Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:22]=[CH:21]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Yield: 91.8 %

Procedure:
In a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol (0.200 g, 0.553 mmol), prepared in step 2 of Example 11, methyl bromoacetate (0.102 g, 0.664 mmol) and cesium carbonate (0.900 g, 2.77 mmol) with the exception that the product was extracted with methylene chloride. Purification on a Biotage Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 Å) using 55% to 95% methylene chloride in hexane as the eluent gave methyl {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetate as an off-white solid (0.22 g, 92%), mp 188–189° C. Elemental Analysis for C29H23NO3.0.16 CH2Cl2 Calc'd: C, 78.34; H, 5.26; N, 3.13. Found: C, 77.73; H, 5.08; N, 3.07.
Reaction SMILES: COCN[C:5]([C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].[CH3:18][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[OH:17][C:16]1[C:7]([C:5](=[O:6])[CH3:18])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: C[Mg]Br
Reactant: COCNC(=O)c1cc2ccccc2cc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc2ccccc2cc1O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
3-Hydroxynaphthalene-2-carboxylic acid methoxymethylamide (600 mg) was dissolved in tetrahydrofuran (36 ml) to prepare a solution. A solution (9.8 ml) of 0.93 M methylmagnesium bromide in tetrahydrofuran was added thereto at −78° C., temperature of the mixture was raised to room temperature, and the mixture was stirred for 1.5 hr. A saturated aqueous ammonium chloride solution was added to stop the reaction, water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with an aqueous potassium carbonate solution, was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 1-(3-hydroxynaphthalen-2-yl)-ethanone (378 mg, yield 78%).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:30][CH:31]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 45.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (3.0 g, 9.7 mmol) was reacted with (R)-tert-butyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (5.0 g, 14 mmol) to afford the desired product (2.0 g, 47%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([CH:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1.[BH4-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([CH:16]=[CH:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1
Reactant: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)OC)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C=Cc1ccc(CCCCCCCC(=O)OC)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1 G of 8-[5-(3-oxooct-1-enyl)thien-2-yl]octanoic acid methyl ester was dissolved in 25 ml of methanol and the solution was cooled to about 0° C. Under vigorous stirring, 0.9 g of sodium borohydride was added and the reaction mixture was warmed slowly to room temperature after a period of 30 minutes. After about 1 hour, the reaction mixture was diluted with water, adjusted to a pH of 5.5 to 6 with dilute hydrochloric acid and extracted with ether. The ether phase was washed with water, dried over sodium sulfate, and then concentrated to dryness under vacuum. The residue was purified by column chromatography (silica gel, using petroleum ether and ethyl acetate as eluants). The product was obtained as 0.9 g of an oil (90% yield); ir (film): 3450 (OH), 1740 (C=O), and 1645 cm-1 (C=C).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[C:8]#[N:9])=[C:4]([F:14])[CH:3]=1.Cl.[CH2:16]([OH:18])[CH3:17]>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[C:8](=[NH:9])[O:18][CH2:16][CH3:17])=[C:4]([F:14])[CH:3]=1
Reactant: CCO
Reactant: CC(C)(C#N)Oc1ccc(Cl)cc1F
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)C(C)(C)Oc1ccc(Cl)cc1F
Reaction time: 48 h

Procedure:
Through a cooled solution of Example 53D (7.2 g, 33.7 mmol) in ethanol (75 mL) and dichloromethane (30 mL) was bubbled HCl gas at 0° C. for 30 minutes. The reaction was kept in a refrigerator for 24-72 hours (checked by LCMS). The reaction mixture was then concentrated and the residue was triturated with diethyl ether. The titled compound was collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][N:11]([C@@H:12]([C:13](=[O:14])[NH2:15])[CH2:16][CH:17]([CH3:19])[CH3:18])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of (2R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (4.2 grams, 14 mmol) in DMF (50 mL) was added cesium carbonate (13.6 grams, 417 mmol). To this reaction was added 4-(toluene-4-sulfonyloxymethyl)-piperidine 1-carboxylic acid tert-butyl ester (ref.: Gilissen, C.; Bormans, G.; De Groot, T.; Verbruggen, A. J. Labeled Cmpd. Radiopharm. 1999, 42, 1289; 10.4 g, 282 mmol). The reaction was stirred at 70° C. for 18 h. The reaction was then quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated to a clear oil. The oil was then purified on a Biotage 40S (eluted with 30% EtOAc in hexanes) to afford a white solid (3.0 g, 44%). MS(ESI), (M+H)+502.1; 1H NMR (DMSO-d6, 500 MHz) δ7.86 (dd, 2H, J=2.0, 6.8), 7.65 (dd, 2H, J=2.0, 6.8) 7.37 (br s, 1H), 7.07 (br s, 1H), 4.19 (t, 1H, J=7.6), 3.92 (br s, 2H), 3.35 (dd, 1H, J=15, 6.8), 3.05 (dd, 1H, J=15, 8.1), 1.85 (br s, 1H), 1.50-1.70 (m, 4H), 1.38 (s, 9H), 1.10-1.20 (m, 1H), 0.80-1.00 (m, 3H), 0.82 (d, 6H, J=7.6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:18]([OH:20])=[O:19])[CH2:15][CH2:16][CH3:17])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.[N+](=[CH2:31])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:18]([O:20][CH3:31])=[O:19])[CH2:15][CH2:16][CH3:17])[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1
Reactant: C=[N+]=[N-]
Reactant: CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Product: CCCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)C(=O)OC

Procedure:
In the manner given in Example 10, a solution of 7-chloro-2-[(1-carboxybutylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-butylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([CH2:17][C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:17]=[C:18]2[OH:19]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Product: Oc1cc(-c2ccccc2)nc2ccc(Cl)cc12

Procedure:
From 100 g of p-chloroaniline and 138.5 ml of ethyl benzoylacetate treated according to Example 4(a) there was obtained 115.6 g of 6-chloro-2-phenyl-4-quinolinol, mp greater than 350°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([OH:29])[CH2:25]2)[C:21](=[O:30])[NH:20][C:19]2([C:31]([OH:33])=[O:32])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH2:25]2)[C:21](=[O:30])[NH:20][C:19]2([C:31]([OH:33])=[O:32])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(O)CN2C1=O
Reactant: Fc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3ccccn3)CN2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.6 %

Procedure:
To a mixture of (14-tert-butoxycarbonylamino-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (150 mg, 0.32 mmol; prepared in Ex. 25, step 4) in 3 mL of DMSO was added potassium t-butoxide (91 mg, 0.81 mmol). The mixture was stirred at rt for 5 min, and then 2-fluoro-pyridine (39 mg, 0.40 mmoL) was added and the mixture was stirred at rt overnight. The reaction was quenched by adding 10 mL of water, and then the pH was adjusted to 4 using 0.1 N HCL. It was then extracted with ethyl acetate, dried, concentrated in vacuo to obtain a yellow oil. This crude product was purified by flash chromatography on silica gel eluting with 10% methanol in ethyl acetate to isolate 100 mg (56%) of 14-tert-butoxycarbonylamino-2,15-dioxo-18-(pyridin-2-yloxy)-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid as a white solid. 1H NMR (500 MHz, MeOD) δ 1.24-1.53 (m, 6H), 1.36 (s, 9H), 1.55-1.68 (m, 3H), 1.73-1.90 (m, 1H), 2.02-2.11 (m, 1H), 2.16 (q, J=8.65 Hz, 1H), 2.35-2.45 (m, 1 H), 2.51 (dd, J=7.63, 2.75 Hz, 2H), 4.06-4.14 (m, 1H), 4.27 (d, J=11.29 Hz, 1 H), 4.33 (s, 1H), 4.58 (t, J=7.93 Hz, 1H), 5.46-5.57 (m, 2H), 5.70 (s, 1H), 6.79 (d, J=8.54 Hz, 1H), 6.93-7.02 (m, 1H), 7.68 (t, J=7.63 Hz, 1H), 8.16 (d, J=4.85 Hz, 1 H). LC-MS (YMC Xterra ODS S7 micrometer column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 4 min. Hold time: 1 min. Flow rate: 4 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.)(Retention time: 2.90 min), MS m/z 543 (M++1).
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[CH2:25]([C:27]1[O:28][C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:30]([C:32](Cl)=[O:33])[N:31]=1)[CH3:26]>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:32]([C:30]1[N:31]=[C:27]([CH2:25][CH3:26])[O:28][C:29]=1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:33])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCc1nc(C(=O)Cl)c(-c2ccccc2)o1
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(C(=O)N(C(=O)OC(C)(C)C)c2coc(CCCCC(C)=O)n2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 2-ethyl-5-phenyl-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 16 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.25. LC-MS-conditions 02: tR=1.11 min, [M+H]+=482.83.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:15][NH:14][CH2:13][CH:12]2[OH:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:15][N:14]([CH2:26][CH2:25][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH:12]2[OH:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CNCC1O
Reactant: O=CCCCc1ccccc1
Product: O=S(=O)(c1ccc(O)cc1)C1CN(CCCCc2ccccc2)CC1O

Procedure:
The title compound, MS: m/e=376.3 (M+H+) was prepared from (3RS,4RS)-4-(4-hydroxy-benzenesulfonyl)-pyrrolidin-3-ol and 4-phenyl-butyraldehyde.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]([NH:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24])[C:13]1=[O:34].C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])[C:13]1=[O:34]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Reaction time: 3 h
Yield: 87 %

Procedure:
To a stirring solution of tert-butyl 2-(1-(benzo[d]thiazol-2-ylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.3 g, 0.623 mmol) in DCM (2 ml) was added TFA (3.36 ml, 43.6 mmol) slowly at 20-25° C. Reaction mixture was stirred for 3 h. Excess solvent was distilled out and then diluted with water. Precipitated product was filtered to get crude product which was then recrystallized in EtOH:EtOAC to get titled product in 87% yield.
Reaction SMILES: [Cl:1]C1C=C2C(C(=O)C(C(O)=O)=CN2C2C=CC=CC=2)=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36](C4C=CN=CC=4)[CH:37]=3)[C:32](=[O:45])[C:31]([C:46]([NH2:48])=[O:47])=[CH:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:36]1[CH:37]=[C:38]2[C:33]([C:32](=[O:45])[C:31]([C:46]([NH2:48])=[O:47])=[CH:30][N:29]2[C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)=[CH:34][CH:35]=1
Reactant: O=C(O)c1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O

Procedure:
7-Chloro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxamide [IV; R=H, R1 =C6H5, R2 =H, R6 =H, X=Cl]was prepared from 3.60 g 7-chloro-1,4-dihydro-4-oxo-1-phenyl3-quinolinecarboxylic acid by the procedure of Example 1, part (h), and was obtained (3.00 g) in the form of a colorless solid, m.p. 297-299° C. when recrystallized from DMF.
Reaction SMILES: [N:1]1C(Cl)=NC(Cl)=NC=1Cl.[C:10]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=[CH:14][C:13]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=O)=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1>CN(C)C=O>[C:27](/[CH:26]=[CH:25]/[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:11][CH:12]=2)=[O:17])=[CH:20][CH:21]=1)#[N:1]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C(O)/C=C/c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Solvent: CN(C)C=O
Product: N#C/C=C/c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Cyanuric chloride (727 mg, 3.94 mmol) was added to a dimethylformamide suspension of (E)-3-[4-[([1,1′-biphenyl]-4-ylcarbonyl)amino]phenyl]-2-propenic acid (900 mg, 2.63 mmol) obtained in Reference Example 74 at room temperature, which was stirred for 1 hour. After the solvent was distilled out under reduced pressure, the residue was dissolved in chloroform, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was stilled out under reduced pressure. The resulting residue was purified by silica gel column chromatography (development solvent; chloroform:ethyl acetate=20:1), to give the titled compound (561 mg) as a colorless powder from diethyl ether.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(Cl)(Cl)Cl>[CH3:3][CH:4]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: CC(C)CCCC(C)CCOCCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)CCCC(C)CCOCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.2 %

Procedure:
Sodium hydride (1.79 g 60% dispersion in oil, 1.07 g, 44.8 mmol) was weighed out in a 250 mL round bottom flask. The mineral oils were washed out with hexane (3×15 mL). DMF (30 mL) was added, followed by (3,7-dimethyloctanyl)oxybutyl bromide (3 g, 10.2 mmol) and then the reaction mixture was stirred at room temperature under N2 for a couple of minutes. Imidazole (3.50 g, 51.4 mmol) was added in portions while cooling the reaction mixture in an ice bath. The addition of the imidazole was exothermic causing the mixture to become a milky off-white and then clear yellow in colour after complete addition of the imidazole. Stirring was continued under N2 at room temperature for 3 d. The reaction mixture was diluted with chloroform (100 mL) to form a thick cloudy mixture and washed with water (2×50 mL). The organic layer was dried (Na2SO4) and the solvent was removed at reduced pressure and then under high vacuum to give the product as a brown clear oil (3.38 g).
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH2:12]([O:19][C:20]1[N:29]=[C:28](OCC2C=CC=CC=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:38][CH3:39])[CH:26]=2)[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O>[CH2:12]([O:19][C:20]1[N:29]=[C:28]([NH:11][CH2:1][C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:38][CH3:39])[CH:26]=2)[N:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CS(C)=O
Product: COc1ccc2nc(OCc3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Reaction time: 1 h
Yield: 17.9 %

Procedure:
1.25 g (8.27 mmol) of piperonylamine was added to a solution of 1.00 g (2.69 mmol) of the 2,4-bisbenzyloxy-6-methoxyquinazoline prepared in Example 90 in dimethyl sulfoxide (10 ml). The obtained mixture was stirred at 160° to 180° C. After one hour, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 0.20 g of The title compound as a colorless needle.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22](O)=[O:23].Cl.[F:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH2:33][NH:32][CH2:31][CH2:30]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22]([N:32]1[CH2:31][CH2:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([F:26])[CH:28]=2)[CH2:33]1)=[O:23]
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)N3CCc4cc(F)ccc4C3)c2cc1OC
Yield: 17.9 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 114 (17.9% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.84 and 3.09 (2t, 2H), 3.50-4.06 (m, 8H), 4.47 and 4.98 (2s, 2H), 6.94-7.43 (m, 5H), 7.52-7.55 (2s, 1H), 7.59-7.65 (m, 1H), 8.13-8.21 (m, 1H), 8.30-8.35 (m, 1H); 19F (376 MHz, DMSO-d6) δ −113.0, −116.1, −116.3; MS (ESI) m/z 462 ([M+H]+).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>CN1C(=O)N(C)CCC1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:11]
Reactant: Oc1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CCOC(COc1ccccc1)OCC
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (5.83 g of a 55% dispersion in mineral oil) was added to a solution of phenol (12.56 g) in DMPU (25 ml) at 5° C. and the mixture was stirred for 30 minutes. Bromoacetaldehyde diethyl acetal (10.05 ml) was added and the mixture was heated at 110° C. for 5 hours, then allowed to cool. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic phase was separated and washed sequentially with aqueous 2M sodium hydroxide solution (2×50 ml) and water (50 ml). The aqueous fractions were combined and re-extracted with ethyl acetate (100 ml). The combined organic extracts were dried (MgSO4) and concentrated. The resultant oil was purified by flash column chromatography, eluting with ethyl acetate/hexane (1:10 v/v) to give 2-phenoxyacetaldehyde diethyl acetal (9.43 g) as an oil; NMR: 1.25(6H,t, J=7.0 Hz), 3.6-3.85(4H,m), 4.05(2 H,d, J=6.0 Hz), 4.85 (1H,t, J=6.0 Hz) and 6.9-7.35(5H,m).