Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][CH3:14])[CH2:9][C@H:8]2[NH:15][C:16](=[O:18])[CH3:17])[C:3]1=[O:19].C(N(CC)CC)C.Cl[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=2)[N:31]=[CH:30][N:29]=1>ClCCl>[CH3:14][NH:13][C@H:10]1[CH2:9][C@@H:8]([NH:15][C:16](=[O:18])[CH3:17])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=4)[N:31]=[CH:30][N:29]=3)[C:3]2=[O:19])[CH2:12][CH2:11]1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CN[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](NC(C)=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(methylamino)cyclohexyl)acetamide (12.5 g, 46.6 mmol) in dichloromethane was added triethylamine (12.98 mL, 93 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (10.83 g, 46.6 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure to dryness. The residue was dissolved in dichloromethane (350 mL) and extracted with a solution of aqueous acetic acid (1×200 mL, 1×100 mL; made from 300 mL of H2O and 16 mL of acetic acid. The acidic aqueous layer (pH 4-5) was extracted with dichloromethane (2×300 mL), basified with Na2CO3 to pH 10-11, and then extracted with dichloromethane (2×350 mL; maintained pH of aqueous layer at 10-11 with Na2CO3 as necessary). The organic phase was washed with saturated NaCl solution (1×200 mL); the NaCl layer was back-extracted with dichloromethane (1×100 mL). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (19.4 g, 90%). LC/MS found [M+H]+=465. HPLC shows the purity as 99.4%, with the largest single impurity as 0.5%. 1H-NMR (500 MHz, CD3OD), δ ppm: 8.77 (1H, s), 8.56 (1H, s), 8.02 (1H, dd, J=8.80, 1.37 Hz), 7.87 (1H, d, J=8.52 Hz), 5.25 (1H, t, J=8.52 Hz), 4.53 (1H, q, J=3.94 Hz), 4.01 (1H, dt, J=11.96, 3.85, 3.71 Hz), 3.46-3.64 (2H, m), 2.77-2.86 (1H, m), 2.47-2.57 (1H, m), 2.41 (3H, s), 2.22 (1H, dq, J=12.51, 12.44, 3.57 Hz), 1.98 (3H, s), 1.95-1.98 (1H, m), 1.92-1.98 (1H, m), 1.84-1.91 (1H, m), 1.78 (1H, t, J=3.44 Hz), 1.71-1.76 (1H, m), 1.62-1.69 (1H, m).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:19][N:20]=[C:21]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:27][CH:28]=1)[CH3:22]>CN(C=O)C>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:19][N:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:27][CH:28]=2)[CH3:22])=[CH:4][CH:5]=1
Reactant: COC(=O)COc1ccc(C(C)=NO)cn1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(C)=NOCc2ccc(C(F)(F)F)cc2)cn1
Reaction time: 12 h
Yield: 102.6 %

Procedure:
To a solution of 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.87 ml, 5.6 mmoles) in DMF (10 mL), cesium carbonate (3.35 gm, 10.2 mmoles) was added followed by addition of methyl 2-((5-(1-(hydroxyimino)ethyl)pyridin-2-yl)oxy)acetate (1.15 gm, 5.1 mmoles) at 25° C. under nitrogen atmosphere and the reaction mixture was stirred at the same temperature for 12 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 2.0 gm (94%) of product as thick liquid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[OH:42][C:43]([C:46]1[CH:55]=[CH:54][C:53]2[CH2:52][CH:51]([C:56](O)=[O:57])[CH2:50][CH2:49][C:48]=2[N:47]=1)([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:56]([CH:51]1[CH2:50][CH2:49][C:48]2[N:47]=[C:46]([C:43]([OH:42])([CH3:44])[CH3:45])[CH:55]=[CH:54][C:53]=2[CH2:52]1)=[O:57])[CH3:4]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: CC(C)(O)c1ccc2c(n1)CCC(C(=O)O)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([C@@H](C)NC(=O)C2CCc3nc(C(C)(C)O)ccc3C2)c(F)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A 4-mL vial was charged with (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (95 mg, 0.34 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (130 mg, 0.34 mmol). A solution of 2-(2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (66 mg, 0.28 mmol) and N,N-diisopropylethylamine (290 μL, 1.7 mmol) in N-methylpyrrolidinone (850 μL) was added and the mixture stirred at room temperature for 1 hour. The reaction was quenched with water (100 μL), filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a light yellow solid (70 mg, 54%). Additional purification by silica chromatography was performed (0-100% EtOAc in hexanes) to obtain a white solid (45 mg, 35%). m/z=464.6 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (br s, 1H), 8.41 (app dd J=7.8 Hz, J=11.0 Hz, 1H), 7.45 (app dd, J=3.0 Hz, J=8.0 Hz, 1H), 7.36 (app dd, J=1.5 Hz, J=8.0 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.07 (d, J=11.5 Hz, 1H), 5.17-5.04 (m, 2H) 3.02 (s, 3H), 2.92-2.73 (m, 4H), 2.68-2.57 (m, 1H), 2.26 (s, 3H), 2.09-1.96 (m, 1H), 1.88-1.66 (m, 1H), 1.39 (s, 3H), 1.39 (s, 3H), 1.35 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCc1ccccn1
Product: O=C(NCc1ccccn1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(pyridin-2-ylmethyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.46 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.78 mmol of pyridine-2-methylamine. LC/MS [8.33 min; 449 (M+1)]
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][CH:12]=[C:13]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)[CH:5]=1.[OH-].[K+].Cl>CO.O>[O:23]([CH2:22][C:21]([N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:15]1[C:13]1[N:14]=[C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:31])=[O:2])[S:11][CH:12]=1)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(-c2nc([C@H]3CCCCN3C(=O)COc3ccccc3)cs2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2nc([C@H]3CCCCN3C(=O)COc3ccccc3)cs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
A solution of 3-{4-[(R)-1-(2-phenoxy-acetyl)-piperidin-2-yl]-thiazol-2-yl}-benzoic acid methyl ester (0.030 g, 0.069 mmol) (prepared as illustrated in example 24) in methanol (0.5 mL) was treated with 1N KOH (0.14 mL, 0.14 mmol). The mixture was stirred at room temperature for 16 h, then diluted with water (0.5 mL) and acidified to pH 1 with HCl 0.5N. A white solid precipitated, which was filtered to yield 3-{4-[(R)-1-(2-phenoxy-acetyl)-piperidin-2-yl]-thiazol-2-yl}-benzoic acid (0.022 g, 76%), MS (ISP): 421.3 (M−H). 1H-NMR (CDCl3, 300 MHz): 13.33 (1H, bs), 8.44 (1H, s), 8.15 (1H, d), 8.04 (1H, d), 7.65 (1H, m), 7.23 (2H, m), 6.92 (3H, m), 5.76+5.33 (1H, bs), 4.94 (2H, m), 4.34+3.80 (1H, bd), 3.32 (3H, m), 1.64 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.CN(C)C=O.[Cl-].[K+].[CH2:23]1[O:25][CH2:24]1>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:23][CH2:24][OH:25])[C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C1CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCO)C(=O)CCC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
199 g. (1mole) of 6-methyl-1,2,3,4-tetrahydrocarbazol-1-one dissolved in 2000 ml. of dimethylformamide are taken initially and 5.6 g. (0.1 mole) of potassium chloride dissolved in 200 ml. of water are added. Thereafter 66.1 g.=74.2 ml. (1.5 mole) of ethyleneoxide are added at room temperature and heated up to 50° C. within 30 minutes, a maximum pressure of 0.2 to 0.5 bar being generated. Stirring is done for 20 hours at 50° C., the solvent is distilled off in a vacuum and, the residue is stirred with a mixture of 800 ml. water and 10 ml. of glacial acetic acid; the product (which takes a crystalline form) is filtered with suction, washed with 500 ml. water and dried at 40° C. in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Br[CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:1]4[CH2:34][CH2:35][CH2:36][C:37]4=[O:38])[CH:3]=3)[C:13]2=[O:14])=[CH:17][CH:18]=1
Reactant: COc1nn(-c2cccc(N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reactant: O=C(Cl)CCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nn(-c2cccc(N3CCCC3=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 80 °C
Yield: 5.2 %

Procedure:
According to Scheme 9 Step 2: To a solution of 2-(3-aminophenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (100 mg, 0.27 mmol) (1 mL) and NEt3 (78 μL, 0.55 mmol) in DMF was added bromobutyryl chloride (36 μL, 0.30 mmol). The reaction mixture was heated at 80° C. for 4 hours then quenched with water and extracted with ethyl acetate. The organic layers were combined and successively washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified on a prepacked silica column (10 g) 8:2 cyclohexane/Ethyl acetate 80/20 to afford 4-(4-chlorobenzyl)-6-methoxy-2-(3-(2-oxopyrrolidin-1-yl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 4.145 as a white solid (6 mg, 5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1)[N:6]=[CH:5]2.[C:23]([C@@H:27]1[CH2:32][CH2:31][C@H:30](O)[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.C1COCC1>[C:23]([C@H:27]1[CH2:32][CH2:31][C@H:30]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)[N:6]=[CH:5]3)[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)C1CCN(Cc2ncc3cc(O)ccc3n2)CC1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ncc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 25 mL round bottom flask was added methyl 1-((6-hydroxyquinazolin-2-yl)methyl)piperidine-4-carboxylate (0.5 g, 1.6 mmol), cis-4-tert-butylcyclohexanol (0.38 g, 0.24 mmol, 1.5 eq), PPh3 (0.87 g, 3.3 mmol, 2 eq) and dry THF (0.5 mL) under N2 atmosphere. Then DIAD (0.53 g, 0.33 mmol, 2 eq) was quickly added in one portion at room temperature. The reaction mixture was stirred at rt for 0.5 h, diluted with water (20 mL) and extracted with DCM (20 ml*3). The combined organic lays were dried over MgSO4 and concentrated. The residue was purified by prep-TLC (DCM/MeOH=15/1) to give methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)quinazolin-2-yl)methyl)piperidine-4-carboxylate (300 mg, yield: 20%) as brown oil. 1HNMR (400 MHz, CDCl3) δ: 9.27 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.8 Hz, 1H), 7.07 (d, J=2.8 Hz, 1H), 4.30˜4.20 (m, 1H), 3.94 (s, 2H), 3.59 (s, 3H), 3.00˜2.98 (m, 2H), 2.28˜2.18 (m, 4H), 1.85-1.82 (m, 6H), 1.40˜1.34 (m, 2H), 1.18˜1.03 (m, 4H), 0.86 (s, 9H); ESI-MS: m/z 440.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:8]2.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=[CH:14][C:15]([O:17][CH2:23][CH3:24])=[O:16])=[CH:8]2
Reactant: COc1cccc2cc(C=CC(=O)O)ccc12
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=Cc1ccc2c(OC)cccc2c1

Procedure:
β-(5-methoxynaphth-2-yl)propenoic acid (0.075 moles) is allowed to reflux with 8-10 pieces of Orierite in absolute ethanol (20 ml) containing concentrated sulfuric acid (5 ml) for 21 hours. The cooled reaction mixture is diluted with chloroform and filtered hot. The filtrate is washed 3 times with water, once with 10% sodium bicarbonate and twice more with water. After drying over sodium sulfate, the solvent is removed to give ethyl β-(5-methoxynaphth-2-yl)propenoate.
Reaction SMILES: [O:1]=[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[NH:3]1.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[N:12]1([C:11]2[C:2]([O:1][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:3][C:4]3[C:9]([N:10]=2)=[CH:8][C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCC3)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 2-oxo-3-(piperidin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.8 mmol) and then Tf2O (393 mg, 1.4 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 3-(piperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red solid (280 mg, crude).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:28]=1[C:29](Cl)=[O:30].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[CH3:37][O:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:27]([O:26][CH3:25])[C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: COc1cccc(OC)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 71 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2,6-dimethoxybenzoyl chloride, the title compound (yield 71%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]([O:14][CH2:15][CH:16]([CH2:18]O)O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)CC[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[C:1]([O:14][CH2:15][CH2:16][CH2:18][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCC(=O)OCC(O)CO
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC

Procedure:
Example 2 was repeated but for the sequence of addition of glycerol monolaurate. Instead of being added with cetyl alcohol, an equal amount of glycerol monolaurate utilized in Example 2 was added after the addition of the TEA.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)C.[O:22]=[C:23]1[C:29]2[NH:30][N:31]=[C:32]([C:33](OCC)=[O:34])[C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][C:33]([C:32]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23](=[O:22])[C:29]=2[NH:30][N:31]=1)=[O:34])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c2c1CCCCC2=O
Reactant: CCc1cccc(CC)c1N
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1NC(=O)c1n[nH]c2c1CCCCC2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 2,6-diethylaniline (0.106 mL, 0.66 mmol) in 5 mL of anhydrous THF under argon, 1M solution of LiN(TMS)2 in THF (0.660 mL, 0.66 mmol) at 0° C. was added dropwise. The mixture was stirred at 0° C. for 0.5 h then ethyl 8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate (0.050 g, 0.22 mmol) in 5 mL of anhydrous THF at 0° C. were added dropwise. Ice bath was removed and the mixture was stirred at room temperature for 1 h. Water (20 mL) was added and the mixture was extracted with AcOEt (2×30 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated to dryness. The crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/hexane 2/8) to afford 0.055 g (80% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.[H][H]>C1(C)C=CC=CC=1.C(O)(C)C.[Pt]>[OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23][C:3]=12
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)CC3
Yield: 52.9 %

Procedure:
A mixture of 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (30) (5 g, 14.60 mmol) and sulfided platinum (5% on carbon, 1 g) in toluene/isopropyl alcohol (200/50 mL) was hydrogenated 16 h at room temperature under atmospheric pressure of hydrogen. The catalyst was filtered off and the filtrate concentrated under vacuum. The solid residue was crystallized from ethanol and re-crystallized from acetone to provide 2.66 g of 44a (53% yield). 1H NMR (CDCl3): 1.03 (t, J=7.5 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 1.42 (s, 6H), 1.64 (m, 2H), 1.84 (t, J=6.5 Hz, 2H), 2.70 (t, J=6.5 Hz, 2H), 2.90 (m, 2H), 3.34 (q, J=7.0 Hz, 2H), 5.98 (s, 1H), 14.61 (s, 1H); 13C NMR (CDCl3): 8.45, 13.89, 16.42, 23.37, 26.62, 31.20, 38.13, 39.38, 77.60, 102.77, 103.43, 105.30, 110.22, 156.41, 157.29, 158.94, 159.76, 165.77, 206.67; IR: 1730 cm−1; MS (ACPI+): 345 (M+1); Anal. Calcd. for C20H24O5: C 69.75, H 7.02; Found C 70.03, H 7.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=O)[O:6][C:5]2=[CH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.O.[NH2:20][NH2:21].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:6])[NH:21][N:20]=[C:5]2[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: NN
Reactant: O=C1OC(=Cc2cccnc2)c2cc(Cl)ccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(Cc2cccnc2)c2cc(Cl)ccc12

Procedure:
5-Chloro-3-(pyrid-3-yl)methylenephthalide (2.68 g) was dissolved in 100 ml of ethanol, followed by the addition of 2.0 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 4 hours, followed by the addition of 200 ml of water. The resulting mixture was neutralized with dilute hydrochloric acid to precipitate crystals, which were recovered by filtration to give 1.87 g of the title compound as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C:15]1[S:16][C:17]([CH:21](O)[C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([Si](C(C)C)(C(C)C)C(C)C)[CH:23]=2)=[C:18]([Cl:20])[N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[C:1]([O:5][C:6](=[O:42])[N:7]([C:15]1[S:16][C:17]([CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[C:18]([Cl:20])[N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccncc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N(Cc1ccncc1)c1nc(Cl)c(Cc2c[nH]c3ncccc23)s1
Temperature: 40 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A mixture of {4-chloro-5-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (519, 0.397 g, 0.57 mmol), triethylsilane (1.0 mL, 6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10 mL) was stirred at 40° C. for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid (520, 126 mg, 49%). MS (ESI) [M+H+]+=456.2.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2)(=[O:24])[CH3:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:30]2)(=[O:24])[CH3:23]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 34 %

Procedure:
283 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 325 mg of 5-acetamidomethylisoindoline hydrobromide, 536 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 154 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 1H-NMR (CDCl3) δ: 8.74 (1H, s, C2 --H), 7.89 (1H, d, J=14Hz, C5 --H), 7.26-7.30 (3H, brs, ARM-H), 5.15 (4H, brs, 2 x --CH2N--), 4.47 (2H, d, J=6Hz, CH2NH2), 4.00 (1H, m, ##STR310## 2.06 (3H, s, --COCH3), 1.17-1.31 (4H, m, ##STR311##