Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.[ClH:24]>C(Cl)Cl>[ClH:24].[ClH:24].[CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Yield: 99 %

Procedure:
(R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was treated with HCl (4M in dioxane, 6 mL) in DCM (20 mL) for 6 hours to provide (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.55 g, 99%). MS (APCI+) [M+H] +219.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@:6]([O:18][CH3:19])([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@:4]([C:21]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[O:23][N:22]=2)([CH3:20])[CH2:3]1.[Na].[CH3:34]I>CS(C)=O>[CH3:34][N:12]1[C:11]2[C:17]3[C:14]([CH2:15][C@@H:16]4[C@@:6]([O:18][CH3:19])([C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@:4]([C:21]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Br:32])[CH:31]=3)[O:23][N:22]=2)([CH3:20])[CH2:3][N:2]4[CH3:1])=[CH:13]1
Reactant: CO[C@]12C[C@](C)(c3noc(-c4cncc(Br)c4)n3)CN(C)[C@@H]1Cc1c[nH]c3cccc2c13
Reactant: CI
Agent: [Na]
Solvent: CS(C)=O
Product: CO[C@]12C[C@](C)(c3noc(-c4cncc(Br)c4)n3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2 g of 6-methyl-8β-methyl-[5-(5-bromo-pyridin-3-yl)-1,2,4-oxadiazol-3-yl]-10α-methoxy-ergoline in ml 30 of dimethylsulphoxide was added at room temperature, 0.5 g of finely ground sodium hydroxyde. After stirring for 30 mins., a solution of 0.9 g of methyl iodide in m 10 of dimethylsulphoxide was added and the stirring was continued for 1 hour.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.C(O)(=O)C.N#N>CO.[Pd]>[C:10]([OH:12])(=[O:11])[CH3:9].[NH2:2][CH2:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)COc1ccc(C=NO)cc1
Agent: [Pd]
Agent: N#N
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)COc1ccc(CN)cc1
Reaction time: 12 h
Yield: 162.3 %

Procedure:
To a solution of methyl {4-[(hydroxyimino)methyl]phenoxy}acetate (30 g, 0.14 mol) in methanol (650 mL) was added glacial acetic acid (6.8 g) and passed N2 for 30 min. To this was added Pd/C (10%, 3 g) and hydrogenated under 2 bars of pressure for 12 h. The reaction mixture was concentrated under vacuum. The crude product was treated with EtOAc (500 mL) and the white product filtered off The solid was dried under vacuum to give the title compound (29 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH:5]=[C:4]([CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>CCOCC>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:24][C:25]([NH:1][C:2]1[N:7]=[C:6]([CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH:5]=[C:4]([CH3:13])[N:3]=1)=[O:26])(=[O:23])=[O:22]
Reactant: COC(OC)c1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: CCOCC
Product: COC(OC)c1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1
Yield: 76.2 %

Procedure:
A solution of 0.3 g of 2-amino-4-dimethoxymethyl-6-methylpyrimidine in 50 ml of ether was stirred overnight at room temperature with 0.46 g of o-chlorobenzenesulfonyl isocyanate. The product was filtered and washed with hexane to provide 0.5 g of the title compound, m.p. 150°-153°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH2:12].C(N(C(C)C)C(C)C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH:12][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: NNc1ccc([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NNc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Yield: 89.9 %

Procedure:
To a stirred and chilled (0° C.) solution containing 25 g (0.133 mol) of 2-chloro-4-nitrophenylhydrazine and 18.06 g (0.14 mol) of ethyldiisopropylamine in 200 ml of tetrahydrofuran was added dropwise 16.75 g (0.139 mol) of pivaloyl chloride. The reaction mixture was briefly heated to reflux and then concentrated under reduced pressure. The residue was treated with water, filtered and dried to give 32.5 g (90% yield) of the desired product as a yellowish solid; m.p. 123° C.
Reaction SMILES: CO[C:3]1[C:7]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:6][S:5](=[O:16])[N:4]=1.[CH3:17][N:18]([CH2:20][C:21]1[O:25][C:24]([CH2:26][S:27][CH2:28][CH2:29][NH2:30])=[CH:23][CH:22]=1)[CH3:19]>CO>[CH3:19][N:18]([CH2:20][C:21]1[O:25][C:24]([CH2:26][S:27][CH2:28][CH2:29][NH:30][C:3]2[C:7]([NH:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:6][S:5](=[O:16])[N:4]=2)=[CH:23][CH:22]=1)[CH3:17]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: COC1=NS(=O)N=C1NCc1cccnc1
Solvent: CO
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)N=C2NCc2cccnc2)o1
Reaction time: 18 h

Procedure:
To the methanol solution of 3-methoxy-4-(3-pyridyl)methylamino-1,2,5-thiadiazole 1-oxide produced in Step A was added a solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (4.0 g; 18.7 mmoles) in 30 ml of methanol. The reaction mixture was stirred at ambient temperatures for 18 hours and the solvent was removed in vacuo. The residue was placed on 500 g of silica gel (230-400 mesh) and purified by flash chromatography using a gradient elution of acetonitrile-methanol. After combining the appropriate fractions, the title compound was obtained as an amber oil (4.25 g) containing one mole of methanol.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][OH:19])[C@H:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13]2)[C:9]([F:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+]>O.CO.[Pd]>[F:26][C:9]1[C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][OH:19])[C@H:14]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13]2)=[N:11][CH:2]=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)c(N2CC[C@@H](CO)[C@H](c3ccccc3)C2)nc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cnc(N2CC[C@@H](CO)[C@H](c3ccccc3)C2)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To a mixture of 488 mg of methyl rel-2-chloro-5-fluoro-6-[(3R,4R)-4-(hydroxymethyl)-3-phenylpiperidin-1-yl]nicotinate, 428 mg of ammonium formate, and 12 mL of methanol was added 70 mg of 10% palladium/carbon while suspending it in 1 mL of water and 6 mL of methanol. The reaction mixture was vigorously stirred at 60° C. for 2 hours. After cooling to room temperature, the insolubles were filtered on a celite layer, and the filtrate was concentrated under reduced pressure. To the obtained residue was added chloroform, followed by washing with saturated aqueous sodium bicarbonate The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 283 mg of methyl rel-5-fluoro-6-[(3R,4R)-4-(hydroxymethyl)-3-phenylpiperidin-1-yl]nicotinate as a colorless foamy substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:13]([S-:15])#[N:14].[K+].BrBr>CC(O)=O>[NH2:14][C:13]1[S:15][C:7]2[CH:6]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: CC(C(=O)O)c1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2 (3.13 g, 1 mmol) in CH3COOH (15 ml) was cooled to −5° in iced bath. A mixture KSCN (6.36 g, 4.04 mmol) in CH3COOH (15 ml) added to the flask that contained 4 and CH3COOH at −5° in iced bath. A solution of bromine (0.80 ml) in CH3COOH (10 ml) is added dropwise to a stirred mixture of 4, KSCN and CH3COOH at −5° in iced bath. The reaction mixture is stirred for 1 h at room temperature. The mixture is extracted with ethyl acetate. The extracts are washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10](Cl)[CH:9]=1)=[O:7].[CH3:30][S-:31].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10]([S:31][CH3:30])[CH:9]=1)=[O:7]
Reactant: C[S-]
Reactant: COc1cccc2c1ccc1nc3cc(Cl)cc(C(=O)NCCN(C)C)c3nc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1ccc1nc3cc(SC)cc(C(=O)NCCN(C)C)c3nc12
Temperature: 60 °C
Yield: 42.3 %

Procedure:
A mixture of 9-chloro-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (85 mg) and sodium thiomethoxide (43 mg) in N,N-dimethylformamide (1 mL) was heated to 120° C. for 6 hours and 60° C. for 16 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield a yellow solid which was purified using flash chromatography to yield the desired title compound (37 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=1>CO>[C:25]([C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: COCCOCCn1ccc2c(Cl)ncnc21
Reactant: C#Cc1cccc(N)c1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3c2ccn3CCOCCOC)c1
Yield: 81 %

Procedure:
Following a procedure analogous to that described in Example 11, the title product was prepared in 81% yield from 4-chloro-7-[2-(2-methoxy-ethoxy)-ethyl]-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq) and m-aminophenyl acetylene (1.2 eq) in methanol: MP: 240-241° C.; LC-MS: 336 (M+); anal. RPP18-HPLC RT: 4.29 minutes.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[C:7]2[CH2:16][CH2:17][CH2:18][C:6]=2[N:5]3[CH2:4][CH2:3]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]2[CH2:16][CH2:17][CH2:18][CH:6]2[N:5]3[CH2:4][CH2:3]1
Reactant: CN1CCc2cccc3c4c(n(c23)CC1)CCC4
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2cccc3c2N(CC1)C1CCCC31
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of 3-methyl-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (0.40 g, 1.7 mmole) in acetic acid (50 mL) was added sodium cyanoborohydride (95 wt. %, 0.21 g, 3.2 mmole) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was diluted with ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate (150 mL) and saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 3:2) provided 0.40 g of the title compound as a light oil. 60 mg of this oil was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 159-161° C. MS (ESI) m/z 243 ([M+H]+).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1)([O-])=O.O>C1COCC1>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
to a solution of 0.82 g of 2-mercapto-5-methyl benzimidazole (5 mmoles) in 10 ml of dry THF is added 200 mg of sodium hydride suspension (60% suspension in mineral oil) (5 mmoles). The reaction mixture is heated at reflux temperature for ½ hour. The mixture is then cooled to room temperature and 0.71 g of 5-nitrofuraldehyde (5 mmoles) in 5 ml of THF is added dropwise. The reaction mixture is stirred for ½ hour and then poured into 200 ml of water. The mixture is extracted twice with 75 ml of EtOAc. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated. The crude product is purified on silica gel using DCM/MeOH 97/3 as eluent. 1.07 g of 5-(5-Methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is isolated as a black glassy solid (yield=83%). Analytical LC/MS method A: ([M+H]+): 259, RT: 3.64 min (gradient 0 to 50% acetonitrile in 7 min).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([Br:15])[C:12]([F:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].O>C1COCC1>[Br:15][C:11]1[C:12]([F:14])=[CH:13][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2cc(F)c(Br)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(F)c(Br)cc2s1
Yield: 9.1 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 25 for the preparation of I-25b above, 6-bromo-5-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester (I-27b: 0.3 g, 10 mmol) in THF (10 mL) was hydrolyzed with LiOH (87 mg, 2.04 mmol) and water (2 mL) to afford 250 mg of the product (yield 88%)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:25][CH2:26][CH:27]=C)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14].[O:29]=[O+][O-]>C(Cl)Cl.CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:25][CH2:26][CH:27]=[O:29])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:14]
Reactant: O=[O+][O-]
Reactant: C=CCCC(C(=O)NCCCc1ccccc1)N1C(=O)c2ccccc2C1=O
Solvent: CO
Solvent: ClCCl
Product: O=CCCC(C(=O)NCCCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Dissolve 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl-5-hexenylamine (1.2 g, 3.19 mmol) in methylene chloride (40 mL) and methanol (4 mL) and cool to -78° C. under a nitrogen atmosphere. Treat with ozone until a blue color persists, degas with nitrogen for 20 minutes and add pyridine (0.2 mL). Quench with dimethylsulfide (4 mL) and stir overnight at room temperature. Dilute with methylene chloride (75 mL) and wash with 5% sulfuric acid (40 mL) and brine (40 mL). Dry (Na2SO4), evaporate the solvent in vacuo and purify by chromatography (hexane/ethyl acetate) to give 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl-5-oxo-pentylamine as a white solid (972 mg, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH2:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](Cl)=[O:42])=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH:25][C:41](=[O:42])[CH2:40][C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC1(C)OCCn2c1nc(C(=O)NN)c(OCc1ccccc1)c2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCCn2c1nc(C(=O)NNC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To stirred solution of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbohydrazide (0.170 g, 0.49 mmol) and Et3N (0.14 mL, 1 mmol) in CH2Cl2 (10 mL) was added 2-(4-fluorophenyl)acetyl chloride (69 mL, 0.5 mmol) and the mixture stirred 2 h at room temperature. The reaction mixture was purified by preparative HPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford the title compound (0.078 g, 33% yield) as a white solid. 1HNMR (500 MHz, CDCl3) δ: 9.97 (1H, d, J=7.0 Hz), 8.42 (1H, d, J=6.7 Hz), 7.54 (2H, d, J=6.7 Hz), 7.35-7.27 (5H, m), 7.05 (2H, t, J=8.6 Hz), 5.36 (2H, s), 4.04-3.98 (4H, m), 3.64 (2H, s), 1.60 (6H, s). HRMS (M+H) calcd for C25H26N4O5F: 481.1887. found: 481.1866.
Reaction SMILES: B(Br)(Br)Br.COC1C=CC(N2CC[N:16]([CH2:19][C:20]3[CH:21]=[C:22]4[NH:31][C:30](=[O:32])[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]4[CH:33]=3)CC2)=CC=1>C(Cl)Cl.CO>[O:32]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]2[CH:33]=[C:20]([C:19]#[N:16])[CH:21]=[C:22]2[NH:31]1
Reactant: COc1ccc(N2CCN(Cc3cc4[nH]c(=O)c5ccccc5n4c3)CC2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc2[nH]c(=O)c3ccccc3n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Under cooling on ice, boron tribromide (0.100 mL, 1.04 mmol) was added to a solution of 2-[4-(4-methoxyphenyl)piperazin-1-ylmethyl]pyrrolo[1,2-a]quinazolin-5(4H)-one (the above Compound 2-16, 200 mg, 0.515 mmol) in methylene chloride (3.0 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with methanol (2.0 mL) under cooling on ice, and then concentrated under reduced pressure. The obtained residue was dissolved in 1M sodium hydroxide aqueous solution (2.0 mL), and 2M hydrochloric acid was added so that pH of the solution was 7. The precipitate was collected by filtration, and dried under reduced pressure, to obtain title Compound 3-1 (43.2 mg, yield: 22%) as an orange powder.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O[C@@H:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([O:26][C@H:28]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][CH:21]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Yield: 33 %

Procedure:
A solution of 4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenol (880 mg, 2.53 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (492 mg, 2.53 mmol), triphenylphosphine (665 mg, 2.54 mmol) and diethyl azodicarboxylate (442 mg, 2.54 mmol) in toluene (30 ml) was refluxed for 20 hours under heating. The residue was poured into water, extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 440 mg (yield: 33%)
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[C:10]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2])(=[O:12])[CH3:11]
Reactant: CCc1ccccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CCc1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
commercial 2-ethylaniline (50 mL, 0.40 mol) was dissolved in acetic anhydride (160 mL, 1.70 mol) and stirred at room temperature for 2 h. Then the reaction mixture was poured into H2O, the whole was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with 5% aqueous NaHCO3, brine, dried (K2CO3), filtered and concentrated to provide the title compound as a white solid (60.0 g, 92%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:29]=[C:30]([Cl:35])[CH:31]=[C:32]([Cl:34])[CH:33]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3cc(Cl)cc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2cc(Cl)cc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Lithium hydroxide monohydrate (0.020 g, 0.48 mmol) was added to a stirred solution of {6-chloro-4-[4-(3,5-dichloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.065 g, 0.122 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(3,5-dichloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.058 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H) 8.26 (d, J=8.80 Hz, 2H) 8.15 (s, 2 H) 8.05-8.08 (m, 1 H) 7.97 (d, J=8.80 Hz, 1 H) 7.91 (s, 1 H) 7.56 (d, J=8.80 Hz, 2 H) 7.48 (d, J=8.60 Hz, 1 H) 6.97 (s, 1 H) 3.84 (s, 2 H) 2.03 (s, 3H). MS calcd. for C25H16Cl3O4S [(M−H)−] 517, obsd. 517.1.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:12]3[N:13]=[C:14]([SH:16])[S:15][C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]([CH2:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[SH:16][C:14]1[S:15][C:11]2[CH:10]=[C:9]([N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:27](=[O:28])[CH2:26][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:17][C:12]=2[N:13]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Sc1nc2ccc(NCc3ccccc3)cc2s1
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)N(Cc1ccccc1)c1ccc2nc(S)sc2c1
Reaction time: 24 h
Yield: 75.6 %

Procedure:
Into a 13×100 mm screw cap Pyrex® vial were added 6-[(phenylmethyl)amino]-1,3-benzothiazole-2-thiol (30.6 mg, 0.11 mmol), poly(vinylpyridine) (25 mg, 0.22 mmol), phenoxyacetyl chloride (25 μl, 0.18 mmol), and THF (2 ml). The vial was purged with Ar, capped, and shaken for 24 h. Amino silica gel (200 mg, 166 mmol) was added, and the suspension was shaken an additional 6 h. The suspension was filtered, and purified by preparative TLC (developing with 35% EtOAc in hexanes) to afford the title compound as a white powder (33.8 mg, 76%); 1H NMR (DMSO-d6) δ=4.48 (s, 2H), 4.83 (s, 2H), 6.73 (d, 2H), 6.88 (t, 1H), 7.27-7.15 (m, 9H), 7.57 (s, 1H); ESIMS: m/z 405 (M−H).