Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[NH:14][N:13]=[N:12][N:11]=1.[N:15]([O-])=O.[Na+].Cl>C(Cl)(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[C:10]3[N:11]([N:12]=[N:13][N:14]=3)[N:15]=[N:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(-c2nnn[nH]2)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)nnn1nnnc21
Yield: 51.1 %

Procedure:
The above-named compound was prepared from 1 g of 5-(2-amino-4-methoxyphenyl)tetrazole, 0.45 g of NaNO2, and concentrated HCl and isolated from the reaction mixture by the procedures of Example 2. The residue obtained by evaporation of the chloroform extracts was a dark reddish-brown solid shown by liquid chromatographic analysis to be largely the named compound plus several minor impurities. The product was purified by percolating its chloroform solution through two 7-10 ml portions of 80-200 mesh alumina and evaporating the treated solution under nitrogen at room temperature. A yield of 0.54 g of orange solid was obtained. This purified material showed only trace impurities on thin layer chromatographic examination and its structure as the named compound was confirmed by magnetic resonance and infrared absorption analyses.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[C@@H:10]([CH:32]([CH3:34])[CH3:33])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:32]([C@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:15]=1)([CH3:34])[CH3:33]
Reactant: Cc1ccc2c(N3CCN(Cc4ccccc4)C[C@@H]3C(C)C)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(N3CCNC[C@@H]3C(C)C)nc(-c3ccccc3O)nc2c1
Yield: 79 %

Procedure:
20 mg of Pd/C was added to a round-bottom flask, and the flask was flushed with nitrogen followed by evacuation of the atmosphere under vacuum. To the flask was then added a solution of 2-(4-((S)-4-benzyl-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.44 mmol) in methanol, followed by the addition of ammonium formate (32 mg, 0.88 mmol). The reaction was refluxed overnight. The reaction was filtered through a bed of Celite to remove the catalyst. The solvent was evaporated to yield 2-(4-((S)-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (126 mg). LC/MS: m/z 363.5 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(C1C=CN=C(C(O)=[O:13])C=1)CC(C)C.C(C1C=CN=C(C(O)=O)C=1)CCCC.[CH2:29]([CH:31]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH2:32][CH3:33])[CH3:30].OO>C(O)(=O)C.C(Cl)Cl>[CH2:29]([CH:31]([C:34]1[CH:35]=[CH:36][N+:37]([O-:13])=[CH:38][CH:39]=1)[CH2:32][CH3:33])[CH3:30]
Reactant: CC(C)CCc1ccnc(C(=O)O)c1
Reactant: CCC(CC)c1ccncc1
Agent: CCCCCc1ccnc(C(=O)O)c1
Agent: OO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)c1cc[n+]([O-])cc1
Yield: 95 %

Procedure:
4-Isopentylpyridine-2-carboxylic acid, compound 10b (R9=1-ethyl-propyl), was made by employing general Method P. To 4-(1-ethyl-propyl)-pyridine (8.5 g, 57 mmol) in acetic acid (30 mL), hydrogen peroxide (17.8 g, 30%, 57 mmol) was added. The resulting reaction mixture was refluxed overnight. The residue obtained on removal of solvent was dissolved in DCM (100 mL), dried over MgSO4. After filtering, the solvent was removed to obtain a brown liquid, 4-(1-ethyl-propyl)-pyridine-N-oxide (9 g, 95%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][N:25]=[C:24]([CH2:27][CH3:28])[CH:23]=2)[C:19]2[C:29](=[O:39])[N:30](C(OC(C)(C)C)=O)[CH2:31][C:18]=2[C:17]=1[F:40])=O)(C)(C)C.Cl.O1CCOCC1.CCO>CO>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][N:25]=[C:24]([CH2:27][CH3:28])[CH:23]=2)[C:19]2[C:29](=[O:39])[NH:30][CH2:31][C:18]=2[C:17]=1[F:40]
Reactant: CCc1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCO
Product: CCc1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)sn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a stirred solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (80 mg, 0.139 mmol) in MeOH (1.0 mL) was added 4N HCl/dioxane (1.0 mL, 4.00 mmol). The mixture was heated to 60° C. for 1 h and was subsequently concentrated in vacuo. The residue was triturated with EtOAc and filtered. The filter cake was washed with EtOAc to give a yellow solid, which was suspended into EtOH. The mixture was stirred at 80° C. for 30 minutes and then cooled to room temperature. The resulting precipitate was collected by filtration and washed with EtOH to give a hydrochloride salt of the title compound as an off-white solid (20.6 mg, 36%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26 (t, J=7.57 Hz, 3H), 1.39-1.55 (m, 2H), 1.56-1.83 (m, 4H), 1.83-2.04 (m, 2H), 2.81 (q, J=7.65 Hz, 2H), 3.77 (br s, 1H), 4.18-4.30 (m, 1H), 4.41-4.53 (m, 2H), 7.16 (d, J=5.86 Hz, 1H), 7.82 (br s, 3H), 8.66 (s, 1H), 8.80 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C18H22FN5OS, 376. found, 376.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH:15]([NH:18][CH3:19])[C:16]#[N:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C1COCC1.O>[Si:1]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH:15]([C:16]#[N:17])[N:18]([CH3:19])[C:27](=[O:28])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CNC(C#N)C1CCC(CO[Si](C)(C)C(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OCc1ccccc1)C(C#N)C1CCC(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To 2-(3-((tert-butyldimethylsilyloxy)methyl)cyclopentyl)-2-(methylamino)acetonitrile (6.0 g, 21.24 mmol) in THF (33 mL), H2O (15 mL) was added, at 0, ° C. Na2CO3 (4.50 g, 42.48 mmol) followed by the dropwise addition of benzyl chloroformate (3.89 mL, 27.6 mmol) over 10 min. The reaction mixture was stirred at 0° C. for 30 min. then at 23° C. for 18 hours. H2O (150 mL) was then added and the organic material was extracted with ethyl acetate (3×100 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The crude material was purified on a Silica gel column (Biotage flash chromatography system), eluted with a gradient of ethyl acetate:hexane (1:4) to (1:1) to afford 3.90 g (44% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.34-7.45 (5 H, m), 5.33 (2 H, s), 5.18-5.25 (1H, m), 3.48-3.59 (2 H, m), 3.00 (3 H, s), 2.35-2.47 (2 H, m), 1.55-2.25 (6 H, m), 0.94 (9 H, s), 0.05 (6 H, s). LCMS (+ESI, M+H+) m/z 417.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)Oc1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1

Procedure:
In analogy to the procedure described in example 113H], [4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a light brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O[C@H:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C@@H:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(O[C@H](CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[(2R)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 485.0 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:19]([N:12]1[C:13]2[C:18](=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1cc(C2=CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), benzoyl chloride (13 μL, 0.12 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:28]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:9])[CH:3]=1)[CH2:8][Br:28]
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To 5-bromo-m-xylene (24.03 g, 0.13 mole) in benzene (125 mL) was added benzoylperoxide (3.04 g, 0.013 mole). The reaction mixture was heated to reflux in a 250 mL round bottom flask. N-bromosuccinimide (18.15 g, 0.10 mole) was added in portions over 15 minutes. After 2 hours, heating was discontinued and the reaction mixture was allowed to cool to room temperature. Precipitated solids were removed by filtration and the filtrate was concentrated. The residue was taken up in hexane and additional solids were removed by filtration. The filtrate was passed through a small pad of silica gel and the filtrate was concentrated. The resultant yellow oil was titurated with MeOH over ice to give 3-bromo-5-methylbenzyl bromide (7.34 g) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([C:18]2[N:19]=[C:20]3[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]3=[N:22][CH:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([C:18]2[N:19]=[C:20]3[C:26]([C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccccc4)c4cc(Cl)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(Cc4ccccc4)c4cc(Cl)ccc34)nc12
Reaction time: 4 h
Yield: 115.9 %

Procedure:
2-(1-Benzyl-6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 151 μmol) was dissolved in dichloromethane (25 mL) and to this was added trifluoroacetic acid (1.72 g, 1.17 mL, 15.1 mmol). The mixture was stirred for 4 h then concentrated in vacuo. The residue was diluted in dichloromethane and re-concentrated again, then suspended in dichloromethane and ethylenediamine (682 mg, 0.766 mL, 11.3 mmol) added. The mixture was stirred for 15 h then concentrated in vacuo. The residue was triturated with water and the solid collected by filtration and dried. The solid was adsorbed onto silica gel and purified by chromatography (silica, SiliCycle 25 g cartridge, 0-5% methanol in dichloromethane, 15 min gradient) to give 2-(1-benzyl-6-chloro-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 175 μmol, quantitative) as a pale yellow powder. MS (M−H)−=443; 1H NMR (DMSO-d6) δ: 12.84 (br. s., 1H), 9.05-9.13 (m, 1H), 8.37-8.50 (m, 2H), 8.08 (d, J=1.1 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.23-7.38 (m, 6H), 5.79 (s, 2H), 4.20 (dq, J=13.6, 6.7 Hz, 1H), 1.30 (d, J=6.4 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[O:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:28][C:29]([OH:33])([CH3:32])[C:30]#[CH:31]>>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:31]#[C:30][C:29]([OH:33])([CH3:32])[CH3:28])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[O:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)no1)CCOc1cc(F)c(Br)cc1-2
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)no1
Yield: 28.6 %

Procedure:
3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure G with slight modifications. 10-bromo-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol to afford 26 mg of the titled compound (28.6% yield). M+1=438.0. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J=8.3 Hz, 1H), 7.99 (br s, 1H), 7.52 (br s, 1H), 7.07 (d, J=10.5 Hz, 1H), 5.56 (s, 1H), 4.58-4.51 (m, 4H), 2.28-2.19 (m, 1H), 1.49 (s, 6H), 1.19-1.09 (m, 2H), 1.03-0.97 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=[C:4]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:11]1[CH2:10][CH2:9][O:8][C:7]2[C:2]([F:1])=[CH:3][C:4]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:5][C:6]1=2)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CC1(C)OB(c2cc(F)c3c(c2)NCCO3)OC1(C)C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCOc2c(F)cc(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: 70 °C
Yield: 76.9 %

Procedure:
A solution of 8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.507 g, 1.613 mmol, Ref. WO20100130034) and K2CO3 (0.512 g, 3.70 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, then treated with allyl bromide (0.8 mL, 9.17 mmol). The reaction tube was sealed and then heated (70° C.) for 22 h. The reaction was cooled then diluted with water (50 mL) and extracted into EtOAc (50 mL). The organic layer was then washed with water, brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by biotage column chromatography (12 g SiO2, 0% (3 CV); 0-40% (15 CV), 40% (2 CV), EtOAc in hexanes) to afford the desired product (0.396 g, 1.241 mmol, 77% yield) as a clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.96-7.01 (m, 2H), 5.84-5.95 (m, 1H), 5.21-5.32 (m, 2H), 4.32-4.38 (m, 2H), 3.94 (d, J=5.8 Hz, 2H), 3.30-3.37 (m, 2H), 1.32 (s, 12H). LCMS (M+H)=320.3.
Reaction SMILES: O[CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[OH:43].C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[O:43][C:3]([N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14])([CH3:2])[CH3:4]
Reactant: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: Oc1cc(F)ccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(Oc1cc(F)ccc1F)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(2-Hydroxy-1-methylethyl)-1H-isoindole 1,3(2H)-dione (Becker, Y. J. J. Org. Chem. 1980, 45, 2145-51) was diluted with 40 mL THF then treated in order with 7.0 g triphenyl phosphine, 4.0 g of 2,5-difluorophenol and finally with 5.0 mL of diethylazocarboxylate. The reaction became warm to the point of reflux and was allowed to cool to room temperature and stirred at room temperature overnight. The solvent was removed in vacuo and the resulting brown oil was taken up in ethyl acetate (EtOAc). The solution was washed sequentially with aqueous sodium bicarbonate, aqueous ammonium chloride, and brine. Removal of the solvent gave an oil which was chromatographed on silica gel, eluting with 10% ethyl acetate-hexane, to afford 5.4 g of the title compound of Step A as a clear colorless oil: 1H NMR (CDCl3) δ1.57 (d, 3H), 4.22 (dd, 1H), 4.57 (t, 1H), 4.82 (m, 1H), 6.55 (m, 1H), 6.70 (m, 1H), 6.95 (m, 1H), 7.72 (m, 2H), 7.82 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:13]([CH2:14]C(OC(C)(C)C)=O)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][O:8][C:9]2=[O:22])([O-:3])=[O:2].FC(F)(F)C(O)=O.N1C2C(=CC=CC=2)C=CC=1>C(OC(=O)C)C>[CH3:14][C:13]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:22])[O:8][CH:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Solvent: c1ccc2ncccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
A microwave vial was charged with tert-butyl 2-(5-nitro-1-oxo-1H-isochromen-6-yl)acetate (800.0 mg, 0.002620 mol), trifluoroacetic Acid (2 mL, 0.02 mol) and subjected to microwave at 100° C. for 20 minutes. The starting material became converted into the corresponding acid. TFA was removed under reduced pressure and the residue was again taken a microwave tube and quinoline (2 mL, 0.02 mol) was added and heated at 120° C. for 20 minutes. The reaction went to completion and ethylacetate (50 mL) was added and washed with 10 mL of 6N HCl. The HCl layer was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with water, brine and dried. The solvent was removed and the brown solid residue was purified by flash chromatography to yield the pure product as a white solid. MS m/z=206.4 (M+H) 1H-NMR (400 MHz, DMSO-d6) δ 8.29 (d, J=8.19 Hz, 1H), 7.71-7.69 (m, 2H), 6.57 (d, J=6.02 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]([CH:16]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[O:21])[C:17](=O)[CH3:18])[C:5](=[O:15])[CH2:6]P(=O)(OCC)OCC)[CH2:3][CH2:2]1.[Cl-].[Li+].C(N(CC)CC)C>O1CCCC1>[CH:1]1([N:4]2[C:5](=[O:15])[CH:6]=[C:17]([CH3:18])[CH:16]2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[O:21])[CH2:3][CH2:2]1
Reactant: CCOP(=O)(CC(=O)N(C1CC1)C(C(C)=O)C(=O)NCc1ccc(Cl)cc1Cl)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=CC(=O)N(C2CC2)C1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a solution of diethyl (2-{cyclopropyl[1-({[(2,4-dichlorophenyl)methyl]amino}-carbonyl)-2-oxopropyl]amino}-2-oxoethyl)phosphonate (0.043 g, 0.087 mmol, prepared as described below) in anhydrous tetrahydrofuran (2.5 ml) at 0° C. was added lithium chloride (0.016 g, 0.39 mmol). The mixture was stirred until all of the lithium chloride dissolved and then triethylamine (0.066 ml, 0.87 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 18 hrs. Evaporation of the solvent in vacuo and purification of the resulting residue by mass-directed automated HPLC gave 1-cyclopropyl-N-[(2,4-dichlorophenyl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxamide (0.012 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8](O)=[O:9])=[O:4].B(OC)(OC)OC.[Cl-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[CH2:8][OH:9])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: COB(OC)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H]1CO
Reaction time: 2 h

Procedure:
Add boranemethyl sulfide complex (177 mL, 0.354 mol), slowly, by means of a dropping funnel, to a stirring solution of trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester (Example 3a) (25.5 g, 0.177 mol), trimethyl borate (60.3 mL, 0.531 mol) and tetrahydrofuran (150 mL) at 0° C. After complete addition, allow the reaction to come to ambient temperature and stir for 2 h more. Pour the reaction mixture into a stirring solution of 50% aqueous sodium chloride solution (1.5 L)-concentrated HCl (10 mL). Extract the mixture with ethyl acetate (EtOAc) (3 times), combine the extracts, dry (Na2SO4) and concentrate the solvent to obtain a colorless oil: 22.6 g.
Reaction SMILES: C(O[C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:18])=[CH:15][N:16]=2)[C:11](=[O:19])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[C:20]([N:28]=C=O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[Br:18][C:14]1[CH:13]=[C:12]2[C:17](=[N:16][CH:15]=1)[N:8]([C:6]([NH:28][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])[CH2:9][CH2:10][C:11]2=[O:19]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2cc(Br)cnc21
Solvent: ClCCl
Product: O=C(NC(=O)N1CCC(=O)c2cc(Br)cnc21)c1ccccc1
Temperature: 50 °C
Yield: 100.2 %

Procedure:
A mixture of 6-bromo-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (228 mg, 1.00 mmol) and benzoyl isocyanate (207 mg, 1.41 mmol, 90%) in 5 mL CH2Cl2 is heated at 50° C. for 2 hrs. The mixture is concentrated to give 375 mg of N-(6-bromo-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl)-benzamide which is carried on without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)/[CH:6]=[CH:7]/[C:8](O)=[O:9].S(Cl)([Cl:18])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)/[CH:6]=[CH:7]/[C:8]([Cl:18])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(/C=C/C(=O)O)cc(OC)c1
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)Cl)cc(OC)c1

Procedure:
A mixture of trans-3,5-dimethoxycinnamic acid (15.30 g, 73.48 mmol) and thionyl chloride (13.11 g, 0.11 mol) were placed in a 250 mL single-necked round-bottomed flask fitted with a magnetic stirring bar and reflux condenser. Dry methylene chloride (80.0 mL) was added to the above mixture. The resulting solution was heated to reflux for 3 hours. Then, the solvent was removed under reduced pressure. The residue was dried under vacuum overnight to give a pale-yellow solid, trans-3,5-dimethoxycinnamic acid chloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[OH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[OH:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:42][CH2:41]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: OC1CCNCC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCC(O)CC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 4-hydroxypiperidine were converted to the title compound.