Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[CH3:22].O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=2)=[CH:15][C:14]=1[CH3:22]
Reactant: FC(F)(F)c1nsc(Cl)n1
Reactant: COc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2nc(C(F)(F)F)ns2)cc1C
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
5-Chloro-3-(trifluoromethyl)-1,2,4-thiadiazole (2.26 g, 12.0 mmol) (synthesis described in DE 3228147) was dissolved in 1,2-dimethoxyethane (50 mL) and 4-methoxy-3-methylphenylboronic acid (2.4 g, 14.4 mmol) and tetrakis(triphenylphosphine)palladium (0.1 g, 0.09 mmol) were added. After 1.5 h at rt, Na2CO3 (19.2 mL, 2M aqueous solution) was added and the mixture was stirred for 4 h at 80° C. and for 14h at rt. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. Due to low conversion the crude product was again reacted with 5-chloro-3-(trifluoromethyl)-1,2,4-thiadiazole (2.4 g, 14.4 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.09 mmol) in DME (50 mL) and Na2CO3 (19.2 mL, 2M aqueous solution). After stirring at 80° C. for 16 h, the reaction mixture was cooled and water was added. The mixture was extracted with ethyl acetate, the organic phase dried over MgSO4, filtered and concentrated under reduced pressure. The crude product (3.2 g) had a purity of ˜90% and was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH:4]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][NH:24][C:25]([C:27]3[O:28][C:29]([O:32][C:33]4[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=4)=[CH:30][CH:31]=3)=[O:26])[CH:19]=2)[C:14]=1[Br:41])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].O>CO>[Br:41][C:14]1[C:15]2[C:20](=[CH:19][C:18]([CH2:23][NH:24][C:25]([C:27]3[O:28][C:29]([O:32][C:33]4[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=4)=[CH:30][CH:31]=3)=[O:26])=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:42])=[O:2]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)ccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
A mixture of 2-[1-bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (0.34 g, 0.508 mmol), prepared in the previous step, 1N NaOH (1.50 mL, 1.5 mmol), 5 mL of water and 50 mL of methanol was stirred under nitrogen at room temperature for 18 h (overnight). The methanol was removed under reduced pressure. The solid that formed was collected by filtration and identified as the sodium salt salt of 2-[1-bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid (0.1537 g, 46%). The clear filtrate was acidified with 1N HCl. The solid that precipitated was collected by filtration and dried under reduced pressure to give the title compound (0.0905 g, 27%) as a white solid, mp 86-100° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:11])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)cc(F)c1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Br)cc(F)c1F
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a solution of 5-bromo-2,3-difluorophenol (19 g, 90 mmol) in acetone (180 mL), K2CO3 (18 g, 0.13 mol) and iodomethane (25.8 g, 0.18 mol) were added. The resulting mixture was refluxed for 4 h. Upon completion, the mixture was cooled to room temperature and filtered, and the filtrate was evaporated to give the crude product, which was further purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=80/1-40/1) to give a light yellow liquid 5-bromo-1,2-difluoro-3-methoxybenzene (19 g). 1H NMR (CDCl3): δ 7.00-6.88 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1.IC.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:1])(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Procedure R′: A 15 mL DMF mixture of 4-bromo-N-tert-butyl-benzenesulfonamide (1022 mg, 3.5 mmol), iodomethane (0.44 mL, 7 mmol), and K2CO3 (987 mg, 7 mmol) is stirred at room temperature overnight. Water and ethyl acetate are added to the mixture. The aqueous layer is extracted several times with ethyl acetate. The combined organic layers are washed with H2O and brine, then dried over Na2SO4 and evaporated. The crude product is purified by silica-gel column chromatography (gradient: 100% CH2Cl2 to 20% EtOAc/CH2Cl2) give the intermediate 4-bromo-N-tert-butyl-N-methyl-benzenesulfonamide (1040 mg, 97% yield). MS (ES+) 251.9 (M-tBu)+, NMR (CDCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([O:20][CH2:21][C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=[N:24][CH:23]=3)=[N:10][C:9]=2[C:46]#[N:47])[CH:5]=[CH:6][CH:7]=1.CO>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([O:20][CH2:21][C:22]3[NH:26][CH:25]=[N:24][CH:23]=3)=[N:10][C:9]=2[C:46]#[N:47])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(OCc3cncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)nc(C#N)c(-c3cccc(F)c3)c2c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(OCc3cnc[nH]3)nc(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 2.5 h

Procedure:
4-(3-fluorophenyl)-6-methoxy-1-[(1-trityl-1H-imidazol-5-yl)methoxy]isoquinoline-3-carbonitrile (255 mg) was dissolved in 4 mL of 5% TFA in CH2Cl2 at 0 C to give a bright yellow solution. The reaction was stirred at 0 C for 2.5 h, then at room temp for 1.5 h. MeOH was added, and the reaction was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The aqueous solution was further extracted with CH2Cl2 (3×). The combined organic solutions were dried over MgSO4 and concentrated. The white solid residue was recrystallized from CH2Cl2-EtOAc to give white solid. The mother liquor was concentrated and purified by flash chromatography (0% to 10% MeOH(10% NH4OH) in EtOAc to give additional white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[NH2:8].[C:13]1(=O)OC(=O)CCC1>>[N:5]1([C:6](=[O:9])[C:7]2[NH:8][CH:13]=[N:1][C:2]=2[N:3]([CH3:12])[C:4]1=[O:11])[CH3:10]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: O=C1CCCC(=O)O1
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O

Procedure:
Following the method of Cook et al., Res. Comm. Chem. Path. Pharm. 13:497(1976), 4,5-diamino-1,3-dimethylpyrimidine-2,6-dione is heated with glutaric anhydride to yield the following: ##STR11##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1)[NH2:18]
Reactant: NN
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Solvent: O
Solvent: CCO
Product: NNc1nc(C(F)(F)F)nc2ccccc12

Procedure:
4-Chloro-2-trifluoromethylquinazoline (46.4 g, 0.2 mole) was taken up in ethanol (500 ml). Hydrazine hydrate (20 ml, 0.4 mole) was added and the contents refluxed for 2 hours. On cooling, the yellow precipitate was filtered and slurried in water (500 ml) to removed hydrazine hydrochloride. Filtration gave the product as a yellow crystalline solid, 34.5 g (76%).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][CH:43]3[CH2:49][CH2:48][CH:47]4[CH:45]([C:46]4([F:51])[F:50])[CH2:44]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[N:57]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1>>[N:57]1([S:61]([NH:64][C:36](=[O:38])[C:35]2[CH:39]=[C:31]([CH:28]3[CH2:29][CH2:30]3)[C:32]([O:41][CH2:42][CH:43]3[CH2:49][CH2:48][CH:47]4[CH:45]([C:46]4([F:50])[F:51])[CH2:44]3)=[CH:33][C:34]=2[F:40])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC3C(C2)C3(F)F)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCC3C(C2)C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.025 g, 22%): 1H NMR (300 MHz, CDCl3) δ11.59 (br s, 1H), 7.11 (d, J=8.2 Hz, 1H), 7.03-6.87 (m, 1H), 4.14-3.77 (m, 6H), 2.94-2.50 (m, 1H), 2.43-1.49 (m, 8H), 1.48-1.06 (m, 2H), 1.06-0.75 (m, 3H), 0.75-0.56 (m, 2H); MS (ES+) m/z 459.07 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C[C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH2:19]C(=O)O1.N1CCCC1C(O)=O.[CH3:32][S:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:43]=1[NH:42][CH:41]=[CH:40]2>C(#N)C.[Cu].C(O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]([C:40]1[C:39]2[C:43](=[C:35]([CH2:34][S:33][CH3:32])[CH:36]=[CH:37][CH:38]=2)[NH:42][CH:41]=1)[CH2:19][C:20]([O:22][CH2:15][CH3:23])=[O:21]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: [Cu]
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1F)c1c[nH]c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.54 g (8.00 mmol) of 2-fluoro-4-(trifluoromethyl)benzaldehyde, 1.15 g (8.00 mmol) of Meldrum's acid and 44 mg (0.38 mmol) of D,L-proline were added to a solution of 1.50 g (7.62 mmol) of the compound from Example 8A in 62 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated to result in 4.47 g of a crude product which was introduced into 48 ml of pyridine and 12 ml of ethanol, and 4 mg (63 μmol) of copper powder were added. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 2.74 g (82% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH:26][CH2:27][C@H:28]([OH:30])[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([N:26]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1)[CH2:27][C@H:28]([OH:30])[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Reactant: C[C@@H](O)CNCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H](O)CN(Cc1ccccc1)c1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.3 %

Procedure:
2,6-Dibromo-3-nitropyridine (2.59 g, 9.20 mmol) and triethylamine (2.70 mL, 19.37 mmol) were added to a solution of (R)-1-(benzylamino)propan-2-ol (1.6 g, 9.68 mmol) in ethanol (35 mL). The solution was stirred at rt for 17 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution (25 mL). The layers were separated, and the organic layer was washed with 5% aqueous sodium chloride solution (25 mL). The ethyl acetate layer was concentrated under reduced pressure to afford an orange syrup. The crude product was purified by column chromatography on silica gel (eluting with 5:1 hexanes-ethyl acetate followed by 3:1 hexanes-ethyl acetate) to afford (R)-1-(benzyl(6-bromo-3-nitropyridin-2-yl)amino)propan-2-ol (3.01 g, 85%) as a bright yellow syrup. MS (ESI, pos. ion) m/z 388, 390 [M+Na]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[O:27]=[C:28]1[N:32]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[NH:29]1>CS(C)=O>[CH3:24][C:21]1[O:22][C:23]2=[C:15]3[C:16](=[CH:17][CH:18]=[C:19]2[N:20]=1)[O:25][CH2:26][CH:13]([CH2:12][N:36]1[CH2:35][CH2:34][CH:33]([N:32]2[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[NH:29][C:28]2=[O:27])[CH2:38][CH2:37]1)[O:14]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCC(n2c(=O)[nH]c4ccccc42)CC1)CO3
Temperature: 82 °C

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.43 g, 1.14 mmole) and 4-(2-keto-1-benzimidazolinyl)-piperidine (0.77 g, 3.54 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated to 82° C. under nitrogen for 4 hours. After completion, the reaction was allowed to cool to room temperature and was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute 0.4 g of the (S)-enantiomer of the title compound, m.p. 218-220° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH:13]1([C:16]2[CH:17]=[C:18]([CH3:28])[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[C:18]([CH3:28])=[CH:17][C:16]([CH:13]4[CH2:14][CH2:15]4)=[CH:21][N:20]=3)[CH2:23][CH2:24]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Yield: 95.4 %

Procedure:
Using 4-bromo-2-fluorobenzoyl chloride (2.5 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (2.7 g) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (4.2 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([O-:22])=[O:21].O1CCOCC1>N1CCCCC1.C(O)C>[N+:20]([CH:23]([CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:11][C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([O-:22])=[O:21]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Solvent: CCO
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C(CC(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 19.7 %

Procedure:
A mixture of 3-(3-nitrophenyl)-1-phenyl-2-propen-1-one (0.5 g), ethyl nitroacetate (0.29 g), piperidine (3 drops), dioxane (5 ml) and ethanol (5 ml) was refluxed for 2 hours. After allowing to cooling at ambient temperature, the reaction mixture was evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (50 ml) eluting with benzene. The fractions containing the object compound were combined and concentrated under reduced pressure to give ethyl 2-nitro-3-(3-nitrophenyl)-5-oxo-5-phenylpentanoate (0.15 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH2:11][Cl:12])=[CH:4][N:3]=1.C(Cl)(Cl)Cl.N1C=CC=CC=1.[C:23](Cl)(Cl)=[O:24]>C1C=CC=CC=1>[ClH:12].[Cl:12][CH2:11][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[C:7]2[O:8][C:23](=[O:24])[O:10][CH2:9][C:6]=12
Reactant: O=C(Cl)Cl
Reactant: Cc1ncc(CCl)c(CO)c1O
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ncc(CCl)c2c1OC(=O)OC2
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.01 mole of 2-methyl-3-hydroxy-4-hydroxymethyl-5-chloromethylpyridine in 50 ml. chloroform and 50 ml. of pyridine is added at 0°-5°C. a solution of 0.011 mole of phosgene in benzene. The mixture is allowed to warm to room temperature and is stirred overnight. The mixture is then concentrated in vacuo and excess saturated sodium bicarbonate solution is added. The precipitate is collected on a filter and sucked dry.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:11][NH:12][C:13]([N:15]1[CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]1)=[O:14]>CN(C)C=O.O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH:17]1[CH2:18][N:15]([C:13]([NH:12][CH3:11])=[O:14])[CH2:16]1
Reactant: Oc1cccc(F)c1
Reactant: CNC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)N1CC(Oc2cccc(F)c2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A stirred slurry of 0.38 g (0.02 mole) of 60% sodium hydride as a mineral oil suspension in 10 ml of dry dimethylformamide was treated under nitrogen with the dropwise addition of 1.12 g (0.01 mole) of 3-fluorophenol in 20 ml of dimethylformamide. After 1 hr, the mixture was heated at 90° C. for 20 min then 2.1 g (0.01 mole) of N-methyl-3-[(methanesulfonyl)oxy]-1-azetidinecarboxamide was added as a solid. The reaction mixture was then stirred at 90° C. for 8 hr. The reaction mixture was cooled by adding ice water then further diluted to 200 ml with water and extracted with 3×50 ml of methylene chloride. Less than 1 g of oil was obtained upon concentrations of the extracts. Extraction with 4×50 ml of benzene gave only a trace of product. The mass spectrum (CI) showed the expected p+1 at 225 m/e. The product solidified on standing and was recrystallized from methanol/water to yield 650 mg (29.0%) of flake-like silver crystals, m.p. 156°-158° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]NC(=O)C.O>C(Cl)Cl>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(=O)NBr
Solvent: O
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 7.8 mmol) in CH2Cl2 (25 ml) was added N-bromoacetamide (1.186 g, 8.6 mmol) in CH2Cl2 (25 ml). The mixture was heated at reflux temperature for 40 mins, then cooled to room temperature, and concentrated under vacuum to give an off-white solid. Cold water (40 ml) was added to the solid, which was then collected by filtration, washed with cold water (5 ml), and dried under vacuum. The product was recrystallized from a minimum amount of isopropanol to yield pure 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.475 g, 81.5%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:4][C:3]=1[OH:15].[C:16]1([CH3:25])[C:17]([N:22]=[C:23]=S)=[CH:18][CH:19]=[CH:20][CH:21]=1>C(O)C>[CH3:9][O:8][C:7]1[C:2]2[N:1]=[C:23]([NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:25])[O:15][C:3]=2[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=1
Reactant: Cc1ccccc1N=C=S
Reactant: COC(=O)Cc1cc(O)c(N)c(OC)c1
Solvent: CCO
Product: COc1cc(CC(=O)O)cc2oc(Nc3ccccc3C)nc12
Temperature: 45 °C
Reaction time: 72 h
Yield: 96.3 %

Procedure:
A mixture of methyl 4-amino-3-hydroxy-5-methoxy-phenylacetate [0.295 g, Reference Example 10(a)] and o-tolylisothiocyanate (2.14 g) in ethanol (25 mL) was left at room temperature for 3 days. The mixture was evaporated and a solution of the residue in ethanol (20 mL) was treated with dicyclohexylcarbodiimide (0.308 g). The mixture was heated at reflux temperature for 2.5 hours and then evaporated. The resulting brown oil was dissolved in methanol (30 mL) and the solution was treated with sodium hydroxide solution (10 mL, 1M) and then heated at 45° C. for one hour. The mixtures was diluted with water and then partially evaporated. The residue was washed twice with diethyl ether and the pH of the aqueous phase was adjusted to 1-2 by addition of dilute hydrochloric acid. The mixture was then extracted with ethyl acetate and the organic phase was washed with water, then with brine, then dried and then evaporated to give the title compound (0.42 g) as a golden solid.
Reaction SMILES: [OH:1][CH:2]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:3][CH2:4][C:5]1[C:12]2[C:8]([O:9][C:10](=[O:13])[CH:11]=2)=[CH:7][C:6]=1[OH:14].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.[C:30]([O-:33])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][CH:15]1[CH:2]([O:1][CH:4]1[CH2:3][CH2:2][CH2:15][CH2:30][O:33]1)[CH2:3][CH2:4][CH:5]1[CH:12]2[CH:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][CH:6]1[O:14][CH:29]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1
Reactant: O=C([O-])O
Reactant: C1=COCCC1
Reactant: O=C1C=C2C(=CC(O)=C2CCC(O)C2Cc3ccccc3C2)O1
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CC2C(CC(OC3CCCCO3)C2CCC(OC2CCCCO2)C2Cc3ccccc3C2)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
Compound 36 from above was dissolved in CH2Cl2 (30 mL) and the mixture was cooled to 0° C. 3,4-dihydro-2H-pyran was added (0.42 g, 5.0 mmol), followed by P-toluenesulfonic acid monohydrate (50 mg, 0.2 mmol). The solution was stirred at room temperature for 2 h, poured into saturated aqueous NaHCO3, and extracted with CH2Cl2. The solution was dried over MgSO4, filtered, and concentrated, and the residue was chromatographed on silica gel to afford 0.4 g (36%) of 37 as a viscous oil. 1H NMR (CDCl3) δ 7.2 (m, 4 H), 5.0 (m, 1 H), 4.7 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[Cl:12][C:10]1[CH:11]=[C:2]([CH:23]=[O:24])[CH:3]=[C:4]2[C:9]=1[O:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC1(C)CCOc2c(Cl)cc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCOc2c(Cl)cc(C=O)cc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
6-Bromo-8-chloro-4,4-dimethyl-3,4-dihydro-2H-chromene (483 mg, 1.75 mmol) in THF (12.0 mL) under N2 atmosphere was cooled to −78° C., and n-BuLi (841 μL, 2.10 mmol) was added dropwise via a syringe. The reaction mixture was stirred at −78° C. for 10 minutes and then DMF (543 μL, 7.01 mmol) was added dropwise via a syringe. The resulting mixture was allowed to warm to room temperature and wet silica gel (5.0 g/0.5 mL of water) was added. The mixture was allowed to stir at room temperature for 10 minutes before it was filtered. The silica gel was rinsed with EtOAc, and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to obtain the title compound as a white solid.