Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1I.[CH3:22][Si:23]([CH3:40])([CH3:39])/[CH:24]=[CH:25]/[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1/[CH:25]=[CH:24]/[Si:23]([CH3:40])([CH3:39])[CH3:22]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1I
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1/C=C/[Si](C)(C)C
Temperature: 120 °C
Yield: 79.5 %

Procedure:
Methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-iodopicolinate (350 mg, 0.824 mmol), and tetrakis triphenylphosphine palladium(0) (95 mg, 0.082 mmol) were combined in a Biotage microwave reaction vessel that was then sealed and purged with nitrogen. (E)-trimethyl(2-(tributylstannyl)vinyl)silane (417 mg, 1.072 mmol) in dioxane (4122 μl) was added and the reaction mixture was heated in a microwave reactor at 120° C. for 30 min The cooled reaction mixture was diluted with ethyl acetate and washed with saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated on to silica. The product was purified by flash chromatography. (SiO2, 0-20% EtOAc:Hex gradient) to provide the title compound as a tan solid (260 mg, 0.655 mmol, 79% yield); 1H NMR (400 MHz, DMSO-d6) d 0.17 (s, 9H), 3.76 (s, 3H), 6.09 (d, J=19.2 Hz, 1H), 6.60 (s, 2H), 6.91 (d, J=19.2 Hz, 1H), 7.75 (dd, J=3.8, 1.9 Hz, 2H), 7.83 (dd, J=10.8, 1.3 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −145.16 , −115.98; ESIMS m/z 398 ([M+H]+).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([CH2:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22].CN([CH:26]=[O:27])C>C1COCC1>[Br:13][C:14]1[C:15]([F:22])=[C:16]([CH:17]=[C:18]([CH2:20][CH3:21])[CH:19]=1)[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: CCc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCc1cc(Br)c(F)c(C=O)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (0.449 mL, 3.20 mmol) in 10 mL THF at −15° C., was added BuLi (1.6M, 1.85 mL, 2.95 mmol). The mixture was stirred 10 min at −10° C., then was cooled to −78° C. A solution of 2-bromo-4-ethyl-1-fluorobenzene (228.1) in 2 mL THF was added, then the mixture was stirred at −70° C. for 25 min. DMF (0.381 mL, 4.92 mmol) was added, then the reaction was removed from the cooling bath and stirred 30 min. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-20% EtOAc/hexanes gradient) to afford 429 mg of Intermediate 398.1 at a colorless solid. LCMS (2 min gradient) RT=1.70 min, 231.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (t, J=7.69 Hz, 3H) 2.67 (q, J=7.47 Hz, 2H) 7.61-7.66 (m, 2H) 10.33 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[CH2:4][N:5]=[C:6]([NH2:20])[NH:7][C:8]1[N:12]=[CH:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:19])=[NH:18])[N:9]=1.[Na].[CH:24]([CH:26]([CH3:32])[C:27](OCC)=O)=[O:25]>CO>[OH:25][C:24]1[C:26]([CH3:32])=[CH:27][N:19]=[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:10]2[CH:11]=[N:12][C:8]([NH:7][C:6]([NH2:20])=[N:5][CH2:4][C:3]([F:2])([F:21])[F:22])=[N:9]2)[N:18]=1
Reactant: CCOC(=O)C(C)C=O
Reactant: N=C(N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Cc1cnc(CCCCn2cnc(NC(N)=NCC(F)(F)F)n2)nc1O
Yield: 11.7 %

Procedure:
A solution of 5-(3-[2-(2,2,2-trifluoroethyl)guanidino]-1,2,4-triazol-1-yl)valeramidine hydrochloride (1 g.) in MeOH (14 ml.) was treated with the sodium salt of ethyl 2-formylpropionate (1.95 g.) and the suspension heated under reflux for 3.5 hours. This suspension was evaporated and the residue partitioned between water and ether. The aqueous layer was acidified with glacial HOAc to pH 3 and further extracted with ether. Neutralisation with aqueous ammonia (s.g. 0.880) and extraction with EtOAc gave a white solid which was crystallised twice from acetonitrile to give 4-hydroxy-5-methyl-2-[4-(3-[2-(2,2,2-trifluoroethyl)guanidino]-1,2,4-triazol-1-yl)butyl]pyrimidine (0.127 g.; 12%), m.p. 235°-237°.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:19])=O>>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][Cl:19])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Product: N#Cc1ccc(Cn2cncc2CCl)cc1

Procedure:
A solution of 1-(4-cyanobenzyl)-5-(hydroxymethyl) imidazole (1.00 g, 4.70 mmol), in thionyl chloride (5 mL), was stirred at 70° C. for 16 hours. The solvent was evaporated in vacuo and the resulting solid suspended in CH2Cl2, collected by filtration and dried in vacuo. The material was sufficiently pure for use in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:12]([CH3:14])([CH3:13])[N:11]([O:15]CC2C=CC=CC=2)[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C:12]([CH3:14])([CH3:13])[N:11]([OH:15])[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)C1(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(O)C1(C)C
Yield: 83.1 %

Procedure:
A solution of 14.77 g (0.0461 mole) of (3S)-3-[(t-butyloxycarbonyl)amino]-4,4-dimethyl-1-(phenylmethoxy)-2-azetidinone in 15 ml of ethanol and 85 ml of ethyl acetate was hydrogenated over 0.75 g of 5% palladium-on-carbon catalyst for 1.5 hours at 1 atmosphere. The reaction mixture was filtered and concentrated to give a white solid. Recrystallization from ethyl acetate gave 8.82 g of the title compound, melting point 148°-149° C., [α]D =+31° (C =1, ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C(O)(=O)C>C(OCC)(=O)C>[CH3:42][C:2]1([CH3:1])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1
Reactant: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@]2(O)C=C[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]12C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 38.6 %

Procedure:
In 10 ml of ethyl acetate was dissolved 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregn-6-en-5α-ol, followed by addition of 0.2 ml of acetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 124 to give 150 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregna-5,7-diene showing the following physical properties.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([OH:36])[CH:31]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:36][C:32]1[CH:31]=[C:30]([CH3:29])[CH:35]=[CH:34][N:33]=1)[CH3:28]
Reactant: Cc1ccnc(O)c1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cc(C)ccn2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 27.1 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 4-methylpyridin-2-ol (0.19 g), 8 M potassium hydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@H:15]3[CH2:17][O:16]3)[C:7]=2[N:18]=1.[NH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1>C(O)C.O>[OH:16][C@@H:15]([CH2:14][CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:18][C:7]1=2)[CH2:17][NH:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: COc1ccc2ncc(=O)n(CC[C@H]3CO3)c2n1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Solvent: O
Solvent: CCO
Product: COc1ccc2ncc(=O)n(CC[C@H](O)CN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
In a mixed solvent (12 ml) of ethanol-water (9:1) were suspended 6-methoxy-4-{2-[(2S)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (Reference Example 72; 290 mg, 1.17 mmol) and 6-[(4S)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 22; 291 mg, 1.17 mmol), and the suspension was stirred in a sealed tube at 80° C. for 16 hours. The solvent was removed from the reaction solution under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 182 mg (31%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:16][C@H:17]([C:22]([O:24]C)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Li+]>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc2occc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(C(=O)N(C)C)c1ccc2occc2c1)C(=O)O
Reaction time: 24 h
Yield: 95.8 %

Procedure:
To a solution of methyl N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (520 mg) in methanol (5 ml) was added a solution of lithium hydroxide (91 mg) in water (3 ml). After stirring vigorously for 24 hours the solvent was removed in vacuo. The residue was diluted with water (10 ml) then neutralised with 2N hydrochloric acid. This solution was applied to an Oasis™ cartridge (2×6 g) and eluted with water (×2) and methanol (×2). The required fractions were combined and evaporated to afford N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (478 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1.[OH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O>O1CCCC1>[CH3:15][O:16][C:17]1[N:22]=[C:21]([NH:23][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[OH:24])[CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1O
Reactant: COc1cccc(N)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(NCc2ccccc2O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
512 mg (2.41 mmol, 1.5 eq) of sodium triacetoxyborohydride are added to a solution of 200 mg (1.61 mmol, 1 eq) of 6-methoxypyridin-2-ylamine (starting material 1) and 236 mg (2.41 mmol, 1 eq) of 2-hydroxybenzaldehyde (starting material 2) in 20 ml of tetrahydrofuran. The solution is stirred at room temperature for 48 h. It is evaporated and the residue is taken up in 100 ml of dichloromethane and then extracted with a saturated aqueous solution of ammonium chloride. The aqueous phase is extracted twice with dichloromethane. The organic phases are combined and dried over sodium sulphate. The residue is chromatographed on silica gel (5/95 ethyl acetate/heptane). 2-[(6-methoxypyridin-2-ylamino)methyl]phenol is obtained in the form of a white solid. Melting point=103° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]([NH:18][C:19](=[O:21])[CH3:20])=[C:6]([Br:22])[CH:5]=1)(=[O:3])[CH3:2].[Li+].[CH3:24][CH:25]([N-]C(C)C)[CH3:26].C(Br)C=C>C1COCC1>[C:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]([N:18]([CH2:26][CH:25]=[CH2:24])[C:19](=[O:21])[CH3:20])=[C:6]([Br:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCN(C(C)=O)c1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Temperature: -78 °C
Yield: 57.7 %

Procedure:
A solution of N-(4-acetyl-5-benzyloxy-2-bromo-phenyl)-acetamide (1.03 g, 2.85 mmol) in anhydrous THF (20 ml) under nitrogen was cooled to −78° C. followed by the dropwise addition of LDA (2.1 ml, 2M solution, 4.3 mmol). The reaction was continued to stir for an hour at −78° C. and then quenched with allyl bromide (0.44 ml, 2.85 mmol). The reaction was allowed to warm to room temperature and continued to stir overnight. The solution was partitioned between EtOAc and water. The organics were collected and washed with water, brine and then dried (MgSO4). Purification by column chromatography in hexane/EtOAc (1:1) afforded a white solid (0.662 g, 58%). LC/MS: RT=2.703 min. 402/404 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[C:10]([O:11]CC2C=CC=CC=2)=[CH:9][N:8]=[C:7]([N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([C:30]#[N:31])=[CH:20]2)[CH:6]=1)[CH3:2].CO>[C].[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[C:10]([OH:11])=[CH:9][N:8]=[C:7]([N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]([C:30]#[N:31])=[CH:20]2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(-n2cc(C#N)c(-c3ccccc3)c2)ncc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1cc(-n2cc(C#N)c(-c3ccccc3)c2)ncc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-benzyloxy-2-(3-cyano-4-phenylpyrrole-1-yl)isonicotinic acid ethyl ester in a mixed solvent of methanol (2 mL) and ethyl acetate (2 mL) was added palladium-carbon powder (0.020 g), and this mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. The insoluble material was removed by suction through a Celite pad. This filtrate was concentrated under reduced pressure. This obtained solid was washed with diethyl ether, dried to give the title compound (0.040 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19].[Cl-].[Ca+2].[Cl-]>>[Cl:17][S:18]([C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[C:5](=[O:16])[C:6]=2[CH:7]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: O=c1c2ccccc2oc2ccc(Cl)cc12
Agent: [Ca+2]
Agent: [Cl-]
Product: O=c1c2cc(Cl)ccc2oc2ccc(S(=O)(=O)Cl)cc12
Temperature: 120 °C
Yield: 98.1 %

Procedure:
80 g (0.347 moles) of 2-chloroxanthone (DHAR, J. Chem. Soc. 117, 1068) are suspended in 210 ml of chlorosulfonic acid (368.1 g; 3.16 moles) in a 500 ml one neck flask provided with refluxing coolant and calcium chloride valve. The mixture is slowly heated in an oil bath up to 120° C. under magnetic stirring. It is maintained at 120°-130° C. until the gas development ceases (2-3 h). The cool reaction mixture is carefully dropwise added to a becker containing ground ice under mechanical stirring. A heavy crystalline product is separated which is filtered on Buchner and washed with iced H2O. It is dried in air. There are obtained 112 g (98%) of raw 2-(chlorosulfonyl) 7-chloroxanthone. After TLC monitoring (silica gel F245 ; toluene, acetic acid 14:1, visualizer UV) the product is used as such for the next reaction.
Reaction SMILES: [Na].[CH2:2]([CH:4]([CH2:12][CH3:13])[CH2:5][CH2:6]C(OCC)=O)[CH3:3].[C:14]([O:21][CH2:22][CH3:23])(=[O:20])[C:15]([O:17]CC)=O>C(O)C>[CH2:2]([CH:4]([CH2:12][CH3:13])[CH2:5][CH2:6][C:15](=[O:17])[C:14]([O:21][CH2:22][CH3:23])=[O:20])[CH3:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CCC(CC)CC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CCC(CC)CC
Yield: 50.7 %

Procedure:
In 100 ml of ethanol is dissolved 4.5 g of sodium, and 27.8 g of ethyl 4-ethylhexanoate and 29 g of diethyl oxalate are added to the solution, and the low-boiling substance is removed by evaporation under reduced pressure at about 70° C. for 40 minutes. After cooling, 500 ml of water and 300 ml of petroleum ether are added to the brown viscous residue, and the mixture is thoroughly shaken. The aqueous layer is separated off and the petroleum layer is extracted twice with 50 ml each of 1N sodium hydroxide solution. The extracts are combined, acidified slightly with concentrated hydrochloric acid and extracted twice with 200 ml each of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. One hundred and ten (110) ml of 10% aqueous dimethylsulfoxide and 10 g of sodium chloride are added to the oily residue, and the mixture is stirred at 160° C. for 2.5 hours. After the reaction mixture is cooled, 500 ml of water is added, followed by extraction with 300 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue is distilled under reduced pressure to give 16.4 g of ethyl 5-ethyl-2-oxoheptanoate as a pale yellow oil.
Reaction SMILES: F[C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.O.[NH2:22][NH2:23]>C(O)C>[F:19][C:15]1[CH:14]=[C:13]([C:12]2[C:3]3[C:2](=[C:9]([O:10][CH3:11])[CH:8]=[C:5]([C:6]#[N:7])[CH:4]=3)[NH:23][N:22]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C#N)cc(C(=O)c2cccc(F)c2)c1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C#N)cc2c(-c3cccc(F)c3)n[nH]c12
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a solution of 640 mg of 4-fluoro-3-(3-fluorobenzoyl)-5-methoxybenzonitrile in 6 ml ethanol was added 3 ml of hydrazine monohydrate at room temperature, followed by stirring at 70° C. for one day. The reaction mixture was evaporated, and the resulting crystals were collected by filtration. The crystals were sequentially washed with ethanol and diethyl ether, to give 590 mg of the title compound as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=2[O:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>CC#N>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[O:13][C:11]1[CH:10]=[CH:9][C:8]2[C:4]([CH2:3][CH2:2][OH:1])=[CH:5][O:6][C:7]=2[CH:12]=1
Reactant: OCCc1coc2cc(O)ccc12
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCCc1coc2cc(Oc3nc4ccccc4s3)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a solution of 3-(2-hydroxy-ethyl)-benzofuran-6-ol (0.42 g, 2.4 mmol) in MeCN (10 mL) was added Cs2CO3 (0.77 g, 2.4 mmol) and 2-chlorobenzthiazole (0.29 mL, 2.4 mmol) and the reaction mixture was stirred (rt, 15 h) and then heated (60° C., 2 h). The reaction mixture was cooled (rt) and partitioned with EtOAc and brine (50 mL each). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-100%) to provide the title compound as an amber oil (0.37 g, 50%). MS (ESI): mass calcd. for C17H13NO3S, 311.4; m/z found, 312.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.73 (d, J=8.0, 1H), 7.67 (d, J=8.0, 1H), 6.61 (d, J=8.5, 1H), 7.58 (br s, 1H), 7.53 (d, J=2.0, 1H), 7.41-7.37 (m, 1H), 7.29-7.26 (m, 2H), 3.97-3.93 (m, 2H), 3.96 (t, J=6.5, 2H), the hydroxyl proton was not detected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[K+]>>[C:5]([C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])#[N:6]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.5 %

Procedure:
m-Fluorobenzonitrile (96.8 g., 0.8 mole) is added in two and one-half hours to a mixture of concentrated sulfuric acid (600 ml.) and potassium nitrate (80.9 g., 0.8 mole) at 3°-6° C., then allowed to warm to 25° C. The mixture is poured over cracked ice (3000 ml.), extracted with chloroform (5 × 250 ml.), dried and the solvent removed. The residue is extracted with pentane and dried to give 3-cyano-4-nitrofluorobenzene (115 g., 86.5%) m.p. 102°-104° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.C([Li:15])CCC>>[Li:15][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1]
Reactant: [Li]CCCC
Reactant: CC1(C)CCCC(C)(C)N1
Product: [Li]N1C(C)(C)CCCC1(C)C
Temperature: -70 °C

Procedure:
After cooling 35 ml of tetradydrofuran to -70° C., 2.1 g (15 mmol) of 2,2,6,6-tetramethylpiperidine and 15 mmol of n-butyl lithium were successively added thereto to obtain a lithium tetramethylpiperidide solution. Separately, 2.04 g (15 mmol) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiouracil was dissolved in 20 ml of tetrahydrofuran and added dropwise to the said lithium tetramethylpiperidide solution to react for an hour at -70° C. Then, a solution of 3.81 g (15 mmol) of iodine in 20 ml of tetrahydrofuran was further added to the reaction solution while maintaining the reaction temperature at -70° C. to react for an hour. After the completion of the reaction, the reaction solution was added to 0.8 ml of acetic acid, allowed to warm to room temperature and distributed between a chloroform layer and a saturated aqueous solution of sodium bicarbonate. The chloroform layer was concentrated to dryness. The residue was crystallized from petroleum ether to obtain 1.835 g of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-5-iodo-6-phenylthiouracil (Yield: 62.8%).