Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:36]([O:38][CH3:39])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>CO.[Pd]>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:36]([O:38][CH3:39])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C

Procedure:
6.8 g of Z-Lys(BOC)-Phe-His-OMe in 140 ml of methanol are hydrogenated in the presence of 1 g of 10 % strength Pd on charcoal. After completion of the hydrogenation the catalyst is filtered off, the filtrate evaporated to dryness and the residue immediately processed further.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]([CH:14]1[CH2:19][CH2:18][C:17]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([NH2:33])[CH:27]=3)=[CH:24][N:25]=2)([OH:20])[CH2:16][C:15]1([CH3:35])[CH3:34])=[O:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:11][C:12]([CH:14]1[CH2:19][CH2:18][C:17]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([NH:33][C:2]4[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=4)[CH:27]=3)=[CH:24][N:25]=2)([OH:20])[CH2:16][C:15]1([CH3:35])[CH3:34])=[O:13]
Reactant: COC(=O)C1CCC(O)(c2ncc(-c3cc(C)cc(N)c3)s2)CC1(C)C
Reactant: Cc1nc(Cl)ncc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: COC(=O)C1CCC(O)(c2ncc(-c3cc(C)cc(Nc4ncc(F)c(C)n4)c3)s2)CC1(C)C
Temperature: 110 °C
Yield: 86.5 %

Procedure:
Racemic 2-chloro-5-fluoro-4-methylpyrimidine (50.0 mg, 0.341 mmol), methyl-4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (128 mg, 0.341 mmol), Pd(OAc)2 (15.3 mg, 0.0680 mmol), Xantphos (59.2 mg, 0.102 mmol), and Cs2CO3 (222 mg, 0.682 mmol) were combined in a flask and degassed with argon. To this solid mixture was added dioxane (2.0 mL), and the resulting mixture was degassed with argon for 5 min. The reaction mixture was heated to 110° C. for 1.5 h. The reaction was cooled to ambient temperature, then diluted with saturated aqueous NaCl and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica (10-30% EtOAc/hexanes gradient) to afford racemic methyl-4-(5-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (143 mg, 0.295 mmol, 86% yield). MS ESI: [M+H]+ m/z 485.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([SH:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24]>N1C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[N:2]=[C:1]([C:3]3[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=3)[S:28][C:21]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Reactant: O=C(O)c1ccc(Cl)cc1S
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccc(Cl)cc3s2)n1
Yield: 50.4 %

Procedure:
tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (1.6 g, 6.9 mmol) and 4-chlorothiosalicylic acid (2.6 g, 13.7 mmol) were dissolved in pyridine (15 ml), and the mixture was refluxed for 13 hrs. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (1.4 g, 51%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:28](O)=[O:29])[CH:6]=1)[CH2:2][CH2:3][CH3:4].P(C#N)(=O)(OCC)OCC.[Cl:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.Cl>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:28]([NH:46][C:45]2[CH:47]=[CH:48][C:42]([Cl:41])=[CH:43][CH:44]=2)=[O:29])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1cc(C(=O)Nc2ccc(Cl)cc2)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h
Yield: 37.9 %

Procedure:
A solution of 5-butyl-1-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]pyrazole-3-carboxylic acid (0.8 g) and diethyl phosphorocyanidate (90% purity, 0.76 g) in DMF (6 ml) was allowed to stir at 0°-5° C. for 1 hour. 4-Chloroaniline (0.25 g) and triethylamine (0.62 g) were added to the solution and the mixture was stirred at room temperature for 3 hours. The reaction solution was made acidic by addition of 1N-HCl and extracted with ethyl acetate. The organic layer was dried and evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give colorless powder (0.38 g, 38%),
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:8]2=[O:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:8]2=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(cccc3[N+](=O)[O-])C2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(N)cccc3C2=O)CC1
Reaction time: 2 h

Procedure:
450 mg of Pd/C (10%) are added to a mixture of 2.1 g (5.4 mmol) of tert-butyl 4-[2-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl) ethyl]-1-piperidinecarboxylate in 25 ml of methanol. The mixture is stirred at atmospheric pressure under an atmosphere of hydrogen for 2 h and, after filtration through Celite, concentrated. The product is purified by column filtration on silica gel (dichloromethane/methanol 9:1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2nc(Nc3cccc(C(C)(C)C)c3)cnc2c1
Agent: Br
Product: CC(C)(C)c1cccc(Nc2cnc3cc(O)ccc3n2)c1
Reaction time: 0.1 h

Procedure:
The mixture of (3-tert-Butyl-phenyl)-(6-methoxy-quinoxalin-2-yl)-amine and hydrobromic acid (48%) was subjected to the microwave at 140° C. for 6 mins. to yield the desired product. The mixture was neutralized with sodium bicarbonate solution and taken in ethyl acetate. The organic layer was washed with water and brine, concentrated, and purified on silica gel.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](O)=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][C:28]=2[NH2:38])=[CH:22][CH:21]=1)(=O)C>>[Cl:33][C:31]1[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:28]2[N:38]=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[N:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][OH:17])=[CH:21][CH:22]=3)[C:27]=2[CH:32]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2N)cc1
Product: CC(NC(=O)OC(C)(C)C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5 from N-(tert-butoxycarbonyl)-alanine and 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (Example 339, step 2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([O:24][C:26](=[O:28])[CH3:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Solvent: c1ccncc1
Product: CCCCCC(OC(C)=O)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 57 %

Procedure:
To a solution of methyl-3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate (1.7 g.) in pyridine at 0° C. was added acetic anhydride (2.7 ml). The reaction was stirred for four days at room temperature. The solvent was removed in vacuo and the remaining oil was purified by HPLC on silica gel using a hexanes/ethyl acetate in 9:1 ratio as an eluent (1.1 g., 57% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[NH2:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([C:44]3[CH:49]=[CH:48][C:47]([C:50]4[NH:54][C:53]([C@@H:55]5[CH2:59][CH2:58][CH2:57][N:56]5[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[N:52][CH:51]=4)=[CH:46][CH:45]=3)=[CH:41][CH:42]=2)[N:37]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[N:36]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[C:63]([O:62][C:60]([N:56]1[CH2:57][CH2:58][CH2:59][C@H:55]1[C:53]1[NH:54][C:50]([C:47]2[CH:48]=[CH:49][C:44]([C:40]3[CH:39]=[C:38]4[C:43]([C:35]([NH:34][C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])=[N:36][N:37]4[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[CH:42][CH:41]=3)=[CH:45][CH:46]=2)=[CH:51][N:52]=1)=[O:61])([CH3:66])([CH3:65])[CH3:64]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(N)nn(C(=O)OC(C)(C)C)c4c3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nn(C(=O)OC(C)(C)C)c2cc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a solution (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (97.1 mg, 0.451 mmol) in CH2Cl2 (2 mL) was added ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ, 181.2 mg, 0.733 mmol) followed by (S)-tert-butyl 3-amino-6-(4-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-indazole-1-carboxylate (209.7 mg, 0.385 mmol) after about 5 min. The reaction mixture as allowed to stir at room temperature for 12 h and the solution was treated with EEDQ (79 mg, 0.365 mmol) and stirred for 48 h. The solution was treated with (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (60 mg, 0.279 mmol). After stirring a further 12 h the mixture was treated with MeOH (4 mL) followed by iPr2NEt (0.1 mL) and allowed to stir for 2 h. The solvent was removed in vacuo and the residue was purified by prep HPLC (CH3CN—H2O—NH4OAc) to give the title compound (197.4 mg, 69%) as a light yellow glass. 1H NMR (400 MHz, DMSO-d6) δ 11.90-11.95 (m, 1H), 11.13-11.20 (m, 1H), 8.33 (s, 1H), 8.09 (d, J=8 Hz, 1H), 7.88 (app d, J=8 Hz, 2H), 7.65-7.78 (m, 3H), 7.55-7.58 (m, 1H), 4.75-4.87 (m, 2H), 4.36-4.43 (m, 1H), 4.06-4.12 (m, 1H), 3.51-3.59 (m, 1H), 3.42-3.47 (m, 1H), 3.35-3.37 (m, 2H, partially obscured by H2O signal), 2.12-2.32 (m, 2H), 1.79-2.01 (m, 4H), 1.66 (s, 9H), 1.40 (s, 9H), 1.32 and 1.15 (s, 9H, rotamers). LCMS: Anal. Calcd. for C40H51N7O7: 741; found: 742 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C
Yield: 87.26 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-02) (1.8 g, 87.26%) was synthesized as a yellow solid from 3-benzyloxy-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-02) (2.0 g, 4.6 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.CCN(C(C)C)C(C)C.[NH2:26][C:27]1[S:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][N:31]=1.Cl.CCOCC>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][C:27]1[S:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][N:31]=1)=[O:6]
Reactant: O=C(O)c1cccnc1F
Reactant: Nc1ncc([N+](=O)[O-])s1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc([N+](=O)[O-])s1)c1cccnc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Fluoronicotinic acid (100 mg, 0.71 mmol) was dissolved in CH2Cl2 (2 mL) with a drop of DMF (catalytic) and cooled to 0° C. then (COCl)2 (0.18 mL, 2.12 mmol) was added dropwise to the stirring solution. The slurry was allowed to warm to room temperature for 2 hours then concentrated to dryness using hexanes to remove the excess (COCl)2. The resulting acid chloride was dissolved in THF (7 mL) and DIPEA (0.26 mL, 1.49 mmol) was added. The solution was cooled to −78° C. and 2-amino-5-nitrothiazole (108 mg, 0.78 mmol) was then added in one portion and the solution was held at −78° C. for 10 mins then warmed to room temperature and stirred for 2 days until judged complete by TLC analysis. The resulting suspension was quenched with 2M HCl in Et2O (0.78 mL, 1.56 mmol) and concentrated to dryness then purified by flash column chromatography (1% MeOH/CH2Cl2) to obtain the title compound VPC16a1052 (118 mg, 62%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.77 (bs, 1H), 8.70 (s, 1H), 8.54-8.44 (m, 1H), 8.41-8.35 (m, 1H), 7.63-7.50 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 163.0 (d, JCF=5.9 Hz), 161.5, 159.4 (d, JCF=242 Hz), 151.3 (d, JCF=15.2 Hz), 142.4, 142.3, 122.3 (d, JCF=4.1 Hz), 115.9 (d, JCF=28.5 Hz); HRMS (ESI) calcd for [C9H5FN4O3S+H]+ 269.0139. found 269.0143.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:27])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[O:1]([CH2:8][CH:9]([OH:27])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1
Agent: [Pd]
Product: Nc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared by catalytic reduction of 1-phenoxy-4-[4-(4-nitrophenyl)-1-piperazinyl]-2-butanol with hydrogen over palladium on carbon.
Reaction SMILES: [O:1]=[C:2]1[O:6][C:5]([C@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)=[N:4][N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[C:13]1([N:3]2[N:4]=[C:5]([C@@H:7]3[CH2:9][C@@H:8]3[C:10]([N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:12])[O:6][C:2]2=[O:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1C[C@@H]1c1nn(-c2ccccc2)c(=O)o1
Reactant: C1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C([C@H]1C[C@H]1c1nn(-c2ccccc2)c(=O)o1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg (0.2 mmol) of cis-2-(5-oxo-4-phenyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-cyclopropanecarboxylic acid, 233 mg (2.0 mmol) of NEM and 67 mg (0.2 mmol) of TOTU were dissolved in 2 ml of DMF and stirred at room temperature for 15 min. 17.3 mg (0.2 mmol) of piperidine were added to the reaction solution. After stirring at room temperature for 16 h, the reaction mixture was filtered and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization the product was obtained as a white solid. Yield: 44 mg.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[C:13]([C:27]2[N:31]([CH2:32][C:33](OC)=[O:34])[N:30]=[N:29][N:28]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[Cl:22])[N:18]=[C:17]([O:23][CH3:24])[C:16]([O:25][CH3:26])=[N:15]2.[Cl-].[NH4+]>ClCCl>[Cl:11][C:12]1[C:13]([C:27]2[N:31]([CH2:32][CH2:33][OH:34])[N:30]=[N:29][N:28]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[Cl:22])[N:18]=[C:17]([O:23][CH3:24])[C:16]([O:25][CH3:26])=[N:15]2
Reactant: COC(=O)Cn1nnnc1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: COc1nc2cc(Cl)c(Cl)c(-c3nnnn3CCO)c2nc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Diisobutylaluminium hydride (1M in tetrahydrofuran, 0.7 mL, 0.7 mmol) was added dropwise to a stirred solution of 6,7-dichloro-2,3-dimethoxy-5-(1-methoxycarbonylmethyl-1H-tetrazol-5-yl)quinoxaline (Preparation 11, 0.126 g, 0.32 mmol) in dichloromethane (15 mL) at −78° C. under nitrogen. After 1 hour, the reaction mixture was allowed to warm to room temperature and diisobutylaluminium hydride (1M in tetrahydrofuran, 0.7 mL, 0.7 mmol) was added, followed 30 minutes later by further diisobutylaluminium hydride (1M in tetrahydrofuran, 0.7 mL, 0.7 mmol). After a further 0.25 hours saturated ammonium chloride solution (20 mL) was added to the mixture and the aqueous phase was extracted with dichloromethane (2×25 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane:methanol (99:1, by volume) to give the title compound (93 mg, 79%) as a white solid.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([S:19][CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClCCl.ClC1C=CC=C(C(OO)=[O:42])C=1>O>[C:1]12([C:11]3[CH:12]=[C:13]([S:19]([CH2:20][C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)=[O:42])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(CSc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(CS(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
844 mg (2 mmol) of methyl 4-[3-(1-adamantyl)-4-methoxyphenylthiomethyl]benzoate and 20 ml of dichloromethane were introduced into a round-bottomed flask and 386 mg (1.9 mmol) of meta-chloroperbenzoic acid were added. The reaction medium was stirred at room temperature for two hours and was then poured into water and extracted with dichloromethane. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and ethyl ether (90/10). After evaporation of the solvents, 270 mg (30%) of the expected ester, having a melting point of 121°-2° C., were recovered.
Reaction SMILES: [CH:1](=[C:8]1[C:12]2=[N:13][C:14]3[CH:15]=[C:16]([NH:22][C:23]([C:25]4[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30][CH3:31])=[O:29])=[O:24])[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:39](O)(=O)C>CN(C)C=O>[CH3:39][N:22]([C:16]1[CH:17]=[CH:18][C:19]2[C:20](=[O:21])[N:11]3[CH2:10][CH2:9][C:8](=[CH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]3=[N:13][C:14]=2[CH:15]=1)[C:23]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:24]
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc3c(=O)n4c(nc3c2)C(=Cc2ccccc2)CC4)c1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)N(C)c2ccc3c(=O)n4c(nc3c2)C(=Cc2ccccc2)CC4)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, methyl ester (0.85 g) dissolved in dimethylformamide (40 ml) was added to a suspension of 50% NaH (0.18 g) in dimethylformamide (5 ml) and the mixture was stirred at room temperature for 1 hour and then reacted with methyl iodide (0.54 g) at room temperature for 17 hours. The reaction mixture was diluted with ice water and then acidified with acetic acid: the precipitate was filtered and purified over a flash column using chloroform-ethyl acetate 3:1 as eluant. A further purification from isopropyl ether gave 3-[N-methyl-N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, methyl ester, m.p. 200°-202° C. (0.42 g), which was dissolved in dimethylformamide (20 ml) and treated with 5% aqueous NaOH (3.6 ml) at room temperature for 2 hours. The precipitate, 3-[N-methyl-N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, sodium salt, m.p. >300° C., was filtered and then dissolved in formic acid: the solution was diluted with water to give a precipitate which was filtered and washed with water until neutral. Crystallization from dichloromethane-methanol gave 0.2 g of 3-[N-methyl-N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-benzoic acid, m.p. 302°-304° C., NMR (CDCl3) δ ppm.: 3.38 (m) (2H, C- 2 protons), 3.61 (s) (3H, CH3), 4.32 (t) (2H, C-1 protons), 7.14 (dd) (1H, C-7 proton), 7.32 (t) (1H, C-5 benzoyl proton), 7.35-7.85 (m) (7H, C-4 and C-6 benzoyl protons and phenyl protons), 7.88 (bs) (1H, --CH=), 8.00 (bd) (1H, C-5 proton), 8.13 (d) (1H, C-8 proton), 8.15 (bs) (1H, C-2 benzoyl proton).