Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:39](#[N:42])[CH:40]=[CH2:41].[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:23]([O:22][CH2:21][CH:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:20][CH2:41][CH2:40][C:39]#[N:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCOCC(O)COCCCCCCCCCCCCCCCC
Reactant: C=CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCC#N
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A mixture of 1,3-di-O-(n-hexadecyl)-glycerol (80 g., 148 mmoles), acrylonitrile (1.49 kg., 28.1 moles) and aqueous 2 N sodium hydroxide (1.2 1.) was heated to 50° C. Tetrabutylammonium hydroxide (19.2 g. of 40 wt. % aqueous solution, 29.15 mmoles) was slowly added, causing the temperature of the exothermic reaction mixture to rise to about 80° to 90° C. The reaction mixture was then stirred for 20 minutes without any external heating, followed by cooling to 20° C. and addition of water (1.0 l.). A solid material, a mixture of unreacted and cyanoethylated 1,3-di-O-(n-hexadecyl)-glycerol, was isolated and treated again with fresh acrylonitrile (1.49 kg., 28.1 moles), aqueous 2 N sodium hydroxide (1.2 l.) and tetrabutylammonium hydroxide (19.2 g. of 40 wt. % aqueous solution, 29.15 mmoles) for 20 minutes with stirring at 50° C., followed by cooling and addition of water (1.0 l.). The resulting 1,3-di-O-(n-hexadecyl)-2-O-(2-cyanoethyl)-glycerol solids were filtered, washed consecutively with water, methanol and acetonitrile, and dried [82 g., 93% yield, m.p. 45°-46° C., ir (CHCl3) 2250 cm-1, n.m.r. (CDCl3) δ3.92 (t, 2, NCCH2CH2O--), 3.33-3.67 (m, 9, --OCH[CH2OCH2C15H31 ]2), 2.62 (t, 2, NCCH2CH2O--) and 0.75-1.58 (m, 62, aliphatic protons)].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])([O-:26])=[O:25].C(=O)(O)[O-].[Na+]>O1CCCC1>[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1)=[O:31])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
A solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.0 g, 9 mmol) and triethylamine (1.3 mL, 9.5 mmol) in tetrahydrofuran (26 mL) at 0° C. was treated with a solution of 3-nitrobenzoyl chloride (1.8 g, 9.5 mmol) in tetrahydrofuran (7.3 mL) and stirred at 20° C. for 1 h. The reaction mixture was treated with saturated sodium bicarbonate and the aqueous layer was separated and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (3.5 g, 105%) as a crude off-white solid that was used without further purification. LCMS for C15H14N3O5 ([M-(t-Bu)+H]+H)+: m/z=316.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C[CH2:13][O:14][C:15](C)=[O:16].O.C([O-])(O)=O.[Na+].ClC(OC)=O>CCOC(C)=O>[CH3:13][O:14][C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: CCOC(C)=O
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a suspension of 5-Amino-indan-1-one (commercially available, 100 mg, 0.679 mmol, 1 eq.) in a 2:1 v/v mixture of EtOAc/H2O (6 mL) is added NaHCO3 (114 mg, 1.36 mmol, 2 eq.). The resulting mixture is cooled to 0° C. followed by the addition of methyl chloroformate (0.052 mL, 0.679 mmol, 1 eq.). After stirring at 0° C. for 15 min., the reaction is warmed to 25° C. and stirred for 12 h. The reaction is diluted with EtOAc and sequentially washed with 1 N HCl (aq) and saturated aqueous NaCl. The resulting organic solution is dried over Na2SO4 and concentrated to give (1-Oxo-indan-5-yl)-carbamic acid methyl ester as a tan solid (124 mg, 89% yield). [MS: (ES+) 206.1 (M+1)+].
Reaction SMILES: FC(F)(F)S([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=O)=O.[N:40]1C2C=CC=CC=2N[CH:41]=1>[C-]#N.[Zn+2].[C-]#N.CN(C)C=O>[NH:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25]([C:41]#[N:40])[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: O=C(c1ccc2c(c1)ncn2S(=O)(=O)C(F)(F)F)N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21
Reactant: c1ccc2[nH]cnc2c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A flask charged with a stir bar, zinc cyanide (0.32 g), trifluoromethanesulfonic acid cis-1-(1-trifluoromethanesulfonyl-1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment at N-1 or N-3 of the benzimidazole, 1.08 g), and N,N-dimethylformamide (5 mL) is sparged with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.31 g) is then added and the resulting mixture is heated to 100° C. and stirred at this temperature for 2 h. After cooling to room temperature, 1-hydroxybenzotriazole hydrate (0.45 g) and water (1.5 mL) are added and stirring is continued at room temperature for 3 h. Ethyl acetate, little methanol, and saturated aqueous Na2CO3 solution are added and the mixture is filtered over Celite. The aqueous phase of the filtrate is separated and neutralized with 2 M aqueous citric acid and extracted with ethyl acetate. The organic phases are combined and washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 96:4→90:10) to give the title compound as a solid. Yield: 0.42 g (68% of theory).
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@@H:24]([CH2:28][S:29][CH3:30])[C:25]([OH:27])=[O:26].C(N(CC)CC)C.Cl>O1CCCC1>[C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7](=[O:9])[O:8][C@@H:24]([CH2:28][S:29][CH3:30])[C:25]([OH:27])=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Reactant: CSC[C@H](O)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSC[C@H](OC(=O)[C@H](C)CSC(C)=O)C(=O)O
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
(S)-3-(Acetylthio)-2-methylpropanoic acid (0.38 g, 2.35 mmol) and 1,1'-carbonyldiimidazole (0.38 g, 2.35 mmol) were stirred under nitrogen, in tetrahydrofuran (10 ml). After 30 min, a solution of (R)-2-hydroxy-3-(methylthio)propanoic acid (0.32 g, 2.35 mmol), triethylamine (0.33 ml, 2.35 mmol) and tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was stirred at 25° for 18 h before evaporation of the solvent. The residue was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and the solvent evaporated. Chromatography on silica with dichloromethane/ethyl acetate as eluant gave the sub-title compound (0.1 g).
Reaction SMILES: Cl[C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:16]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:8].[NH:23]1[CH2:25][CH2:24]1>C(Cl)Cl>[N:23]1([C:2]2[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH:16]=2)[C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:8])[CH2:25][CH2:24]1
Reactant: C1CN1
Reactant: COC(=O)CCNC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1cc(N2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 83.7 %

Procedure:
A stirred solution of the above amide (315 mg, 0.95 mmol) in CH2Cl2 (35 mL) was treated with aziridine (197 μL, 3.81 mmol) at room temperature for 8 h. The mixture was partitioned between more CH2Cl2 and water, and the organic layer was dried and concentrated under reduced pressure. The residue was dissolved in EtOAc and filtered through a short column of silica gel to give 8 (269 mg, 84%): mp (CH2Cl2/iPr2O) 137° C.; 1H NMR [(CD3)2SO] δ8.86 (t, J=5.6 Hz, 1 H, NH), 8.66 (s, 1H, H-3), 7.40 (s, 1H, H-6), 3.63 (s, 3H, Me), 3.51-3.43 (m, 2H, NHCH2), 2.61 (t, J=6 8 Hz, 2H, CH2CO), 2 48 (s, 4H, aziridine-H). Anal. Calcd for C13H14N4O7: C, 46.15;H, 4 17; N, 16 57. Found: C, 45.89,H, 3.89; N, 16.45%.
Reaction SMILES: [CH:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])=O.Cl.[NH2:23]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])#[N:23]
Reactant: CCOC(=O)c1c[nH]c(C=O)c1-c1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1c[nH]c(C#N)c1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of ethyl 5-formyl-4-(nitrophenyl)-1H-pyrrole-3-carboxylate (24.55 g, 85.17 mmol) in pyridine (400 mL) was added hydroxylamine hydrochloride (6.51 g, 93.7 mmol). The solution was stirred at rt for 2 h, and then acetic anhydride (17.68 mL, 187.4 mmol) was added. The solution was heated (80° C.) for 17 h and then cooled to rt. The reaction mixture was partially concentrated in vacuo and then diluted with ethyl acetate (300 mL) and water (300 mL). The layers were separated and the aqueous layer was back extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to dryness. The crude material was then triturated with dichloromethane-diethyl ether (1:1 v/v, 300 mL). The solid was collected, washed with diethyl ether (150 mL), and dried under vacuum to afford the desired product (18.94 g, 78%). 1H-NMR (300 MHz, DMSO-d6) 13.24 (br s, 1H), 8.25-8.32 (m, 2H), 7.92 (s, 1H), 7.69-7.76 (m, 2H), 4.13 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.0 Hz, 3H); HPLC RT (Method A) 2.97 min; TLC Rf=0.20 (95:5 v/v CH2Cl2-EtOAc).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].C1C=CC=CC=1>O>[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[N:13]=[C:1]([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: Nc1ccccc1Cl
Solvent: c1ccccc1
Solvent: O
Product: CC(=Nc1ccccc1Cl)c1ccccc1

Procedure:
A solution of acetophenone (130 ml), 2-chloroaniline (130 ml) and benzene (200 ml) was refluxed in the presence of molecular sieve with continuous removal of water. o-Chloro-N-(α-methyl benzylidene) aniline (XXI) was obtained by fractional distillation. XXI had a boiling point of 111° C. at 0.1 millimeter.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([F:20])[F:19])=[CH:14][CH:13]=2)[C:7]1=[O:21])(=O)=O.Cl.[F:23][C@H:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][CH:18]([F:20])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][CH:6]([N:26]3[CH2:27][CH2:28][C@@H:29]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[C@H:24]([F:23])[CH2:25]3)[C:7]2=[O:21])=[CH:13][CH:14]=1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(N2CC[C@@H](c3ccc(O)cc3)[C@H](F)C2)CCN1Cc1ccc(C(F)F)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
A solution of (S)-1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl methanesulfonate (500 mg, 1.57 mmol) in 5.0 mL of acetonitrile was added dropwise over 1.5 h to a stirred mixture of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol, hydrochloride (363 mg, 1.57 mmol, from example 46, step M) and N,N-diisopropylethylamine (1.09 mL, 6.26 mmol) in 5.0 mL of acetonitrile maintained at 85° C. After complete addition, the reaction mixture was stirred at 85° C. for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (0-100% EtOAc/hexanes) to afford a diasteromeric mixture of 1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (235 mg, 35% yield) due to partial epimerization. A sample of the diastereomeric mixture (780 mg) was separated by preparative chiral SFC (column=Lux Cellulose-2 (21×250 mm, 5 μm); isocratic solvent=20% methanol (with 15 mM ammonia)/80% CO2; temp=35° C.; flow rate=60 mL/min; injection volumn=1.0 mL (˜20 mg/mL in MeOH) stacked @ 13 min intervals; λ=210 nM; Peak 1=19.6 min, Peak 2=24.5 min) to afford 389 mg of Example 114, P-1 and 242 mg of Example 114, P-2. Data for Example 114, P-1: LC-MS m/z 419.3 (M+H+); 1H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.91-6.80 (m, 2H), 6.65 (t, J=56.4 Hz, 1H), 4.96 (s, 1H), 4.77-4.43 (m, 3H), 3.68 (t, J=8.8 Hz, 1H), 3.42-3.33 (m, 1H), 3.29-3.14 (m, 2H), 2.85 (d, J=10.4 Hz, 1H), 2.78-2.69 (m, 1H), 2.69-2.57 (m, 1H), 2.48 (td, J=9.9, 4.9 Hz, 1H), 2.21-2.11 (m, 1H), 2.04 (dq, J=13.0, 8.6 Hz, 1H), 1.94-1.82 (m, 2H)). The relative and absolute configuration of Example 114, P-1 was confirmed by single crystal X-ray analysis. Data for Example 114, P-2: LC-MS m/z 419.3 (M+H+); 1H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.87-6.81 (m, 2H), 6.65 (t, J=56.5 Hz, 1H), 4.95 (s, 1H), 4.74-4.42 (m, 3H), 3.66 (t, J=8.9 Hz, 1H), 3.28-3.15 (m, 3H), 3.07-2.99 (m, 1H), 2.72-2.58 (m, 2H), 2.49-2.40 (m, 1H), 2.20-2.12 (m, 1H), 2.04 (dq, J=13.0, 8.7 Hz, 1H), 1.93-1.87 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13].Cl>C1COCC1>[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1
Reactant: CCCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNS(=O)(=O)c1ccc(CC2CCN(C(C)=O)CC2)cc1
Yield: 71.5 %

Procedure:
1-Propylamine (0.586 ml, 7.13 mmol) and triethylamine (0.993 ml, 7.13 mmol) were added to a solution of 4-(1-acetylpiperidin-4-ylmethyl)benzenesulfonylchloride (1.5 g, 4.75 mmol) in THF (20 ml) and this mixture was refluxed for 5 h. After having been cooled, 1N hydrochloric acid (20 ml) was added. The resulting mixture was extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with saturated sodium chloride solution (40 ml), and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel 25 g, ethyl acetate to ethyl acetate/methanol=10/1) to give the title compound (1.15 g, 71%) as pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]4[O:38][CH:37]=[N:36][C:35]=4C(O)=O)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu]=O.C(OCC)(=O)C>[O:38]1[C:34]([C@H:31]2[CH2:32][CH2:33][C@H:28]([N:18]3[C:17](=[O:42])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]4[N:25]=[CH:26][N:27]=[C:19]34)[CH2:29][CH2:30]2)=[CH:35][N:36]=[CH:37]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3ocnc3C(=O)O)CC2)c2ncnn12
Agent: O=[Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3cnco3)CC2)c2ncnn12
Temperature: 180 °C
Reaction time: 16 h

Procedure:
A mixture of 5-(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)-1,3-oxazole-4-carboxylic acid (0.94 g), copper(II) oxide (0.005 g) and quinoline (5 mL) was stirred at 180° C. for 16 hr. 1 N Hydrochloric acid and ethyl acetate were added to the reaction mixture, and the insoluble material was filtered off through celite. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.65 g, 75%).
Reaction SMILES: C([C@@:4]1([OH:28])[C@:8](C(=O)C)([OH:9])[C@@H:7]([CH2:13][O:14]C(=O)C)[O:6][C@H:5]1[N:18]1[C:27]2[N:26]=[CH:25][N:24]=[C:22](O)[C:21]=2[N:20]=[CH:19]1)(=O)C.S(Cl)([Cl:31])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:31][C:22]1[N:24]=[CH:25][N:26]=[C:27]2[C:21]=1[N:20]=[CH:19][N:18]2[C@@H:5]1[O:6][C@H:7]([CH2:13][OH:14])[C@@H:8]([OH:9])[C@H:4]1[OH:28]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 60 %

Procedure:
50 g of 2′,3′,5′-O-triacetylinosine was dissolved in 400 ml of chloroform. 30 ml of thionyl chloride and 7.2 ml of dimethylformamide were added, and the solution was refluxed with heating for 2 to 4 hours. The reaction mixture was poured into ice cold water, and the separated chloroform layer was washed with saturated aqueous solution of sodium hydrogencarbonate and brine. After drying over sodium sulfate anhydride, the solvent was distilled off. The residue was dissolved in 20% ammonia methanol solution and the container was sealed. After stirring for 3 to 5 hours, the solution was concentrated under reduced pressure. The precipitated crystalline was separated by filtration and dried to give 6-chloro-9-β-D-ribofuranosyl-9H-purine (yield: 60%).
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([F:25])[C:17]=1[CH:18]=[O:19]>O1CCCC1.[Zn]>[F:15][C:16]1[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([F:25])[C:17]=1[CH:18]([OH:19])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: Cc1ccc(F)c(C=O)c1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1ccc(F)c(C(O)CC(=O)OC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
To a suspension of zinc (1.256 g, 19.21 mmol) in dry tetrahydrofuran (18 mL) was added chlorotrimethylsilane (1.228 mL, 9.61 mmol). After 20 min, tert-butyl 2-bromoacetate (1.420 mL, 9.61 mmol) was added. The reaction was stirred at rt for 10 min, then heated at 40° C. for 20 min. The reaction mixture was cooled to 0° C. under Ar, and 2,6-difluoro-3-methylbenzaldehyde (1.5 g, 9.61 mmol) in 3 mL of dry THF was added. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was quenched with 5% aqueous NaHCO3, filtered, and rinsed with EtOAc. The filtrate was washed with water and brine, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography to yield the desired product (1.46 g, 56%). MS (ESI) m/z: 295.1 (M+Na)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[I:14])=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:8]=2[I:17])=[O:4].[H-].[Na+].Br[CH2:21][C:22]1[CH:26]=[C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[O:24][N:23]=1.BrCC1ON=C(C2SC(Cl)=CC=2)C=1>CN(C=O)C.O>[Cl:32][C:29]1[S:28][C:27]([C:25]2[O:24][N:23]=[C:22]([CH2:21][N:6]3[C:7]4[C:12](=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:8]=4[I:17])[C:13]([I:14])=[C:5]3[C:3]([OH:2])=[O:4])[CH:26]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1[nH]c2c(I)ccc(OC)c2c1I
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: Clc1ccc(-c2cc(CBr)on2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(I)c2c1c(I)c(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 200 mg 3,7-Diiodo-4-methoxy-1H-indole-2-carboxylic acid methyl ester in 2 ml DMF 20 mg (60% in oil) sodium hydride were added at RT. After stirring for 30 min 121 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, ChristopherJ.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was heated for 1 h at 60° C. After subsequent cooling of the reaction to RT and addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate. After concentration under reduced pressure the residue was treated with 30 mg lithium hydroxide monohydrate in THF/water 2:1. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid to pH 2 and the precipitate collected by filtration and washed with 3 ml water The product was obtained as a white solid which was dried under reduced pressure. Yield: 200 mg.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O>[ClH:1].[CH2:26]([O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Nc1ccccc1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Nc2ccccc2C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (3.0 g, 0.013 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and benzyl anthranilate (3.4 g, 0.015 mole) are added to pyridine (25 ml), and thereto is added dicyclohexylcarbodiimide (3.1 g, 0.015 mole), and the mixture is stirred at room temperature for 72 hours. After the completion of the reaction, water (10 ml) is added to the reaction mixture, and the mixture is stirred for 30 minutes, and the undissolved materials are filtered off. The filtrate is concentrated to driness. The resulting residue is washed with ethyl acetate (100 ml) and recrystallized from water to give N-(o-benzyloxycarbonylphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (3.2 g) as white crystals. m.p. 93°-95° C.