Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]([CH:10]([OH:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].[CH3:20]O>>[NH2:5][C@@H:6]([C@H:10]([OH:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: COc1ccc(C(O)C(N)C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)[C@H](O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Thionyl chloride (12.3 mL, 169 mmol) was added dropwise to methanol (250 mL) at 0° C. followed by addition of 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoic acid (25.0 g, 118 mol). The reaction mixture was stirred at ambient temperature for 1 h and heated under reflux for 3 h. The mixture was cooled to ambient temperature and then concentrated to dryness. The residue was purified by flash column chromatography on silica gel (DCM/methanol=60:1) to afford (2S,3R)-methyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (15.7 g, 59% yield, threo-) as a colorless oil. Further separation by chiral preparative HPLC afforded (2S,3R)-methyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (7.0 g, 45% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)c(Cl)c1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 350 g of 4-nitro-3-(3,4-dichlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(3,4-dichlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][C:7]1[N:8]=[CH:9][C:10]([NH:13]C(=O)OC(C)(C)C)=[N:11][CH:12]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([CH2:5][CH2:6][C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CCS(C)(=O)=O)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)CCc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 5-(2-(methylsulfonyl)ethyl)pyrazin-2-ylcarbamate (320 mg, 1.062 mmol) in DCM (6 mL) was added TFA (2.5 mL, 32.4 mmol) and stirred at room temperature for 1 hour. The solvent was concentrated off to constant mass. The product was free based by using solid supported carbonate 2.5 grams at 0.8 mmol/gram with 6 mL of acetonitrile and stirred for 5 min. The solid support was filtered off and flush with acetonitrile. The product was concentrated to constant mass to give the desired product used as is, assume quantitative yield (1.062 mmol). LCMS (m/z): 202.1 (MH+), 0.20 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:39]>>[CH3:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:32]=1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1CBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: Cc1cccc(C)c1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-1,3-dimethylbenzene following the procedure of Example 478: MS (ES) m/z 511.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.[Li][CH3:17]>C(OCC)C>[CH3:15][C:2]1([CH3:1])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12](=[O:14])[CH3:17]
Reactant: [Li]C
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Solvent: CCOCC
Product: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (220 mg, 1.00 mmol) in diethyl ether (10 mL) is added a solution of MeLi (1.6 M, 1.4 mL, 2.10 mmol) in diethyl ether at such a pace that the reaction mixture is refluxing gently. Upon completion of the addition stirring is continued at rt for 30 min. The reaction is quenched by adding sat. aq. NH4Cl (3 mL). The organic layer is separated, dried over Na2SO4 and the solvent is evaporated to give the title compound (165 mg) as a pale yellow oil. LC-MS: tR=1.03 min, [M+1]+=221.20; 1H NMR (CDCl3): δ 3.00 (ddd, J=1.8, 4.7, 18.8 Hz, 1H), 2.80 (d, J=18.8 Hz, 1H), 2.38 (s, 6H), 1.93-1.90 (m, 2H), 1.14 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: C(O)(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=O.[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14]>>[CH2:4]([O:6][C:9]1[CH:10]=[CH:2][C:3]([CH3:4])=[C:14]2[C:13]([O:16][C:17](=[O:19])[C:18]=12)=[O:15])[C:3]1[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1ccc(OCc2ccccc2)c2c1C(=O)OC2=O

Procedure:
The crude phthalic acid prepared above is heated in 150 ml acetic anhydride for two hours. The solvent is removed under reduced pressure and the crystalline residue collected and washed with ether. The anhydride may be recrystallized from nitromethane to give an analytical sample m.p. 200°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:38])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][C:19]=2[O:27][CH:28]2[CH2:37][CH2:36][C:31]3(OCC[O:32]3)[CH2:30][CH2:29]2)=[N:6][CH:7]=1.Cl.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:38])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][C:19]=2[O:27][CH:28]2[CH2:37][CH2:36][C:31](=[O:32])[CH2:30][CH2:29]2)=[N:6][CH:7]=1
Reactant: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCC3(CC2)OCCO3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.2 %

Procedure:
N-(5-Chloropyridin-2-yl)-2-[2-(1,4-dioxaspiro[4.5]dec-8-yloxy)-4-isopropyl-benzoylamino]benzamide (960 mg, 1.75 mmol) was dissolved in THF (30 mL). The solution was cooled to ice-water bath temperature and 5 M HCl (5.6 mL, 28 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stir for 6 h. Water (100 mL) was added, and the pH was adjusted to 8 with 5 M NaOH. THF was removed on the rotary evaporator and the precipitated white solid was filtered, washed with water, and dried under vacuum to give 790 mg (90%) of the desired ketone as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]Br)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][C:27]1[NH:28][CH2:29][CH2:30][N:31]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:31]2[CH2:30][CH2:29][N:28]=[C:27]2[CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Reactant: CC1=NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2CCN=C2C)c1
Reaction time: 2 h

Procedure:
To (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.070 g, 0.17 mmol) and 2-methyl-2-imidazoline (0.017 g, 0.18 mmol) in DMF (1 mL) at 0° C. was added sodium hydride (60% in mineral oil; 0.011 g, 0.18 mmol), and the reaction was stirred for 2 hours. After work-up with EtOAc, H2O, and citric acid, the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[CH2:5][CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[Cl-].C[NH2+]C.[CH2:22]([N:24]([CH2:27]C)[CH2:25][CH3:26])C>CN(C)C=O>[CH3:27][N:24]([CH2:25][CH2:26][CH2:5][CH2:4][CH2:3][C:2]([NH:17][CH2:16][CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=12)=[O:1])[CH3:22]
Reactant: CCN(CC)CC
Reactant: NCCc1c2n(c3ccccc13)C(=O)CCC2
Agent: C[NH2+]C
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C)CCCCCC(=O)NCCc1c2n(c3ccccc13)C(=O)CCC2
Temperature: 90 °C

Procedure:
8.9 g (0.022 mole) D4, 3.2 g (0.44 mole) dimethylammonium chloride and 6 g triethylamine were dissolved in 150 ml N,N-dimethylformamide and heated for 6 h at 90° C. The solvent was evaporated in vacuo and the residue extracted with 100 ml chloroform and 100 ml water. The organic layer was separated and dried. The solvent was evaporated and the residue crystallised from ethyl acetate.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][C:11]1([C@@H:14]2[O:22][CH2:21][C:17]3=[N:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:13][CH2:12]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@:17]12[CH2:21][O:22][C@@H:14]([C:11]3([CH3:10])[CH2:12][CH2:13]3)[CH2:15][C@H:16]1[CH2:20][O:19][NH:18]2
Reactant: CC1([C@H]2C[C@H]3CON=C3CO2)CC1
Reactant: Fc1ccc(I)c(F)c1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1([C@H]2C[C@H]3CON[C@@]3(c3ccc(F)cc3F)CO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (7.86 g, 25.9 mmol) was added drop-wise to a solution of rel-(3aR,5R)-5-(1-methylcyclopropyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C56) (4.255 g, 23.5 mmol) in toluene (500 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 6.22 g, 25.9 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 9.9 mL, 24.8 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1.5 hours, then was quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (400 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 3.2 g, 10.8 mmol, 46%. LCMS m/z 296 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.92 (q, J=8.3 Hz, 1H), 6.88 (dt, J=8.4, 2.4 Hz, 1H), 6.78 (ddd, J=11.6, 8.8, 2.4 Hz, 1H), 6.28 (br s, 1H), 4.04 (dd, J=12.4, 1.6 Hz, 1H), 3.82 (d, J=12.8 Hz, 1H), 3.72 (d, J=6.8 Hz, 1H), 3.53 (dd, J=6.8, 4.8 Hz, 1H), 3.01-3.06 (m, 1H), 2.95 (d, J=12.0 Hz, 1H), 1.83 (dd, J=13.2, 6.0 Hz, 1H), 1.62 (q, J=12.4 Hz, 1H), 1.09 (s, 3H), 0.52-0.56 (m, 1H), 0.43-0.48 (m, 1H), 0.36-0.41 (m, 1H), 0.28-0.33 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)C=O.[CH:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]([C:19]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[S:20])[N:4]=[CH:5][N:6]=1
Reactant: S=C=NC1CCCCC1
Reactant: Nc1nc[nH]n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncnn1C(=S)NC1CCCCC1
Yield: 14 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (6.07 g), dimethylformamide (30 ml) and cyclohexyl isothiocyanate (20.5 ml) were used as reagents. After the reaction, the mixture was subjected to silica gel column chromatography (hexane-ethyl acetate), whereby 2.26 g of a white solid was obtained (yield 14%). The, solid was subjected to recrystallization from ethyl acetate to give colorless transparent crystals.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2I)[O:9][C:8]1=[O:24].C(O)C.[CH:37]([C:40]1[CH:41]=[CH:42][C:43]([O:49][C:50]([F:53])([F:52])[F:51])=[C:44](B(O)O)[CH:45]=1)([CH3:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.O.CCOC(C)=O.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>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[C:42]2[CH:41]=[C:40]([CH:37]([CH3:39])[CH3:38])[CH:45]=[CH:44][C:43]=2[O:49][C:50]([F:51])([F:53])[F:52])[O:9][C:8]1=[O:24]
Reactant: CC(C)c1ccc(OC(F)(F)F)c(B(O)O)c1
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
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: CCO
Solvent: c1ccccc1
Solvent: O
Product: CC(C)c1ccc(OC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2[C@H]2OC(=O)N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 80 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one in 2 mL of benzene, 1 mL of water, and 0.5 mL ethanol was added 100 mg of 5-isopropyl-2-(trifluoromethoxy)phenyl boronic acid, 0.15 mL of 2M aqueous sodium carbonate, and 21 mg of Pd(PPh3)4. A reflux condenser was attached, and the mixture was heated to 100° C. The mixture was stirred at 100° C. for 24 hours, and then was diluted with 10 mL of EtOAc and 10 mL of water. The phases were separated and the aqueous phase was extracted with 10 mL of EtOAc. The combined organic phases were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 2 to 100% over 10 CV. The product was repurified using the same conditions to provide the title compound. Mass spectrum (ESI) 674.4 (M+1).
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.CN1CCCC1=O>O>[CH3:13][C:14]1[CH:18]=[CH:17][N:16]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[N:15]=1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Reactant: Cc1cc[nH]n1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2nccc3[nH]c(=O)ccc23)n1
Temperature: 200 °C

Procedure:
A stirred mixture containing 13.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 18 ml of 3-methyl-1H-pyrazole and 75 ml of N-methylpyrrolidinone was heated in an oil bath at 170°-180° C. for 18 hours, after which a tlc analysis indicated some remaining starting material. The temperature of the oil bath was raised to 200° C.; and, the reaction mixture was heated for an additional 5 hours and then poured into water. The solid that separated was collected, dried and combined with 1.7 g of corresponding material obtained in another run starting with 2.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one. The combined solids were recrystallized from dimethylformamide and dried in an oven for three days at 100° C. to yield 6.6 g of 5-(3-methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.[I:14]I>O1CCCC1>[I:14][C:5]1[N:1]([CH2:6][CH2:7][OH:8])[N:2]=[CH:3][CH:4]=1
Reactant: II
Reactant: OCCn1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCCn1nccc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a cold (0° C.) solution of 2-pyrazol-1-yl-ethanol (0.5 g, 4.46 mmol) in tetrahydrofuran (15 mL), under an atmosphere of nitrogen, was added N,N,N′,N′-tetramethyl-ethylenenediamine (1.34 ml, 8.92 mmol, 2.0 eq.) followed by n-butyllithium (2.5M in hexane, 4.0 ml, 10 mmol, 2.2 eq.) at such a rate as to maintain the temperature below 5° C. The resulting yellow solution was stirred at 0° C. for 0.5 hr before adding a solution of iodine (1.36 g, 5.35 mmol, 1.2 eq.) in tetrahydrofuran (10 mL). The resulting mixture was stirred for 20 min before concentrating the mixture by evaporation under reduced pressure. The residue was partition between ethyl acetate (50 mL) and aqueous citric acid (1M, 100 ml). The organic phase was washed with 10% aqueous sodium thiosulphate solution, saturated brine (20 mL) and dried over sodium sulphate. The resulting mixture was filtered and the filtrate concentrated under reduced pressure to give a brown oil. The crude oil was purified by chromatography on silica gel (60 g) eluting with a gradient of ethyl acetate in heptane (50:50) to give the title compound as a white solid (0.4 g, 38%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([F:30])=[C:6]([CH3:29])[CH:7]=[CH:8][C:9]([F:28])=[C:10]([C:13]1[C:22]([OH:23])=[CH:21][C:20]2[C:19]([CH3:25])([CH3:24])[CH2:18][CH2:17][C:16]([CH3:27])([CH3:26])[C:15]=2[CH:14]=1)[CH2:11][CH3:12])[CH3:2].C(O[C:35](=O)/[C:36](/F)=[C:37](\C)/C=C/C(/F)=C(\C1C(O)=CC2C(C)(C)CCC(C)(C)C=2C=1)/CC)C.C([O-])([O-])=O.[K+].[K+].C(I)CC>CC(C)=O>[CH2:1]([O:3][C:4](=[O:31])/[C:5](/[F:30])=[C:6](\[CH3:29])/[CH:7]=[CH:8]/[C:9](/[F:28])=[C:10](\[C:13]1[C:22]([O:23][CH2:35][CH2:36][CH3:37])=[CH:21][C:20]2[C:19]([CH3:24])([CH3:25])[CH2:18][CH2:17][C:16]([CH3:27])([CH3:26])[C:15]=2[CH:14]=1)/[CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)/C(F)=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C(F)=C(C)C=CC(F)=C(CC)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCI
Solvent: CC(C)=O
Product: CCCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure F and using 2,6-difluoro-7-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-nona-2,4,6-trienoic acid ethyl ester (Intermediate 24, 2-E/Z mixture, 180 mg, 0.42 mmol), K2CO3 (290 mg, 2.1 mmol), and PrI (0.21 mL, 2.1 mmol) in acetone (2 mL), followed by HPLC (2.5% EtOAc-hexane) separation of the 2-E/Z product mixture, the title compound was obtained as a clear syrup (80 mg, 41%).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl[C:13]1[N:14]=[CH:15][S:16][CH:17]=1>C(O)C>[C:2]1([CH2:1][S:8][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cscn1
Reactant: SCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(CSc2cscn2)cc1
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
Benzylmercaptan (24.8 g) was added slowly to a solution of 10.8 g of sodium methoxide in 100 ml ethanol. After 10 minutes, the reaction mixture was heated to 65° and a solution of 23.8 g of 4-chlorothiazole [prepared by the method of P. Reynaud et al., Bull. Soc. Chim. France, 1735 (1962)] in 25 ml ethanol was added dropwise. When addition was complete, the reaction mixture was refluxed 36 hours. The reaction mixture was cooled, and the bulk of the solvent evaporated. Cold water (300 ml) was added to the residue, and the aqueous mixture was extracted with 200 ml ether followed by 200 ml methylene chloride. The combined organic solution was washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated. Distillation of the resulting yellow oil gave 15.6 g of 4-(phenylmethylthio)thiazole, bp 122-134 (0.6 mm).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: Ic1ccccc1
Reactant: O=[N+]([O-])c1cc[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccn(-c2ccccc2)c1
Yield: 91.2 %

Procedure:
A mixture of 3-nitropyrrole (270 mg, 2.41 mmol), iodobenzene (0.267 mL, 2.39 mmol), 8-hydroxyquinoline (60 mg, 0.41 mmol) and K2CO3 (600 mg, 4.34 mmol) in DMSO (3 mL) was degassed with argon before being charged with CuI (45 mg, 0.23 mmol). The mixture in a sealed tube was heated at 130 C for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 3-nitro-1-phenyl-1H-pyrrole (410 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[C:5]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:3]1[C:2]([OH:1])=[C:7]([C:6]([CH3:13])=[C:5]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(O)ccc(OS(C)(=O)=O)c1C
Solvent: CC#N
Product: CCOC(=O)c1c(C)c(OS(C)(=O)=O)cc(Br)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
To a solution of ethyl 6-hydroxy-2-methyl-3-((methylsulfonyl)oxy)benzoate (116c, 1.3 g, 4.8 mmol) in acetonitrile (63 mL) was added N-bromosuccinimide (1.1 g, 6.2 mmol). The reaction was stirred at room temperature for 20 hours. The reaction mixture was concentrated under vacuum then diluted with water (30 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (30% EtOAc/Heptane) to give ethyl 3-bromo-2-hydroxy-6-methyl-5-((methylsulfonyl)oxy)benzoate (116d, 1.3 g, 79% yield) as a yellow solid.