Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[Cl:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[Cl:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C)c(Cl)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(C)c(Cl)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 7-chloro-6-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]1([CH2:12][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1cc2cc(OCC3CC3)ccc2[nH]1

Procedure:
To a solution of 7.3 g 5-hydroxy-indole in 130 ml of dry acetone are added 10.5 ml bromomethyl cyclopropane and 22.7 g anhydrous potassium carbonate. The mixture is heated to reflux for 24 h and an additional amount of 5 ml bromomethyl cyclopropane are added. The mixture is heated to reflux for additional 4 days. The mixture is filtered and the solvent is removed under reduced pressure. The residue is dissolved in dichloro methane and washed with an aqueous solution of hydrochloric acid (2 M), 10% aq. NaHCO3 and water. The organic layer is dried and the solvent is removed under reduced pressure. After purification by column chromatography (silica gel; toluene, acetone 95:5), 9.62 g, 94%) of the title compound are obtained as an oil. 1H-NMR (CDCl3): 0.36 (m, 2H, cyclopropyl CH2), 0.64 (m, 2H, cyclopropyl CH2), 1.30 (m, 1H, cyclopropyl CH), 3.83 (d, 2H, J=7.0 Hz, CH2O), 6.45 (s, 1H, aromatic), 6.90 (dd, 1H, aromatic), 7.09-7.27 (m, 3H, aromatic), 8.05 (bs, 1H, NH). 13C-NMR (CDCl3): 3.1 (2 cyclopropyl CH2), 10.4 (cyclopropyl CH), 74.2 (CH2O), 101.2, 101.6, 104.0, 104.6, 149.8 (aromatic)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CN(C=O)C.Cl.[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH2:38])[CH3:34]>C1COCC1>[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH:38][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:34]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1cc(F)c(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 7.8 %

Procedure:
By using 4.41 g of benzyl 2,4-difluoro-5-nitrophenyl ether, 5.05 g of triethylamine, 30 ml of DMF, 30 ml of THF and 2.32 g of glycine ethyl ester hydrochloride, 454 mg (8%) of N-(4-benzyloxy-5-fluoro-2-nitrophenyl)glycine ethyl ester was obtained.
Reaction SMILES: C[N:2]([CH3:13])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:14][C:15]1[CH:16]=C([CH:19]=[CH:20][CH:21]=1)N>CCO.O>[Br:14][C:15]1[CH:16]=[C:13]([NH:2][CH2:3][CH2:4][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Br)c1
Reactant: CN(C)CCC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(CCNc1cccc(Br)c1)c1ccccc1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
A mixture of 3-(dimethylamino)-1-phenylpropan-1-one (0.1 mol) and 3-bromoaniline (0.1 mol) in 1:1 EtOH/H2O (100 mL) was heated at 80° C. overnight. The resulting mixture was concentrated and the residue was washed with H2O and then EtOH several times to give to give 3-(3-bromophenylamino)-1-phenylpropan-1-one (27 g, 90%). 1H NMR (400 MHz, CDCl3): δ=3.52 (m, 2H), 4.33 (m, 2H), 4.51 (m, 1H), 6.8 (m, 1H), 7.05 (m, 2H), 7.28 (m, 1H), 7.72 (m, 2H), 7.80 (m, 1H), 8.2 (m, 2H).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([O:26][CH2:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])=[CH:18][CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:35]([C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28](=[O:29])[CH2:27][O:26][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:42])=[CH:17][CH:18]=1)([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1ccc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1ccc(OCC(=O)N2CCC[C@@H]2C(=O)O)c2ccccc12
Reaction time: 8 h

Procedure:
A solution of 172 mg (0.30 mmol) (R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-1-yloxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 140 mg (quantitative) of the title compound as a light brown powder.
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1.CC1(C)C(C)(C)OB([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)O1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:29]1[C:30]2[C:26](=[C:25]([C:7]3[CH:16]=[N:15][C:10]4[O:11][CH2:12][CH2:13][NH:14][C:9]=4[CH:8]=3)[CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1cc(-c2cnc3c(c2)NCCO3)c2cc[nH]c2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 139.8 %

Procedure:
To 3 ml of tetrahydrofuran (THF)/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-indole (109 mg, 0.45 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (172 mg, 0.15 mmol) were added and stirred at 80° C. for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain 7-(1H-indol-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (130 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:19]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=2)[N:20]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 3.5 g of 4-hydrazinobenzoic acid are boiled under reflux for 2 h in 75 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. After drying, 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid remains as colorless crystals of m.p. 264-265 C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=[CH:29][C:30]2[N:35]([OH:36])N=[N:33][C:31]=2[CH:32]=1.CC1C(N)=CON=1.CCN(C(C)C)C(C)C>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:11]=2[C:12]([NH:33][C:31]2[C:30]([CH3:29])=[N:35][O:36][CH:32]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Agent: Cc1nocc1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nocc1NC(=O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 119; 100 mg, 0.32 mmol in N,N-dimethylformamide (4 ml) was added EDC (122 mg, 0.64 mmol), HOBT (63.4 mg, 0.41 mmol), 3-methyl-4-isoxazolamine (86 mg, 0.64 mmol), DIPEA (0.22 ml, 1.27 mmol) and the mixture was stirred at room temperature overnight. The mixture was then heated to 70° C. overnight (NOTE: it would be better to prepare the acid chloride and react this with the amine). The mixture was diluted with water (25 ml) and extracted with ethyl acetate (3×25 ml). The organics were combined, evaporated under reduced pressure on a buchi and the residue was purified using an MDAP to yield the title compound. 33 mg.
Reaction SMILES: [CH3:1][N:2]([CH3:46])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:45])/[C:14](/[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)=[C:15](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:16][CH2:17][O:18][Si](C(C)C)(C(C)C)C(C)C)=[CH:8][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:46][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:45])/[C:14](/[C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:39][CH:40]=2)=[C:15](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:16][CH2:17][OH:18])=[CH:10][CH:11]=1
Reactant: COCOc1ccc(/C(C(=O)Nc2ccc(OCCN(C)C)cc2)=C(/CCO[Si](C(C)C)(C(C)C)C(C)C)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(/C(C(=O)Nc2ccc(OCCN(C)C)cc2)=C(/CCO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5f (95 mg, 0.147 mmol) in THF (2 ml) was added a 1M solution of tetrabutylammonium fluoride (0.18 ml) in THF under ice cooling, and the mixture was stirred at room temperature for 30 min. H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by silica gel flash column chromatography (eluent: AcOEt to CHCl3/MeOH, 5:1) gave 5 g (90%). 5 g: colorless oil; 1H-NMR (CDCl3) δ 2.74 (2H, t, J=5.7 Hz), 3.02 (2H, t, J=5.6 Hz), 3.43 (3H, s), 3.63 (2H, t, J=5.6 Hz), 4.06 (2H, t, J=5.7 Hz), 5.09 (2H, s), 6.79 (2H, d, J=8.3 Hz), 6.88 (2H, d, J=9.1 Hz), 6.99 (2H, d, J=8.6 Hz), 7.09 (2H, m), 7.16-7.21 (3H, m), 7.45 (2H, d, J=8.8 Hz), 7.82 (1H, brs).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[C:9]([NH:11][CH2:12][C@H:13]([CH:26]([CH3:28])[CH3:27])[CH2:14][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=[CH2:17])=[O:10].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:37].[Mg+2]>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[C:9]([NH:11][CH2:12][C@H:13]([CH:26]([CH3:27])[CH3:28])[CH2:14][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[C@@H:16]1[CH2:17][O:37]1)=[O:10]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: C=C[C@H](C[C@H](CNC(=O)c1ccccc1OCCCOC)C(C)C)NC(=O)OC(C)(C)C
Agent: [Mg+2]
Solvent: CO
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CO1)C(C)C
Reaction time: 72 h

Procedure:
The solution of 1.48 g of tert-butyl (3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methyl-1(S)-vinylpentyl)carbamate in 30 ml of methanol is admixed with 7.81 g of magnesium monoperoxyphthalate and stirred over 72 hours. The reaction mixture is poured onto water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellowish oil. Rf=0.30 (1:1 EtOAc-heptane, run 2×); Rt=18.64 (gradient II).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1/[CH:31]=[CH:32]\[C:33](O)=[O:34]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])/[CH:32]=[CH:31]\[C:30]1[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=1[O:28][CH3:27])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1/C=C\C(=O)O
Product: COc1ccccc1/C=C\C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 32 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with cis-2-methoxycinnamic acid under the conditions described in example 86 to yield 32% of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C([O:13][CH:14]=[C:15]([C:21](OCC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:22][C:21]1[C:7]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][CH:8]=2)[NH:6][C:14](=[O:13])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cccc([N+](=O)[O-])c2[nH]c1=O
Temperature: 80 °C
Yield: 24.8 %

Procedure:
A mixture of 2-nitroaniline (6.907 g) and diethyl ethoxymethylenemalonate (10.812 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The mixture is cooled to 80° C. Diphenyl ether (60 mL) is added and the mixture is heated to 250° C. for 2 h. The solution is cooled to room temperature. The resulting solid is collected, washed with hexanes and dried to yield 3.447 g of ethyl 4-hydroxy-8-nitroquinolone-3-carboxylate as a gold solid. To a mixture of this ester (1.2 g) in 66 mL of 1:1 MeOH:THF is added 18 mL of 1M LiOH. The reaction is maintained at 40° C. overnight. The reaction mixture is cooled to room temperature, then diluted with 35 mL glacial acetic acid. The resulting precipitate is collected, washed with H2 0 and hot isopropanol, and dried to yield 0.639 g of 4-hydroxy-8-nitroquinoline-3-carboxylic acid as a yellow solid. A mixture of this acid (0.20 g) and p-chlorobenzylamine (0.10 mL) are dissolved in 25 mL xylenes and heated to reflux. PCl3 (0.037 mL) is added dropwise and the mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature and H2O is added to quench excess PCl3. An orange solid precipitates, which is collected, washed with ether, and dried. The crude product is recrystallized with hot MeOH to yield 0.0367 g of the desired product as a yellow solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCC(OCC)=O)=N2)C=CC=CC=1.[C:32]1([C:38]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:39]2[CH:43]=[N:42][C:41]([C:44](OC)=[O:45])=[N:40]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:54]1([C:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:39]2[CH:43]=[N:42][C:41]([CH2:44][OH:45])=[N:40]2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: COC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCOC(=O)CCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: OCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
By a method similar to that in Reference Example 26 and using, instead of ethyl 3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoate, methyl 1-(triphenylmethyl)-1H-1,2,4-triazole-3-carboxylate obtained in Reference Example 34, the title compound was obtained as a white powder (5.35 g, 58%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]([F:58])([F:57])[CH2:34][NH:35][C:36]([C:38]1([CH2:52][CH2:53][CH2:54][CH2:55]Br)[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[O:45][C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:37]>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH2:55][CH2:54][CH2:53][CH2:52][C:38]4([C:36](=[O:37])[NH:35][CH2:34][C:33]([F:58])([F:57])[F:32])[C:51]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[O:45][C:44]5[C:39]4=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(Cc2ccccc2)CC3)CC1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C1c2cc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5Oc5ccccc54)CC3)ccc2CCN1Cc1ccccc1

Procedure:
Step (b) of Example 97 was repeated, except that the compound prepared in step (a) of Example 97 and the compound prepared in step (a) of Example 96 were used. Thus, the title compound was prepared.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([OH:37])[C:18]3[C:27]([C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4F)=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][C:22]([OH:36])=[CH:23]4)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+]>CN(C=O)C.O>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[O:37][C:29]4[C:28](=[CH:33][C:32]([F:34])=[CH:31][CH:30]=4)[C:27]4[C:18]3=[C:19]3[C:24](=[CH:25][CH:26]=4)[CH:23]=[C:22]([OH:36])[CH:21]=[CH:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c3c(ccc2c1)-c1cc(F)ccc1OC3c1ccc(OCCN2CCCCCC2)cc1
Temperature: 50 °C

Procedure:
Dissolve 5-{[4-(2-azepan-1-yl-ethoxy)-phenyl]-hydroxymethyl}-6-(2,5-difluorophenyl)-naphthalen-2-ol (770 mg, 1.54 mmol) in 20 mL dry DMF and add sodium t-butoxide (1.18 g, 12.32 mmol). Heat the mixture to 50° C. for two hours. Dilute with water and extract multiple times with methylene chloride. Dry the organic layer and purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. The yield is 370 mg (50%): 1H-NMR (CDCl3, 300 MHz) δ7.76 (dd, J=12.6, 8.4 Hz, 2H); 7.58 (d, J=9.0 Hz, 1H); 7.43-7.40 (m, 1H); 7.15 (d, J=2.4 Hz, 1H); 7.05-7.01 (m, 3H); 6.89 (s, 1H); 6.83-6.80 (m, 2H); 6.66-6.63 (m, 2H); 4.00-3.98 (m, 2H); 2.92-2.92 (m, 2H); 2.78-2.78 (m, 4H); 1.66-1.59 (m, 8H). The racemic compound is purified using chiral chromatography (conditions P). The two isomers eluted with retention times of 9.9 and 13.5 minutes.
Reaction SMILES: CN(C)C=O.[CH2:6]([CH:8]1[O:10][CH2:9]1)Br.C(=O)([O-])[O-].[K+].[K+].[NH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([OH:35])=[C:30]([C:33]#[N:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)=[CH:20][C:19]=1[F:38]>C(OCC)(=O)C.O>[NH2:17][C:18]1[CH:37]=[CH:36][C:21]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:6][CH:8]4[CH2:9][O:10]4)=[C:30]([C:33]#[N:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)=[CH:20][C:19]=1[F:38]
Reactant: BrCC1CO1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding dimethylformamide (6 ml), epibromohydrin (1.3 ml) and potassium carbonate (380 mg) to 4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (400 mg), the mixture was stirred overnight at room temperature. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (400 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[N:9][OH:10].[Cl:11]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:11][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[N:9][OH:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cnccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1cnccc1Cl
Yield: 75.4 %

Procedure:
Dissolve 4-chloropyridine-3-carboxaldehyde oxime (2.60 g, 0.017 mol) in N,N-dimethylformamide (20 mL). Add N-chlorosuccinimide (2.48 g, 0.018 mol) in small portions and stir overnight at ambient temperature. Pour the mixture into water and extract with ethyl acetate. Wash the combined extracts with water and dry over sodium sulfate. Concentrate in vacuo to give 2.45 g (75%) of crude product as a yellowish solid. 1H NMR was consistent with structure.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5](O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(C)=[CH:14][C:15](O)=[O:16]>C(OCC)C>[CH:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][CH2:14][C:15](=[O:16])[C:3]=2[CH:4]=1
Reactant: CC(C)=CC(=O)O
Reactant: COc1ccc(O)cc1OC
Solvent: CCOCC
Product: O=C1CCOc2ccccc21
Reaction time: 1 h
Yield: 168.3 %

Procedure:
The amount of 10 g of 3,4-dimethoxyphenol and 7.8 g of 3,3-dimethyl acrylic acid were combined in a 125 ml. erlenmeyer flask and dissolved with the addition of 40 ml anhydrous ethyl ether. The ether was removed in vacuo and while the contents of the flask remained liquid, 50 gm of polyphosphoric acid was added. The flask and contents were placed on a steam bath and heated with stirring for 1 hour. At the end of 1 hour, 75 ml. of water was added and the contents stirred into solution for 5 minutes. The solution was allowed to cool and a substantial sticky precipitate formed. The aqueous layer was decanted and extracted with 100 ml. of ether. The ether extract was washed successively with 150 ml. of water, 100 ml. of 5% sodium carbonate and 100 ml. of saturated NaCl solution. The ether extract was dried over anhydrous sodium sulfate. The sticky residue formed on cooling was dissolved in 300 ml. of chloroform and washed successively with 150 ml. of water, two 150 ml. portions of 5% sodium carbonate solution and 150 ml. of saturated NaCl solution. The chloroform solution was dried over anhydrous sodium sulfate. The ethereal and chloroform extracts were combined and the solvents removed in vacuo leaving 16.17 gm of off-white crystalline chromanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25]C)=[O:24])=[C:21]2[C:16]([C:17]3[CH:30]=[CH:29][O:28][C:18]=3[C:19](=[O:27])[NH:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[I-].[Li+]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]2[C:16]([C:17]3[CH:30]=[CH:29][O:28][C:18]=3[C:19](=[O:27])[NH:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1[nH]c(=O)c1occc12
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1[nH]c(=O)c1occc12
Yield: 88.9 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4-oxo-4,5-dihydrofuro[2,3-c]quinoline-6-carboxylate (Intermediate 87, 0.220 g) and lithium iodide (0.055 g) in pyridine (13 mL) was irradiated in the microwave at 150° C. for 30 minutes. After cooling, the mixture was concentrated in vacuo and the residue was suspended in 1M HCl. The solid was collected by filtration and triturated with acetone then dried under vacuum to give 7-(2-bromo-4-fluorobenzenesulfonylamino)-4-oxo-4,5-dihydro furo[2,3-c]quinoline-6-carboxylic acid (0.190 g) as a grey solid.