Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:34])([CH2:28]OS(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:34])([CH2:28][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 50 °C
Yield: 34.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (200 mg) was dissolved in dimethylformamide (10 ml), to which 1H-1,2,4-triazole (83 mg) and potassium carbonate (168 mg) were added, and the mixture was heated at 50° C. for 20 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with water (15 ml), 1N-hydrochloric acid (15 ml×2) and a saturated aqueous solution of sodium chloride (15 ml). The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:ethyl acetate). The desired fraction was concentrated and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H) -imidazolone (Compound 44, 65 mg) as a colorless crystalline powder.
Reaction SMILES: CCCC(C1(CC)C(=O)N=C([O-])NC1=O)C.[Na+:17].[C:18]([OH:39])(=[O:38])[CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:18]([O-:39])(=[O:38])[CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[Na+:17]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CCCC(C)C1(CC)C(=O)N=C([O-])NC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)[O-]
Reaction time: 0.5 h

Procedure:
Male albino guinea pigs weighing 400-600 g each (Dunkin Hartley strain) were anesthetized by administration of sodium pentobarbitone, 60 mg/kg intraperitoneally. The trachea was cannulated for artificial ventilation by a Starling pump (5-8 ml at 72 strokes per minute) via a Fleisch 0000 pneumatachograph. The difference in pressure across this device was measured with a Grass differential pressure transducer. This gives a flow signal which was fed into a Hewlett-Packard 8816A analogue computer. Transpulmonary pressure (TPP) was measured with another differential pressure transducer via side arms to the thoracic cavity and the tracheal cannula. The signals for low and TPP were applied to the analogue computer so that there was approximately 180° phase difference. The computer derived the dynamic compliance and resistance from the in-going signals. Drugs were administered intravenously via the external jugular vein. A 1 mg/ml solution of sodium arachidonate was prepared as follows. Arachidonic acid (10 mg, 99 percent pure) was dissolved in 0.2 ml absolute ethanol and the solution was diluted to 10 ml with 0.2 percent weight per volume sodium carbonate solution. Challenge doses of 100-500 micrograms per kg were given via the cannulated left external jugular vein and "washed in" with 0.5 ml of 0.85 percent weight per volume sodium chloride solution (saline) containing 10 units/ml of heparin. These doses were given at 30 minute intervals to produce a large but submaximal bronchoconstriction. After 2 or 3 similar responses to the same dose of sodium arachidonate had been obtained, the test substance in saline (0.1 to 1 ml) was injected intravenously. At various times thereafter, a challenge was given. The test substances used were as follows: human plasma Cohn subfraction IV4 (unheated or heated to 60° C. for 15 minutes and cooled to 20° C.); Cohn subfraction IV4 purified as described above; dexamethasone sodium phosphate; hydrocortisone sodium succinate; aldosterone; aspirin calcium salt; indomethacin sodium salt; and a drenocorticotrophin (ACTH).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([NH:29][CH:25]3[CH2:28][CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: NC1CCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)NC3CCC3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), cyclobutylamine (43 uL, 36 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 35 mg (42% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.48-1.66 (m, 6 H), 1.68 (s, 9 H), 1.72-1.87 (m, 2 H), 1.95-2.08 (m, 2 H), 2.28-2.50 (m, 1 H), 3.31-3.41 (m, 2 H), 3.68-3.83 (m, 1 H), 3.90-3.99 (m, 2 H), 4.53 (d, J=7.62 Hz, 2 H), 7.96 (dd, J=8.80, 1.6 Hz, 1 H), 8.04 (d, J=9.0 Hz, 1 H), 8.19 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=406.0; Anal. Calcd for C21H31N3O3S+1.20 TFA+0.60 EtOAc+0.2H2O (598.86): C, 51.75; H, 6.29; N, 7.02. Found: C, 51.70; H, 6.25; N, 7.03.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([OH:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N+:2]=[N-:3].Cl[C:16]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:1]([CH2:4][CH2:5][CH:6]([O:14][C:16]1[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19])[C:7]([F:12])([F:13])[C:8]([F:10])([F:11])[F:9])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCC(O)C(F)(F)C(F)(F)F
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)nc1OC(CCN=[N+]=[N-])C(F)(F)C(F)(F)F
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 5-azido-1,1,1,2,2-pentafluoro-3-pentanol (500 mg, 2.28 mmol) in dimethylformamide (10 ml) was added 2-chloro-6-(trifluoromethyl)nicotinonitrile (565 mg, 2.74 mmol) followed by caesium carbonate (2.20 g, 6.75 mmol). The reaction mixture turned brown. After 2 h, the reaction mixture was added to water (10 ml) and extracted with diethyl ether (2×15 ml). The combined organics were washed with brine (20 ml) and dried over anhydrous sodium sulfate. Removal of the solvents yielded a brown liquid. Purification by silica gel chromatography using hexanes/ethyl acetate (10:1 then 1:1) gave the title compound as a yellow liquid (780 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[F:10].[F:11][CH:12]([F:15])[CH2:13][NH2:14].C(N(CC)CC)C>C(#N)C.Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:14][CH2:13][CH:12]([F:15])[F:11])=[CH:4][C:3]=1[F:10]
Reactant: NCC(F)F
Reactant: Fc1cc(CCl)cnc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1cc(CNCC(F)F)cnc1Cl
Yield: 57 %

Procedure:
At 45° C., 520 mg (2.89 mmol) of 6-chloro-3-chloromethyl-5-fluoropyridine (VII-3), 1.05 ml (14.44 mmol) of 2,2-difluoroethylamine and 400 μL (2.89 mmol) of triethylamine are stirred in 50 ml of acetonitrile for about 48 hours. After about 16 and 32 hours, in each case another 0.42 ml (5.78 mmol) of 2,2-difluoroethylamine are added. After concentration of the reaction mixture under reduced pressure, the residue is taken up in 1 N aqueous hydrochloric acid and the mixture is washed with ethyl acetate. The aqueous phase is made alkaline using 2.5 N aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate. The combined organic phase is dried over sodium sulphate and concentrated under reduced pressure, giving 370 mg (57% of theory) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]-2,2-difluoroethylamine.
Reaction SMILES: [Cl:1][C:2](=[CH2:5])[C:3]#[N:4].C1CC=CC=1.[C:11]1([CH3:17])[CH:16]=CC=[CH:13][CH:12]=1>>[Cl:1][C:2]1([C:3]#[N:4])[CH2:16][CH:11]2[CH2:17][CH:5]1[CH:13]=[CH:12]2
Reactant: C=C(Cl)C#N
Reactant: Cc1ccccc1
Agent: C1=CCC=C1
Product: N#CC1(Cl)CC2C=CC1C2
Temperature: 25 °C
Reaction time: 60 h
Yield: 56.5 %

Procedure:
To a solution of 2-chloroacrylonitrile (50.0 g, 571 mmol) in toluene (150 ml) was slowly added cyclopentadiene (37.7 g, 571 mmol). The reaction was stirred for 60 h at ambient temperature under a nitrogen atmosphere. The reaction was then concentrated by rotary evaporation to remove the majority of the toluene. The compound was purified by vacuum distillation (100-150° C., 15 mm Hg) to afford the nitrile as a white solid (49.7 g, 56.5%).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]4[CH:21]=[C:22]([C:34](=[O:36])[CH3:35])[CH:23]=[CH:24][C:25]=4[O:26]CC4C=CC=CC=4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[ClH:39]>C(O)(=O)C>[ClH:39].[F:1][C:2]1[CH:38]=[CH:37][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]4[CH:21]=[C:22]([C:34](=[O:36])[CH3:35])[CH:23]=[CH:24][C:25]=4[OH:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(OC/C=C/CN2CCC(c3noc4cc(F)ccc34)CC2)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc(O)c(OC/C=C/CN2CCC(c3noc4cc(F)ccc34)CC2)c1
Temperature: 75 °C

Procedure:
The mixture of (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]2-butenyl]oxy]-4-benzyloxyphenyl]ethanone (5.5 g, 10.7 mmol), acetic acid (50 ml), and hydrochloric acid (6 ml) was heated at 75° C. for 2 hours. At the end of reaction, the solvent was reduced to about 20 ml on a rotary evaporator. The solution was poured into ice water (350 ml) and extracted with dichloromethane (3×250 ml). The dichloromethane solution was washed with brine and dried over Na2,SO4. A solid formed on concentration of the solvent. This was collected by filtration (3.4 g). Recrystallization from hot methanol (40 ml) gave 1.82 g of (E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-hydroxyphenyl]-ethanone hydrochloride as white crystals, 37.5%, m.p.=208°-210° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4].[CH3:23][S:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH2:29][C:28]4[CH:31]=[CH:32][C:25]([S:24][CH3:23])=[CH:26][CH:27]=4)[CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=[O:4]
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3CCCNC3)ccc21
Reactant: CSc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CSc1ccc(CN2CCCC(Nc3ccc4c(cnn4C(=O)C(C)(C)C)c3)C2)cc1
Yield: 71.6 %

Procedure:
Into a 25 mL round bottom flask were combined 2,2-dimethyl-1-(5-(piperidin-3-ylamino)-1H-indazol-1-yl)propan-1-one (0.250 g, 0.8 mmol), 1,2-dichloroethane (5 mL), 4-(methylthio)benzaldehyde (0.127 g, 0.8 mmol), glacial acetic acid (50 μL, 0.8 mmol), and sodium triacetoxyborohydride (0.229 g, 1.1 mmol). The reaction was evacuated and refilled with nitrogen. The reaction was monitored by HPLC and was complete upon the disappearance of the starting amine. The reaction was diluted with saturated sodium bicarbonate (10 mL) and dichloromethane (5 mL). After mixing, the organic phase was isolated, dried over MgSO4, filtered and concentrated to give the crude product. Chromatography of the residue on silica gel gave the title compound as an off-white solid (250 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:19])([CH3:18])[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24].C(N(CC)CC)C>C(O)(=O)C>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])([CH3:19])[C:10](=[O:20])[NH:9]2)=[CH:6][CH:7]=1)=[O:24]
Reactant: CC1(C)C(=O)NC(c2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)NC(c2ccc(NC(=O)CCl)cc2)c2ccccc21

Procedure:
30.0 g. (0.1125 moles) of 1-(4'-aminophenyl)-1,4-dihydro-4,4-dimethyl-3(2H)-isoquinolinone are reacted in 280 ml. of glacial acetic acid with 14.7 g. (0.13 moles) of chloroacetyl chloride, in the presence of 13.5 g. (0.13 moles) of triethylamine. The reaction conditions are the same as described in Example 1. The crude product is recrystallized from ethanol to yield 25.15 g. of the title compound; m.p.: 218°-219°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH3:54][NH:55][CH3:56]>CS(C)=O.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([N:55]([CH3:56])[CH3:54])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:33]=[C:34]([C:42]([F:44])([F:43])[F:45])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=3)[C:28]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(N(C)C)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 40 °C
Reaction time: 72 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg) is dissolved in dimethylsulfoxide (2 ml), and thereto is added a 2M solution (300 μl) of dimethylamine in tetrahydrofuran under ice-cooling. The mixture is stirred at 40° C. for 72 hours in a closed vessel, and partitioned by adding water and ethyl acetate to the reaction solution. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=4:1→2:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-dimethylamino-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (78 mg). MS (m/z): 682 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:51])[CH2:10][C@@H:11]([N:34]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42](C3C=CN=CC=3)=[CH:41][CH:40]=2)=[CH:35]1)[C:12]([NH:14][C@H:15]1[CH2:31][C:30]2=[CH:32][N:23]([C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18][NH:17][C:16]1=[O:33])=[O:13])C1C=CC=CC=1.C(O)=O.[CH3:55][C:56](O)=O>CCOC(C)=O.CCO.C1COCC1.[Pd]>[O:33]=[C:16]1[C@@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:34]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([C:56]4[CH:55]=[CH:10][CH:11]=[CH:12][N:14]=4)=[CH:41][CH:40]=3)=[CH:35]2)[CH2:10][C:9]([OH:8])=[O:51])[CH2:31][C:30]2=[CH:32][N:23]([C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18][NH:17]1
Reactant: CC(=O)O
Reactant: O=C(C[C@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C[C@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccc(-c3ccccn3)cc2)c1
Reaction time: 1.5 h
Yield: 46 %

Procedure:
To a solution of N-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17 ]octadeca-11(18),12,14,16-tetraen-9(S)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester (185 mg, 0.280 mmol) in EtOAc/EtOH/THF was added in succession 10% palladium on carbon (50 mg) and 88% formic acid (0.1 mL). After 1.5 hours, HOAc (1 mL) was added. After 16 hours, more 10% palladium on carbon (25 mg), 88% formic acid (0.1 mL), and HOAc (1 mL) was added. At 24 hours, more 10% palladium on carbon (25 mg) was added. After 25 hours total elapsed time, the catalyst was filtered off. The filtrate was concentrated to a crude solid. The product dissolved in a minimal amount of MeOH/EtOAc, and inorganic particulates were filtered away. The filtrate was concentrated to a solid that was triturated with CH2Cl2 /hex to give 76 mg (46%) of N-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17 ]octadeca-11(18),12,14,16-tetraen-9(S)-yl)-3(R)-[3-[4-(pyridinyl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow solid, mp>172° C. (d). 1H NMR (CD3COOD): δ 8.91 (d, 2H, J=6.6 Hz), 8.23 (d, 2H, J=6.6 Hz), 7.93 (d, 2H, J=8.5 Hz), 7.75 (d, 2H, J=8.5 Hz), 7.62 (d, 1H, J=7.4 Hz), 7.40-7.33 (m, 2H), 7.17 (t, 1H, J=7.5 Hz), 7.10 (t, 1H, J=7.4 Hz), 7.04 (s, 1H), 6.93 (t, 1H, J=2.6 Hz), 6.79 (bm, 1H, partially exchanged), 6.58 (s, 1H), 5.34 (t, 1H, J=7.5 Hz), 4.72 (dd, 1H, J=4.6, 11.2 Hz), 4.35-4.30 (m, 1H), 4.23-4.15 (m, 1H), 3.74-3.65 (m, 2H), 3.56-3.42 (m, 2H), 3.31-3.00 (m, 4H), 2.91-2.85 (m, 1H), 2.74-2.67 (m, 1H). Anal. Calculated for C34H33N5O5.0.4 H2O: C, 68.19; H, 5.69; N, 11.70. Found: C, 68.13; H, 5.77; N, 11.81.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]#[N:8].C[O:10][C:11](=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][Cl:22])[CH:14]=1.CO>C1COCC1.O.C(O)(=O)C>[Cl:22][CH2:21][CH2:20][O:19][C:15]1[CH:14]=[C:13]([CH2:12][C:11](=[O:10])[CH2:6][C:7]#[N:8])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1cccc(OCCCl)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)Cc1cccc(OCCCl)c1
Yield: 99 %

Procedure:
To a 1.0 L three-necked round-bottomed flask was added 150 mL of anhydrous THF and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 52.5 mL, 131 mmol) was added dropwise. Anhydrous CH3CN (7.2 mL, 138 mmol) in 150 mL of anhydrous THF was subsequently added dropwise to the flask amidst stirring and cooling. After 1 h of stirring, [3-(2-chloroethoxy)phenyl]-acetic acid methyl ester (15 g, 66 mmol) in 20 mL of anhydrous THF was added dropwise to the resulting white colloidal mixture in the flask. The reaction mixture was stirred for an additional 2 h, followed by the addition of 4:1 mixture of MeOH: acetic acid (AcOH) at −78° C. The solution was diluted with 500 mL water and extracted with EtOAc (4×150 mL). The organic layer was separated, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. Residual AcOH was removed by concentrating in vacuo with toluene. The residue was passed through silica gel eluting with CH2Cl2 to yield 4-[3-(2-chloroethoxy)phenyl]-3-oxo-butyronitrile as an off-white solid, 16.0 g (99% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:37])([F:38])[F:39])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1
Reactant: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.75 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide are dissolved in 100 ml tetrahydrofuran and to this solution 0.48 ml of tetra-n-butylammonium fluoride (˜75% in H2O) is added at 0° C. The reaction mixture is allowed to warm to room temperature and stirred for 60 minutes.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([CH3:26])([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:17]2[O:21]C(C)(C)C(C)(C)[O:18]2)=[CH:13][CH:12]=1)[CH3:9])(C)(C)C.[O:29]1CC[CH2:31][CH2:30]1.O>C(O)(=O)C.C1(C)C=CC=CC=1>[C:30]([O:6][CH2:7][C:8]([CH3:9])([CH3:26])[O:10][C:11]1[CH:12]=[CH:13][C:14]([B:17]([OH:18])[OH:21])=[CH:15][CH:16]=1)(=[O:29])[CH3:31]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)OCC(C)(C)Oc1ccc(B(O)O)cc1
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of tert-butyl(dimethyl){2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propoxy}silane (5.0 g) in acetic acid (30 mL)-tetrahydrofuran (10 mL)-water (10 mL) was stirred for 2 days. The reaction mixture was diluted with toluene and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), pyridine (2.4 mL), acetic anhydride (1.5 g) and N,N-dimethyl-4-aminopyridine (0.1 g) were added and the mixture was stirred for 2 hr. Small pieces of ice were added to the reaction mixture, and the mixture was stirred for 30 min, extracted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in 1 M hydrochloric acid (10 mL)-tetrahydrofuran (10 mL)-water (10 mL), sodium periodate (3.2 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was triturated with diisopropyl ether to give the title compound as a pale-yellow solid (1.6 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[O:14]=[C:11]1[CH2:10][CH2:9][CH:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reaction time: 2.5 h
Yield: 95.6 %

Procedure:
tert-Butyl-4-hydroxycyclohexylcarbamate (17 g) and Celite (17 g) were suspended in dry DCM (100 mL). PCC (25.5 g) was added portion-wise within 10-15 minutes. The reaction was stirred under nitrogen for 2.5 hours. The solvent was removed under reduced pressure and the residue was re-dissolved in EtOAc/n-hexane (1000 mL) and filtered through celite. The organic layer was dried over Na2SO4. Evaporation of the solvents gave the title compound as a colorless solid (16.1 g, quantitative).