Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[O:11][CH3:12].CN(C)CCN(C)C.C([Li])CCC.[CH:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>CCOCC.CCCCCC.O>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:26]([OH:33])[C:5]2[C:4]([CH3:10])=[C:3]([O:11][CH3:12])[C:2]([CH3:1])=[CH:7][C:6]=2[O:8][CH3:9])[CH:28]=1
Reactant: COc1cc(C)c(OC)c(C)c1
Reactant: O=Cc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: COc1cc(C)c(OC)c(C)c1C(O)c1cccnc1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
3.0 g of 1,3-dimethyl-2,5-dimethoxybenzene and 3.1 g of tetramethylethylenediamine were dissolved in 30 ml of dry ether and 17 ml of a 1.6M solution of n-butyllithium in hexane was added dropwise thereto in a nitrogen atmosphere at room temperature. After 1 hour, the mixture was cooled to -65° C. and a solution of 2.9 g of nicotinaldehyde in 10 ml of ether was added thereto. After 30 minutes, the reaction was ceased by adding water and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. After distilling off the solvent, 6.4 g of a crude product of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:9]([F:12])([F:11])[F:10])([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].C[Li].[CH2:17]([Li])CCC.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>>[C:22]([O:7][CH2:6][CH:5]([CH3:17])[CH2:4][C:3]([C:9]([F:10])([F:11])[F:12])([OH:8])[C:2]([F:13])([F:14])[F:1])(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: [Li]CCCC
Reactant: C=C(C)C(=O)Cl
Reactant: OCCCC(O)(C(F)(F)F)C(F)(F)F
Agent: [Li]C
Product: C=C(C)C(=O)OCC(C)CC(O)(C(F)(F)F)C(F)(F)F
Yield: 76 %

Procedure:
The title compound was prepared by method of Example 4, substituting 43 g (0.181 mol) of 1,1,1-trifluoro-2-trifluoromethyl-4-methyl-2,5-pentanediol (2) for 1,1,1-trifluoro-2-trifluoromethyl-2,5-pentanediol (4) and 226 mL (0.362 mol) of methyllithium (1.6M in ether) in lieu of the n-butyllithium, and using 20.7 g (0.199 mol) of methacryloyl chloride, to yield 35 g (76%) of the title compound as a clear colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[N:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=3)[C:9]2=[O:12])=[N:4][CH:3]=1
Reactant: Oc1nccc2ncc(Br)cc12
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)cnc2ccn1Cc1cccc(F)c1

Procedure:
The alkylation of 7-bromo-1-hydroxy-5-azaisoquinoline (1.00 g, 4.40 mmol) using 3-fluorobenzyl bromide (1.27 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 2-(3-Fluorobenzyl)-7-(3-phenyl-prop-1-ynyl)-2H-5-azaisoquinolin-1-one
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])(C)C.COC[O:20][CH3:21]>S(=O)(=O)(O)O>[CH2:1]([C:4]1[CH:1]=[C:5]([CH3:10])[CH:6]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:21]=1[OH:20])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]=1[OH:16]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COCOC
Agent: O=S(=O)(O)O
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Yield: 66.4 %

Procedure:
Into a reactor similar to that described in Example 1 hereinabove there are charged 220 g (1 g-mol) of 2,6-ditert.-butyl-4-methylphenol, 2.2 g of concentrated sulfuric acid and at the temperature of 120° C. 76 g (1.0 g-mol) of methylal are fed into the reactor for 1 hour. The reaction mass is treated following the procedure described in the foregoing Example 1 to give 112.9 g of 2,2'-methylene-bis-(4-methyl-6-tert.butylphenol) which constitutes 99.1% of theory, as calculated for the reacted 2,6-ditert.butyl-4-methylphenol (conversion of the latter is 67.0%). The unreacted methylal and 2,6-ditert.butyl-4-methylphenol are recycled back into the process.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)CC2.[C-]#N.[Na+].ClC1[N:18]=[C:17]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH:16]=C(C)N=1>CS(C)=O>[F:25][C:23]1[CH:24]=[C:19]([C:17]2[CH:16]=[C:6]([CH3:5])[N:1]=[C:8]([C:7]#[N:4])[N:18]=2)[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: Cc1cc(-c2cc(F)cc(F)c2)nc(Cl)n1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(-c2cc(F)cc(F)c2)nc(C#N)n1
Temperature: 32.5 °C
Reaction time: 3 h
Yield: 530 %

Procedure:
To a solution and 13 mg of 1,4-Diazabicyclo[2.2.2]octane (DABCO) in 5 ml of DMSO and 60 mg (1.22 mmol) of sodium cyanide were added 280 mg (1.16 mmol) of 2-Chloro-4-(3,5-difluoro-phenyl)-6-methyl-pyrimidine. After stirring for 3 h at 30-35° C., the mixture was worked according to standard procedures to yield the title compound (142 mg, 53%) as a light yellow crystalline solid, negative-ion MS (ISP): m/e=230.4 [M−H]−.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][SH:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>O.C(O)C>[CH2:12]([S:7][CH2:6][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: CC(CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCSCC(C)C(=O)O
Temperature: 0 °C

Procedure:
3-Allylsulfanyl-2-methyl-propanoic acid was prepared as described by Zhou et al. J. Org. Chem. 2004, 69, 7072. An ice-cold mixture of 2-methyl-3-sulfanyl-propanoic acid (5 g, 42 mmol) and sodium hydroxide (3.33 g, 83 mmol) in water (50 mL) was treated with a solution of allyl bromide (5.98 g, 49 mmol) in ethanol (100 mL) over 30 minutes. Ice bath was removed after 45 minutes and after 14 hours at room temperature, volatiles were removed under reduced pressure. The residue was cooled in ice, acidified to pH 6 with 1N HCl and extracted with ethyl acetate, washed with water, dried over MgSO4, concentrated under reduced pressure and dried in vacuo at room temperature for 14 hours to leave a clear liquid. Acidification of the aqueous layer to pH 4 afforded an additional 2.7 g of material. Total yield 4.44 g (74%): IR (KBr thin film) 1708 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.83-5.73 (m, 1H), 5.14-5.13 (m, 1H), 5.10-5.09 (m, 1H), 3.15 (d, J=7.3 Hz, 2H), 2.80 (dd, J=13.2, 7.0 Hz, 2H), 2.69 (sextet, J=7.1 Hz, 1H), 2.53 (dd, J=12.8, 6.5 Hz, 1H), 1.28 (d, J=7.1 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 179.01, 131.63, 114.92, 37.38, 32.72, 31.00, 14.19; EIMS m/z 160.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>ClCCl>[CH3:14][S:15]([O:6][CH2:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of 2-cyclopropylethanol (2.1 g, 24.4 mmol) in dichloromethane (50 ml) at 0° C. under nitrogen was added triethylamine (4.1 ml, 1.2 mol. equiv.). Methanesulphonyl chloride (2.5 ml, 1.3 mol. equiv.) was added, dropwise, and the reaction allowed to stir for 18 hours at room temperature. Water (50 ml) and dichloromethane (50 ml) were added. The organic phase was separated, washed with water (2×50 ml) and then dried over anhydrous sodium sulphate. The solution was filtered and the solvent removed from the filtrate by evaporation under reduced pressure to give the title compound as an oil (4 g). TLC Rf=0.9 (silica, methanol:dichloromethane, 1:19, by volume). LRMS m/z=182 (m+18)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.O>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][CH2:14][O:15][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])[CH3:12])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(CCO)S(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(CCO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 95.2 %

Procedure:
A solution of 4-bromo-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide (1.339 g) in chloroform (15 mL) was stirred in an ice bath, during which tert-butyldimethylchlorosilane (1.04 g) and N,N-dimethyl-4-aminopyridine (84 mg) were added thereto. Triethylamine were added dropwise, and the mixture was returned to room temperature and stirred for 16 hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→60:40) to give 4-bromo-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-methylbenzenesulfonamide as a colorless powder (1.77 g, 100%).
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[C:14]([CH3:26])=[N:15][N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]=2[O:18][CH3:19])=[CH:11][C:10]([CH3:27])=[N:9]1)=O)(C)(C)C.C(OC(N1C(C)=CC(C2C(C)=NN(C3C=CC=CC=3)C=2OC)=N1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][C:17]1[N:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[C:14]([CH3:26])[C:13]=1[C:12]1[NH:8][N:9]=[C:10]([CH3:27])[CH:11]=1
Reactant: COc1c(-c2cc(C)nn2C(=O)OC(C)(C)C)c(C)nn1-c1ccccc1
Agent: COc1c(-c2cc(C)n(C(=O)OC(C)(C)C)n2)c(C)nn1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(-c2cc(C)n[nH]2)c(C)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of O-methylated products, compounds (C) and (D) (0.013 g 0.035 mmol), in dichloromethane (1 ml) add trifluoroacetic acid (1 ml). Stir this mixture at room temperature for 1 hour, and then evaporate the mixture to dryness. Dilute the residue with dichloromethane, wash sequentially with water, aqueous sodium bicarbonate solution, and water. Dry the organic layer (sodium sulfate) and concentrate to give 0.006 g (0.022 mmol) of the title compound.
Reaction SMILES: [O:1]([CH:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.N[CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[OH:61][C:54]1[C:53]([CH2:52][CH2:20][NH:21][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH3:10])=[CH:19][CH:18]=2)=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: CCC(Oc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Oc1ccccc1)c1ccc(C(=O)NCCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Yield: 30.9 %

Procedure:
A mixture of 4-(1-phenoxypropyl)benzoic acid (256 mg, 1.0 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (570 mg, 1.5 mmol), triethylamine (0.45 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The mixture was washed with water (20 mL), dried over sodium, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)ethyl)-4-(1-phenoxypropyl)benzamide (Compound I-44) as a white solid (125 mg, 32%). LRMS (M+H+) m/z: calcd 390.19. found 390. HPLC purity (214 nm): 95%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.28 (t, J=5.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.17 (t, J=8.0 Hz, 2H), 6.87-6.83 (m, 3H), 5.84 (s, 1H), 5.27 (t, J=6.0 Hz, 1H), 4.27 (d, J=5.1 Hz, 2H), 2.68 (s, 3H), 2.51 (s, 3H), 1.89-1.80 (m, 2H), 0.92 (t, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[C:20]([CH3:32])([CH3:31])[O:21][C:22](=[C:26]([C:29]#[N:30])[C:27]#[N:28])[C:23]=2[C:24]#[N:25])=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N:33]([O-])=O.[Na+].[F:37][B-:38]([F:41])([F:40])[F:39].[H+]>O>[F:37][B-:38]([F:41])([F:40])[F:39].[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]2[C:20]([CH3:32])([CH3:31])[O:21][C:22](=[C:26]([C:29]#[N:30])[C:27]#[N:28])[C:23]=2[C:24]#[N:25])[CH:15]=[CH:16][C:2]=1[N+:1]#[N:33])([OH:12])=[O:11]
Reactant: O=N[O-]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1ccc(N)c(OCCCCCC(=O)O)c1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1ccc([N+]#N)c(OCCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-{2-amino-5-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-phenoxy}-hexanoic acid (0.30 g, 0.69 mmol) at 5° C. in 3.2 mls of fluoroboric acid (50%) was added a solution of sodium nitrite (0.29 g, 4.27 mmol) in 2 mls of water. The cooling bath was removed and the mixture was allowed to stir at room temperature for 2 hours. The resulting yellow solid, 2-(5-carboxy-pentyloxy)-4-[2-(4-cyano-5-dicyanomethylene-2,2-dimethyl-2,5-dihydro-furan-3-yl)-vinyl]-benzenediazonium tetrafluoroborate, was removed by vacuum filtration and air dried (0.35 g, 97%). 1H NMR (400 MHz, DMSO) δ: 8.66 (d, 1H, J=8.4 Hz), 8.07 (s, 1H), 7.97 (d, 1H, J=9.2 Hz), 7.86 (d, 1H, J=16.4 Hz), 7.55 (d, 1H, J=16.4 Hz), 4.52 (t, 2H, J=6.4 Hz), 2.27 (t, 2H, J=7.2 Hz), 1.86 (m, 2H), 1.83 (s, 6H), 1.61 (m, 2H), 1.53 (m, 2H). IR (neat): 2360, 2341, 2264, 2230, 1730, 1586, 1481, 1307, 1106.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.C[CH2:14][N:15](C(C)C)C(C)C.CN>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:3]=1)[NH:15][CH3:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Agent: CN
Solvent: CN(C)C=O
Product: CNc1cc(Cl)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloro 2,5-difluoro nitrobenzene (2.0 g, 0.010 mol) in DMF (15 ml) was added DIPEA (4.5 ml, 0.026 mol) followed by MeNH2 (5 ml, 0.010 mol, 2M in THF) and the resulting solution was stirred at room temperature for 12 h. The reaction was quenched with H2O and extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to get crude product which was purified column chromatography to get the title compound 5-chloro-4-fluoro-N-methyl-2-nitroaniline as a yellow solid, 1H NMR (400 MHz, DMSO-d6), δ: 8.20 (s, 1H), 8.09 (d, J=10 Hz, 1H), 7.22-7.20 (d, J=6.4 Hz, 1H), 2.95 (s, 3H). MS (M+1): 205.12
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[C:21]2[CH:20]([CH3:22])[CH2:19][N:18]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][C:16]=2[CH:15]=[C:14]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:40]=[O:41]>>[CH2:6]([N:13]1[C:21]2[CH:20]([CH3:22])[CH2:19][N:18]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:17][C:16]=2[C:15]([CH:40]=[O:41])=[C:14]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC1CN(Cc2ccccc2)Cc2cc(-c3ccccc3)n(Cc3ccccc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CN(Cc2ccccc2)Cc2c(C=O)c(-c3ccccc3)n(Cc3ccccc3)c21
Temperature: 50 °C

Procedure:
Phosphoryl chloride (1.68 g) was added dropwise to cooled dimethyl-formamide (1.60 g). A suspension of 1,5-dibenzyl-4,5,6,7-tetrahydro-7-methyl-2-phenyl-1H-pyrrolo[3,2-c]pyridine (3.92 g) in dimethylformamide (20 ml) was added portionwise. The resulting red solution was heated at 50° C for 4 hours, allowed to cool and poured on to 250 g ice. The mixture was basified with 2N sodium hydroxide, warmed gently for a few minutes, and the solid product collected by filtration, washed with water and dried. Two recrystallisations from methanol gave 2.86 g of the title compound as white needles. M.pt. 120°-1°. (Found: C, 83.2; H, 6.9; N, 6.5. C29H28N2O requires: C, 82.8; H, 6.7; N, 6.7%).
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC#N.[BrH:44].N([O-])=O.[Na+]>O>[Br:44][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 1 L 3-necked flask equipped with a magnetic stirrer was added 58.0 g (99.0 mmol) of methyl 2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate followed by 500 mL of MeCN and then 500 mL of 48% aqueous HBr. The dark brown solution was cooled to 0° C. in an ice water/brine bath and treated with a solution of 8.20 g (119 mmol) of sodium nitrite in 50 mL of water over a 5 minute period. After 30 minutes LCMS indicated complete consumption of the starting material. The solution was treated with 18.5 g (129 mmol) of CuBr over 2 minutes and then warmed to 50° C. After 30 minutes at 50° C. LCMS indicated complete reaction. The solution was cooled to RT and partitioned between 1 L of EtOAc and 1.5 L of water. The phases were separated and the aqueous solution extracted with EtOAc (2×200 mL). The combined EtOAc solutions were washed with 5% aqueous NaCl (1×1 L), 5% aqueous sodium bisulfite (2×300 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated aqueous brine (1×300 mL), and dried over sodium sulfate. The drying agent was removed by filtration through a pad of silica gel and the filtrate concentrated to dryness at reduced pressure to give 64.3 g of crude methyl 2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a reddish-brown foam. The crude product was carried forward without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (q, J=4.29 Hz, 1H) 8.16 (s, 1H) 7.92-8.03 (m, 2H) 7.79 (d, J=2.73 Hz, 1H) 7.65 (d, J=2.73 Hz, 1H) 7.41 (t, J=8.93 Hz, 2H) 7.24 (s, 1H) 3.81-3.89 (m, 3H) 3.45-3.53 (m, 3H) 2.85 (d, J=4.59 Hz, 3H) 2.04-2.16 (m, 1H) 0.71-1.07 (m, 3H) 0.40 (br. s., 1H). LCMS (ESI): 649 (M+H+).
Reaction SMILES: [Si](O[CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1)(C(C)(C)C)(C)C.C[Si]([Br:25])(C)C>C(Cl)Cl>[Br:25][CH:9]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:10]1
Reactant: C[Si](C)(C)Br
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(F)cc2)O1
Solvent: ClCCl
Product: Fc1ccc(C2CCC(Br)O2)cc1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (202, 593 mg, 2.0 mmol) was mixed in 10 mL of dry methylene chloride (degassed by bubbling argon prior to use). This solution was cooled to -70° C. While stirring at the same temperature under dry argon, trimethylsilyl bromide (290 μL, 2.2 mmol) was added dropwise. The stirring was continued for an additional 1.5 h to produce 2-bromo-5-(4-fluorophenyl) tetrahydrofuran (203) which was not isolated and was used in subsequent chemistry without further purification (see below).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].Cl[CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+].C1(O)C=CC=CC=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCl
Reactant: Cc1cccc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1OCC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,6-Dimethylphenol (102.8 g, 0.842 mol) and chloroacetic acid (159.6 g, 1.68 mol) in 1000 ml of H2O was added to a 3-L, 3-necked round bottom flask with mechanical stirring and a water-cooled condenser. A solution of NaOH (134.9 g, 3.37 mol) dissolved in 500 ml of water was slowly added to the above mixture via addition funnel and heat to reflux. After 2 hours, additional chloroacetic acid (79.4 g, 0.84 mol) and NaOH solution (67.2 g, 1.68 mol in in 200 ml water) was added to the reaction mixture. After 19 hours, additional chloroacetic acid (39.8 g, 0.42 mol) and NaOH solution (33.6 g, 0.84 mol in in 100 ml water) was added to the reaction mixture and refluxing was continued until starting phenol was consumed. The reaction flask was cooled in and ice-water bath and acidified to pH=1 with conc. HCl, causing a precipitate to form. The resulting slurry was stirred in the ice bath for 1 hour then filtered. The solid was dissolved in hot (100° C.) water and cooled to crystallize the product as white plates, mp=136-137° C., yield=78.8 g, 52%.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:26])[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1>C(OC(=O)C)(=O)C>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:26])[C:14]2[C:15](=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: CCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc([N+](=O)[O-])ccc32)c2ccccc21
Temperature: 90 °C
Yield: 76.2 %

Procedure:
A mixture of 3.68 g (0.01 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-5-nitrobenzoic acid, prepared as described in part A above, and 2.0 g (0.012 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine in 10.0 ml of acetic anhydride was heated at 90° C. for one hour and then allowed to cool to 25° C. The solid which separated was collected by filtration, washed with diethylether and dried to obtain 3.8 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-6-nitrophthalide (Formula III: Ro =R1 =R3 =Y1 =H; R2 =NO2 ; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3) as an orange solid which melted over the range 185°-187° C. The nuclear magnetic resonance spectrum was in accord with the assigned structure. A benzene solution of this product developed a black-purple color when spotted on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:14][O:15][CH2:16][CH2:17]Br>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])[C:8](=[O:12])[N:9]2[CH2:17][CH2:16][O:15][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2=O
Reactant: COCCBr
Product: COCCN1C(=O)C(=O)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a red solid, using 6-methoxy-isatin prepared as described in Pavlidis et al. and 2-bromoethyl methyl ether following Method B. Pavlidis, V. H., et al., The Synthesis of a Novel Series of Substituted 2-Phenyl-4H-3,1-benzoxazin-4-ones, Synthetic Communications, 1994, 24:4, 533-548. NMR (CDCl3): δ 3.35 (s, 3H), 3.65 (t, 2H), 3.87 (s, 3H), 3.94 (t, 2H), 6.64 (d, 1H), 7.58 (t, 1H), 7.79 (d, 1H), 13.93 (br s, 1H).