Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:23])[N:9]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:23])[N:9]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=4)[N:10]=[C:4]3[C:3]=2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:33][CH:32]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccc(F)cc1
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: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(F)cc3)ccn2c1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a suspension of 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (135 mg, 0.32 mmol), 4-fluorophenylboronic acid (180 mg, 1.29 mmol), and 2.0 M aqueous sodium carbonate (0.70 mL) in toluene (2.5 mL) was added (Ph3P)4Pd (55 mg, 0.048 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 2 h. Analysis by HPLC/MS indicated about 10% of the starting 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one remained. Additional catalyst (15 mg, 0.013 mmol) was added. The reaction mixture was stirred at 100° C. for 1 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-80%) in hexanes to afford the desired product, which was contaminated with triphenylphosphine oxide. The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 15 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The yellow residue was dissolved in acetonitrile, frozen and lyophilized to afford 66 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.49 min, [M+H]+=480.0.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 42 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and ethyl chloroformate. Yield: 42% of theory, C28H29N7O5 (543.6) Rf value: 0.20 (silica gel; dichloromethane/ethanol=19:1) EKA mass spectrum: (M+H)+ =544
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:17][C@@H:16]2[CH3:33])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.C(Cl)Cl.[C:46](Cl)(=[O:48])[CH3:47]>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1)[C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:18]([N:25]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:46](=[O:48])[CH3:47])[CH2:17][C@@H:16]1[CH3:33])=[O:14]
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of (3,5-bis(trifluoromethyl)phenyl)((2S,4R)-4-(4-chlorophenylamino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)methanone (19.44 g, 0.037 mol) in acetyl chloride (5 mL) was cooled to 0° C. and triethylamine (6.59 mL, 0.037 mol) was added dropwise over 30 min, a precipitate forms during this time. An additional 250 mL of methylene chloride was added to completely dissolve all the precipitate. The reaction was allowed to stir overnight at room temperature. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate and 1N sodium hydroxide while cooled to 0° C. The aqueous layer was extracted 3 times with ethyl acetate washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-((2S,4R)-1-(3,5-bis(trifluoromethyl)benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-(4-chlorophenyl)acetamide (H-31) (18.2 g, 86%).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:27])[C:16]([C:18]2C3C(=NC=CC=3)[NH:20][CH:19]=2)=[O:17])[C@H:11](C)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[N:31]=[CH:32][C:33]([O:44][CH3:45])=[C:34]2[C:38]=1NC=C2C(=O)C([O-])=O.[K+]>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:27])[C:16]([C:18]2[C:34]3[C:38](=[C:30]([Cl:29])[N:31]=[CH:32][C:33]=3[O:44][CH3:45])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)[O-])c12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Agent: [K+]
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12

Procedure:
Compound 5an, N-(benzoyl)-N′-[(7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetyl]-piperazine was prepared by the same method which was used to prepare compound 5a except that Potassium (7-chloro-4-methoxy-6-azaindol-3-yl)-oxoacetate was employed as the starting material to give a white solid. The compound was purified by silica gel chromatography using EtOAc as the eluting solvent. MS m/z: (M+H)+ calcd for C21H20ClN4O4: 427.12; found 427.12. HPLC retention time: 1.28 minutes (column A).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:10][O:11][C:12](=[O:33])/[CH:13]=[CH:8]/[C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.045 g (27.12 mmol) of 6-bromopyridine-3-carbaldehyde were dissolved in 50 ml of THF. 9.068 g (27.12 mmol) of 2-(triphenylphosphoranylidene)acetic acid methyl ester were added and the mixture was stirred at RT for 4 hours. After evaporation, the residue stirred with methanol and the solid was filtered off. The filtrate was evaporated and the residue was purified by chromatography (silica gel, ethyl acetate/n-heptane 1:4). Yield: 5.01 g (76.3%)
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].NCCC(O)=O.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C.O>[CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[C:4](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: NCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1
Yield: 84.7 %

Procedure:
A suspension of 100 kg of 4-methyl-3-oxo-N-phenylpentanamide (Example B) in 660 kg of hexanes is treated with agitation under nitrogen with 8 kg of β-alanine, 47 kg of benzaldehyde, and 13 kg of glacial acetic acid. The resulting suspension is heated to reflux with removal of water for 20 hours. An additional 396 kg of hexanes and 3 kg of glacial acetic acid is added and reflux continued with water removal for one hour. The reaction mixture is cooled to 20°-25° C. and the product is isolated by filtration. The product is purified by slurrying in hexanes at 50°-60° C., cooling, and filtration. The product is slurried twice with water at 20°-25° C., filtered, and dried in vacuo to yield 110 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, mp 143.7°-154.4° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][S:6][C:5]1=[N:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=1.[Br:20]N1C(=O)CCC1=O>O1CCOCC1.C(OCC)(=O)C>[Br:20][C:7]1[S:6][C:5](=[N:9][C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[N:4]([CH2:3][O:2][CH3:1])[CH:8]=1
Reactant: COCn1ccsc1=Nc1cccc(C(=O)OC)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCn1cc(Br)sc1=Nc1cccc(C(=O)OC)n1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
6.38 g (20.6 mmol) of methyl 6-(3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridine-2-carboxylate was dissolved in 60 ml of 1,4-dioxane and 3.67 g (20.6 mmol) of N-bromosuccinimide was added thereto at room temperature. The reaction mixture was heated under reflux for 30 minutes, cooled to room temperature, diluted with 200 ml of ethyl acetate and washed with 150 ml of water for three times. After that, the reaction mixture was washed with 150 ml of brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give 7.10 g (19.8 mmol) of the title compound as a white solid.
Reaction SMILES: [C:1]([C@H:4]([O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1)[CH3:5])([OH:3])=O.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51]>>[C:50]([NH:49][CH2:48][CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:40][C:1]([C@H:4]([O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:8]1)[CH3:5])=[O:3])(=[O:52])[CH3:51]
Reactant: CC(=O)NCCc1ccccc1N
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O[C@H](C)C(=O)O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O[C@H](C)C(=O)Nc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Example 3a, 0.165 g of tert-butyl 3-(1(R)-carboxyethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1 carboxylate and 0.066 g of N-[2-(2-aminophenyl)ethyl]acetamide (Example 34c) are reacted. The title compound is obtained as a yellow oil. Rf=0.22 (95:5 dichloromethane-methanol); Rt=5.34.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:8](=[O:9])[C:7]([O:10][CH3:11])=[CH:6][C:5]([C:12]#[N:13])=[CH:4]1.C[O-].[Na+].CO.CS(O)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C@@:31]([C:36]2[CH:37]=[N:38][C:39]([F:42])=[CH:40][CH:41]=2)(N)[C@@H:32]([NH2:34])[CH3:33])=[CH:27][CH:26]=1>CO>[CH2:2]([N:3]1[CH:4]=[C:5]([C:12]2[NH:34][C@@H:32]([CH3:33])[C@:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)([C:36]3[CH:37]=[N:38][C:39]([F:42])=[CH:40][CH:41]=3)[N:13]=2)[CH:6]=[C:7]([O:10][CH3:11])[C:8]1=[O:9])[CH3:1]
Reactant: CCn1cc(C#N)cc(OC)c1=O
Reactant: C[C@H](N)[C@](N)(c1ccc(F)cc1)c1ccc(F)nc1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1cc(C2=N[C@@](c3ccc(F)cc3)(c3ccc(F)nc3)[C@H](C)N2)cc(OC)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 2.5 %

Procedure:
1-ethyl-3-methoxy-2-pyridone-5-carbonitrile (30 mg) was dissolved in methanol (1 mL), and 25% sodium methoxide-methanol solution (6.6 mL) was added thereto. The mixture was stirred at room temperature for 17 hours, and methanesulfonic acid (11 μL) and a solution of (1S,2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine (44.5 mg) in methanol (1 mL) were successively added. The mixture was stirred at room temperature for two days and concentrated in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed with brine, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the organic solvent was evaporated in vacuo to give a residue, which was purified by column chromatography on silica gel (chloroform:methanol=10:1) to give the title compound (1.8 mg) as a brown solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH:24][C:26]4[CH:27]=[CH:28][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:30][CH:31]=4)[N:23]=3)[CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)cn3nc(N)nc23)cc1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cc(C(F)(F)F)cn4n3)cc2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(4-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (21% yield). MP 126-134° C. 1H NMR (400 MHz, (CDCl3, δ, ppm): 8.82 (s, 1H), 8.25 (d, J=7.8 Hz, 2H), 8.13 (d, J=7.3 Hz, 2H), 7.79 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H), 6.88 (s, 1H), 3.21 (bm, 4H), 3.13 (s, 3H), 2.66 (bm, 4H), 2.40 (s, 3H). MS=531.0 (MH)+.
Reaction SMILES: O.[C:2]1(=[O:8])O[C:5](=[O:6])[CH:4]=[CH:3]1.[CH2:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].P(=O)(O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:9]([N:21]1[C:5](=[O:6])[CH:4]=[CH:3][C:2]1=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCN1C(=O)C=CC1=O
Temperature: 215 °C

Procedure:
A glass flask having an inner volume of 3 liters was fitted with a thermometer, a stirrer, and a water separator. In this reactor, 240 g of a solution containing 120 g of maleic anhydride in xylene was placed. Then, a solution containing 220 g of dodecylamine in 1880 g of xylene was added gradually and piecemeal over a period of 120 minutes at 40° C. to the reactor. After the addition was completed, the mixture in the reactor and 65.4 g of orthophosphoric acid (purity 89% by weight) added thereto were heated at 215° C. for 1 hour under 4.4 kg/cm2. G to effect reaction. The resultant reaction mixture was cooled to 30° C., washed with 400 ml of water, and separated into a water layer and a xylene layer. The xylene layer was separated by filtration to effect removal of insolubles. The xylene layer was distilled to expel xylene. Consequently, there was obtained 258 g of slightly impure N-dodecyl maleimide. This product was found to have purity of 85.3% by weight, indicating the yield to be 69.9 mol % based on dodecylamine.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=2)=[C:5]([O:23]C)[CH:4]=1)#N.C[S-].[Na+].O.Cl.[CH3:30][N:31](C)C=O>C(OCC)C>[C:30]([C:8]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:21])([CH3:22])[CH:10]=2)[CH:7]=1)#[N:31]
Reactant: COc1cc(C#N)ccc1C1=CC(C)(C)Oc2ccc(C#N)cc21
Reactant: CN(C)C=O
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)C=C(c2cc(C#N)ccc2O)c2cc(C#N)ccc2O1
Temperature: 25 °C

Procedure:
1.58 g of 4-(4-cyano-2-methoxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 1.05 g of sodium methanethiolate were heated at 100° C. for 20 minutes in 15 ml of dimethylformamide. The mixture was allowed to cool to room temperature and then poured into water and diethyl ether. The aqueous phase was acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed three times with water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (2:3) for the elution. After o recrystallization of the product from toluene there were obtained 1,1 g of 4-(5-cyano-2-hydroxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile of melting point 213°-215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[CH2:13]([C:12]1[C:11]2[C:2](=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=2)[NH:1][N:15]=1)[CH3:14]
Reactant: CCCc1ccc(C(=O)OC)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
To a solution of methyl 3-amino-4-propylbenzoate (5.07 g) in acetic acid (150 ml) was dropwise added a solution of sodium nitrite (2.07 g) in water (5 ml) for 5 min. After stirring for 20 min, the reaction mixture was concentrated, and then toluene and a saturated aqueous sodium hydrogencarbonate solution were added to the residue. The separated toluene layer was dried over sodium sulfate and concentrated. The residue was allowed to stand and partially solidified. The solid was washed with hexane and dried to give the object compound (2.44 g) as a brown solid.
Reaction SMILES: [OH-:1].[Na+].BrBr.[F:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C>O.O1CCOCC1>[F:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:1]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)c(F)c1
Yield: 82.7 %

Procedure:
23.30 g of sodium hydroxide was dissolved in 118 mL of water and was ice-cooled, to which 9.23 mL of bromine was added dropwise over 20 minutes and then a solution of 9.80 g of 1-(2-fluoro-4-methoxyphenyl)-1-ethanone in 88 mL of 1,4-dioxane was added dropwise over one hour at −10° C. The resultant reaction mixture was cooled to room temperature, to which water was added, and then an aqueous phase was separated therefrom. A solution of 7.23 g of sodium thiosulfate in 100 mL of water was added to the aqueous phase, and then 12M hydrochloric acid was further added until the pH value of this aqueous phase reached 2. The resultant precipitate was filtered therefrom and washed with water to yield 8.20 g of 2-fluoro-4-methoxybenzoic acid as white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:17][CH:18]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(CCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(CCOS(C)(=O)=O)cc1
Temperature: -10 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Tert-butyl [4-(2-hydroxyethyl)phenoxy]acetate (6.000 g, 23.781 mmol) and triethylamine (9.9 ml, 71.341 mmol) were dissolved in DCM. The mixture was cooled to −10° C. and methanesulfonyl chloride (2.8 ml, 35.671 mmol) was added dropwise to the mixture. The reaction mixture was allowed to reach room temperature and was stirred for 16 hours. The mixture was diluted with DCM. The organic layer was washed with water, brine and 0.3M KHSO4, dried with MgSO4, and evaporated under reduced pressure. Obtained 7.5 g of light-yellow crystals (yield 95.5%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[CH2:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:28][CH:27]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: CCN1CCNCC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.54 mmol) in dichloromethane (30 mL) was added acetic acid (1 mL) followed by the addition of 1-ethylpiperazine (121 mg, 1.63 mmol). After the addition, the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. NaBH(OAc)3 (173 mg, 0.81 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. dichloromethane was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give 8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (135 mg, yield 47%) as white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.22 (t, 3H), 2.36-2.44 (m, 1H), 2.74-3.11 (m, 8H), 4.01-4.10 (m, 3H), 4.33 (dd, 1H), 4.78 (dd, 1H), 7.13-7.31 (m, 10H), 7.37 (d, 1H), 7.47 (s, 1H), 7.58 (t, 3H); LC-MS (ESI) m/z: 452 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1[O:22][CH2:21]1.O>CO>[OH:22][CH2:21][CH2:20][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1
Reactant: C1CO1
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Solvent: O
Solvent: CO
Product: OCCN1CCOC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 2 h

Procedure:
The mixture of 6.5 g of 7,7-diphenyl-hexahydro-1,4-oxazepine, 1.2 g of ethylene oxide, 0.5 ml of water and 20 ml of methanol is stirred at 40°-45° for 4 hours and at 50° for 21/2 hours. It is cooled, the precipitate formed, filtered off and recrystallized from benzene-hexane, to yield the 4-(2-hydroxyethyl)-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 122°-123° (its hydrochloride melts at 190°-192°).