Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[OH:11])([CH3:3])[CH3:2].[NH2:12][C:13]1[C:14]([C:34]#[N:35])=[C:15]([CH:31]=[CH:32][CH:33]=1)OCC1CCN(C(OC(C)(C)C)=O)CC1>>[NH2:12][C:13]1[CH:33]=[CH:32][CH:31]=[C:15]([O:11][C@@H:5]2[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]2[CH:1]([CH3:3])[CH3:2])[C:14]=1[C:34]#[N:35]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(N)c2C#N)CC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol and 2 as a white solid (51%). MS 273 (MH+).
Reaction SMILES: I[C:2]1[C:6]2[C:7]([NH:11]C(=O)OCC)=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([O-:25])=[O:24]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:6]3[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=3[NH:4][CH:3]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)Nc1nccc2[nH]cc(I)c12
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccc2[nH]cc(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 80 °C
Yield: 25.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.009 mmol, 0.1 eq) was added to ethyl 3-iodo-1H-pyrrolo[3,2-c]pyridin-4-ylcarbamate (0.031 g, 0.094 mmol, 1.0 eq), sodium carbonate (0.07g, 0.66 mmol, 7.0 eq) and 4-nitrophenyl boronic acid (0.055g, 0.33 mmol, 3.5 eq) in a degassed solution of 1/1 dioxane/water (1 mL) at room temperature. The reaction mixture was heated to 80° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water and the pH adjusted to 7.0 with dilute aqueous HCl. The solution was extracted with 10/1 CHCl3/MeOH, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by loading it onto a 1.5 g Varian SCX cationic exchange cartridge (eluting sequentially with 1/1 DCM/MeOH, MeOH, 0.1N NH3 in MeOH, and to elute the product 1.0 N NH3 in MeOH) and the appropriate fractions were isolated and concentrated in vacuo to afford the product (0.006 g, 26%) as a solid. MS(ESI+) m/z 255 (M+H)+. Calculated: 255.0882, found: 255.0887.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH:13][C:14]1[C:19](Br)=[C:18]([CH2:21][CH3:22])[N:17]=[CH:16][N:15]=1)[CH3:12].[CH3:23][S-:24].[Na+]>CN1CCCC1=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH:13][C:14]1[C:19]([S:24][CH3:23])=[C:18]([CH2:21][CH3:22])[N:17]=[CH:16][N:15]=1)[CH3:12]
Reactant: C[S-]
Reactant: CCc1ncnc(NC(C)c2ccc3ccccc3c2)c1Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1ncnc(NC(C)c2ccc3ccccc3c2)c1SC

Procedure:
4.99 g (0.014 mol) of 4-[1'-(β-naphthyl)-ethylamino]-5-bromo-6-ethylpyrimidine are dissolved in 18 ml of N-methylpyrrolidone, and the solution is heated at 60° C. with 3.2 g of sodium methanethiolate (CH3SNa) for 5 hours. The mixture is then extracted with water and ethyl acetate, the extract is washed and the solvent is removed using a rotary evaporator. Purification by chromatography on silica gel (eluant: 3 parts ethyl acetate and 7 parts hexane) yields, in addition to the starting product, 1.42 g of pure substance in the form of a colourless oil. Analysis: C19H21N3S (M=323.46).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([C:8]2[NH:13][CH2:12][CH2:11][O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.[Pd]>[O:10]1[CH2:11][CH2:12][NH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=2[NH2:14])=[N:9]1
Reactant: Cc1cccc(C2=NOCCN2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C2=NOCCN2)c1N
Temperature: 21 °C
Reaction time: 72 h

Procedure:
3 g (13.6 mmol) of 3-(3-methyl-2-nitrophenyl)-5,6-dihydro-4H-[1,2,4]oxadiazine are dissolved in 40 ml of ethanol, and 0.3 g of Pd/C (5%) is added. The mixture is then stirred at 21° C. under a hydrogen pressure of 3 bar for 72 h. The reaction mixture is then filtered and the ethanol is distilled off under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:16])[CH2:13][O:12][N:11]([CH3:14])[C:10](=[NH:15])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)#[N:18].C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:17]([C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([C:8]3([CH3:16])[CH2:13][O:12][N:11]([CH3:14])[C:10](=[NH:15])[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=1)#[N:18]
Reactant: CN1OCC(C)(c2cccc(Br)c2)NC1=N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1OCC(C)(c2cccc(-c3cccc(C#N)c3)c2)NC1=N
Yield: 44 %

Procedure:
A mixture of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC7; R6=Me, R1=Me) (0.025 g, 0.088 mmol, 1 eq), 3-cyanophenylboronic acid (0.019 g, 0.13 mmol, 1.5 eq), FibreCat (40 mg), anhydrous ethanol (1.5 mL), and a 1N K2CO3 aqueous solution (0.12 mL, 0.12 mmol, 1.4 eq) in a microwave vial was heated in a microwave reactor (Emrys Optimizer) at 110° C. for 15 min. The mixture was filtered, concentrated and purified by prep HPLC (B) to give 0.012 g (44%) of 5-(3-(3-cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC8; R6=Me, R1=Me, R21=3-cyanophenyl) as a white solid. 1H NMR (CDCl3) δ 10.67 (s, 1H), 8.05 (br s, 1H), 7.85 (m, 2H), 7.50-7.66 (m, 5H), 7.35 (m, 1H), 4.22 (dd, J1=11.8 Hz, J2=48.6 Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 307.3 (M+H)
Reaction SMILES: C(C1C=CC(N2N=C(C(OC)=O)C=N2)=CC=1)=O.[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([N:26]2[N:30]=[C:29]([C:31]([O:33][CH:34](C)[CH3:35])=[O:32])[CH:28]=[N:27]2)=[CH:22][CH:21]=1)=[O:19]>>[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([N:26]2[N:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:28]=[N:27]2)=[CH:24][CH:25]=1)=[O:19]
Reactant: CC(C)OC(=O)c1cnn(-c2ccc(C=O)cc2)n1
Agent: COC(=O)c1cnn(-c2ccc(C=O)cc2)n1
Product: CCOC(=O)c1cnn(-c2ccc(C=O)cc2)n1

Procedure:
If methanol or isopropanol is used in place of ethanol in the reaction with the carboxylic acid chloride of 2-(p-tolyl)-4-carboxy-2H-1,2,3-triazole, the corresponding methyl ester or, respectively, isopropyl ester is obtained. These esters can be converted, in the manner described above, into 2-(p-formyl-phenyl)-4-carbomethoxy-2H-1,2,3-triazole (melting point: 125° to 127° C.) and, respectively, 2-(p-formyl-phenyl)-4-carboisopropoxy-2H-1,2,3-triazole (melting point: 100° to 102° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N:4]1[CH:3]=[C:2](/[CH:10]=[CH:9]/[C:8]([O:12][CH3:13])=[O:11])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cncnc1
Yield: 66 %

Procedure:
A solution of 5-bromopyrimidine (22.82 g, 144 mmol), methyl 2-propenoate (14.83 g, 172 mmol), palladium(II) acetate (0.322 g, 1.435 mmol), tri-o-tolylphosphine (0.874 g, 2.87 mmol), and TEA (32.0 g, 316 mmol) in DMF (100 mL) was heated at 130° C. under N2 for 7 h. After cooling, the reaction mixture was partitioned between water (200 mL) and DCM (200 mL). The organic phase was collected, washed with water (200 mL×4), brine, dried over sodium sulphate, and concentrated in vacuo to give the crude title compound as a pale yellow solid (18.4 g, 95 mmol, 66.4%). LCMS: rt=1.01 min, [M+H+]=165
Reaction SMILES: [NH2:1][C@@H:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15]1)=[O:4].Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][N:35]2[CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:31]2[N:39]=[CH:38][N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH3:29])=[C:7]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:15]2)[CH:8]=1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
A mixture of 2,2-dimethylpropionic acid 2-{(S)-3-[2-((S)-2-aminopropionylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester, (0.591 g, 1.45 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.346 g, 1.45 mmol), and DIPEA (0.74 mL, 4.32 mmol) in n-butanol (7 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 2-8% 2M NH3/MeOH in DCM) affording the title compound as a colourless gum (0.583 g, 66%). LCMS (Method J): RT 2.39 min [M+H]+ 611.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S([O:38][C:39]1[CH2:44][CH2:43][CH2:42][C:41](=O)[C:40]=1[CH3:46])(=O)=O>C(OCC)C>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:41]4[CH2:42][CH2:43][CH2:44][C:39](=[O:38])[C:40]=4[CH3:46])=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12
Reactant: CC1(C)OB(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)OC1(C)C
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)CCCC1=O
Solvent: CCOCC
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)CCCC1=O
Yield: 53.6 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 10, Step B (0.350 g, 0.780 mmol) and 2-methyl-3-oxo-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.222 g, 0.858 mmol) were reacted by the procedure described in Example 1, Step F. The crude product was purified by flash column chromatography on silica gel, eluting with 50% ethyl acetate in hexane to afford an orange oil. The oil was dissolved in diethyl ether and precipitated with petroleum ether to afford orange solid (0.180 g).
Reaction SMILES: Br[CH:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:7].CC(C)([O-])C.[K+]>CN(C)C=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[CH:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]2=[O:7])=[CH:10][CH:11]=1
Reactant: CC(Br)CCNC(=O)Nc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCNC(=O)N1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 38.6 %

Procedure:
To a solution of 1-(3-bromobutyl)-3-(4-fluorophenyl)urea (1750 mg, 6.1 mmol) in N,N-dimethylformamide (30 mL) was added potassium tert-butoxide (920 mg, 7.0 mmol), and the mixture was stirred at 50° C. for 6 hr. The solvent was evaporated under reduced pressure, and ethyl acetate/tetrahydrofuran and 6N aqueous hydrochloric acid solution were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=50/50→100/0) to give the title compound (490 mg, 39%) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C@@H:15]3[C@@H:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][C:18]4([CH2:20][CH2:19]4)[CH2:17][NH:16]3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]([C@@H:15]3[C@@H:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][C:18]4([CH2:19][CH2:20]4)[CH2:17][N:16]3[C:23]([O:25][CH3:26])=[O:24])=[O:14])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC2(CC2)C[C@H](C(=O)OC(C)(C)C)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 198.1 %

Procedure:
Methyl chlorofomate (55 μL, 700 μL) was added to a solution of tert-butyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (248.4 mg, 0.62 mmol) and di-isopropylethylamine (0.70 mmol, 0.125 mL) in 5 mL acetonitrile. The mixture was stirred at RT for 3 h. Solvent was removed to afford a residue which was dissolved in ethyl ether (15 mL), washed with water (3×2 mL) and dried over Na2SO4. The solution was filtered and concentrated to afford 281 mg of the 7-tert-butyl 5-methyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5,7-dicarboxylate.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:10]=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-Isopropoxy-benzaldehyde 14-1 (20 g, 122 mmol) in methanol (400 mL), sodium borohydride (5 g) is added in several portions at 0° C. The resulting mixture is then stirred at rt for 3 h. The reaction is quenched by addition of saturated NH4OH. Extracted (EtOAc), concentrated, a colorless oil 14-2 (MH+, 166) is obtained and use without purification. Re-dissolve (3-Isopropoxy-phenyl)-methanol 14-2 in ether (244 mL) PBr3 (11.5 mL, 122 mmol) is added dropwise at 0° C. The reaction mixture is stirred at 0° C. then rt for 3 h, quenched (MeOH), extracted (EtOAc), concentrated, a colorless oil 14-3 is obtained. (MH+, 288)
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][CH:17]2[C:20]([OH:22])=[O:21])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]O>>[CH3:23][O:21][C:20]([CH:17]1[C:18]2[C:14](=[CH:13][CH:12]=[C:11]([C:3](=[O:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)[CH2:15][CH2:16]1)=[O:22]
Reactant: CO
Reactant: O=C(c1ccccc1)c1ccc2c(c1)C(C(=O)O)CC2
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1CCc2ccc(C(=O)c3ccccc3)cc21

Procedure:
Analogously to the description in Example 2, 13 g of 6-benzoyl-indane-1-carboxylic acid methyl ester and 75 ml of 2 N sodium hydroxide solution in 500 ml of methanol give 6-benzoyl-indane-1-carboxylic acid of boiling point 200° C./0.04 mm Hg as a yellowish, viscous oil.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[C:2]#[CH:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16](Br)[CH:17]=[CH2:18]>CN(C)C=O>[CH2:18]([N:5]1[C@H:4]([CH2:1][C:2]#[CH:3])[CH2:8][O:7][C:6]1=[O:9])[CH:17]=[CH2:16]
Reactant: C#CC[C@@H]1COC(=O)N1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CC[C@@H]1COC(=O)N1CC=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled suspension of Example 153B (1 g, 7.99 mmol) and Cs2CO3 (3.91 g, 11.99 mmol) in N,N-dimethylformamide (10 mL) was added dropwise allyl bromide (1.06 g, 8.79 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (3×40 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated to give the title compound which was used without further purification. MS (ESI+) m/z 166.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[C:68]([CH:71]=[CH:72][CH:73]=1)[CH2:69][OH:70]>C(Cl)Cl>[OH:70][CH2:69][C:68]1[CH:67]=[C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])[CH:73]=[CH:72][CH:71]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1cccc(CO)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(CO)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 104 mg, 0.27 mmol) was added followed by the addition of DIPEA (80 uL,) and 3-amino benzyl alcohol (Aldrich, 80 uL). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified reverse phase HPLC (24 g column, eluent, ACN/water, 20-90) to give a white solid. 40 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][OH:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N+:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O-:9])=[CH:13][CH:12]=1
Reactant: ONc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCO
Product: [O-][N+](=Cc1ccc(Br)cc1)c1ccc(Cl)cc1

Procedure:
p-Chlorophenylhydroxylamine (0.05 moles) was dissolved in warm 95% ethanol (20 cc) and was treated with p-bromobenzaldehyde (0.05 moles) with vigorous stirring. The solid which formed was collected, washed with 95% ethanol, and was recrystallized from ethanol to give α-p-bromophenyl-N-p-chlorophenylnitrone.
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].C1(=O)O[CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>C(OC(C)C)(=O)C.O>[OH:15][CH2:16][CH2:17][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: O=Cc1cccc(O)c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=Cc1cccc(OCCO)c1

Procedure:
To a 5 L flask equipped with an internal temperature probe and a mechanical stirrer was added dimethyl sulfoxide (500 mL), 3-hydroxybenzaldehyde (100.0 g, 0.819 mol), ethylene carbonate (108 g, 1.23 mol), and potassium carbonate (136 g, 0.983 mol). The resulting mixture was stirred at 110 to 125° C. until all 3-hydroxybenzaldehyde starting material was consumed. (Additional portions of ethylene carbonate may be added to drive the reaction to completion). The reaction mixture was then cooled to below 25° C. and diluted with isopropyl acetate (1.0 L) and water (1.5 L). The mixture was stirred until the residual potassium carbonate was completely dissolved. The layers were separated and the organic layer was washed with an additional portion of water (1.5 L). Additional isopropyl acetate was added (1.0 L), and then distilled off to leave a final volume of ˜1 L of dry organic solution of 3-(2-hydroxyethoxy)benzaldehyde.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][CH:11]2[NH:15][C:14](=O)[CH2:13][CH2:12]2)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Na+].[Cl-].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH:15]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(Cc2c[nH]c3ncccc23)N1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1cnc2[nH]cc(CC3CCCN3)c2c1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A mixture of 313 mg (1.46 mM) of 5-(1H-Pyrrolo[2,3-b]pyridin-3ylmethyl)-pyrrolidin-2-one and 170 mg (4.47 mM) of lithium aluminum hydride was refluxed in 10 mL of dioxane for 5 hours. The solution was cooled to room temperature and the excess lithium aluminum hydride decomposed with 1 mL of saturate NaCl. To this mixture was added 300 mL of ethyl acetate, and 15 g of anhydrous Na2SO4. The reaction mixture was filtered, and evaporated to yield 254 mg of the amine as a dark oil, this material was used directly in the next synthetic step. Mass spectrum: m/e=202(p=1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:15][CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]>[Pd].CO>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH3:34])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:15][CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:8])([CH3:7])[CH3:9]
Reactant: C[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 97.5 %

Procedure:
A solution of 10.5 g. (14.5 mmoles) of Z-29-32-OtBu in 130 ml. of methanol is hydrogenated in the presence of 1 g. of palladium-on-carbon. When the reaction terminates, the catalyst is removed by filtration, and the filtrate is evaporated to dryness. The residue is triturated with petroleum ether. 8.35 g. (97.5 %) of H-29-32-OtBu are obtained. M.p.: 81-82°C; Rf11 = 0.1; [α]D = -24.3° (c = 1, in ethanol).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[S:33])[CH:26]=1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:32](=[S:33])[NH:31][C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: S=C=Nc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (246 mg, 1.00 mmol) and triethylamine (0.139 ml, 1.00 mmol) in tetrahydrofuran (6 ml) was added 3-pyridylisothiocyanate (0.167 ml, 1.50 mmol), the mixture was stirred at room temperature for 3 hours and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (233 mg, 61.0%) as a solid.