Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH3:21]>[Pd]>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([O:22][CH2:23][CH3:24])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:21]
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2ccccc2)cc1C)C(=O)OC
Agent: [Pd]
Product: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 17 d], (2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-propionic acid methyl ester was hydrogenated over 10% palladium on charcoal to give (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester as colorless liquid.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][Br:31])([CH3:7])[CH3:6])C.C1C(O)=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C(C)(OC1C=CC(OCCC2N=C(C3C=CC=CC=3)OC=2C)=CC=1COC1C=C(C)C=CC=1)C)C.[OH-].[Na+]>C(O)C>[Br:31][CH2:30][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CBr
Agent: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1COc1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1cccc(O)c1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(CBr)c1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
The following example exemplifies the general procedure for the parallel synthesis of analogs utilizing the DynaVac carousel. To a 50 mL glass tube with screw cap and nitrogen inlet were charged 2-{2-bromomethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (0.040 g, 0.080 mmol), and 0.012 mL (0.12 mmol) of m-cresol dissolved in 1 mL of absolute ethanol, followed by the addition of powdered potassium carbonate (325 mesh) (0.022 g, 0.16 mmol). The mixture was heated to 80° C. for 4 h. MS analysis of the reaction indicated that 2-methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-m-tolyloxymethylphenoxy}propionic acid ethyl ester, MS (ES) m/e 530 (M+1) had formed. Next 0.4 mL of 5N NaOH was added and the reaction was heated for 3 h at 55° C. The ethanol was removed in vacuo and the residue was treated with 0.75 mL of 5N HCl and 1 mL of MeCl2 and poured into a 3 mL ChemElute column to remove the aqueous layer. The column was eluted with additional MeCl2 until nothing UV active remained on the column. The solvent was removed in vacuo. The crude residue was purified by mass-directed reverse phase HPLC to provide 0.032 g (38%) of 2-{2-bromomethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid, MS (ES) m/e 502 (M+1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([NH:19]C(=O)C)[CH:18]=1)[CH2:4][CH2:5][CH3:6].[CH3:38][S:39]([Cl:42])(=[O:41])=[O:40].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CCOCC>[ClH:42].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([NH:19][S:39]([CH3:38])(=[O:41])=[O:40])[CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(C)=O)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine (Example 62, 0.2 mmol, 88 mg) in DCM (1.0 mL) at 0° C. was added methanesulfonyl chloride (0.3 mmol, 24 μL) and DIEA (0.3 mmol, 53 μL). And the mixture was stirred at room temperature for 1 hour. It was then condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to afford N-{5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-methanesulfonamide dihydrochloride (72 mg).
Reaction SMILES: C([O:5][C:6](=[O:52])[CH:7]([NH:12][C:13](=[O:51])[C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=1[S:24][S:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][C:27]=1[C:36](=[O:50])[NH:37][CH:38]([C:43]([O:45]C(C)(C)C)=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([S:24][S:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][C:27]=2[C:36](=[O:50])[NH:37][CH:38]([C:43]([OH:45])=[O:44])[CH2:39][CH:40]([CH3:41])[CH3:42])=[C:14]([CH:19]=1)[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:52])=[O:5])=[O:51])(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1ccc(SSc2ccc(NC(C)=O)cc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(SSc2ccc(NC(C)=O)cc2C(=O)NC(CC(C)C)C(=O)O)c(C(=O)NC(CC(C)C)C(=O)O)c1
Yield: 77.3 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]2-{5-acetylamino-2-[4-acetylamino-2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-phenyldisulfanyl]-benzoylamino}-4-methyl-pentanoic acid tert-butyl ester (0.2 g, 0.2 mmol) from Example 44, 10 mL dichloromethane, and 10 mL trifluoroacetic acid. The crude product was recrystallized from dimethylformamide/water to afford 0.1 g of the title compound, mp 241°-242° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=[C:2]1[C:11](=[N:15][O:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH:19]1[C:36](=[O:37])[N:21]2[C:22]([C:33]([OH:35])=[O:34])=[C:23]([CH2:26][S:27][C:28]3[S:29][CH:30]=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=[C:2]1[C:11](=[N:15][O:16][CH3:17])[C:12]([NH:18][CH:19]1[C:36](=[O:37])[N:21]2[C:22]([C:33]([OH:35])=[O:34])=[C:23]([CH2:26][S:27][C:28]3[S:29][CH:30]=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12)=[O:14]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)C1=CSc2ccccc2O1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1=CSc2ccccc2O1

Procedure:
2-(1,4-Benzoxathiin-2-yl)-2-methoxyiminoacetic acid (syn isomer, 0.85 g.) was allowed to react with 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.09 g.) in a similar manner to that of Example 1 to give the captioned compound (1.50 g.), yellow powder, mp. 157° to 161° C. (dec.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7]12[O:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2>[OH-].[Na+]>[OH:6][CH:4]([CH3:5])[CH2:3][O:2][CH2:1][O:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:7]1
Reactant: C1CCC2OC2C1
Reactant: COCC(C)O
Agent: [Na+]
Agent: [OH-]
Product: CC(O)COCOC1CCCCC1
Yield: 27.4 %

Procedure:
45 g (0.5 mole) of propylene glycol methyl ether (PM), 33 g (0.33 mole) of cyclohexene oxide and 0.3 g (0.007 mole) of sodium hydroxide were charged in a 100 ml eggplant type flask equipped with a reflux tube, and a reaction was allowed to proceed under reflux at a temperature for a reflux reaction for 10 hours. Results of the analysis of the resultant reaction mixture by GC showed that the conversion of PM was 20%. Then, the obtained reaction mixture was subjected to distillation, to thereby obtain 17 g of 2-hydroxycyclohexyloxymethoxypropane, i.e., propylene glycol methyl 2-hydroxycyclohexyl ether (hereinafter referred to as "PGMHCHE"). The IR spectrum of the product is shown in FIG. 3. Other properties of the product were measured and results are shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH2:29][CH:30]=O>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:29]1[CH:30]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: O=CCc1c(Cl)cccc1Cl
Product: Oc1cccc(-c2c(-c3c(Cl)cccc3Cl)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2,6-dichloro-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 431.8; HRMS: calcd for C22H12Cl2F3NO+H+, 434.03208; found (ESI, [M+H]+), 434.033.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[CH:18][C:13]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(-c2ccc(Cl)cn2)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (18.0 ml, 353.7 mmol) is slowly added to a soln. of 2-amino-5-chloropyridine (15.0 g, 116.7 mmol) in 47% aq. HBr (75.0 ml) at −10° C. An aq. soln. of NaNO2 (28.1 g, 407.3 mmol) is slowly added. The mixture is stirred for 1 h at −10 to −5° C., then for 1 h at 5° C. The mixture is neutralised with 5M aq. NaOH soln. maintaining the temperature below 25° C. The precipitate is filtered and recrystallized from pentane to give 2-bromo-5-chloropyridine. 2-Bromo-5-chloropyridine (5.0 g, 26.0 mmol), p-tolylboronic acid (4.0 g, 29.4 mmol) and tetrakis(triphenylphosphine)palladium (1.44 g, 1.2 mmol) are dissolved in toluene:EtOH 9:1 (1375 ml). A 2M aq. Na2CO3 soln. (62.5 ml) is added to the reaction mixture. The mixture is stirred at 90° C. for 24 h, cooled to rt and filtered over celite. The toluene layer is separated and washed with brine. The aq. layers are extracted with AcOEt. The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown solid which is purified by FC (silica gel, eluent toluene) to give 5-chloro-2-p-tolyl-pyridine. (R)-3-Quinuclidinol (2.97 g, 23.4 mmol) is added to a suspension of NaH (0.96 g of a 60% dispersion in mineral oil, 22.8 mmol) in DMF (90 ml). The mixture is stirred for 1 h at rt. 5-Chloro-2-p-tolyl-pyridine (4.00 g, 19.6 mmol) is added and the mixture is heated for 135 h at 135° C. The reaction mixture is diluted with toluene and washed with 1 M aq. NaOH soln. and brine. The aq. layers are re-extracted with toluene (3×). The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown oil which is purified by FC (silica gel, eluents: AcOEt, then AcOEt/MeOH/NEt3 87:10:3) and recrystallized from CH3CN to give (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane; mp ° C.: 110-112; [α]Drt=+21.2° (0.50, MeOH), M+H+ 295.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: ClCCCBr
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCc2cc(OCCCCl)ccc21

Procedure:
In a 500 mL round bottom flask, 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (10 g, 61.0 mmol), 1-bromo-3-chloro-propane (9.6 g, 61.0 mmol), and potassium carbonate (9.3 g, 67.1 mmol) in acetonitrile (300 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, separated, dried over MgSO4. Purification with silica gel chromatography eluting with hexanes/ethyl acetate (3:1) produced 10.6 g (73%). Mp 85-87° C. MS m/z 239 (M+H).
Reaction SMILES: [N+](C1C=CC(OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:38][C@H:39]([C:47]([OH:49])=[O:48])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:46])[NH2:45]>O1CCOCC1.O>[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH:38][C@H:39]([C:47]([OH:49])=[O:48])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:45])[NH2:46])=[O:34])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
To a solution of 37 g (0.1 mol) of p-nitrophenyl ether of benzyloxycarbonylproline in 360 ml of dioxane there is added a solution of 16 g (0.09 mole) of arginine in 160 ml of water under vigorous stirring. After two hours the solvent is evaporated and the residue is dissolved in 100 ml of dimethylformamide. The solution is stirred at room temperature (25° C.) for 72 hours and then poured into 1 liter of ethylacetate. After residence of the reaction mixture for 12 hours in a cooler the resulting precipitate is filtered-off, washed on the filter with ethylacetate and diethyl ether. After recrystallization of the product from a mixture of ethanol-diethyl ether (1:5) there are obtained 35 g (96%) of benzyloxycarbonyl-prolyl-arginine having the following properties: melting point 137°-140° C., [L]D20 -46.6° (c 1.0; H2O); Rf 0.53 (A, "Eastman"); 0.66 (B, "Eastman"), Ehis 0.56 (pH 2.4).
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[C:28]#[N:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[C:28]([C:27]1[CH:30]=[CH:31][C:32]([O:33][C:2]2[C:7]3[O:8][CH2:9][CH2:10][N:11]([CH:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[C:6]=3[N:5]=[CH:4][N:3]=2)=[C:25]([F:24])[CH:26]=1)#[N:29]
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Oc4ccc(C#N)cc4F)ncnc32)CC1
Temperature: 120 °C
Reaction time: 72 h
Yield: 7.8 %

Procedure:
To a solution of isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A (10.0 mg, 0.029 mmol) and 3-fluoro-4-hydroxybenzonitrile (12.07 mg, 0.088 mmol) in DMF (0.4 mL) was added K2CO3 (12.17 mg, 0.088 mmol). The reaction mixture was stirred in a sealed vial for 3 days at 120° C. The reaction mixture was cooled to RT. The reaction mixture was diluted with MeOH, filtered and purified by reverse phase HPLC (H2O/CH3CN) to give isopropyl 4-(4-(4-cyano-2-fluorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazin-8(7 H)-yl)piperidine-1-carboxylate (1.0 mg, 2.265 μmol, 7.72% yield) as Example 148 as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (d, J=6.05 Hz, 6H) 1.55-1.79 (m, 4 H) 2.85-2.95 (m, 2 H) 3.44-3.54 (m, 2 H) 4.05-4.15 (m, 2 H) 4.24-4.35 (m, 2 H) 4.84-4.95 (m, 2 H) 7.29-7.40 (m, 1 H) 7.45-7.52 (m, 2 H) 7.88 (s, 1 H). LRMS (ESI): 442.5 [M+H]+.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[N:9]=[C:8](Cl)[C:7]([C:11](=O)[CH3:12])=[CH:6][N:5]=1>C1COCC1>[Cl:3][C:4]1[N:9]=[C:8]2[NH:1][N:2]=[C:11]([CH3:12])[C:7]2=[CH:6][N:5]=1
Reactant: CC(=O)c1cnc(Cl)nc1Cl
Reactant: NN
Solvent: C1CCOC1
Product: Cc1n[nH]c2nc(Cl)ncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of hydrazine (Aldrich, 102.4 mg, 3.2 mmol) in THF (5 mL), 1-(2,4-dichloro-pyrimidin-5-yl)-ethanone (Example 21, 191 mg, 1 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL) and the mixture was extracted with EtOAc/THF(3×5 mL, 1:1 mixture of EtOAc:THF ). The extract was dried with sodium sulfate and concentrated to give a solid. 126 mg, 75%. MS (M+H)+, 169.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1.[CH3:11][C:12]([O:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:22]=2[O:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])[CH3:13].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:8]([NH:7][C:5]1[S:6][C:2]([C:26]2[CH:27]=[CH:28][C:22]3[O:21][CH2:20][CH2:19][N:18]([C:16]([O:15][C:12]([CH3:13])([CH3:11])[CH3:14])=[O:17])[CH2:24][C:23]=3[CH:25]=2)=[CH:3][N:4]=1)(=[O:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: CC(=O)Nc1ncc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CCO3)s1
Temperature: 93 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
A mixture of N-(5-bromothiazol-2-yl)acetamide (1.00 g, 4.52 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (1.54 g, 5.43 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.33 g, 0.40 mmol), potassium carbonate (2.50 g, 18.1 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was degassed with nitrogen for 5 minutes and then stirred at 93° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL), filtered over celite. The filtrate was washed with brine (2×50 mL), dried over sodium sulfate, filtered, concentrated. The residue was purified by flash chromatography (20% to 80% ethyl acetate-hexane gradient) to give 1,1-dimethylethyl 7-[2-(acetylamino)-1,3-thiazol-5-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.99 g, 2.54 mmol, 56.2% yield); MS (EI) for C19H23N3O4S: 390 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]=[C:7](OC)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2].Cl.Cl.[NH2:18][CH:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:20]([NH:22][C:23]1([C:30]#[N:31])[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:21].C(N(CC)C(C)C)(C)C>CO>[C:30]([C:23]1([NH:22][C:20](=[O:21])[CH:19]([NH:18][C:7](=[N:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1)#[N:31]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: CCNC(=O)N=C(OC)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C)CC1)c1ccccc1
Yield: 42.9 %

Procedure:
A solution of 1-ethyl-3-(methoxy-phenyl-methylene)-urea (350 mg, 1.70 mmol), 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt (512 mg, 1.40 mmol) and N,N-diisopropylethylamine (352 mg, 2.73 mmol) in dry methanol (5.0 mL) was stirred at room temperature for 60 h. The reaction mixture was concentrated and the resulting residue was chromatographed over 50 g of flash silica gel using dichloromethane to 5% methanol in dichloromethane as the eluant. This provided the desired product as a light yellow solid (280 mg, 43%) which was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to 90% acetonitrile in water. MS, m/z 467=M+1.
Reaction SMILES: OC1CC(=O)C(CCCCCCC(OC)=O)=C1.CC(OC1CCCCO1)(CCCCC)C#C[Al](C#CC(OC1CCCCO1)(C)CCCCC)C#CC(OC1CCCCO1)(C)CCCCC.[Ga].[B].[OH:69][CH:70]1[CH2:74][C:73](=[O:75])[CH:72]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]([O:84][CH3:85])=[O:83])[CH:71]1[C:86]#[C:87][C:88]([CH3:101])([O:94]C1CCCCO1)[CH2:89][CH2:90][CH2:91][CH2:92][CH3:93]>C(O)(=O)C>[OH:69][CH:70]1[CH2:74][C:73](=[O:75])[CH:72]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]([O:84][CH3:85])=[O:83])[CH:71]1[C:86]#[C:87][C:88]([OH:94])([CH3:101])[CH2:89][CH2:90][CH2:91][CH2:92][CH3:93]
Reactant: CCCCCC(C)(C#CC1C(O)CC(=O)C1CCCCCCC(=O)OC)OC1CCCCO1
Agent: CCCCCC(C)(C#C[Al](C#CC(C)(CCCCC)OC1CCCCO1)C#CC(C)(CCCCC)OC1CCCCO1)OC1CCCCO1
Agent: COC(=O)CCCCCCC1=CC(O)CC1=O
Agent: [B]
Solvent: CC(=O)O
Product: CCCCCC(C)(O)C#CC1C(O)CC(=O)C1CCCCCCC(=O)OC

Procedure:
The 3-hydroxy-3-alkylated acetylenic compounds of this invention are prepared by employing the appropriately alkylated alkynyl boron, alkynyl gallium or alkynyl aluminum reactant. For example, treatment of methyl 3-hydroxy-5-oxocyclopent-1-eneheptanoate with tri(3methyl-3-[tetrahydropyran-2-yl]oxy-1-octynyl) aluminum, gallium or boron affords the epimeric methyl 3-hydroxy-2-(3-methyl-3-[tetrahydropyran-2-yl]oxy-1-octynyl)-5-oxocyclopentaneheptanoate. Typically, that compound may be hydrolyzed with a hydrolyzing agent such as hydrolytic acid, e.g. aqueous acetic acid, to yield the instant methyl 3-hydroxy-2-(3-hydroxy-3-methyl-1-octynyl)-5-oxocyclopentaneheptanoate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([Cl:13])[N:6]=[C:7]2Cl.[CH3:14][O-:15].[Na+]>O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([Cl:13])[N:6]=[C:7]2[O:15][CH3:14]
Reactant: C[O-]
Reactant: Clc1cc2c(Br)cccc2c(Cl)n1
Agent: [Na+]
Solvent: O
Product: COc1nc(Cl)cc2c(Br)cccc12
Temperature: 70 °C

Procedure:
A mixture of 5-bromo-1,3-dichloroisoquinoline (580 mg, 2.1 mmol) and NaOMe (0.5 M in MeOH, 5.0 mL, 2.5 mmol) was heated at 70° C. for one hour. The mixture was poured into water then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, then concentrated to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.23 (d, J=9.0 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H); 7.65 (s, 1H), 7.39 (t, J=8.5 Hz, 1H), 4.20 (s, 3H). LC6: 3.86 min. (M+H) 272.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:50]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>>[C:53]([O:52][C:50]([N:57]1[CH2:62][CH2:61][N:60]([C:34](=[O:36])[C:33]2[CH:32]=[CH:31][C:30]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:13]=[N:14][C:9]([N:8]([CH2:39][C:40]6[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=6)[CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=6)=[N:10][CH:11]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:38][CH:37]=2)[CH2:59][CH2:58]1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cn2)cc1
Yield: 83.8 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (70.4 mg, 0.107 mmol) obtained in Step A in Example 1-D-19 and 1-Boc-piperazine (31.7 mg, 0.170 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 4-{4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-benzoyl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (74.2 mg), and then the PMB groups and BOC group were removed according to the above Deprotection method 3, to obtain the desired compound (D-112) as a colorless powder (41.4 mg, 80%).