH:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:8])[CH:20]=4)=[CH:28][N:27]3[N:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: O=C(O)C1CCOC1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)C1CCOC1
Yield: 58.1 %

Procedure:
In the same manner as in Example 55 and using tetrahydrofuran-3-carboxylic acid (57.0 mg, 0.491 mmol), tetrahydrofuran (5 mL), thionyl chloride (83.0 μL, 0.957 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (140 mg, 0.433 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (106 mg, 58%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:31][C@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Reactant: CC[C@@H](N)C(C)(C)O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(C)(C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (1.25 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.25 mL, 20.4 eq, 1.43 mmol) followed by (R)-3-amino-2-methyl-pentan-2-ol (22 mg, 2.68 eq, 0.19 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with hexane:ether:MeOH (50:50:0→50:50:2) to afford the title compound as a white solid; Yield: 4.2 mg (16%). 1H-NMR (d-CDCl3, 250 MHz): δ 1.01 (t, 3H, J=7.50 Hz, —NHCH(CH2CH3)C(CH3)2OH), 1.23+1.30 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.68-1.89 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 3.69-3.86 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.58-4.74 (m, 1H, —CH(CH3)2), 4.75-4.94 (m, 2H, —HNCH2-Bz), 7.22-7.45 (m, 6H, 5×Bz-H+HNCH2-Bz), 7.57 (s, 1H, —N═CH—N). FABMS m/z (relative intensity): 383 ([M+H]+, 75), 323 (60), 308 (20), 246 (20), 192 (60), 176 (100), 165 (40). Accurate Mass (M+H): Actual: 383.2559, Measured: 383.2544.
Reaction SMILES: C(OC([NH:8][CH:9]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[N:11]([O:16][S:17]([OH:20])(=[O:19])=[O:18])[C:10]1=[O:21])=O)(C)(C)C.[Na].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[NH2:8][CH:9]1[C:12]2([CH2:15][CH2:14][CH2:13]2)[N:11]([O:16][S:17]([OH:20])(=[O:18])=[O:19])[C:10]1=[O:21]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(OS(=O)(=O)O)C12CCC2
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NC1C(=O)N(OS(=O)(=O)O)C12CCC2
Reaction time: 0.5 h

Procedure:
3-[(t-Butoxycarbonyl)amino]-2-oxo-1-(sulfooxy)-1-azaspiro[3.3]heptane, monosodium salt (0.3 g, 0.87 mmole) was slurried in 2.5 ml of dry dichloromethane and 1.0 ml of anisole at -10° C. under argon, and then treated with 4.0 ml of trifluoroacetic acid. After 0.5 hour, a solid had formed. After 1.5 hours, 4 ml of dry toluene was added, and the mixture evaporated in vacuo to give a solid, 3-amino-2-oxo-1-(sulfooxy)-1-azaspiro[3.3]heptane, which was triturated twice with hexane and dried in vacuo at 25° C. for 1 hour.
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:26]2[CH:27]=[CH:28][C:29]([O:40]S(C(F)(F)F)(=O)=O)=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH:31]=2)([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:10]=1)=O)(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[NH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:26]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:29]([OH:40])=[CH:28][CH:27]=2)([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:10]=1
Reactant: COc1ccc(C2(c3ccc(OS(=O)(=O)C(F)(F)F)c(-c4cccc(OC)c4)c3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2(c3ccc(O)c(-c4cccc(OC)c4)c3)N=C(N)c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To [3-(6-hydroxy-3′-methoxy-biphenyl-3-yl)-3-(4-methoxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester (Scheme #2, F) (10.0 mg, 18.6 umol) was added trifluoroacetic acid in dichloromethane (10%, 1-2 mL) and reaction stirred 60 minutes. The solvents were removed under reduced pressure and the resulting gum put under high vacuum at 50° C. over night to give the title compound as a waxy solid (10.4 mg). 1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J=7.8 Hz, 1 H), 7.85-7.67 (m, 3 H), 7.32-7.18 (m, 4 H), 7.03-6.85 (m, 8 H), 3.74 (d, J=2.7 Hz, 6 H); MS (APCI+) m/z 437 [M+1]+; tR=2.14 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([OH:29])[CH:28]=1)[C:24]#[N:25].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:46][CH:47]1[CH:52](O)[CH2:51][CH2:50][N:49]([CH2:54][CH:55]([N:59]2[CH:63]=[C:62]([C:64]3[C:65]4[CH:72]=[CH:71][N:70](COCC[Si](C)(C)C)[C:66]=4[N:67]=[CH:68][N:69]=3)[CH:61]=[N:60]2)[CH2:56][C:57]#[N:58])[CH2:48]1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C(Cl)Cl>[C:57]([CH2:56][CH:55]([N:59]1[CH:63]=[C:62]([C:64]2[C:65]3[CH:72]=[CH:71][NH:70][C:66]=3[N:67]=[CH:68][N:69]=2)[CH:61]=[N:60]1)[CH2:54][N:49]1[CH2:50][CH2:51][CH:52]([O:29][C:27]2[CH:26]=[C:23]([CH:22]=[C:21]([F:20])[CH:28]=2)[C:24]#[N:25])[CH:47]([F:46])[CH2:48]1)#[N:58]
Reactant: N#Cc1cc(O)cc(F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(O)C(F)C4)c3)ncnc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#CCC(CN1CCC(Oc2cc(F)cc(C#N)c2)C(F)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
To a mixture of resin of triphenylphosphine (63.8 mg, 0.133 mmol) and 3-fluoro-5-hydroxybenzonitrile (12.5 mg, 0.0910 mmol) in methylene chloride (0.6 mL) was added di-tert-butyl azodicarboxylate (22.3 mg, 0.0970 mmol) (DBAD). The mixture was stirred for 15 minutes before adding a solution of 4-(3-fluoro-4-hydroxypiperidin-1-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (30.3 mg, 0.0606 mmol) (diastereomer 2) in methylene chloride (0.2 mL). The reaction was stirred overnight at room temperature then another portion of resin of triphenylphosphine and DBAD was added and the solution was stirred for 6 hours, then the solvent was evaporated. The vial and resin were washed with DCM and filtered. The filtrates were washed with 10% aq. NaOH. The organic was dried over MgSO4, filtered, and concentrated. The crude was diluted with methanol and purified with preparative LCMS (Sunfire C18 column eluting with a gradient MeCN/H2O containing 0.1% TFA at 30 mL/min) to give the desired product (11 mg, 29%). The product was synthesized from diastereomer 1 using same procedure in 14% yield. LCMS (M+H)+: 619.3.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:17]2[CH:28]=[C:27]3[C:29]4[C:23]([CH3:30])([CH2:24][CH2:25][CH2:26]3)[CH2:22][CH2:21][CH2:20][C:19]=4[CH:18]=2)[C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH2:4][N:5]([C:17]2[CH:18]=[C:19]3[C:29]4[C:23]([CH3:30])([CH2:22][CH2:21][CH2:20]3)[CH2:24][CH2:25][CH2:26][C:27]=4[CH:28]=2)[C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:15][CH:16]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(N(CC2CC2)c2cc3c4c(c2)CCCC4(C)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCCc3cc(N(CC4CC4)c4ccc(C(=O)O)cc4)cc(c31)CCC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
A suspension of ethyl 4-[N-cyclopropylmethyl-(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]benzoate (0.063 g) in ethanol (5 ml) was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred overnight at 50° C. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.042 g, yield: 71%) as colorless needles (melting point: 234-235° C.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][NH:7]2>FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2
Reactant: O=C1CCNc2cccc(F)c21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc2c1CCCN2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-fluoro-2,3-dihydro-1H-quinolin-4-one obtained in Reference Example 3 (64 mg) in trifluoroacetic acid (5 ml), triethylsilane (0.37 ml) was added and stirred at room temperature for 16 hours. After distilling off the solvent under reduced pressure, the residue was diluted with water, adjusted to pH 11 by addition of 1M aqueous sodium hydroxide, and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=3:1). The resulting residue was diluted with chloroform, added to 1M aqueous hydrochloric acid (15 ml) and partitioned. The aqueous layer was adjusted to pH 11 by addition of 2.5M aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure to give the titled compound, i.e., 5-fluoro-1,2,3,4-tetrahydroquinoline (39 mg) as a light-yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([N:22]2[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]3[C:31]4[C:36]([CH:37]=[CH:38][C:23]2=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:19]=[CH:20][CH:21]=1>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[CH:17]=[C:18]([N:22]2[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]3[C:31]4[C:36]([CH:37]=[CH:38][C:23]2=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:19]=[CH:20][CH:21]=1)=[O:6]
Reactant: O=C(O)c1ccccc1I
Reactant: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Solvent: O=S(Cl)Cl
Product: O=C1CC(=O)N(c2cccc(NC(=O)c3ccccc3I)c2)c2ccc3ccccc3c2N1
Yield: 38.4 %

Procedure:
2-Iodobenzoic acid (50 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 53, (1), the title compound (21 mg, yield 38%) was obtained as pale brown crystals in the same manner as that of Example 1, (4). The structure was confirmed by NMR and MS.
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C>C1COCC1>[CH2:23]([O:22][C:14]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1)=[O:21])[CH3:24]
Reactant: Brc1nsc2nc3ccccc3n12
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1nsc2nc3ccccc3n12
Yield: 53.8 %

Procedure:
A mixture of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole (0.2 g, 0.78 mmole), diethyl malonate (0.15 g, 0.94 mmol) and triethylamine (0.13 mL, 0.94 mmole) in 8 mL of THF was refluxed under a nitrogen atmosphere for 36 h. The resulting mixture was extracted with ethyl acetate, washed with water and 10% aqueous sodium sulfate. The organic layer was dried over magnesium sulfate to give the crude product, which was purified by flash chromatography (35% ethyl acetate:65%. hexane) to afford 0.14 g (54%) of the title compound as a yellow oil:
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[Br:9][C:10]1[S:14][C:13]2=[N:15][CH:16]=[CH:17][N:12]2[N:11]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:9][C:10]1[S:14][C:13]2=[N:15][CH:16]=[C:17]([I:8])[N:12]2[N:11]=1
Reactant: Brc1nn2ccnc2s1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1nn2c(I)cnc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
NIS (3.83 g, 16.2 mmol, 1.1 eq) was added to a solution of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (3.0 g, 14.7 mmol, 1 eq) in dry DMF (50 mL). The mixture was stirred at RT for 4 h and then poured into aq. Na2S2O3 (10%) and diluted with EtOAc. The organic phase was washed with water, dried and concentrated to give the desired product (pale brown solid; 4.34 g, yield 89%). 1H (300 MHz, CDCl3): δ/ppm 7.29 (1H, s).
Reaction SMILES: [CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH:17]=[CH:18][C:13]3=[CH:12][C:11]=2[C:19]([OH:21])=[O:20])=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)C.[H][H]>[Pd].O>[CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH2:17][CH2:18][C:13]3=[CH:12][C:11]=2[C:19]([OH:21])=[O:20])=[N:5]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)C1(C)N=C(c2nc3c(cc2C(=O)O)CCO3)NC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 5.9 %

Procedure:
A solution of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3-b]pyridine-5-carboxylic acid (1.7 g 0.056 mol) and 1.0 g (0.0072 mol) potassium carbonate in 200 mL 9:1 ethanol:water is added to 100 mg 5% palladium on carbon catalyst in a 500 mL pressure bottle. The bottle is fitted to a Parr hydrogenation apparatus, pressurized to 30 psi, with hydrogen, then shaken at room temperature for 10 hours. The catalyst is removed by filtration through a sintered glass funnel, and the filtrate concentrated in vacuo to 10 mL. Acidification of the residue to pH 2 gives a white precipitate which is removed by filtration, washed with water and air dried to give 1.0 g (63%) of 2,3-dihydro-6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo-[2,3-b]pyridine-5-carboxylic acid as an off-white solid, mp 189°-192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20](F)[CH:19]=1>CS(C)=O.O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:19]=1)[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Aniline (930 mg, 10.0 mmol) was added to a solution of DIPEA (1.94 g, 15.0 mmol) and 4-bromo-2-fluoro-1-nitrobenzene (2.2 g, 10.0 mmol) in DMSO (16 mL). The reaction mixture was stirred at 60° C. for 4 h. Upon completion, the mixture was diluted with water (50 mL), and the resulting precipitate collected by filtration, washed with water and dried in vacuo. The crude product was used in next step without further purification. LCMS (m/z): 293.1/294.1 [M+H]+/[M+2H]+