Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[N:5](C(OCC)=O)[CH2:6]2>Cl>[CH3:1][N:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CCN(C)C2C1C
Agent: Cl
Product: CC1NCC2CCN(C)C21

Procedure:
16.9 g (79.6 mol) of ethyl 2,8-dimethyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight with 130 ml of concentrated hydrochloric acid. The mixture is concentrated, the residue is taken up in 50 ml of water, and the mixture is rendered alkaline with potassium carbonate and extracted five times using 50 ml of chlorform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: B(Cl)(Cl)Cl.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:15].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+].Cl.CS[C:25]#[N:26]>ClCCCl>[C:25]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:15])#[N:26]
Reactant: CSC#N
Reactant: Oc1ccc2ccccc2c1
Agent: Cl
Agent: ClB(Cl)Cl
Agent: [Al+3]
Solvent: ClCCCl
Product: N#Cc1c(O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To 6 ml of a solution of 2.02M of boron trichloride in 1,2-dichloroethane were added a solution of 1.44 g of β-naphthol in 30 ml of 1,2-dichloroethane, 0.82 ml of methyl thiocyanate and 1.33 g of aluminium chloride under ice-cooling. After stirring at room temperature for 3 hr., the reaction mixture was poured into 33 ml of 4N aqueous NaOH and stirred at 75°-78° C. on an oil bath for 30 min. The reaction solution was mixed with 30 ml of 6N HCl and extracted with ether. After drying the ether layer over anhydrous magnesium sulfate, the solvent was distilled off. The residue was recrystallized from ether-benzene to yield 1.49 g of 1-cyano-2-naphthol as crystals melting at 160°-161° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:26])[C@@H:6]([C@H:16]([OH:25])[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:27]I>CN(C)C=O.O>[CH3:3][O:4][C:5](=[O:26])[C@@H:6]([CH:16]([O:25][CH3:27])[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CI
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCc1ccccc1)C(OC)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 114 mg, 2.86 mmol) was added to a solution of (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (800 mg, 2.38 mmol) in dry dimethylformamide followed by addition of methyl iodide (0.74 ml, 11.9 mmol) and the reaction mixture was stirred for two hours at rt. The reaction was diluted with water and extracted with Ethyl acetate. The organic extracts were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless oil solid (660 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.[CH3:16][C:17]([CH3:20])([O-])[CH3:18].[K+].BrCC(C)=C>C(OCC)C.CCCCCC>[CH3:18][C:17]([CH2:20][CH2:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH2:16]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc2ccccc2[nH]1
Agent: C=C(C)CBr
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C(C)CCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 47 %

Procedure:
To a stirred solution of 2-methylindole (1 g) in diethylether (76 ml) under nitrogen was added a 1.6 M solution of n-butyllithium in hexane (14.3 ml) slowly dropwise via syringe. Potassium tert-butoxide (1.711 g) was then added, producing a bright yellow mixture. After stirring at room temperature under nitrogen for 50 minutes, the mixture was cooled to −78° C., whereupon 3-bromo-2-methylpropene (1.54 ml) was added dropwise via syringe, giving a red-orange solution. The reaction mixture was stirred at −78° C. for 2 hours, then quenched with water (10 ml). After warming to room temperature, water (150 ml) and 1 N hydrochloric acid (1 ml) was added to neutralize the reaction mixture. The mixture was extracted with ethyl acetate (250 ml), and the organic layer was washed with brine (100 ml) and dried with sodium sulfate. The solvent was removed under reduced pressure, and the crude residue was purified by flash chromatography (4% ethyl acetate/hexane) to afford 2-(2-methyl-1-butene-4-yl)indole (664 mg. 47%) as a waxy yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:17]([O:19]C)=[O:18])=[CH:5][C:6]([C:13]([O:15]C)=[O:14])=[N:7]2.[OH-].[Na+]>CO>[C:13]([C:6]1[CH:5]=[C:4]([C:17]([OH:19])=[O:18])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=1)([OH:15])=[O:14]
Reactant: COC(=O)c1cc(C(=O)OC)c2c(Cl)cc(Cl)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(C(=O)O)c2c(Cl)cc(Cl)cc2n1
Yield: 76.5 %

Procedure:
5,7-Dichloro-2,4-dimethoxycarbonylquinoline (Example 15a) (28 g) was dissolved in 50% aqueous methanol (700ml) with sodium hydroxide (35.8 g) and the solution was heated at reflux for 18 h. After cooling, the methanol was removed by evaporation and the residue was diluted with water to a volume of approximately 700 ml. Concentrated hydrochloric acid was added to the aqueous solution at 90° C. and the white solid produced was filtered while the filtrate was still hot. The solid was dried in a vacuum oven at 100° C. (20 mmHg) for 48 h to give the title compound (19.5 g, m.p. 246° C.);δ (360 MHz, DMSO) 8.09 (1H, s, 3-H), 8.13 (1H, d, J=2.2 Hz, 6-H or 8-H), 8.32 (1H, d, J=2.2 Hz, 6-H or 8H); m/e 354 (M+); Found: C, 43.48 ; H, 2.45; N, 4.58% C11H5Cl2NO4.H2O requires C, 43.45; H, 2.32; N, 4.61%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=1[CH:29]=O>>[F:25][C:26]([F:39])([F:40])[C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:28]=1[CH2:29][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2,5-bis(trifluoromethyl)benzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 558.0.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:42][N:43]([CH:52]=[O:53])[O:44]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]([CH3:31])[CH3:30])[CH2:25]4)[N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].CO>[CH:1]1([CH2:6][C@H:7]([CH2:42][N:43]([CH:52]=[O:53])[OH:44])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]([CH3:31])[CH3:30])[CH2:25]4)[N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)[C@H]1CCN(c2nccc(NC(=O)[C@@H]3CCN(C(=O)OCc4ccccc4)N3C(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)n2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)[C@H]1CCN(c2nccc(NC(=O)[C@@H]3CCNN3C(=O)[C@H](CC3CCCC3)CN(O)C=O)n2)C1
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A mixture of phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidinecarboxylate (91 mg, 0.125 mmol) and Pearlman's catalyst (17.58 mg, 0.025 mmol) in methanol (7.4 ml) was degassed and placed under 1 atm of H2 at ambient temperature. After 2 hrs, the reaction mixture was filtered and concentrated to give a residue which was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-{2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinyl}-3-pyrazolidinecarboxamide (45 mg, 0.089 mmol, 71% yield). MS (ES+) m/z 503.1 (MH+). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.05-1.23 (m, 2H) 1.33-1.45 (m, 1H) 1.45-1.68 (m, 4H) 1.69-1.96 (m, 5H) 2.12-2.31 (m, 2H) 2.34 (s, 6H) 2.42-2.57 (m, 1H) 2.83-2.96 (m, 2H) 3.18-3.30 (m, 2H) 3.40-3.53 (m, 2H) 3.65-3.83 (m, 2H) 3.84-3.99 (m, 2H) 4.68 (q, J=7.16 Hz, 1H) 7.34 (d, J=5.56 Hz, 1H) 7.85 (s, 0.7H) 8.16 (d, J=5.81 Hz, 1H) 8.25 (s, 0.3H)
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C@:27]([OH:31])([C:29]#[CH:30])[CH3:28]>N1CCCCC1.[Cu]I.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>[OH:31][C@:27]([C:22]1[N:21]=[CH:26][CH:25]=[CH:24][N:23]=1)([CH3:28])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1
Reactant: C#C[C@@](C)(O)c1ncccn1
Reactant: Cn1c(C(N)=O)nc2c1C1CC(C1)c1ccc(I)cc1-2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cn1c(C(N)=O)nc2c1C1CC(C1)c1ccc(C#C[C@@](C)(O)c3ncccn3)cc1-2
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution 9-iodo-3-methyl-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (100 mg, 0.26 mmol) in piperidine (2 mL) was introduced (2R)-2-(pyrimidin-2-yl)but-3-yn-2-ol (156 mg, 1.05 mmol) and copper(I) iodide (2.5 mg, 0.01 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2.5 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (6 mL), water (2×10 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) was followed by suspension of the product in acetonitrile (0.8 mL). The solid was collected by filtration to furnish the title compound (51 mg, 0.13 mmol, 50%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 1.69 (d, J=10.72 Hz, 2H), 2.06 (br. s., 2H), 2.93 (qd, J=7.99, 3.15 Hz, 2H), 3.46 (td, J=7.25, 3.78 Hz, 1H), 3.62 (td, J=8.12, 3.63 Hz, 1H), 3.99 (s, 3H), 5.16-5.44 (m, 2H), 6.99 (d, J=7.57 Hz, 1H), 7.15 (d, J=7.57 Hz, 1H), 7.33 (br. s., 1H), 7.52 (br. s., 1H), 8.49 (s, 1H), 8.85 (br. s., 2H); M+H=400.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>CC(C)=O>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN(C)CCCl
Reactant: COc1ccc(C#N)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccc(C#N)c(OCCN(C)C)c1
Temperature: 60 °C
Yield: 71.1 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzonitrile (200 mg, 1.341 mmol) in acetone (5 mL) were added cesium carbonate (1.312 g, 4.023 mmol) and (2-chloroethyl)-dimethylamine hydrochloride (390 mg, 2.682 mmol). The resulting mixture was heated at 60° C. for overnight. The solid was filtered off and washed with methylene chloride (6×10 mL). The filtrate was washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-5% methanol in methylene chloride yielded 2-(2-dimethylamino-ethoxy)-4-methoxy-benzonitrile as a pale-yellow oil (210 mg, 71%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:2]=1.[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: O=C1CCC(c2cccnc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: O[C@H]1CC[C@@H](c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
To a solution of 4-(3-pyridyl)cyclohexanone (3.22 g, 18.4 mmol) in MeOH (25 ml) was added portionwise NaBH4 (348 mg. 9.30 mmol) at 0° C., and stirred for 30 min at room temperature. The reaction mixture was poured into 0.5M HCl and basified with sat. NaHCO3 aq. and then extracted with CH2Cl2. The organic layer was dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=5/1) to yield cis-4-(3-pyridyl)cyclohexanol (510 mg, 16%) as a colorless powder.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
3-Iodo-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.33 mmol) and SnCl2 dihydrate (2.63 g, 11.7 mmol) in EtOAc (25 mL) were heated to 75° C. for 4 hours. The reaction mixture was cooled to room temperature, and saturated aqueous NaHCO3 (25 mL) was added. The resulting precipitate was filtered through celite. The layers were separated. The organic portion was washed with water, brine, dried over Na2SO4 and concentrated to give 3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.933 g, 100%) as a powder, which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]#[CH:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Au+].ClP(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:9]/[CH:12]=[CH:11]\[C:10]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C#CC(=O)OCC
Agent: [Au+]
Agent: Cl[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C\OC(=O)c1ccccc1
Temperature: 60 °C
Yield: 99.5 %

Procedure:
To a suspension of benzoic acid (24.4 g, 200 mmol), silver hexafluorophosphate(V) (253 mg, 1 mmol), chlorotriphenylphosphine gold(I) (495 mg, 1 mmol) in toluene (125 mL) was added ethyl prop-2-ynoate (5.1 mL, 50 mmol). The reaction mixture was stirred and heated at 60° C. for 16 hrs. The volatiles were removed to give a residue, which was dissolved in ethyl acetate (200 mL) with some trace insoluble material being removed by filtration. The filtrate was washed with saturated aqueous NaHCO3 (with gas evolved—CAUTION) until there was no further gas evolution, and evaporated to give a light brown oil. This oil was purified via flash chromatography (eluting with a gradient of 0%-100% EtOAc in heptanes) to give the title compound (10.96 g, 99% yield) as a colorless oil, which solidified to afford needle-liked crystals. 1H NMR (400 MHz, chloroform-d) δ ppm 8.24-8.32 (m, 2H) 7.85 (d, J=7.09 Hz, 1H) 7.63-7.72 (m, 1H) 7.48-7.58 (m, 2H) 5.44 (d, J=7.21 Hz, 1H) 4.29 (q, J=7.21 Hz, 2H) 1.38 (t, J=7.15 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ ppm 164.15 (s, 1C) 162.55 (s, 1C) 144.54 (s, 1C) 134.31 (s, 1C) 130.66 (s, 2C) 128.74 (s, 2C) 127.90 (s, 1C) 103.38 (s, 1C) 60.30 (s, 1C) 14.28 (s, 1C).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:33])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:47](OC(=O)C)([F:49])[F:48]>O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:33][CH:47]([F:49])[F:48])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:27])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of {2-ethyl-8-fluoro-4-oxo-3-[4-(pyrrolidine-1-carbonyl)benzyl]-1,4-dihydroquinolin-5-yloxy}acetic acid methyl ester (0.25 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.22 g) and acetic acid chlorodifluoromethyl ester (0.28 mL) was stirred at 80° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:1 by volume) gave title compound, 0.14 g.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[N:13][N:14]=[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:10]3=[N:9][C:8]=2[OH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:25][C:26]1[N:27]([CH3:31])[N:28]=[CH:29][N:30]=1.[H-].[Na+].C(Cl)Cl>CN(C)C=O>[C:1]1([C:7]2[N:11]3[CH:12]=[N:13][N:14]=[C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:10]3=[N:9][C:8]=2[O:22][CH2:25][C:26]2[N:27]([CH3:31])[N:28]=[CH:29][N:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1ncnc1CCl
Reactant: Oc1nc2c(-c3ccccc3)nncn2c1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncnc1COc1nc2c(-c3ccccc3)nncn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3,8-diphenylimidazo[1,2-d][1,2,4]triazin-2-ol (500 mg, 1.74 mmol) and 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (320 mg, 1.91 mmol) in anhydrous N,N-dimethylformamide under an atmosphere of nitrogen was added sodium hydride (153 mg of a 60% dispersion in oil, 3.8 mmol). The reaction mixture was stirred at room temperature for 72 h. The mixture was partitioned between EtOAc (80 ml) and water (150 ml), the organic layer was separated, and the aqueous layer extracted with a further two portions of EtOAc (80 ml). The combined EtOAc layers were washed with saturated NaCl solution (100 ml), separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 2% MeOH in CH2Cl2+0.5% NH3), and the product recrystallised from CH2Cl2 to afford 235 mg (0.6 mmol, 35%) as a white solid. (Found: C, 63.66; H, 4.23; N, 24.54; C21H17N7O.0.5H2O.0.07CH2Cl2 requires C, 63.47; H, 4.59; N, 24.59%); m.p. 179° C. (from CH2Cl2); δH (400 MHz; CDCl3) 3.95 (3H, s, NCH3), 5.75 (2H, s, OCH2), 7.46 (1H, t, J 7.3, aromatic), 7.52-7.60 (5H, m, aromatics), 7.63 (2H, d, J 7.6, aromatics), 7.88 (1H, s, triazole H5), 8.57-8.65 (2H, br m, aromatics), 9.43 (1H, s, imidazotriazine H5); m/z (ES+) 384 (M++H, 100%).
Reaction SMILES: [Br:1]Br.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5]>[Fe]>[Br:1][C:11]1[CH:12]=[C:7]([S:4]([CH3:3])(=[O:5])=[O:6])[CH:8]=[CH:9][C:10]=1[CH3:13]
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: BrBr
Agent: [Fe]
Product: Cc1ccc(S(C)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of elemental iron (67 mg, 1.2 mmol) in Br2 (2.05 mL, 39.9 mmol) was added 4-methanesulfonyl-1-methyl-benzene (340 mg, 2.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hrs. TLC (petroleum ether:EtOAc 3:1) indicated the reaction was completed. Then the mixture was poured into an ice-cold aqueous Na2S2SO3 (1M, 10 mL) and extracted with EtOAc (20 mL×3), washed with brine (10 mL×3), dried over sodium sulfate, concentrated in vacuum, and the residue was purified by a Biotage silica gel cartridge (petroleum ether/EtOAc 3:1, Rf˜0.6) to give the title compound (300 mg, 80%) as a white solid.
Reaction SMILES: [BrH:1].[Br:2][CH:3]1[CH2:18][CH2:17][C:6]2[N:7]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=[C:8]3[S:9][C:5]=2[C:4]1=O.[NH2:20][C:21]([NH2:23])=[S:22]>C(O)C>[BrH:2].[BrH:1].[NH2:23][C:21]1[S:22][C:3]2[CH2:18][CH2:17][C:6]3[N:7]4[C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[N:10]=[C:8]4[S:9][C:5]=3[C:4]=2[N:20]=1
Reactant: NC(N)=S
Reactant: O=C1c2sc3nc4ccccc4n3c2CCC1Br
Agent: Br
Solvent: CCO
Product: Nc1nc2c(s1)CCc1c-2sc2nc3ccccc3n12
Yield: 61 %

Procedure:
2-Bromo-1,3-cyclohexadione prepared in Example 1, Route 1 (A) was reacted with 2-mercaptobenzimidazole in the same manner as that of Example 1, Route 1 (B) to give 1,2-dihydrobenzimidazo[2,1-b]benzothiazole-4(3H)-one (Compound (IIb) of Reaction Scheme II), which was subjected to bromination in the same manner as that of Example 1, Route 1 (C) to give 3-bromo-1,2-dihydrobenzimidazo[2,1-b] benzothiazole-4(3H)-one hydrobromide. The hydrobromide (1.45 g) and thiourea (0.15 g) were placed into ethanol (50 ml), and the mixture was heated to reflux for 2 hours, cooled, and the filtered to give the titled compound (61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.[C:21]1([CH2:27][C:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:31]1([C:30]2[C:28](=[O:29])[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Product: COc1ccc(C2=C(c3ccccc3)C(=O)C(c3ccccc3)=C2c2ccc(OC)cc2)cc1

Procedure:
The tetracyclone is prepared from 4,4'-dimethoxybenzil and 1,3-diphenylacetone (XV) by the procedure described in "Organic Syntheses," Coll., Vol. 3, E. C. Horning, Ed., Wiley, N.Y., 1955, pp 806-807: mp 227°-228° C. (mp 226.8-227.2° C. reported in Coan et al J. Am. Chem. Soc., 77, 60 (1955).