Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([OH:18])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4])=[CH:15][CH:14]=1
Reactant: C#CC(=O)OC
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
A solution of 7.5 ml (90 mmol) of methyl propiolate in 80 ml of tetrahydrofuran was treated at -78° under argon 10 with 56.3 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 8.4 ml (80 mmol) of 4-fluorobenzaldehyde in 80 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 80 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 800 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-(4-fluorophenyl)-4-hydroxy-2-butynoate as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,4,6-trichloroaniline to yield 2-[(2,4,6-trichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:46])[CH2:14][N:15]2[C:24](=[O:25])[C:23]3[N:22]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:21]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH:37]C(OC(C)(C)C)=O)[CH2:32]4)=[N:20][C:19]=3[N:18]([CH3:45])[C:16]2=[O:17])[CH:10]=[CH:11][CH:12]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:46])[CH2:14][N:15]2[C:24](=[O:25])[C:23]3[N:22]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:21]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH2:37])[CH2:32]4)=[N:20][C:19]=3[N:18]([CH3:45])[C:16]2=[O:17])[CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: COC(=O)COc1cccc(C(=O)Cn2c(=O)c3c(nc(N4CCCC(NC(=O)OC(C)(C)C)C4)n3CC=C(C)C)n(C)c2=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COc1cccc(C(=O)Cn2c(=O)c3c(nc(N4CCCC(N)C4)n3CC=C(C)C)n(C)c2=O)c1

Procedure:
Prepared by treating 1-(2-{3-[(methoxycarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with trifluoroacetic acid in methylene chloride at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][C:21]=1[C:10]([CH:9]([CH3:13])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:12]
Reactant: COc1ccc(C(C)C(=O)O)cc1
Reactant: COc1cccc(OC)c1
Product: COc1ccc(C(C)C(=O)c2ccc(OC)cc2OC)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 56.6 %

Procedure:
2-(p-Methoxyphenyl)propionic acid (0.39 g, 4 mmol) and 1,3-dimethoxybenzene (0.5 g, 0.5 ml, 4 mmol) were mixed in polyphosphoric acid (PPA) (10 g) and the reaction mixture was mechanically stirred at 75° C. for 5 h. The reaction mixture was then allowed to cool to room temperature and mechanically stirred for a further 12 h. The reaction was then quenched with ice water and the product extracted with CHCl3(3×25 ml). The CHCl3 layer was dried (Na2SO4) and the solvent removed under reduced pressure The residual crude product was purified by silica gel column chromatography (eluent 7:2 CH2Cl2:EtOAc) to give the pure 2,4,4′-trimethoxy-α-methyldesoxybenzoin (0.68 g, 58%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:33][CH3:34])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:33]([N:15]([CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:16]1[CH2:17][C:18]2[CH:19]=[C:20]([NH:26][C:27](=[O:32])[C:28]([F:29])([F:30])[F:31])[CH:21]=[CH:22][C:23]=2[CH2:24][CH2:25]1)[CH3:34]
Reactant: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 4-({ethyl-[7-(2,2,2-trifluoro-acetylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (800 mg, 1.7 mmol) in methylene chloride (20 mL) under an inert atmosphere was added trifluoroacetic acid (5 mL) and the solution was allowed to stir at room temperature for 1 h. The reaction was concentrated in vacuo and partitioned between 10% KOH and EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated to afford N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-2,2,2-trifluoro-acetamide as an oil which was used directly for the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.CCCCC.CON(C)[C:29]([CH:31]1[CH2:33][CH2:32]1)=[O:30]>CCOCC>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=1[C:29]([CH:31]1[CH2:33][CH2:32]1)=[O:30]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CON(C)C(=O)C1CC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: Cc1ccc(N)c(C(=O)C2CC2)c1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
To a stirred solution of p-tolyl-carbamic acid tert-butyl ester (1.0 g, 4.8 mmol) in Et2O (10 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (6.5 mL, 11.1 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopropanecarboxylic acid methoxy-methyl-amide (0.92 g, 6.3 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (15 mL) and TFA (15 mL) and stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 0.80 g crude (2-amino-5-methyl-phenyl)-cyclopropyl-methanone as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][CH3:13])=[C:4]([N+:14]([O-])=O)[CH:3]=1.[Cl:17][CH2:18][CH2:19][C:20](Cl)=O>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[N:12]([CH3:13])[C:20]([CH2:19][CH2:18][Cl:17])=[N:14][C:4]=2[CH:3]=1
Reactant: CNc1c([N+](=O)[O-])cc(Br)c2ccccc12
Reactant: O=C(Cl)CCCl
Product: Cn1c(CCCl)nc2cc(Br)c3ccccc3c21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 80.3 g (0.286 mole) of 4-bromo-N-methyl-2-nitro-1-naphthylamine, prepared as described in the first part of Example 36, and 41 cc (0.426 mole) of 3-chloropropanoyl chloride is stirred for 2 hours at 60° C. and for a further 2 hours at 80° C. The excess of acyl chloride is distilled off at 40° C. under vacuum and the residue, taken up with methylene chloride, is washed first with a saturated NaHCO3 solution and then with water.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(C(OCC2C=CC=CC=2)=O)[C:10](=[O:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:10](=[O:30])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)CC1(C(=O)OCc2ccccc2)CCN(Cc2ccccc2)CC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCN(Cc2ccccc2)CC1=O

Procedure:
A mixture of benzyl 1-benzyl-4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-4-carboxylate (18.5 g, 45.2 mmol) and 10% palladium-on-carbon (1.5 g) in EtOAc (50 ml) is treated with 15 psi of hydrogen for 2 hours. The reaction mixture is filtered through a celite pad, washing with EtOAc (100 ml). The combined filtrate is concentrated in vacuo to afford the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[O:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J26) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.22 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.05 g).
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOCC.[Cl-].[CH2:16]([N+:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[C:25]([CH2:31][CH3:32])[CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([CH2:29][CH3:30])=[C:25]([CH2:31][CH3:32])[CH:24]1[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: CCc1cc[n+](Cc2ccccc2)cc1CC
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC1=C(CC)C(Cc2ccccc2)N(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
The Grignard reagent prepared from magnesium (85.5 g.), benzyl chloride (407 g.) and ether (3020 ml.) was added to the slurry of 1-benzyl-3,4-diethylpyridinium chloride in benzene (2250 ml.). After refluxing the mixture was quenched in ice and ammonium chloride (453 g.). Ammonium hydroxide was added to the mixture. The ether layer was washed with water and concentrated. A solution of sodium borohydride (52 g.) in water (260 ml.) was added to a solution of the residue (712 g.) in ethanol (2 l.). The mixture was stirred, allowed to stand overnight and filtered. The filtrate was concentrated under vacuum. Water and ether were added to the residue. The ether layer was washed with water, dried and concentrated. The residue was distilled under vacuum. The main fractions darkened on exposure to air. Therefore, the sodium borohydride reduction was repeated excluding water. Sodium borohydride (42 g.) was added portionwise with stirring to a solution of the combined main fractions (517 g.) in ethanol (100%, 1 l.). The mixture was stirred for 6 hours, allowed to stand overnight and concentrated. Water and ether were added. The ether layer was washed with water, dried and concentrated. Since the reduction still appeared incomplete, it was repeated using dimethylformamide as the solvent. Sodium borohydride (40 g.) was added portionwise to a solution of the residue in dimethylformamide (1 l.). The mixture was stirred and allowed to stand overnight. Water was added and the mixture was extracted with ether. The ether extracts were washed with water, dried and concentrated. The residue was distilled under vacuum, affording 1,2-dibenzyl-3,4-diethyl-1,2,5,6-tetrahydropyridine (172 g., b.r. 154°-178° C./0.1 mm., mostly at 174° C.).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:15][CH:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([NH:28][C:29]1[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:36][C:37]([C:41]1[N:28]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH:14]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[CH2:15]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:6]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]=1)([F:42])[CH3:38]
Reactant: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(CN2CC(C3CCOCC3)C2)nc2c(N3CCOCC3)nc(-n3c(C(C)(F)F)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.3 %

Procedure:
To a mixture of N-{9-methyl-6-morpholin-4-yl-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purin-2-yl}benzene-1,2-diamine (0.234 g, 0.49 mmol) and 2,2-difluoropropionic acid (0.057 g, 0.51 mmol) and DIPEA (0.185 mL, 1.08 mL) in DMF (14 mL) was added HATU (0.223 g, 0.59 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 7.5:92.5). The solution was concentrated in vacuo, the residue was diluted in acetic acid (30 mL) and the reaction mixture was stirred at 90° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (Si—PPC, MeOH:DCM, 0:100 to 7.5:92.5) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 468 as a white solid (0.063 g, 24%). LCMS (Method I): RT=3.34 min, [M+H]+ 553.3. 1H NMR (400 MHz, DMSO-d6): δ 7.84-7.82 (m, 1 H); 7.75-7.72 (m, 1 H); 7.42-7.36 (m, 2 H); 4.58 (dd, J=7.85, 6.0 Hz, 2 H); 4.40-4.00 (m, 4 H); 4.32 (t, J=6.0 Hz, 2 H); 3.78 (s, 3 H); 3.77 (s, 2 H); 3.77-3.73 (m, 4 H); 2.85 (d, J=11.1 Hz, 2 H); 2.68-2.66 (m, 1 H); 2.26 (t, J=19.02 Hz, 3H); 2.09 (t, J=11.1 Hz, 2 H); 1.57 (d, J=12.5 Hz, 3 H); 1.03 (d, J=12.5 Hz, 2 H)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[C:26]([F:28])[C:25]([OH:29])=[C:24]([F:30])[CH:23]=1)=[O:18])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:29][C:25]3[C:24]([F:30])=[CH:23][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:27][C:26]=3[F:28])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reactant: ClCc1cccc(SC2CCC2)n1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 71 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.040 g, 0.18 mmol) obtained in Step C of Preparation Example 37 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.045 g, 0.18 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.050 g, 69%).
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:35])([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]4)=[N:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:36].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[N:49]1([CH2:55][CH2:56]O)[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>ClCCl>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:35])([C:32]([O:34][CH2:56][CH2:55][N:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)=[O:33])[CH2:28][CH2:27]4)=[N:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:36]
Reactant: OCCN1CCOCC1
Reactant: Cc1nc2ccc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2ccc(-c3cnc(N4CCC(C)(C(=O)OCCN5CCOCC5)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
The sodium salt of Example 44 (200 mg, 0.378 mmol) was suspended in dichloromethane (25 mL). A drop of DMF was added, followed by oxalyl chloride (50 mg, 0.39 mmol). The mixture was stirred at room temperature for 2 h, then 2-(morpholin-4-yl)ethanol (99 mg, 0.75 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was washed with aqueous sodium bicarbonate solution and the organic layer was concentrated in vacuo. Chromatography (silica, 0 to 10% MeOH in DCM), followed by freeze-drying, gave the title compound (35 mg, 15%) as an off-white solid. δH (DMSO-d6) 8.64 (s, 2H), 8.37 (s, 1H), 7.55-7.43 (m, 2H), 7.31-7.10 (m, 4H), 7.04-7.01 (m, 1H), 4.35 (s, 2H), 4.34-4.28 (m, 2H), 4.25-4.21 (m, 2H), 3.52-3.48 (m, 4H), 3.36-3.25 (m, 2H), 2.60-2.54 (m, 2H), 2.42-2.38 (m, 4H), 2.32 (s, 3H), 2.10-2.04 (m, 2H), 1.45-1.35 (m, 2H), 1.19 (s, 3H). LCMS (pH10): MH+ (621.8), RT 2.01 minutes.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)OC(=O)[CH:6]=[CH:5]2.[O:13]1C2C(=CC=CC=2)C=CC1=O>>[OH:13][C:11]1[CH:2]=[CH:3][C:4]([CH:5]=[CH2:6])=[CH:9][CH:10]=1
Reactant: O=c1ccc2ccccc2o1
Reactant: O=c1ccc2cc(O)ccc2o1
Product: C=Cc1ccc(O)cc1

Procedure:
6-hydroxycoumarin:coumarin=0.23:0.52:0.15:0.10
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[CH:38]=[CH:37][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]3[N:33]([CH3:34])[C:32](=[O:35])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]=4[CH3:36])[N:25]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][N:11]=1>CN(C=O)C>[CH3:34][N:33]1[C:32](=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[CH3:36])[N:25]=[C:24]1[CH:23]=[CH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[O:15])[C:13]2[CH:37]=[CH:38][C:10]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)nc4)cc3)n(C)c(=O)c12
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(OCCN(C)C)nc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.1 %

Procedure:
To a solution of 2-dimethylaminoethanol (53 mg) in DMF (3 ml) was added 60% sodium hydride (29 mg) and the mixture was stirred at room temperature for 10 minutes. Then, 2-[2-[4-(6-chloronicotinoyl)phenyl]vinyl]-3,5-dimethyl-4(3H)-quinazolinone (208 mg) was added and the mixture was further stirred at room temperature for 2 hours. This reaction mixture was extracted with ethyl acetate and the organic layer was washed serially with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to 10 ml. To this organic was added 1N-hydrochloric acid (2 ml) and the mixture was extracted with water. The aqueous layer was diluted with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness to provide 169 mg of yellow powder.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.CCOC(C)=O>[Br:9][CH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: Cc1sccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: N#Cc1ccsc1CBr
Yield: 46.3 %

Procedure:
2-Methyl-thiophene-3-carbonitrile [see Beaton, et al.; Tetrahedron Lett. 39, 10, 1998, 1227-1230] (1.36 g, 11 mmol), N-bromosuccinimide (2.56 g, 14.4 mmol), and a catalytic amount of benzoyl peroxide were stirred in benzene (30 mL) at 80° C. for 2 h. The solution was diluted with EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (10% EtOAc/hexanes) gave 1.03 g (46%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.39 (d, 1H, J=5.6 Hz), 7.17 (d, 1H, J=5.6 Hz), 4.79 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]([C:31](OC4C=CC=CC=4)=[O:32])C(=O)OC4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[N:40]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:31]([N:48]4[CH2:49][CH2:50][CH:45]([N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[CH2:46][CH2:47]4)=[O:32])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (12.1 g, 23.2 mmol) synthesized in Production example 5-2 was dissolved in dimethylformamide (150 ml); 4-(1-pyrrolidinyl)piperidine (14.4 g, 93.3 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and concentrated to about 100 ml. The residue was allowed to be kept cool at 5° C. for overnight to precipitate crystals. The crystals were filtered off, washed with ethyl acetate to yield the title compound (7.8 g, 16.9 mmol, 73%) as white crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[CH2:7]([Mg]Br)[CH:8]=[CH2:9]>C(OCC)C>[CH3:1][C:2]([CH3:6])([CH:3]([OH:4])[CH2:9][CH:8]=[CH2:7])[CH3:5]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)C=O
Solvent: CCOCC
Product: C=CCC(O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of trimethylacetaldehyde (10.2 mL, 90.9 mmol) in diethyl ether (200 mL) at 0° C. was treated with allylmagnesium bromide (100 mL, 1 M in ether), stirred at 0° C. for 1 hour, quenched with saturated ammonium chloride and extracted with diethyl ether. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated to give the title compound (11.6 g).