Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.Br[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:21]3[CH:22]=[C:23]([NH2:24])[CH:25]=[CH:26][CH:27]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1ccc2cc(-c3cccc(N)c3)ccc21
Temperature: 25 °C
Yield: 46 %

Procedure:
1-methylindole-5-boronic acid pinacol ester (0.224 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (5-60% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.059 g in 46% yield.
Reaction SMILES: ON=CC1C=CC([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12])=CC=1.C[O-].[Na+].C(Br)C=CC>O>[CH2:18]([O:17][C:15]([CH2:14][NH:13][C:11](=[O:12])[NH2:10])=[O:16])[CH3:19]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C=NO)cc1
Agent: CC=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CNC(N)=O

Procedure:
A solution of N-[4-(hydroxyiminomethyl)phenyl]-N'-ethoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of crotyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the corresponding N-[4-crotyloxyiminomethyl)phenyl]-N'-ethoxycarbonylmethylurea.
Reaction SMILES: N.[Li].C([N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([CH2:16][CH2:17][C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[C:11]1=[O:24])C1C=CC=CC=1>CO.C1COCC1>[CH3:15][C@H:14]1[NH:10][C:11](=[O:24])[C@@H:12]([CH2:16][CH2:17][C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)[CH2:13]1
Reactant: C[C@@H]1C[C@H](CCC2(C)OCCO2)C(=O)N1Cc1ccccc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1C[C@H](CCC2(C)OCCO2)C(=O)N1
Reaction time: 0.33 h

Procedure:
Into a 3-necked 500 mL flask at -78° C. was condensed 200 mL of ammonia. Lithium (64 mg, 9.25 mmol) was washed with MeOH, then THF and then added to the ammonia. After 20 minutes, 11-6 (560 mg, 1.85 mmol), dissolved in 25 mL of THF, was added. After 30 minutes, the reaction was quenched with NH4Cl; 200 mL of THF was added, the cooling bath was removed and the solution purged with argon for 30 minutes to remove the ammonia. The solution was dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc→5% MeOH/EtOAc) gave 11-7 as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([C:15]#[C:16][C:17]([O:19]CC)=O)([OH:14])[C@@H:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([SnH:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]2([O:14][C:17](=[O:19])[C:16]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15]2)[C@@H:9]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C#C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)C1=C[C@@]2(CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)OC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
A mixture of (2S,3R)-ethyl 3-(1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidin-3-yl)propynoate (Description 9, 524 mg, 1.4 mmol) and tetrakis(triphenylphosphine)palladium (0) (50 mg) in toluene (10 ml) was degassed with nitrogen for 30 min. Tributyl tin hydride (0.405 mM, 1.5 mmol) was added dropwise and the resulting mixture was stirred at 23° C. for 2 h. The solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate (50 ml). The mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound as a gum (538 mg, 0.87 mmol, 62%). 1H NMR (250 MHz, CDCl3) δ7.63 (1H, s), 7.30 (5H, m), 5.11 (1H, m, 310 (1H, m) 2.19 (1H, m), 1.80 (3H, m), 1.30-150 (12H, m), 1.40 (9H), s), 1.02 (6H), m), and 0.88 (9H), t, J 7.22 Hz), m/z (ES+) 619 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:15]O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: COC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirring solution of 3-nitrophenylacetic acid (10.4 g, 57.3 mmol) in MeOH (250 ml) at RT was added HCl gas until saturation was achieved. The resulting solution was stirred at 70° C. for 1 h. The reaction was cooled and concentrated under reduced pressure. The semisolid residue was dissolved in Et2O, washed with H2O (2×), satd. NaHCO3 (2×), brine (1×) and dried (MgSO4). Filtration and evaporation provided methyl 2-(3-nitrophenyl)acetate as a low-melting solid (10.7 g, 96% yield), which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 8.14-8.04 (m, 2H), 7.64-7.58 (m, 1H), 7.47 (brt, J=8.10 Hz, 1H), 3.72 (s, 2H), 3.68 (s, 3H); MS (ESI) m/z: 196.0 (M+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:10][C:11]([NH:13][C:14]1[S:18][N:17]=[C:16]([CH2:19][C:20]([OH:22])=O)[N:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[NH2:23][C@@H:24]1[C:40](=[O:41])[N:26]2[C:27]([C:37]([OH:39])=[S:38])=[C:28]([C:31]3[S:32][C:33]([CH3:36])=[N:34][N:35]=3)[CH2:29][S:30][C@H:25]12.C[Si](C)(C)NC(=O)C.C(=O)([O-])O.[Na+].Cl>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[C:6]([O:10][C:11]([NH:13][C:14]1[S:18][N:17]=[C:16]([CH2:19][C:20]([NH:23][C@@H:24]2[C:40](=[O:41])[N:26]3[C:27]([C:37]([OH:39])=[S:38])=[C:28]([C:31]4[S:32][C:33]([CH3:36])=[N:34][N:35]=4)[CH2:29][S:30][C@H:25]23)=[O:22])[N:15]=1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: Cc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)ns1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4nsc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)s1
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
Phosphorus oxychloride (473 μl) was added dropwise to a mixture of N,N-dimethylformamide (388 μl) and ethyl acetate (1 ml) under ice-cooling. After being stirred for 10 minutes at the same temperature, the mixture was cooled until a precipitate appeared. To the suspension was added tetrahydrofuran (17 ml). The suspension was stirred at the same temperature for 30 minutes. To the suspension was added 2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetic acid (1.0 g). The mixture was stirred at the same temperature for 30 minutes to give an activated acid solution. On the other hand, to a suspension of 7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (1.16 g) in tetrahydrofuran (17 ml) was added N-trimethylsilylacetamide (3.7 g). The suspension was stirred at 20-40° C. for 40 minutes to give a clear solution. To the solution was added the activated acid solution prepared above at -20° C. The mixture was stirred at -20~5° C. for 40 minutes. The reaction mixture was added to a mixture of ethyl acetate (100 ml), sodium hydrogen carbonate (1.59 g) and water (100 ml). To the separated aqueous solution was added ethyl acetate (100 ml). The mixture was adjusted to pH 2 with 1N-hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β-[2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (1.17 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][N:7]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[C:9]([OH:11])=[O:10]>N1C=CC=CC=1>[CH3:5][O:6][N:7]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:1](=[O:3])[CH3:2])[CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CON=C(C(=O)O)c1cccc(OC(C)=O)c1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
Acetyl chloride (4.1 g.) was added with stirring and ice-cooling to a solution of 2-methoxyimino-2-(3-hydroxyphenyl) acetic acid (syn isomer) (5 g.) in pyridine (20 ml.) and the mixture was stirred for 50 minutes at ambient temperature. The reaction mixture was poured into ice-water, adjusted to pH 2.1 and extracted three times with ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was thoroughly removed under reduced pressure to give 2-methoxyimino-2-(3-acetoxyphenyl)acetic acid (syn isomer) (6.1 g.).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27](=[O:41])[NH:28]/[C:29](=C(/OCC)\CCC)/[C:30]([NH:32][NH2:33])=O)([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][N:21]3[C:6]([CH2:8][CH2:13][CH3:12])=[N:33][N:32]=[C:30]3[CH2:29][NH:28][C:27]([O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:41])=[CH:18][CH:19]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: CCC/C(OCC)=C(\NC(=O)OC(C)(C)C)C(=O)NN
Solvent: CCO
Product: CCCc1nnc(CNC(=O)OC(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Yield: 30366.2 %

Procedure:
4′-Aminomethylbiphenyl-2-carboxylic acid t-butyl ester (1.5 g, 5.2 mmol) and [1-ethoxy-but-(E)-ylidene-hydrazinocarbonylmethyl] carbamic acid t-butyl ester (1.0 g, 3.5 mmol) were combined and dissolved in ethanol (50 mL). The mixture was heated at 50° C. for 2 hours and then 70° C. overnight. The mixture was then cooled and concentrated. The product was purified by silica gel chromatography (0-20% MeOH:DCM) to obtain intermediate (23a) (400 g). MS m/z: [M+H+] calcd for C29H38N4O4, 507.6. found 507.3.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][N:5]([S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[C@H:6]([C:31]([OH:33])=O)[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:14]([NH:22][S:23]([C:26]1[S:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].C1C([N+]([O-])=O)=CC=C(O)C=1.C1CCC(N=C=NC2CCCCC2)CC1.O.[NH2:70][NH2:71]>CCOC(C)=O.C(O)C>[CH3:3][CH:2]([CH2:4][N:5]([S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[C@H:6]([C:31]([NH:70][NH2:71])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:14]([NH:22][S:23]([C:26]1[S:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:1]
Reactant: CC(C)CN([C@@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)C(=O)O)S(=O)(=O)c1ccc(N)cc1
Reactant: NN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CN([C@@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)C(=O)NN)S(=O)(=O)c1ccc(N)cc1
Reaction time: 8 h
Yield: 30 %

Procedure:
A solution of Nα-(4-aminobenzenesulfonyl)-Nα-isobutyl-Nε-[N′α-(2-thiophenesulfonyl)-L-phenylalanyl]-L-lysine (650 mg, 1.0 mmol, example 46) dissolved in EtOAc (20 mL) was treated with p-nitrophenol (139 mg, 1.0 mmol) and DCC (206 mg, 1.0 mmol) and was left in a refrigerator overnight. Afterwards, the precipitate was filtered off through celite and the solvent evaporated. The crude residue was used without further purification. A portion of the residue (55 mg, 0.072 mmol) was added to a solution of hydrazine hydrate in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 25 mg, 30% of the desired material.
Reaction SMILES: Cl.[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C1([C@@H]2CCC[C@H]2N)C=CC=CC=1>>[CH:2]1([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Agent: N[C@@H]1CCC[C@H]1c1ccccc1
Product: N[C@@H]1CCC[C@H]1C1CCCCC1

Procedure:
By the procedure described in Example 3(A) only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of trans-2-phenylcyclopentylamine hydrochloride, M.P. 142°-143° C., the hydrochloride salt of trans-2-cyclohexylcyclopentylamine was obtained, M.P. 199°-200° C. Following the procedure of Example 1 only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of trans-2-cyclohexylcyclopentylamine hydrochloride and employing a reaction time of 38 days, the desired product was obtained, M.P. 208°-210° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:10]2[S:11][C:12]([CH3:15])=[C:13]([CH3:14])[C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl>C(O)C>[Cl:18][C:17]1[C:7]([O:6][CH2:5][C:4]([OH:20])=[O:3])=[CH:8][C:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=2[C:16]=1[Cl:19]
Reactant: CCOC(=O)COc1cc2c(C)c(C)sc2c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc2c(Cl)c(Cl)c(OCC(=O)O)cc2c1C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a mixture of 22.0 g of ethyl[(6,7-dichloro-2,3-dimethylbenzo[b]thien-5-yl)oxy]acetate and 600 ml of 95% ethanol is added 600 ml of 20% sodium hydroxide solution and the mixture is refluxed for 2 hrs. Most of the solvent is removed in vacuo to give a white slurry to which is added 600 ml of a 6N hydrochloric acid. After stirring for about 3 hrs, the mixture is filtered. The solid is taken up in 1:1-ethyl acetate-ethyl ether. The organic layers are washed, dried and filtered and the solvent is removed to give a solid. Recrystallization from acetone-hexane gives 17.1 g of [(6,7-dichloro-2,3-dimethylbenzo[b]thien-5-yl)oxy]acetic acid, mp 218°-219°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCCCCCNCc1ccc(F)c(C(=O)OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of methyl 2-fluoro-5-[(hexylamino)methyl]benzoate in DCM (13 mL) were added 4-bromobenzenesulfonyl chloride (200 mg; 0.79 mmol) and TEA (0.13 mL; 0.94 mmol). The reaction mixture was stirred at room temperature for 2 hours under N2 atmosphere. The mixture was poured into a saturated solution of NaHCO3 and extracted with DCM (2×100 mL). The combined organic layers were then washed with a saturated solution of NH4Cl (150 mL) and with brine (150 mL), dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (c-Hex/EtOAc, 95:5) gave 96 mg (25%) of the title compound as a colorless oil. HPLC, Rt: 5.13 min (purity=99.1%). LC/MS: M+(ESI): 486.23; 1H NMR (CDCl3) δ: 7.78 (m, 1H), 7.72 (m, 4H), 7.55 (m, 1H), 7.12 (m, 1H), 4.31 (s, 2H), 3.93 (s, 3H), 3.09 (t, J=7.5 Hz, 2H), 1.85 to 1.05 (m, 8H), 0.81 (t, J=6.9 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:19])[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:19])[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1
Reactant: CCC(=O)N(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCC(=O)N(C)C1CCNCC1
Yield: 60 %

Procedure:
31 g of the amine obtained in Stage B are hydrogenated in 350 ml of ethanol with 1 g of palladium hydroxide at atmospheric pressure and room temperature. The mixture is filtered and evaporated to yield the desired product in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:20][C@H:21]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)=[N:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[OH:19])=[N:9]2)=[CH:4][CH:3]=1.[OH:33][C:34]1C=CC=[CH:36][C:35]=1C1N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)C2C(=CC=C(C#CCO)C=2)N=1>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([OH:19])=[C:12]([C:8]2[N:7]=[C:6]([NH:20][C@H:21]3[CH2:25][CH2:24][NH:23][CH2:22]3)[C:5]3[C:10](=[CH:11][C:2]([CH2:36][CH2:35][CH2:34][OH:33])=[CH:3][CH:4]=3)[N:9]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3cc(F)ccc3O)nc3cc(Br)ccc23)C1
Product: OCCCc1ccc2c(N[C@H]3CCNC3)nc(-c3cc(F)ccc3O)nc2c1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 59 and 60, replacing (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate with (S)-tert-butyl 3-(7-bromo-2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate in Synthesis 59-A.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[Cu][C:13]#[N:14]>CN1C(=O)CCC1>[Cl:11][C:4]1[N:3]=[C:2]([C:13]#[N:14])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Product: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 0.67 h
Yield: 44.5 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (6.00 g, 31.1 mmol) in NMP (23.0 mL) was added copper(I) cyanide (3.06 g, 34.2 mmol) at room temperature. After stirred for 40 min at 180° C., the reaction mixture was cooled to room temperature, and then poured into ice water. After stirring for 10 min, the mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=10:1) to give 6-chloro-3-nitropicolinonitrile (2.54 g, 44%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.79 (1H, d, J=8.4 Hz), 8.58 (1H, d, J=8.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:34]1([CH2:40][C@H:41]2[CH2:46][O:45][CH2:44][CH2:43][NH:42]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(Cl)Cl>CN(C=O)C>[CH2:40]([C@H:41]1[CH2:46][O:45][CH2:44][CH2:43][N:42]1[CH2:20][C:18]1[S:17][C:13]2[N:14]([CH3:16])[CH:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[C:11](=[O:22])[C:12]=2[CH:19]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Reactant: c1ccc(C[C@H]2COCCN2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOC[C@@H]3Cc3ccccc3)sc21
Temperature: 90 °C
Yield: 58.4 %

Procedure:
N-(4-Chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 1, 100 mg) and diisopropylethylamine (0.13 mL) is added to a mixture of (S)-3-(phenylmethyl)morpholine (93 mg, prepared as described by Shawe, T. T. Syn. Comm. 1997,27,1777-1782) in DMF (5 mL). The mixture is heated at 90° C. for 3 hours. After cooling to room temperature, the solution is poured into CH2Cl2 (125 mL) and washed with water (2×100 mL). The organic layer is dried (Na2SO4) and the solution filtered. Evaporation of the solvent gives a residue which is purified by column chromatography (methanol/CH2Cl2, 0-6%) to obtain 80 mg of the title compound. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 10.61, 8.71, 7.41-7.20, 4.54, 4.20, 3.96, 3.91, 3.59, 3.41, 3.20, 2.89, 2.82-2.66, 2.40; MS (ESI+) m/z 522 (M+H).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[NH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.Cl>O>[C:10]1([C:8]2[CH:7]=[N:6][C:2](=[O:1])[N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#C[O-]
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C1N=CC(c2ccccc2)=N1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Potassium cyanate (2.00 g, 24.7 mmol) was added in portions, over 15 min, to a stirred solution of 2-aminoacetophenone hydrochloride (3.85 g, 22.4 mmol) in water (130 mL) at 70° C., while the pH of the solution was maintained at pH 1 to 3 by addition of conc. hydrochloric acid. The reaction mixture was stirred at 70° C. for 4 h, then allowed to cool to ambient temperature and stood for 18 h. The title compound was isolated by filtration. MS: m/z=161 (M+1).
Reaction SMILES: C([Si](C(C)(C)C)(C1C=CC=CC=1)[O:6][CH2:7][CH:8]([CH3:38])[O:9][C:10]1[CH:11]=[C:12]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][CH2:25][OH:26])[CH2:22][N:23]=1)=[CH:15]2)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].CO>O1CCCC1.CCCCCC.C(OCC)(=O)C>[OH:26][CH2:25][CH2:24][CH:21]1[S:20][C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:27][C:28]2[CH:29]=[CH:30][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:32][CH:33]=2)=[CH:11][C:10]=3[O:9][CH:8]([CH3:38])[CH2:7][OH:6])=[N:23][CH2:22]1
Reactant: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
2-(2-{7-(2-{[Di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl)ethanol (270 mg) was dissolved in tetrahydrofuran (2 mL), tetrabutylammonium fluoride (0.6 mL) was added, and the mixture was stirred at room temperature for 18 hr. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (methanol:ethyl acetate:hexane=0:20:80 to 5:95:0, volume ratio) to give the title compound (117 mg, yield 65%) as a white solid. The obtained white solid was recrystallized from ethyl acetate-diethyl ether to give colorless crystals. melting point 165-169° C. MS 491 (MH+).