Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[C:59]([C:63]([F:66])([F:65])[F:64])=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[C:59]([C:63]([F:66])([F:65])[F:64])=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:43][CH:42]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5c[nH]nc5C(F)(F)F)cccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5c[nH]nc5C(F)(F)F)cccc4c3=O)cc2)CCC1
Yield: 28 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[4-oxo-2-phenyl-8-(3-trifluoromethyl-1H-pyrazol-4-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (8 mg, 28%). 1H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 8.11 (dd, J=8.1 and 1.8 Hz, 1H), 7.74 (dd, J=7.4 and 1.6 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.36-7.27 (m, 3H), 7.26-7.18 (m, 4H), 7.08 (d, J=8.4 Hz, 2H), 3.27 (bs, 3H), 2.36-2.26 (m, 2H), 2.08-1.87 (m, 3H), 1.65-1.53 (m, 1H). LCMS (Method E): RT=3.41 min, [M+H]+=502.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:18][C:19]1[CH:20]=[C:21]([O:26][C:27]2[C:32]([F:33])=[C:31](F)[CH:30]=[CH:29][C:28]=2[N+:35]([O-:37])=[O:36])[CH:22]=[C:23]([Cl:25])[CH:24]=1.OS([O-])(=O)=O.[Na+]>C1COCC1>[Br:18][C:19]1[CH:20]=[C:21]([O:26][C:27]2[C:32]([F:33])=[C:31]([CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:30]=[CH:29][C:28]=2[N+:35]([O-:37])=[O:36])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Oc1cc(Cl)cc(Br)c1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 3.95 g, 98.6 mmol) was added to anhydrous THF (100 mL) and cooled to 0° C. under nitrogen. A solution of di-tert-butyl malonate (9.79 g, 45.3 mmol) in THF (20 mL) was added dropwise and the reaction mixture was stirred 30 min. A solution of 2-[(3-bromo-5-chlorophenyl)oxy]-3,4-difluoro-1-nitrobenzene (15.0 g, 41.1 mmol) was added dropwise in THF (50 mL) was added dropwise, the reaction was allowed to warm to RT and stirred for 90 min. The reaction was cooled to 0° C., a solution of saturated aqueous NaHSO4 (200 mL) was added and the aqueous mixture was extracted with EtOAc (3×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound a brown solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.05 (d, 1H), 7.58 (d, 1H), 7.48 (s, 1H), 7.20 (s, 1H), 7.12 (s, 1H), 3.82-3.80 (m, 1H), 1.35 (s, 18H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:30][CH:29]([O:31][CH2:32][CH:33]=[CH2:34])[CH2:28][C@H:24]1[C:25](O)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:35]([O:39][C:40](=[N:46][NH:47][C:48]([NH2:50])=[O:49])[CH2:41][CH:42]([NH2:45])[CH:43]=[O:44])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40](=[N:46][NH:47][C:48]([NH2:50])=[O:49])[CH2:41][C@H:42]([NH:45][C:25](=[O:26])[C@@H:24]1[CH2:28][C@@H:29]([O:31][CH2:32][CH:33]=[CH2:34])[CH2:30][N:23]1[C:21](=[O:22])[C@H:17]([CH:18]([CH3:19])[CH3:20])[NH:16][C:14](=[O:15])[C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2])[CH:43]=[O:44])([CH3:38])([CH3:36])[CH3:37]
Reactant: C=CCOC1C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(C)=O)C(C)C)C1
Reactant: CC(C)(C)OC(CC(N)C=O)=NNC(N)=O
Product: C=CCO[C@@H]1C[C@@H](C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C)N(C(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(C)=O)C(C)C)C1
Yield: 20 %

Procedure:
N-Acetyl-tyrosinyl-valinyl-4-allyloxyproline (420 mg, 0.88 mmol) and 3-amino-4-oxobutyric acid tert-butyl ester semicarbazone (184 mg, 0.8 mol, Graybill et al., Int. J. Protein Res., 44, pp. 173-82 (1994)) to give 100 mg (20%) of the title compound as a white amorphous solid: 1H NMR (CD3OD) δ 7.24-7.2 (1H, m), 7.04-6.97 (2H, d), 6.73-6.65 (2H, d), 5.98-5.86 (1H, m), 5.35-5.24 (1H, d), 5.17-5.12 (1H, m), 4.12-3.98 (2H, m), 3.72-3.67 (1H, m), 2.98-2.92 (3H, m), 2.38-2.32 (1H, m), 2.1-2.02 (2H, m), 1.92 (3H, s), 0.98-0.89 (6H, 2×d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl.C(O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:19]([C:18]3[CH:13]=[CH:14][C:15]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:17]=3)[N:20]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCC(=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Yield: 75.5 %

Procedure:
A 250 mL one-necked round-bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 3-(4-chlorophenyl)-3-ketopropionaldehyde (18.3 g, 0.1 mol ), 4-sulfonamidophenylhydrazine hydrochloride (11.2 g, 0.05 mol) and 100 mL of absolute ethanol. The solution was heated to reflux for 15 hour and then diluted with 100 mL of water and allowed to stand whereupon a white solid formed that was isolated by filtration on a Buchner funnel and air dried to provide 12.6 g, 76% of 4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide, mp 185°-187° C. 1H nmr (CDCl3 /300 MHz) 7.89(d, J=8.7 Hz, 2H), 7.76(d, J=1.8 Hz, 1H), 7.43(d, J=8.7 Hz, 2H), 7.34(d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 6.53 (d, J=1.8 Hz, 1H), 4.93 (brs, 2H), mass spectrum MH+ =334.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:25]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:26])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)C1CCCC1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)C1CCCC1
Yield: 60.7 %

Procedure:
Using the general method of Example 205, 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.83 mmol) was reacted with cyclopentanecarbonyl chloride (1.04 g, 7.83 mmol) to provide 1.67 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclopentanecarboxamide as a solid, m.p. 207.8-208.9° C. Analysis: Calculated for C20H25N5O: % C, 68.35; % H, 7.17; % N, 19.93;
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCOCC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOC1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.204 g, 0.74 mmol) in dry DCM (20 mL) were added 4-(aminooxy)tetrahydro-2H-pyran 31 (0.131 g, 1.11 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.142 g, 1.11 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.201 g, 1.11 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N-(tetrahydro-2H-pyran-4-yloxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 32 (0.26 g, 93%) as a clear thick oil.
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:26])=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:27]=[CH:28][CH:29]=[C:4]12)[CH3:2].ClS([N:34]=[C:35]=O)(=O)=O.CN(C=O)C>C1COCC1>[CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:26])=[C:9]([F:25])[CH:10]=2)[N:5]2[C:27]([C:35]#[N:34])=[CH:28][CH:29]=[C:4]12)[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC1c2ccc(C#N)n2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a 250 ml round bottom flask with addition funnel was added 2 g (4.8 mmol) of the product from Example 4 and 50 ml of THF. The solution was cooled to −78° C. and 0.50 ml (5.76 mmol) of chlorosulfonyl isocyanate in 20 ml of THF added dropwise via the addition funnel. After the addition was complete the solution was stirred at this temperature for 3 hr until all of the product had disappeared by TLC. Added 1 ml of DMF and allowed the solution to warm to room temperature, whereupon product begins to form. After stirring overnight the reaction was quenched with saturated sodium bicarbonate solution, then extracted 3 times with ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to afford an oil, which was chromatographed on silica gel eluting with 30% ethyl acetate:hexane to afford 1.81 g (83%) of product as a solid, which was recrystallized from ethyl acetate hexane, mp 176-178° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:16]([C:18]3[S:22][C:21]([CH3:23])=[N:20][C:19]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[O:17])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[CH:10]12[N:11]([C:16]([C:18]3[S:22][C:21]([CH3:23])=[N:20][C:19]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[O:17])[CH2:12][CH:13]1[CH2:14][CH2:15][NH:8][CH2:9]2
Reactant: Cc1nc(-c2ccccc2F)c(C(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)s1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2F)c(C(=O)N2CC3CCNCC32)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8-[4-(2-fluoro-phenyl)-2-methyl-thiazole-5-carbonyl]-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester in dioxane (8 mL) was added trifluoro acetic acid (3 mL), the reaction mixture was stirred for 16 h at room temperature. The solvent and the excess of trifluoro acetic acid were removed under reduced pressure. The resulting trifluoro acetic acid salt of the title compound was used crude without further purification (54.0 mg, 56%). MS (ESI) mass calcd. for C17H18FN3OS, 331.41; m/z found, 332.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:21].[H-].[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[CH2:32]Cl.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:32][C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[Cl:24])=[O:19])[C:3]=1[Cl:21]
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)OCc3ccc(Cl)cc3Cl)n2)c1F
Reaction time: 24 h
Yield: 35 %

Procedure:
4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared by the methods described in U.S. Pat. No. 7,314,849 B2; 828 mg, 2 5 mmol) was dissolved in DMF (4 mL). Sodium hydride (NaH, 60% disperson in mineral oil; 154 mg, 3.85 mmol) was added portion wise. To the mixture was added 2,4-dichloro-1-(chloromethyl)benzene (586 mg, 3.0 mmol). The reaction mixture was allowed to stir for 24 hours (h). Water was added to the reaction mixture, and the aqueous phase was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried with Na2SO4, filtered, and concentrated. Purification by normal phase chromatography gave a white solid (440 mg, 35%): mp 165-168° C., 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, J=8.6, 7.8 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 5.50 (s, 2H), 4.83 (s, 2H), 3.97 (d, J=0.8 Hz, 3H); ESIMS m/z 489 ([M−H]).
Reaction SMILES: [F:1][C:2]1[C:3]([C:18]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([OH:26])=O)[CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][C:14]1([CH3:17])[CH2:16][CH2:15]1)=[N:5]2.CC[N:29](C(C)C)C(C)C.N>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[C:3]([C:18]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH2:29])=[O:26])[CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([NH:13][C:14]1([CH3:17])[CH2:15][CH2:16]1)=[N:5]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C)[nH]3)c2nc1NC1(C)CC1
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2ccc(F)c(-c3cc(C(N)=O)c(C)[nH]3)c2nc1NC1(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-methyl-1H-pyrrole-3-carboxylic acid (417c) (0.119 g, 0.336 mmol), 0-(˜7-azabenzotriazol-1-yl)-n,′n,′n,′n′-tetramethyluronium-hexafluorophosphate (GenScript Corporation, 0.160 g, 0.420 mmol), DIPEA (0.146 mL, 0.839 mmol), in DMF (1.679 mL) was stirred at RT for 5 min before addition of ammonia (2.0 M solution in MeOH, Sigma Aldrich, 0.336 mL, 0.672 mmol). The resulting mixture was stirred at RT overnight. Reaction mixture was diluted with DCM and washed with water and brine to remove DMF. Purification by Biotage (0-100% EtOAc/hexanes then 30-100% EtOAc:EtOH(3:1)/hexanes) produced desired product. The residue was diluted with DCM and re-washed two times with alternating water and brine washes to remove DMF and provide 5-(6-fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-methyl-1H-pyrrole-3-carboxamide (0.031 g, 0.88 mmol, 26% yield). 1H NMR (300 MHz, MeOH) δ ppm 0.84-0.94 (m, 4H) 1.56 (s, 3H) 2.38 (s, 3H) 2.55 (s, 3H) 7.01-7.17 (m, 2H) 7.25-7.35 (m, 1H) 7.37-7.47 (m, 1H) 12.84-13.00 (m, 1H). m/z (ESI, +ve) 354.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.Br[C:29]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:29]2([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:26]=1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: COC(=O)C1(Br)CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)C1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CCCC1
Temperature: 25 °C

Procedure:
A mixture of 1-chloro-4-(β-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.46 g), 1-bromo-1-methoxycarbonylcyclopentane (0.87 g), potassium iodide (0.1 g) and potassium carbonate (0.5 g) in methanol (5 mL) is stirred at reflux for 16 h. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→4:1).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:27])[F:26])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[CH2:28]([C:30]1[CH:34]=[N:33][N:32]([CH3:35])[C:31]=1[NH2:36])[CH3:29]>>[CH2:28]([C:30]1[CH:34]=[N:33][N:32]([CH3:35])[C:31]=1[NH:36][C:11]([C:13]1[C:21]2[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=2[C:16]([O:24][CH:25]([F:26])[F:27])=[CH:15][CH:14]=1)=[O:12])[CH3:29]
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Reactant: CCc1cnn(C)c1N
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(CC)cnn3C)c2o1

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (100 mg) and 4-ethyl-2-methyl-2H-pyrazol-3-ylamine (64 mg). Purification by column chromatography on silica eluting with 5% methanol in dichloromethane afforded the title compound as an off white solid (55 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])#[N:2].[OH:18]O>C1COCC1>[OH:18][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC[C@H](C)COc1ccc(B(O)O)cc1C#N
Reactant: OO
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc(O)cc1C#N

Procedure:
A mixture of compound 47 (3.00 g, 0.014 mol), hydrogen peroxide (30% w/v, 150 ml) and THF (200 ml) was heated under reflux for 3 h. The water /THF mixture was removed in vacuo and the oily residue was dissolved in diethyl either and washed with water. The ether was dried (MgSO4) and evaporated in vacuo to give a viscous, fawn oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19]O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:33][C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1[C:3]([CH2:19][S:33][C:34]2[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[N:35]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1([CH2:16][CH2:17][CH3:18])[O:12][CH2:13][CH2:14][O:15]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCC1(CCOc2ccnc(CO)c2C)OCCO1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCCO1
Reaction time: 0.83 h
Yield: 79.8 %

Procedure:
The (3-methyl-4-(2-(2-propyl-1,3-dioxolan-2-yl)ethoxy)pyridin-2-yl) methanol (450 mg, 1.6 mmol) obtained in the step (3e) was mixed with tetrahydrofuran (10 ml). The mixture was cooled on ice in a nitrogen atmosphere. To this, triethylamine (0.446 ml, 3.2 mmol), and methanesulfonyl chloride (0.186 ml, 2.4 mmol) were added and stirred for 50 minutes under ice-cooling. To the reaction mixture, 2-mercaptobenzimidazole (240 mg, 1.6 mmol) was added and stirred at room temperature overnight. To the reaction mixture, an aqueous solution of sodium hydrogen carbonate was added and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. After silica gel was added to the solution, the solution was concentrated. The dried residue was subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the title compound (528 mg, 79.8%) as a colorless viscous oil.
Reaction SMILES: [N:1]1([C:6]2([CH2:16][CH:17]=O)[CH2:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[O:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][NH2:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(C(F)(F)F)=O>>[N:1]1([C:6]2([CH2:16][CH2:17][NH:25][CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[CH2:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[O:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: NCc1cccs1
Reactant: O=CCC1(n2cccn2)CCOC2(CCCC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: c1csc(CNCCC2(n3cccn3)CCOC3(CCCC3)C2)c1
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of 2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (15 mg, 0.06 mmol) and thiophen-2-ylmethanamine (19 uL, 0.18 mmol) was stirred at rt for 1 h before NaBH(OAc)3 (25.4 mg, 0.12 mmol) was added. The solution stirred overnight. After removal of solvent, the residue was purified by HPLC to provide {2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}(thiophen-2-ylmethyl)amine (17 mg, 61% yield) as a TFA salt. LCMS m/z 346 (M+1) observed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.O1CCCC1.O.C(=O)([O-])[O-].[Na+].[Na+].[I:24]I>>[OH:10][C:8]1[C:7]([I:24])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:11]
Reactant: II
Reactant: COC(=O)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(I)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To solution of 5-hydroxy-nicotinic acid methyl ester (2.50 g, 16.3 mmol) in tetrahydrofuran (50.0 mL, 616 mmol)/water (50.0 mL, 2780 mmol) was added sodium carbonate (5.19 g, 49.0 mmol) and iodine (10.4 g, 40.8 mmol). The reaction mixture was stirred at room temperature 4h. The aqueous layer containing product was separated and wash with hexane. The organic layer was neutralized to pH 7 with HCl, extracted EtOAc 4×. The combined organic layers was dried Na2SO4, concentrated. The crude product was purified by flash chromatography (EtOAc/DCM) (eluted at 40 EtOAc) to give methyl 5-hydroxy-6-iodonicotinate (81.2%) MS: (ESI+) 280.0
Reaction SMILES: [C:1]([N:5]1[CH2:34][CH2:33][CH2:32][CH2:31][C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]([O:22]C)=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:35])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[C:1]([N:5]1[CH2:34][CH2:33][CH2:32][CH2:31][C:8]2[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]([OH:22])=[O:21])[C:16]([O:24][CH3:25])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc2c(cc1OC)CCn1c3c(c(-c4cccs4)c1-2)CCCCN(C(C)(C)C)C3=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1C(=O)O)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 80 °C
Reaction time: 5 h
Yield: 98.6 %

Procedure:
To a solution of 480 mg 26a in 10 mL methanol was added a solution of 164 mg potassium hydroxide in 10 mL water. The mixture was stirred at 80° C. for 5 h and then at 50° C. for 16 h. The reaction mixture was poured into a 2M solution of citric acid in water and was extracted with 2×50 mL dichloromethane. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give 460 mg of compound 26b.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7](F)[CH:6]=1)([F:4])[F:3].C(=O)([O-])[O-].[K+].[K+].[C:20]([C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1)#[N:21].O>CN(C=O)C>[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([C:2]([F:4])([F:3])[F:1])=[CH:6][C:7]=1[O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:20]#[N:21])=[O:10]
Reactant: N#Cc1cccc(O)c1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2cc(C(F)(F)F)ccc2C=O)c1
Temperature: 110 °C

Procedure:
A mixture of 4-(1,1,1-trifluoromethyl)-2-fluoro-benzaldehyde (2.5 g), potassium carbonate (1.79 g) and 3-cyanophenol (1.54 g) in DMF (20 ml) was heated at 110° C. for 2 h then cooled. Water (200 ml) was added and the mixture extracted with ethyl acetate, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 2:1 to give a colourless oil, yield 2.0 g.