Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.O.[CH3:23]O>>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([OH:17])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:23])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(CC(=O)O)C2CC2)cc1O
Reactant: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(c1ccc(OC)c(O)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-cyclopropyl-3-(3-hydroxy-4-methoxyphenyl)propanoic acid (1.40 g) in methanol (50 mL) was added dropwise thionyl chloride (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (4.30 g) as a colorless oil. Ethyl acetate (250 mL) was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.00 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:28][CH:29]([CH3:31])[CH3:30])=[C:13]([C:15]2[NH:27][C:18]3=[N:19][C:20]([C:23](OC)=[O:24])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:28][CH:29]([CH3:31])[CH3:30])=[C:13]([C:15]2[NH:27][C:18]3=[N:19][C:20]([CH2:23][OH:24])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3cc(OCc4ccccc4)ccc3OC(C)C)[nH]c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CO)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a mixture of methyl 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine-5-carboxylate (0.45 g) in tetrahydrofuran (10 ml) was added lithium aluminum hydride (82 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (0.26 g, yield 61%) as colorless crystals. melting point 167-168° C. purity 99%. M+H: 390. 1H NMR (CDCl3) δ: 1.52 (6H, d, J=6.0 Hz), 4.74-4.82 (1H, m), 5.16 (2H, s), 7.00-7.50 (8H, m), 8.06 (1H, d, J=8.1 Hz), 8.19 (1H, d, J=3.0 Hz).
Reaction SMILES: [C:1]([C@@H:3]([NH:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1C(OC(C)(C)C)=O)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[C:1]([C@@H:3]([NH:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1)=[O:24])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[CH:9][CH:10]=1)#[N:2]
Reactant: Cn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)[C@@H]4CCCCN4C(=O)OC(C)(C)C)cc3)cc21
Solvent: O=CO
Product: Cn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)[C@@H]4CCCCN4)cc3)cc21
Yield: 66 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (87 mg) in formic acid (1 mL) was stirred at 50° C. for 15 min. The solvent was removed in vacuo and the residue was purified by flash silica chromatography eluting with 1:29 ammonia in methanol/DCM to give a white solid, which was triturated with diethyl ether to give the title compound (46 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9](=[CH:12]N(C)C)[C:10](=O)[C:4]=2[CH:3]=1.[NH2:19][C:20]([NH2:22])=[NH:21]>>[NH2:21][C:20]1[N:22]=[CH:12][C:9]2[CH2:8][C:7](=[O:16])[NH:6][C:5]3[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=3[C:10]=2[N:19]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Reactant: N=C(N)N
Product: Nc1ncc2c(n1)-c1cc(Br)ccc1NC(=O)C2

Procedure:
In a manner similar to that described in method H, 7-bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-k) and guanidine were converted to I-44 (79%): HRMS Calcd. for C12H9BrN4O: 305.0037, Found 305.0042.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[O:13]=[C:14]1[N:20]2[CH2:21][C@@H:16]([CH2:17][CH2:18][C@H:19]2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[O:23])[N:15]1OC(OC1C=CC=CC=1)=S.C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1>[O:13]=[C:14]1[N:20]2[CH2:21][C@@H:16]([CH2:17][CH2:18][C@H:19]2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[O:23])[NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OC(=S)Oc2ccccc2)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3)CC1

Procedure:
AIBN (0.1 eq.) is added to a solution of tert-butyl 4-[({(2S,5R)-7-oxo-6-[(phenoxycarbonothioyl)oxy]-1,6-diazabicyclo[3.2.1]oct-2-yl}carbonyl)amino]piperidine-1-carboxylate in dry benzene and the resulting mixture is heated to reflux. A solution of tributyltin hydride (1.25 eq.) in benzene is added over a period of one hour and the resulting mixture is refluxed for an additional 3 hours. The reaction mixture is concentrated under vacuum and the residue is purified by silica gel chromatography to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16]>C(O)=O.CO>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:1]([C:4]1[N:5]=[C:6]([C:10](=[N:16][C:15]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[Cl:13])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: O=CO
Solvent: CO
Product: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
In a 200 ml round bottom flask, 2.0 g of 2,6-diacetylpyridine (M=163.176 g/mol, 0.0123 mol) and 75 ml of methanol were placed. Next 3.81 g of 2-chloro-4,6-dimethylaniline (M=155.627 g/mol, 0.0245 mole) and three drops of formic acid were added and the solution stirred at room temperature under nitrogen for four days, at which time no precipitate had formed. The reaction then was refluxed for 24 h. GC analysis indicated that the reaction was incomplete. Refluxing was continued for a total of 1 week. Solvent was stripped from the reaction mixture via rotary evaporator. Flash chromatography through a basic alumina column (eluted with hexane/ethyl acetate 20:1) lead to isolation of an oil. The oil was then crystallized from methanol/methylene chloride to receive pale yellow crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([N:6]([CH2:16][CH3:17])[C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[C:9]([CH3:15])[CH:8]=1)[CH3:5]>CO>[CH2:16]([N:6]([CH2:4][CH3:5])[C:7]1[N:12]=[C:11]([C:13]([NH:2][OH:3])=[NH:14])[CH:10]=[C:9]([CH3:15])[CH:8]=1)[CH3:17]
Reactant: CCN(CC)c1cc(C)cc(C#N)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCN(CC)c1cc(C)cc(C(=N)NO)n1
Reaction time: 18 h
Yield: 86 %

Procedure:
To a cold (0° C.) solution of potassium tert.-butylate (494 mg, 4.40 mmol) in methanol (10 mL), hydroxylamine hydrochloride (262 mg, 3.73 mmol) is added. The mixture is stirred for 30 min before 6-diethylamino-4-methyl-pyridine-2-carbonitrile (238 mg, 1.26 mmol) is added. Stirring is continued at rt for 18 h before the solvent is evaporated. The residue is dissolved in 1 N aq. HCl. The solution is extracted with EA. The pH of the aq. phase is adjusted to pH ˜9 by adding sat. aq. NaHCO3. The mixture is extracted with EA and the org. extract is dried over MgSO4, filtered, concentrated and dried to give 6-diethylamino-N-hydroxy-4-methyl-pyridine-2-carboxamidine (241 mg) as a yellow oil; LC-MS: tR=0.69 min, [M+1]+=223.05.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.[H][H].[ClH:22]>C1COCC1.C(OCC)(=O)C.[Pd]>[ClH:22].[NH2:17][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([NH2:16])=[O:15])[CH2:9]1
Reactant: [H][H]
Reactant: NC(=O)C1CCCN(c2ccc(F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)C1CCCN(c2ccc(F)cc2N)C1

Procedure:
The solution of 2.67 g of 1-(4-fluoro-2-nitrophenyl)piperidine-3-carboxamide in 100 ml of THF was admixed with 260 mg of Pd/C. This mixture was hydrogenated in a shaking vessel at atmospheric pressure until the theoretical amount of hydrogen had been taken up. The mixture is then acidified with hydrogen chloride dissolved in ethyl acetate, the solid is filtered off with suction and washed with methanol, and the filtrate is concentrated under reduced pressure. The residue is triturated with tert-butyl methyl ether and the solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [ClH:1].[C:2]([N-:4][C:5](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH2:6][CH3:7])#[N:3].[Na+]>>[NH2:12][C:11]1[C:8]([C:9]#[N:10])=[C:5]([CH2:6][CH3:7])[N:4]=[C:2]([Cl:1])[N:3]=1
Reactant: Cl
Reactant: CCC([N-]C#N)=C(C#N)C#N
Agent: [Na+]
Product: CCc1nc(Cl)nc(N)c1C#N
Temperature: 0 °C

Procedure:
With stirring, 200 ml of conc. hydrochloric acid are slowly added dropwise to 37.57 g of ca. 80% strength (178.76 mmol) of sodium cyano[1-(dicyanomethylidene)propyl]-azanide such that the reaction temperature does not exceed 30° C. The reaction mixture is then added to ca. 600 ml of ice water and the solid that is formed is isolated by filtering off with suction. After drying, 33.89 g of 4-amino-2-chloro-6-ethylpyrimidine-5-carbonitrile with the melting point 226.5° C. are obtained.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH2:18]Br>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH2:18][CH2:1][C:2]#[N:3]
Reactant: CC#N
Reactant: COc1ccc(Br)c(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CCC#N)c1
Temperature: -78 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of MeCN (6.2 g, 151.22 mmol, 10.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of n-BuLi (15.1 mL, 2.50 equiv, 2.5 M in hexane) dropwise with stirring at −78° C. The resulting solution was stirred for 1 h at −78° C. in a liquid nitrogen bath. To this was added a solution of 1-bromo-2-(bromomethyl)-4-methoxybenzene (4.2 g, 15.11 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise with stirring at −78° C. The resulting solution was allowed to react, with stirring, for an additional 1 h while the temperature was maintained at −78° C. in a liquid nitrogen bath. The reaction mixture was then quenched by the addition of aqNH4Cl and extracted by EA (100 ml*3). The organic layers was concentrated and applied onto a silica gel column with PE/EA (10:1). This resulted in 2.29 g (63%) of 3-(2-bromo-5-methoxyphenyl)propanenitrile as a yellow semi-solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:36]=[CH:35][S:34][CH:33]=5)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[S:34]1[CH:35]=[CH:36][C:32]([CH2:31][NH:30][C:26]2[CH:25]=[C:24]([C:23]3[C:18]4[C:19](=[N:20][C:15]([NH:14][CH:11]5[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]5)=[N:16][CH:17]=4)[NH:21][N:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:33]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)c4)n[nH]c3n2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of {4-[3-{3-[(thiophen-3-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (120 mg, 0.185 mmol) in dichloromethane (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for another two hours at this temperature. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (5 mL) and dried to give crude product. It was purified by prep-HPLC to give N-(3-{3-[(thiophen-3-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-cyclohexane-1,4-diamine as solid. (Yield 75 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccccc1-c1coc2cc(O)cc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccccc3C)coc2c1
Yield: 89.1 %

Procedure:
In 1 l of acetone was suspended 114 g of 5-chloro-7-hydroxy-3-(2-methylphenyl)-4-oxo-4H-1-benzopyran, and 60.4 g of anhydrous potassium carbonate and 73.0 g of ethyl bromoacetate were added thereto, followed by refluxing for 1.5 hours. After cooling, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Recrystallization of the residue from ethanol gave 132 g of the entitled compound having a melting point of 122° to 123° C.
Reaction SMILES: [C:1]1(=[O:13])[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([N-]C(C)C)(C)C.[Li+].C(OC(=O)C)(=O)C>C1COCC1>[C:15]1([CH2:14][N:21]2[CH2:26][CH2:25][CH:24]([CH:27]=[C:2]3[CH2:3][C:4]4[NH:5][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=5[C:12]=4[C:1]3=[O:13])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCc2[nH]c3ccccc3c21
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=C1C(=CC2CCN(Cc3ccccc3)CC2)Cc2[nH]c3ccccc3c21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1,2,3,4-tetrahydrocyclopent[b]-indol-1-one (440 mg, 2.6 mmol) and 1-benzylpiperidine-4-carboxaldehyde (581 mg, 2.86 mmol) in 90 ml dry THF was added 5.4 mmol of lithium diisopropylamide at -78° C. The mixture was stirred at -78° C. for 30 minutes, then warmed up to 0° C. for 1.5 hours, and then to r.t. for 15 minutes. Acetic anhydride (0.265 g, 2.6 mmol) was added, the mixture was stirred at r.t. for 1.5 hours and quenched ammonium chloride, water and extracted with chloroform. The organic layer was dried, concentrated, and purified through silica gel to give the title compound. 1HNMR (CDCl3)δ 1.45-1.7 (m, 3H), 1.8-2.3 (m, 4H), 2.8-3.0 (m, 2H), 3.46 (s, 2H), 3.55 (s, 2H), 6.5 (m, 1H), 7.1-7.4 (m, 8H), 7.9 (m, 1H), 9.2 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(CC)CC)(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC(CC)CC)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of 2-benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid diethyl ester (0.520 g) in ethanol (5 mL) was treated with sodium hydroxide (2.91 mL, 1 N) and then stirred at room temperature for 8 h. The reaction mixture was diluted with water and acidified with HCl and the product was then extracted with ethyl acetate to give 2-benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid monoethyl ester (0.461 g).
Reaction SMILES: C(OC([N:11]1[CH:16]=[CH:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:13](=[O:25])[CH2:12]1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[O:25])=[CH:19][CH:20]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C=CN1Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CNCCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-benzyloxycarbonyl-1-(4-fluorobenzyl)-3,4-dihydro-pyrazin-2(1H)-one (0.5 g, 1.45 mmol) and Pearlman's catalyst (26 mg; 20% palladium hydroxide on carbon) in methanol (25 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature overnight. The product mixture was filtered through a pad of Celite, and then concentrated under vacuum to provide 1-(4-fluorobenzyl)piperazin-2-one.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]([CH:19]1[CH2:21][CH2:20]1)[CH2:8][O:9][C:10]1[C:11](Cl)=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[Cl:16])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([Si:5]([CH3:22])([CH3:23])[O:6][CH:7]([CH:19]1[CH2:21][CH2:20]1)[CH2:8][O:9][C:10]1[C:11]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[Cl:16])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)[Si](C)(C)OC(COc1c(Cl)nc(Cl)nc1Cl)C1CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC(COc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
To a solution of 5-[2-(tert-butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethoxy]-2,4,6-trichloro-pyrimidine (411 mg, 1.03 mmol) in IMS (5 mL) was added triethylamine (215 μL, 1.55 mmol) followed by morpholine (94 μL, 1.08 mmol). The reaction mixture was stirred at RT for 4 hours before being concentrated in vacuo. The resultant residue was purified by column chromatography (SiO2, gradient 0-20% ethyl acetate in cyclohexane) to afford 4-{5-[2-(tert-Butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethoxy]-2,6-dichloro-pyrimidin-4-yl}-morpholine as a colorless gum (387 mg, 84%). LCMS: RT=5.22 min, [M+H]+=448/450/452.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([CH:34]1[CH2:36][CH2:35]1)[NH2:33]>>[CH:34]1([C:32]2[N:33]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:25])([F:24])[F:26])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]4)=[O:9])[CH2:11]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: O=C(O)C1CC(c2cccc(OC(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)C1CC1
Product: O=C(N1CCC(O)CC1)N1CC(c2cccc(OC(F)(F)F)c2)CC(c2nc(C3CC3)no2)C1

Procedure:
60 mg (0.14 mmol) of the compound from Example 194A and 22 mg (0.22 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 45 mg (64% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2cccnc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc2cccnc2n1

Procedure:
A solution of 2-methyl-1,8-naphthyridine (Chem. Pharm. Bull., 19, 1857 (1971)), N-chlorosuccinimide (1.1 equivalent), and a catalytic amount of benzoylperoxide in CCl4 were irradiated at reflux with a 225 watt lamp for 5 hours. After cooling, the solid was filtered and the filtrate evaporated to dryness. The crude residue was chromatographed to give the title product.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[C:19]([O:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([Cl:8])[O:10][C:11]=2[CH:17]=1)(=[O:21])[CH3:20]
Reactant: Oc1ccc2nc(Cl)oc2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2nc(Cl)oc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (1.48 ml) was added to a suspension of 2-chloro-1,3-benzoxazol-6-ol (1.63 g) [see Preparation 34] in dichloromethane (20 ml), and after 5 minutes acetic anhydride (1.01 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0, changing 40:10, changing to 0:100, by volume, hexane:ethyl acetate to afford 2-chloro-1,3-benzoxazol-6-yl acetate (1.63 g) as an oil.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(Cl)Cl>[C:1]1([C:7]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][C:11]=2[C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1-c1ccccc1
Reaction time: 1.5 h

Procedure:
Methyl 4-phenylpyrrole-3-carboxylate (920 mg., 4.6 mmoles) and benzoyl chloride (0.53 ml., 4.6 mmoles) were combined in 50 ml. methylene chloride and stirred under nitrogen at room temperature. Stannic chloride (1.15 ml., 10 mmoles) was added. The resulting solution was stirred for 1.5 hours. Hydrochloric acid (1 N, 25 ml.) was added slowly. The mixture was stirred for 10 minutes, the methylene chloride layer separated, back-washed with two 20 ml. portions of water, approximately 50 mg. of solids removed by filtration, and the filtrate evaporated to dryness. Recrystallization of the residue from acetone afforded purified methyl 4-phenyl-5-benzoylpyrrole-3-carboxylate (673 mg., m.p. 201°-203° C.).