Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.[CH3:12][NH:13][OH:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:39])[C:23]2[CH:28]=[N:27][C:26]([C:29]([O:31]C)=O)=[C:25]3[O:33][C:34]([CH3:38])([CH3:37])[O:35][CH2:36][C:24]=23)=[CH:18][CH:17]=1.O>O1CCCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([OH:39])[C:23]2[CH:28]=[N:27][C:26]([C:29]([N:13]([OH:14])[CH3:12])=[O:31])=[C:25]3[O:33][C:34]([CH3:38])([CH3:37])[O:35][CH2:36][C:24]=23)=[CH:20][CH:21]=1
Reactant: CNO
Reactant: COC(=O)c1ncc(C(O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(O)C(=O)c1ncc(C(O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Temperature: 78 °C
Reaction time: 0.17 h
Yield: 13.7 %

Procedure:
1.8 mL of lithium bis(trimethylsilyl)amide solution (1.809 mmol, 9 eq, 1M in tetrahydrofuran) was added to 0.041 g of N-methylhydroxylamine hydrochloride (0.249 mmol, 1.1 eq.) in 5.0 mL of tetrahydrofuran (−78° C.) and stirred for 10 min at 78° C. 0.070 g of methyl 5-((4-fluorophenyl)(hydroxy)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate solution (0.201 mmol, 1 eq.) in 3.0 mL of tetrahydrofuran was then added followed by stirring for 30 min at −78° C. Water was then added to the reaction mixture followed by extraction with ethyl acetate. The resulting organic phases were then combined and concentrated under reduced pressure yielding 0.01 g of crude product (14% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[F:19].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[F:19])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Nc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccnc(Cl)c2)c(F)c1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
Add 2-chloropyridin-4-amine (500 mg, 3.9 mmol), 1,2-difluoro-4-nitrobenzene (620 mg, 3.9 mmol), Cs2CO3 (3.2 g, 9.8 mmol) to DMF (15 mL). Stir the reaction at 110° C. for 16 hrs. Cool to room temperature, add water (100 mL), extract with EtOAc (15 mL×3). Combine the organic layers and wash with brine, dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (280 mg, 27%). MS: (M+1): 268.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18](=O)[NH:19][C:20]2[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=2[NH2:27])[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1C(C(=O)NC2C=CC(Br)=CC=2N)CC2(CC2)C1)=O)C1C=CC=CC=1>CC(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=3[N:27]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1NC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Agent: Nc1cc(Br)ccc1NC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CC2(CC2)CC1c1nc2ccc(Br)cc2[nH]1
Temperature: 40 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 6-(2-Amino-5-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester and 6-(2-Amino-4-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (1.446 g, 3.25 mmol) was dissolved in AcOH (20 mL) and the reaction mixture was stirred at 40° C. for 18 hours then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted 2x with EtOAc and the combined organics were dried over MgSO4, filtered and concentrated to provide 6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (1.385 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].O[CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[O:28][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[O:28][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)C(C)Oc1cccc(CO)c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1cccc(COc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)c1
Yield: 35.3 %

Procedure:
Into 10 ml of anhydrous tetrahydrofuran were dissolved 0.3 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenol, 0.186 g of methyl 2-[3-(hydroxymethyl)phenoxy]propionate and 0.232 g of triphenylphosphine; 0.179 g of diisopropyl azodicarboxylate was added dropwise under ice-cooling and stirring and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure; the obtained residue was subjected to silica gel column chromatography to give 0.166 g of methyl 2-[3-({2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy}methyl)phenoxy]propionate [Compound 2-1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]1[S:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:23][C:22]([Cl:33])=[N:21][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:17][C:18]2[S:26][C:25]3[C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:23][C:22]([Cl:33])=[N:21][C:20]=3[CH:19]=2)[C@@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
A mixture of (3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.92 g), 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1 g) and potassium carbonate (1.59 g) in MeCN (10 ml) was heated to reflux for 5 days. The reaction mixture was subsequently cooled, diluted with chloroform, washed with brine and dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash column chromatography to yield (3S,5R)-4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester, 170 (1.2 g). Treatment of this compound with HCl in DCM/MeOH produced 2-chloro-6-(2S,6R)-2,6-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, 171, which was then methylated using 37% formaldehyde solution and sodium borohydride in MeOH, furnishing 172.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:15])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)CCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of 4-(4-fluorophenyl)-butyric acid (6.7 g) in chloroform (15 ml) at 0° C. was added 0.1 ml DMF followed by the addition of oxalyl chloride (3.35 ml) over 20 min. The solution was stirred for 2 h then concentrated. The crude acid chloride was dissolved in chloroform (150 ml) and cooled to 0° C., whereupon concentrated ammonia solution (6 ml) was added over 15 min and the resulting solution stirred for 2 h. The reaction mixture was washed with water and the organic phase dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed over silica using a gradient elution from ether to 2:1 acetone/ether to yield the title compound (2.86 g, 43%). 1H-NMR (CDCl3) δ 1.96 (2H, app q), 2.21 (2H, t), 2.65 (2H, t), 5.41 (2H, br s), 6.96 (2H, m), 7.14 (2H, m). MS(APCI+)M+1=182, C10H12FNO requires 181.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18])=[S:11]
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: Cc1nn(C)c(C)c1N
Product: Cc1cccc(Cl)c1NC(=S)Nc1c(C)nn(C)c1C
Yield: 66.8 %

Procedure:
Prepared using Method A from 4.0 g (21.8 mmol) of 2-chloro-6-methyl-phenyl isothiocyanate and 2.7 g (21.8 mmol) of 4-amino-1,3,5-trimethylpyrazole to give 4.5 g of title compound as a white solid (67% yield, m.p. 201-202° C.).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([NH:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:19])=[O:18])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[S:3].Cl[CH:35](OC(Cl)CCl)[CH2:36]Cl.C(O)(C)C>O>[C:28]1([CH:21]([NH:20][S:17]([C:13]2[CH:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:2]4[S:3][CH:35]=[CH:36][N:1]=4)[CH:6]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:18])=[O:19])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCC(Cl)OC(Cl)CCl
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(N)=S)c2)c1)c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(Nc3nccs3)c2)c1)c1ccccc1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
0.97 g of Ethyl 3-[({3′-[(aminocarbothioyl)amino][1,1′-biphenyl]-3-yl}sulfonyl)-amino]-3-phenyl-propanoate 14.1.1 and 0.48 g of 1,2-dichloroethylether were heated in water and i-propanol was added such that a clear solution resulted. After 1 h an additional 100 mg of 1,2 dichloroethylether were added and reflux was continued for 1 h. After aqueous work-up and flash chromatography, 0.62 g of the title compound resulted.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[C@@H:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([O:34]C)=[O:33].[OH-].[Li+].CO>O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[C@@H:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.2 %

Procedure:
A solution of (S)-methyl 2-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (295 mg, 0.533 mmol, 1 equiv) and lithium hydroxide (44.77 mg, 1.07 mmol, 2.0 equiv) in a 3:1 mixture of methanol and water (5 ml t/v) was stirred at ambient temperature for 24 hrs. The reaction was concentrated in vacuo and purified using preparatory high performance liquid chromatography. The combined pure fractions were lyophilized to afford the acetate salt of the title compound as a white solid (61 mg, 21%); 1H NMR (400 MHz, DMSO-d6): δ 1.57-1.66 (m, 2H), 1.87-1.91 (m, 2H); 2.79-2.86 (m, 4H); 3.27-3.42 (bs, 4H); 3.85 (t, 2H, J=6.8 and 6.4 Hz); 4.11 (d, 1H, J=4.8 Hz); 4.94 (d, 1H, J=3.2 Hz); 5.68 (s, 1H); 6.74-6.80 (m, 3H); 6.95-6.98 (m, 3H); 7.17-7.21 (m, 3H); 7.33-7.42 (m, 5H); 10.85 (s, 1H); 12.5 (bs, 1H); MS for C31H33ClN5O4 m/z 540.07 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:7]=O.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[NH:10][NH2:11]>>[CH2:14]([O:13][C:9](=[O:12])[NH:10][N:11]=[CH:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])[CH3:15]
Reactant: Cc1[nH]cnc1C=O
Reactant: CCOC(=O)NN
Product: CCOC(=O)NN=Cc1nc[nH]c1C

Procedure:
A mixture of 7.0 gm. of 5-methyl-4-imidazolecarboxaldehyde and 7.3 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 195°-203° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][CH2:12][C:13]1([CH2:26][OH:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[Cl:11][CH2:12][C:13]1([CH:26]=[O:27])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CCl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C=O)(CCl)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a −78° C. solution of oxalyl chloride (5.1 mL, 57 mmol) in dichloromethane (100 mL) in an oven-dried round-bottomed flask was added dimethylsulfoxide (8.2 mL, 114 mmol) in dichloromethane (17 mL). The mixture was stirred for 2 minutes and tert-butyl 4-(chloromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (13.7 g, 52 mmol) in dichloromethane (50 mL) was added over 10 minutes. The solution was stirred for 15 minutes at −78° C. and triethylamine (36 mL, 260 mmol) was added. The mixture was stirred at −78° C. for 15 minutes and was warmed to room temperature. The mixture was stirred for 15 minutes at room temperature and was quenched with saturated aqueous NaHCO3 (200 mL). The aqueous solution was washed with Et2O (2×300 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound (SM-3a) as a yellow oil that solidified upon standing under nitrogen atmosphere at room temperature (13.7 g, 99%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.48-1.60 (m, 2H), 2.00-2.07 (m, 2H), 3.07 (t, 2H), 3.57 (s, 2H), 3.69-3.79 (m, 2H), 9.55 (s, 1H).
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:10]#[N:11])[CH:6]=[CH:7][C:8]#[N:9])C.[CH3:12]N>CN(C=O)C>[CH3:12][NH:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]#[N:11])=[CH:4][N:2]=1
Reactant: CN
Reactant: CN(C)C=C(C#N)C=CC#N
Solvent: CN(C)C=O
Product: CNc1ccc(C#N)cn1

Procedure:
7.4 g of dimethylaminomethylene-glutacononitrile, 100 ml of DMF and 4.4 g of 35.6% strength aqueous methylamine solution were held for 2 hours at 80° C. in an 0.3 l V4A autoclave. After the mixture had been removed and concentrated, 6.4 g of 2-methylamino-5-cyanopyridine (purity 93%) were obtained, which corresponds to 90.2% of theory.
Reaction SMILES: C[N:2]1C=CN=C1.P(Cl)(Cl)(Cl)=O.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH3:35])[O:23][C@H:22]1[N:36]1[CH:43]=[C:42]([F:44])[C:40](=O)[NH:39][C:37]1=[O:38])(=O)C1C=CC=CC=1.[OH-].[NH4+]>C(#N)C>[F:44][C:42]1[C:40]([NH2:2])=[N:39][C:37](=[O:38])[N:36]([CH:43]=1)[C@@H:22]1[O:23][C@H:24]([CH3:35])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: Cn1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-methylimidazole (0.8 ml) and phosphoryl chloride (0.28 ml) in acetonitrile (20 ml) was added 2',3'-di-O-benzoyl-5'-deoxy-5-fluorouridine (500 mg) obtained above at 0° C. After stirring of the reaction mixture for 1.5 hours at room temperature 28% ammonium hydroxide (2.5 ml) was added to the mixture at 0° C., and the mixture was stirred for 1 hour at room temperature. Acetonitrile and ammonia were removed under reduced pressure. The residue was acidified with 1N-HCl and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 155 mg of 2',3'-di-O-benxoyl- 5'-deoxy-5-fluorocytidine, mp 192°~194° C.; MS 476 ((M+Na)+).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][N+:21]([O-])=[CH:20][CH:19]=2)[CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15]>>[Cl:3][C:22]1[CH:23]=[C:18]([C:10]2[CH:9]=[C:8]([O:7][CH3:6])[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:19]=[CH:20][N:21]=1
Reactant: COc1cc(-c2cc[n+]([O-])cc2)cc(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2ccnc(Cl)c2)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Phosphorus oxychloride (2 mL) was added to 4-(3,4,5-Trimethoxyphenyl)pyridine-N-oxide (27 mg) at 0° C., and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and neutralized with a saturated aqueous solution of sodium hydrogencarbonate at 0° C. The neutralized product was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the title compound.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([O-:3])=[O:2]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=CC(=O)OCCCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Dinitroethane (12 g, 0.10 mol) and potassium hydroxide (6 g, 0.11 mol) were dissolved in 100 mL of water to form a first solution. 500 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Butyl acrylate (36 mL, 0.25 mol) was mixed with 300 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 3 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid butyl 4,4-dinitropentanoate (21.5 g, yield: 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: CCO
Reactant: COc1ccccc1CCC(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1ccccc1OC
Temperature: 25 °C

Procedure:
A solution of 25.0 g (139.0 mmol) 3-(2-methoxyphenyl)propionic acid in 250 mL ethanol is treated at 0° C. with 5.0 mL concentrated sulfuric acid. The reaction mixture is heated to reflux for 2 hr. The reaction mixture is cooled to room temperature and volatiles removed by rotary evaporation. The residue is diluted with 250 mL dichloromethane, washed with 200 mL water, 200 mL sat. NaHCO3, and 200 mL brine. The resulting organic layer is dried over anhydrous Na2SO4 and the solvent removed in vacuo to yield ethyl 3-(2-methoxyphenyl)propanoate, 28 g, as a tan oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CS(=O)(=O)c1ccc(OCCC2CCNCC2)cc1

Procedure:
The product is obtained according to the procedure of Preparation 1 using 2-(N-tert-butyloxycarbonyl-4-piperidyl)ethanol and p-methylsulphonylphenol in Step 1.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:27][N:28]=1)=[CH:20]2)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8])C.[BH4-].[Li+].Cl>O1CCCC1.CO>[OH:3][CH2:4][CH2:5][N:6]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:27][N:28]=1)=[CH:20]2)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:9]
Reactant: CCOC(=O)CN(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(c1cccs1)N(CCO)c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of N-{2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-(2-thienylsulfonyl)glycine ethyl ester (100 mg) in tetrahydrofuran (10 mL) and methanol (2 mL) was added lithium borohydride (18.0 mg), and the mixture was stirred at room temperature for 4 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (70 mg, yield 76%) as white crystals. MS:507(MH+).
Reaction SMILES: NC1N=CC=C2C=1N[C:8](=[O:11])C2.[F:12][C:13]1[N:27]=[CH:26][CH:25]=[CH:24][C:14]=1[C:15]([N:17]([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[O:16]>>[CH:8]([C:24]1[C:14]([C:15]([N:17]([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:22])[CH3:23])=[O:16])=[C:13]([F:12])[N:27]=[CH:26][CH:25]=1)=[O:11]
Reactant: CC(C)N(C(=O)c1cccnc1F)C(C)C
Reactant: Nc1nccc2c1NC(=O)C2
Product: CC(C)N(C(=O)c1c(C=O)ccnc1F)C(C)C

Procedure:
The 7-amino-6-aza-oxindole 16 can also be prepared by lithiation of 2-fluoro-N,N-diisopropylnicotinamide 17 followed by quenching, such as with DMF, to give the 4-formyl-2-fluoro-N,N-diisopropylnicotinamide 18. The 4-formyl-2-fluoro-N,N-diisopropylnicotinamide can be reacted with an amine to give the 4-aminomethyl-2-fluoro-N,N-diisopropylnicotinamide 19 which can be reacted with another amine then cyclized under acidic conditions to afford the 7-amino-6-aza-oxindole 16.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24](O)=[O:25])[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[C:27]1([CH3:37])[C:28]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCCC1.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([NH:36][S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH3:37])(=[O:34])=[O:35])=[O:25])[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: COc1ccc(-c2ccc(NCc3cc(C(=O)O)oc3C)cc2)nc1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(NCc3cc(C(=O)NS(=O)(=O)c4ccccc4C)oc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.8 %

Procedure:
A suspension of 4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylic acid hydrochloride salt (166) (30 mg, 0.08 mmoles) in tetrahydrofuran (5 ml) was treated with toluene-2-sulphonamide (41 mg, 0.24 mmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.176 mmoles) and 4-(N,N-dimethylamino)-pyridine (10 mg, 0.08 mmoles) and the mixture stirred at room temperature for 16 hours. Triethylamine (24.3 mg, 0.24 mmoles) was added and the mixture was stirred for a further 18 hours. The reaction mixture was concentrated and the residue was purified by HPLC to afford compound 167 as a yellow glass (1.1 mg)). LC/MS System A; Rt=2.72 mins, m/z (ES+)=492 (M+H for C26H25N3O5S) and m/z (ES−)=490 (M−H for C26H25N3O5S).