Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>CCCCCC>[CH2:17]1[C:12]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:13]=2[CH2:14][CH2:15][CH2:16]1
Reactant: O=C1CCCCC1Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: c1ccc2c(c1)CC1=C2CCCC1
Temperature: 60 °C
Yield: 22.6 %

Procedure:
Aluminium chloride (53.7 g, 0.40 mol) was added portion wise to 2-benzylcyclohexanone (25 g, 0.13 mol) in 100 mL of hexane. The mixture was heated at 60° C. for 4 h then cooled and poured onto ice acidified with HCl (aq). The organic layer was decanted and the aqueous layer was extracted with 100 mL of hexane. The organics were washed once with a dilute HCl solution, a dilute sodium bicarbonate solution and finally with water. The organic layer was dried, filtered and the hexane was removed. The resulting oil was distilled at 110-135° C. at 4 mm Hg, followed by crystallization from methanol gave (5 g, 23%) of tetrahydrofluorene as a white solid, mp 57° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:20]O>ClCCl>[CH3:20][O:13][C:12](=[O:14])[CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: CO
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)Cc1ccc2ncccc2c1

Procedure:
To a stirred solution of quinolin-6-yl-acetic acid (10 g, 53.0 mmol) in 100 ml of methanol was added 2.5 ml of concentrated H2SO4 The mixture was heated to reflux for 3 hours. The reaction mixture was concentrated to give a brown residue, which was diluted with 100 ml of dichloromethane, washed with sat. aq. NaHCO3 and brine, then the organic layer was dried over anhydrous Na2SO4 and concentrated to return the title compound as a brown oil (7.9 g, 73.6%).
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Product: CCCCCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid pentylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (94% yield). m.p. 123-125° C. 1H NMR (300 MHz, CDCl3) δ 8.03, 7.85, 7.62, 7.54, 7.35, 6.97, 4.06-3.99, 3.91-3.69, 3.44, 3.33, 1.62-1.55, 1.37-1.33, 0.95-0.81. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.5, 132.4, 129.5, 127.2, 127.1, 126.9-127.8, 112.5, 77.2, 46.4, 44.6, 44.4, 41.3, 39.4, 29.3, 29.1, 22.4, 14.0. MS (ES+) m/z 450.2 (M+1), 472.2 (M+Na).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([CH3:24])[CH2:21][C@H:20]1[C:25]([OH:27])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CC#N.CCOC(C)=O>[CH3:24][C@@H:22]1[CH2:23][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[C@H:20]([C:25]([O:27][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[O:4])=[O:26])[CH2:21]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Reaction time: 15 h
Yield: 96.4 %

Procedure:
To a solution of 2-bromo-1-(4-bromophenyl)ethanone (505 mg, 1.82 mmol) in MeCN (18 mL) was added (2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (500 mg, 2.18 mmol) and triethyl amine (0.27 mL, 2.0 mmol). After stirring for 15 h, the solution was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 35% EtOAc/hexanes) to afford (2S,4S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (748 mg, 97%).
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:42])[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH:39]([CH3:41])[CH3:40])[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:30])[C:15]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:16][CH:17]=1)=O)C1C=CC=CC=1.[H][H]>>[NH2:11][C:12]1[C:13](=[O:42])[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH:39]([CH3:40])[CH3:41])[C:33](=[O:38])[C:34]([F:36])([F:35])[F:37])=[O:30])[C:15]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: COc1cc(OC)cc(-c2ccc(NC(=O)OCc3ccccc3)c(=O)n2CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1
Product: COc1cc(OC)cc(-c2ccc(N)c(=O)n2CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1

Procedure:
2-[3-Benzyloxycarbonylamino-6-(3,5-dimethoxyphenyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was subjected to the conditions described in Example 159, except with shaking under a 2.7 bar hydrogen atmosphere, to give the title compound. Chromatography solvent: Dichloromethane:methanol (98:2, 95:5); TLC: Rf =0.35, dichloromethane:methanol (95:5); MS: m/z=456(M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:17][S:18]([CH3:21])(=[O:20])=[O:19].Br[CH:23]=[C:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][CH2:27][C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]1=2>>[CH:35]1[C:26]2[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:24](=[CH:23][C:7]3[C:2]([CH3:1])=[C:3]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH:4]=[CH:5][CH:6]=3)[C:25]=2[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: Cc1c(C=C2c3ccccc3CCc3ccccc32)cccc1NS(C)(=O)=O
Yield: 13.2 %

Procedure:
Following the procedures essentially as described in Example 219, below, and using N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (120 mg, 0.386 mmol) and 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.351 mmol), purification by UV-guided semi-preparatory reverse-phase HPLC affords 18 mg (13%) of the title compound as a yellow oil. MS (ES) 407 M+NH4), 388 (M−H); HPLC shows 96% purity.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:20][C:21]1[N:25]([CH:26]2[CH2:32][CH:31]3[N:33]([CH2:34][CH2:35][C:36]4([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:28]([CH2:29][CH2:30]3)[CH2:27]2)[C:24]2[CH:48]=[CH:49][CH:50]=[CH:51][C:23]=2[N:22]=1.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:6][C:2]([OH:1])([CH3:7])[C:3]([N:39]1[CH2:38][CH2:37][C:36]([CH2:35][CH2:34][N:33]2[CH:28]3[CH2:29][CH2:30][CH:31]2[CH2:32][CH:26]([N:25]2[C:24]4[CH:48]=[CH:49][CH:50]=[CH:51][C:23]=4[N:22]=[C:21]2[CH3:20])[CH2:27]3)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:41][CH2:40]1)=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)C(C)(C)O)CC1
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
2-hydroxy-2-methylpropanoic acid (36 mg, 0.35 mmole) was dissolved in 0.92 ml of 1,2-dichloroethane. To this was added 1,1′-carbonyldiimidazole (37 mg, 0.23 mmole) and shaken for 30 min. 2-Methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (50 mg, 0.12 mmole) was added as a dry powder and shaking was resumed overnight. 1 ml of NaHCO3 sat. was added to the reaction mixture and shaken, followed by filtration through a hydrophobic frit and concentrated to an oil. The oil was separated on silica using gradient flash chromatography (0-8% MeOH in CHCl3) to afford 2-methyl-1-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)-1-oxo-2-propanol 20 23.7 mg (38%) as a white glassy solid. 1H NMR (300 MHz, CDCl3) δ 7.7-7.6 (m, 1H), 7.1-7.4 (m, 8H), 4.7 (s, 1H), 4.0 (s, 2H), 3.2-3.4 (m, 4H), 2.6 (s, 3H), 2.2-2.5 (m, 5H), 2.1-1.7 (m, 11H), 1.7-1.5 (m, 2H).
Reaction SMILES: S(O[CH2:12][C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[C-:22]#[N:23].[Na+]>CS(C)=O.O>[C:22]([CH2:12][C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:15][CH2:16]1)#[N:23]
Reactant: [C-]#N
Reactant: CCOC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CCC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(CC#N)CCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
To a stirred solution of Intermediate 220A (0.5 g, 1.601 mmol) in DMSO (2.5 mL) was added NaCN (0.196 g, 4.00 mmol) and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with water and extracted with diethyl ether (3×30 mL) The combined organic layer was washed with water, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 220B as a brown oil (0.110 g, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.19-4.01 (m, 2H), 3.01-2.97 (m, 2H), 2.45-2.32 (m, 2H), 2.08-1.83 (m, 4H), 1.25-1.18 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([CH2:19][C:20](O)=[O:21])[N:9]=2)=[CH:4][C:3]=1[CH3:23].CCN(C(C)C)C(C)C.[N:33]1([C:39]2[N:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]([CH2:19][C:20]([N:36]3[CH2:37][CH2:38][N:33]([C:39]4[N:40]=[CH:41][CH:42]=[CH:43][N:44]=4)[CH2:34][CH2:35]3)=[O:21])[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1cc(-c2cc(-c3ccccc3)n(CC(=O)O)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2cc(-c3ccccc3)n(CC(=O)N3CCN(c4ncccn4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg 3-(4-fluoro-3-methyl-phenyl)-5-phenyl-pyrazol-1-yl acetic acid was dissolved in 2 mL DMF. 83 mg PFTU and 33 μL DIPEA were added to this solution and the mixture was stirred for 15 min at RT. Then, 25 μL 2-(1-piperazinyl)-pyrimidine was added and stirring was continued for 8 h. Then, 1 mL of a K2CO3 solution (5%) and 10 mL CH2Cl2 were added, the organic phase was separated and washed two times with water. The solvent was removed and the residue was crystallized from ACN to yield 46 mg of the desired compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Reactant: C1COCCN1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCOCC4)c23)ccc1OCc1ccccc1
Yield: 58 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and morpholine to give the title compound in 58% yield; NMR Spectrum: 2.22 (s, 3H), 2.50-2.52 (m, 4H), 2.79 (t, 2H), 3.54-3.56 (m, 4H), 4.42 (t, 2H), 5.14 (s, 2H), 7.02 (d, 1H), 7.32-7.48 (m, 7H), 8.20 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 461 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([OH:18])=O)(=[O:10])=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.Cl.[CH3:38][NH:39][O:40][CH3:41].Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([N:39]([O:40][CH3:41])[CH3:38])=[O:18])(=[O:9])=[O:10]
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a mixture of 3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carboxylic acid (2.5 g, 7.8 mmol) described in Production Example 1-1 and tetrahydrofuran (25 mL) was added 1,1′-carbonyldiimidazole (2.0 g, 12 mmol) at room temperature, followed by stirring at that temperature for 30 minutes. Imidazole (1.1 g, 16 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.2 g, 12 mmol) were added successively at room temperature to the reaction mixture, followed by stirring at that temperature for 5 hours. A 1 N aqueous solution of hydrochloric acid (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the title compound (1.5 g, 53% yield).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]([NH:7][C:8]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:14]2[C:15]([C:21](=[O:23])[CH2:20][CH2:19][O:18]2)=[CH:16][CH:17]=1)=[O:6])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)cccc1OCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCCC2=O
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A solution of methyl 2-tert-butylcarbonylamino-6-(2-carboxyethoxy)-benzoate (Intermediate 78, 2.73 g) in DCM (50 mL) was stirred at room temperature. DMF (5 drops) was added, followed by oxalyl chloride (2.0 g). After 30 minutes of stirring, the mixture was concentrated in vacuo and the residue was redissolved in DCM and evaporated to dryness. The residue was dissolved in DCM (50 mL) and aluminium chloride (3.38 g) was added. The resultant mixture was stirred at room temperature for 5 hours then diluted with more DCM and washed with ice/water. After separation, the aqueous phase was extracted with more DCM and the combined organic layers were washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 10-40% to give methyl 7-tert-butylcarbonylamino-4-oxochroman-8-carboxylate (1.16 g) as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:10]1[O:12][CH2:11]1.[OH-].[Na+]>>[OH:12][CH2:11][CH2:10][N:6]1[C:2]([CH3:9])([CH3:1])[C:3](=[O:8])[NH:4][C:5]1=[O:7]
Reactant: C1CO1
Reactant: CC1(C)NC(=O)NC1=O
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C(=O)NC(=O)N1CCO

Procedure:
Thus, to make the non-methylolated hydantoin fatty acid ester, or MHEDMH ester (Ia), 5,5-dimethylhydantoin, or DMH (ii) [C5H8O2N2 =128 mol. wt.], is reacted with ethylene oxide in a first step per reaction scheme (1a), e.g. in the presence of a catalyst such as sodium hydroxide, to form monohydroxyethyl dimethylhydantoin, or 1-(2-hydroxyethyl)-5,5-dimethylhydantoin [i.e., 1-(2-hydroxyethyl)-5,5-dimethyl-1,3-diazacyclopentane-2,4-dione], or MHEDMH (vi) [C7H12O3N2 =172 mol. wt⟧
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:14]([NH2:19])[C:15]([NH2:18])=[N:16][N:17]=1)=[CH:7][CH:6]=2.[CH:20]([CH:22]=O)=O.C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:14]3[N:19]=[CH:20][CH:22]=[N:18][C:15]3=[N:16][N:17]=1)=[CH:7][CH:6]=2
Reactant: O=CC=O
Reactant: Nc1nnc(Cc2ccc3ncc(Br)cc3c2)n1N
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2ccc(Cc3nnc4nccnn34)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(3-bromo-quinolin-6-ylmethyl)-[1,2,4]triazole-3,4-diamine (977 mg, 3 mmol), glyoxal (40% solution in water, 5 mL), acetic acid (10 mL) and water (2 mL) was stirred at ambient temperature for 18 hours. After such time the mixture was filtered and the filtrate was concentrated onto silica gel and via flash column chromatography (SiO2 12 g, dichloromethane/CH3OH, 0-10%) to return the title compound a white solid (298 mg, 29%). Analytical data presented in Table 1.
Reaction SMILES: O/[CH:2]=[C:3](\[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1)/[C:4]([O:6]C)=O.[C:15](=[NH:37])([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:22][CH:21]=1)[NH2:16].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[O:6]=[C:4]1[C:3]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:2][NH:37][C:15]([O:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)=[CH:24][CH:25]=2)=[N:16]1
Reactant: COC(=O)/C(=C/O)Cc1cncnc1
Reactant: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1nc(OCCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 160 °C
Yield: 28.4 %

Procedure:
To the suspension of methyl (2E)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (105 mg, 0.542 mmol) and 2-(4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate (171 mg, 0.361 mmol) in NMP (4 mL) was added K2CO3 (150 mg, 1.084 mmol). The mixture was heated with a microwave reactor at 160° C. for 1 h. Purification via MDAP then afforded the title compound (48 mg, 28.4% yield). LCMS: rt=3.258 min, [M+H+]=469
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)=[O:28])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:13])=[O:7]>CO>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)=[O:28])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:13])=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc2c1cnn2C1CCCCO1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
An aqueous solution of sodium hydroxide (1 M, 190 μL, 0.19 mmol) was added to a solution of N-[2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (108 mg, ˜0.169 mmol) in methanol (1 mL). The solution was allowed to stir at room temperature for 2 days, then it was concentrated and held under high vacuum for 1 h to give N-[2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (100 mg, 97%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=4)[N:25]=3)[CH2:30][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: Cc1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(-c2csc(N3CCN(C(=O)Nc4onc(C)c4C)CC3)n2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 43.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (244 mg, 0.848 mmol), 1-[4-(3-methylphenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.269 ml, 1.54 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 132 mg (43.0%) of the desired product as a solid. mp 175-176° C.
Reaction SMILES: [OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][C:19](/[C:22](=[N:24]/[OH:25])/[NH2:23])=[CH:18][CH:17]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5]1.C(=O)(O)[O-].[Na+].Cl.NO>CC(O)C.C(OCC)(=O)C>[OH:1][CH:2]([C:16]1[CH:17]=[CH:18][C:19](/[C:22](=[N:24]/[OH:25])/[NH2:23])=[CH:20][CH:21]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5]1
Reactant: CCOC(=O)C[C@H]1CCCN(C[C@@H](O)c2ccc(/C(N)=N/O)cc2)C1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc(/C(N)=N/O)cc2)C1
Temperature: 85 °C

Procedure:
To a mixture of ethyl 2-((R)-1-((S)-2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (18C-Isomer A) and sodium bicarbonate (378 mg, 4.50 mmol) in 2-propanol (10 mL) was added hydroxylamine hydrochloride (156 mg, 2.250 mmol). The reaction mixture was heated at 85° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated to yield 346 mg of ethyl 2-((3R)-1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate. MS (M+1)=336. HPLC Peak RT=0.12 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:35]([OH:37])=[O:36])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20]CC2C3C=CC=CC=3C3C2=CC=CC=3)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:38]([NH:46][C@H:47](C(O)=O)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:12]([C:35]([OH:37])=[O:36])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:47]([NH:46][C:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:45])[CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:20])[CH2:1][CH:2]([CH3:7])[CH3:3])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-N(-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-benzoyl-L-phenylalanine (321 mg, 1.2 mmol). The final product was purified by preparative HPLC to yield 44 mg (58%) of the desired material.