Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1.C[O-].[Na+].N1C=CC=C[C:19]1=O>CN(C)C=O.CO>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH3:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: O=c1cccc[nH]1
Reactant: O=c1[nH]cc(-c2ccncn2)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccncn2)cc(Br)c1=O
Temperature: 60 °C

Procedure:
20 g of 3-bromo-5-(4-pyrimidyl)-2(1H)-pyridone are suspended in 200 ml of dimethylformamide. A solution of 4.6 g of sodium methoxide in 300 ml of dry dimethylformamide and 15 ml of methanol is added to the pyridone suspension with stirring. The reaction mixture is filtered, 5.3 ml of methyl iodide are added to the filtrate and the mixture heated to 60° C. for 2 hours. After cooling to RT, the solution is concentrated in vacuo resulting in a liquid residue which crystallizes out upon addition of distilled H2O. The solid is stirred with 400 ml of distilled H2O, filtered, washed with H2O, isopropyl alcohol, and ether and dried, yielding 3-bromo-1-methyl-5-(4-pyrimidyl)-2-pyridone, M.P. 208°-210° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][C:2]=1[OH:12].[CH2:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl.CN1C(=O)CCC1>C(O)(C)C>[CH3:15][C:14]([CH3:17])([CH3:16])[CH2:13][NH:18][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:2]([OH:12])[CH:3]=1
Reactant: CC(C)(C)CN
Reactant: Oc1cc(O)c2ccccc2n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CC(C)O
Product: CC(C)(C)CNc1cc(O)nc2ccccc12
Temperature: 180 °C
Reaction time: 1 h

Procedure:
2,4-Quinolinediol (15 g, 93 mmol), neopentyl amine (33 mL, 280 mmol), 6 N HCl in isopropanol (15 mL), and 40 mL NMP were place in a sealed tube and heated to 180° C. for 40 h. The reaction was then poured onto water (800 mL), stirred for 1 h and filtered. The cake was washed with water, collected and dried in vacuo (50 mTorrr, 60° C.) to afford 17.85 g (81.5%). 1H NMR (360 MHz, DMSO): 0.97 (s, 9H), 3.02(d, 2H, J=6.06 Hz), 5.41(s, 1H), 6.58(t, 1H, J=6.06 Hz), 7.08(t, 1H, J=7.67 Hz), 7.21(d, 1H, J=8.07 Hz), 7.43(dd, 1H, J=7.67, 7.27 Hz), 8.03(d, 1H, J=8.07 Hz), 10.73(s, 1H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[C:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([CH:42]=[O:43])=[CH:37][CH:38]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CC(C)=O>[Cl:19][C:20]1[C:25]([CH:42]([C:36]2[CH:35]=[C:34]3[C:39]([CH:40]=[CH:41][C:32]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:33]3)=[CH:38][CH:37]=2)[OH:43])=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: Clc1cnccn1
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (0.820 mL, 0.686 g, 4.86 mmol) in dry THF (15 mL), cooled by CO2(s)/acetone, is added nBuLi (2.5M in hexanes; 1.95 mL, 4.88 mmol). The cooling bath is replaced with an ice/water bath for 15 min, and then the solution is re-cooled to −78° C. After 5 min, a solution of 2-chloropyrazine (0.370 mL, 0.475 g, 4.14 mmol) in THF (0.5 mL) is added. 25 min later, a solution of 2-phenylquinoline-7-carbaldehyde (890 mg, 3.82 mmol) in dry THF (7 mL) is added slowly over 5 min from a syringe which is then rinsed with THF (1 mL), and the mixture is stirred at −78° C. for 2 h and then warmed up to 0° C. for 0.5 h. The reaction is quenched by adding citric acid (0.25M aqueous solution). The mixture is extracted with EtOAc (4×30 mL), and the combined EtOAc extracts are washed with water, sodium bicarb solution, and brine and dried over MgSO4. The crude material is chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (4×50 mL, then 1-16)→2% EtOAc in CH2Cl2 (17-30)→5% (31-59)→7% (60-85)→10% (86-110)] to obtain the title compound as an off-white foam. 1H NMR (CDCl3, 400 MHz) δ 4.80 (d, J=7.6 Hz, 1H), 6.25 (d, J=7.6 Hz, 1H), 7.43-7.56 (m, 3H), 7.58 (dd, J=1.8, 8.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.06 (brs, 1H), 8.10-8.15 (m, 2H), 8.20 (d, J=8.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H). MS (ES+): m/z 348.0/350.0 (100/37) [MH+]. HPLC: tR=3.3 min (MicromassZQ, polar—5 min).
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[ClH:1].[ClH:1].[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][CH2:58]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(F)c34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cccc(F)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (104, see example 48) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[O:13][CH3:14].CN(CCN(C)C)C.C([Li])(C)(C)C.[Br:28]Br>C(OCC)C>[Br:28][C:5]1[C:4]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: BrBr
Reactant: COCOc1ccc(OC)c(OC)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COCOc1ccc(OC)c(OC)c1Br
Reaction time: 1 h

Procedure:
To a stirred solution of 1,2-bis(methyloxy)-4-{[(methyloxy)methyl]oxy}benzene (4.0 g) and TMEDA (3.93 ml) in dry diethyl ether (50 ml) was added tert-butyllithium (1.7M in pentane, 23.76 ml) at −70 C. The reaction was stirred at this temperature for 1 h before adding bromine (0.15 ml). This was allowed to stir at 0 C for 3 h. The reaction was quenched by addition of 20% aqueous sodium dithionite and extracted with ethyl acetate. The organics were washed with dilute hydrochloric acid, aqueous sodium bicarbonate, brine and dried over sodium sulphate to yield a crude product. This was purified through silica, eluting with 0-10% ethyl acetate in hexane to give the title compound, 1.4 g
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:16])[C:5]([C:8]([OH:15])([CH:12]([OH:14])[CH3:13])[C:9]([OH:11])=[O:10])(O)[N:6]=1>C(O)C>[NH2:1][C:2]1[N:6]=[C:5]([C:8]([OH:15])([CH:12]([OH:14])[CH3:13])[C:9]([OH:11])=[O:10])[C:4](=[O:16])[N:3]=1
Reactant: CC(O)C(O)(C(=O)O)C1(O)N=C(N)NC1=O
Solvent: CCO
Product: CC(O)C(O)(C(=O)O)C1=NC(N)=NC1=O
Yield: 22 %

Procedure:
A solution of 2 g of the crude compound of Example 18 (8.23 mmol), solubilized in 80 ml of anhydrous ethanol, is refluxed for one hour. After evaporation and purification on silica gel (eluent: 35% MeOH/5% H2 O/CH2Cl2 then 40% MeOH/5% H2O/CH2Cl2) 400 mg are obtained with a yield of 22%.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:11])[CH3:10]
Reactant: NC(=O)c1nc[nH]n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1nc(C(N)=O)n[nH]1

Procedure:
A mixture of 0.2 g. of 1,2,4-triazole-3-carboxamide and 0.5 ml. of acetic anhydride is heated on an oil bath at a temperature of 150° C. for 20 minutes. The wet solid mass is triturated with diethyl ether and collected and washed with diethyl ether yielding 0.2 g. of colorless solid. This solid is recrystallized from acetonitrile giving a colorless solid, m.p. 212°-215° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][NH:13][C:14](=[S:15])[NH2:16])=[O:11])=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: NC(=S)NNC(=O)Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 67.8 %

Procedure:
5 g of 4-fluorophenylacetic acid (32.44 mmol, 1 eq.) are placed in 50 mL of dichloromethane with stirring. 3.25 g of thiosemicarbazide (35.68 mmol, 1 eq.), 4.38 g of hydroxybenzotriazole (32.44 mmol, 1 eq.) and 6.22 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32.44 mmol, 1.2 eq.) are successively added with continued stirring at room temperature. After 18 hours at room temperature, the dichloromethane is evaporated off. The residue is taken up in ethyl acetate, washed three times with water, once with brine and three times with 1N hydrochloric acid. The organic phase is dried over sodium sulfate and evaporated to give 5 g of 2-[(4-fluorophenyl)acetyl]hydrazinecarbothioamide. M-isobutene+=228.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)c(Cl)c1
Temperature: 50 °C
Yield: 99.7 %

Procedure:
To methyl 2-chloro-4-methylbenzoate (1.00 g, 5.42 mmol) in THF (10 mL) MeOH (5 mL) and H2O (2.5 mL) is added 2N LiOH (8.12 mL, 16.2 mmol). The reaction mixture is heated at 50° C. for 2.5 hr, cooled to room temperature, then quenched with 5N HCl (3.24 mL). The mixture is concentrated to remove the TBF and MeOH. A white precipitate is formed and is filtered. After drying, 0.922 g (100%) of 2-chloro-4-methylbenzoic acid is isolated. ESIMS m/e 169 (M−−1; 35Cl) and 171 (M−−1; 37Cl).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Li+].Cl>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(Cc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(Cc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
0.65 g (1.3 mmol) of methyl 3-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-ethoxypropionate is placed in 10 ml of tetrahydrofuran, 0.5 ml of methanol and 1.9 ml (1.9 mmol) of aqueous 1M lithium hydroxide solution. After stirring at room temperature for 2 hours, the reaction medium is diluted with ethyl acetate, acidified to pH 6 with aqueous 1N hydrochloric acid solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated. 0.54 g of 3-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-ethoxypropionic acid is obtained in a yield of 92%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[C:15]([O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O.C(O)C.C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([C:25]2[CH:26]=[CH:27][C:22]([C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:21])=[CH:23][CH:24]=2)=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cnc(N)nc2)cc1
Temperature: 120 °C
Yield: 86.6 %

Procedure:
Sodium carbonate (0.636 g, 6.0 mmol) in water (2.0 mL) was added to a mixture of 5-bromopyrimidin-2-amine (0.348 g, 2.0 mmol), [4-(tert-butoxycarbonyl)phenyl]boronic acid (0.533 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) in ethanol (3 mL) and toluene (3 mL). The mixture was heated at 120° C. for 3 h. After cooling to RT, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (470 mg, 86.6%) which was directly used in next step. LCMS: (M+H)=272.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[O:15]>>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:16][C:14](=[O:15])[C:13]([OH:18])=[O:17]
Reactant: COc1cccc(C=O)c1OC
Reactant: CC(=O)C(=O)O
Product: COc1cccc(C=CC(=O)C(=O)O)c1OC

Procedure:
The condensation reaction between 2,3-dimethoxy-benzaldehyde and pyruvic acid in the presence of a base to yield 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid is well known.
Reaction SMILES: C[C@@H:2]([NH2:32])[C@H:3]1[O:8][C@H:7]([O:9][C@H:10]2[C@H:15]([OH:16])[C@@H:14]([O:17][C@H:18]3[O:23][CH2:22][C@@:21]([OH:25])([CH3:24])[C@H:20]([NH:26][CH3:27])[C@H:19]3[OH:28])[C@H:13](O)[CH2:12][C@@H:11]2[NH2:30])[C@H:6]([NH2:31])[CH2:5][CH2:4]1.C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2O)OC1.C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CNC)CC[C@H]3N)[C@@H](N)C[C@H]2O)OC1>>[CH3:24][C@@:21]1([OH:25])[C@H:20]([NH:26][CH3:27])[C@@H:19]([OH:28])[C@@H:18]([O:17][C@@H:14]2[C@@H:15]([OH:16])[C@H:10]([O:9][C@H:7]3[O:8][C@H:3]([CH2:2][NH2:32])[CH2:4][CH2:5][C@H:6]3[NH2:31])[C@@H:11]([NH2:30])[CH2:12][CH2:13]2)[O:23][CH2:22]1
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)N)CC[C@H]3N)[C@@H](N)C[C@H]2O)OC[C@]1(C)O
Agent: CNC[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@](C)(O)[C@H](NC)[C@H]3O)[C@H](O)C[C@@H]2N)O1
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2O)OC[C@]1(C)O
Product: CN[C@@H]1[C@@H](O)[C@@H](O[C@H]2CC[C@H](N)[C@@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H]2O)OC[C@]1(C)O

Procedure:
SU-1, upon termination, fires single shot 658 yielding SU-2, which shifts the shift register 480 one bit position and increments the counter 482 one count. This is the same type of shift and look as employed in the SP sequence. SU-3 following SU-2 tests the counter 482 for 7. If not 7, line 286 is potentialized, firing single shot 662 to produce SU-4. Pulse SU-4 opens gate 540 (FIG. 3N) to test the shifted bit in shift register 480 for 0 or 1. If 0, line 290 is hot to fire single shot 658 via OR 656 to repeat the shift, count, and test routine until a 1 is detected. This 1 test at SU-4 potentializes line 288 to fire single shot 666 to yield the SU-5 pulse, which pulse gates the output of the counter 482 by means of OR 486 and gate 548 to cable 224 and destination register 454 (FIG. 3S).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:21]([CH:27]4[CH2:29][CH2:28]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:30]([N:33]1[CH2:37][CH2:36][NH:35][C:34]1=[O:38])(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:37][CH2:36][N:35]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH:24]5[CH2:26][CH2:25]5)=[CH:22][C:21]([CH:27]5[CH2:29][CH2:28]5)=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:34]1=[O:38])(=[O:32])[CH3:31]
Reactant: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)c(C#N)c2)C1=O
Yield: 47.1 %

Procedure:
Using 5-bromo-2-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.35 g) described in Preparation Example 245 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (702 mg) was obtained.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([Br:16])[N:6]=1)=[O:4].[CH3:17][S:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>>[CH3:17][S:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7]([Br:16])[N:6]=1)=[O:4]
Reactant: CSc1ccccc1CN
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Product: CSc1ccccc1CNC(=O)c1nc(Br)c2cccnc2c1O
Temperature: 25 °C

Procedure:
To a 25 mL round bottomed flask with a stirring bar, reflux condenser and a nitrogen inlet was added 5-bromo-8-hydroxy-[1,6]naphthyridine-7-carboxylic acid methyl ester (0.511 g, 1.81 mmol) dry toluene (12.5 mL) and 2-methylthiobenzylamine (0.346 g, 2.26 mmol). This mixture was heated at reflux for 24 h. The mixture was cooled to ambient temperature and the toluene was removed in vacuo. The residue was triturated with a little Et2O/hexane, collected on a frit and dried in vacuo to give 8-hydroxy-5-bromo-[1,6]naphthyridine-7-carboxylic acid 2-methylsulfanylbenzylamide as a crystalline solid.
Reaction SMILES: [C:1]1([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=3)[C:16](=[O:26])[NH:15][C:14]2=[O:27])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.B(Br)(Br)Br>ClCCl>[C:1]1([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)[C:16](=[O:26])[NH:15][C:14]2=[O:27])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COc1cccc([C@@H]2C(=O)NC(=O)[C@H]2c2cn3c4c(cccc24)CCC3)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1cccc(O)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-methoxyphenyl)pyrrolidine-2,5-dione in dichloromethane (10 mL) at −78° C. under an atmosphere of nitrogen was slowly added boron tribromide (1.0 M in dichloromethane) (5.2 mL). The resulting mixture was stirred at −78° C. for 30 minutes and at room temperature for 3 hours. The reaction mixture was cooled to −78° C. then quenched by the addition of methanol (5 mL). The mixture was allowed to warm to room temperature and maintained at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane (80 mL), washed with saturated aqueous sodium bicarbonate (15 mL), water (15 mL) and saturated sodium chloride (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate:hexane:dichloromethane (5:5:1, v/v) to give (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-hydroxyphenyl)pyrrolidine-2,5-dione as a brown solid (1.15 g, 63%); Mp 108-110° C. 1H NMR (CDCl3) 400 MHz δ: 8.69 (s, 1H), 7.18 (t, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 6.99 (d, 1H, J=6.8 Hz), 6.97 (d, 1H, J=2.0 Hz), 6.93 (d, 1H, J=6.4 Hz), 6.76 (m, 1H), 6.69 (d, 1H, J=1.6 Hz), 5.67 (brs, 1H), 4.32 (d, 1H, J=6.0 Hz), 4.20 (d, 1H, J=6.0 Hz), 4.07 (t, 2H, J=5.6 Hz), 2.96 (t, 2H, J=6.0 Hz), 2.19 (m, 2H), LC/MS: 347.3 [M+H].
Reaction SMILES: Cl.[F:2][C@H:3]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=2)[C:20]1=[O:33].CCN(C(C)C)C(C)C>CN(C=O)C>[F:2][C@H:3]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][N:5]([CH:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=3)[C:20]2=[O:33])[CH2:4]1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Reactant: COc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@H]2F)cc1F
Temperature: 120 °C
Yield: 126.1 %

Procedure:
A mixture of (3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride (30 mg, 0.11 mmol, from step G), 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.19 mmol, intermediate 6,) and DIPEA (0.02 mL, 0.11 mmol) in DMF (3 mL) was heated to 120° C. for 90 min in a microwave reactor. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure to obtain 60 mg of 3-((3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one (diastereomeric pair), which was used in the next step without purification. LCMS (Method P) RT=1.12 min, m/z 433 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([F:14])[CH:8]=1.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][NH2:26]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([F:14])[CH:8]=2)[N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[Cl:18])[N:26]=1)=[O:16]
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)c(F)c1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
4-(4-bromo-3-fluoro-phenyl)-2-oxo-3-butenoic acid methyl ester (665.0 mg, 2.3 mmol) prepared in Step 2 and 2-chlorophenylhydrazine hydrochloride (455.0 mg, 2.6 mmol) were added to acetic acid (10.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 835.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].OO.C(=O)([O-])[OH:12].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C([O-])O
Reactant: Cc1ccncc1C
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc[n+]([O-])cc1C
Temperature: 75 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Firstly, under an argon gas atmosphere, 27.3 g of 3,4-dimethylpyridine (Aldrich) (255 mmol) in 150 mL acetic acid solution was cooled on ice, and 25 mL of 35% hydrogen peroxide aqueous solution was added thereto, stirred at 75° C. for 3 hours. Then additional 17.5 mL of 35% hydrogen peroxide aqueous solution was added and stirred at 75° C. for 3 hours. The reaction solution was neutralized by adding an aqueous solution of sodium hydrogen carbonate, extracted with methylene dichloride. The extract was dried on salt cake and concentrated to give a solid. The obtained solid was washed with ethyl acetate to give 29.55 g of 3,4-dimethylpyridine-N-oxide (94% yield).