Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[C:13](O)[CH:14]=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1.CC1C=CC(S([O:30][CH2:31][C@@H:32]2[O:34][CH2:33]2)(=O)=O)=CC=1.O>CN(C)C=O>[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:30][CH2:31][C@H:32]4[CH2:33][O:34]4)=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: Oc1cccc(-c2noc3cc(F)ccc23)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a cold (0° C.) solution of sodium hydride (1.80 g, 45.0 mmol) in dimethylformamide (anhydrous,40 mL) and under a nitrogen atmosphere, add dropwise a solution of 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol (10 g, 43.63 mmol) in dimethylformamide (anhydrous, 50 mL). Precipitate forms. Cool (0° C.) reaction mixture for 20 minutes and the material solidifies. Add dimethylformamide (anhydrous, 120 mL) and (2R)-(−)-glycidyl tosylate (10.47 g, 45.87 mmol) dissolved in dimethylformamide (40 mL), dropwise, over a period of time of 0.5 hours, while cooling with an ice bath. After this addition, the reaction mixture becomes homogeneous. Warm reaction mixture to room temperature and stir overnight. Pour reaction mixture into cold water (600 mL), stir for 1 hour under an ice bath, filter and wash the filter cake with water to obtain an off-white solid. Add dichloromethane (200 mL) to the off-white solid, wash with saturated sodium chloride and dry (MgSO4). Directly purify by column (silica) chromatography (dichloromethane) and triturate with pentane to give the title compound as an off-white solid (9.70 g, 78% Yield). MS shows [M+H]+=286. NMR and microanalysis (C, H, N) are consistent with the final, desired compound. mp=132-133° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([O:17][C:15](=[O:16])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: CCOC(=O)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C(=O)OCC)(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.7 %

Procedure:
Sodium hydride (520 mg) was dissolved in THF (7 ml), and the solution was cooled to 0° C. and thereto were added diethyl 2-phenylmalonate (2.36 g) and tetrabutyl ammonium iodide (6 mg). The resulting mixture was stirred at room temperature for 0.5 hour and ethyl 3-bromopropionate (1.3 g) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through a Celite, and the filtrate was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:7) to give 2-ethoxycarbonyl-2-phenylpentanedioic acid diethyl ester (2.65 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].[H-].[Na+]>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:12]=[C:11]([S:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[N:10]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(-c2nc(SCc3cccnc3)[nH]c2-c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1c(SCc2cccnc2)nc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1

Procedure:
Starting substances: 500 mg (1.2 mmol) of T70 from Example 31; 270 mg (1.6 mmol) of ethyl bromoacetate; 72 mg (3 mmol) of NaH
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.C(N1CCOCC1)C.CP(OP(CC)(C)=O)(CC)=O.[C:28](NCC(O)=O)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CN(C=O)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:1][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH3:7]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)CN
Agent: CCN1CCOCC1
Agent: CCP(C)(=O)OP(C)(=O)CC
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
At 0° C., 7.0 g (0.05 mol) of H-Gly-OC2H5.HCl, 15 ml of N-ethyl morpholine and 20 g of methylethylphosphinic acid anhydride were added successively to a solution of 10.5 g (0.05 mol) of carbobenzoxy-glycine in 20 ml DMF, while stirring and cooling thoroughly. The mixture was brought to room temperature, while stirring. After 16 hours of standing at room temperature the solvent was distilled off in vacuo, and the residue was dissolved in a mixture of 200 ml of ethyl acetate and 100 ml of a 5% potassium bisulfate solution. The ethyl acetate solution was washed twice with 100 ml each of saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].C([O-])([O-])=O.[K+].[K+].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.[C:40]([O:44][C:45]([NH:47][C@@H:48]([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C@@H:49]([OH:76])[CH2:50][CH:51]([NH:65]C(=O)OCC1C=CC=CC=1)[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][N:60]=2)=[CH:55][CH:54]=1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(OCC)(=O)C>[CH2:77]([C@H:48]([NH:47][C:45](=[O:46])[O:44][C:40]([CH3:42])([CH3:41])[CH3:43])[C@@H:49]([OH:76])[CH2:50][CH:51]([NH:65][C:7](=[O:9])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][N:60]=2)=[CH:55][CH:54]=1)[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CC(Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)NC(Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoic acid (Degussa, 8.74 g, 46.18 mmol, 1.1 equivalents), K2CO3 (11.60 g, 83.96 mmol, 2equivalents), DEPBT (15.08 g, 50.38 mmol, 1.2 equivalents) in ethyl acetate (400 mL) was stirred at room temperature under N2 for 1 hour, treated with the product of Example 111-11 (20 g, 41.98 mmol) and stirred at room temperature under N2 for 24 hrs. The reaction mixture was washed with H2O (200 mL), 10% NaHCO3 (200 mL), and H2O (2×200 mL). The organic layer was concentrated, and the residue charged with ethyl acetate (30 mL), heated to 70° C. for 1 hr, added heptanes (120 mL) dropwise, stirred at 70° C. for 30 minutes, cooled to room temperature overnight. The slurry was filtered and washed with 100 mL of 1:1 heptane/ethyl acetate, and dried in 50° C. vacuum oven overnight to give the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=[N:21]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].Br[C:35]1[C:36]([CH3:41])=[N:37][NH:38][C:39]=1[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:35]3[C:36]([CH3:41])=[N:37][NH:38][C:39]=3[CH3:40])[CH:22]=[N:21]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: Cc1n[nH]c(C)c1Br
Reactant: CC(C)NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]c(C)c1-c1cnn(C2(CC#N)CN(c3cnc(C(=O)NC(C)C)cn3)C2)c1
Temperature: 53 °C
Yield: 42 %

Procedure:
A mixture of 5-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide (256 mg, 0.567 mmol, from Example 2, step 2), 4-bromo-3,5-dimethyl-1H-pyrazole (119 mg, 0.681 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (67 mg, 0.085 mmol) and cesium carbonate (550 mg, 1.7 mmol) in 1,4-dioxane (2 mL)/water (1 mL) was purged with nitrogen three times. The reaction was heated to 53° C. for 2 h. The mixture was diluted with EtOAc, washed with brine, concentrated. The resulting reside was purified first on silica gel (eluting with 0-100% EtOAc/hexanes followed by 10% methanol/dichloromethane), and then by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.1 g, 40%). 1H NMR (500 MHz, DMSO-d6) δ 8.64 (1H, d, J=1.5 Hz), 8.12 (1H, s), 8.06 (1H, d, J=8.0 Hz), 7.96 (1H, d, J=1.0 Hz), 7.71 (1H, s), 4.72 (2H, d, J=9.5 Hz), 4.49 (1H, d, J=9.5 Hz), 4.08 (1H, m), 3.68 (2H, s), 2.22 (6H, s), 1.16 (6H, d, J=6.5 Hz) ppm. LCMS calculated for C21H26N9O (M+H)+: m/z=420.2. Found: 420.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.Cl.[NH2:14][C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27](=[O:40])[C@@H:28]([CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH2:39])=[N:35][N+:36]([O-:38])=[O:37])[NH2:29])=[CH:21][CH:20]=1)=[O:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:26][C:27](=[O:40])[C@@H:28]([CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH2:39])=[N:35][N+:36]([O-:38])=[O:37])[NH:29][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])=[CH:23][CH:24]=1)=[O:16]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)c2cc3ccccc3[nH]2)cc1
Yield: 20 %

Procedure:
Prepared analogously to Example 69a) from 1H-indole-2-carboxylic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 20% of theory.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:17][C:18]1[C:30]([Cl:31])=[C:29]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:28]=[C:27]2[C:19]=1[C:20]1[C:25]([CH2:37][CH2:38]O)([CH2:26]2)[CH2:24][CH2:23][C:22](=[O:40])[CH:21]=1>O1CCCC1>[C:1]([O:4][CH2:38][CH2:37][C:25]12[CH2:24][CH2:23][C:22](=[O:40])[CH:21]=[C:20]1[C:19]1[C:27](=[CH:28][C:29]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[C:30]([Cl:31])[C:18]=1[Cl:17])[CH2:26]2)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: O=C(O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCO)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)OCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reaction time: 0.5 h

Procedure:
A solution of dry tetrahydrofuran (50 ml) containing acetic acid (6.6 mg, 11 mMole) is treated with 1,1'-carbonyldiimidazole (178 mg; 11 mMole) and the mixture stirred under anhydrous conditions for 30 minutes. {[5,6-Dichloro-9a-(2-hydroxyethyl)-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-7-yl]oxy}acetic acid (3.71 g, 10 mMole) is added and the mixture stirred for 16 hours. The solvent is removed by evaporation at reduced pressure. The residue is dissolved in methylene chloride, treated with 11 mM of HCl, washed with water, and dried over MgSO4. The solvent is removed by evaporation at reduced pressure to give the desired product which is recrystallized from acetonitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>ClCCl.CO.C[O-].[Na+]>[NH:1]1[CH2:2][CH:3]=[C:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1=CCNCC1
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1=CCNCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 1,2,3,6-tetrahydro-4-pyridinecarboxylate (44.7 g, 234 mmol) in dichloromethane (200 mL) was treated with aqueous K2CO3 (saturated) and the phases were separated. The aqueous layer was dried under reduced pressure and the residue was triturated with dichloromethane (100×3 mL) and dissolved in methanol (100 mL). The solution was treated with a saturated solution of NaOH (10 g, 250 mmol) in methanol (250 mL) and sodium methoxide in methanol (0.5M, 200 mL, 100 mmol). After stirring at room temperature for two days, the mixture was concentrated under reduced pressure. The residue was triturated with methanol (200×5 mL) and dried under reduced pressure to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 6.60 (m, 1H), 3.38 (m, 2H), 2.88 (m, 2H), 2.30 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([N:12]3[CH2:27][CH2:26][C:14]4([CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)[CH2:13]3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]1([N:7]2[C:11]([N:12]3[CH2:27][CH2:26][C:14]4([CH2:15][CH2:16][NH:17][CH2:18]4)[CH2:13]3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3nnnn3-c3ccccc3)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-n2nnnc2N2CCC3(CCNC3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 7-(1-phenyl-1H-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg) was dissolved in 10% TFA solution in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 24 hours. After removal of solvents, the residue, crude 2-(1-phenyl-1H-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane, was used in the further reactions without purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([C@@H:23]([OH:25])[CH3:24])=[CH:19][C:18]=4[Cl:26])[CH2:13][C@H:12]3[CH3:27])[NH:7][C:6]=2[CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.BrC1C2N=C(N3CCN(C4N=CC([C@H](O)C)=CC=4Cl)C[C@H]3C)NC=2C=C(C(F)(F)F)C=1.[F:63][C:64]1[CH:65]=[C:66](B(O)O)[CH:67]=[C:68]([F:71])[C:69]=1[F:70]>>[Cl:26][C:18]1[CH:19]=[C:20]([C@@H:23]([OH:25])[CH3:24])[CH:21]=[N:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:8]2[NH:9][C:10]3[C:2]([C:66]4[CH:65]=[C:64]([F:63])[C:69]([F:70])=[C:68]([F:71])[CH:67]=4)=[CH:3][C:4]([C:28]([F:31])([F:29])[F:30])=[CH:5][C:6]=3[N:7]=2)[C@H:12]([CH3:27])[CH2:13]1
Reactant: C[C@H](O)c1cnc(N2CCN(c3nc4c(Br)cc(C(F)(F)F)cc4[nH]3)[C@H](C)C2)c(Cl)c1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: C[C@@H]1CN(c2ncc([C@@H](C)O)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Product: C[C@H](O)c1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)[C@H](C)C2)c(Cl)c1

Procedure:
The diastereoisomeric mixture of (1S)-1-{6-[(3R)-4-(4-bromo-6-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-ethanol and (1R)-1-{6-[(3R)-4-(4-bromo-6-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-ethanol (416 mg, 0.8 mmol, Example 166a) reacted with 3,4,5-trifluorophenylboronic acid (282 mg, 1.6 mmol, Lancaster) under the conditions of Example 158 to give the title compound as a mixture of diastereoisomers. Separation of the mixture by preparative HPLC on a Chiralcel OD column, eluting with 9:1 hexane/EtOH afforded the fast running title compound. The configuration (1S) was assigned at random. (ESI, neg. ion) m/z: 570 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH2:7].[C:11]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH:7][CH:11]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCN(CCN)CCN
Reactant: O=C1CCCCCCCCCCCCCC1
Product: NCCN(CCN)CCNC1CCCCCCCCCCCCCC1

Procedure:
Following the general procedure of Example 33, but starting with tris-(2-aminoethyl)amine and cyclopentadecanone, the title compound is produced; IR (liquid film) 3361, 3287, 2928, 2857, 2810, 1460, 1350, 1282, 1116, 1043, 893, 843, 711. (PLA2)
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)=[O:14].C(O)C.C(O)(=O)C>CC(C)=O.CO.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([NH:12][N:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4]2)=[O:14])=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)Nn1cnc2ccccc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(NC(=O)Nn2cnc3ccccc3c2=O)cc1
Reaction time: 3 h

Procedure:
5% Pd/C (0.5 g) is added to a mixture of 1-(3,4-dihydro-4-oxo-3-quinazolinyl)-3-(p-nitrophenyl)urea (1.32 g, 4.06 mmol), ethanol (50 mL) and acetic acid (5 mL). The reaction mixture is placed on a Parr hydrogenator at 50 psi H2 for 3 hours, diluted with acetone and filtered. The filtrate is concentrated in vacuo to obtain a brown oil. The oil is dissolved in methanol, decolorized with activated carbon and concentrated in vacuo to give the title product as a tan solid, 0.9 g, mp >305° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]([O:27]C)=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[C:25]([OH:27])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Temperature: 70 °C
Yield: 72.1 %

Procedure:
A solution of methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (30 mg, 0.061 mmol) in Methanol (0.500 mL), Tetrahydrofuran (THF) (0.500 mL) and Water (0.500 mL) was treated with NaOH (54.7 mg, 1.368 mmol) and heated to 70° C. for 3 hours. The mixture was cooled to 0° C., treated with HCl (1M) until pH<2 and extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to afford 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetic acid (21.5 mg, 0.044 mmol, 73% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) ppm 13.33 (s, 1H) 7.58-7.69 (m, 2H) 7.42-7.54 (m, 3H) 7.23-7.38 (m, 4H) 5.89-5.95 (m, 1H) 5.74-5.81 (m, 1H) 5.07-5.15 (m, 1H) 3.50-3.59 (m, 3H) 0.88 (s, 9H); LCMS (m/z) ES+=479 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].O[Li].O>CO.C1COCC1.O>[C:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[O:12][CH2:11]2)[CH2:16][CH2:17]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1cccc2c1OCC2CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC2COc3c(C(=O)O)cccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{[7-(methoxycarbonyl)-2,3-dihydro-1-benzofuran-3-yl]methyl}piperazine-1-carboxylate (250 mg, 0.66 mmol) in 20 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (139 mg, 3.32 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and the residue was added 30 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=7 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was re-crystallized from DCM to give 3-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-2,3-dihydro-1-benzofuran-7-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[Cl-].[Li+].[BH4-].[Na+].[Cl-].[Na+]>C(O)C.O1CCCC1>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C@@H:4]([CH2:3][OH:2])[NH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:18][CH:19]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(N[C@H](CO)Cc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
27.25 g of O-benzyl-N-benzyloxycarbonyltyrosine methyl ester was dissolved in a mixed solvent of 185 ml of ethanol and 122 ml of tetrahydrofuran, and to the solution were added 5.8 g of lithium chloride and 5.2 g of sodium borohydride under ice cooling. The reaction mixture was stirred at a room temperature for 18 hours, and after the addition of 500 ml of saturated sodium chloride aqueous solution, extracted twice with 300 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under a reduced pressure to obtain 25.4 g of the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](Cl)=[O:20])[CH:8]=2)[N:3]=1.[CH3:25][C:26]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:27]=1[CH2:28][NH2:29]>C(Cl)Cl.O>[NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:29][CH2:28][C:27]3[C:26]([CH3:25])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=3[CH3:35])=[O:20])[CH:8]=2)[N:3]=1
Reactant: CCCN1Cc2cc(Oc3cccc(C(=O)Cl)c3)ccc2N=C1N
Reactant: Cc1cc(C)c(CN)c(C)c1
Solvent: O
Solvent: ClCCl
Product: CCCN1Cc2cc(Oc3cccc(C(=O)NCc4c(C)cc(C)cc4C)c3)ccc2N=C1N
Temperature: 0 °C

Procedure:
A mixture of 3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzoyl chloride (0.0008 mol) in DCM (20 mL) was stirred at 0° C. and 2,4,6-trimethylbenzylamine (0.0013 mol) was added. Then TEA (q.s.) was added, and the reaction mixture was stirred at room temperature. The mixture was stirred in H2O and the organic layer was separated. The remaining layer was washed again with H2O, then the organic layer was separated, dried, and filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2:(CH3OH:NH3)). The purest product fractions were collected, and the solvent was evaporated. The residue was triturated under diisopropyl ether:CH3CN, and then the resulting solids were filtered off and dried to yield the title compound as a solid.