Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:12])=[CH:5]2.Cl.CN(C)CCCN=C=NCC.[CH3:37][O:38][C:39]1[CH:50]=[C:49]2[C:42]([NH:43][CH:44]=[C:45]2[CH2:46][CH2:47][NH2:48])=[CH:41][CH:40]=1>CN(C)C=O>[CH3:37][O:38][C:39]1[CH:50]=[C:49]2[C:42](=[CH:41][CH:40]=1)[NH:43][CH:44]=[C:45]2[CH2:46][CH2:47][NH:48][C:15]([CH:14]([NH:13][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:12])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(F)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCNC(=O)C(Cc3ccccc3)NC(=O)c3cc4cc(F)ccc4[nH]3)c2c1
Reaction time: 72 h

Procedure:
To 5.0 μmol of 2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (50 μL of a 0.1 mM solution in dimethylformamide) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 μL of a 0.11 mM solution in DMF, 5.5 μmol) followed by 5-methoxytryptamine (50 μL of a 0.11 mM solution in DMF, 5.5 μmol). The reaction was agitated for 3 days and then concentrated to dryness. The crude product was partitioned between chloroform (0.5 mL) and water (0.25 mL) and the organic layer was then concentrated to give the title compound. TSPMS ion (expected) 499 (499); HPLC RT 6.78 (25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]=[C:6]([NH2:8])[S:5][N:4]=1.[C:9](Cl)(=[O:17])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O>ClCCl>[C:11]1([O:10][C:9](=[O:17])[NH:8][C:6]2[S:5][N:4]=[C:3]([O:2][CH3:1])[N:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1nsc(N)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1nsc(NC(=O)Oc2ccccc2)n1
Reaction time: 16 h

Procedure:
3-Methoxy-1,2,4-thiadiazol-5-amine a (500 mg, 3.82 mmol) and phenyl carbonochloridate b (600 mg, 3.82 mmol) were dissolved in 20 mL of dichloromethane, followed by addition of triethylamine (0.8 mL, 5.73 mmol). After reacting for 16 hours, 30 mL of H2O were added into the reaction mixture to dilute the solution. The aqueous phase and organic phase were separated, the aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product phenyl(3-methoxy-1,2,4-thiadiazol-5-yl)carbamate c (200 mg, yield 20.8%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([NH2:14])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([NH:14][CH2:23][CH3:24])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1cc(C(=O)OC)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
A mixture of 3-amino-5-(trifluoromethyl)-benzoic acid methyl ester (J. Med. Chem. (1969) 12, 299-303; 4.23 g, 19.3 mmol), potassium carbonate (8.0 g, 57.9 mmol) and iodoethane (3.12 mL, 38.6 mmol) in 20 mL N,N-dimethylformamide is stirred at 65° C. for 14 hours in a tightly closed vessel. After cooling, the reaction mixture is filtered and the filtrate evaporated to dryness under reduced pressure. The residue is treated with water and extracted three times with ethyl acetate. The combined extracts are dried (Na2SO4) and the solvent is evaporated off under reduced pressure. The resulting residue is purified by column chromatography on silica gel, eluent hexane/methylene chloride (1:1).
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N:16]3[C:21](=[O:22])[NH:20][CH2:19][CH:18]=[N:17]3)=[CH:11][C:10]=2[Cl:23])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N:16]3[C:21](=[O:22])[NH:20][CH2:19][CH:18]=[N:17]3)=[CH:11][C:10]=2[Cl:23])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(Cc2c(Cl)cc(N3N=CCNC3=O)cc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(Cc2c(Cl)cc(N3N=CCNC3=O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
In 1.5 ml of ethanol was suspended 0.15 g of 2-[4-(4-acetylbenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one. To the suspension was added 0.1 g of sodium borohydride. The mixture was stirred for one hour at room temperature. The reaction mixture was poured into 10 ml ice-water, followed by extraction with 10 ml of ethylacetate. The extract was dried over anhydrous magnesium sulfate, and concentrated. This residue was purified by column chromatography (Merck Silica Gel 60; hexane-acetone=1:1) to provide 0.13 g of the title compound as colorless crystals, m.p. 119-120° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(#N)C.[O:18]1[CH2:23][CH2:22][CH:21](/[CH:24]=[CH:25]/[C:26]#[N:27])[CH2:20][CH2:19]1.N12CCCN=C1CCCCC2>>[O:18]1[CH2:23][CH2:22][CH:21]([CH:24]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:25][C:26]#[N:27])[CH2:20][CH2:19]1
Reactant: N#C/C=C/C1CCOCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCOCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.25 g, 0.00644 mol) in acetonitrile (20 mL, 0.4 mol) was added (2E)-3-(tetrahydro-2H-pyran-4-yl)acrylonitrile (1.00 g, 0.00729 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.09 mL, 0.00729 mol). The resulting mixture was stirred at room temperature overnight. After being evaporated to dryness, the residue was purified on silica gel, eluting with 0-100% EtOAc in hexanes, to provide the desired product (1.30 g, 60.93%). LCMS (M+H) 332.4.
Reaction SMILES: [CH3:1][N:2]([CH3:66])[C@H:3]1[CH2:63][C@@H:62]([CH3:64])[O:61][CH:5]([O:6][C@@H:7]2[C@@H:23]([CH3:24])[C:22](=[O:25])[C@@H:21]([CH3:26])[C:20](=[O:27])[O:19][C@H:18]([CH2:28][CH3:29])[C@:17]3([CH2:30][O:31][Si](C(C)(C)C)(C)C)[C@H:13]([N:14]([CH2:40][CH2:41][CH2:42][CH2:43][N:44]4[CH:48]=[C:47]([C:49]5[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=5)[N:46]=[CH:45]4)[C:15](=[O:39])[O:16]3)[C@@H:12]([CH3:55])[C:11](=[O:56])[C@H:10]([CH3:57])[CH2:9][C@:8]2([O:59][CH3:60])[CH3:58])[C@@H:4]1[OH:65].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH3:66][N:2]([CH3:1])[C@H:3]1[CH2:63][C@@H:62]([CH3:64])[O:61][CH:5]([O:6][C@@H:7]2[C@@H:23]([CH3:24])[C:22](=[O:25])[C@@H:21]([CH3:26])[C:20](=[O:27])[O:19][C@H:18]([CH2:28][CH3:29])[C@:17]3([CH2:30][OH:31])[C@H:13]([N:14]([CH2:40][CH2:41][CH2:42][CH2:43][N:44]4[CH:48]=[C:47]([C:49]5[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=5)[N:46]=[CH:45]4)[C:15](=[O:39])[O:16]3)[C@@H:12]([CH3:55])[C:11](=[O:56])[C@H:10]([CH3:57])[CH2:9][C@:8]2([O:59][CH3:60])[CH3:58])[C@@H:4]1[OH:65]
Reactant: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc(-c4cccnc4)c3)C(=O)O[C@]12CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc(-c4cccnc4)c3)C(=O)O[C@]12CO
Reaction time: 48 h
Yield: 48 %

Procedure:
To (3aR,4R,7R,9R,10R,11R,13 R,15R,15aR)-3a-({[tert-butyl(dimethyl)silyl]-oxy}methyl)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in tetrahydrofuran was added acetic acid (2 eq) and tetrabutylammonium fluoride/1.0M in tetrahydrofuran (2 eq). After standing for 48 hours, ethyl acetate was added and the solution was washed with NaHCO3(sat.), NaCl(sat.), dried over MgSO4, filtered, and concentrated. Purification by RP HPLC afforded (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-(hydroxymethyl)-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)-butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (48% yield) as a white solid. MH+(828.50).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13]C>ClCCl>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:19]2[N:18]=[C:17]([CH:16]=[CH:15][C:9]3[CH:8]=[C:7]([OH:6])[C:12]([OH:13])=[CH:11][CH:10]=3)[O:21][N:20]=2)[CH:23]=1
Reactant: COc1ccc(C=Cc2nc(-c3cccnc3)no2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C=Cc2nc(-c3cccnc3)no2)cc1O
Reaction time: 0.62 h

Procedure:
To a cooled solution of 0.35 mL of 1M boron tribromide (3.7 mmol) in 2 mL dichloromethane, 0.500 g (1.6 mmol) of 3-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-yl}-pyridine (compound of Example 54) dissolved in 5 mL of dichloromethane was added over a period of 15-20 min at −45° C. to −40° C. The reaction mixture was stirred at −45° C. to −40° C. for 30-45 min and allowed to attain a temperature of 25° C. to 30° C. slowly, over a period of 1 h. The reaction mixture was further stirred at 25° C. to 30° C. for 4-5 h. After completion of the reaction, the reaction mixture was quenched in 10 mL of chilled 5% sodium bicarbonate solution, below 20° C. (pH: 8-9). 10 mL of ethyl acetate was added to the reaction mixture to dissolve the solid and stirred for 10-15 min. The organic layer was separated and the aqueous layer was washed with 10 mL of 10% sodium chloride solution. The organic layer was collected and distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:38][S:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:46](=[O:47])[C:45]3[CH:44]=[CH:43][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:50][CH:49]=3)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 60 %

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C), according to the procedure of Example 43 except that p-(methylsulfonyl)benzoic acid was used as the acid. The crude product was purified by flash chromatography (gradient elution using 0.5-10% MeOH/CH2Cl2) to afford a 60% yield of the desired compound as a white solid, homogeneous by TLC in 5% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 735 (M+Na)+, 751 (M+K)+ ; mp 131°-133° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.O.O.O.O.O.O.[F:18][C:19]([F:27])([F:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[O:21]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[C:11]([C:20]([OH:21])([C:22]([F:25])([F:24])[F:23])[C:19]([F:27])([F:26])[F:18])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Nc1cccc2cnccc12
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2cnccc12
Temperature: 150 °C
Yield: 21 %

Procedure:
5-Aminoisoquinoline (288 mg, 2.00 mmol) and p-toluenesulfonic acid (5 mg) were combined and treated with hexafluoroacetone hexahydrate (0.29 mL, 462 mg, 2.10 mmol). The mixture was stirred in a sealed pressure tube and heated to 150° C. for 18 hours. The reaction was allowed to cool to room temperature and partitioned between CH2Cl2(20 mL) and water (10 mL). The organic layer was passed thru Na2SO4 and then filtered through activated charcoal. The charcoal was washed with methanol (3×10 mL) and the filtrate and washings were collected and concentrated under reduced pressure to provide the title compound (130 mg, 30%) as a yellow solid. MS (ESI+) m/z 311 (M+H)+; MS (ESI−) m/z 309 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 6.64 (br s, 2H), 7.30 (d, J 8.7, 1H), 7.40 (d, J 8.7, 1H), 8.09 (d, J 6.1, 1H), 8.49 (d, J6.1, 1H), 9.14 (s, 1H); 13C NMR (DMSO, 100 MHz) δ 107.02, 110.60, 113.95 (1), 115.46 (1), 122.03, 124.92, 124.92, 125.94, 126.98 (1), 128.17, 142.43 (1), 144.82, 151.85 (1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:25]([O-:27])=[O:26])=[C:12]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:13]=2)=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:25]([O-:27])=[O:26])=[C:12]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:13]=2)=[CH:5][CH:4]=1)=[O:1]
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc(CO)s3)ccc2[N+](=O)[O-])cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(C=O)s3)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
A suspension of alcohol 190 (0.178 g, 0.463 mmol) in DCM (5.0 mL) was treated with solid Dess-Martin periodinane (0.399 g, 0.94 mmol) and stirred under nitrogen atmosphere at room temperature for 20 h. The reaction mixture was quenched with an aqueous solution of Na2S2O3, stirred for 60 min, diluted with DCM/MeOH mixture, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated to give title compound 191 (0.155 g, 88% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:21][CH:20]=4)=[N:16][N:15]=3)[C:11]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:10][CH:9]=2)=[CH:4][CH2:3]1.CCN(CC)CC.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>C(Cl)Cl>[C:39]([O:38][C:36]([NH:35][C:11]1[C:12]([C:14]2[O:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:23][CH:24]=3)=[N:16][N:15]=2)=[N:13][C:8]([C:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:50](=[O:53])[CH2:51][CH3:52])[CH2:3][CH:4]=2)=[CH:9][N:10]=1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(N)CC4)cnc3NC(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CC=C(c2cnc(NC(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)n2)CC1
Yield: 110.5 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[6-(4-aminocyclohexen-1-yl)-3-(tert-butoxycarbonylamino)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (20 mg, 0.03 mmol) in anhydrous DCM (200 μL) was added Et3N (5 mg, 7 μL, 0.05 mmol) and the reaction mixture was cooled in an ice water bath. A solution of propanoyl chloride (3.843 mg, 3.625 μL, 0.04154 mmol) in DCM (0.1 mL) was added dropwise to the above reaction mixture. The reaction mixture was diluted with DCM and washed once with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 10% MeOH in EtOAc to yield tert-butyl N-[[4-[5-[3-(tert-butoxycarbonylamino)-6-[4-(propanoylamino)cyclohexen-1-yl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (21 mg, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]3)=[CH:13][C:12]=2[N+:31]([O-])=O)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CO.[H][H]>C1COCC1.CCO.[Pd]>[NH2:31][C:12]1[CH:13]=[C:14]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:15]=[CH:16][C:11]=1[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)c3cccc(F)c3)c([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A mixture of tert-butyl 4-{4-[(3-fluorophenyl)sulfonyl]-3-nitrophenyl}-1,4-diazepane-1-carboxylate (58.0 g, 121 mmol) and Pd/C (8.70 g, 15% by wt.) in 1.5 L of a 2:2:1 THF:MeOH:EtOH solvent is exposed to hydrogen gas (25 psi) in a Parr bottle. The pressure of hydrogen is constantly monitored and kept near 25 psi. After 16 h, the mixture is filtered, solids rinsed with MeOH and CH2Cl2, and filtrate concentrated to give a brown solid. The solid is triturated with EtOAc and hexane to give 53.4 g (98%) of the title compound as an off white solid.
Reaction SMILES: C[N:2](C)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].Cl.[NH2:17]N.CO.C(Cl)Cl>C(O)CCC>[F:11][C:10]([F:13])([F:12])[C:9]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:3]=2[NH:2][N:17]=1
Reactant: NN
Reactant: CN(C)c1ccncc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCCCO
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)c1n[nH]c2ccncc12
Temperature: 200 °C
Yield: 84.2 %

Procedure:
A suspension of 1-(4-(dimethylamino)pyridin-3-yl)-2,2,2-trifluoroethanone (259 mg, 1.187 mmol) and hydrazine monohydrochloride (244 mg, 3.56 mmol) in butan-1-ol (2.5 mL) was heated to 200° C. for 35 min. The reaction mixture was applied to a 10 g SPE cartridge that had been pre-conditioned with 3% MeOH/DCM and eluted with the same system to give a light yellow solid (189 mg, 1.0 mmol, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.Cl[C:14]1[C:23]2[C:18](=[C:19]([C:24](F)(F)F)[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.Cl.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:14]1[C:23]2[C:18](=[C:19]([CH3:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: COc1ccc2[nH]c(C)c(-c3ccnc4c(C)cccc34)c2c1
Temperature: 140 °C
Yield: 93.7 %

Procedure:
A mixture of 5-methoxy-2-methylindole (346 mg) and 4-chloro-8-trifluoromethylquinoline (380 mg) in NMP (1 ml) and 4M HCl in dioxane (0.1 ml) was heated at 140° C. for 50 min. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol-acetone as eluent) to give the sub-title compound (465 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[NH:23][C:22](=[O:31])[CH2:21][C:20]2=[O:32])=[CH:15][CH:14]=1.CC1C(C)=CC=CC=1C(Cl)=O>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[NH:23][C:22](=[O:31])[CH2:21][C:20]2=[O:32])=[CH:15][CH:14]=1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: Cc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Agent: Cc1cccc(C(=O)Cl)c1C
Product: Cc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c(C)cccc43)cc2)c1C
Yield: 92 %

Procedure:
2,3-Dimethylbenzoic acid (21 mg, 0.140 mmol) was made into acid chloride in a conventional manner. By using 1-(4-aminophenyl)-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (20 mg, 0.071 mmol) mentioned above, and 2,3-dimethylbenzoyl chloride mentioned above, the title compound (27 mg, yield 92%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[N+:23]([O-])=O)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.C([O-])=O.[NH4+].O>C(O)C.[Pd]>[NH2:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[NH:13][CH:7]([C:4]1[CH:3]=[CH:2][C:1]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:6][CH:5]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC(Nc1ccc([N+](=O)[O-])cc1N)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-(1,1′-biphenyl)-4-yl-3-(2,4-dinitroanilino)propanoate (320 mg, 760 μmol) in ethanol (3 mL) was added palladium on carbon (64 mg, 10% active Pd), ammonium formate (239 mg, 3.80 mmol) and water (1 mL). The solution was stirred at room temperature for 1.5 hour, and was then filtered through a pad of Celite®. The filter pad was washed with ethyl acetate, and the filtrate evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane, to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=3.44 min, MH+ 392].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][C@@H:18]3[CH2:33][OH:34])=[O:16])[N:12]=[C:11]2[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:42]([O:44]C1C=C(N2C=C(C(N3CCN(C(OCC4C=CC=CC=4)=O)C[C@@H]3C(OC)=O)=O)N=C2C2C=CC(C)=CC=2)C=CC=1)[CH3:43].[BH4-].[Li+]>CO>[C:42]([O:34][CH2:33][C@H:18]1[CH2:19][NH:20][CH2:21][CH2:22][N:17]1[C:15]([C:13]1[N:12]=[C:11]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH:14]=1)=[O:16])(=[O:44])[CH3:43]
Reactant: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3C(=O)OC)nc2-c2ccc(C)cc2)c1
Reactant: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3CO)nc2-c2ccc(C)cc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: CCOc1cccc(-n2cc(C(=O)N3CCNC[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Reaction time: 1 h

Procedure:
Benzyl (3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-(hydroxymethyl)piperazine-1-carboxylate To a solution of 4.10 g (7.04 mmol) of 1-benzyl 3-methyl (3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1,3-dicarboxylate from Step A in 75 mL of anhydrous methanol at 0° C. under a nitrogen atmosphere was added 460 mg (21.1 mmol) of lithium borohydride. An additional 460 mg (21.1 mmol) of lithium borohydride was added to the reaction mixture every hour for 3 hours and stirred for one hour after the final addition. The reaction was quenched with a saturated aqueous ammonium chloride solution (50 mL) followed by concentration in vacuo to remove the methanol. The residue was diluted with water (15 mL) and extracted with dichloromethane (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified on a Biotage® purification apparatus (silica gel, 65% ethyl acetate in hexanes) to yield the title compound as a colorless solid. LC/MS 555.2 (M+1).