Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23]O)=[N:21][N:20]=[C:19]2[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:34]3[C:33](=[O:35])[C:32]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]4[C:30]3=[O:40])=[N:21][N:20]=[C:19]2[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 1B, 5-chloro-2',6'-difluoro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in methylene chloride is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 5-chloro-2',6'-difluoro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[O:9][C:10]([NH:12][C@@H:13]([CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:14]([O:16]C)=[O:15])=[O:11])[CH2:2][CH2:3][C:4]#[CH:5].O.[OH-].[Li+].OS([O-])(=O)=O.[K+]>C1COCC1.CO>[CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[O:9][C:10]([NH:12][C@@H:13]([CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:14]([OH:16])=[O:15])=[O:11])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)OC)C1CCOCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)O)C1CCOCC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a solution of the product from Step 1 (1.88 g, 5.81 mmol) in THF (20 ml) and MeOH (10 mL) was added an aq. 2M solution of lithium hydroxide monohydrate (14.53 ml, 29.1 mmol). The reaction was stirred at 50° C. for 20 hours at which stage TLC indicated no more starting material. The reaction was treated with 10% aq. KHSO4 and extracted with EtOAc. The organic fractions were washed with brine, dried over sodium sulfate, evaporated and dried to provide the desired compound, which was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[C:5]([NH:7][C@H:8]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)[CH2:9][S:10][CH2:11][CH3:12])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:38].C(O)(=O)C.ClCl>ClCCl.ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:27])[C:5]([NH:7][C@H:8]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)[CH2:9][S:10]([CH2:11][CH3:12])=[O:38])=[O:6]
Reactant: CCSC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: ClCl
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CCS(=O)C[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 97 %

Procedure:
Prepared analogously to Example 85 from 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(ethylsulfanyl)ethyl]-4-(pyrrolidin-1-ylcarbonyl)benzamide, 3-chloroperoxybenzoic acid, and glacial acetic acid in dichloromethane. Yield: 97%; Rf value: 0.31 (silica gel; dichloromethane/ethanol=9:1); C23H24C12N4O3S (507.44); mass spectrum: (M+H)+=507/509/511 (chlorine isotope).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[C:4]=1[OH:22].[OH-].[Na+].C(S(O)=O)(N)=N.Cl>O.C(O)C>[N:12]1[N:11]([C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([CH2:2][OH:1])[C:4]=2[OH:22])[N:19]=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=12
Reactant: COc1cc(CO)c(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: Cl
Agent: N=C(N)S(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CO)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
In a 500 ml round bottom flask equipped with a magnetic stirrer, regular addition funnel, powder addition funnel, and nitrogen inlet was added 23.6 g (77.7 mmol) 2-(hydroxymethyl)-4-methoxy-6-((2-nitrophenyl)diazenyl)phenol and 200 ml ethanol. NaOH (18.8 g, 470 mmol) was dissolved in 100 ml deionized water and approximately one-fourth was added dropwise to the reaction mixture. The mixture was heated to 80° C. and 25.1 g (232 mmol) formamidine sulfinic acid and the remaining sodium hydroxide solution were concurrently added dropwise to the reaction mixture over 30 minutes. The mixture was stirred at 80° C. for 3 hours, poured into 3.5 L water, and then acidified to pH 4 using 1 N HCl. The resultant solid was collected by filtration and worked up as in Example 5 to give a light yellow solid (4.3 g, 20.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]([NH:8]/[C:9](/[CH3:18])=[C:10](/[CH2:16][CH3:17])\[C:11]([O:13]CC)=O)=[O:7])[CH3:2].C[O-].[Na+].Cl>CCO>[CH2:16]([C:10]1[C:11]([OH:13])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:19])[C:6](=[O:7])[NH:8][C:9]=1[CH3:18])[CH3:17]
Reactant: CCOC(=O)CC(=O)N/C(C)=C(/CC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c(CC)c(C)[nH]c1=O
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A 50-mL round bottom flask was charged with ethyl (Z)-3-[(3-ethoxy-3-oxo-propanoyl)amino]-2-ethyl-but-2-enoate (540 mg, 2 mmol, 1 eq.), sodium methoxide (750 mg, 6.8 mmol, 3.4 eq. 25 wt. % in MeOH) and EtOH (10 ml). The mixture was stirred under reflux for 1 hr. After cooling to room temperature, the mixture was acidified by addition of 2N HCl aq. (5 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to afford crude ethyl 5-ethyl-4-hydroxy-6-methyl-2-oxo-1H-pyridine-3-carboxylate (205 mg, 46% yield) as yellow solid.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[NH:10][CH:11]=2)=[CH:3][CH:2]=1.C(OCC)(=O)C>Cl>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][NH2:14])[NH:10][CH:11]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Yield: 89 %

Procedure:
tert-butyl 2-(4-[1,1′-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate (4.8 g; 0.013 mol) is stirred in 120 ml of a solution of ethyl acetate saturated in hydrochloric acid for 2 hours 30 minutes at a temperature of 55° C. The solid obtained is filtered and washed with ether. A light beige-coloured powder is obtained with a yield of 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[N:21]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:23][C:24]=2[C:25]([F:28])([F:27])[F:26])=[O:19])=[CH:13][N:12]=1)[C:5](O)=[O:6].[CH3:35][O:36][C:37](=[O:43])[C@@H:38]([NH2:42])[CH:39]([CH3:41])[CH3:40].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:35][O:36][C:37](=[O:43])[CH:38]([NH:42][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[N:21]=[C:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:23][C:24]=3[C:25]([F:27])([F:26])[F:28])=[O:19])=[CH:13][N:12]=2)=[C:2]([Cl:1])[CH:3]=1)[CH:39]([CH3:41])[CH3:40]
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)c(Cl)c1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A mixture of 3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid (50 mg, 0.1 mmol), (S)-2-amino-3-methyl-butyric acid methyl ester (17 mg, 0.1 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (21 mg, 0.15 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.15 mmol) in anhydrous dichloromethane (3 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a solid. The solid was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give 2-(3-chloro-4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoylamino)-3-methyl-butyric acid methyl ester (41 mg, 66%) as a white solid. LCMS calcd for C29H24ClF3N4O5 (m/e) 600, obsd 601 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]3[N:16]=[N:17][N:18]([CH3:19])[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].CS(O[CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][N:37]=2)[CH2:32][CH2:31]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)(=O)C>[CH3:19][N:18]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:29][CH:30]4[CH2:35][CH2:34][N:33]([C:36]5[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][N:37]=5)[CH2:32][CH2:31]4)=[C:3]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[N:13]=[C:12]([C:14]#[N:15])[C:11]=2[N:16]=[N:17]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Reactant: Cc1ccnc(N2CCC(COS(C)(=O)=O)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccnc(N2CCC(COc3ccc(-c4cc5c(nnn5C)c(C#N)n4)cc3C(F)(F)F)CC2)c1

Procedure:
6-(4-Hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.626 mmol, 0.2 g), (1-(4-methylpyridin-2-yl)piperidin-4-yl)methyl methanesulfonate (0.752 mmol, 0.214 g), cesium carbonate (0.940 mmol, 0.306 g) and tetrabutylammonium iodide (0.313 mmol, 0.116 g) were stirred in DMF (1 ml) at 50° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and dried over Na2SO4. The resulting residue was triturated with ether and filtered. The solid was sonicated in methanol, filtered and dried to afford 1-methyl-6-(4-((1-(4-methylpyridin-2-yl)piperidin-4-yl)methoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile. (134 mg)
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)=[C:37]([OH:55])[C:36]3=[O:56])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)=[C:37]([O:55][CH3:3])[C:36]3=[O:56])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C1C(O)=C(c2ccc(F)cc2)C(c2cccc(F)c2F)N1c1ccc2nc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: OCCO
Product: COC1=C(c2ccc(F)cc2)C(c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/4.2 v/v, 31 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-4-(4-fluorophenyl)-3-hydroxy-1H-pyrrol-2(5H)-one (0.5 g, 1.2 mmol, 1 eq) and MeOH (10 ml); yield 0.160 g (60%); MS m/z: 436.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 10.5 (b, 1H), 7.88 (s, 1H), 7.72 (s,1H),7.59-7.56 (m, 1H), 7.26-7.00 (m, 4H), 6.91-6.86 (m,3H),6.38 (bs, 1H), 4.20 (s, 3H); HPLC (METHOD [A]): rt 15.20 min (97.35%)
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:7]([C:9]1[C:10](=[O:37])[N:11]([CH3:36])[C:12]2[C:17]([C:18]=1[O:19][P:20]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8].[N+]([O-])([O-])=O.[NH4+].[Ce]>CC#N>[C:38]1([NH:6][C:7]([C:9]2[C:10](=[O:37])[N:11]([CH3:36])[C:12]3[C:17]([C:18]=2[O:19][P:20]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:21])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:8])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccc(CN(C(=O)c2c(OP(=O)(Cc3ccccc3)Cc3ccccc3)c3ccccc3n(C)c2=O)c2ccccc2)c(OC)c1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: Cn1c(=O)c(C(=O)Nc2ccccc2)c(OP(=O)(Cc2ccccc2)Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
N-(2,4-dimethoxybenzyl)-N-phenyl-4-dibenzylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (116 mg, 0.165 mmol) was added to a solution of cerium ammonium nitrate (CAN, 226 mg, 0.412 mmol, 2.5 eq.) in aq. MeCN (95%, 8.0 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated at reduced pressure, and then partitioned between EtOAc and water. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated at reduced pressure. The residue was purified by silica column chromatography (heptane-EtOAc, 1:1, then 1:2) to give the title compound (61 mg, 67%).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN=C=NCCCN(C)C.Cl.O>C(Cl)Cl>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:35]([C@@H:32]3[CH2:33][CH2:34][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:31]3)=[O:36])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
To mixture of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.50 g, 8.24 mmol) and (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.08 g, 9.07 mmol, Peptech) in DCM (30 mL) was added EDC.HCl (1.90 g, 9.89 mmol). After stirring for about 4.5 h at ambient temperature, water (30 mL) was added and the layers were separated. The aqueous layer was then extracted with EtOAc (15 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was dissolved in DCM (15 mL) and purified by silica gel chromatography eluting with a gradient of 40-100% EtOAc in heptane to give tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (4.20 g, 97%): LC/MS (Table 2, Method a) Rt=2.27 min; MS m/z: 515 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:34][CH2:35][CH3:36])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:26][S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:34][CH2:35][CH3:36])[CH:16]2[CH2:17][C:18]3[CH:19]=[C:20]([O:26][S:27]([C:30]([F:33])([F:31])[F:32])(=[O:29])=[O:28])[CH:21]=[CH:22][C:23]=3[CH2:24][CH2:25]2)[CH2:10][CH2:9]1
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 4-{[propyl-(7-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, (220 mg, 0.41 mmol) in methylene chloride (5.0 mL) under an inert atmosphere was added trifluoroacetic acid (1.0 ml). The reaction was stirred at room temperature for 1h. The reaction was concentrated in-vacuo and partitioned between 1N NaOH (20 ml) and EtOAc (30 ml). The organic layer was separated, dried (MgSO4), and concentrated to afford trifluoro-methanesulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (114 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:11][C:12]1[O:13][C:14]2[C:19]([C:20](=[O:26])[C:21]=1[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=[CH:16][CH:15]=2>O1CCCC1.[Cu]Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([CH3:11])[CH:21]([C:22]([O:24][CH3:25])=[O:23])[C:20](=[O:26])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: COC(=O)c1c(C)oc2ccccc2c1=O
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)c2ccccc2OC1(C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 62 %

Procedure:
A suspension of copper(I) chloride (454 mg, 4.58 mmol) in tetrahydrofuran (5.0 mL) was stirred in a dry flask under nitrogen on ice. A solution of (3,4-dichlorophenyl)magnesium bromide (0.5 M) in THF (9.17 mL, 4.58 mmol) was added over about a 2 min. period. The resulting mixture was stirred on ice for 5 min, and then treated with a solution of methyl 2-methyl-4-oxo-4H-chromene-3-carboxylate (500 mg, 2.29 mmol) in THF (6.0 mL) over about a 2 min. period. The mixture was stirred on ice for 10 min, and then allowed to warm to rt. After 4.5 h at rt, the reaction mixture was quenched by adding 9:1 saturated aqueous ammonium chloride/aqueous ammonia (20 mL). Upon completion of addition, the reaction mixture was stirred at rt for 10 min. and then ethyl acetate and additional ammonium chloride were added. The aqueous and organic layers were mixed well and then separated. The organic layer was washed twice with saturated ammonium chloride, dried over sodium sulfate and then concentrated under vacuum to yield a residue. The residue was purified by column chromatography (silica gel, 9:1 hexane-ethyl acetate) to provide methyl 2-(3,4-dichlorophenyl)-2-methyl-4-oxochroman-3-carboxylate as a colorless gum (518 mg, 62%). By NMR, this material was mixture of the enol form and 2 diastereomeric keto forms (ratio about 1:1:2). Mass spectrum m/z 387.01, 389.03 (M+Na)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.C1[O:19]C1>[OH-].[Na+].C(O)(=O)C>[CH2:13]1[O:16][CH2:14]1.[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[OH:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CO1
Product: CCCCCCCCCc1ccccc1O
Temperature: 120 °C
Reaction time: 8 h
Yield: 500.2 %

Procedure:
To a 1,000 ml autoclave equipped with an ethylene oxide inlet tube, 220 g (0.998 moles) of nonylphenol having a branched mixture of nonyl group and an ortho/para ratio of 1/9 and 0.83 g (8.3 mmoles as sodium hydroxide) of 40% aqueous sodium hydroxide solution were charged. The reaction system was substituted with nitrogen, heated to 120° C., successively evacuated to 50 mmHg, and dehydrated for an hour under reduced pressure. After the dehydration, the reaction system was returned to atmospheric pressure by feeding nitrogen and heated to 150° C. While maintaining the temperature, 440 g (9.99 moles) of ethylene oxide was fed to the reaction system over 8 hours under increased gauge pressure of 0.2 to 0.4 MPa to carry out ethylene oxide addition reaction of nonylphenol. After ethylene oxide charge, the reaction system was further kept at the same temperature for an hour. After cooling the reaction system, the reaction system was neutralized with 0.52 g (8.7 mmoles) of acetic acid to obtain 660 g of nonylphenol ethylene oxide adduct. Nonylphenol ethylene oxide adduct thus obtained had an average ethylene oxide addition mole number of 10.0.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[C:14]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]=4[N:16]=[CH:17][C:12]=3[C:11](=[O:29])[NH:10][C:9]2=[O:30])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)#[N:32].B.N1C=CC=CC=1C.[OH-].[Na+]>CO.C(O)(=O)C>[O:30]=[C:9]1[N:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[CH2:7][CH2:6]2)[C:13]2[C:14]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:15]=3[N:16]=[CH:17][C:12]=2[C:11](=[O:29])[NH:10]1
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n(C3CCNCC3)c12
Reactant: N#Cc1ccc(C=O)cc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccn1
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n(C3CCN(Cc4ccc(C#N)cc4)CC3)c12
Yield: 39.7 %

Procedure:
1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione hydrochloride (50 mg, 0.111 mmol) and 4-cyanobenzaldehyde (29 mg, 0.22 mmol) in a mixture of methanol (2 ml) and acetic acid (0.2 mL) were stirred with 2-picoline borane (50 mg, 0.47 mmol) at room temperature for 2 days. After addition of 1 M aqueous sodium hydroxide, the reaction mixture was extracted with a mixture of ethyl acetate and 2-propanol, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=10/1 (v/v)) to give the title compound as a colorless solid (23.4 mg, yield 40%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:18][C:19]1[C:20]([O:39][CH3:40])=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[C:26]([N:29]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[N:30]1)[CH:25]=[C:24]2O.C(OC(C(CCC=CCCCCCCCCCC)CCC)=O)C>>[Cl:18][C:19]1[C:20]([O:39][CH3:40])=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[C:26]([N:29]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[N:30]1)[CH:25]=[C:24]2[O:9][C@@H:7]1[CH2:6][N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@H:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:8]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc2c(O)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Agent: CCCCCCCCCCC=CCCC(CCC)C(=O)OCC
Product: COC(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Yield: 90 %

Procedure:
Compound 112 was synthesized from N-Boc-trans-4-hydroxy-L-proline-methyl ester 111 and compound 88a as beige foam in 90% yield, following the procedure as described for compound 54c.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:31]2[CH2:32][CH2:33][CH:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:30]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Cc1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methylphenyl)pyrrolidine oxalate (15.1 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (2.7 mg). Calcd for C22H22N2O2: 346.1681, found 346.1692.