Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].BrC(Cl)(Cl)C(Cl)(Cl)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.ClCCl>[Cl:1][C:2]1[C:7]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]2[N:4]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:13][N:12]=2)[N:3]=1
Reactant: C[Si](C)(C)c1cc(NNC(=O)c2ccccc2F)nnc1Cl
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Temperature: 1 °C
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
To a stirred suspension of 3-chloro-6-[2-(2-fluorobenzoyl)hydrazino]-4-(trimethylsilyl)pyridazine (9.72 g, 28.7 mmol) and 1,2-dibromotetrachloroethane (18.68 g, 57.4 mmol) in anhydrous acetonitrile (170 ml), cooled under nitrogen to 1° C., was added portionwise, over 21 min, solid triphenylphosphine (30.10 g, 115 mmol), keeping the temperature below 5° C. The mixture was stirred at 2° C. for 10 min, then anhydrous triethylamine (32.0 ml, 230 mmol) was added dropwise over 18 min, keeping the temperature below 6° C. The mixture was then stirred at 0-3° C. under nitrogen for 85 min. The mixture was then diluted with dichloromethane (150 ml) and washed with water (200 ml). The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20-40% EtOAc/hexane) to afford 7.67 g (83%) of the title compound as a white solid; 1H NMR (360 MHz, CDCl3) δ0.48 (9H, s), 7.30 (1H. dd, Jd=10.1 and 8.8 Hz), 7.36 (1H. td, J=7.6 and 1.1 Hz), 7.58 (1H, m). 7.90 (1H, td. J=7.3 and 1.8 Hz), 8.30 (1H, s); MS (ES+) m/e 321/323 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23](=[O:30])[CH2:24][C:25](OCC)=[O:26])=[C:10]1[C:31]([O:33][CH2:34][CH3:35])=[O:32].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23]([OH:30])[CH2:24][CH2:25][OH:26])=[C:10]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCC(O)CCO)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 27.3 %

Procedure:
A solution of ethyl 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetoacetate (0.99 g) (see European patent application publication no. 0132375) in tetrahydrofuran (10 ml) was added dropwise over five minutes to a stirred, ice-cooled suspension of lithium aluminium hydride (0.19 g) in tetrahydrofuran (20 ml). The ice-cooled mixture was stirred for 40 minutes, quenched into water and partitioned between ethyl acetate and 1M hydrochloric acid. The layers were separated and the organic layer was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (8 g) using dichloromethane plus 0-50% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated and the residue triturated with ether/hexane. The resulting solid was collected, washed with ether and dried to give the title compound (0.25 g), m.p. 86°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[NH:9][CH:8]=1)=[O:6].[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[N:25]=1.[CH3:32]N(C)C=O>>[Br:23][C:24]1[N:25]=[C:26]([CH2:30][N:9]2[C:10]3[C:15](=[N:14][C:13]([CH3:32])=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:2]([F:1])[CH:3]=3)=[CH:8]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1F
Reactant: BrCc1cccc(Br)n1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccc(C)nc3c2=O)cc1F

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 120 mg (0.402 mmol) of 3-(3-Fluoro-4-methoxy-benzoyl)-1H-[1,5]naphthyridin-4-one, 121.1 mg (0.483 mmol) of 2-bromo-6-bromomethyl-pyridine, 19.3 mg (0.483 mmol, 60% dispersion in oil), and 2 mL of N,N dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3-fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C22H15BrFN3O3 [M+H]: 468.03.
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.O[C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][C:37]=1[NH:43][C:44]([C:46]1[O:50][N:49]=[C:48]([O:51][CH2:52][C@@H:53]([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH3:54])[CH:47]=1)=[O:45]>C(#N)C.O>[OH:42][C:39]1[CH:40]=[CH:41][C:36]2[O:45][C:44]([C:46]3[O:50][N:49]=[C:48]([O:51][CH2:52][C@@H:53]([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH3:54])[CH:47]=3)=[N:43][C:37]=2[CH:38]=1
Reactant: C[C@@H](COc1cc(C(=O)Nc2cc(O)ccc2O)on1)NC(=O)OC(C)(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H](COc1cc(-c2nc3cc(O)ccc3o2)on1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
Triethylamine (2.83 mL) was added to a solution of triphenylphosphine (2.0 g) and hexachloroethane (1.5 g) in acetonitrile (25 mL), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was further added a solution of tert-butyl [(1S)-2-({5-[(2,5-dihydroxyphenyl)carbamoyl]isoxazol-3-yl}oxy)-1-methylethyl]carbamate (1.0 g) in acetonitrile (5 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (503 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]([CH3:7])[S:5][CH2:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[Cl:12]Cl>C(Cl)Cl>[ClH:12].[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][S:5][C:6]=1[CH3:7]
Reactant: COC(=O)C1=C(N)C(C)SC1
Reactant: ClCl
Solvent: ClCCl
Product: COC(=O)c1csc(C)c1N
Product: Cl
Reaction time: 12 h
Yield: 115.6 %

Procedure:
5.6 g of methyl 4-amino-5-methyl-2,5-dihydrothiophene-3-carboxylate (2) (30 mmol, content: 93%) were dissolved in 30 ml of CH2Cl2. 2.3 g of chlorine (33 mmol) were introduced into this solution at room temperature over a period of 60 min. The reaction mixture was subsequently stirred for another 12 h and then, for workup, concentrated under reduced pressure. 7.2 g of methyl 4-amino-5-methylthiophene-3-carboxylate hydrochloride (5) were obtained (59% of theory, content: 42%, determined as the free amine).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[C:10]([NH2:18])[C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=O.[C:21]([Cl:26])(=O)[CH:22]([CH3:24])[CH3:23]>>[ClH:26].[CH:22]([C:24]1[O:17][C:11]2[C:10]([N:18]=1)=[CH:9][C:8]1[CH:7]3[CH2:16][CH:14]([CH2:15][NH:5][CH2:6]3)[C:13]=1[CH:12]=2)([CH3:23])[CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Product: CC(C)c1nc2cc3c(cc2o1)C1CNCC3C1
Product: Cl

Procedure:
2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-ethanone and isobutyryl chloride were converted to the title compound following the procedures described in EXAMPLE 47 (TLC 25% EtOAc/hexanes Rf 0.14). 1H NMR (400 MHz, CD3OD) δ 7.65 (2H), 3.49 (br s, 2H), 3.41 (d, J=12.0 Hz, 2H), 3.33-3.19 (3H), 2.45 (m, 1H), 2.18 (d, J=11.5 Hz, 1H), 1.45 (d, J=7.0 Hz, 6H). APCl MS m/e 243.2 [(M+1)+]. (HCl salt) mp 249-251° C.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].P(=O)(O)(O)[OH:25]>O>[CH2:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:25].[CH2:12]([CH2:11][CH2:10][NH2:9])[CH2:13][CH2:14][CH2:15][NH2:7]
Reactant: O=C1CCCCCN1
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: O=P(O)(O)O
Solvent: O
Product: NCCCCCCN
Product: O=C(O)CCCCCCCCCCC(=O)O

Procedure:
1.0 kg of ε-caprolactam, 3.0 kg of 12-aminododecanoic acid and 200 g of fluoromica (average particle size 8 μm, CEC corresponding to 0.14 mole) were added to 1.5 kg of water. Into a 30 L volume reactor which was in advance charged with 4 kg of ε-caprolactam were introduced the above-described mixture and 16.1 g (0.14 mole) of 85 wt % phosphoric acid aqueous solution. The pellets of nylon 6/12 resin composition were prepared in the same manner as in Comparative Example 3. After being refined in 95° C. hot water and dried, the pellets were injection molded in an injection molding machine (IS80G-3A Model, manufactured by Toshiba Machine, Ltd.) at a cylinder temperature of 250° C. and a mold temperature of 50° C. for an injection time of 6 seconds and a cooling time of 10 seconds to prepare 2 mm thick plates and 3.2 mm thick specimens for testing.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:12]([P:16](Cl)Cl)([CH3:15])([CH3:14])[CH3:13].C([O:21]CC)C>>[CH:1]([O:4][P:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[OH:21])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(C)O
Reactant: CC(C)(C)P(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)OP(O)C(C)(C)C

Procedure:
A mixture of 24.7 g of isopropanol and 17.2 g of triethylamine in 35 ml of diethylether is added drop by drop to 30 g of t-butyldichlorophosphine in 100 ml diethylether. The temperature is kept between 5 to 10°. The solid is filtered off and the filtrate evaporated. The crude oil is purified by distillation to yield t-butylphosphonous acid-isopropylester as an oil, b.p. 82°/2 kPa, n20D =1.4222.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([S:16][CH2:17][C:18]([O:20]C)=O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:22]C(C)([O-])C.[K+].CI.O>O1CCCC1>[CH3:22][N:1]1[C:2]2=[C:3]3[C:8](=[N:9][C:10]4[CH2:11][CH2:12][CH2:13][CH:14]([C:15]=42)[S:16][CH2:17][C:18]1=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4]3
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CSC1CCCc2nc3ccccc3c(N)c21
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)CSC2CCCc3nc4ccccc4c1c32
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a mixture of methyl [(9-amino-1,2,3,4-tetrahydroacridin-1-yl)thio]acetate (5.06 g) in tetrahydrofuran (100 ml) was added potassium t-butoxide (2.3 g). The mixture was stirred for 30 mins and methyl iodide (1.6 ml) was added. Stirring was continued for 2 hrs, and the reaction mixture was poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were purified by flash chromatography (ethyl acetate/dichloromethane) to give 3.42 g (72%) of the 1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino-[4,3,2-ef][1,4]benzthiazepin-2-one, mp 241°-245° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Yield: 58.1 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (6.0 g, 20.32 mmol), N-bromosuccinimide (3.80 g, 21.33 mmol) and benzoyl peroxide (246 mg, 1.01 mmol) in CCl4 was refluxed for 1 h. Solid was filtered off through a plug of silica gel. Filtrate was concentrated and purified by silica chromatography, eluting with EtOAc. All fractions contain the desired product was combined and concentrated. Residue was suspended in 150 mL of (3/1) MeOH/EtOAc and was refluxed for 1 h. After cooled, solid was collected, rinsed with MeOH and dried on vacuo to provide the title compound 4.42 g (11.8 mmol) in 58% yield as a white solid. 1H NMR in CDCl3, δ ppm: 11.7 (s, 1H), 8.36 (d, 1H, J=9.2 Hz), 7.63 (d, 1H, J=2.4 Hz), 7.55-7.10 (m, 6H), 4.06 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[C:32]#[N:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:25]2[C:24]3[C:29](=[CH:30][C:21]([O:20][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:22]([C:32]#[N:33])[CH:23]=3)[N:28]=[CH:27][CH:26]=2)=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1c(N)ccc(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(N)ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)c1C
Temperature: 100 °C
Yield: 42.7 %

Procedure:
4-Amino-2,3-xylenol (2.80 g) purchased from Tokyo Chemical Industries was dissolved in dimethylsulfoxide (15 ml), and after gradually adding sodium hydride (816 mg) at room temperature, the mixture was stirred for 20 minutes. 7-Benzyloxy-4-chloro-6-cyanoquinoline (3.0 g) was added, and the mixture was heated at 100° C. for 4 hours while stirring. After cooling to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water, 1N aqueous sodium hydroxide and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained crude product was washed with ethyl acetate to obtain the title compound (1.72 g) as light brown crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH2:36][O:37]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH2:36][OH:37])[CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)no3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)no3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M41) (680 mg, 1.05 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (294 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:21]=1[C:22](Cl)=[O:23].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:21]=1[C:22]([N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C(=O)n2ccnc2-c2ccccc2)c(C)c1
Yield: 78.3 %

Procedure:
144.2 g (1.00 mole) of 2-phenylimidazole are dissolved at 90° C. in 900 ml of toluene. 104.2 g (1.03 moles) of triethylamine are added to this solution, and a solution of 182.6 g (1.00 mole) of 2,4,6-trimethylbenzoyl chloride in 300 ml of toluene is added dropwise at 90° C. in the course of 2 hours, triethylamine hydrochloride being precipitated. The latter is filtered off with suction at room temperature and extracted by washing with toluene. Concentrating the filtrate gives 296 g of crude product, recrystallisation of which from 580 ml of acetonitrile gives a total of 227.3 g of 1-(2,4,6-trimethylbenzoyl)-2-phenylimidazole (78.3% of theory).
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:9]1[C@@H:12]([C@H:13]([C:15](SC2C=CC=CC=2)=[S:16])[CH3:14])[NH:11][C:10]1=[O:24])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([O:30][C:31]([N:33]1[CH2:37][C@@H:36]([SH:38])[CH2:35][C@H:34]1[C:39](=[O:43])[N:40]([CH3:42])[CH3:41])=[O:32])[CH:28]=[CH2:29]>C(#N)C>[CH2:27]([O:30][C:31]([N:33]1[CH2:37][C@@H:36]([S:38][C:15]([C@@H:13]([C@H:12]2[NH:11][C:10](=[O:24])[C@@H:9]2[C@H:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:25])[CH3:26])[CH3:8])[CH3:14])=[S:16])[CH2:35][C@H:34]1[C:39](=[O:43])[N:40]([CH3:41])[CH3:42])=[O:32])[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N(C)C
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)Sc1ccccc1
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@@H](SC(=S)[C@H](C)[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a mixture of (3S,4S)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(phenylthio)thiocarbonyl}ethyl]-2-oxoazetidine (100 mg) and cuprous chloride (30 mg) in acetonitrile (1 ml) was added (2S,4S)-1-allyloxycarbonyl-2-(dimethylcarbamoyl)-4-mercaptopyrrolidine (130 mg) and the mixture was stirred at the ambient temperature for 5 hours. The mixture was purified by preparative thin layer chromatography (developed with ethyl acetate) to give (3S,4S)-4-[(1R)-1-{((2S,4S)-1-allyloxycarbonyl-2-(dimethylcarbamoyl)pyrrolidin- 4-ylthio)thiocarbonyl}ethyl]-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-2-oxoazetidine (105 mg).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:25])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][Si](C)(C)C)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].P([O-])([O-])([O-])=[O:27]>C(Cl)(Cl)Cl>[OH:4][CH:5]([CH3:25])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=2)=[CH:12][CH:13]=1.[C:1]([O:4][CH:5]([CH3:25])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:27])[CH:19]=[CH:18][CH:17]=[CH:16][NH:15]2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)CCc1ccc(-c2ccc(O[Si](C)(C)C)cn2)cc1
Reactant: O=P([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CC(=O)OC(C)CCc1ccc(C2(O)C=CC=CN2)cc1
Product: CC(O)CCc1ccc(-c2ccc(O)cn2)cc1

Procedure:
12 g of 2-[4-(3-acetoxy-1-butyl)phenyl]-5-trimethylsilyloxy-pyridine, 300 ml of 0.3M phosphate buffer solution (pH 7.0), 30 ml of chloroform and 3.0 g of lipase (genus Arthobacter) are reacted to give 4.5 g of (-)-2-[4-(3-hydroxy-1-butyl)-phenyl]-5-hydroxy-pyridine and 4.2 g of (-)-2-[4-(3-acetoxy-1-butyl)phenyl]-2-hydroxy-pyridine.
Reaction SMILES: [C:1]([C:9]1[C:10]([OH:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C:16](=[O:19])[CH:15]=[C:14]2[CH3:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+].CCCCCC.C(OCC)(=O)C>CC#N>[C:24]([C:23]1[O:21][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([O:17][C:16](=[O:19])[CH:15]=[C:14]3[CH3:20])=[C:9]2[C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(=O)oc2c(C(=O)c3ccccc3)c(O)ccc12
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(=O)oc2c1ccc1oc(C(=O)c3ccccc3)c(-c3ccccc3)c12
Yield: 71 %

Procedure:
A mixture of 8-benzoyl-7-hydroxy-4-methyl-chromen-2-one (30 mg, 0.1 mmol), 2-bromoacetophenone (22 mg, 0.11 mmol), and K2CO3 (143 mg, 1.03 mmol) in CH3CN (5 mL) was refluxed overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 then hexane/ethyl acetate=1/1, Rf=0.33 hexane/ethyl acetate=1/1) to provide 8-benzoyl-4-methyl-9-phenyl-furo[2,3-h]chromen-2-one as a yellow solid (71% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:20])=O.[CH3:22]O>>[ClH:20].[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:22])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1cc(-c2ccc(C(=O)O)cc2)ccn1
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(-c2ccnc(C)c2)cc1

Procedure:
In methanol (100 ml), 4-(2-methylpyridin-4-yl)benzoic acid hydrochloride (5.00 g) was dissolved. To the resulting solution, thionyl chloride (1.73 ml) was added dropwise, followed by heating under reflux for 3.5 hours. The reaction mixture was distilled to remove the solvent and pale brown crystals thus precipitated were washed with ethyl acetate, whereby the title compound (4.70 g, 89%) was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:5][OH:6].[F:19][CH2:20][C:21](OCC)=[O:22].[OH-].[Na+].Cl>FC(F)(F)CO.CO.O>[F:19][CH2:20][C:21]([NH:2][CH2:3][CH:4]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:5][OH:6])=[O:22]
Reactant: COc1ccc2cccc(C(CN)CO)c2c1
Reactant: CCOC(=O)CF
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: OCC(F)(F)F
Product: COc1ccc2cccc(C(CO)CNC(=O)CF)c2c1
Temperature: 40 °C

Procedure:
The compound obtained in Step B (5.6 mmol), in the form of the base, is dissolved in 40 ml of 2,2,2-trifluoroethanol; ethyl fluoroacetate (10.3 mmol) is added and the mixture is refluxed for 12 hours. When the reaction is complete, the mixture is poured into water and the aqueous phase is extracted twice with 60 ml of ether; the organic phase is washed with water, dried and evaporated. The oil obtained is dissolved in 30 ml of methanol and 10 ml of water; sodium hydroxide (8.25 mmol) is added and the mixture is heated at 40° C. for 30 minutes. The mixture is then poured into water; the aqueous phase is neutralised with 15 ml of hydrochloric acid solution (1 M) and is then extracted twice with 60 ml of ether. The organic phase is washed with water, dried and evaporated. The oil obtained is precipitated from a mixture of ether and petroleum ether (40/60); the precipitate formed is filtered off under suction and then recrystallised from toluene to yield the title compound in the form of a white solid.