Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[OH:16][C:17]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)C>[CH2:23]([C:17]1([OH:16])[CH2:22][CH2:21][N:20]([CH:2]([CH3:15])[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)=[O:4])[CH2:19][CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CC(Cl)C(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C(=O)c1ccc2c(c1)CC(=O)N2)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
5-(2-Chloropropionyl)-2(1H,3H)-indolone (2.5 g, 11.2 mmol), 4-hydroxy-4-benzylpiperidine (2.1 g, 11.2 mmol), and triethylamine (1.56 ml, 11.2 mmol) were combined in ethanol and refluxed overnight. The mixture was cooled to room temperature and concentrated at reduced pressure. The residue was partitioned between ethyl acetate and water and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over calcium sulfate, and concentrated. The crude product was flash chromatographed on silica gel eluting first unreacted 5-(2-chloropropionyl) -2(1H,3H)-indolone with 1:1 ethyl acetate:hexane. Continued elution with ethyl acetate gave 3.6 g of product as a light brown foam. Recrystallization from ethyl acetate/hexane gave 1.23 g of purified title product. Less pure fractions from the column and mother liquors from the recrystallization were rechromatographed as above with 1:1 and then 3:1 ethyl acetate:hexane. Product fractions were triturated with ether/hexane to give 0.2 g more product for a total yield of 1.43 g, 34%; m.p. 188°-192° C.; NMR 8.22 (s, 1H), 8.08 (d, J=8 Hz, 2H), 7.99 (s, 1H), 7.31-7.13 (m, 5H), 6.89 (d, J=8 Hz, 1H), 4.03 (q, J=6.8 Hz, 1H), 3.57 (s, 2H), 2.72 (s, 2H), 2.72-2.58 (m, 3H), 2.46 (distorted t, 1H), 75-1.40 m, 4H), 1.26 (d, J=6.8 Hz, 3H), 1.23-1.19 (m, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[C:23]([OH:25])=O.[CH:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH:27]1[NH2:36])[CH2:33]2>ClCCl>[CH:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH:27]1[NH:36][C:23]([C:14]1[CH:15]=[N:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=1)=[O:25])[CH2:33]2
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnc2ccccc2n1
Yield: 35.4 %

Procedure:
Prepared from 1,1′-carbonyldiimidazole (161 mg, 1.00 mmol), 2-quinoxalinecarboxylic acid (174 mg, 1.00 mmol), 2-adamantanamine (136 mg, 0.90 mmol), and dichloromethane (3.5 mL) yielding 98 mg (35%) of (144):
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH2:22])[CH2:19]2)=[N:14]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]([NH:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)=[O:32].[Na+].[I-]>CN(C=O)C.CCOC(C)=O>[F:40][C:38]1[CH:39]=[C:34]([NH:33][C:31](=[O:32])[CH2:30][NH:22][CH:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][N:13]([C:6]4[C:5]5[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=5)[N:9]=[CH:8][CH:7]=4)[N:14]=3)[CH2:19]2)[CH:35]=[C:36]([F:41])[CH:37]=1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Reactant: O=C(CCl)Nc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCC(=O)Nc3cc(F)cc(F)c3)C4)c2n1
Temperature: 50 °C
Reaction time: 15 h
Yield: 64.6 %

Procedure:
To a solution of 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (30 mg, 0.1 mmol) in DMF (1 mL) were added K2CO3 (40 mg, 0.3 mmol) and 2-chloro-N-(3,5-difluoro-phenyl)-acetamide (20 mg, 0.1 mmol), and the mixture was stirred for 15 h. A catalytic amount of NaI was added and the mixture heated at 50° C. for 15 h. The mixture was diluted with EtOAc (25 mL), washed with brine (4×10 mL), dried (MgSO4) and concentrated. The resulting residue was purified on SiO2 (0-5% CH3OH/CH2Cl2) to provide 30 mg (64%) of the title compound as a pale yellow solid. MS (ESI): exact mass calculated for C24H22F2N6O2, 464.18; m/z found, 465.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.30 (br s, 1H), 9.08 (s, 1H), 8.76 (d, J=9.2, 1H), 8.24 (d, J=5.9, 1H), 8.19 (d, J=5.1, 1H), 7.15 (d, J=9.1, 1H), 6.93-6.87 (m, 2H), 6.26 (tt, J=8.9, 2.3, 1H), 3.89 (s, 3H), 3.59 (d, J=17.7, 1H), 3.36 (d, J=17.7, 1H), 3.26-3.23 (m, 1H), 3.08-3.02 (m, 1H), 2.93-2.85 (m, 2H), 2.62 (dd, J=15.7, 5.7, 1H), 2.12-2.08 (m, 1H), 2.00-1.96 (m, 1H).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]1[CH2:10][O:9][CH2:8][CH2:7]1>>[CH3:2][CH:3]([C:4]#[CH:5])[CH2:8][O:9][CH2:10][C:6]1[CH:7]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Product: C#CC(C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of BuLi (4.32 ml, 6.92 mmol) (1.6M in hexanes) was added dropwise to a stirred solution of the dibromo alkene (above, 1.1 g, 3.29 mmol) in dry THF (15 ml) under N2, such that the internal temperature <−70° C. The reaction was stirred at this temperature for 30 minutes and then quenched with saturated aqueous ammonium chloride (1 ml) before being allowed to warm to RT. The mixture was partitioned between diethyl ether and water. The aqueous layer was extracted with diethyl ether (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 1-4% Et2O/isohexane) to give the alkyne (0.55 g) as a colourless liquid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](Cl)=[O:28])[CH:23]=[CH:24][CH:25]=1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([CH:3]2[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCOCC1
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(CC(=O)C2COCCC2=O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
Tetrahydro-4H-pyran-4-one (0.138 mL, 1.50 mmol) was dissolved in toluene (1 mL) and cooled to 0° C. LHMDS (1.573 mL, 1.57 mmol) was added. 3-Methoxyphenylacetyl chloride (0.117 mL, 0.75 mmol) was added after 2 minutes. After 5 minutes, acetic acid (0.129 mL, 2.25 mmol) and water was added. The organic phase was separated and the crude product was purified by flash column chromatography (EtOAc 0-40% in heptane) yielding 3-(2-(3-methoxyphenyl)acetyl)dihydro-2H-pyran-4(3H)-one (86 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.Cl.[F:13][CH2:14][CH2:15][NH2:16]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:16][CH2:15][CH2:14][F:13])[S:8][C:4]=2[CH:3]=1
Reactant: NCCF
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: Cl
Solvent: CO
Product: FCCNc1nc2ccc(Br)cc2s1
Temperature: 120 °C
Yield: 54.5 %

Procedure:
A mixture of 6-bromo-2-chlorobenzo[d]thiazole (248 mg, 1 mmol), 2-fluoroethanamine hydrochloride (200 mg, 2 mmol), and TEA (303 mg, 3 mmol) in 3 mL MeOH was heated at 120° C. in a microwave reactor for 20 min. After cooling to rt, the mixture was concentrated and chromatographed (6% to 60% EtOAc in hexane) to afford 6-bromo-N-(2-fluoroethyl)benzo[d]thiazol-2-amine as a white solid (150 mg, 54%). MS (ESI) m/z 276.9 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH:18]1[CH2:23][CH2:22][C:21]([N:30]([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[Si]([Cl:37])(C)(C)C>C(OCC)(=O)C>[ClH:37].[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH:18]1[CH2:19][CH2:20][C:21]([N:30]([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)OCCCCc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
4-(2-(4-(Dimethylamino)-4-phenylcyclohexyl)-1H-indol-3-yl)butyl acetate (non-polar diastereomer) (234 mg, 0.54 mmol) was dissolved in ethyl acetate (50 ml). Me3SiCl (136 μl, 1.08 mmol) was then added dropwise at RT. The mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 178 (155 mg, m.p. 238-241° C., 61%, NMR purity <95%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH:16]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[NH2:18][CH:19]1[CH2:23][N:22]([C:24]2[CH:25]=[CH:26][C:27]3[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[C:21](=[O:35])[CH2:20]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH2:16][NH:18][CH:19]3[CH2:20][C:21](=[O:35])[N:22]([C:24]4[CH:25]=[CH:26][C:27]5[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:23]3)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1
Reactant: COc1cnc2ccc(=O)n(CCC=O)c2n1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cnc2ccc(=O)n(CCCNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2n1
Temperature: 25 °C
Reaction time: 13 h
Yield: 29.3 %

Procedure:
3-(3-Methoxy-6-oxopyrido[2,3-b]pyrazin-5(6H)-yl)propanal (292 mg, 1.25 mmol) and 6-(4-amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 310 mg, 1.25 mmol) were dissolved in a mixed solvent (33 ml) of dichloromethane/N,N-dimethylformamide (10:1). Acetic acid (0.143 ml, 2.50 mmol) and anhydrous sodium sulfate (600 mg) were added to the solution and the mixture was stirred at room temperature for 13 hours. Sodium triacetoxyborohydride (531 mg, 2.50 mmol) was added to the reaction solution, the mixture was stirred for 4 hours and the solvent was removed under reduced pressure. A lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue, the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice and extracted with a lower layer solvent of chloroform/methanol/water (7:3:1). After drying the extract with anhydrous sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 170 mg (29%) of the title compound in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1)#[CH:2].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1>C(N(CC)CC)C.C(OCC)C.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.[Cu]I>[CH3:13][O:12][C:11]1[C:4]2[C:3]([C:1]#[C:2][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[CH:7][S:6][C:5]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C#Cc1csc2cccc(OC)c12
Reactant: Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cccc2scc(C#Cc3ccc(C)cc3)c12

Procedure:
3-Ethynyl-4-methoxybenzo[b]thiophene (0.15 g) was dissolved in triethylamine (10 mL). To the solution were added 4-bromotoluene (0.11 mL), tetrakis(triphenylphosphine)palladium (0) (92 mg) and copper (I) iodide (30 mg), and the mixture was heated for ref lux under an argon atmosphere for 10 hours. The reaction mixture was diluted with diethyl ether, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=50/1) to give 4-methoxy-3-[2-(4-methylphenyl)ethynyl]benzo[b]thiophene (27 mg). This material was dissolved in ethanol (1.5 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4-methoxy-3-[2-(4-methylphenyl)ethyl]-benzo[b]thiophene (27 mg). This material was dissolved in dichloromethane (1.5 mL). To the solution was added boron tribromide (0.011 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. Then the mixture was stirred under ice-cooling for 1 hour. The reaction mixture poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=15/1) to give the title compound (10 mg).
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH3:38])[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH3:38])[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: COc1cc(C(N)CC(=O)O)ccc1OCc1ccccc1
Product: COC(=O)CC(N)c1ccc(OCc2ccccc2)c(OC)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-methoxy-4-benzyloxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 7.26-7.44 (m, 5H), 6.75-6.94 (m, 3H), 5.13 (s, 2H), 4.35 (t, 1H, J=5 Hz), 3.89 (s, 3H), 3.61 (s, 3H), 2.59 (d, 2H, J=5 Hz), 1.84 (d, 2H, J=5 Hz)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCCc1ccc2c(c1)OCO2
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCc1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 1-acetoxy-2-[(3,4-methylenedioxy)-phenyl]ethane (1.7 g, 8.09 mmol) in acetic acid (10 ml) was added, dropwise, concentrated HNO3 (4.5 ml). This was stirred at room temperature for 30 min. The reaction mixture was poured into water (100 ml). The precipitated solid was filtered, washed with water and dried under high vacuum to get 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane (1.8 g, 88% yield).
Reaction SMILES: F[C:2]1C(N)=NC(N)=NC=1.[OH:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].IC>>[OH:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([O:15][CH3:2])=[O:14]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: Nc1ncc(F)c(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])ccc1O
Yield: 77 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-methoxy-4-methoxycarbonyl)phenyl)-5-fluoro-2,4-pyrimidinediamine, 2-hydroxy-5-nitrobenzoic acid (1 g, 5.5 mmol), potassium carbonate (3 g, 22 mmol) and iodomethane (1 mL, 16 mmol) gave methyl 2-hydroxy-5-nitrobenzoate (880 mg, 77%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:12]([O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)([CH3:15])([CH3:14])[CH3:13].[BH4-].[Na+]>CC#N>[C:12]([O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:11][CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)Oc1ccccc1C=O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
N-Boc-ethylenediamine (2.6 g, 16 mmol) and 8 (2.9 g, 16 mmol) were added to 250 mL of CH3CN and the reaction mixture was refluxed under argon for 4 hr. After cooling down to room temperature, the solvent was removed and the residue was redissolved in MeOH. The solvent was then evaporated and NaBH4 (3 g, 16 mmol) was added and stirred overnight. The solvent was evaporated, followed by extraction with CH2Cl2. The CH2Cl2 extract was concentrated and purified by a silica gel column using 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2 as eluent to yield the desired product as a pale yellow oil (97%). 1H NMR (CDCl3) δ 7.204 (dd, 1H, Ar), 7.115 (ddd, 1H, Ar), 7.007 (dd, 1H, Ar), 6.930 (ddd, 1H, Ar), 3.718 (s, 2H, —CH2—), 3.175 (d, 2H, —CH2—), 2.638 (t, 2H, —CH2—), 1.402 (s, 9H, —C(CH3)3), 1.382 (s, 9H, —C(CH3)3). Mass Spect.=323.23 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=[C:15]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=[C:15]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1
Reactant: CCOC(=O)CCc1cc(CCNC(=O)OC(C)(C)C)cc(Cc2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1cc(CCN)cc(Cc2cccnc2)c1
Yield: 72.1 %

Procedure:
A solution of ethyl 3-[3-(2-t-butoxycarbonylaminoethyl)-5(3-pyridylmethyl)phenyl]propanoate (Preparation 39; 4.10 g) and trifluoroacetic acid (4.1 ml) in dry dichloromethane (41 ml) was stirred for 6 hours, additional 4.1 ml portions of trifluoroacetic acid being added after 2 and 5 hours. The solution was evaporated under vacuum and the residue basified with aqueous sodium bicarbonate solution. The mixture was extracted several times with dichloromethane and the combined extracts were dried (MgSO4) and evaporated under vacuum. Water (ca 75 ml) was added and this mixture was acidified to pH 4 with glacial acetic acid and then extracted several times with ethyl acetate. The aqueous layer was basified with aqueous ammonia solution (SG 0.880) and extracted several times with dichloromethane. The combined dichloromethane extracts were washed with water, dried (MgSO4) and evaporated under vacuum to give the title compound as an oil (2.24 g); Rf 0.10 (SS 2); δ (CDCl3): 1.07(2H,br), 1.20(3H,t,J=7.1 Hz), 2.56(2H,t,J=7.8 Hz), 2.66(2H,t,J=6.9 Hz), 2.85-2.93(4H,m), 3.90(2H,s), 4.09(2H,q,J=7.1 Hz), 6.84 (2H,s), 6.88(1H,s), 7.16-7.20(1H,m), 7.43(1H,d,J=7.8 Hz), 8.43-8.47(2H,m).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+]>C(O)CCCC>[NH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCO
Product: NC1CCCCNC1=O
Temperature: 137 °C

Procedure:
30 mmols of L-lysine hydrochloride 1 is neutralized with 30 mmols of NaOH and then 270 mmols of Al2O3 is added, followed by 120 ml of 1-pentanol. This mixture is heated to 137° C. and is refluxed for four hours. The yield of α-amino-ε-caprolactam 2 produced by this reaction is about 96%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:29]=[CH:28][C:26]([NH:27][C:14]([C@@H:9]3[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Proceeding as in Reference 5, but substituting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid and 4-(4-fluorophenoxy)aniline, gave (2S,4R)-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][CH2:46][C:47]([NH:49][C@@H:50]([C:55]([NH:57][C@H:58]([C:61]([NH:63][C@H:64]([C:69]([O:71]C(C)(C)C)=[O:70])[CH2:65][C:66](=[O:68])[NH2:67])=[O:62])[CH2:59][OH:60])=[O:56])[CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])[CH3:11])=[O:8].FC(F)(F)C(O)=O.Cl.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)O.NCC(O)=O.N[C@H](C(O)=O)C.N[C@H](C(O)=O)CC(C)C>O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][CH2:46][C:47]([NH:49][C@@H:50]([C:55]([NH:57][C@H:58]([C:61]([NH:63][C@H:64]([C:69]([OH:71])=[O:70])[CH2:65][C:66](=[O:68])[NH2:67])=[O:62])[CH2:59][OH:60])=[O:56])[CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH3:11])=[O:8]
Reactant: CC(C)C[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Agent: CC(C)C[C@H](N)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)C[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O

Procedure:
450 mg of pGlu-Ala-Lys(Boc)-Ser-Gln-Gly-(D)-Leu-Ser-Asn-OBut is treated with 5 ml of trifluoroacetic acid at room temperature for 40 minutes and the reaction product is purified as in Example 1-(VIII). Yield 260 mg (58%); [α]D23 -40.0° (c=0.31, H2O); Rf4 (Avicel)=0.23, amino acid analysis (hydrolyzed with HCl); Lys, 0.95(1); Asp, 0.92(1); Ser, 1.79(2); Glu, 2.05(2); Gly, 1.01(1); Ala, 1.05(1); Leu, 1.05(1); average recovery 81%.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:35][C:36]2[CH:41]=[CH:40][N:39]=[CH:38][C:37]=2[C:42]([OH:44])=[O:43])=[N:14][C:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:19]=2)=[N:16][CH:17]=1)(C(C)(C)C)(C)C.[ClH:45]>O1CCOCC1>[ClH:45].[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([C:15]2[N:14]=[C:13]([NH:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][C:37]=3[C:42]([OH:44])=[O:43])[C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][N:16]=2)=[N:19]1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)ncc1OCCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
183 mg of 4-({5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]pyrimidin-4-yl}amino)pyridine-3-carboxylic acid (derived from 30-3 as SM via step 1 of the procedure described in 13-1 and subsequent ester hydrolysis) 0.297 mmol, 1. eq.) were dissolved in 10 ml of 4 M hydrogen chloride solution in dioxane and stirred at room temperature for 24 hours. The precipitate was filtered off, washed with dichloromethane and the filter cake was dried under vacuo to yield 157 mg (0.26 mmol, 88.4%) of the analytically pure target compound.