Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]([CH3:18])([CH3:17])[CH2:3]1.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([O:10][N:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([NH:1][C:19](=[O:22])[CH:20]=[CH2:21])[CH2:3][C:4]2([CH3:18])[CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CC(=O)Cl
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 3.0 grams of 4-amino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine, 0.92 ml of acryloyl chloride and 1.8 ml of triethylamine in methylene chloride. The title compound is isolated as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH2:7]2)[CH2:2]1.CCN(CC)CC.[F:26][C:27]1[C:28]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][C:29]=2[S:30][C:31]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[F:26][C:27]1[C:28]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][C:29]=2[S:30][C:31]=1[C:32]([N:1]1[CH2:2][CH:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH2:7]2)[CH2:4]1)=[O:33]
Reactant: O=C(c1ccccc1)N1CC[C@H](NC2CNC2)C1
Reactant: O=C(Cl)c1sc2ccc(-c3ccccc3)cc2c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CC[C@H](NC2CN(C(=O)c3sc4ccc(-c5ccccc5)cc4c3F)C2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
To a solution of compound 5e (42.7 mg, 0.131 mmol) and Et3N (0.07 mL, 0.5 mmol) in CH2Cl2 (2 mL) at 0° C. was slowly added a solution of compound 13e (36.3 mg, 0.125 mmol) in CH2Cl2 (1 mL). The reaction was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, % MeOH/EtOAc) to give compound Cpd 173 (16.7 mg). MS m/z (M+H+) 500.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH3:13]O>OS(O)(=O)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH2:11][CH3:12]
Reactant: CCc1cc(Br)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1cc(Br)ccc1C(=O)OC
Temperature: 90 °C
Reaction time: 48 h

Procedure:
To a solution of 4-bromo-2-ethyl-benzoic acid (1.35 g, 5.89 mmol) in MeOH (40 mL) was added H2SO4 (1 drop). The mixture was stirred at 90° C. for 48 hours, at which time the volatiles were removed in vacuo. The residue was dissolved in Et2O, washed with satd NaHCO3 and brine, dried over MgSO4, and concentrated to a clear oil (1.01 g, 70%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:8][CH2:9][CH2:10][C:11](=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[CH3:24][OH:25]>O>[CH3:24][O:25][C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:7]([CH3:6])=[CH:8][CH2:9][CH2:10][C:11](=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CO
Reactant: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CC(=O)CCC=C(C)CCCC(C)(C)OC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
The product can be obtained in the form of a mixture of E and Z isomers by adding dropwise 3 ml of concentrated sulfuric acid to a solution of 7.6 g of the product of Example 3 in 45 ml of methanol and stirring the mixture at room temperature for 40 hours. The mixture was diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated to dryness and the residue was chromatographed over silica and was eluted with a 9-1 benzene-ethyl acetate mixture to obtain 1.3 g of methyl 11-methoxy-7,11-dimethyl-3-oxo-6-dodecenoate in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[CH2:9]([O:11][C:12]([C:14]1[C:15](Cl)=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][C:20]([Cl:30])=[CH:19][CH:18]=2)=[O:13])[CH3:10]>CN(C=O)C>[CH2:9]([O:11][C:12]([C:14]1[C:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:16][C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][C:20]([Cl:30])=[CH:19][CH:18]=2)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To the stirred solution of 2,2,2-trifluoro-ethanol (0.051 ml, 0.69 mmol) in 4 ml of DMF, was added NaH (28 mg, 0.69 mmol) portion wise at 0° C. The mixture was stirred for 30 min at room temperature and then a solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (200 mg, 0.58 mmol) in 2 ml dry DMF was added. The resulting reaction mixture was stirred for 5 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl solution and then diluted with further water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5% ethyl acetate in hexane) to obtain 6-chloro-4-phenyl-2-(2,2,2-trifluoro-ethoxy)-quinoline-3-carboxylic acid ethyl ester (140 mg, 59%) as off white solid. LC-MS: 410 (M+H)+.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@@H:27]2[NH:32][CH2:31][CH2:30][N:29]([C:33]3[C:42]4[N:41]=[C:40]([C:43]([F:46])([F:45])[F:44])[S:39][C:38]=4[NH:37][C:36]4[CH:47]=[CH:48][CH:49]=[CH:50][C:35]=4[N:34]=3)[CH2:28]2)[CH:22]=[CH:23][CH:24]=1>CO.ClC(Cl)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@@H:27]2[N:32]([CH3:1])[CH2:31][CH2:30][N:29]([C:33]3[C:42]4[N:41]=[C:40]([C:43]([F:45])([F:46])[F:44])[S:39][C:38]=4[NH:37][C:36]4[CH:47]=[CH:48][CH:49]=[CH:50][C:35]=4[N:34]=3)[CH2:28]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: COc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2C)c1
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
Add sodium triacetoxyborohydride (0.23 g, 1.1 mmol) and aqueous formaldehyde (37% w/w, 0.083 mL, 1.1 mmol) to a solution of (S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1 yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.36 g, 0.74 mmol) in methanol: dichloroethane (1:1) and stir. After 1.5 hours, concentrate the reaction under reduced pressure to remove methanol, and then dilute with a saturated aqueous solution of sodium bicarbonate and dichloromethane, and separate the layers. Extract the aqueous layer with dichloromethane (2×), combine organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 1% 2M ammonia in methanol added (40–100% in hexane over 30 minutes, then 100% for 10 minutes) to give the title compound (0.223 g, 60%): mass spectrum (APCI+, m/e): 502 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.48 (s, 1H), 7.19–7.10 (m, 1H), 6.97–6.81 (m, 3H), 6.76–6.67 (m, 4H), 3.96–3.76 (br. m, 2H), 3.68 (s, 3H), 3.15–3.02 (m, 1H), 2.93–2.81 (m, 1H), 2.80–2.69 (m, 1H), 2.65–2.34 (m, 2H), 2.27–2.04 (m, 5H), 1.91–1.75 (m, 1H), 1.66–1.48 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>>[CH2:20]([N:23]([CH2:24][CH2:25][CH3:26])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1)[CH2:21][CH3:22]
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Reactant: CCCNCCC
Product: CCCN(CCC)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1 h-indazol-5-yl)-amide (Intermediate 16) and dipropylamine (Aldrich), the title compound was obtained as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1N)([CH3:3])[CH3:2].C(C1C=CC([N+]([O-])=[O:24])=CC=1N)C>>[CH:1]([C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[OH:24])([CH3:3])[CH3:2]
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1N
Product: CC(C)c1ccc([N+](=O)[O-])cc1O

Procedure:
The title compound was prepared from 2-isopropyl-5-nitroaniline (prepared using a similar procedure to that described by E. Dyszer et al., Przemysl. Chem. 42 (8) 433-5 (1963)), according to the method outlined in Description 51, as a dark brown oil (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8]O[C:6]1=[O:10].[CH:16]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:23]2[CH2:8][CH2:9][CH:5]([CH2:4][C:3]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=3[Cl:1])[C:6]2=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1OCCC1Cc1ccc(Cl)cc1Cl
Reactant: NC1CCCCCC1
Product: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1C1CCCCCC1
Temperature: 140 °C
Yield: 33.1 %

Procedure:
Charge vial with 3-(2,4-dichloro-benzyl)-dihydro-furan-2-one (300 mg, 1.2 mmol) and cycloheptylamine (139 mg, 1.2 mmol) and heat to 140° C. for 3 hours. Then heat to 195° C. overnight. Cool to room temperature and purify over silica gel which affords 135 mg (32%) of the title compound: Mass spectrum (apci) m/z=340.2 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:20])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[C:21]([C:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[NH:26][N:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[NH:25][N:26]=[C:27]([C:29]([NH:1][C@@H:2]([CH3:20])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:30])[CH:28]=1)(=[O:23])[CH3:22]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c([N+](=O)[O-])c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)n[nH]1
Yield: 42.9 %

Procedure:
(S)-5-acetyl-N-(1-(3-(4-cyano-3-nitrophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (500 mg, 1.843 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (341 mg, 2.212 mmol). The product was triturated twice using diethyl ether. Yield 42.9%. 1H-NMR (400 MHz; DMSO-d6): δ 1.11-1.27 (m, 3H), 2.48 (s, 3H), 4.21-4.57 (m, 3H), 7.03 (d, 1H), 7.29 (s, 1H), 7.86 (d, 1H), 8.09-8.72 (m, 4H), 14.1 (bs, 1H).
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].C(OCC)(=O)C>O1CCOCC1>[C:20]([NH:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NOCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NOCc1ccc(C(=O)O)cc1)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of 4-aminooxymethyl-benzoic acid, hydrochloride 111 (2.0 g, 0.010 mol) in dioxane (20 mL) and half saturated Na2CO3 solution (20 mL) was added Fmoc-Cl (2.8 g, 0.011 mol) and the mixture was stirred for 2 h. Ethyl acetate (100 mL) was added and the pH of the aqueous phase was adjusted to 1-3 by careful addition of HCl(conc.). The mixture was poured in to a separating funnel and the organic phase was isolated, washed once with water (100 mL), dried over Na2SO4 and the solvent was removed on a rotavap to give an oil that solidified upon standing. The crude product was purified by flash column chromatography (petroleum ether, ethyl acetate, AcOH 60:40:1). Yield: 3.5 g (92%) 1H-NMR (250 MHz, DMSO-d6) =4.05 (1H, t, J=6.3 Hz), 4.27 (2H, d, J=6.3 Hz), 4.51 (2H, s), 7.08-7.22 (6H, m), 7.46 (2H, d, J=7.4 Hz), 7.66 (2H, d, J=7.1 Hz), 7.72 (2H, d, J=8.4 Hz), 10.29 (1H, br. s), 12.78 (1H, br. s). 13C-NMR (63 MHz, DMSO-d6) =47.04, 66.03, 76.91, 120.51, 125.41, 127.45, 128.03, 128.89, 129.33, 129.63, 130.82, 141.19, 144.01, 157.12, 167.48. MS (ES) m/z=389 (MH+). 1The material was prepared as previously described: Deles, J. et al.; PJCHDQ; Pol. J. Chem.; EN; 53; 1979; 1025-1032
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH:3]1[CH:11]=[CH:10][CH2:9][CH2:8][CH:4]1[C:5]([OH:7])=O.Cl.[CH3:15][O:16][NH2:17].C1(C)C(C)=CC=CC=1>O>[CH3:15][O:16][N:17]1[C:1](=[O:13])[CH2:2][C:3]2[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=2[C:5]1=[O:7]
Reactant: CON
Reactant: O=C(O)CC1C=CCCC1C(=O)O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: CON1C(=O)CC2=C(CCCC2)C1=O

Procedure:
A mixture of tetrahydrohomophthalic acid (9.2 g., 0.05 mole) and methoxyamine hydrochloride (4.25 g., 0.05 mole) in 125 ml. of xylene is refluxed for 90 minutes, with water collected in Dean Stark trap as it formed. The reaction mixture is cooled and concentrated by vacuum to one-half its original volume, then diluted with ethyl acetate, washed with water and dried over sodium sulfate. Recrystallization from isopropanol and ethanol, followed by drying at 100° C. for 4 hours yields 2-methoxy-5,6,7,8-tetrahydroisoquinoline-1,3(2H,4H)-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1([O:41][C@H:40]([CH2:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O.C([SiH](CC)CC)C.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:15]([O:14][C@@H:13]1[C@@H:22]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:40]([CH2:42][O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[O:41][C@H:11]1[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 1-(2,4-dimethoxyphenyl)-2,3,4,6-tetra-O-benzyl-D-glucopyranose (1.7 g) and triethylsilane (0.59 g) in acetonitrile (20 mL) was added boron trifluoride diethyl ether complex (0.40 g) under ice-cooling, and the mixture was warmed to room temperature and stirred overnight. A saturated potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was stirred for 30 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The organic layer washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1) to give the title compound (1.1 g).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1[C:11]([CH:12]=CC)=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>C(OCC)(=O)C.C(O)(=O)C>[CH3:4][O:5][C:6]1[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:8][CH:9]=[CH:10][C:11]=1[CH:12]=[O:1]
Reactant: CC=Cc1cccc(Oc2ccccc2Cl)c1OC
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1c(C=O)cccc1Oc1ccccc1Cl

Procedure:
Ozone gas was introduced into a solution of 2-chlorophenyl 2-methoxy-3-(1-propenyl)phenyl ether (17.60 g) in a mixture of ethyl acetate (120 ml) and acetic acid (5 ml) at 5° C. for an hour. Thereafter, nitrogen gas was introduced to the reaction mixture to remove the excess of ozone gas, and then dimethyl thioether was added thereto. The mixture was washed with aqueous solution of sodium bicarbonate and water successively, dried over magnesium sulfate and then evaporated. The oily residue was dissolved in diethyl ether, washed with an aqueous solution of sodium bicarbonate, dried and then evaporated to give oily 2-methoxy-3-(2-chlorophenoxy)benzaldehyde (7.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([NH2:23])=[N:20][C:21]=1[F:22].CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:21]1[N:20]=[C:19]([NH2:23])[CH:18]=[CH:17][C:16]=1[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH:8]=1
Reactant: Nc1ccc(Br)c(F)n1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(N)nc3F)cc2c1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
5-Methoxybenzofuran boronic acid (230 mg, 1.20 mmol), 5-bromo-6-fluoro-pyridin-2-ylamine (191 mg, 1.00 mmol), Pd(PPh3)2Cl2 (16.8 mg, 0.024 mmol) and Et3N (317 μL, 2.27 mmol) were mixed in EtOH (10 mL) in a microwave vial. The reaction mixture was stirred at 140° C. for 15 minutes in a microwave reactor. The volatiles were then removed under reduced pressure, the residue was suspended in water and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude product by flash column chromatography using 25% ethyl acetate in hexane gave 6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridin-2-ylamine (130 mg) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ: 8.05-8.21 (m, 1 H) 7.36 (d, J=8.59 Hz, 1 H) 7.03 (d, J=1.95 Hz, 1 H) 6.97 (d, J=3.12 Hz, 1 H) 6.86 (dd, J=8.78, 2.54 Hz, 1 H) 6.45 (d, J=6.63 Hz, 1 H) 4.66 (br. s., 2 H) 3.86 (s, 3 H)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:20]([NH2:22])=[O:21])[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C(Cl)(Cl)(Cl)Cl>[O:9]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[CH2:26][Br:1])[C:20]([NH2:22])=[O:21])[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: Cc1ccc(C(N)=O)cc1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(N)=O)ccc1CBr
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
N-Bromosuccinimide (NBS) (0.507 g, 2.85 mmol) was added to a solution of 3-t-butyldimethylsiloxy-4-methyl benzamide (Compound 7.1) in 30 mL CCl4. The mixture was irradiated with a 275 W sunlamp (Sears, #34-7105) at 60° C. Each irradiation took 10 minutes followed by 10 minutes to let the lamp cool down. It took 2 hours of irradiation over a period of 4 hours to complete the reaction. After the solvent was removed at reduced pressure, the residue was subjected to flash silica gel chromatography to yield the product as a white solid (0146 g, y=81.7%). 1H NMR (CDCl3) δ0.318(s,6H), 1.05(s,9H), 4.51(s,2H), 6.10(b,2H), 7.25(d,J=7.8 Hz,1H), 7.32(s,1H), 7.39(d,J=7.9 Hz,1H); 13 C NMR (CDCl3) δ-4.08, 18.28, 25.76, 27.87, 117.99, 118.07, 119.49, 131.23, 132.54, 134.97, 168.46.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[CH3:10].S(Cl)([Cl:13])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:13])=[CH:4][C:3]=1[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)ccc1Br
Solvent: ClCCl
Product: Cc1cc(CCl)ccc1Br
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a stirred solution of 1.1 (2.0 g, 9.947 mmol) in DCM (50 mL) at 23° C. was added thionyl chloride (1.451 mL, 19.89 mmol) and allowed to stir overnight. The reaction was concentrated and then purified by combiflash (0 to 10% EtOAc/hexanes) to provide 1.2 (1.9940 g, 91.32% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]([C:40]([O:42]C(C)(C)C)=[O:41])([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:14])(C)(C)C>C(Cl)Cl>[CH2:25]([C:26]([OH:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([C:40]([OH:42])=[O:41])([C:13]([OH:14])=[O:12])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39]
Reactant: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (2 mL) is added to a compound from step 4 (0.022 mmol) and the reaction is stirred at r.t. for 1 hour. The mixture is diluted with DCM (10 mL) and concentrated. The material is taken up in EtOAc (10 mL) and washed with H2O (20 mL). The organic layer is dried over Na2SO4, filtered and concentrated. The crude material is dissolved in 1 mL MeOH and purified via MS-triggered HPLC (Sunfire 30×50 mm 5 um column ACN/H2O w/0.1% TFA 75 ml/min, 1.5 ml injection, 45-70% ACN over 3.5 min).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=S)=[N:5]1.[NH3:18]>CCO>[OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:18])=[N:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:5]1
Reactant: N
Reactant: OCCn1ccc(NC(=S)NCC(F)(F)F)n1
Solvent: CCO
Product: NC(=NCC(F)(F)F)Nc1ccn(CCO)n1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazole (20.0 g.) in 5 N ammonia in EtOH solution (700 ml.) was added yellow mercuric oxide (64.8 g.) with stirring. Stirring was continued for a period of 2 hours. The mixture was filtered through diatomaceous earth and the solvent then evaporated to dryness in vacuo. The residual oil was triturated with ether to give 1-(2-hydroxyethyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (18.5 g.; 99%), m.p. 82°.
Reaction SMILES: [CH2:1]1[O:8][C@@H:7]2[O:9][C@H:2]1[C@@H:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:4]1[O:6][C@@H:5]12.[Br-].C([OH:21])C>>[CH2:11]([O:10][C@@H:3]1[C@H:2]2[CH2:1][O:8][C@H:7]([O:9]2)[C@H:5]([OH:21])[C@H:4]1[OH:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CO[C@H]2[C@@H]3O[C@@H]3[C@@H]3OC[C@H]2O3)cc1
Reactant: CCO
Agent: [Br-]
Product: O[C@@H]1[C@@H](O)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1

Procedure:
Briefly, Jespersen first described synthesis of IFG in a six step synthesis starting from 1,6:2,3-dianhydro-4-O-benzyl-β-D-mannopyranose. This method employed introducing a hydroxymethyl group at C-7 by epoxide opening with vinylmagensium bromide, followed by ozonolysis in ethanol to give 1,6-anhydro-4-O-benzyl-β-D-glucopyranose. Hydrolysis of the anhydro bond with sulfuric acid and oxidative carbon chain cleavage provided a pentodialdose, which was cyclized by reductive amination with ammonia to produce the 4-O-benzyl derivative of IFG. The protecting group was removed by hydrogenation under acid conditions (hydrogen and palladium-on-carbon) to produce the HCl salt of IFG.