Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:27][C:5]=1[C:6]([NH:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])=[O:7].Cl>CO>[OH:3][C:4]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)=[CH:27][C:5]=1[C:6]([NH:8][C:9]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])=[O:7]
Reactant: COC(=O)c1ccc(-c2cccc(OC)c2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(-c2ccc(C(=O)O)c(NC(=O)c3cc(C4CCN(C)CC4)ccc3O)c2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.27 mL) was added to a methanol (1.0 mL) suspension of the obtained methyl 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate (0.026 g), followed by stirring at 50° C. for 3 hours. After cooling the reaction mixture to room temperature and adjusting the pH to 6.0 with 2.0 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 0.025 g of 2-(2-hydroxy-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoic acid as a light yellow solid.
Reaction SMILES: CCCCC[C@H](O)/C=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18]CC(O)=O)[C@@H:12]([OH:23])[CH2:11][C@H:10]1O.C([O:30]C(Cl)=O)C(C)C.C(N([CH2:39][CH3:40])CC)C>>[OH:30][C:40]1[C:39]2[C:14]3[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:23])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CCN(CC)CC
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: CC(C)COC(=O)Cl
Product: O=C1c2ccccc2-c2c(O)cccc21

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2 α , 0.347 ml. of triethylamine, 0.326 ml. of isobutylchloroformate, and 0.612 g. of 4-hydroxy-9-fluorenone, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-water (99:1) followed by ethyl acetate-acetone-water (70:30:1). The residue obtained by concentration of selected fractions, 0.650 g., is crystallized from ethyl acetate-hexane (10:7) as the title compound, white free-flowing crystals, m.p. 83.8°-86.8° C. having Rf 0.27 (TLC on silica gel in ethyl acetate).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][NH:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.COC(C)(C)C>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][NH:7][C@H:6]([CH2:4][OH:3])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COCCCN1CCOc2ccc(CO[C@H]3CN[C@H](CO)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.10 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-2-carboxylic acid ethyl ester in 10 ml of tetrahydrofuran are added 17.0 mg of lithium aluminium hydride at 0° C. The reaction mixture is stirred for 1 hour at this temperature, diluted with tert-butyl methyl ether and quenched by addition of 2.0 ml of aqueous saturated sodium sulfate solution. The mixture is allowed to warm to room temperature, filtered and dried over sodium sulfate. The solvent is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH:21]=[CH2:22])=[CH:19][N:18]=[C:17]3[N:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:24]=[C:25]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[C:16]=23)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.O>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]3[N:23]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH:24]=[C:25]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[C:16]=23)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1cnc2c(c(NC(=O)C3CC3)cn2C(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: CCc1cnc2c(c(NC(=O)C3CC3)cn2C(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 3.5 h
Yield: 46.4 %

Procedure:
10% Pd/C (65 mg, 0.061 mmol) was added to a solution of (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-vinyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (64 mg, 0.12 mmol) in ethanol (6 mL). The mixture was stirred under a hydrogen atmosphere (balloon) for 3.5 hours. The mixture was filtered through a pad of Celite® and washed with methanol, and the filtrate evaporated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-80% CH3CN/water, 25CV) to give (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-ethyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (29.4 mg, 46% yield) as a solid. LCMS (APCI+) m/z 528 (M+H)+, Retention time=4.37 minutes.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22](I)=[C:21]([CH3:26])[CH:20]=2)[CH:15]=[CH:16][C:17]=1[I:18].C(=O)([O-])[O-].[K+].[K+]>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[CH3:26][C:21]1[CH:20]=[C:19]([C:14]2[CH:15]=[CH:16][C:17]([I:18])=[C:12]([CH3:11])[CH:13]=2)[CH:24]=[CH:23][C:22]=1[N:4]([C:1](=[O:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Cc1cc(-c2ccc(I)c(C)c2)ccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)N(c1ccccc1)c1ccc(-c2ccc(I)c(C)c2)cc1C
Yield: 69.3 %

Procedure:
16.2 g (0.12 mol) of acetanilide, 56.4 g (0.13 mol) of 3,3'-dimethyl-4,4'-diiodobiphenyl, 18.0 g (0.13 mol) of anhydrous potassium carbonate, 1.71 g (0.027 mol) of copper powder, and 30 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 192° C. to 203° C. for 13 hours. The reaction product was then extracted with 160 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 7/1 mixture of toluene and ethyl acetate) to obtain 36.7 g (yield: 69.3%) of N-(3,3'-dimethyl-4'-iodo-4-biphenylyl)acetanilide. Subsequently, 13.2 g (0.030 mol) of N-(3,3'-dimethyl-4'-iodo-4-biphenylyl)acetanilide thus obtained, 6.09 g (0.036 mol) of diphenylamine, 5.11 g (0.037 mol) of anhydrous potassium carbonate, 0.44 g (0.007 mol) of copper powder, and 10 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 198° to 211° C. for 13 hours. The reaction product was then extracted with 100 ml of toluene. The insoluble contents were then removed by filtration. The filtrate was then concentrated to obtain an oily matter. The oily matter thus obtained was then dissolved in 50 ml of isoamyl alcohol. The material was then hydrolyzed with 1 ml of water and 2.38 g (0.036 mol) of 85% potassium hydroxide at a temperature of 130° C. The reaction solution was then subjected to steam distillation to distill off isoamyl alcohol. The residue was extracted with 200 ml of toluene, washed with water, and then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 1/3 mixture of toluene and n-hexane) to obtain 9.27 g (yield: 70.1%) of 3,3'-dimethyl-N,N,N'-triphenylbenzidine. The melting point of the product was from 104.0° C. to 105.0° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:16]([OH:18])[CH3:17])=[C:6](F)[CH:5]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[CH:16]([CH3:17])[O:18][C:6]=2[CH:5]=1
Reactant: CC(O)c1cnccc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1Oc2cc(Cl)ccc2-c2ccncc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
To a stirred suspension of NaH (3.81 mg, 0.159 mmol) in anhydrous THF (5 mL), was added a THF (5 mL) solution of 1-(4-(4-chloro-2-fluorophenyl)pyridin-3-yl)ethanol (20 mg, 0.079 mmol) dropwise and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (15 mL) and the product was extracted with ethyl acetate (3×20 mL). The combined organics were washed with water (1×15 mL) and brine (1×15 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via preparative TLC (40% ethyl acetate in hexane) to afford 8-chloro-5-methyl-5H-chromeno[3,4-c]pyridine (12 mg, 0.052 mmol, 63% yield). 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=5.2 Hz, 1H), 8.42 (s, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.49 (d, J=5.2 Hz, 1H), 7.06 (m, 2H), 5.36 (q, J=6.6 Hz, 1H), 1.66 (d, J=6.6 Hz, 3H); LCMS (ESI) m/e 232 [(M+H)+, calcd for C13H11ClNO 232.1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11][CH:10]([CH2:18][OH:19])[CH2:9]2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].O.[C:26]1([CH3:36])[CH:31]=CC(S(O)(=O)=O)=C[CH:27]=1.CC(=C)C>ClCCl>[C:26]([O:19][CH2:18][CH:10]1[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=2)([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11]1)([CH3:36])([CH3:31])[CH3:27]
Reactant: COC(=O)C1=CCC(CO)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1=CCC(COC(C)(C)C)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
A solution of methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylate (Example 7, Step 9; 36.7 mg, 0.101 mmol) in dichloromethane (2 mL) was placed in a sealable tube, treated with p-toluenesulfonic acid hydrate (96 mg, 0.506 mmol) and cooled on dry ice. Liquid isobutylene (1-2 mL) was added, the tube was sealed and the mixture was stirred at rt for 72 h. After this time, the tube was cooled and unsealed, and the isobutylene was allowed to evaporate. The resulting mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 5-25% ethyl acetate-hexane, to provide methyl (4RS,6RS)-4-(tert-butoxymethyl)-6-(4-chloro-3-(trifluoro-methyl)phenyl)-6-methylcyclohex-1-enecarboxylate (22 mg, 52%). Mass spectrum m/z 436.0 (M+NH4+). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=2.2 Hz, 1 H), 7.37 (d, J=8.6 Hz, 1 H), 7.30 (dd, J=8.4, 2.2 Hz, 1 H), 7.27 (dd, J=5.5, 2.9 Hz, 1 H), 3.64 (s, 3 H), 3.15 (dd, J=8.8, 4.4 Hz, 1 H), 3.07 (dd, J=8.6, 6.4 Hz, 1 H), 2.47 (m, 1 H), 1.96 (m, 1 H), 1.69 (m, 1 H), 1.64 (s, 3 H), 1.54 (m, 2 H), 1.11 (s, 9 H).
Reaction SMILES: [OH-].[NH4+:2].[OH-].[Na+].Cl[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1>O.C(O)C>[NH2:2][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of ammonium hydroxide (6.6 g, 0.124 mol) and sodium hydroxide (4.8 g, 0.120 mol) in water (45 mL) was added to 2,6-dichloro-3-nitropyridine (12.0 g, 0.62 mol) in ethanol (240 mL). The reaction was refluxed for 2 h, cooled to room temperature and filtered. The pale yellow solid was dried overnight to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.87 (d, J=9 Hz, 1H), 7.8 (br s, 1H), 6.73 (d, J=9 Hz, 1H), 5.9 (br s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:31][C:25]4[N:26]=[CH:27][NH:28][C:29](=[O:30])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[O:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:31][C:25]4[N:26]=[CH:27][NH:28][C:29](=[O:30])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1[nH]cnc2[nH]c(-c3cccc4ccc(Cl)nc34)cc12
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cnc2[nH]c(-c3cccc4ccc(Oc5ccccc5)nc34)cc12
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
NaH (60% in mineral oil; 0.063 g, 1.576 mmol) was suspended in 1 mL DMF and phenol (0.148 g, 1.576 mmol) was added. After 10 min, 6-(2-chloroquinolin-8-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one hydrochloride (Example 19b; 0.075 g, 0.225 mmol) was added, and the reaction was sealed and heated at 70° C. for 2 h, then at 90° C. for 1 h. The reaction was treated with TFA (0.121 ml, 1.576 mmol) and 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 20-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo to give 6-(2-phenoxyquinolin-8-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (0.022 g, 0.062 mmol, 28% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (1H, br. s), 11.64 (1H, br. s), 8.50 (1H, d, J=8.8 Hz), 8.22 (1H, dd, J=7.5, 1.5 Hz), 7.90 (1H, dd, J=8.0, 1.4 Hz), 7.81 (1H, d, J=3.7 Hz), 7.49-7.58 (3H, m), 7.30-7.42 (4H, m), 7.13 (1H, d, J=2.3 Hz). m/z (ESI, +ve) 355.0 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[S:12][C:11](=S)[NH:10][C:8]=2[N:9]=1.OO.Cl>O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[S:12][C:11](=[O:1])[NH:10][C:8]=2[N:9]=1
Reactant: Nc1ncc2sc(=S)[nH]c2n1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1ncc2sc(=O)[nH]c2n1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
To a solution of NaOH (0.6 g, 15 mmol, 3 eq) in water (20 ml) was added 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-thione (0.92 g, 5 mmol, 1.0 eq). The mixture was stirred to dissolve. An aqueous solution of H2O2 (0.68 g, 2.3 ml (30%), 20 mmol, 4 eq) was slowly added dropwise to the above solution, keeping the temperature below 50° C. The reaction was then cooled down to room temperature (about 25° C.). Concentrated HCl (37%, 6 ml) was added to the above solution until the pH is less than 1. The mixture is stirred at room temperature for 30 minutes. Celite (2 g) was added to the suspension and the suspension was filtered and washed with water (10 ml). To the filtrate was added 50% NaOH solution to adjust the pH to 5-5.5, stirred for 30 minutes, filtered, washed with water, and dried at 50° C. under vacuum to give 0.52 g (62%) of 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-one as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 6.70 (s, 2H, ex. D2O), 8.2 (s, 1H), 12.2 (br s, 1H, ex. D2O); MS (+)-ES [M+H]+ m/z 169.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[CH:13][N:12]=[C:11]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O.[OH-].[K+]>CCO>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cnc(-n2cccn2)nc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13 %

Procedure:
To a solution of benzyl 4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 2-d, (2 g crude) in EtOH(20 ml)/THF (20 ml)/water (20 ml) was added KOH (0.87 g, 15.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then concentrated under vacuum and the residue was diluted with water and basified to pH=2 with HCl followed by extraction with ethyl acetate. The organic layer was brine washed, dried over sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with the eluent of petroleum ether/ethyl acetate=7/1 to afford the compound 2-e (200 mg, 13%).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH2:20][NH2:21].O>C(O)(C)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([NH:20][NH2:21])=[N:3][CH:4]=2)=[CH:11][CH:12]=1)#[N:17]
Reactant: NN
Reactant: N#Cc1ccc(CNC(=O)c2ccc(Cl)nc2)cc1
Solvent: O
Solvent: CC(C)O
Product: N#Cc1ccc(CNC(=O)c2ccc(NN)nc2)cc1
Yield: 20.5 %

Procedure:
Combined 6-chloro-N-(4-cyanobenzyl)nicotinamide (500 mg, 1.840 mmol) and hydrazine (0.578 mL, 18.40 mmol) in isopropanol (5 mL) and heated at 90° C. for 5 h. The supernatant was decanted and concentrated in vacuo to give a white solid which was stirred vigorously with water (ca. 10 mL) for 2 hours, then was filtered and the solid dried to give the title compound (batch 1, 101 mg) as a pink solid. The fine solids from the reaction (after supernatant was removed) was stirred vigorously with water (ca. 10 mL) for 2 hours, then filtered and dried in the lyophilizer to give the title compound (batch 2, 179 mg) as a tan solid. Large solids from the reaction (after supernatant was removed) were crushed and stirred vigorously with water (10 mL) for 1 hour, then filtered and dried in the lyophilizer to give the title (batch 3, 135 mg) as a beige solid. The combined yield was 415 mg (84% yield). MS m/z 268 [M+H]+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:10]([NH:12][C@@H:13]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[O:11])[C@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>CO.[Pd]>[NH2:1][C@@H:2]([C:10]([NH:12][C@@H:13]([C:26]([O:28][CH3:29])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[O:11])[C@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](NC(=O)OCc1ccccc1)[C@H](C)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](N)[C@H](C)OC(C)(C)C
Reaction time: 4 h
Yield: 95 %

Procedure:
4.03 g of Z-D-Thr(tBu)-D-Tyr(tBu)-OMe (7.45 mmoles) were dissolved in 250 ml of CH3OH. After addition of 850 mg of 10% Pd on activated charcoal (Fluka, cat. No 75990) a hydrogen stream was blown on the solution at room temperature under shaking for 4 h. The hydrogenation reaction was monitored by TLC. After removal of the catalyst by filtration and evaporation of the filtrate, 2.88 g (7.08 mmoles, yield 95%) of H-D-Thr(tBu)-D-Tyr(tBu)-OMe were obtained in the form of pure oil (TLC).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].N1C=CN=C1.CN(C)C=[O:28]>CCOCC>[Si:1]([O:19][CH2:15][C:16]#[C:17][CH2:18][OH:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC#CCO
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCC#CCO
Temperature: 22 °C
Reaction time: 16 h

Procedure:
A solution of 175 g of tert-butyldimethylsilyl chloride in 100 ml of a 1:1 mixture of hexane and dimethylformamide is slowly added in drops to a solution of 100 g of 2-butin-1-ol and 158 g of imidazole in 300 ml of dimethylformamide at 0° C. under nitrogen, and it is stirred for 2 hours at 0° C. and for 16 hours at 22° C. The reaction mixture is diluted with 2.5 l of ether, washed once with water, once with 5% sulfuric acid, once with water, once with saturated sodium bicarbonate solution and washed neutral with semi-saturated sodium chloride solution. After drying on sodium sulfate and filtration, it is concentrated by evaporation in a vacuum. The residue that is thus obtained is purified by chromatography on silica gel. 74.3 g of the title compound is obtained with hexane/0-40% ether as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1N.S(=O)(=O)(O)[OH:11].S(O)(O)(=O)=O.ClC1C=CC(Cl)=CC=1N>>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[OH:11]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=S(=O)(O)O
Product: Oc1cc(Cl)ccc1Cl

Procedure:
40 Grams of 2,5-dichloroaniline and 250 g of 75% aqueous sulfuric acid solution were charged into a ceramic ball mill having one liter capacity. A suspension of fine particles of 2,5-dichloroaniline sulfate was prepared by a method similar to that described in Example 5. The suspension was transferred into a beaker having one liter capacity. The ceramic ball mill used was washed with 77 g of 75% aqueous sulfuric acid solution and the washings were transferred into the beaker. Diazotization of 2,5-dichloroaniline sulfate in the form of suspension of fine particles was carried out by a method similar to that described in Example 5 except that 18.2 g of sodium nitrite powder was added in 15 minutes. The diazotized solution was hydrolyzed by a method similar to that described in Example 5. 35.5 Grams of 2,5-dichlorophenol (100° - 105° C/20 mmHg) was obtained. The yield was found to be 88.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][NH:22][C:23](=[O:36])[CH2:24][NH:25]C(OCC2C=CC=CC=2)=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].CCOCC>C1(OC)C=CC=CC=1.Br.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][NH:22][C:23](=[O:36])[CH2:24][NH2:25])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(CNC(=O)OCc1ccccc1)NCc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: COc1ccccc1
Product: NCC(=O)NCc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 25.3 %

Procedure:
To a solution of 5-chloro-2-[3-(N-carbobenzoxyglycyl)aminomethyl- 4H-1,2,4-triazol-4-yl]-benzophenone (2.1 g) in anisole (4 ml), 30% hydrogen bromide-acetic acid is added. The resultant mixture is stirred for 1 hour and mixed with ether. The precipitate is filtered, washed with ether and dissolved in methylene chloride (20 ml). The methylene chloride layer is washed with saturated aqueous sodium bicarbonate, water and saturated aqueous saline solution in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with methanol to give 5-chloro-2-(3-glycylaminomethyl-4H-1,2,4-triazol-4-yl)-benzophenone as a colorless oil (0.39 g).
Reaction SMILES: N1(N)C=CC=C1.C[O:8]C(=O)CCC1C(=O)N(N)C(=O)NC=1.N1(N[C:28]([C:30]2[CH:31]=[N:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:34][CH:35]=2)=[O:29])C=CC=C1>>[C:36]1([C:33]2[N:32]=[CH:31][C:30]([C:28]([OH:29])=[O:8])=[CH:35][N:34]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Nn1cccc1)c1cnc(-c2ccccc2)nc1
Reactant: COC(=O)CCc1c[nH]c(=O)n(N)c1=O
Agent: Nn1cccc1
Product: O=C(O)c1cnc(-c2ccccc2)nc1

Procedure:
Following procedures similar to those of Example 64 but substituting pyrrol-1-ylamine for 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid pyrrol-1-ylamide (62%) as a solid. MS: 265 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.25 (d, 2H), 6.76 (d, 2H), 7.48-7.63 (m, 3H), 8.52 (d, 2H), 8.95-9.60 (br, 2H).