Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3](CC)[CH:4]=[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6](=[O:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)C.[NH2:24]N>C(O)(C)C>[C:9]1([C:7]2[C:6](=[O:15])[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:4][NH:3][N:24]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(C=C(C(=O)C(=O)c1ccccc1)c1ccccc1)CC
Reactant: NN
Solvent: CC(C)O
Product: O=c1c(-c2ccccc2)c[nH]nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product solution from Example 1 was cooled to 0° C. and mixed with 20 ml. of isopropyl alcohol and 2 ml. of hydrazine. The mixture was stirred for 10 minutes, and was then warmed to room temperature and stirred for 15 hours. The product was then collected by filtration. The yield was 6.0 g. of 3,5-diphenyl-4(1H)-pyridazinone, m.p. 328°-32° C., which was identified by infrared and nuclear magnetic resonance analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[C:19]([NH:23][S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cc2cccc(N)c2)cc1-c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Cc2cccc(NS(C)(=O)=O)c2)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a 4 mL vial was added P-255 (60 mg, 0.17 mmol), followed by pyridine (2 mL) then methanesulfonyl chloride (13 μL) at 0° C. The resulting solution was allowed to stir at room temperature overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×5 mL). The combined organics were concentrated under vacuum, and the residue was purified by silica gel column chromatography with methanol/dichloromethane to yield 36.7 mg (55%) of P-271). 1H NMR (400 MHz, CDCl3) 2.98 (s, 3H), 3.79 (s, 3H), 3.94 (s, 2H), 6.53 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.99-7.17 (m, 5H), 7.22-7.35 (m, 3H), 7.34-7.41 (m, 1H), 7.48 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl>[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH:5][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of leucine methyl ester (5 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml) was cooled to 0° C. and treated dropwise with allyl chloroformate. After addition, the solution was stirred at ambient temperature for 2 h, diluted with dichloromethane, washed successively with 1N HCl and aqueous NaHCO3, dried over Na2 SO4, and concentrated to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][N:21]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1cnccn1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cnccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-pyrazinecarboxylic acid as starting materials, MS (LC/MS): 409.6 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[N:3]=[C:4]([C:9]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][N:10]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: Nc1ncc(Br)nc1-c1noc(-c2ccccc2)n1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(-c3noc(-c4ccccc4)n3)n2)cc1
Temperature: 110 °C
Yield: 67 %

Procedure:
A mixture of 5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyrazin-2-amine (100 mg, 0.3143 mmol), (4-methylsulfonylphenyl)boronic acid (94.29 mg, 0.4714 mmol) and PdCl2(PPh3)2 (11.03 mg, 0.01572 mmol) in DMF (2 mL) was treated with Na2CO3 (471.4 μL of 2 M, 0.9429 mmol) and the reaction placed under an atmosphere of nitrogen and heated at 110° C. in a sealed tube for 16 hours. The resultant precipitate was filtered, washed with water and dried under vacuum (83 mg, 67% Yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=3)[CH:19]=[C:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:13][CH:14]=2)O1.C(OO)(C)=[O:38]>C1COCC1>[OH:38][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=2)[CH:19]=[C:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(B4OC(C)(C)C(C)(C)O4)cn3)c2)CC1
Reactant: CC(=O)OO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(O)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (3.45 g, 7 mmol) in THF (15 mL) was added AcOOH (4.6 mL, 60.67 mmol) at 0° C. The temperature was allowed to warm to RT and the reaction was stirred for 3 h. The reaction was quenched with Na2SO3 solution at 0° C. and the pH of the solution was adjusted to 7-7.5. Then the mixture was extracted with ethyl acetate and the organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (1:3 acetone:hexane) to give the title compound (2.02 g, 75%). 1H NMR (500 MHz, DMSO-d6): δ 9.67 (s, 1H), 7.72 (s, 1H), 7.28 (m, 2H), 6.98 (d, J=7.2 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.85 (d, J=7.5 Hz), 6.83 (s, 1H), 6.35 (s, 1H), 3.41 (m, 2H), 3.31 (m, 2H), 2.38 (m, 2H), 2.27 (m, 2H), 1.41 (s, 9H); m/z (383.1, M+ H+).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[NH2:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH2:8][CH2:7][C:6]([NH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Reactant: CCC1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=CNC1=CCC(CC)CC1)C(=O)OCC

Procedure:
A mixture of 12.6 g of 4-ethylcyclohexanone, 17.0 g of diethyl aminomethylenemalonate, and 950 mg of p-toluenesulfonic acid in 170 ml of toluene is heated at reflux for 48 hours with a water separator, under nitrogen atmosphere. The solvent is removed under nitrogen atmosphere and under vacuum, and the residue purified by flash column chromatooraphy on a silica qel column eluted with methylene chloride. The desired product, diethyl N-(4-ethylcyclohexen-1-yl)-aminomethylenemalonate is obtained as an oil. The purified product in 90 ml Dowtherm is aded to 300 ml Dowtherm preheated to 250° under nitrogen atmosphere. After heating at 240°-245° for 4 hours the reaction mixture is cooled and allowed to stand at room temperature overnight. The precipitate which formed is filtered off, washed with hexane and air-dried. Recrystallization form isopropanol after treatment with decolorizing carbon affords ethyl 4-hydroxy-6-ethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate m.p. 218°-220°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(#N)C.CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:41]2[CH2:42][CH2:43][CH2:44][C@H:40]2[CH2:39][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:31])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3CCC[C@H]3CN3CCCC3)c1C)C(=O)N2

Procedure:
5-[5-(2,6-Dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol) was coupled with (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (50 mg, 1.2 eq.), HOBt (42 mg, 1.2 eq.), EDAC.HCl (60 mg, 1.2 eq.) and TEA (3 eq.) in acetonitrile: DMF (3:1) to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][C:32]1[CH:37]=[C:36]([O:38][C:39](F)(F)F)[CH:35]=[CH:34][C:33]=1[S:43](Cl)(=[O:45])=[O:44]>>[CH3:39][O:38][C:36]1[CH:35]=[CH:34][C:33]([S:43]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:45])=[O:44])=[C:32]([CH3:31])[CH:37]=1
Reactant: Cc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)c(C)c1

Procedure:
4-Methoxy-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2-methyl-4-trifluoromethoxybenzenesulfonylchloride (53 mg, 0.455 mmol) according to general method 3 to give before Boc-deprotection 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 571.2; Calcd 571.12; 1H NMR δ 773-7.09 (m, 8H), 6.86 (d, 1H), 6.69 (dd, 1H), 6.48 (d, 1H), 3.29-3.17 (m, 8H), 2.62 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15](Cl)Cl>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:6]2[CH2:15][C@H:7]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(Br)cc1
Reactant: ClCCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
To a mixture of ethyl 4-bromocinnamate and Pd(OAc)2 (0.05 eq) in methylene chloride (1M) at 0° C. was added dropwise a solution of CH2N2 in ether until the reaction was completed by NMR analysis. The mixture was filtered through a plug of silica gel and concentrated to afford the title compound as an oil.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Cl>C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26][N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3Cc2ccc(Cl)cc2Cl)n1
Reaction time: 1.5 h

Procedure:
A suspension of 7.97 g. of 7-H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 500 ml. of dry dimethylformamide is stirred under nitrogen as 4.61 g. of ca. 50% sodium hydride-mineral oil dispersion is added carefully. After stirring for 1.5 hours, a solution of 8.99 g. of 2,4-dichlorobenzyl chloride in 30 ml. of dry dimethylformamide is added during ca. 10 minutes. Stirring is continued for 5 hours and then 25 ml. of glacial acetic acid is added to the reaction mixture. After removal of solvent (in vacuo), the residue is stirred throughly with a mixture of excess aqueous potassium carbonate solution and 100 ml. of 1 N sodium hydroxide solution and filtered. The crude product is dissolved in 5 liters of boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 500 ml. and chilled. The crystalline solid is collected and again recrystallized from methanol to afford 6.33 g. of the title compound, m.p. 249°-250° C., NMR (dDMSO and D2O): δ 5.58 (singlet, N--CH2 --C6H3Cl2), 6.68 (doublet, J=8 Hz, 5H), 7.10 (doublet, J=3 Hz, 9H), 7.52 (doublet, J=3 Hz, 8H), 7.68 (doublet, J=8 Hz, 6H) p.p.m.; λmax95%EtOH 258 mμ (26,000) and 315 mμ (8,500).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][CH3:15])=[N:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2].C1C=C([Cl:22])C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][CH3:15])=[N:8][C:9]([Cl:22])=[CH:10][C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CC)ccnc1CC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(CC)cc(Cl)nc1CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
To a solution of 2.73 g (14.12 mmol) 2,4-diethyl-pyridine-3-carboxylic acid ethylester in chloroform (109 ml) was added 6.97 g, (70% pure, 28.29 mmol) mCPBA at 0° C. The reaction mixture was stirred at RT for 6 h and was then diluted with chloroform and washed with a sat. NaHCO3 sol and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in POCl3 (70 ml) and the reaction mixture was heated at 110° C. for 6.5 h. Then excess POCl3 was evaporated and cold water was added to the residue. The mixture was basified with a sat. NaHCO3 sol to pH ˜10 and was extracted EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of this residue by CC (hexane/EtOAc 9:1) provided 1.6 g (7.02 mmol, 20%) 6-chloro-2,4-diethyl-pyridine-3-carboxylic acid ethylester.
Reaction SMILES: [CH2:1]([OH:3])C.C([O-])=O.[NH4+].C(O)=O.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Pd].O>[C:12]1([CH:11]([OH:18])[CH2:1][OH:3])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: CCO
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: O
Product: OCC(O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 60 %

Procedure:
Pd/C (5 mol %) is weighed into a reaction flask. A solvent mixture consisting of ethanol and water (4:1) and ammonium formate (30 mol %) is added, the reaction flask is capped with a rubber septa and the mixture is heated (80° C.) for 2 minutes. Formic acid (3 equivalents) and then benzyl alcohol are added by syringe. The reaction is run for 10-40 minutes and the reaction is quenched with brine. The product is extracted by DCM and the organic phase is dried by Na2SO4. The product 1-phenyl-2-propanol was analyzed by 1H NMR and produced in 60% yield.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[O:19]1[CH:21]2[CH2:22][CH:23]([O:28][CH3:29])[CH:24]([O:26][CH3:27])[CH2:25][CH:20]12>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:20]2[CH2:25][CH:24]([O:26][CH3:27])[CH:23]([O:28][CH3:29])[CH2:22][CH:21]2[OH:19])=[CH:14][CH:13]=1
Reactant: COC1CC2OC2CC1OC
Reactant: COc1ccc(O)cc1
Agent: O=C(O)c1ccccc1
Product: COc1ccc(OC2CC(OC)C(OC)CC2O)cc1
Yield: 96 %

Procedure:
A reaction was conducted as described in Example 6 except that benzoic acid and PGE were replaced with the same molar amounts of 4-methoxyphenol and 1,2-epoxy-4,5-dimethoxycyclohexane. Desired 2-(4-methoxyphenoxy)-4,5-dimethoxycyclohexanol was formed in analytical yield of 96% and isolated in a yield of 92%.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([O:11][C:12](=[O:44])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([C:31]2[N:35]4[CH:36]=[CH:37][C:38]([CH:40]([OH:43])CO)=[CH:39][C:34]4=[N:33][N:32]=2)[CH:27]=[CH:26]3)[CH2:17][CH2:16]1)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[C:7]([O:11][C:12](=[O:44])[NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([C:31]2[N:35]4[CH:36]=[CH:37][C:38]([CH:40]=[O:43])=[CH:39][C:34]4=[N:33][N:32]=2)[CH:27]=[CH:26]3)[CH2:17][CH2:16]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(C(O)CO)ccn45)nc23)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(C=O)ccn45)nc23)CC1
Reaction time: 0.17 h

Procedure:
To a slurry of silica gel (0.1 g) in DCM (3 mL) was added sodium periodate (0.13 mL, 0.087 mmol). The reaction was stirred for 10 minutes. tert-Butyl(1-(2-(7-(1,2-dihydroxyethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (30 mg, 0.058 mmol) in DCM (2 mL) was then added to the slurry. The reaction was stirred for 30 minutes, then filtered and washed with DCM (20 mL). The organic layer was concentrated to give crude product.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:29](B1OC(C)(C)C(C)(C)O1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[CH2:29]([C:14]1[N:15]=[C:11]([C:10]2[C:2]([CH3:1])=[N:3][N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=23)[S:12][C:13]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1Cc1ccccc1
Yield: 41.9 %

Procedure:
Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (450 mg, 1.1 mmol) produced in Example 15(i), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 4.6 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (70 mg, 0.086 mmol), cesium carbonate (670 mg, 2.1 mmol), water (5 mL) and 1,2-dimethoxyethane (30 mL) as starting materials and in the same manner as in Example 13-B (iii), the title compound (174 mg, 43%) was obtained as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:16][CH2:17][CH3:18])[C:12]=1[O:13]CC)[C:7]([OH:9])=[O:8])[CH3:2]>Br.C(O)(=O)C>[CH2:17]([O:16][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:12]=1[OH:13])[C:7]([OH:9])=[O:8])[CH3:18]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1OCC
Agent: Br
Solvent: CC(=O)O
Product: CCOc1cc(C(=O)O)cc(OCC)c1O

Procedure:
100 g of 3,4,5-triethoxybenzoic acid was dissolved in 150 ml of a 48% aqueous HBr solution and 300 ml of acetic acid, and the resultant solution was heated at 100° C. for 2 hr while stirring. The reaction mixture was cooled, and the formed precipitate was separated by filtration and washed with water. The solid was recrystallized from 1 l of ethanol to prepare 50 g of the product compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:13])[C:4](=[S:12])[S:5][C:6]=1[C:7]([O:9]CC)=O.Cl.[C:15](N)(=[NH:17])[CH3:16].C[O-].[Na+]>C(O)C.CO>[CH3:13][N:3]1[C:2]2[N:1]=[C:15]([CH3:16])[NH:17][C:7](=[O:9])[C:6]=2[S:5][C:4]1=[S:12]
Reactant: CCOC(=O)c1sc(=S)n(C)c1N
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1nc2c(sc(=S)n2C)c(=O)[nH]1

Procedure:
Ethyl 4-amino-3-methylthiazoline-2-thione-5-carboxylate (1.4g, 6.4 mmoles), prepared according to the procedure of Gewald, J. Prakt. Chem., 32, 26-30 (1966), was suspended in approximately 40ml of ethanol. Acetamidine hydrochloride (0.6g, 6.4 mmole) and 2.77g (12.8 mmole) of a 25% solution of sodium methoxide in methanol were added to the suspension and the resultant mixture refluxed for approximately 20 hours. The ethanol was removed in vacuo and the residue was suspended in water and neutralized with concentrated hydrochloric acid. The resultant precipitate was filtered and dried to provide 1g of 3,5-dimethyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: II.Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:12][CH:13]([CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[O:26].Cl>O1CCCC1.[Zn]>[OH:26][CH:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH3:27])[CH3:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)CCCCCCCCCCCC=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
Activated zinc (118 mg), a small crystal of iodine, and tetrahydrofuran (3 ml) were stirred and heated under reflux. To the mixture was added a solution of tert-butyl bromoacetate (312 mg) and 13-methyltetradecanal (226 mg) in tetrahydrofuran (3 ml), and the reactants were stirred and heated under reflux for 1 hour. Anhydrous conditions were maintained throughout the experiment. The cooled solution was poured into 0.1 N hydrochloric acid (5.6 ml) and the pH was adjusted to 2.0 with 2 N hydrochloric acid. The excess of zinc was filtered off and the crude products were extracted with ethyl acetate. The ethyl acetate solution was washed with aqueous sodium hydrogen carbonate and brine, and then dried over magnesium sulfate. The ethyl acetate was evaporated off under reduced pressure to give the crude ester, which was purified by column chromatography on silica gel (Merck) and eluted with a mixture of cyclohexane and ethyl acetate (19:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was dried by high vacuum pump to afford an oil of tert-butyl 3-hydroxy-15-methylhexadecanoate (180 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:17]([F:23])=[CH:18][CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCc2ccc(F)c(-c3ccccc3Cl)c2O1
Yield: 66.6 %

Procedure:
Treatment of ((2R)-8-(2-chlorophenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate (0.7 g, 1.56 mmol) with sodium azide (0.61 g, 9.40 mmol) in DMSO (20 mL) according to the procedure described for Example 69, Step 9 provided 0.33 g (67%) of (2R)-2-(azidomethyl)-8-(2-chlorophenyl)-7-fluorochroman as a pale yellow oil.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][C:11]1[CH:18]=CC=C[C:12]=1C#N>>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[S:1][C:12]=1[C:11](=[O:10])[CH3:18]
Reactant: N#Cc1ccccc1S
Reactant: N#Cc1ccccc1O
Product: CC(=O)c1sc2ccccc2c1N

Procedure:
The procedure was similar to step S1A, while the starting material was 2-mercapto-benzonitrile (3A) in stead of 2-hydroxy-benzonitrile.