Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11])[CH:2]1[O:4][CH2:3]1.[N-:13]=[N+:14]=[N-:15].[Na+]>O1CCOCC1>[N:13]([CH2:3][CH:2]([OH:4])[CH2:1][N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)C1OCCN1CC1CO1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)C1OCCN1CC(O)CN=[N+]=[N-]
Temperature: 80 °C

Procedure:
Into a 500 ml., three-neck flask equipped with a mechanical stirrer, thermometer attached to a thermowatch, temperature controller and a condenser with a drying tube, is charged 171g. (1 mole) of 3-glycidyl-2-isopropyloxazolidine, 71.5g (1.1 mole) sodium azide and 250 cc of dioxane. The mixture is stirred and heated at 80°C for 6-8 hours and the solvent is then removed in vacuo to afford 3-(3-azido-2-hydroxypropyl)-2-isopropyl-1,3-oxazolidine.
Reaction SMILES: [NH:1]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([N:22]([CH3:35])[C@H:23]([C:31]([NH:33][NH2:34])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:46](O)(=[O:48])[CH3:47]>CN(C=O)C>[NH:1]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([N:22]([CH3:35])[C@H:23]([C:31]([NH:33][NH:34][C:46]([CH3:47])=[O:48])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N(C)[C@@H](Cc1ccccc1)C(=O)NN
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1

Procedure:
In the same manner as Example 14-(I), 426 mg of Z-Tyr-(D)-Ala-Gly-MePhe-NH-NH2 and 0.06 ml of acetic acid are used toproduce 405 mg of the indicated compound (85%). m.p.142°-143°C.; Rf1 =0.33; [α]D27 -31.8°(c=0.4, DMF)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.[Br:13]N1C(=O)CCC1=O.[Cl-].[NH4+]>CN(C=O)C>[CH3:1][NH:2][C:3]1[C:8]([Br:13])=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccc(C(F)(F)F)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CNc1ncc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a mixture of N-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine (3.48 g) and DMF (20 ml), N-bromosuccinimide (4.27 g) was added, and stirred at room temperature for 1 hour. Into the reaction mixture, saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 4.8 g of N-methyl-(3-bromo-5-trifluoromethyl-pyridin-2-yl)-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:22]=[C:21]2[C:23]3=[C:24]4[C:14]([CH:15]=[CH:16][CH:17]=[C:18]4[CH:19]=[CH:20]2)=[CH:13][CH:12]=[C:11]3[CH:10]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:2]1([NH:1][C:16]2[CH:15]=[C:14]3[C:24]4=[C:23]5[C:21]([CH:22]=[CH:9][CH:10]=[C:11]5[CH:12]=[CH:13]3)=[CH:20][CH:19]=[C:18]4[CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Brc1cc2ccc3cccc4ccc(c1)c2c34
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2cc3ccc4cccc5ccc(c2)c3c45)cc1

Procedure:
In a three-neck-round floor flask of 250 ml, after 127.5 m mole of aniline, 102 m mole of 2-bromopyrene, 1.53 m mole of tris(dibenzyllidene acetone)dipalladium, 3.06 m mol of BINAP (2,2′-bis(disphenylphosphino)-1,1′-binaphthyl, and 132.6 m mole of sodium-tert-butoxide were melted in 100 mL of toluene and they were mixed for 24 hours in a bath of 1000, when a reaction was terminated, toluene was removed from a reaction mixture and then the reaction mixture was extracted using dichloromethane and water and distilled under a reduced pressure, a solvent of a solution passing through a silica gel column was distilled under a reduced pressure, and thus 5.5 g of an N-phenylpyrene-2-amine liquid was obtained.
Reaction SMILES: [O:1]1[C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[N:28]=[CH:27][N:26](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:25]=5)[CH:22]=4)[N:17](C4CCCCO4)[N:16]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=[N:2]1>Cl.O1CCOCC1>[NH:26]1[CH:27]=[N:28][C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:11]2[CH:10]=[C:9]([NH:8][C:6]([C:5]3[O:1][N:2]=[CH:3][CH:4]=3)=[O:7])[CH:14]=[CH:13][CH:12]=2)=[N:25]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccno1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccno1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
Isoxazol-5-yl-N-(3-{1-perhydro-2H-pyran-2-yl-5 [1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the crude product was extracted in ethyl acetate and purified by preparative HPLC (0.005 g, 5% yield over 2 steps): 1H NMR (CD3OD) 8.65 (t, 1H), 8.73 (s, 1H), 8.45 (s, 1H), 8.38 (br s, <1H), 8.10 (d, 1H), 7.92 (d, 1H), 7.82 (d, 1H), 7.58 (t, 1H), 7.32 (d, 1H); ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.[CH3:15][C:16]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:19]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([C:16]([CH3:18])([CH3:17])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 500ml round-bottom flask equipped with a magnetic stir-bar, N2inlet was added ethyl glycolate (10g, 96.0mmoles, 1eq) and dry CH2Cl2(200ml, 0.5M). This was followed by the addition of triethylamine (40ml, 0.288moles, 3eq) and DMAP (1.17g, 9.6mmoles, 10mol %) followed by the dropwise addition of TBDPSCl (27.5ml, 0.106moles, 1.1eq) in dry CH2Cl2(20ml). The reaction mixture was allowed to stir at room temperature overnight at which time the reaction mixture was diluted with CH2Cl2and washed with 1N HCl, saturated sodium bicarbonate, H2O and dried over Na2SO4. After filtration the volatiles were removed in vacuo to yield 30g (91%) of titled compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]=3[CH:17]=[C:16]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH:15]=1)[CH2:5][CH2:6][O:7]2.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OC4CCOc5cc(F)cc(F)c54)cc(C(=O)N(C)C)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a solution of 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)-sulfonyl]-1H-benzi midazole-6-carboxamide (280 mg, crude, STEP 8) in tetrahydrofuran (8 mL) and methanol (4 mL) was added sodium hydroxide (165 mg, 4.1 mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture was quenched with saturated sodium dihydrogenphosphate aqueous solution, and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from dichloromethane only to ethyl acetate:methanol 10:1) to afford the title compound as a white solid (74 mg, 65% for 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6](S(C2C=CC=CC=2)(=O)=O)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].O1CCCC1.[OH-].[K+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a mixture of the resulting 1-benzenesulfonyl-5-methanesulfonylindole-2-carboxylic acid methyl ester (3.5 g), tetrahydrofuran (45 ml) and methanol (12 ml), potassium hydroxide (0.79 g) was added at 0° C. and the mixture was stirred at the same temperature for 3 hours. 2N hydrochloric acid was added thereto, and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.2 g of a white amorphous 5-methane sulfonylindole-2-carboxylic acid methyl ester as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([O:34]C)=[O:33])=[N:30][CH:31]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[N:30][CH:31]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)nc4)C3)nc3scnc23)cc1OC
Temperature: 35 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of methyl 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)picolinate (80 mg, 0.15 mmol) in dioxane/H2O (60 mL/6 mL) was added NaOH (60 mg, 1.5 mol), the reaction mixture was heated to 35° C. with stirring for 1 hour, then dioxane was removed in vacuo, and the aqueous layer was adjusted to pH˜4-5 with conc. HCl, the precipitate was collected by filtration and washed with water (5 mL) and dried to afford 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)picolinic acid as brown solid (67 mg, 84.8%). 1H NMR (300 MHz, DMSO): δ 9.56 (s, 1H), 9.06 (s, 1H), 8.96 (d, 1H, J=6.3 Hz), 8.79 (s, 1H), 8.33 (dd, 1H, J1=8.1 Hz, J2=1.8 Hz), 8.07 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 7.50 (brs, 1H), 6.90 (d, 1H, J=8.7 Hz), 4.60-4.58 (brs, 1H), 3.76-3.52 (m, 10H), 2.30-2.24 (m, 1H), 2.11-2.07 (m, 1H). LC-MS: 522 [M+H]+, tR=1.31 min. HPLC: 98.03% at 214 nm, 97.82% at 254 nm, tR=3.20 min.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCN(C(=O)OC)C(CC2CCCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1CCC(C(=O)O)CC1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 2-(cyclohexylmethyl)piperidine-1,4-dicarboxylate (2.20 g, 7.40 mmol) was dissolved in THF (25 mL) and water (25 mL). LiOH (0.266 g, 11.1 mmol) was added and the resulting mixture was stirred at room temperature overnight and heated under reflux for 30 min. The reaction mixture was partitioned between 1 M KHSO4 and diethyl ether. The organic phase was dried (Na2SO4), filtered through Celite® and the solvent was evaporated. The crude product was dissolved again in THF (25 mL) and water (25 mL). LiOH (0.23 g) was added to the reaction flask. The reaction mixture was stirred overnight. The reaction was worked up as above to give the product. 1H NMR (600 MHz, cdcl3) δ 0.85 (ddd, 2H), 1.19 (dddd, 5H), 1.38-1.48 (m, 1H), 1.61 (d, 4H), 1.72 (tt, 2H), 1.97 (qd, 3H), 2.56-2.65 (m, 1H), 3.02-3.14 (m, 1H), 3.67 (d, 3H), 3.88 (d, 1H), 4.22 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:27]=[C:28]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:29]=[CH:30][CH:31]=1
Reactant: Brc1cccc(Br)c1
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(Br)c1)C2=O
Temperature: 150 °C
Yield: 67.8 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (762 mg, 4.01 mmol), cuprous iodide (153mg, 0.802 mmol) and potassium carbonate (554 mg, 4.01 mmol) were deposited in a sealed type vessel. 6 mL DMSO and 1,3-dibromobenzene (1.89 g, 8.01 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (153 mg, 0.802 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 100% ethyl acetate/hexanes) to yield 2-(3-Bromo-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (939 mg, 2.72 mmol). MS (ESI) 345.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([OH:8])=[O:7])[CH:2]=[CH2:3].C1(C)C=CC=CC=1.[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([O:4][CH2:5][C:6]([O:8][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=[CH2:16])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCOCC(=O)O
Reactant: C=CCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCOC(=O)COCC=C
Yield: 56.6 %

Procedure:
2.5 g of crude 2-allyloxyacetic acid are introduced into 40 ml of toluene, and 4.7 g (30 mmol) of 9-decen-1-ol and 0.38 g (2.0 mmol) of p-toluenesulfonic acid are added. The mixture is then heated with a water separator until visible amounts of water no longer separate out. The mixture is then cooled, and the organic phase is washed once with saturated NaHCO3 solution, dried over Na2SO4 and filtered, and the product is freed from the solvent. Flash chromatography (cyclohexane/EtOAc=20:1, Rf=0.29) gives 3.1 g (62%) of dec-9-enyl 2-allyloxy-acetate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[C:25]=[O:26]>C1COCC1>[CH3:22][CH:21]([CH3:23])[CH:16]([NH:15][C:13]([C:11]1[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)=[O:26])=[CH:3][CH:4]=2)=[CH:9][N:10]=1)=[O:14])[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)o1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(5-(4-aminophenyl)oxazole-2-carboxamido)-3-methylbutanoate (Intermediate 1, 150 mg) in THF (3 ml) was added 1-isocyanato-3-(trifluoromethyl)benzene (132 mg) and the mixture was stirred overnight at RT. The mixture was then concentrated, purified by column chromatography (EtOAc:Pet ether, 2:8) and crystallized in CHCl3/Pet ether to give the title compound. Yield: 210 mg (88%). 1HNMR (DMSO-d6, 300 MHz): δ 9.13 (s, 1H), 9.09 (s, 1H), 8.99 (d, 1H), 8.03 (d, 1H), 7.82 (s, 1H), 7.8 (d, 2H), 7.64 (d, 2H), 7.58 (dd, 1H), 7.55 (dd, 1H), 7.34 (m, 1H), 4.3, (m, 1H), 3.68 (s, 3H), 2.24 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 505 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4cnc(C(F)(F)F)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-trifluoromethyl-pyrazine following a procedure analogous to that described for Example 79. LC (method 7): tR=1.56 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14])[C:6]([CH3:12])=[N:7]2.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[CH3:12][C:6]1[C:5]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])=[CH:4][C:3]2[C:8](=[N:9][CH:10]=[CH:11][C:2]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:7]=1
Reactant: Cc1nc2nccc(Cl)c2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: Cc1nc2nccc(N3CCOCC3)c2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Yield: 30.4 %

Procedure:
5-Chloro-2-methyl-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide (100 mg, 0.26 mmol) was dissolved in THF (10 ml) together with morpholine (45 μl, 0.52 mmol) and refluxed for 18 hours. The reaction was cooled and evaporated, the residue was purified by flash chromatography using CH2Cl2/CH3OH (20:1→10:1) as eluent to give 34 mg (30%) of 2-methyl-5-morpholino-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide as a pale mass.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]([C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)[C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]=2[C:15]=1[C:14]([F:17])=[CH:13][CH:12]=3.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClCCCl>[F:17][C:14]1[C:15]2[C:16]3[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]=3[C:7]([C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[CH:6][C:5]=2[N:4]1[CH2:3][CH2:2][NH:1][C:24]1=[O:25]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Solvent: ClCCCl
Product: O=C1Nc2ccc(F)c3c(N4CCNC4=O)cc(-c4ccc[nH]4)c1c23

Procedure:
To a suspension of 5-(2-amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one (from Example 9 above) (31.1 mg, 0.1 mmol) in 1,2-dichloroethane (3 mL) was added 1,1′-carbonyidiimidazole (Aldrich, 162 mg, 1.0 mmol) at room temperature. The reaction mixture was heated under reflux overnight. The reaction was then quenched with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were successively washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate and hexanes, filtered, and dried to give 6-fluoro-5-(2-oxo-imidazolidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 19.5 mg, 58.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[S:32]>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:31](=[S:32])[N:30]([CH3:34])[CH3:29])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Reactant: CN(C)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cc(OC(=S)N(C)C)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.4 %

Procedure:
A mixture of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 2.14 mmol), finely ground potassium carbonate (591 mg, 4.28 mmol), and N,N-dimethylformamide (10 mL) was stirred at room temperature for 20 minutes. Dimethylthiocarbamoyl chloride (290 mg, 2.35 mmol) was added in one portion. After being stirred for 2 hours, the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (15 mL) and brine (20 mL), then dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 0-30% ethyl acetate in hexanes) to afford (4-dimethylthiocarbamoyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (491 mg, 71.5%) as a yellow oil.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH3:20][C:21](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:20]([N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Agent: [K+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.33 h
Yield: 81.6 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (110 ml) was added potassium tert-butoxide (2.65 g). The mixture was stirred for 20 mins, bromoethane (5.88 ml) was added, and the reaction mixture was refluxed for 6.5 hrs. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic extractions were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was adhered to silica and flash chromatographed (20% ethyl acetate/hexane) to yield 4.53 g (82%) of 1-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one