Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:25])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>C(O)C.[Ni]>[CH3:3][C:2]([CH3:25])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: C#CC(C)(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CCO
Product: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 20 h

Procedure:
To a solution of 1-[1,1-dimethylethoxycarbonyl]-4-[3-(1,1-dimethylprop-2-ynylamino)-2-pyridinyl]piperazine (PREPARATION 65, 1.00 g) in absolute ethanol (20 ml) under nitrogen is added wet Raney Nickel (650 mg). The mixture is put under a hydrogen atmosphere at 40 psi (Parr) for 20 hr, filtered through a pad of celite, and concentrated. The residue is then taken up in methylene chloride (40 ml), washed with saline (10 ml), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound, NMR (CDCl3) 7.64, 7.03, 6.85, 4.56, 3.56, 2.97, 1.71, 1.48, 1.33 and 0.88.
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4](C(O)=O)[S:5][C:6]=2C(O)=O)[O:2]1>[Cu].CS(C)=O>[CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[CH:4][S:5][CH:6]=2)[O:2]1
Reactant: O=C(O)c1sc(C(=O)O)c2c1OCCO2
Agent: [Cu]
Solvent: CS(C)=O
Product: c1scc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
3,4-Ethylenedioxythiophene-2,5-dicarboxylic acid (460 g) and a copper powder (46 g) were added to DMSO (1200 g) at room temperature. The reaction mixture was stirred under an oxygen atmosphere for 30 minutes at room temperature and then heated at 120° C. for 6 hours. The reaction mixture was then poured into ice water (1200 mL), and the crude product was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was removed by evaporation. The residue was vacuum-distilled at 30 mmHg to give 283 g of 3,4-ethylenedioxythiophene at high purity (99.7% or higher). The purity was confirmed by gas chromatographic analysis (compared to decane as an internal standard). The chemical structure was confirmed by mass analysis and 1H-NMR.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:30][CH:31]1[CH2:36][C:35](=O)[CH2:34][CH2:33][CH:32]1[C:38]([O:40][CH2:41][CH3:42])=[O:39].Cl>C1COCC1.O.CCOC(C)=O>[CH:2]([CH:35]1[CH2:34][CH2:33][CH:32]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:31]([CH3:30])[CH2:36]1)=[O:3]
Reactant: CCOC(=O)C1CCC(=O)CC1C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(C=O)CC1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) suspension of (methoxymethyl)triphenylphosphonium chloride (155 g, 452 mmol) in THF (700 mL) was added potassium tert-butoxide (1.0 M in THF, 452 mL, 452 mmol) at such a rate that the internal temperature did not exceed 7° C. The mixture was stirred for 1 hour at 0° C., and then a solution of ethyl 2-methyl-4-oxocyclohexanecarboxylate (64 g, 347 mmol) in THF (150 mL) was added via canula at such a rate that the internal temperature did not exceed 7° C. The mixture was then slowly warmed to room temperature and stirred for 14 hours. The reaction mixture was then cooled to 10° C. and diluted with water (200 mL) followed by 6 M HCl (500 mL). The resulting mixture was stirred for 3 hours, and then diluted with additional water (400 mL) and EtOAc (700 mL). The organic layer was separated, and the aqueous layer was extracted a second time with EtOAc (700 mL). The organic layers were combined, dried over MgSO4, filtered, absorbed on silica gel, and purified by silica gel chromatography to afford ethyl 4-formyl-2-methylcyclohexanecarboxylate, which was used immediately in the subsequent step.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>CCOC(C)=O.O>[O:13]1[C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH2:8]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reaction time: 1 h
Yield: 80.3 %

Procedure:
55% sodium hydride (6.02 g) was added under ice-cooling to a DMSO (250 mL) suspension of trimethylsulfoxonium iodide (33.1 g), and stirring was performed at room temperature for 1 hour. A DMSO (125 ml) solution of tert-butyl 4-oxopiperidine-1-carboxylate (25.0 g) was added, and heated and stirred at 60° C. for 1 hour. Purified water was added to the mixture, and extraction was performed with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (21.5 g),
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54]([O:58][C:59]([NH:61][C:62]1[S:63][CH:64]=[C:65]([CH2:67][C:68](O)=[O:69])[N:66]=1)=[O:60])([CH3:57])([CH3:56])[CH3:55].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:68](=[O:69])[CH2:67][C:65]4[N:66]=[C:62]([NH:61][C:59]([O:58][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:60])[S:63][CH:64]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Temperature: -30 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethyl-thio)-3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg: 1.06 mMol.) and 2-(2-t-butoxycarbonylaminothiazol-4-yl)acetic acid (287 mg: 1.11 mMol.) in dichloromethane (8 ml) cooling at -30° C. are added N-methylmorpholine (0.27 ml: 2.46 mMol.) and phenyl dichlorophosphate (0.19 ml: 1.27 mMol.), and the mixture is stirred at -30° C. for 40 minutes. The reaction mixture is quenched with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=3:1) to give 7β-[2-(2-t-butoxycarbonylaminothiazol-4-yl)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (812 mg) as pale yellow foam. Yield: 77%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:37]([CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCN
Product: CCCS(=O)(=O)NCCOc1ncnc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC
Yield: 89.8 %

Procedure:
According to Example 4a) 100 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide was reacted with 93 mg 1-propanesulfonylchloride to give 110 mg 4-tert.-butyl-N-{6-[2-(1-propanesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=5.43 min, [M−1]−=577.49.
Reaction SMILES: C(=O)([O-])O.CO.C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:37]2[CH:42]=[CH:41][C:40]([O:43]C(=O)C)=[CH:39][CH:38]=2)[C:18]2[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])=[O:21])=[CH:13][CH:12]=1)(=O)C>[Na]>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH:17]([C:14]2[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=2)[C:18]2[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])=[O:21])=[CH:38][CH:39]=1
Reactant: COc1ccc(NC(=O)c2ccccc2C(c2ccc(OC(C)=O)cc2)c2ccc(OC(C)=O)cc2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na]
Solvent: CO
Product: COc1ccc(NC(=O)c2ccccc2C(c2ccc(O)cc2)c2ccc(O)cc2)c(OC)c1
Yield: 56 %

Procedure:
In a mixture of 50 ml of saturated aqueous sodium. hydrogencarbonate solution and 50 ml of methanol was suspended 2.6 g of Compound 2 prepared in Example 1, and the suspension was heated under reflux for 30 minutes. The resulting mixture was concentrated under reduced pressure, and water was added to the residue. The resulting mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized to afford 1.23 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH:25]=[N:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:27])[CH3:30]
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(N=CC(=O)OCC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethyl bromoacetate were reacted together to give N2,N4-bis(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 23.41 min.; purity: 96.3%; MS (m/e): 483.08 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[C:25]2[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[C:26]=2[CH:27]=[N:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[C:25]3[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[C:26]=3[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(Cl)c21
Product: CCC(=O)NC1CCc2c(-c3cc(Cl)c4c(c3)CCC(=O)N4C)cncc21
Yield: 65 %

Procedure:
In analogy to the procedure described for the preparation of example 28, 8-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-8) and (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-3) were used to give the title compound as a white powder in 65% yield. MS: 384.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][N:4]=[CH:5][C:6](=[O:8])[CH3:7])[CH3:2].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]=[O:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(O)(=O)C>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:6](=[O:8])[CH3:7])[C:20]=2[OH:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Reactant: CCNN=CC(C)=O
Solvent: CC(=O)O
Product: CCn1nc(C(C)=O)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 15.6 %

Procedure:
2-Oxopropanal ethylhydrazone (4.736 mmol, 540.6 mg) synthesized in Reference Synthetic Example 2 and (4-tert-butylphenyl)(oxo)acetaldehyde (4.736 mmol, 901.0 mg) synthesized in Reference Synthetic Example 4 were dissolved in acetic acid (20 mL) and stirred at 100° C. for about 3.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel thin layer chromatography (n-hexane/AcOEt=1/2, 3/1 and 4/1) to give the desired product as an orange liquid (212 mg, yield 160).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[S:13][CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5]1)[CH3:3]>C(O)(=O)C.Cl>[CH3:1][CH:2]([CH:4]1[CH2:5][C:6](=[O:7])[CH2:11][CH2:12][S:13]1)[CH3:3]
Reactant: CC(C)C1CC2(CCS1)OCCO2
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)C1CC(=O)CCS1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-(1-Methylethyl)-1,4-dioxa-8-thiaspiro[4.5]decane was dissolved in acetic acid (50 mL) and 2 N aqueous hydrochloric acid (70 mL). After being stirred at room temperature for 15 h, the mixture was extracted with ether (300 mL), and the ether extract washed with water (2×50 mL), 10% aqueous sodium hydroxide (3×50 mL), and finally with water (2×50 mL). The dried (Na2SO4) solution was evaporated, and the residue purified by column chromatography on silica, giving 3.6 (22% over two steps) of the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:25][CH2:24]3)=[O:22])[O:18][C:17]2=[O:40])=[CH:12][CH:11]=1)=O)(C)(C)C.[ClH:41]>C(OCC)(=O)C>[ClH:41].[ClH:41].[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH2:27][CH2:28]3)=[O:22])[O:18][C:17]2=[O:40])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CC(C(=O)N3CCN(CC(=O)OCc4ccccc4)CC3)OC2=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1ccc(N2CC(C(=O)N3CCN(CC(=O)OCc4ccccc4)CC3)OC2=O)cc1

Procedure:
0.74 g of benzyl 2-{1-[3-(4-tert-butoxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperazinyl}acetate is stirred in 30 ml of HCl solution in ethyl acetate at room temperature. The precipitate formed is filtered off through suction, washed with a little ethyl acetate and dried. Benzyl 2-{1-[3-(4-aminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperazinyl}acetate, dihydrochloride, is obtained, m.p. 224°-226°.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH:14]=2)=[CH:9][CH:8]=1.C(O)(=O)C>O.O1CCCC1>[CH2:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][N:20]1[CH2:19][C:15]1[CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:29])=[O:4])=[CH:12][CH:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
Lithium hydroxide (126 mg) in water (5 mL) was added to a solution of [3′-(1,3-dihydro-iso-indol-2-ylmethyl)-biphenyl-4-yl]-acetic acid methyl ester (0.47 g) in tetrahydrofuran (10 mL) and stirred at room temperature for 72 hour. The reaction mixture was acidified with glacial acetic acid and evaporated. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous was separated and extracted with ethyl acetate (2×20 mL). The combined organics were washed with brine (20 mL), dried (sodium sulfate) and evaporated to give a the subtitle compound as a brown oil (450 mg).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[O:12][C:13]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=1.C(N(CC)CC)C.[CH3:38][N:39]=[C:40]=[O:41]>C(Cl)Cl>[C:16]([C:14]1[N:15]=[C:11]([C:5]2[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])[O:12][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:40]([NH:39][CH3:38])=[O:41])[CH2:29][CH2:30]2)=[N:21][CH:20]=1)(=[O:17])[NH2:18]
Reactant: CN=C=O
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4-carboxamide dihydrochloride (0.060 g, 0.13 mmol) in DCM (3 mL) was added triethylamine (40 uL, 0.29 mmol) followed by methyl isocyanate (12 uL, 0.20 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by preparative HPLC and then by SPE using a MP-TsOH resin (500 mg) cartridge to afford 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2-yl)-N-methylpiperazine-1-carboxamide (0.0057 g, 0.013 mmol, 10%) as a yellow solid. 1H NMR (DMSO) 2.58 (3H, d), 3.40 (4H, m), 3.61 (4H, m), 6.54 (1H, br. q), 6.99 (1H, d), 7.38 (2H, t), 7.65 (1H, br. s), 7.67 (1H, br. s), 7.72 (1H, m), 8.37 (1H, dd), 8.95 (1H, d). LCMS (2) Rt: 2.27 min; m/z (ES+) 443.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]3[CH:20]=[N:21][N:22]=[C:18]3[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[C:16]([C:33]3[CH:38]=[CH:37][N:36]=[C:35](Cl)[CH:34]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40][C@H:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]3[CH:20]=[N:21][N:22]=[C:18]3[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[C:16]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:48][C@H:41]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH3:40])[CH:34]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc(-c3ccnc(Cl)c3)c(-c3cccc(C(F)(F)F)c3)c3nncn23)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cc(-c2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)n3cnnc3c2-c2cccc(C(F)(F)F)c2)ccn1)c1ccccc1
Temperature: 90 °C

Procedure:
5-(1-(t-Butoxycarbonyl)-1,2,3,6-tetrahydropyrid-4-yl)-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine (0.93 g, 1.7 mmol), (S)-α-methylbenzylamine (0.48 g, 4 mmol), palladium acetate (0.06 g, 0.26 mmol) and racemic BINAP (0.16 g, 0.26 mmol) were combined in toluene (15 ml) and the resulting solution was degassed with nitrogen. Sodium t-butoxide (0.48 g, 5 mmol) was added and the resulting mixture was heated to 90° C. for 1 hour. The mixture was partitioned between sat. ammonium chloride and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to a syrup. The residue was purified by column chromatography on silica gel (30% ethyl acetate in hexane) gave the product as a syrup; MS m/z (M+H)+ 642.4; C35H34F3N7O2 require 641.3.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:5]([CH:6]([OH:13])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[F:17].O[PH2]=O>>[C:9]([NH:8][CH2:7][CH:6]([OH:13])[C:5]1[CH:14]=[CH:15][CH:2]=[C:3]([F:17])[C:4]=1[F:16])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)NCC(O)c1ccc(N)c(F)c1F
Agent: O=[PH2]O
Product: CC(C)(C)NCC(O)c1cccc(F)c1F

Procedure:
By using the procedure of Example 18, 4-amino-α-[(tert-butylamino)methyl]-2,3-difluorobenzyl alcohol is deaminated with H3PO2 to afford the title compound. Similarly, 2,3-difluoro-α-[(isopropylamino)methyl]benzyl alcohol is obtained from its corresponding 4-amino compound.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][CH:10]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=CC1CCCCCCCCCCC1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CCCC2CCCCCCCCCCC2)cc1
Reaction time: 8 h

Procedure:
To 6.4 g (22.5 mmoles) of 1-(3-phenyl-1-propenyl)cyclododecane in 50 mL of ethanol is added 0.48 g of 10% palladium on carbon. The reaction mixture is subjected to hydrogen (50 psi) atmosphere using a Paar hydrogenerator and shaken overnight after which time no starting material is evident by TLC. The reaction mixture is filtered through Celite which is washed with additional ethanol. The filtrate is evaporated and the crude residue (5.8 g) is used directly for the next step: NMR (CDCl3) δ1.2-1.4 (m, 10H), 1.6 (m, 2H), 2.55 (t, 2H, J=8 Hz), 7.2 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:8][C:9](Cl)=[N:10][CH:11]=1)=[O:5])[CH3:2].[Cl:17][C:18]1[N:19]=[N:20][C:21]([N:26]2[CH2:31][CH2:30][NH:29][C@H:28]([CH3:32])[CH2:27]2)=[C:22]([CH3:25])[C:23]=1[CH3:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:8][C:9]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[N:19][C:18]([Cl:17])=[C:23]([CH3:24])[C:22]=3[CH3:25])[CH2:27][C@H:28]2[CH3:32])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Product: CCOC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Yield: 97.2 %

Procedure:
Following the protocol above with 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester (400 mg, 1.57 mmol, 1 eq) and 3-chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (400 mg, 1.66 mmol, 1 eq) affords 700 mg of desired product as a white solid (97%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=2)[N:3]=1
Reactant: NCc1cccc(Cl)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1cccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)c1

Procedure:
2-Chloro-6-[(3-chlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][C:12]([O:14][CH2:15]C)=[O:13].Cl.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH:26]([OH:31])[C:27](=N)OC.O>C(O)C>[NH2:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:27]([CH:26]([C:20]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=3[Cl:18])[OH:31])=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCNc1c(N)cccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)CCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reaction time: 12 h
Yield: 90.2 %

Procedure:
To a stirred solution of ethyl N-(2,6-diaminophenyl)-beta-alaninate (4.11 g, 18.4 mmol) in ethanol (36.8 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (5.59 g, 20.7 mmol) at room temperature. After 12 h, the reaction mixture was poured into water (120 mL). The resulting solid was collected by filtration and washed with ethyl acetate to afford the desired product as colorless solid (6.77 g, 16.6 mmol, 90%).