Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([CH:4]([NH2:16])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)=[N+]=[N-].[CH3:17]O>>[F:15][C:7]1[CH:6]=[C:5]([CH:4]([NH2:16])[CH3:17])[CH:10]=[CH:9][C:8]=1[C:11]([F:12])([F:13])[F:14]
Reactant: [N-]=[N+]=NC(N)c1ccc(C(F)(F)F)c(F)c1
Reactant: CO
Product: CC(N)c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 34 %

Procedure:
C-Azido-C-(3-fluoro-4-trifluoromethyl-phenyl)-methylamine (0.4 g) was dissolved in methanol (6 mL). The flask was evacuated and filled with nitrogen atmosphere before catalytic amount of Pd/C was added to the flask. The reaction was put under hydrogen atmosphere and stirred at r.t. over night. The flask was evacuated and filled with nitrogen before the reaction mixture was filtered through a celite pad. The solvent was removed and the crude product was purified on a colon (silica, CH2Cl2 followed by CH2Cl2/MeOH, 9:1) yielding 120 mg (34%) of 1-(3-Fluoro-4-trifluoromethyl-phenyl)-ethylamine. 1H NMR δ (CDCl3): 1.42 (3H, d), 4.22 (1H, q), 7.21-7.30 (m, 2H), 7.58 (1H, t).
Reaction SMILES: ClOC(C)(C)C.[CH2:7]1[S:10][CH2:9][CH2:8]1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.CCCCCCC=CCCC>ClCCl>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[CH2:9][CH2:8][CH2:7][S:10]2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C1CSC1
Agent: CC(C)(C)OCl
Agent: CCCC=CCCCCCC
Solvent: ClCCl
Product: Brc1ccc(N2CCCS2)cc1
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
A solution of tert.-Butyl hypochlorite (947 mg) in dichloromethane (15 mL) is added drop wise over a period of 1 h to a solution of trimethylene sulfide (0.63 mL) and 4-bromoaniline (1.50 g) in dichloromethane (60 mL) at −70° C. The reaction mixture is stirred for 15 min prior to the addition of a solution of 1,8-diazabycyclo[5.4.0]undec-7-ene (1.37 mL) in dichloromethane (10 mL). The reaction mixture is allowed to warm to −15° C. and quenched with water. The organic phase is separated, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20-40:60) to give the title compound. LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=244, 246 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[K+]>C1COCC1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: CCOC(=O)c1cnc(Nc2ccc(OC)c(OC)c2)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C(=O)O)s2)cc1OC
Temperature: 55 °C
Yield: 66.7 %

Procedure:
A mixture of 3.9 g (12.78 mmol) 2-(3,4-Dimethoxy-phenylamino)-thiazole-5-carboxylic acid ethyl ester and 12.78 ml 5M KOH in 23.5 ml THF was heated to 55° C. for 22 h. After acidification with HCl aq. The mixture was extracted with ethyl acetate and the combined organic layers washed with water, dried with MgSO4 and evaporated to dryness. Additionally precipitaed material from the aqueous phase was filtered off and dried. 2.39 g (67%) of the title compound was obtained as beige crystals. MS (m/e): 279.0 (M−H, 100%)
Reaction SMILES: [CH2:1]([N:4]=[C:5]([NH2:15])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)[CH2:2][CH3:3].I([O-])(=O)(=O)=[O:17].[Na+].CCOC(C)=O.CO>CO.O>[CH2:1]([N:4]=[C:5]([NH2:15])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13]([CH3:14])=[O:17])[N:8]=1)[CH2:2][CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCN=C(N)Nc1ccnc(SC)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN=C(N)Nc1ccnc(S(C)=O)n1

Procedure:
A solution of 4-(2-propylguanidino)-2-methylthiopyrimidine (1.6 g.) in MeOH (25 ml.) was heated on a steam bath while a solution of sodium metaperiodate (1.6 g.) in water (15 ml.) was added dropwise over 15 minutes. Further sodium metaperiodate in water (10% w/v) was added until analysis by t.l.c. on silica using EtOAc/MeOH 4:1 v/v as eluant showed absence of starting material. The reaction mixture was evaporated in vacuo, and the residue partitioned between methylene chloride and water. The organic phase was worked up to give 4-(2-propylguanidino)-2-methylsulphinylpyrimidine, m.p. 179°-180°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24].C(O[K])(C)=O.[C:30]([O:34][C:35](=[O:43])[C:36]1[CH:41]=[C:40](Br)[CH:39]=[N:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]([O:34][C:35](=[O:43])[C:36]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]3[C:21](=[CH:22][CH:23]=2)[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[CH2:6][C:5]3=[O:24])[CH:39]=[N:38][CH:37]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: [Fe+2]
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)c1
Temperature: 100 °C

Procedure:
Tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (19.8 g, 50.0 mmol), bis(pinacolato)diboran (14.0 g, 55.0 mmol), Pd(OAc)2 (560 mg, 2.50 mmol), DPPF (2.77 g, 5.00 mmol), and AcOK (5.82 g, 60.0 mmol) were suspended in dioxane (250 mL) and heated at 100° C. for 10 hours. After cooling down to room temperature, 5-bromo-nicotinicacid tert-butyl ester (14.2 g, 55.0 mmol), Pd(PPh3)4 (5.78 g, 5.00 mmol) and 2M Na2CO3 aq. (125 mL, 250 mmol) were added to the reaction mixture; and then heated at 100° C. for 15 hours. The reaction mixture was diluted with EtOAc and H2O, organic layer was washed with brine and dried over MgSO4. After filtration, the solvents were removed in vacuo and the residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to 6/4) and the obtained brown solid was crystallized from EtOAc/hexane (1/1) to afford 5-{1′-tert-butoxycarbonyl-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid tert-butyl ester as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([Cl:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[N:38]=[C:39]=[O:40]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:39]([NH:38][C:32]4[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=4[F:30])=[O:40])=[C:22]([Cl:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chloroaniline (260 mg) was dissolved in chloroform (10 ml). 2,4-Difluorophenyl isocyanate (198 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (10/1) to give 337 mg (yield 94%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=O)=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[CH3:14][NH:15][C:16]([C:18]1[N:19]([CH3:24])[N:20]=[CH:21][C:22]=1[NH2:23])=[O:17]>>[CH3:24][N:19]1[C:18]([C:16](=[O:17])[NH:15][CH3:14])=[C:22]([NH:23][C:11]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH:8]([CH3:9])[CH3:10])[N:4]=2)=[O:13])[CH:21]=[N:20]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: CC(C)c1ncc(Br)c(C(=O)O)n1
Product: CNC(=O)c1c(NC(=O)c2nc(C(C)C)ncc2Br)cnn1C

Procedure:
The product was obtained starting from 5-bromo-2-isopropyl-pyrimidine-4-carboxylic acid (intermediate A-4, step 1; 300 mg, 1.22 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (245 mg, 1.59 mmol) according to the method described in example 64, step 6 after extraction with ethyl acetate and purification by silica gel chromatography using ethyl acetate as light brown solid (472 mg, 96%).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:51]2[N:52]=[C:53]([NH:56]C(OC(C)(C)C)=O)[S:54][CH:55]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][S:42][CH:43]3[CH2:50][N:46]4[CH:47]=[N:48][CH:49]=[N+:45]4[CH2:44]3)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:56][C:53]1[S:54][CH:55]=[C:51](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]2)/[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][S:42][CH:43]3[CH2:44][N:45]4[CH:49]=[N:48][CH:47]=[N+:46]4[CH2:50]3)[CH:38]=[N:37]2)=[O:24])[N:52]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)[O-])[C@@H]2Cn2ncc(CSC3Cn4cnc[n+]4C3)n2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)[O-])[C@@H]2Cn2ncc(CSC3Cn4cnc[n+]4C3)n2)cs1
Yield: 9.2 %

Procedure:
Prepared in analogous manner to example 138, step 3 using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium-6-yl)thio)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonate (23 mg, 0.025 mmol), anisole (5.5 μL, 0.050 mmol), TFA (116 μL, 1.50 mmol) and DCM (300 μL). The crude residue purified by reverse phase prep HPLC (Xselect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (1.5 mg, 8%). LCMS: Rt=0.60 min, m/z=654.4 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 9.02 (d, J=4.8 Hz, 2H), 7.84 (s, 1H), 7.17 (s, 1H), 5.65 (d, J=5.8 Hz, 1H), 5.12-4.97 (m, 3H), 4.94-4.89 (m, 1H), 4.64-4.50 (m, 4H), 4.09 (s, 2H), 1.48-1.36 (m, 2H), 1.32-1.24 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17](I)[N:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][NH:31][CH3:32])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.CC(N(C)C)=O>ClCCl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17]([N:31]([CH2:30][C:29]4[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=4)[CH3:32])[N:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])=[CH:4][CH:3]=1
Reactant: CNCc1ccc(F)cc1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 43.9 %

Procedure:
Part C. To a sealed tube was added 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (100 mg, 0.22 mmol, 1.0 equiv), 4-fluoro-N-methyl-benzylamine (58 μL, 0.44 mmol, 2.0 equiv), diisopropylethylamine (17 μL, 0.44 mmol, 2.0 equiv) and dimethyl acetamide (1 mL). The reaction mixture was stirred at 100° C. After 5 hr, the reaction mixture was cooled to room temperature and diluted with dichloromethane, washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography [SiO2, ethyl acetate/heptane, 10:90 to 70:30, v/v] and recrystallization from ether/pentane to afford 2-{6-[(4-fluoro-benzyl)-methyl-amino]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (45 mg, 44%). 1H NMR (400 MHz, CD2Cl2) δ 8.57 (s, 1H), 8.06 (s, 1H), 7.24-7.34 (m, 4H), 6.98-7.05 (m, 4H), 6.18 (bs, 1H), 4.80 (s, 2H), 4.54 (d, J=8.0 Hz, 2H), 3.13 (s, 3H), 2.70 (s, 3H); HRMS (M+H)+=466.15.
Reaction SMILES: [C:1]1(=O)[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([CH2:11][NH3+:12])[CH2:9][NH3+:10]>>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[NH:12][CH2:11][CH2:8][CH2:9][N:10]=1
Reactant: [NH3+]CCC[NH3+]
Reactant: O=C1CCCCO1
Product: OCCCCC1=NCCCN1
Yield: 49 %

Procedure:
Using a method similar to Example 1, valerolactone was reacted with 1,3-DAP. At a temperature of 170° C. in the liquid in the flask, 48% of the open-chain amide and 49% of 2-(4-hydroxybutyl)-1,3-diazacyclohex-1-ene were obtained after 8 hours. After a further 8 hours at 180° C. and 8 hours at a liquid-phase temperature of 190° C., the ratio shifted further to 5% of amide and 92% of 2-(4-hydroxybutyl)-1,3-diazacyclohex-1-ene. The subsequent product diazabicyclodecene was obtained in an amount of only 1 or 3%.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1>CN(C)C=O>[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: Cc1cc2ccccc2s1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1sc2ccccc2c1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.4 %

Procedure:
Sulfuryl chloride (9.5 mmoles, 0.76 ml) was added to a stirred solution of dimethylformamide (DMF; 11.2 mmoles, 0.87 ml) at 0° C., and the resulting faint yellow solution was stirred for 20 min at 0° C. 2-Methylbenzo[b]thiophene (5.6 mmoles, 0.83 g) was then added, the reaction mixture was diluted with 2 ml of DMF, and then heated to 85° C. After 2.5 hrs at 85° C., the brown reaction mixture was cooled to ambient temperature and added to ice (≈100 ml). The aqueous phase was extracted with ethyl acetate (100 ml), and the organic phase was dried (MgSO4), filtered and concentrated to collect an orange-brown solid. Flash chromatography (4% ethyl acetate/hexanes) provided 0.89 g (64%) of 2-methylbenzo[b]thiophene-3-sulfonyl chloride as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([NH2:30])[CH2:28][OH:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:30][CH:27]([CH3:26])[CH2:28][OH:29])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and DL-2-amino-1-propanol employing methods similar to those described in Example 2 and was obtained a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.73 (1H, br s), 10.73 (1H, br s), 10.02 (1H, br s), 8.18 (0.56H, s), 8.14 (0.44H, s), 7.34-7.22 (3H, m), 7.14-7.09 (2H, m), 4.78 (1H, t, J=5 Hz), 3.98 (2H, s), 3.48-3.41 (1H, m), 3.23-3.20 (2H, m), 1.14 (0.58H, d, J=6.6 Hz), 1.08 (0.42H, d, J=6.6 Hz); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1370.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[CH3:27])[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[CH3:27])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1C)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1CC(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 48.3 %

Procedure:
Adapting a literature protocol (Dayal, et al., Steroids, 1990, 55(5), 233-237), a reaction mixture of methyl 2-benzyloxycarbonylamino-3-(2-methyl-4-nitro-phenyl)propanoate (4d) (1.94 g, 5.20 mmol) and commercial lithium hydroxide monohydrate (LiOH.H2O) (436 mg, 10.4 mmol) in a mixture of tetrahydrofuran (THF)/methanol (MeOH)/water (20:10:10 mL v/v/v) was stirred at room temperature. The reaction was followed by TLC and LC/MS to completion. Acidic aqueous work-up at about pH 4 and subsequent crystallization from ethyl acetate (EtOAc) furnished 900 mg (48% yield) of the target compound (4e) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.96-7.92 (m, 1H), 7.90-7.80 (m, 1H), 7.36-7.18 (m, 6H), 5.62 (d, 1H), 5.00 (d, 1H), 4.93 (d, 1H), 4.60-4.50 (m, 1H), 3.26 (dd, 1H), 2.98 (dd, 1H), 2.38 (s, 3H) ppm. LC/MS: Rt=1.818 min; ESI (pos.) m/z=359.1 (M+H+)+; ESI (neg.) m/z=357.0 (M−H+)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Fc1c(Cl)cnc2[nH]ccc12
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
5-Chloro-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 9.18 mmol) was placed in THF (15 mL) at 0° C. TBAF (10.094 mL, 10.094 mmol) was added dropwise and stirred for 30 minutes. The reaction was then quenched with saturated aqueous NaHCO3 and extracted into DCM. The combined organic fractions were dried, filtered, and concentrated to give the crude product that was purified by column chromatography (500:6 DCM:MeOH) to give 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridine (1.4 g, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([OH:12])[CH3:11].O[C:14]1[C:15]([N+:20]([O-:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:14]1[C:15]([N+:20]([O-:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:11]
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
1-(2,6-dichloro-3-fluorophenyl)ethanol (29.1 g, 139 mmol) and 3-hydroxy-2-nitropyridine (24.1 g, 153 mmol) were dissolved in anhydrous tetrahydrofuran (300 mL), and triphenylphosphine (PPh3, 51.1 g, 195 mmol) was added and the mixture was stirred for 1 h at room temperature. At 0° C., to the reaction liquid was added diisopropyl azodicarboxylate (DIAD, 38.4 mL, 195 mmol) dropwise. The resultant mixture was stirred overnight at room temperature. The resultant mixture was evaporated under reduced pressure to remove solvent, then purified via silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to yield the target product as white crystals (41.2 g, 124 mmol; yield=89%).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl.C(OCC)(=O)C.O>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1)#[CH:2]
Reactant: CC(=O)Cl
Reactant: C#Cc1ccc(N)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ccc(NC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-ethynylaniline (commercially available) (1.0 eq.), and triethylamine (1.0 eq.) in methylene chloride (0.04 M), acetyl chloride (1.5 eq.) was added slowly. Then the reaction mixture was stirred at 0° C. for 1 hour. After warmed to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give N-(4-ethynylphenyl)acetamide as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([Cl:24])[C:10]3[O:15][CH2:14][CH2:13]C(C#N)(O[Si](C)(C)C)[C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:1]1([C:7]2[CH:8]=[C:9]([Cl:24])[C:10]3[O:15][CH2:14][CH2:13][CH:27]([C:26]([OH:29])=[O:28])[C:11]=3[CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: C[Si](C)(C)OC1(C#N)CCOc2c(Cl)cc(-c3ccccc3)cc21
Agent: Cl
Product: O=C(O)C1CCOc2c(Cl)cc(-c3ccccc3)cc21
Temperature: 25 °C

Procedure:
To a 500 ml. single neck reaction flask equipped with a magnetic stirrer, reflux condenser, and nitrogen inlet was added 6-phenyl-8-chloro-4-cyano-4-trimethylsilyloxy-3,4-dihydro-2H-1-benzopyran (3.0 g.). In one portion was added stannous chloride dihydrate (15 g.) followed by glacial acetic acid (20 ml.) and concentrated hydrochloric acid (20 ml.). The reaction flask was immediately flushed with nitrogen and plunged into a preheated (140° C.) oil bath. With vigorous stirring the reaction mixture was heated at reflux for 65 hrs., cooled to room temperature, diluted with 500 ml. chloroform, the layers separated, and the aqueous layers again saturated with chloroform. The combined organic layers were extracted with three 150 ml. portions of 2 N aqueous potassium hydroxide, and the combined basic aqueous layers back-extracted with one 150 ml. portion of ether. Acidification of the basic aqueous layer with ice bath cooling, extraction with three 250 ml. portions of chloroform, drying of the combined organic layers over magnesium sulfate, filtration, and removal of the volatiles afforded 6-phenyl-8-chloro-3,4-dihydro-2H-1-benzopyran-4-carboxylic acid. Filtration of a chloroform solution of the acid through 400 ml. of silica gel (EM Reagents, 70-230 mesh) with elution by three liters of chloroform removes a small amount of an -hydroxy acid impurity. Recrystallization from cyclohexane yielded 0.93 g. (38%) of the acid, m.p. 187°-188° C.
Reaction SMILES: [Cl:1][CH:2]1[C:10]2[C:5](=CC=CC=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.O[CH:24]1[C:32]2C(=NC=C[N:31]=2)C(=O)[N:25]1C1C=CC2C(=NC(OC)=CC=2)N=1.S(Cl)(Cl)=O>CN(C)C=O>[Cl:1][CH:2]1[C:10]2[C:5](=[N:25][CH:24]=[CH:32][N:31]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: COc1ccc2ccc(N3C(=O)c4nccnc4C3O)nc2n1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C1c2nccnc2C(Cl)N1c1ccc2ccc(Cl)nc2n1

Procedure:
5-Chloro-6-(7-chloro-1,8-naphthyridin-2-yl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazine is prepared in a manner similar to that described in Example 6 for the preparation of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone, but starting with 5-hydroxy-6-(7-methoxy-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (23.2 g), sulphinyl chloride (300 cc) and dimethylformamide (1 cc). 5-Chloro-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]-pyrazine (21 g ) m.p. 264° C., is thereby obtained.