Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].S(=O)(=O)(O)O.[CH3:14][C:15]([CH3:21])=[CH:16][C:17](OC)=[O:18]>>[CH3:14][C:15]1([CH3:21])[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:17](=[O:18])[CH2:16]1
Reactant: COC(=O)C=C(C)C
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CC1(C)CC(=O)Oc2cc(O)ccc21
Temperature: 130 °C
Yield: 24.6 %

Procedure:
A mixture of 103 g of resorcinol and 4.6 g of conc. sulfuric acid was heated at 130° C. with stirring, and 58 g of methyl 3,3-dimethylacrylate was added. The mixture was heated at 130° C. for 3 hours with stirring. The reaction mixture was worked up in a customary manner, and the residue after concentration was purified by column chromatography to give 24 g (yield 27%) of 4,4-dimethyl-7-hydroxycoumarin (melting point 84°-85° C.). The product was worked up in the same way as in Referential Example 16 to give 16.8 g (yield 75%) of the desired product as colorless crystals (melting point 88°-88.5° C.).
Reaction SMILES: CC1C=CC2NN=NC=2C=1.[O:11]1[CH2:16][CH2:15][N:14](NC(Cl)=O)[CH2:13][CH2:12]1.C(N(C1C=CC=CC=1)[C:24]([N:26]1[C:30]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=2[N:28]=[N:27]1)=[O:25])C>>[O:11]1[CH2:12][CH2:13][N:14]([C:24]([N:26]2[C:30]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=3[N:28]=[N:27]2)=[O:25])[CH2:15][CH2:16]1
Reactant: O=C(Cl)NN1CCOCC1
Reactant: CCN(C(=O)n1nnc2cc(C)ccc21)c1ccccc1
Agent: Cc1ccc2[nH]nnc2c1
Product: Cc1ccc2c(c1)nnn2C(=O)N1CCOCC1

Procedure:
Compound 2 was prepared by treating 5-methylbenzotriazole (C) (8.89 g, 67 m.mole) with morpholinocarbamoyl chloride (E) (10 g, 67 m.mole) in a manner similar to that described in the preparation of (1). The product which included the 6-methyl isomer was crystallized from methanol (100 ml). Yield, 13.2 g, 81 percent, m.p. 81° to 82° C. (uncorr.).
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.CS([Cl:31])(=O)=O>>[Cl:31][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(NCc1ccc(CO)cc1)c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccc(CCl)cc1)c1ccccn1
Yield: 45.2 %

Procedure:
Reaction of pyridine-2-sulfonic acid 4-hydroxymethyl-benzylamide (140 mg, 0.50 mmol), Et3N (88 μL, 0.60 mmol), and MsCl (47 μL, 0.60 mmol) for 2 h at reflux followed by column chromatography on silica gel (CH2Cl2/MeOH 99:1) gave the title compound (67 mg, 45%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.28 (d, 2H, J=6.0 Hz), 4.54 (s, 2H), 5.17 (br s, 1H), 7.23-7.49 (m, 4H), 7.47-7.52 (m, 1H), 7.88 (ddd, 1H, J=7.5, 7.5, 1.7 Hz), 7.97 (d, 2H, J=7.5 Hz), 8.69 (d, 1H, J=4.8 Hz). ES-MS m/z 319 (M+Na).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>COCCOC>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)[CH:24]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1cccnc1
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2cccnc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 3-hydroxypyridine, using dry DME as reaction solvent: 1H NMR (300 MHz, CDCl3) δ 8.14 (dd, J=5.1, 1.6 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.59 (ddd, J=8.5, 6.8, 1.7 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 7.04 (dd, J=8.8, 2.5 Hz, 1H), 6.91 (dd, J=6.8, 5.4 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 4.56 (t, J=6.1 Hz, 2H), 4.11 (q, J=8.5 Hz, 2H), 3.96 (t, J=6.1 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:44][C@@H:43]([CH3:45])[CH2:42][C@H:18]4[S:19](=[O:41])(=[O:40])[C:20]([CH3:39])([CH3:38])[C:21]([N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:22][C@:17]4([CH3:46])[C:15]=3[CH:16]=2)=[O:9])=[N:6][CH:7]=1.[O:47]1[CH:51]=[CH:50][N:49]=[C:48]1[CH2:52]O.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>C1COCC1>[CH3:38][C:20]1([CH3:39])[S:19](=[O:41])(=[O:40])[C@@H:18]2[CH2:42][C@H:43]([CH3:45])[O:44][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]4[CH:4]=[CH:3][C:2]([O:1][CH2:52][C:48]5[O:47][CH:51]=[CH:50][N:49]=5)=[CH:7][N:6]=4)=[O:9])=[CH:16][C:15]=3[C@@:17]2([CH3:46])[N:22]=[C:21]1[N:23]([C:24]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:30])[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37]
Reactant: OCc1ncco1
Reactant: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(NC(=O)c3ccc(O)cn3)ccc2O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(NC(=O)c3ccc(OCc4ncco4)cn3)ccc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
To a 0° C. solution of tert-butyl N-[(4aR,6S,11bR)-10-[(5-hydroxypyridine-2-carbonyl)amino]-3,3,6,11b-tetramethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (80 mg, 0.121 mmol), 2-oxazolemethanol (0.096 mL, 1.214 mmol) and triphenylphosphine (96 mg, 0.364 mmol) in THF (3 mL) was added diisopropyl azodicarboxylate (0.072 mL, 0.364 mmol) dropwise. The reaction was stirred at ambient temperature for 16 h. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was concentrated. The crude product was purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in heptane, to provide tert-butyl N-[(4aR,6S,11bR)-3,3,6,11b-tetramethyl-10-[[5-(oxazol-2-ylmethoxy)pyridine-2-carbonyl]amino]-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (19 mg, 0.026 mmol, 21.15% yield) as a colorless oil. MS m/z=762.0 (M+Na).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]#[N:18])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[C:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2)#[N:18]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CNC2

Procedure:
A solution of N-t-butoxycarbonyl-5-cyanoisoindoline (D15) (130 mg) in DCM (3 ml) at rt was treated with TFA (1 ml) and after 1 h it was evaporated. The residue was re-evaporated from MeOH/toluene to give the title compound (D16) (140 mg). 1H NMR δ (CDCl3): 7.70 (2H, m), 7.50 (1H, m), 4.75 (4H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:30]=[CH:29][C:14]([O:15]C2C=C(N3CC4CC3CN4)C=NC=2)=[CH:13][CH:12]=1.COC1C=CC([O-])=CC=1.[Na+]>CN(C)C=O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:15][C:14]2[CH:29]=[CH:30][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COc1ccc(Oc2cncc(N3CC4CC3CN4)c2)cc1
Reactant: Brc1cncc(Br)c1
Agent: COc1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cncc(Br)c2)cc1

Procedure:
In an alternative approach to the synthesis of pyridine-substituted pyridyl diazabicyclic compounds, 3,5-dibromopyridine can be converted into the corresponding 3-bromo-5-alkoxy- and 3-bromo-5-aryloxypyridines by the action of sodium alkoxides or sodium aryloxides. Procedures such as those described by D. L. Comins et al., J. Org. Chem. 55: 69-73 (1990) and H. J. den Hertog et al., Recueil Trav. Chim. Pays-Bas 74: 1171-1178 (1955), are used. This is exemplified by the preparation 2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane. Reaction of 3,5-dibromopyridine with sodium 4-methoxyphenoxide in N,N-dimethylformamide gives 3-bromo-5-(4-methoxyphenoxy)pyridine. Coupling of 3-bromo-5-(4-methoxyphenoxy)pyridine with (1S,4S)-N-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane in the presence of a catalytic amount of tris(dibenzylideneacetone)dipalladium(0) and 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and sodium tert-butoxide in toluene provides (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane. Removal of the N-tert-butoxycarbonyl group, using trifluoroacetic acid, produces (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([O:19]C)=[O:18])=[CH:7][C:6]=2[CH:21]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([OH:19])=[O:18])=[CH:7][C:6]=2[CH:21]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CCC(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
In THF (36 ml)/methanol (36 ml) was dissolved methyl 7-bromo-1-isopentyl-2,3-dihydro-1-benzazepine-4-carboxylate (1.8 g). To the solution was added 1N sodium hydroxide solution (18 ml), and the mixture was stirred at room temperature for 24 hours. pH was adjusted to approximate 5 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=6/1) to give 7-bromo-1-isopentyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.51 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[ClH:15].[CH3:16]O>>[ClH:15].[ClH:15].[CH3:16][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CO
Reactant: N[C@@H](CNCc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)C(N)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To 1N HCl/MeOH (50 mL) at 0° C. was added (S)-2-Amino-3-benzylamino-propanoic acid (0.5 g, 2.57 mmol). Reaction was stirred at room temperature overnight. Volatiles were removed to give the product 2-Amino-3-benzylamino-propanoic acid methyl ester dihydrochloride salt as a white solid (0.7 g, 97.5%). MS: m/z=209 M+1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26]O.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>C1COCC1>[CH3:22][O:23][C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:21]
Reactant: COC(=O)C(C)(C)CO
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cn1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 40 h
Yield: 40.3 %

Procedure:
To a stirred solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.17 mmol), 3-Hydroxy-2,2-dimethyl-propionic acid methyl ester (0.026 mL, 0.20 mmol) and triphenylphosphine (53 mg, 0.20 mmol) in dry THF (1.5 mL) is added diisopropyl azodicarboxylate (0.041 mL, 0.20 mmol) in a drop wise manner. The mixture is stirred at room temperature for 40 hrs. Then the solvent is removed under vacuum and the residue is purified by two preparative TLC's (first one is developed with 30% EtOAc in Hexanes, second one is developed with 1% MeOH in CH2Cl2) to give 28 mg (41%) of 2,2-Dimethyl-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][C@H:24]1[OH:30].[C:31](OC(=O)C)(=[O:33])[CH3:32].CN(C1C=CC=CN=1)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][C@H:24]1[O:30][C:31](=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)C[C@H]1O
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)C[C@H]1OC(C)=O
Temperature: 0 °C

Procedure:
To a solution of compound of example 106 (3.35 g, 7.79 mmol) in dry CHCl3 (25 mL) was added acetic anhydride (1.76 g, 17.43 mmol) at 25° C. with stirring, followed by the addition of dimethylaminopyridine (0.033 g, 1% w/w). The mixture was stirred for 0.5 h. It was poured into ice water (50 mL), basified using a saturated aqueous Na2CO3 solution and extracted using CHCl3 (3×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated. The oil obtained was purified using a silica gel column and 0.1% MeOH+1% liquor NH3 in CHCl3 as eluant to get the title compound.
Reaction SMILES: I[C:2]1[O:3][C:4]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28].O>C(O)(=O)C>[CH3:17][C:16]1[C:4]2[O:3][C:2]([N+:27]([O-:32])=[O:28])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Cc1cccc2c(-c3ccccc3)c(I)oc12
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
To a stirred solution of 5.0 g (0.015 mole) of 2-iodo-7-methyl-3-phenylbenzofuran from Example 9 in 100 ml of acetic acid is added 2.8 g (0.022 mole) of cyclohexene-4-carboxylic acid, then dropwise 2.0 g (0.022 mole) of dinitrogen tetroxide in 10 ml of acetic acid. The mixture is poured into cold water, then extracted with diethyl ether. The ether extracts are washed with water, 5% sodium hydroxide solution, water and saturated sodium chloride solution and dried. The extracts are then concentrated to provide a solid residue which is recrystallized from aqueous ethanol to provide yellow crystals of 7-methyl-2-nitro-3-phenylbenzofuran, m.p. 122°-127° C., which is shown to be identical to the product of Example 2 by its infrared spectrum.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32](=[CH2:34])[CH3:33].O>CN(C=O)C>[CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH2:33][C:32](=[CH2:31])[CH3:34])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[CH3:2]
Reactant: C=C(C)CBr
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Temperature: 50 °C
Yield: 85.9 %

Procedure:
To a suspension of (R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.020 g, 0.059 mmol) and K2CO3 (0.041 g, 0.295 mmol) in 1 mL DMF was added methallyl bromide (0.077 mL, 0.767 mmol) and the reaction mixture was heated to 50° C. for 16 h. The reaction mixture was poured into 25 mL water and extracted with EtOAc (2×25 mL). The extracts were washed with 25 mL each water and brine, dried over MgSO4, filtered and concentrated to a yellow oil. Column chromatography (5–10% EtOAc in hexane gradient) gave 0.020 g (87%) of (R)-3-ethyl-3,4-dihydro-8-isopropoxy-4-methallyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. Rf0.7 (9:1 hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 1H, J=9.0), 7.18 (s, 1H), 7.12 (d, 1H, J=9.0), 5.47 (septet, 1H, J=6.2), 4.91 (s, 2H), 4.33 (dd, ABX, 1H, J=10.6, 2.0), 3.96 (dd, ABX, 1H, J=10.7, 2.6), 3.86 (d, 1H, J=17.0), 3.80 (d, 1H, J=17.0), 3.25–3.20 (m, 1H), 1.79 (s, 3H), 1.65–1.59 (m, 2H), 1.38 (d, 3H, J=6.1), 1.37 (d, 3H, J=6.1), 0.97 (t, 3H, J=7.5).
Reaction SMILES: [CH:1]1([N:4]2[C:13]([C:14]#[N:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:23])[CH:10]=3)[C:5]2=[O:24])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:31]([O:38][CH2:39][CH2:40]Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([O:38][CH2:39][CH2:40][O:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:24])[N:4]([CH:1]1[CH2:2][CH2:3]1)[C:13]([C:14]#[N:15])=[C:12]2[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N#Cc1c(-c2cccc(F)c2)c2cc(O)ccc2c(=O)n1C1CC1
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2cccc(F)c2)c2cc(OCCOCc3ccccc3)ccc2c(=O)n1C1CC1
Temperature: 120 °C

Procedure:
A mixture of the phenol 62 (80 mg, 0.25 mmol), K2CO3 (104 mg, 0.75 mmol) and benzyloxyethyl bromide (64 mg, 0.3 mmol) in DMF (3 mL) was heated in a microwave reactor at 120° C. for 15 min. The mixture was filtered and directly purified using an automated high pressure chromatography unit.
Reaction SMILES: [CH2:1]([C:5]12[CH2:21][C:20](=[O:22])[CH:19]=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[C:11]([Cl:15])[C:10]([O:16]C)=[C:9]([F:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4].[Br:23]N1C(=O)CCC1=O.[Cl-].[Li+]>CN(C=O)C>[Br:23][C:19]1[C:20](=[O:22])[CH2:21][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([F:18])=[C:10]([OH:16])[C:11]=3[Cl:15])[C:6]=12
Reactant: CCCCC12CCc3c(cc(F)c(OC)c3Cl)C1=CC(=O)C2
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCC12CCc3c(cc(F)c(O)c3Cl)C1=C(Br)C(=O)C2
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of 3a-butyl-6-chloro-8-fluoro-7-methoxy-3,3a,4,5-tetrahydro-cyclopenta[a]naphthalen-2-one (22 mg, 0.07 mmol) in DMF (0.12 mL) was treated with N-bromosuccinimide (12 mg, 0.07 mmol) at room temperature under N2 for 100 minutes, after which very little reaction had occurred. The reaction was thus heated to 60° C. for 50 minutes, then diluted with DMF (0.5 mL). Lithium chloride (29 mg, 0.68 mmol) was added and the reaction was heated to 100° C. After stirring at 100° C. for 1.5 hours the reaction was heated at 120° C. for 50 minutes. The reaction was cooled to room temperature and then partitioned between EtOAc/H2O. The organic portion was washed several times with water, then with brine, dried over MgSO4, filtered and then concentrated under vacuum. The crude material was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 2.5% MeOH in CH2Cl2. The low Rf band was eluted with 5% MeOH in CH2Cl2 and concentrated under vacuum to give 1-bromo-3a-butyl-6-chloro-8-fluoro-7-hydroxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an off-white film.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C>CN(C=O)C>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([CH2:12][C@@H:3]([NH:2][C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:4][C@@H:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](C)C(=O)OCC
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride salt (1 g, 2.87 mmol) in DMF (10 mL) is added TEA (0.42 mL, 3.02 mmol) followed by ethyl 2-chloro-2-oxoacetate (392 mg, 2.87 mmol). The crude is stirred at it for 1 hr. To the crude is added an additional 0.2 ml of ethyl 2-chloro-2-oxoacetate followed by triethylamine (1.26 mL, 9.06 mmol). The crude is quenched with water and diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 50% EtOAc/heptane to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (970 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:19])[C:8]3[C:13]([S:14](=[O:18])(=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)#[N:2].[CH2:20](N)[CH2:21][NH2:22].C[O-].[Na+]>CO>[NH:2]1[CH2:20][CH2:21][N:22]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:19])[C:8]3[C:13]([S:14](=[O:17])(=[O:18])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Reactant: NCCN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1c2ccccc2S(=O)(=O)c2cc(C3=NCCN3)ccc21

Procedure:
To 13.5 g (0.05 mol) of 3-cyanothioxanthen-9-one 10,10-dioxide was added ethylenediamine, 6.0 g (0.1 mol), and sodium methoxide, 0.5 g (0.01 mol), in 100 ml methanol and the mixture was heated at reflux for 3 days. The reaction mixture was filtered hot and the solid was washed with two 50 ml portions of methanol. The crude product was recrystallized from ethanol to yield 3-(2-imidazolin-2-yl)thioxanthen-9-one 10,10-dioxide, 11.0 g, as bright orange crystals, m.p. 241°-242° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]([CH3:22])=O>CCCCCC.C(OCC)(=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:20]#[C:22][C:12]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC#CC#CCOc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
In a flask were placed 3.78 g (0.024 mole) of 1-chloro-2,4-nonadiyne thus obtained, 3.32 g (0.02 mole) of ethyl 4-hydroxybenzoate, 5.5 g (0.04 mole) of potassium carbonate, and 50 ml of acetone and the mixture was refluxed by heating for 11 hours. After allowing to cool the reaction mixture to room temperature, the reaction mixture was poured in 250 ml of ice-water and the product was extracted with methylene chloride. After distilling off the solvent of the organic layer, the residue formed was purified by a silica gel column chromatography(developing solvent: hexane/ethyl acetate=3/1) to provide 4.0 g (yield 70%) of ethyl 4-(2,4-nonadiynyloxy)-benzoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10](OC([O-])=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CO.[Ni]>[C:13]([O:12][C:10](=[O:11])[NH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: N#Cc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccnc(Cl)n1
Yield: 83.5 %

Procedure:
2-Chloropyrimidine-4-carbonitrile (24 g), 40.8 g of t-butyl dicarbonate (Boc2O) in 1.2 L of methanol and 5 g of Raney nickel (Raney 2400) were charged in an autoclave. The autoclave was sealed and purged with hydrogen. The hydrogenation was run at 30 psi hydrogen gas. The reduction was carried out to completion and the reactor was vented and purged with nitrogen. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated. The residue was purified by chromatography to yield the title compound (35 g, 84%) as white solid of melting point of 86-88° C.