Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([CH:8]([N:11]2[C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26](C(OCC)=O)[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br>O>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([CH:8]([N:11]2[C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[CH:19][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCN(c2ccc(-n3cnn(C(CC)C(=O)c4ccc(Cl)cc4)c3=O)cc2)CC1
Agent: Br
Solvent: O
Product: CCC(C(=O)c1ccc(Cl)cc1)n1ncn(-c2ccc(N3CCNCC3)cc2)c1=O
Product: Cl
Yield: 157.7 %

Procedure:
A mixture of (±)-ethyl 4-[4-[2-[1-(4-chlorobenzoyl)propyl]-2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl]phenyl]-l-piperazinecarboxylate (15 g) in a hydrobromic acid solution 48% in water (150 ml) was stirred and refluxed overnight. The solvent was evaporated, the residue was dissolved in CH2Cl2 and washed with NaHCO3 /H2O. The organic layer was dried, filtered and evaporated. The residue was dissolved in 2-propanol and crystallized into the hydrochloric acid salt (1:2) in 2-propanol. The precipitate was faltered off and recrystallized from CH3CN, yielding 7.9 g (2.2%) of (±)-2-[1-(4-chlorobenzoyl)propyl]-2,4-dihydro-4-[4-(1-piperazinyl)phenyl]-3H-1,2,4-triazol-3-one dihydrochloride.monohydrate; mp. 175.9° C. (interm. 7).
Reaction SMILES: [CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:2].[N:59]1(C(OC(C)(C)C)=O)[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:57]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:35])[N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[CH:14]=2)=[C:6]([C:37]2[CH:42]=[C:41]([CH:40]=[CH:39][N:38]=2)[C:43]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:53])([F:54])[F:55])[CH:47]=2)=[O:56])[CH:5]=1)[CH3:58]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCNCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.5 h
Yield: 177.4 %

Procedure:
To a mixture of 16-(3-(4-(diethyl amino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-4,7,10,13-tetraoxahexadecan-1-oic acid (292 mg, 0.36 mmol), tert-butyl piperazine-1-carboxylate (75 mg, 0.40 mmol) and DIPEA (142 mg, 1.1 mmol) in DMF (3 mL) was added HATU (160 mg, 0.42 mmol). After 30 minutes, the solvent was removed under vacuum and the residue was dissolved in DCM (50 mL). This was washed with water (4×25 mL), dried (Na2SO4) and concentrated. The resulting oil was dissolved in DCM (2 mL) and TFA (2 mL) was added dropwise. After 30 minutes, the solvents were removed under vacuum. The residue was dissolved in 50% ACN/water (30 mL) and freeze dried to give the title compound (560 mg) as a TFA salt.
Reaction SMILES: [CH3:1]O.C(N(CC)CC)C.[C:10]1([N:16](CCl)[C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:24](OCC)(=[O:26])C>>[C:10]1([N:16]([O:26][CH3:24])[C:17](=[O:21])[N:18]([CH3:20])[CH2:19][CH3:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)N(CCl)c1ccccc1
Reactant: CCOC(C)=O
Reactant: CO
Solvent: CCN(CC)CC
Product: CCN(C)C(=O)N(OC)c1ccccc1

Procedure:
A solution of 3.3 g (0.1 mole) of methanol and 10.1 g (0.1 mole) of triethylamine were added dropwise to a solution of 23 g (0.1 mole) of 3-phenyl-3-chloromethyl-1,1-dimethylurea in 125 ml of ethyl acetate, while stirring and cooling externally, is such a way that the reaction temperature did not exceed 20° C. After stirring for one hour at room temperature, the precipitate so produced was filtered off and well washed with about 50 ml of ethyl acetate. The combined filtrates and wash solutions were freed of the solvent in vacuo and the resulting oil was taken up in 100 ml of benzene and twice washed with 50 ml of water at a time. The organic phase was dried over sodium sulfate and the solvent was distilled off. The oily residue was taken up in 100 ml of benzene and twice washed with 50 ml of water at a time. The organic phase was dried over sodium sulfate and the solvent was distilled off. The oily residue was taken up in 100 ml of a 1:1 mixture of ether and petroleum ether, the solution was filtered and the solvent of the filtrate was distilled off in vacuo. 17.5 g (84% of theory) of 3-phenyl-3-methoxy-methyl-1,1-dimethylurea were left as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:6]1.[CH:20]([NH:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:20]([N:23]([C:16](=[O:18])/[CH:15]=[CH:14]/[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:3]=[C:2]([CH3:1])[CH3:19])[CH:6]=1)[NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)([CH3:22])[CH3:21]
Reactant: Cc1cccc(C(=O)NNC(C)C)c1
Reactant: CC(C)=CCn1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)=CCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(C)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acrylic acid (100.0 mg, 0.39 mmol), N′-isopropyl-3-methylbenzohydrazide (113.4 mg, 0.59 mmol) and HATU (224.3 mg, 0.59 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.10 ml, 0.59 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (35% EtOAc) for refinement and dried so that white (E)-N′-isopropyl-3-methyl-N′-(3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (115.0 mg, 68.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCC(O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(CCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Yield: 56.8 %

Procedure:
By the general method described in Step 6 of Example 1, 6-(3-nitroquinolin-4-ylamino)-1-phenylhexan-1-ol (4.0 g, 11 mmol) was oxidized with DMSO (1.28 g, 16.4 mmol), oxalyl chloride (1.53 g, 12.0 mmol), and triethylamine (3.32 g, 32.8 mmol) to provide 6-(3-nitroquinolin-4-ylamino)-1-phenylhexan-1-one (2.27 g) as light orange crystals after recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:23]1[CH2:28][CH2:27][CH:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][CH:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:27][CH2:28]1)=[O:6]
Reactant: C1CC(OCCN2CCOCC2)CCN1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCOCC2)CC1
Reaction time: 1 h
Yield: 16.6 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1)(0.2 g, 0.67 mmol), 4-(2-(piperidin-4-yloxy)ethyl)morpholine (79) (0.144 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white foam (0.055 g, 16.6% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.60-1.48 (1H, m), 1.83-1.64 (2H, m), 1.94-1.88 (1H, m), 2.59-2.57 (4H, m), 2.64 (2H, t), 3.14-3.05 (1H, m), 3.49-3.37 (1H, m), 3.58-3.51 (1H, m), 3.66-3.60 (3H, m), 3.74-3.72 (4H, m), 4.06-3.94 (1H, m), 4.28 (2H, s), 7.01 (1H, t), 7.32-7.26 (2H, m), 7.77-7.70 (3H, m), 8.48-8.44 (1H, m), 10.77 (1H, s); m/z (LC-MS, ESI+), RT=1.57 (M+H 495).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ncc2Cl)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(-c2cc(N3CCNCC3)ncc2Cl)c(C)c1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of tert-butyl 4-(5′-chloro-3,5-dimethyl-2,4′-bipyridin-2′-yl)piperazine-1-carboxylate (5.6 g, 14 mmol) in CH2Cl2 (50 mL) was added TFA (25 mL). Then the mixture was stirred for 18 hours. TLC (CH2Cl2/MeOH=10:1) showed the starting material was consumed completely. After removal of the solvent, the residue was dissolved in CH2Cl2 (180 mL), basified with 3 N aq. NaOH until pH=11, washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford title compound (4.1 g, 97%) as orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9](=[O:12])[C:10](=[CH:15][N:16]([CH3:18])[CH3:17])[CH2:11]1)=[O:5])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: O
Product: CCOC(=O)N1CCC(=O)C(=CN(C)C)C1

Procedure:
To a round bottomed flask was loaded 8.56 grams of 4-oxo-piperidine-1-carboxylic acid ethyl ester, 10.3 ml of dimethylformamide dimethylacetal, and the mixture was refluxed at 90° C. for two hours. Then it was poured into 75 ml water and extracted with 2×250 ml dichloromethane. The combined organic layers was washed with 50 ml brine and dried over magnesium sulfate. Filter off the drying agent and concentrate gave 28 grams of 3-Dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid ethyl ester. This material (12.8 grams) was then loaded into a round bottomed flask along with 3.42 grams of (5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 100 ml 2-methoxyethanol. The mixture was refluxed for 18 hours. Then it was cooled down to 23° C. and concentrated to 5 ml. Then 50 ml ethyl ether was added and the precipitate was filtered and vacuum dried to yielded 1.5 grams of product. MS: 278.1 (M+H). H-NMR (CDCL3): δ 8.60 (s, 1H), 4.98 (s, 2H), 4.78 (s, 2H, CH2), 4.22 (q, 2H, J=4.8 Hz), 3.75 (t, 2H, CH2, J=4 Hz), 3.51 (t, 2H, J=4 Hz), 1.32 (m, 3H, CH3, J=4.8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].COC(=O)OC.Cl[S:18]([OH:21])(=[O:20])=[O:19]>C1CCCCC1>[C:8]([C:3]1[CH:4]=[C:5]([S:18]([OH:21])(=[O:20])=[O:19])[CH:6]=[CH:7][C:2]=1[OH:1])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1O
Reactant: O=S(=O)(O)Cl
Solvent: COC(=O)OC
Solvent: C1CCCCC1
Product: CC(=O)c1cc(S(=O)(=O)O)ccc1O
Temperature: 60 °C
Yield: 52 %

Procedure:
To a solution of 2′-hydroxyacetophenone (5.43 g, 40 mmol) in cyclohexane (28 mL) was added dimethylcarbonate (28 mL). The mixture was stirred under nitrogen and heated to 60° C. Chlorosulfonic acid was added over a period of 15 min. Liberated HCl was removed by trapping with solid NaOH. On completion of the addition, the reaction mixture was heated to 70° C. for 1 h and then cooled to rt. The solid was filtered off, washed with a mixture of dimethyl carbonate and cyclohexane (1:1, 20 mL) and dried under vacuum to give 3-acetyl-4-hydroxybenzene sulfonic acid as yellow solid (4.5 g, 52%). 3-Acetyl-4-hydroxybenzene sulfonic acid (2.16 g, 10 mmol) was suspended in 20 mL anhydrous pyridine. 4-Methoxybenzoyl chloride (3.4 g, 20 mmol) was added slowly at rt. Stirring continued under nitrogen for 15 h. Excess pyridine was removed under reduced pressure. The solid obtained was dried under vacuum. This material was used without further purification. This crude compound (˜10 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered KOH (2.8 g, 50 mmol) was added and the reaction mixture was stirred at rt for 14 h under nitrogen. Water (10 mL) was added and the mixture was concentrated to dryness. The crude product was taken in 10 mL of glacial AcOH. Five drops of concentrated HCl was added and the reaction mixture was stirred at 110° C. for 4 h, then cooled to rt. The yellow solid was isolated by filtration, washed with AcOH and dried under vacuum to give 2-(4-methoxy phenyl)-4-oxo-4H-chromen-6-sulfonic acid (0.475 g, 14%) as yellow solid. The product (0.375 g, 1.13 mmol) was suspended in HI (7 mL). Glacial AcOH (3 mL) was added and the reaction mixture was stirred at 110° C. for 2 h, then cooled to rt. The solid was isolated by filtration, washed with AcOH and dried under vacuum. The crude compound was triturated with ether to afford 2-(4-hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid (0.2 g, 55%) as yellow solid. MS (ES) m/z: 319.88 (M+1), 318.85 (M); 13C-NMR (DMSO-d6): δ 177.5, 163.7, 161.7, 156.1, 146.1, 132.1, 129.1, 123.1, 122.3, 122.2, 118.7, 116.6, 105.5.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Reactant: CCC(O)[C@@H](N)CC
Solvent: CCCCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)[C@H](CC)Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.18 mL, 15 eq, 1.03 mmol) followed by (3RS,4S)-4-amino-hexan-3-ol (110 mg, 13 eq, 0.94 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 10 mg (37%).(57% de 4S,3R: 43% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.85-1.06 (m, 6H, —NHCH(CH2CH3)CH(CH2CH3)OH, 1.57 (d, 6H, J=6.79 Hz, & —CH(CH2)2), 1.43-1.64 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.45 (d, 1H, J=6.16 Hz, OH) 3.56-3.70 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.91-4.02 (m, 1H, —NHCH(CH2CH3) CH(CH2CH3) OH), 4.58-4.71 (m, 1H, —CH(CH3)2), 4.86-4.98 (m, 2H, —HNCH2-Pyr), 5.21-5.32 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 6.76-6.94 (m, 1H, —HNCH2-Pyr), 7.16-7.26 (m, 1H, Pyr-H), 7.38 (d, 1H, J=7.74 Hz, Pyr-H), 7.58 (s, 1H, —N═CH—N—), 7.64-7.70 (m, 1H, Pyr-H), 8.60 (d, 1H, J=4.45 Hz, Pyr-H). FABMS m/z (relative intensity): 384 ([M+H]+, 100), 324 (35), 307 (37), 297 (25), 289 (20). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2523.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.O>[C:12]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH2:31][CH2:30]2)=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Yield: 100 %

Procedure:
To a solution of 1.13 g of 3,3-diphenylpropionic acid and 1.06 g of 1-(2-methoxyphenyl)piperazine in 25 mL of N,N-dimethylformamide at a temperature within the range of 0-5° C., were added, in succession, 0.9 mL of 93% diethyl cyanophosphonate and 0.77 mL of triethylamine under stirring. The resultant solution was then stirred at room temperature for 5 h, poured into 250 mL of water and extracted with ethyl acetate. The organic phase was then washed with water, dried on anhydrous sodium sulphate, and evaporated to dryness under vacuum. The obtained oily residue was then puirified by flash-chromatography (chloroform-ethyl acetate 9:1). This procedure afforded the title compound (100%).
Reaction SMILES: CN(CCCN1CN(CCCN(C)C)CN(C[CH2:20][CH2:21]N(C)C)C1)C.[CH2:25]([N:29]=[C:30]=[O:31])[CH2:26][CH2:27][CH3:28].[N-]=C=[O:34]>C(O)C>[CH2:25]([NH:29][C:30](=[O:34])[O:31][CH2:20][CH3:21])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN=C=O
Reactant: [N-]=C=O
Reactant: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Solvent: CCO
Product: CCCCNC(=O)OCC
Temperature: 60 °C

Procedure:
In a 250 ml round-bottomed flask, 0.02 g of Desmorapid Z, 34.1 g of n-butyl isocyanate were initially introduced and heated to 60° C. Thereafter, 15.9 g of ethanol were added dropwise and the mixture was further kept at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, cooling was effected and the product was obtained as a clear liquid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15]CC)[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]1([Mg]Cl)[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:19]([OH:20])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:18]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cl[Mg]C1CCCC1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)C2CCCC2)c2[nH]c(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) under argon and cooled to 0° C. Cyclopentylmagnesium chloride (2.0 M, 0.14 mL, 0.28 mmol) was added dropwise and reaction was allowed to stir for 10 minutes then quenched with water. Reaction mixture was extracted three times with EtOAc and combined organic layers were washed once with water and concentrated. Residue was taken up in EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL) and heated to 65° C. for 2 hours. Reaction was concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:17][CH2:16][C@@H:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][N:13]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:12]1=[O:28].[O:29]=[C:30]1[N:39]([CH:40]2[CH2:45][CH2:44][N:43]([C:46](Cl)=[O:47])[CH2:42][CH2:41]2)[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31]1>ClCCCl>[CH:25]1([CH2:24][N:13]2[CH2:14][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:17][C@@H:11]([NH:10][C:46]([N:43]3[CH2:44][CH2:45][CH:40]([N:39]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:29])[CH2:41][CH2:42]3)=[O:47])[C:12]2=[O:28])[CH2:27][CH2:26]1
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: N[C@@H]1CC[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CC[C@@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
Diisopropylethylamine (0.16 mL, 0.90 mmol) was added to a solution of (3R,6S)-3-amino-1-(cyclopropylmethyl)-6-phenylazepan-2-one (116 mg, 0.45 mmol) and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride (132 mg, 0.45 mmol) in 1,2-dichloroethane (10 mL) and the mixture heated to reflux. After 1 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane→5% methanol/dichloromethane) gave the title compound (32 mg). MS 516 (M+1).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].S(=O)(=O)(O)[OH:17]>O>[OH:17][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(O)cccc1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Alternatively, the desired subtitled compound was prepared by adding 22.6 g (0.33 mol) of sodium nitrite in small portions to a cooled (-10° C.) solution of 45 g (0.30 mol) of 3-amino-2-methylbenzoic acid and 106 g (58 mL; 1.08 mol) of concentrated sulfuric acid in 400 mL of water, while maintaining the temperature below 7° C. The resultant reaction mixture was stirred for approximately 30 minutes at -10° C., poured into a solution of 240 mL of concentrated sulfuric acid in 1.2 L water, and then slowly heated to 80° C. (heavy gas evolution occurs between the temperatures of 40°-60° C.). When the gas evolution stopped, the reaction mixture was cooled to room temperature and the subtitled compound was extracted five times with ethyl acetate (600 mL). The combined organic phases were combined with 500 mL of an aqueous saturated sodium carbonate solution. The resultant layers were separated and the aqueous layer was acidified to pH 2 with concentrated hydrochloric acid. The titled compound was then extracted using ethyl acetate (500 mL) and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a crude material. This material was purified using two recrystallizations from a ethyl acetate/chloroform mixture to provide 23.2 g of a light orange powder.