Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.CC1C2C=C3[C:33]4([C:41]5[C:36](=[CH:37]C=C[CH:40]=5)N[C:34]4=[O:42])COC3=CC=2ON=1.BrCC1CCOCC1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:40][CH:41]4[CH2:36][CH2:37][O:42][CH2:34][CH2:33]4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: Cc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Agent: BrCC1CCOCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(CC2CCOCC2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 4-bromomethyltetrahydropyrane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: mp 199-201° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 1H), 7.14-7.12 (m, 1H), 7.05-7.00 (m, 2H), 6.91-6.89 (m, 1H), 6.75 (s, 1H), 6.41 (s, 1H), 4.71 (ABq, 2H), 4.12-3.95 (m, 2H), 3.75-3.54 (m, 2H), 3.39-3.28 (m, 2H), 2.19-2.02 (m, 7H), 1.62-1.28 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.9, 159.1, 142.8, 138.5, 132.6, 129.4, 128.7, 125.8, 124.0, 123.7, 123.2, 111.4, 108.5, 79.9, 67.4, 58.0, 46.0, 33.9, 30.8, 20.3, 19.3; MS (ES+) m/z 364.3 (M+1).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])SC)#[N:2].[CH:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:27])[CH2:25][NH2:26])=[CH:20][CH:19]=1>C(O)C>[C:1]([NH:3][C:4]([NH:26][CH2:25][CH:24]([OH:27])[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1)=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Reactant: NCC(O)c1ccccc1
Solvent: CCO
Product: Cc1[nH]cnc1CSCCN=C(NC#N)NCC(O)c1ccccc1
Yield: 20.3 %

Procedure:
With 5 ml of ethanol were mixed 1 g of N-cyano-N'-{2-[(5-methyl-4-imidazolyl)methylthio]ethyl}-S-methylisothiourea and 2.6 g of DL-β-hydroxyphenethylamine, and the resulting mixture was subjected to reaction under reflux for 5 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was washed with 20 ml of diethyl ether and then purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform:methanol=10:1 by volume) to obtain 0.27 g (yield 20%) of amorphous N-cyano-N'-(β-hydroxyphenethyl)-N"-{2-[(5-methyl-4-imidazolyl)methylthio]ethyl}guanidine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([OH:19])=O.[CH:20]([NH:23][NH:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[O:26])=[O:19]
Reactant: CC(C)NNC(=O)c1ccsc1
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccsc2)C(C)C)c1C
Yield: 50.5 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (207 mg, 0.81 mmoles) and thiophene-3-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.81 mmoles) in DMF (8 mL) was treated with triethylamine (0.34 mL, 2.44 mmoles), HOBT (132 mg, 0.98 mmoles) and EDCI (156 mg, 0.98 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (172 mg, 50%). LC-MS m/e 421.46 (M+H+)
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[C:49]([OH:51])=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:53].O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[C:49]([O:51][CH3:53])=[O:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.4 %

Procedure:
To the solution of acid 104 (1.7 g, 2.35 mmol) in CH2Cl2 (7.8 mL) was added TMSCHN2 (1.4 mL, 2.82 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. H2O was added to the reaction mixture and then extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography provided the desired methyl ester 105 (560 mg, 32%) as a solid. MH+737.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[N:17]=1)=[O:14].CC1(C)C(C)(C)OB(C2CCN(C(OC(C)(C)C)=O)CC=2)O1.[O:45]1[CH2:50][CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH2:47][CH2:46]1>>[O:45]1[CH2:46][CH:47]=[C:48]([C:18]2[N:17]=[C:16]([NH:15][C:13]([NH:12][C:7]3[C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[O:14])[CH:21]=[CH:20][CH:19]=2)[CH2:49][CH2:50]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C(Nc1cccc(I)n1)Nc1ccnc2c(F)cccc12
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: O=C(Nc1cccc(C2=CCOCC2)n1)Nc1ccnc2c(F)cccc12

Procedure:
The title compound was prepared as described in example 27 step 2, substituting 1-(6-bromo-quinolin-4-yl)-3-(6-trifluoromethyl-pyridin-2-yl)-urea by 1-(8-fluoroquinolin-4-yl)-3-(6-iodopyridin-2-yl)urea (example 47, step 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate by 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CC1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@H]3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
Into a 20-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (500 mg, 1.67 mmol, 1.00 equiv), 2-methylpyrrolidine (285 mg, 2.92 mmol, 2.00 equiv), potassium carbonate (693.8 mg, 4.01 mmol, 3.00 equiv), N,N-dimethylformamide (6 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 12×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 590.7 mg (92%) of methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil. Then the isomer was sent for chiral-prep-HPLC to get the product of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (178 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:15])=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)[CH3:2].CN(CCN(CCN(C)C)C)C.[Li]CCCC.CN([CH:36]=[O:37])C>C1COCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:6]([F:15])=[C:5]([CH:4]=1)[CH:36]=[O:37])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1ccc(F)c(N2CCOCC2)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(F)c(N2CCOCC2)c1
Temperature: -45 °C
Reaction time: 0.33 h

Procedure:
To a solution of Intermediate 230.1 (102 mg, 0.487 mmol) and PMDTA (0.132 mL, 0.634 mmol) in 3 mL THF at −78° C., was added BuLi (1.6 M in THF, 0.365 mL, 0.584 mmol). The mixture was allowed to warm to −45° C. over 20 min, then was recooled to −78° C. DMF (75 μL) was added, then the reaction mixture was removed from the cooling bath and stirred 20 min before being quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 35% EtOAc/hexanes gradient) to afford 77 mg of Intermediate 406.1. LCMS (2 min gradient) RT=1.47 min, 238.18 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[C:4](F)[CH:3]=1.[CH3:15][O-:16].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[C:4]([O:16][CH3:15])[CH:3]=1
Reactant: Cc1ncc(-c2ccc(Br)cc2F)o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)ccc1-c1cnc(C)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a mixture of 5-(4-bromo-2-fluorophenyl)-2-methyl-1,3-oxazole (10 g) in DMF (80 mL) was added sodium methoxide (28% methanol solution, 11.3 g) at 0° C., and the mixture was stirred at 80° C. for 2 hr under a nitrogen atmosphere. The reaction mixture was cooled to 0° C., and diluted with water, and the resultant solid was collected by filtration to give the title compound (10.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[S:29][C:30]([CH2:33]Cl)=[CH:31][CH:32]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:33][C:30]3[S:29][C:28]([Cl:27])=[CH:32][CH:31]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2ccc(Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 25 °C

Procedure:
119 mg (0.39 mmol) of the compound from Example 5A and 107 mg (0.77 mmol) of potassium carbonate were dissolved in 5 ml of acetonitrile, and 65 mg (0.39 mmol) of 2-chloro-5-(chloromethyl)thiophene were added. The mixture was stirred under reflux for 2 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were washed with 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→8:1→5:1→1:1). This gave 114 mg (65% of theory) of the target compound.
Reaction SMILES: Cl[S:2]([C:5]1[C:16]([CH3:17])=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[CH3:18])(=[O:4])=[O:3].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][S:2]([C:5]2[C:16]([CH3:17])=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH3:18])(=[O:4])=[O:3])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1
Reactant: COC(=O)COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)COc1cc(C)c(S(=O)(=O)Nc2ccc(OC)cc2[N+](=O)[O-])c(C)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of methyl (4-chlorosulfonyl-3,5-dimethylphenoxy)acetate (Intermediate A1, 7.6 g, 0.026 mol), 4-methoxy-2-nitroaniline (4.0 g, 0.024 mol), and pyridine (50 mL) was stirred at room temperature for 16 hr, in a 90° C. bath for 5 hr, and in a 130° C. bath for 30 min. The mixture was cooled and stirred with toluene for 10 min. The resulting suspension was filtered, and the filtrate was concentrated, diluted with 150 mL toluene and 100 mL ethyl acetate, washed with 1 M hydrochloric acid and water, and concentrated to about 50 mL. The mixture was left overnight in a freezer. The solid was collected and washed with several portions of cold toluene. After drying, it weighed 8.2 g (74%). Another 0.45 g portion of the title compound was recovered from extraction of aqueous phases and crystallization of a second crop from the toluene filtrate.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].[CH3:10][CH2:11][CH2:12][C:13](=O)[CH2:14][C:15](=O)[CH2:16][CH2:17][CH3:18]>C(O)(=O)C>[CH3:7][C:4]1[C:3]([C:8]#[N:9])=[C:2]2[N:1]=[C:13]([CH2:12][CH2:11][CH3:10])[CH:14]=[C:15]([CH2:16][CH2:17][CH3:18])[N:6]2[N:5]=1
Reactant: CCCC(=O)CC(=O)CCC
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: CC(=O)O
Product: CCCc1cc(CCC)n2nc(C)c(C#N)c2n1

Procedure:
A stirred mixture of 4.88 g of 5-amino-3-methylpyrazole-4-carbonitrile and 6.25 g of 4,6-nonanedione in 50 ml of glacial acetic acid was heated at reflux for 10 hours. The reaction mixture after reflux was worked up as described in Example 50 to give 7.80 of 2-methyl-5,7-dipropylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, mp 73°-74° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].O[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:31]([O:30][C:29]([NH:28][CH2:27][CH2:26][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23])=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CCOC(=O)C(Cc1ccc(O)c([N+](=O)[O-])c1)Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c1)Oc1ccccc1
Yield: 90.3 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(4-hydroxy-3-nitrophenyl)-2-phenoxypropionate (270 mg), which is the product of Reference example 53(a), t-butyl 2-hydroxyethylcarbamate (322 mg), triphenylphosphine (535 mg) and a solution of diethylazodicarboxylate in toluene (40%, 0.93 ml) and the reaction mixture was treated to afford the desired compound (349 mg) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:30][CH2:31][N:32]=3)[C:15]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:30][CH2:31][N:32]=3)[C:15]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)=[N:16][C:17]=2[C:18]=1[O:19][CH3:20]
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c(O)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 60 °C
Reaction time: 17 h
Yield: 113.7 %

Procedure:
N-[8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (20 g, 45.1 mmol) was added portionwise over 1 h to a round bottom flask containing TFA (400 mL) precooled with an ice bath. The reaction mixture was heated to 60° C. and allowed to stir at this temperature for 17 h at which time it was cooled to room temperature. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2 and hexane and concentrated under reduced pressure. The material thus obtained was dissolved in MeOH and CH2Cl2 (250 mL, 1:1) and concentrated under reduced pressure. The resulting solids were dried overnight under vacuum with low heat to give N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (17.3 g, 66%): 1H NMR (DMSO-d6+2 drops TFA-d) δ: 13.41 (1H, s), 12.21 (1H, br s), 9.38 (1H, s), 8.78 (1H, d), 8.53 (1H, d), 7.85 (1H, d), 7.59 (1H, m), 7.17 (1H, d), 4.54 (2H, m), 4.21 (2H, m), 3.98 (3H, s); mass spectrum m/z 481 ((M+1)+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])(C)C.FC(F)(F)C(O)=O.C(=O)([O-])ON1C(=O)CC(C[C:34]2[C:46]3C[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:38]=3[CH:37]=[CH:36][CH:35]=2)C1=O>ClCCl>[CH:43]1[C:44]2[CH:4]([CH2:1][O:5][C:6]([NH:8][C:9]([CH3:16])([CH3:17])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])[C:46]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: O=C([O-])ON1C(=O)CC(Cc2cccc3c2Cc2ccccc2-3)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C/C=C/C(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.5 g, 2.1 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml) and stirred for 60 min and concentrated in vacuo. Then a 10% aqueous solution of sodium carbonate (30 ml) and dioxane (30 ml) were added followed by 9H-fluorenylmethyl-succinimidyl carbonate (0.67 g, 2.1 mmol) and stirred overnight. The mixture was washed with petrol ether (2×20 ml) and the aqueous layer was acidified with 4N sulphoric acid (pH~3) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with 1N sulfuric acid, water (4×20 ml), brine (20 ml), dried (Magnesiumsulfate) and concentrated in vacuo. The obtained product was precipitated from dichloromethane/ether and filtered to give 280 mg of (2E)-5-(((9H-flouren-9-yl)methoxy)carbonylamino)-5-methyl-hex-2-enoic acid, which was used without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.[CH2:37]([N:39]1[CH:44]=[CH:43][C:42](I)=[CH:41][C:40]1=[O:46])[CH3:38]>>[CH2:37]([N:39]1[CH:44]=[CH:43][C:42]([C:17]2[CH:16]=[CH:15][C:14]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:36])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:19][CH:18]=2)=[CH:41][C:40]1=[O:46])[CH3:38]
Reactant: CCn1ccc(I)cc1=O
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CCn1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 1-ethyl-4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.228 min, m/z=971.4; 1H NMR (CDCl3) 1.10 (s, 3H), 1.14 (s, 3H), 1.36 (m, 3H), 1.53 (d, 3H), 2.17 (s, 2H), 2.21-2.32 (m, 2H), 2.32-2.48 (m, 1H), 2.88 (m, 1H), 4.00 (m, 2H), 5.68 (m, 1H), 6.39 (d, 1H), 6.78 (s, 1H), 6.99 (d, 2H), 7.27-7.38 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26]([CH3:28])=[O:27])[CH:12]=3)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([S:26]([CH3:28])(=[O:39])=[O:27])[CH:12]=3)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(S(C)=O)cc21
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To 439 mg of ethyl 9-p-chlorobenzyl-6-methylsulfinyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetate from Example 24, in 10 cc of methylene chloride was added 353 mg of m-chloro perbenzoic acid. The resulting mixture was stirred for 18 hours at room temperature. The reaction mixture was diluted with ether and washed consecutively with a solution of sodium bicarbonate, water and brine. The crude product obtained after evaporation of the organic layer was purified on silica gel by flash chromatography eluting with 30% hexane/ethyl acetate and yielded 200 mg (42%) of the pure title compound.
Reaction SMILES: Cl.[OH:2][C:3]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[N:14]2[CH2:15][CH2:16][N:17]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([OH:18])=[C:8]([O:19][CH3:20])[C:7]=2[N:6]=1.Cl[CH:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:2][C:3]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[N:14]2[CH2:15][CH2:16][N:17]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([O:18][CH2:34][CH2:33][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:8]([O:19][CH3:20])[C:7]=2[N:6]=1
Reactant: CCC(Cl)C(=O)OC
Reactant: COc1c(O)ccc2c1N=C(C=C(O)c1cccnc1)N1CCN=C21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCOc1ccc2c(c1OC)N=C(C=C(O)c1cccnc1)N1CCN=C21
Temperature: 120 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
A mixture of 5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol hydrochloride (Example 1-4) 50.4 mg (0.14 mmol), methyl chloro-butyrate 22.2 mg (0.16 mmmol) and potassium carbonate 186.9 mg (1.35 mmmol) in N,N-dimethylformamide 1 mL was stirred at 120° C. for 4 hours. The reaction mixture was poured into water and extracted into dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtrated and the solvent was evaporated. The residue was washed by diethyl ether to give the title compound 35.0 mg as yellow solid. Yield 59.3%.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]2[C:14]=1[CH2:13][CH2:12][N:11]([C:15]([C:17]1[CH:25]=[CH:24][C:20]3[NH:21][N:22]=[N:23][C:19]=3[CH:18]=1)=[O:16])[CH2:10]2)=[O:5])C.[OH-].[Na+].C(O)C.Cl>O>[NH:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:15]([N:11]3[CH2:12][CH2:13][C:14]4=[C:6]([C:4]([OH:5])=[O:3])[NH:7][N:8]=[C:9]4[CH2:10]3)=[O:16])=[CH:18][C:19]=2[N:23]=[N:22]1
Reactant: CCOC(=O)c1[nH]nc2c1CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1[nH]nc2c1CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 25 °C
Yield: 68.8 %

Procedure:
Starting material 40 (2.6 g, 6.4 mmol) was mixed with 2 N NaOH (15 ml) and ethanol (15 ml) and stirred at ambient temperature. Additional 15 ml 2 N NaOH were added. After the reaction was completed, the mixture was reduced to dryness, the solid was dissolved in water, adjusted to pH 2 with 2N HCl and the resulting precipitate was filtered and dried. Thus the desired product 41 (1.4 g, 4.4 mmol, 57%) could be isolated as solid.