Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[I:22]N1C(=O)CCC1=O.P(O)([O-])([O-])=O.[Na+].[Na+]>ClCCl>[I:22][C:13]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]([CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(C(C)C)cc1C
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(I)c(C(C)C)cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To methyl 4-isopropyl-2-methylbenzoate (compound 198.1, 2.31 g, 12.0 mmol, 1.0 equiv) in a 100 mL round bottom flask was carefully added TFA (24 mL) and the mixture was cooled to 0° C. N-Iodosuccinimide (2.70 g, 12.0 mmol, 1.0 equi) was added portionwise over 2 minutes and the resulting mixture was added under nitrogen and stirred at 0° C. for 20 min then at room temperature for 15 hours. The mixture was carefully diluted. To a mixture of dichloromethane (50 mL) and added to saturated aqueous disodium phosphate to maintain a pH above 3 (total disodium phosphate about 500 mL). The mixture was shaken well, separated and the aqueous was extracted with additional DCM (5×25 mL). The combined organics was washed with a mix of saturated sodium sulfite (10 mL) plus water (40 mL) followed by brine (50 mL), dried (Na2SO4), filtered and removed in vacuo. The crude product was purified by silica column chromatography (hexanes to 3% ethyl acetate) to obtain the title compound as a light tan oil (3.59 g, 94%). 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.08 (s, 1H), 3.87 (s, 3H), 3.17 (septet, J=6.8 Hz, 1H), 2.59 (s, 3H), 1.23 (d, J=6.8 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]2[CH:10]3[O:20][CH:13]([CH2:14][C:15]=2[C:16]=1[C:17](O)=[O:18])[CH2:12][CH2:11]3)=[O:5].[CH2:29]([NH2:31])[CH3:30].N>>[CH2:29]([NH:31][C:17]([C:16]1[C:15]2[CH2:14][CH:13]3[O:20][CH:10]([CH2:11][CH2:12]3)[C:9]=2[S:8][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[C:21]([C:25]([F:26])([F:28])[F:27])=[CH:22][CH:23]=[CH:24][C:2]=1[F:1])=[O:18])[CH3:30]
Reactant: O=C(Nc1sc2c(c1C(=O)O)CC1CCC2O1)c1c(F)cccc1C(F)(F)F
Reactant: CCN
Agent: N
Product: CCNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1CC1CCC2O1

Procedure:
The title compound was prepared from the product of Example 4A and ethylamine according to the procedure described for Example 4B. MS (DCI/NH3) m/z 443 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C([O-])(O)=O.[Na+]>ClCCl>[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCCCCCCCCCCCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCCOC1CCCCO1
Temperature: 0 °C

Procedure:
100.26 g (0.35 mol) of methyl 16-hydroxyhexadecanoate, 0.60 g (3.5 mmol) of p-toluenesulfonic acid and 350 ml of dichloromethane were introduced into a 1-l flask equipped with a stirrer and a dropping funnel. 32.39 g (0.385 mol) of dihydropyran was added dropwise thereto while stirring at 0° C. After the completion of the addition, the mixture was stirred at room temperature for an hour to thereby complete the reaction. Next, the reaction mixture was neutralized by adding 0.59 g (7 mmol) of NaHCO3. After filtering and removing solvent under reduced pressure; a crude product of methyl 16-(2-tetrahydropyranyloxy)hexadecanoate was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:21].[Na+].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([OH:21])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2O)CC1
Temperature: 25 °C

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.85 g, 6.19 mmol, prepared in Example 5a) in DMSO (6 mL) was added a 2.5M aqueous solution of NaOH (30 mL). The resulting suspension was heated to reflux for 12 h before allowing to cool to room temperature. The suspension was then diluted with water (20 mL), acidified to pH=5 with 6M HCl, and extracted with EtOAc. The organic phase was concentrated in vacuo and the resulting solids were purified by flash chromatography (silica gel, 5.5:1 EtOAc:Hexanes). Product 3′-Hydroxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester was obtained as white solids (538 mg, 31.0%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[PH2:24])[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([Li])[CH2:42][CH2:43][CH3:44].S([O-])(=O)(=O)C>CCCCCC.C1COCC1>[C:13]([C:9]1[CH:8]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[P:24]2[C:44]3[C:43](=[CH:2][CH:1]=[CH:5][CH:10]=3)[CH2:42][CH:41]2[CH:7]([CH3:8])[CH3:6])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[O:11][CH3:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2P)cc1C(C)(C)C
Reactant: [Li]CCCC
Agent: CS(=O)(=O)[O-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2P2c3ccccc3CC2C(C)C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
Under a nitrogen atmosphere, 1.0 g (1.72 mmol) of 2-(bis(3,5-di(tert-butyl)-4-methoxyphenyl)phosphino)phenylphosphine was added to 30 ml of THF, followed by cooling with an ice bath. Then, a 1.6M solution of 1.1 ml (1.72 mmol) of n-butyllithium in hexane was added dropwise thereto and, after dropping, the mixture was stirred for 1 hr, a solution of 448 mg (1.72 mmol) of MESYLATE in 10 ml of THF was added dropwise thereto, stirred for 1 hr and, after removing the ice bath, the mixture was stirred for 1 hr at room temperature. Following recooling with an ice bath, a 1.6M solution of 1.6 ml (2.58 mmol) of n-butyllithium in hexane was added dropwise thereto, after dropping, the ice bath was removed and the mixture was stirred overnight at room temperature. 1 ml of water was added to the reaction mixture to quench the reaction and the solvent was distilled off. 10 ml of water was added to the residue and extracted 3 times each with 20 ml of Et2O, and the combined organic layer was washed with 10 ml of water, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 337 mg of the title compound. (Yield: 27%)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7](C(OC(C)(C)C)=O)[C:8](=[O:19])[N:9]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O[C:31](=[O:33])[CH3:32])(=O)C.[CH2:34](OCC)C>N1C=CC=CC=1>[C:8]([NH:9][C:10]1[CH:11]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH2:6][NH:7][C:31](=[O:33])[CH3:32])(=[O:19])[CH3:34]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2N(C(=O)OC(C)(C)C)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCc1ccc(Br)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of compound (14) (0.5 g, 2.5 mmol) in pyridine (5 mL) was added acetic anhydride (0.95 mL, 10 mmol), and the reaction was stirred overnight at room temperature. To the mixture was added diethyl ether (20 mL), and the mixture was washed successively with H2O (10 mL), 1M HCl (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and evaporated to obtain 0.70 g (99%) of compound 15 as an off-white solid. IR (KBr) νmax. cm−1: 3312 (NH), 3042 (Ar—H), 1690 (C═O), 1522, 1410 (C═C). 1H NMR (500 MHz, CDCl3) S=2.11 (s, 3H, CH3); 2.23 (s, 3H, CH3); 5.05 (s, 2H, CH2); 7.46 (m, 2H, H-3, H-5); 7.89 (d, 1H, J=8.2 Hz, H-6). Calculated (%) for C11H13BrN2O2 (284.02); C: 46.33, H: 4.60, N: 9.82. found (%); C: 46.28, H: 4.63, N: 9.76.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:6]2[C:11]([C:12]=1[C:13](O)=[O:14])=[CH:10][CH:9]=[C:8]([O:16][CH3:17])[CH:7]=2)([CH3:3])[CH3:2].[F:25][C:26]([F:36])([F:35])[C:27]1[N:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1>>[CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:6]2[C:11]([C:12]=1[C:13]([NH:34][CH2:33][C:30]1[CH:31]=[N:32][C:27]([C:26]([F:36])([F:25])[F:35])=[CH:28][CH:29]=1)=[O:14])=[CH:10][CH:9]=[C:8]([O:16][CH3:17])[CH:7]=2)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Reactant: NCc1ccc(C(F)(F)F)nc1
Product: COc1ccc2c(C(=O)NCc3ccc(C(F)(F)F)nc3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139) and (6-(trifluoromethyl)pyridin-3-yl)methanamine by General Procedure C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[N:1]1([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1ccc2c(c1)CCCN2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCCc4ccccc43)c2cc1OC
Yield: 91 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 91% yield from 1,2,3,4-tetrahydroquinoline (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 130°-131° C.; LC-MS: 322 (MH+); anal. RP18-HPLC RT: 4.08 min.).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[S:7][CH:8]=1.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([OH:38])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH:21]=[CH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:3][C:4]4[N:5]=[C:6]([CH2:9][N:10]5[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]5)[S:7][CH:8]=4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CN1CCN(Cc2nc(CCl)cs2)CC1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN2CCN(C)CC2)n1
Temperature: 70 °C
Reaction time: 21 h
Yield: 19.3 %

Procedure:
1-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}-4-methylpiperazine hydrochloride (0.067 g, 0.238 mmol) and 4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (0.080 g, 0.238 mmol) were suspended in DMF (4 mL) and potassium carbonate (0.164 g, 1.19 mmol) was added. The mixture was stirred at 70° C. for 21 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford the title compound as a colorless solid (0.025 g, 0.046 mmol, 19% yield). 1H NMR (400 MHz; CDCl3): 2.08 (s, 5H); 2.39 (s, 3H); 2.59-2.74 (m, 6H); 3.44-3.78 (m, 5H); 3.86 (s, 2H); 3.98 (s, 3H); 5.30 (s, 2H); 7.10 (s, 1H); 7.33 (s, 1H); 7.37 (s, 1H); 7.43 (d, 1H); 7.61 (dd, 1H); 7.99 (d, 1H); 8.60 (s, 1H); MS (EI) for C25H26Cl2N6O2S: 545 (MH+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([O:47][CH3:48])[CH:41]=1)[OH:39]>>[OH:39][CH:38]([C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[C:42]([O:47][CH3:48])[CH:41]=1)[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: COc1cc(C(O)CN)ccc1O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc(O)c(OC)c2)N(C(=O)c2ccc(-c3ccccc3OC)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methoxy[1,1′-biphenyl]-4-carboxylic acid, and 4-[(1RS)-2-amino-1-hydroxyethyl]-2-methoxyphenol, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=534.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)C1C=CC=CC=1.[OH-].[NH4+]>CO.[OH-].[OH-].[Pd+2]>[CH2:14]([O:13][C@H:11]1[C@H:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][NH:8][CH2:12]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CO[C@@H]2CN(Cc3ccccc3)C[C@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(CO[C@@H]2CNC[C@H]2OCc2ccccc2)cc1
Reaction time: 20 h
Yield: 97 %

Procedure:
To a solution of (3R,4R)-1-benzyl-3,4-dibenzyloxypyrrolidine (26.8 g, 71.7 mmol) in methanol (600 ml) was added palladium hydroxide on activated charcoal (20% Pd, 2,7 g) and 25% ammonium hydroxide (6 ml). The mixture was hydrogenated in a Parr apparatus at 20 psi for 20 hours. The mixture was filtered and evaporated to dryness in vacuo to give (3R,4R)-3,4-dibenzyloxypyrrolidine (19.7 g, yield: 96%) as an oil.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OS(O)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([C:28]2([C:34]([CH:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:37](OCC)=[O:38])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:24]=[CH:25][C:26]=1[F:27]>CCOC(C)=O>[F:27][C:26]1[CH:25]=[C:24]2[C:23](=[CH:22][C:21]=1[F:20])[C:28]1([CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:34](=[O:35])[C:36]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:37]2[OH:38]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(F)c(F)c2)CCOCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cc(F)c(F)cc2C2(CCOCC2)C1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
P2O5 (4.45 g, 31.3 mmol) was added to H2SO4 (4.17 mL, 78.3 mmol), the mixture was cooled to 0° C., and diethyl 2-(4-(3,4-difluorophenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (3.01 g, 7.83 mmol) was added at 0° C. The reaction mixture was stirred for 4 hours and then poured into ice, diluted with 200 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 75 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound which was used without further purification. MS (m/z)=339 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1([C:30]2[NH:31]C3C=CC=C4C(=O)NCCC=2C=34)C=CC=CC=1.BrC1NC2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=CC(B(O)O)=CC=1)=O.CN>>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][C:14]([CH2:15][NH:31][CH3:30])=[CH:17][CH:18]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: CN
Agent: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23
Agent: O=Cc1ccc(B(O)O)cc1
Product: CNCc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1

Procedure:
4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 for 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with methylamine (1.62 mmol) as described for Compound PPP to yield 8-fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 32 mg (31%) as a yellow solid: m.p. 1543-155° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.28 (s, 3H), 3.04 (m, 2H), 3.40 (m, 2H), 3.69 (s, 2H), 7.32 (dd, J=9.0, 2.4 Hz, 1H), 7.44 (m, 3H), 7.57 (d, J=8.1 Hz, 2H), 8.25 (br t, 1H), 11.67 (br s, 1H). HRMS (MALDI MH+) Calcd for C19H18N3OF: 324,1512. Found: 325.1524. Anal. (C19H18N3OF.0.3 H2O) C, H, N.
Reaction SMILES: [CH2:1]([C:3]1([OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH3:10])[CH3:2].C([Li])CCC.CCCCCC.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>CCOCC>[C:23]([O:11][C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH3:10])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)Cl
Reactant: CCC1(O)CCCCC1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C(C)C(=O)OC1(CC)CCCCC1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-ethyl-2-methoxycyclohexanol from the previous step (10 g, 0.063 mole) in 50 ml ether was placed in a three neck flask equipped with a water condenser, addition funnel and a nitrogen inlet. This solution was cooled in an ice/water bath and n-butyllithium, 1.6 molar in hexane (45 ml, 0.072 mole) was added dropwise. The contents were allowed to warm to room temperature and stirred for 30 minutes. The mixture was cooled again in ice/water bath and methacryloyl chloride (7.31 g, 0.070 mole) in 25 ml ether was added dropwise and heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature and quenched with 125 ml of deionized water. The organic phase was separated and the water phase was extracted with 50 ml ether. The combined ether solutions were washed with 100 ml brine and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator and the crude product was chromatographed on a neutral alumina column using hexane as elutant. The product was a clear liquid (9.79 g) which was characterized by NMR and IR.
Reaction SMILES: C[CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][C:35]=4[F:63])[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[OH:64])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[Li+].[OH-]>C1COCC1.CO>[OH:64][C@@H:14]1[CH2:15][C@H:16]2[C@:21]([CH3:22])([CH2:20][CH2:19][C@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]3[CH:39]=[CH:38][C:37]([C@H:40]4[CH2:57][C@@:55]5([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]5([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]5[C:41]4=[C:42]4[C:47]([CH2:48][CH2:49]5)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]4)=[CH:36][C:35]=3[F:63])[CH3:33])[CH2:17]2)[C@@H:23]2[C@@H:13]1[C@H:12]1[C@:26]([CH3:27])([C@@H:25]([OH:28])[CH2:24]2)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:2][C:3]([OH:5])=[O:4])[CH2:10][CH2:11]1
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](O)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)c(F)c3)C[C@@]21C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](O)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]45)c(F)c3)C[C@@]21C
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
The compound of Example 3D (360 mg, 0.408 mmol) was dissolved in 6 ml of THF and CH3OH (1:1). Then 2.5 ml of LiOH solution (1M, aqueous) was added at 0° C. The resulting mixture was stirred for 5 hour at ambient temperature. The organic solvent was removed in vacuo, and enough water was added to make one phase. The solution was acidified with acetic acid to precipitate a light yellow solid, which was extracted with EtOAc (3 times). The combined organic layer was washed with brine and dried over Na2SO4 Concentration in vacuo gave the title compound (350 mg, 98% yield). 1H NMR (300 MHz, CDCl3) δ 6.83–6.74 (m, 3 H), 5.78 (s, 1 H), 4.34 (d, J=7.2 Hz, 1 H), 3.98 (m, 1 H), 3.84 (m, 1 H), 3.52–3.33 (m, 5H), 2.92 (s, 3H), 2.80–1.10 (m, 44H), 1.89 (s, 3H), 0.99 (d, J=6.0 Hz, 3 H), 0.89 (s, 3 H), 0.69 (s, 3 H), 0.55 (s, 3 H); MS (ESI) m/e 868 (M+H)+, 866 (M−H)—.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[C:25]([C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:42][C:41]([C:43]([OH:45])=O)=[C:40]([CH3:46])[CH:39]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1)(=[O:27])[NH2:26].[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>>[C:25]([C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:42][C:41]([C:43]([NH:50][CH2:51][C:52]4[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=4)=[O:45])=[C:40]([CH3:46])[CH:39]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1)(=[O:27])[NH2:26]
Reactant: Cc1cc(N2CCN(Cc3ccc(C(N)=O)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(C(N)=O)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 71 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-carbamoylbenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a cream solid in 71% yield: mp 188° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.45 (d, J=4.0 Hz, 1H), 8.31, (t, J=5.8 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.42-7.32 (m, 4H), 6.24 (s, 1H), 4.44 (s, 2H), 4.39 (d, J=5.8 Hz, 2H), 3.84 (t, J=7.8 Hz, 2H), 3.45 (t, J=7.8 Hz, 2H), 2.37 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.5, 162.9, 155.5, 148.8, 147.8, 140.0, 139.0, 135.4, 135.0, 133.4, 127.7, 127.4, 123.3, 119.9, 112.0, 46.8, 42.5, 41.5, 15.7; MS (ES+) m/z 450.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][CH2:14][C:15]([C:17]4[CH:21]=[CH:20][N:19]([Si](C(C)C)(C(C)C)C(C)C)[CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][CH2:14][C:15]([C:17]4[CH:21]=[CH:20][NH:19][CH:18]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(F)ccc2/C1=C1/C=C(c2cc[nH]c2)CO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of (3E)-6-fluoro-3-{4-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]furan-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one (Example 33; 90 mg) in a mixture of trifluoroacetic acid (7 mL) and CH2Cl2 (7 mL) was stirred at room temperature for 3 days. The mixture was evaporated to dryness, and re-dissolved in 1:1THF/MeOH (6 mL). The solution was slowly added into diluted NaHCO3 solution (100 mL) with stirring. The precipitates were filtered, washed with water, and dried in vacuum to give (3E)-6-fluoro-3-[4-(1H-pyrrol-3-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as brown solid. Yield: 40 mg.