Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Br:32]Br>C1COCC1.CCOC(C)=O>[Br:32][C:24]1[O:23][C:22]([CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:26][CH:25]=1
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(Br)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (201 mg, 0.554 mmol) was dissolved in anhydrous THF (5 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., cooled to −78° C. and bromine (3 equiv) was added dropwise. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated Na2S2O3, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude aryl bromide, which was purified by flash chromatography (0-1.5% EtOAc/hexanes) to afford the title compound as a clear oil (218 mg, 90%): 1H NMR (CDCl3, 600 MHz) 7.28-7.26 (m, 2H), 7.17-7.16 (m, 3H), 6.92 (s, 1H), 4.74 (t, 1H, J=7.2 Hz), 2.59 (t, 2H, J=7.8 Hz), 1.90-1.79 (m, 2H), 1.60-1.59 (m, 2H), 1.53-1.34 (m, 6H), 0.88 (s, 9H), 0.07 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 167.8, 143.6, 129.3, 129.1, 127.7, 126.5, 122.1, 69.5, 37.0, 36.8, 32.3, 30.0, 26.6, 26.6, 25.9, 19.1, −4.1, −4.3.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([OH:3])=O.[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH:7]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[C:1]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][C:13]([F:12])([F:23])[F:24])=[CH:16][CH:17]=1)=[O:3])=[O:8]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=Cc1cccc(C(=O)NCc2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
to a solution of 300 mg of 3-carboxybenzaldehyde (2 mmoles) and 382 mg of 4-(trifluoromethoxy)benzylamine (2 mmoles) in 5 ml of DCM is successively added 540 mg of 1-hydroxybenzotriazole (HOBt) (4 mmoles) and 0.63 mg of diisopropylcarbodiimide (DIC) (4 mmoles). The reaction mixture is stirred overnight at room temperature and then poured into 20 ml of 10% KH2SO4 solution. The mixture is extracted twice with 15 ml of ethyl acetate. The combined organic extracts are washed with 20 ml of water and 20 ml of brine, dried over MgSO4 and concentrated giving 670 mg of 3-formyl-N-(4-trifluoromethoxy-benzyl)-benzamide (yield=85%). Analytical LC/MS method A: ([M+H]+): 324, RT: 5.24 min (gradient 5 to 85% acetonitrile in 7 min). Compound 60 is prepared as described for example 2 starting with 21.3 mg of of N-Boc-3,5-diketopiperidine (0.1 mmole), 8.3 mg 3-aminopyrazole (0.1 mmole) and 32.3 mg of 3-formyl-N-(4-trifluoromethoxy-benzyl)-benzamide (0.1 mmole) in a mixture of 0.5 ml of ethanol and 0.5 ml of DMF, resulting in 22.5 mg of product 60 after purification by preparative LC/MS. (method A, yield=38%). Analytical LC/MS method A: ([M+H]+): 484, RT: 2.51 min (gradient 2 to 80% acetonitrile in 7 min).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[C:22]([O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH:34]([CH3:38])[C:35](Cl)=[O:36])=[CH:31][CH:30]=2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[C:22]([O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH:34]([CH3:38])[C:35]([O:12][CH:10]([CH3:11])[CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:36])=[CH:31][CH:30]=2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: CC(O)COCc1ccccc1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(COCc1ccccc1)OC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Temperature: 0 °C

Procedure:
16.6 g of 1-benzyloxy-2-propanol and 10.6 g of triethylamine were dissolved in 200 ml of toluene, then cooled to 0° C. To this solution was dropwise added a solution of 34.7 g of 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionyl chloride in 80 ml of toluene at 0° to 5° C. with stirring. After the dropwise addition, the mixture was gradually heated and, at 40° to 50° C., it was stirred for one hour to complete the reaction. After cooling to room temperature, it was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, followed by drying. Upon distilling off toluene under reduced pressure, there were obtained 43.3 g of pale yellow, viscous, oily 1-methyl-2-benzyloxyethyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate. nD20 1.5710.
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.[C:33](=[O:36])([O-])[O-].[K+].[K+]>O>[NH2:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:32][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([O:36][C:33]4[CH:29]=[CH:30][CH:31]=[C:26]([NH2:25])[CH:27]=4)=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1cccc(Oc2ccc(C(=O)c3ccc(C(=O)c4ccc(Oc5cccc(N)c5)cc4)cc3)cc2)c1
Yield: 74.9 %

Procedure:
In a one liter reaction vessel 50 grams (0.16 mol) of 1,4-bis(4-fluorobenzoyl)benzene, 42 grams (0.39 mol) of m-aminophenol, 54 grams of anhydrous potassium carbonate and 400 ml of sulforane were charged and reacted at 150°-160° C. for six hours. After ending the reaction, the reaction mixture was poured into water to make a total volume of two liters. Then the separated crystals were filtered, washed with water and dissolved into 400 ml of 2-methoxyethanol with heating. The resultant solution was added with eight grams of active carbon, stirred, hot filtered and cooled. The separated crystals were filtered and recrystallized again from 2-methoxyethanol and active carbon to afford 60 grams (75% yield) of 1,4-bis[4-(3-aminophenoxy)benzoyl]benzene as pale brown crystals having a melting point of 161°-163° C. and the purity of 99.3% in accordance with high-speed liquid chromatography.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Reactant: O=C(O)c1ccc(F)c2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2ccc(F)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 4-fluoro-1H-indole-7-carboxylic acid and 86 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 96 mg (72%) product as a colorless viscous oil. MS (ISP) 447.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:16]=1[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)=[O:18].O>CN(C=O)C>[Cl:14][C:15]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:16]=1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:11]2[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=3[CH:9]=[CH:10]2)=[CH:25][CH:26]=1)=[O:18]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: Cn1ncc2[nH]ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:3) to provide the title compound as white powder (511 mg, yield 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[N:26][NH:25][C:24]2=[O:28])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:25]1[C:24](=[O:28])[N:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:30])[F:29])=[CH:22][CH:21]=2)[CH:27]=[N:26]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(C(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 37.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.64 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.87 g of 4-(4-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-trifluoromethylphenyl)-3(2H,4H)-1,2,4-triazolone (1.26 g) was obtained as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[C:35](=[S:48])[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[O:5][CH2:6][CH:7]([OH:31])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[S:29])[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[C:12]([OH:30])[CH:11]=1.[C:49](O)(=[O:53])[C:50]([CH3:52])=[CH2:51].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:49]([O:31][CH:7]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[S:29])[C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)=[C:12]([OH:30])[CH:11]=1)[CH2:6][O:5][C:4]1[CH:32]=[CH:33][C:34]([C:35](=[S:48])[C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:40][CH:41]=2)=[C:2]([OH:1])[CH:3]=1)(=[O:53])[C:50]([CH3:52])=[CH2:51]
Reactant: Oc1cc(OCC(O)COc2ccc(C(=S)c3ccc(-c4ccccc4)cc3)c(O)c2)ccc1C(=S)c1ccc(-c2ccccc2)cc1
Reactant: C=C(C)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC(COc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1)COc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
The title compound is prepared by reacting the alcohol compound of Example 12 with an excess amount of methacrylic acid in refluxing toluene in the presence of a catalytic amount of toluenesulfonic acid.
Reaction SMILES: O1C2(CCC(C3C4C(=CC=C(F)C=4)NC=3)CC2)OCC1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[C:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:42][CH2:41][N:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])[CH2:39][CH2:38]2)[CH2:33][CH:32]=1>>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:38][CH2:39][N:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])[CH2:41][CH2:42]2)[CH2:33][CH2:32]1
Reactant: COc1ccccc1N1CCN(C2CC=C(c3c[nH]c4ccc(F)cc34)CC2)CC1
Agent: Fc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Product: COc1ccccc1N1CCN(C2CCC(c3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 88.1 %

Procedure:
This compound was prepared in the manner described above for intermediate 2c by replacing 4-(5-fluoro-1H-3-indolyl)-cyclohex-3-en-ethylene ketal with 5-fluoro-3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]cyclohex-1-enyl}-1H-indole (2.0 g) to afford 1.77 g (84%) of product as a mixture of cis and trans isomer.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[N:4][O:5][C:6]=1[N:7]([C:16]([O:18]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O.[C:25]1([C:31]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[S:33][N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[Cl:1][C:2]1[C:3]([CH3:24])=[N:4][O:5][C:6]=1[NH:7][C:16]([N:39]1[CH2:40][CH2:41][N:36]([C:34]2[S:33][N:32]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:35]=2)[CH2:37][CH2:38]1)=[O:18]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1noc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)c1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1Cl

Procedure:
A solution of bis(2,2,2-trichloroethyl) (4-chloro-3-methylisoxazol-5-yl)imidodicarbonate (200 mg, 0.418 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (203 mg, 0.836 mmol), diisopropylethylamine (0.144 ml, 0.836 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (111 mg, 66.1%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1)#[N:2].CP(C)C.[S:26]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:31][C:28]1[CH:29]=[CH:30][S:26][CH:27]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]2=1)#[N:2]
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Reactant: OCc1ccsc1
Agent: CP(C)C
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccsc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
Add sequentially to a slurry of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 3) (100 mg, 0.36 mmol) in THF (2 mL) at 0° C.: trimethylphosphine (1.0 M in toluene, 530 μL, 0.53 mmol), 3-thiophenemethanol (61 mg, 50 μL, 0.53 mmol), and 1,1′-(azodicarbonyl)-dipiperidine (ADDP, 134 mg, 0.53 mmol). Warm up to room temperature and stir in a sealed vial for 18 h. Evaporate the reaction solvent and dissolve the residue in EtOAc (5 ML). Add water (2 mL) and load onto a Varian Chem Elut CE1005 solid-phase extraction cartridge (Varian part number 12198006). Elute with EtOAc, collect, and concentrate (about 50 mL). Purify the crude product on silica gel (12 g) eluting with 30-90% EtOAc/hexanes to give the title compound in 11% yield as a colorless oil. MS (ES): m/z 378 (M+1), 376 (M−1); 1H NMR (CDCl3): δ 7.81 (s, 1H), 7.40 (dd, 1H, J=8.4, 1.2 Hz), 7.33 (d, 1H, J=8.4 Hz), 7.30 (m, 1H), 6.86-6.81 (m, 2H), 5.60 (d, 1H, J=7.5 Hz), 5.29 (s, 2H), 4.41 (m, 1H), 3.16 (dd, 1H, J=15.2, 5.1 Hz), 2.90-2.72 (m, 2H), 2.63 (dd, 1H, J=15.4, 7.5 Hz), 2.36 (m, 1H), 2.16 (m, 1H), 2.02 (m, 1H), 1.18 (dd, 7H, J=6.8, 3.7 Hz), 1.18 (dd, 6H, J=6.8, 3.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]5[O:27][CH2:28][O:29][C:23]=5[CH:22]=4)=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[CH2:9]([NH:8][C:5]1[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]5[O:27][CH2:28][O:29][C:23]=5[CH:22]=4)=[CH:17][C:15]=3[N:16]=2)=[CH:3][C:2]([N:1]2[C:39](=[O:40])[C:33]3[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[C:42]2=[O:41])=[CH:7][CH:6]=1)[CH2:10][CH3:11]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole (157 mg, 0.40 mmol) and 1,2,4-benzenetricarboxylic anhydride (76 mg, 0.40 mmol) the title compound was obtained (82 mg, 36%). 1H NMR (DMSO) δ 13.78(s, 1H), 8.49(t, 1H), 8.42(dd, 1H), 8.30(s, 1H), 8.12(d, 1H), 8.07(d, 1H), 8.00(d, 1H), 7.78(d, 1H), 7.64(dd, 1H), 7.47(dd, 1H), 7.35(d, 1H), 7.24(dd, 1H), 7.04(d, 1H), 7.01(d, 1H), 6.08(s, 2H), 3.35(m, 2H), 1.76(m, 2H), 1.07(t, 3H). MS 562.2 m/z (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]([C:14](=[O:30])[C@H:15]([CH:27]([CH3:29])[CH3:28])[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[OH-].[K+]>C(O)C>[C:17]([NH:16][C@H:15]([C:14]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][C:4]([OH:31])=[O:3])=[O:30])[CH:27]([CH3:28])[CH3:29])([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
N-CBZ-L-Valyl-N-(benzyl)glycine ethyl ester (17.3 g, 0.0406mol) was dissolved in ethanol (200 mL) and treated with 1N KOH (45 mL) in portions of 8.0 mL at 0-5C. The mixture was allowed to stir at room temperature over night. The ethanol was removed under reduced pressure, and the residue was treated with water. Extracted three times with ethyl acetate and afterwards the aqueous layer was acidified with 2N HCl. The product was extracted into ethyl acetate and washed with saturated aqueous sodium chloride. After drying over MgSO4, filtration and evaporation under reduced pressure afforded the product as a white semisolid (14.1 g) melting at 41°-45° C.
Reaction SMILES: [CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@H:4]([C:15]([OH:17])=[O:16])[NH:3]1.O.C(N(CC)CC)C.[CH3:26]I.[C:28](=[S:30])=[S:29]>CO>[CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@H:4]([C:15]([OH:17])=[O:16])[N:3]1[C:28]([S:30][CH3:26])=[S:29]
Reactant: S=C=S
Reactant: CI
Reactant: C[C@@H]1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CSC(=S)N1[C@@H](C(=O)O)Cc2c([nH]c3ccccc23)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.6 %

Procedure:
(1RS,3SR)-trans-1-Methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.15 g) is dissolved in methanol (30 ml)--water (3 ml) and thereto are added triethylamine (1.9 g) and carbon disulfide (912 mg). The mixture is stirred at room temperature for 20 minutes, and to the mixture is added methyl iodide (1.7 g) and the mixture is stirred at room temperature for 2 hours and then distilled under reduced pressure to remove the solvent. To the residue is added water, and the aqueous solution is acidified with 10% HCl and extracted with ethyl acetate. The extract is washed with water, dried and distilled to remove the solvent. The residue is recrystallized from aqueous ethanol to give the title compound (1.13 g, 70.6%) as colorless needles, m.p. 173°-176° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][C:22](=O)[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](CC)CC)C.[Li+].CCN(C(C)C)C(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][CH:23]=[CH:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC[BH-](CC)CC
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1C=CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.58 h
Yield: 81.9 %

Procedure:
A three-necked flask equipped with a thermometer and a nitrogen inlet was charged with (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (10.05 g, 22.16 mmol) and toluene (36 mL) and lowered into −55° C. cooling bath. When the internal temperature of the mixture reached −50° C., lithium triethylborohydride (23 mL of 1.0 M/THF, 23 mmol) was added dropwise over 30 min and the mixture stirred for 35 min while maintaining the internal temperature between −50° C. and −45° C. Hunig's base (16.5 mL, 94 mmol) was added dropwise over 10 min. Then, DMAP (34 mg, 0.278 mmol) was added in one batch, followed by the addition of trifluoroacetic anhydride (3.6 mL, 25.5 mmol) over 15 min, while maintaining the internal temperature between −50° C. and −45° C. The bath was removed 10 min later and the reaction mixture was stirred for 14 h while allowing it to rise to ambient temperature. The reaction mixture was diluted with toluene (15 mL), cooled with an ice-water bath and treated slowly with water (55 mL) over 5 min. The phases were separated and the organic layer washed with water (50 mL, 2×) and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; 5% EtOAc/hexanes) to afford (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (7.947 g, 82% yield) as a colorless viscous oil. LC-MS: [M+Na]+=460.19. Rt=2.41 min under the following HPLC conditions: Solvent gradient from 100% A: 0% B to 0% A: 100% B (A=0.1% TFA in 1:9 MeOH/water; B=0.1% TFA in 9:1 MeOH/water) over 2 min and hold for 1 min; detection at 220 nm; PHENOMENEX® Luna 3.0×50 mm S10 column. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.58 (m, 4H), 7.49-7.40 (m, 6H), 6.47 (br s, 1H), 5.07/5.01 (overlapping br d, 1H), 4.18 (br s, 1H), 3.89 (br s, 0.5H), 3.69 (br s, 1.5H), 2.90-2.58 (br m, 2H), 1.40/1.26 (overlapping br s, 9H), 0.98 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[C:21](Cl)=[CH:20][C:17]([NH:18][CH3:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1.C(O)(C(F)(F)F)=O.O>CN(C=O)C>[Cl:13][C:14]1[C:21]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:20][C:17]([NH:18][CH3:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1
Reactant: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(N2CCOCC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Morpholine (174 mg, 2.0 mmol) followed by potassium carbonate (304 mg, 2.2 mmol) were added to a mixture of 4,5-dichloro-N-methyl-2-nitroaniline (442 mg, 2.0 mmol) in DMF (10 mL) and stirred at rt overnight. The reaction mixture was acidified with TFA:H2O 1:1 and purified by chromatography to give the sub-title compound.