Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[C-]#N.[Na+].[Na+].[I-].[CH3:36][N:37](C=O)C>O>[O:27]=[C:4]1[N:3]([CH2:28][CH2:29][CH3:30])[C:2]([C:36]#[N:37])=[N:10][C:9]2[N:8]=[C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)[NH:6][C:5]1=2
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCCn1c(C#N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 67.5 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
A mixture of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.1 g, 0.23 mmol), NaCN (0.016 g, 0.35 mmol), NaI (0.069 g, 0.46 mmol) and DMF (2 ml) were stirred for 48 h at 65-70° C. Reaction mixture was cooled to 20-25° C. and water was added. Solid material was separated. It was filtered off and washed with water. The product was dried under vacuum to obtain 6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile (0.075 g, 77%) as an off white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1.OS(O)(=O)=O.CCOC(C)=O>CN(C=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: CC(C)Nc1nc(Cl)nc2c1CCC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(NC(C)C)c3c(n2)C(c2ccccc2)CC3)ccc1-n1cnc(Cl)c1
Temperature: 94 °C
Reaction time: 20 h
Yield: 49.8 %

Procedure:
To a solution of 2-chloro-N-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (154 mg, 0.535 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (114 mg, 0.508 mmol) in DMF (2.5 mL) was added Conc. H2SO4 (0.040 mL, 0.749 mmol). The mixture was stirred at 94° C. for 20 hrs. After cooled down to room temperature, 100 mL of EtOAc was added, washed with saturated NaHCO3/H2O, dried over Na2SO4, and removed. The residue was purified via Biotage (12 g, hexanes-100% EtOAC) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (120 mg, 0.253 mmol, 47.2% yield). LC-MS (M+H)+=475.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.92 (1H, d, J=2.1 Hz), 7.51 (1H, d, J=1.5 Hz), 7.31 (2H, d, J=7.3 Hz), 7.22-7.25 (2H, m), 7.22 (1H, s), 7.08 (1H, s), 7.04 (1H, d, J=8.5 Hz), 7.01 (1H, d, J=1.5 Hz), 6.74 (1H, dd, J=8.4, 2.3 Hz), 4.38-4.46 (1H, m), 4.33 (1H, d, J=7.9 Hz), 4.18-4.24 (1H, m), 3.49 (3H, s), 2.72-2.80 (1H, m), 2.61-2.71 (2H, m), 2.07-2.14 (1H, m), 1.33 (6H, t, J=6.6 Hz).
Reaction SMILES: [C:1](=[O:14])([O:12][CH3:13])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH3:11].OS(O)(=O)=O.[N+:20]([O-])([O-:22])=[O:21].[K+]>>[C:1](=[O:14])([O:12][CH3:13])[O:2][C:3]1[CH:8]=[C:7]([N+:20]([O-:22])=[O:21])[C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH3:11]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1cc(F)ccc1OC(=O)OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCc1cc(F)c([N+](=O)[O-])cc1OC(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
2-Ethyl-4-fluorophenyl methyl carbonate (2.4 g, 12.11 mmol) was added dropwise to H2SO4 (7.2 mL) to generate a yellow homogeneous solution. The solution was then cooled to 0° C. and KNO3 (1.469 g, 14.53 mmol) was added portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water. The aqueous layer was extracted with dichloromethane (3×10 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexane) provided 2-ethyl-4-fluoro-5-nitrophenyl methyl carbonate (1.7 g, 58% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.20 (d, J=6.8 Hz, 1H), 7.64 (d, J=12.1 Hz, 2H), 3.88 (s, 3H), 2.62 (q, J=7.5 Hz, 1H), 1.15 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=O)[C:5]=12.P(Cl)(Cl)(Cl)(Cl)Cl.[C:22]1([CH3:28])C=CC=CC=1>CN(C)C=O>[CH3:3][N:4]1[CH2:28][CH2:22][N:7]([C:6]2[C:5]3=[CH:1][CH:2]=[CH:3][N:4]3[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:6][CH2:5]1
Reactant: O=C1Nc2ccccc2Cn2cccc21
Reactant: Cc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN1CCN(C2=Nc3ccccc3Cn3cccc32)CC1

Procedure:
A mixture of 2 g. of 5,10-dihydro-11H-pyrrolo[2,1-c]-[1,4]benzodiazepin-11-one (Example 1), 2 g. of phosphorus pentachloride and two drops of N,N-dimethylformamide in 50 ml. of toluene is heated on the steam bath for several hours. The solvent is removed by distillation, 25 ml. of chloroform is added and the mixture evaporated again. The residue is dissolved in 25 ml. of chloroform and this solution slowly added to 10 ml. of N-methylpiperazine in 40 ml. of toluene. This mixture is heated for several hours, finally to the boiling point of toluene, and then evaporated to an oily residue. The residue is taken up in ether (500 ml) and extracted into dilute acetic acid. The aqueous acetic acid layer is made basic with concentrated ammonium hydroxide and the product which precipitates is extracted into ether. The ether solution is dried over anhydrous potassium carbonate, and evaporated to a residue which contains the desired product. When purified by recrystallization it shows m.p. 139°-141° C. (base).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C@@H:16]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1)[CH2:17][N:18]([CH:31]([CH3:33])[CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@H:16]([NH:15][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:17][NH:18][CH:31]([CH3:33])[CH3:32])=[CH:35][C:36]=1[C:41]([F:42])([F:43])[F:44]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CC(C)N(C[C@@H](N)c1ccc(Cl)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)NC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Compound 55 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-isopropyl-4-nitro-benzenesulfonamide to give the title compound as a white solid. LC/MS [454 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.26 (s, 1H), 9.01 (d, 1H), 8.55 (s, 1H), 8.38 (d, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.76 (d, 1H), 7.67 (d, 1H), 5.47 (s, 1H), 3.15 (d, 1H), 3.02 (s, 1H), 2.80-2.69 (m, 1H), 0.96 (dd, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[N:13]=[C:12](Cl)[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:17][O-:18].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[N:13]=[C:12]([O:18][CH3:17])[CH:11]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1nc(Cl)cnn1-c1cc(Cl)cc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF was dissolved 2.77 g of 2-(3,5-dichloro-phenyl)-5-chloro-2,3-dihydro-1,2,4-triazin-3-one followed by addition of sodium methoxide in an equimolar amount to the starting compound, and the mixture was stirred at room temperature for 1 hour. After completion of this reaction, the reaction mixture was concentrated under reduced pressure and ice-water was added to the residue. The resulting crystals were collected by filtration, dried and dissolved in 100 ml of chloroform. The chloroform solution was dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (Merck Silica Gel 60; dichloromethane-methanol=10:1) to provide 0.4 g of white crystals (m.p. 164° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17].[Na]>CCO.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccccn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccn2)CCN(C)C1
Yield: 2.5 %

Procedure:
The title compound was prepared according to General Method 3. 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (See Example 1) (400 mg, 2 mmol), 2-vinylpyridine (500 mg, 5 mmol), sodium (30 mg, 1.3 g atom), and CuSO4 (20 mg, catalytic) were heated in EtOH (8 mL) at 150° C. overnight (16 h). The contents were evaporated to dryness under vacuo. Water was added and the contents were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 15 mg of 2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(pyridin-2-yl)ethyl)-1H-pyrido[4,3-b]indole as a trifluoroacetate salt.
Reaction SMILES: F[C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)=O.P(Cl)(Cl)(Cl)=O>C(O)C>[C:3]1([C:4]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:21]=3[N:13]([CH2:14][CH2:15]4)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:2]=1
Reactant: O=C(Nc1ccccc1N1CCc2ccccc21)c1ccccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: c1ccc(C2=Nc3ccccc3N3CCc4cccc2c43)cc1
Reaction time: 1 h

Procedure:
A solution of 15.0 g of 1-(2-benzamidophenyl)indoline of Example 19, and 45 ml of phosphorus oxychloride is refluxed under N2 for 4 hours and then the excess reagent is removed to leave a syrup which is dissolved in absolute ethanol, boiled one hour, then concentrated again to a dark purple syrup which eventually solidifies affter prolonged standing. This material is slurried in absolute ethanol, and treated dropwise with enough Bu3N to change the color from purple to orange-brown, whereupon the product base crystallizes voluminously. After refrigeration overnight, the resultant orange-brown flakes are collected, washed with ethanol and hexane, and dried to afford 1,2-dihydro-6-phenylindolo[1,7-ab][1,5]benzodiazepine, m.p.141°-143° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.O1CCCCC1[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH3:28])=[CH:23][CH:22]=1.Cl>O1CCCC1>[Br:13][C:9]1[CH:8]=[C:7]([C:27]([C:24]2[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=2)=[CH2:28])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(OC2CCCCO2)cc1
Reactant: Brc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(O)cc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of n-butyllithium (1.6 M solution in hexane, 41.6 mL, 1.1 eq) was added dropwise to a solution of 1,3-dibromobenzene (7.6 mL, 1.1 eq) in tetrahydrofuran (30 mL) at −78° C. After stirring 30 min at −78° C. 1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethanone (12.6 g, 57 mmol, 1 eq) in tetrahydrofuran (25 mL) was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 h, then treated with 1 N HCl (10 mL), extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo. The crude was dissolved in toluene (40 mL) and p-toluenesulfonic acid (50 mg) was added. The mixture was heated at 150° C. for 3 h. The solvent was removed under reduce pressure and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colorless oil (1.2 g, 10%);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][O:27][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:30](=[O:32])[CH3:31])[CH2:25][CH2:26][O:27][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COCCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: CC(=O)Cl
Product: COCCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {6-methoxy-2′-[(2-methoxy-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[N:18]3[C@@H:13]([CH:14]=[CH:15][CH2:16][C:17]3=[O:19])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H][H]>CO.[Pt]=O>[F:9][C:6]1[CH:5]=[C:4]([C@H:10]2[N:18]3[C@H:13]([CH2:14][CH2:15][CH2:16][C:17]3=[O:19])[CH2:12][CH2:11]2)[CH:3]=[C:2]([F:1])[C:7]=1[F:8]
Reactant: O=C1CC=C[C@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N12
Yield: 99.8 %

Procedure:
Platinum oxide (100 mg) was added to a solution of (3S,8aR)-3-(3,4,5-trifluorophenyl)-2,3,6,8a-tetrahydro-1H-indolizin-5-one (680 mg) in methanol (20 mL), and the reaction solution was stirred in a hydrogen atmosphere at 1 atm at room temperature for 2.5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 684 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([C:3]1[N:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1)#[N:2].C(N(CC)CC)C.[SH2:17]>C(O)C>[CH3:9][N:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:3]1[C:1](=[S:17])[NH2:2]
Reactant: S
Reactant: Cc1ccc(C#N)n1C
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(N)=S)n1C

Procedure:
5 g of 2cyano-1,5-dimethylpyrrol are dissolved in 40 ml of ethanol and treated with 10 ml of triethylamine. 50 ml of an ethanolic H2S solution (3.8 g/100 ml) are added and the mixture is heated for ca. 15 hours in an autoclave at 70°. The reaction mixture is cooled and the solvent is evaporated off to obtain ca. a quarter of its volume. 1,5-dimethylpyrrol-2-carbothioamide crystallizes upon cooling at 0° in the form of a light yellow precipitate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=O.O.[NH4+:11].[Cl-]>[Zn].CC(=O)OCC>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[N:11][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[O-:3]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Product: [O-][N+](=Nc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
0.204 mL (2.0 mmol) of nitrobenzene and either of 17.2 mg (the amount required for swelling of the reactant, nitrobenzene, in 100%) of Polymer supported reagent-1 synthesized in Example 3 or 14 mg (the amount required for swelling of the reactant, nitrobenzene, in 100%) of Polymer supported reagent-2 synthesized in Example 4 were put into a 50 mL, two-neck flask equipped with a water cooler, and the resulting mixture was stirred at a nitrogen atmosphere for 20 minutes to swell the the polymer supported reagent with the reactant. To this were added 0.262 g (4.0 mmol) of Zn powders, 0.214 g (4.0 mmol) of NH4Cl, and 15 mL of distilled water, and then the reduction reaction was conducted at 80° C. for 200 minutes. After the completion of the reaction, 30 mL of an organic solvent, EA was added thereto and stirred at room temperature for 30 minutes. The resulting mixture was then filtered to separate firstly the solid mixture and the liquid mixture solution. The liquid mixture solution as obtained was put into a separating funnel to separate a water layer and an EA layer. To the separated water layer was added 20 mL of EA and stirred to extract the product remained in the water layer. This procedure was repeated 3 times. To the EA solution as combined was added 1.0 g of anhydrous magnesium sulfate and the resulting mixture was stirred for 30 minutes and then filtered. From the filtered EA solution, an excessive amount of EA was evaporated by using an evaporator to obtain azoxybenzene as a main product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[CH3:24][N:25]1[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]1.C([BH3-])#N.[Na+]>CC(O)=O.CO>[CH3:20][C:16]1([CH3:21])[NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][CH2:30][C:29]5[N:25]([CH3:24])[CH:26]=[N:27][CH:28]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Reactant: Cn1cncc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1cncc1CNc1ccc2c(c1)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
To a stirred solution of Example 42 (0.03 g, 0.10 mmol) in 5% AcOH in MeOH (1 mL) was added 1-methyl-5-imidazolecarboxaldehyde (0.01 g, 0.14 mmol). The reaction mixture was stirred at r.t. for 20 minutes. Sodium cyanoborohydride (0.02 g, 0.39 mmol) was then added, and the reaction mixture stirred for a further 10 minutes before being concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.01 g, 32%) as a yellow oil. δH (CDCl3) 8.28 (1H, s), 8.17 (1H, s), 7.22 (1H, s), 7.17 (1H, d, J 2.6 Hz), 6.82 (1H, d, J 8.7 Hz), 6.47 (1H, dd, J 8.9 and 2.8 Hz), 5.82 (1H, s), 4.34 (2H, s), 4.29-4.22 (2H, m), 4.19-4.11 (2H, m), 3.86 (3H, s), 2.86 (2H, s), 1.39 (6H, s). LCMS (ES+) 425.42 (M+H)+, RT 1.85 minutes (Method 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([CH2:10][C@H:11](S(C)(=O)=O)[CH3:12])[C:3]=1[F:17].[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([C@@H:11]([CH3:12])[CH2:10][C:4]1[C:5]([F:9])=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=1[F:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](Cc1c(F)c(F)cc(F)c1F)S(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-1,2,4,5-tetrafluoro-3-(2-(methylsulfonyl)propyl)benzene (2.3 g, 8.03 mmol) in anhydrous DMF (10 mL) was added sodium azide (1.045 g, 16.07 mmol) and the solution was heated to 80° C. and stirred for 2 h. Then, the temperature was cooled to rt and 20 mL of water was added, extracted with EtOAc/hexane (1/1 v/v), dried over anhydrous MgSO4 and evaporated to give crude oil, which was passed through silica gel pad and evaporated under reduced pressure to give the product. This was used as starting material for next reduction without more purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[F:32][C:31]1[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:15]([CH3:18])(=[O:17])=[O:16])=[N:27][C:28]([NH:42][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:29][CH:30]=1
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2nc(NCCc3ccccc3)ncc2F)c1)C1CCNCC1

Procedure:
Intermediate 77 was coupled with phenethylamine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 484. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H), 8.17 (s, 1H), 7.98 (d, 1H), 7.49 (m, 2H), 7.26 (m, 5H), 4.55 (s, 2H), 3.89 (m, 1H), 3.62 (t, 2H), 333 (m, 2H), 3.03 (s, 3H), 2.98 (m, 2H), 2.90 (t, 2H), 1.89 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH:25]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:32])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(O)C1CCCCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H]3CCCN3C(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 92b) and cyclohexanecarboxylic acid as brown solid (39%). MS 440 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[NH2:13][C:14]([NH2:16])=[NH:15].Cl>O1CCOCC1>[NH:15]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:14]([NH2:16])=[NH:13]
Reactant: N=C(N)N
Reactant: O=C(O)CCCCCCCCBr
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)NCCCCCCCCC(=O)O

Procedure:
9-Bromo-nonanoic acid (5 gm; 21.1 mmoles) was dissolved in dioxane (50 ml) and the free guanidine solution from A was added. The mixture was refluxed overnight, and the white precipitate was filtered and washed three times with cold water and then lyophilized from one equivalent of 0.5M HCl. The yield was 2.77 g (85%) and the structure of the title compound was verified by FAB-MS, NMR, and elemental analysis.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:12]([O:14]C)=[O:13])([CH3:4])([CH3:3])[CH3:2].C(O)(C)(C)C>O>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:12]([OH:14])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cl)c(OCC(=O)OC(C)(C)C)c1
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)COc1cc(C(=O)O)ccc1Cl
Yield: 89.9 %

Procedure:
Methyl 3-(2-tert-butoxy-2-oxoethoxy)-4-chlorobenzoate (0.7 g) in 9:1 tert butanol:water was subjected to Antarctica B lipase for 6 d. Filtration and evaporation of the solvent yielded the subtitle compound as an off-white solid (0.6 g).
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]([OH:21])=O)[C:14](=[O:22])[N:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC(C)N=C=NC(C)C.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][C:33]1=[O:38]>C1C=CC=CC=1>[C:1]([NH:11][C:12]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][C:33]2=[O:38])=[O:21])[C:14](=[O:22])[N:13]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Reactant: O=C1CNCCN1
Agent: CC(C)N=C=NC(C)C
Solvent: c1ccccc1
Product: O=C(Nc1ccn(CC(=O)N2CCNCC2=O)c(=O)n1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
(N4-CBz-cytosin-1-yl)acetic acid (2.42 g, 8 mmol) was azeotroped with benzene (3×25 mL) and dried under vacuum. 32 mL of anhydrous DMF was added under N2 followed by the addition of DIC (1.57 mL, 8 mmol). The reaction was stirred at room temperature for 2-3 minutes, then treated with piperazinone (8.8 mmol, 881.1 mg), and the reaction mixture was left to stir for 48 hours. The reaction mixture was concentrated by rotary evaporation, washed successively with 0.1 N citric acid solution (2×10 mL) and water (2×15 mL), and then dried in a dessicator, affording N-[(N4-CBz-cytosin-1-yl)acetyl]-piperazinone as a white solid.