Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].C(N(CC)CC)(C)C.[C:41]1([SH:47])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:3]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Reactant: Sc1ccccc1
Agent: CCN(CC)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(Sc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirring solution of benzyl 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (46 mg) in anhydrous DMF (1 ml) is added N-isopropyl-N,N-diethylamine (13 mg) and thiophenol (11 mg). The resulting solution is stirred in the cold for 15 mins. and at room temperature for 45 mins, then diluted with ethyl acetate (10 ml). The mixture is thoroughly washed with water (5×2 ml) and brine, dried with MgSO4, filtered, and evaporated to dryness. The residue is purified on a silica gel GF plate to yield benzyl 6-(1-hydroxyethyl)-3-phenylthio-1-azabicyclo[3.2.0]hept-b 2-en-7-one-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[N:19][OH:20])[C:11]1=[O:21].[OH-:22].[Na+]>CO.O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12](=[N:19][OH:20])[C:11]([OH:21])=[O:22]
Reactant: Cc1ccc(Cl)c(N2C(=O)C(=NO)c3ccccc32)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=NO)C(=O)O)c1Cl

Procedure:
A solution of 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione-3-oxime (2.25 9) in 6 N NaOH (10 ml) and 4 ml MeOH is heated at 50° C. for two days without a reflux condenser. The resulting residue is taken up in water (50 ml) and filtered. It is neutralized with 1 N HCl with ice bath cooling. The precipitate is collected by filtration. The residue is air dried, dissolved in ether, and filtered. 2-[(2,6-Dichloro-3-methylphenylamino]-α-(hydroxylimino)-benzeneacetic acid (0.28 g, 50%) is precipitated from the ether solution by the addition of hexane, mp 152°-154° C. dec.
Reaction SMILES: C(O)=O.[CH:4]([NH2:6])=O.[NH2:7][C:8]1[NH:9][C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[CH:11][C:12]=1[C:13](OCC)=[O:14]>CN(C)C=O>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]2[NH:9][C:8]3[N:7]=[CH:4][N:6]=[C:13]([OH:14])[C:12]=3[CH:11]=2)=[CH:19][CH:20]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)[nH]c1N
Solvent: CN(C)C=O
Solvent: O=CO
Product: Oc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Temperature: 140 °C
Reaction time: 48 h

Procedure:
After adding 84 ml of formic acid, 338 ml of formamide and 169 ml of dimethylformamide to 56.7 g of the ethyl 2-amino-5-(4-benzyloxyphenyl)-1H-pyrrole-3-carboxylate synthesized in Production Example 153-1, the mixture was stirred at 140° C. for 48 hours and then allowed to stand at room temperature for 24 hours. The precipitated solid was filtered out and dried under reduced pressure to obtain 41 g of the title compound.
Reaction SMILES: CC1C=CC([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:39]=[CH:38][C:20]([O:21][C:22]4[CH:31]=[C:30]5[C:25]([CH:26]([C:32]([O:34]C)=[O:33])[CH2:27][CH2:28][O:29]5)=[CH:24][C:23]=4[C:36]#[N:37])=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:9]=2)=CC=1.O[Li].O.O1[CH2:48][CH2:47]OCC1.Cl>C1COCC1>[C:36]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:22]=1[O:21][C:20]1[CH:38]=[CH:39][C:17]([C:15](=[O:16])[NH:14][C:11]3[CH:10]=[C:9]([C:8]4[CH:13]=[CH:12][C:47]([CH3:48])=[CH:10][CH:9]=4)[CH:8]=[CH:13][CH:12]=3)=[CH:18][CH:19]=1)[O:29][CH2:28][CH2:27][CH:26]2[C:32]([OH:34])=[O:33])#[N:37]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(C)cc5)cc4)cc3)c(C#N)cc21
Reactant: C1COCCO1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 187.5 %

Procedure:
A mixture of methyl 7-(4-(4′-methylbiphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (33 mg, 0.063 mmol), 1M solution of LiOH—H2O (127.3 μl, 0.127 mmol), and THF (1.5 ml) was stirred for 17 hours at ambient temperature. The mixture was quenched with 4M HCl dioxane (47.73 μL, 0.190 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 29.8 mg of the title compound as a white solid (93%). MS (apci) m/z=505.1 (M+H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH:6]1[CH:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH:8]([C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7]1.[O:22]1CCOCC1.[ClH:28]>>[ClH:28].[CH:20]1[C:21]2[CH:8]3[CH2:7][CH:6]([C:2]([O:1][CH2:5][CH2:4][NH2:3])=[O:22])[CH:15]([C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc2c(c1)C1CC(C3=NCCO3)C2c2ccccc21
Reactant: C1COCCO1
Agent: Cl
Product: NCCOC(=O)C1CC2c3ccccc3C1c1ccccc12
Reaction time: 2.5 h

Procedure:
A solution of 11-(2-oxazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (4.122 g) in 1.074 N hydrochloric acid (13.9 ml) is allowed to stand at room temperature for 2.5 hours. The reaction mixture is mixed with dioxane to dissolve the precipitate formed and evaporated at room temperature under reduced pressure to remove the solvent. The residue is recrystallized from anhydrous ethanol-ether to give 2-aminoethyl 9,10-dihydro-9,10-ethanoanthracene-11-carboxylate hydrochloride 1/2 hydrate (4.641 g) as crystals melting at 155 to 158° C. IR (Nujol), 3379, 1735 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2ccccc2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of Example 17D (202.1 mg, 0.64 mmol) and triethylamine (0.14 mL) in anhydrous dichloromethane (5 mL) was added benzoyl chloride (0.08 mL, 0.64 mmol) dropwise. The mixture was allowed to stir for 6 hours at room temperature and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and H2O (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to an oil, which was chromatographed using a Biotage 40M eluting with 20% hexane/80% ethyl acetate to provide (2S, 4R)-4-(benzoylamino-methyl)-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a brown oil. MS (ESI) m/e 420 (M+H)+, 418 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[CH2:41][OH:42]>>[OH:42][CH2:41][C@@H:37]1[CH2:38][CH2:39][CH2:40][N:36]1[C:30](=[O:31])[CH:29]([C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:34])[F:35])=[O:6])[CH:13]=[CH:12][CH:11]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)=[CH:24][CH:25]=1)[CH3:33]
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Reactant: OC[C@@H]1CCCN1
Product: CC(C(=O)N1CCC[C@H]1CO)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and (2S)-pyrrolidin-2-ylmethanol. LCMS (M+H)+: m/z=567.3
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C[O-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C1CCCCC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a mixture of 7-chloro-1H-indole-6-carboxylic acid (3.8 g, about 19.4 mmol) in MeOH (50 ml) at r.t. under N2 was added cyclohexanone (6.13 ml, 59.1 mmol), followed by a solution of NaOMe in MeOH (17.5 ml, 76.6 mmol, 25% wt). The reaction mixture was stirred at reflux for 16 hr. After cooling to r.t., the mixture was added another bath of cyclohexanone (6.13 ml, 59.1 mmol), followed by another solution of NaOMe in MeOH (17.5 ml, 76.5 mmol, 25% wt), and then re-stirred at reflux for another 7 hr. After cooling to r.t., the mixture was evaporated, added with water (100 ml), acidified with hydrochloric acid (5N) and left standing at r.t. overnight. The aqueous mixture was decanted, and the residue washed twice with hydrochloric acid (30 ml, 1N) and twice with water (30 ml). The residue was further washed three times with hexane, and then dried to give 5.5 g of 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid. Another 2.6 g of the product was obtained from another reaction using 2.27 g of 7-chloro-1H-indole-6-carboxylic acid. Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=275.94, 277.94, HPLC Rt=1.750 min. To a mixture of the 7-chloro-3-cyclohexenyl-1H-indole-6-carboxylic acid (8.1 g) obtained from above in a mixture of THF/MeOH (25 ml/25 ml) at r.t. under N2 was added Pd(OH)2/C (764 mg, 20%). The mixture was then flushed with a stream of hydrogen gas using a balloon, and then stirred under hydrogen (using a balloon) for 27 hr. After removing the hydrogen balloon, the mixture was then flushed with a stream of N2, and then filtered through a cake of celite. The filtrate was evaporated to give 7-chloro-3-cyclohexyl-1H-indole-6-carboxylic acid (7.7 g). Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=278.01, 280.00, HPLC Rt=1.773 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:14])=[C:6]([NH2:15])[CH:5]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([S:24](Cl)(=[O:26])=[O:25])[CH:23]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:14])=[C:6]([NH:15][S:24]([C:22]2[CH:23]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=2[O:28][CH3:29])(=[O:25])=[O:26])[CH:5]=1
Reactant: COC(=O)c1cc(N)c(O)c(C(F)(F)F)c1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2cc(Cl)ccc2OC)c(O)c(C(F)(F)F)c1

Procedure:
A suspension of 3-amino-4-hydroxy-5-trifluoromethyl-benzoic acid methyl ester (4.66 g, 19.8 mmol) and 5-chloro-2-methoxybenzenesulfonyl chloride (4.78 g, 19.8 mmol) in toluene (38 mL) was heated at reflux for 48 h. After cooling, the precipitate was collected by filtration and washed with toluene to afford 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-trifluoromethyl-benzoic acid methyl ester. Off-white solid, MS (ISP)=438.0 (M−H)−.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([S:29](OC3C=CC([N+]([O-])=O)=CC=3)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].Cl>C(COC)OC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:29]([C:24]2[C:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:22][CH:21]=3)=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:31])=[O:30])=[N:5][CH:6]=1
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1nc(Br)cnc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccc(CC(C)C)cc1
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.094 g) was added to a solution of 2-amino-5-bromo-3-methoxypyrazine (0.159 g) in dimethoxyethane (4 ml). The solution was stirred for 10 minutes and then 4-nitrophenyl 4'-isobutyl-2-biphenylsulphonate (0.321 g) was added. The solution was allowed to stand for 5 hours and then water (20 ml) was added. 2M Hydrochloric acid (2 ml) was added and the mixture was extracted with ethyl acetate (2×30 ml). The extracts were dried (MgSO4) and volatile material was removed by evaporation. The residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column. The resulting solid was recrystallised from a mixture of ether and hexane to give N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-isobutyl-2-biphenylsulphonamide (0.09 g), m.p. 154°-156° C.; 1H NMR (d6 -DMSO): 0.9 (d,6H), 1.8-2.0 (m,1H), 2.5 (d,2H), 3.85 (s,3H), 7.1 (s,4H), 7.3 (d,1H), 7.5-7.7 (m,2H), 7.8 (br s,1H), 8.05 (d,1H), 10.2-10.3 (br, 1H); mass spectrum (+ve FAB, methanol/NBA): 478 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]1[CH2:15][CH:14]1[C:16](O)=O.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:32][N:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[N:35][C:34]1=[NH2+:41].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:40][C:36]1[CH:37]=[C:38]([CH3:39])[N:33]2[N:32]=[C:16]([CH:14]3[CH2:15][CH:13]3[C:3]3[N:2]([CH3:1])[CH:6]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]=3)[N:41]=[C:34]2[N:35]=1
Reactant: Cn1cc(-c2ccccc2)nc1C1CC1C(=O)O
Reactant: Cc1cc(C)n(N)c(=[NH2+])n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)n2nc(C3CC3c3nc(-c4ccccc4)cn3C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylic acid (70 mg, 0.289 mmol) in DMF (2.0 mL) was added 1-amino-4,6-dimethylpyrimidin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (98 mg, 0.289 mmol) followed by O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (93 mg, 0.289 mmol) and triethylamine (0.040 mL, 0.289 mmol) at rt. After 2 h stirring at rt, the reaction mixture was stirred at 70° C. for 12 h. The crude product was purified by prep HPLC using Phenomenex column and MeOH—H2O-TFA as eluent (20% to 100% over 12 min gradient; flow: 40 mL/min) Collected the pure fractions and removed solvent. Obtained 5,7-dimethyl-2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine as a white solid in 47% yield. Prepared hydrochloride salt by adding 1.0 M HCl and MeOH and removing solvent. 1H NMR (500 MHz, METHANOL-d4) δ 6.28 (s, 1H), 6.18-6.14 (m, 2H), 5.97 (s, 1H), 5.92-5.88 (m, 2H), 5.87-5.84 (m, 1H), 2.39 (s, 3H), 1.72-1.69 (m, 1H), 1.62-1.57 (m, 1H), 1.29-1.27 (m, 3H), 1.17 (s, 3H), 0.70 (dt, J=9.2, 6.1 Hz, 1H), 0.62-0.59 (m, 1H); MS (ESI) 345 (M+H); Rf=1.84 (Condition A).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Cl)[CH:10]=2)=[CH:5][CH:4]=1.C[O:22][C:23](=[O:36])[CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([SH:35])=[C:31]2[C:27]=1[CH2:28][CH2:29][CH2:30]2>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH2:15][S:35][C:32]2[CH:33]=[CH:34][C:26]([O:25][CH2:24][C:23]([OH:36])=[O:22])=[C:27]3[C:31]=2[CH2:30][CH2:29][CH2:28]3)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(COc2cccc(CCl)c2)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 79B and 12C. MS m/z 503 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([S:14](=[O:29])(=[O:28])[N:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].BrC(Br)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O1CCCC1>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([N:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[S:14]([C:11]2[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:5]([CH:10]=2)[C:6]([O:8][CH3:9])=[O:7])(=[O:28])=[O:29])=[CH:25][CH:24]=1)[CH3:27]
Reactant: C1COCCN1
Reactant: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(C)=O)c(C(=O)OC)c2)cc1
Agent: O=C(Br)Br
Solvent: C1CCOC1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(=O)CN3CCOCC3)c(C(=O)OC)c2)cc1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution of phenyltrimethylaminotribromide (100 mg, 0.266 mmol) in tetrahydrofuran (THF) (0.5 mL) was added dropwise over 5 minutes, to a solution of methyl 2-acetyl-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)benzoate (105 mg, 0.251 mmol) in THF (1.5 mL) at room temperature, under nitrogen. The orange solution was stirred for 1 hour to give a yellow solution containing a white precipitate. Analysis showed major product to be the desired intermediate bromoketone. The precipitate was filtered off and the solution was treated with morpholine (0.066 mL, 0.754 mmol). The resulting suspension was stirred for 30 minutes and partitioned between ammonium chloride solution (10 mL) and ethyl acetate (2×5 mL). The dried (MgSO4) extract was evaporated to give the desired product (65 mg), as an orange gum, which was used directly in the next step. LCMS [LCMS1] Rt 1.06 min, m/z (ES+) 503 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH2:22][CH3:23])[CH2:12][C:13]([O:15][C:16](C)(C)C)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]>CO.Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH2:22][CH3:23])[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCNC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCNC[C@H](CC(=O)OC)Nc1ccc(C#N)c(Cl)c1
Temperature: 60 °C

Procedure:
The 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-(ethylamino)butanoate from the previous step was dissolved in a mixture of MeOH (150 mL) and 4N HCl/dioxane (20 mL) and heated to 60° C. for 3 h. The solvents were concentrated to a slurry, Et2O (200 mL) was added, the solid filtered, washed well with Et2O to give the titled compound (4.0 g).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of Boc-L-Lys(Z)OMe 31 (2.00 g, 12.6 mmol) in DCM (30 mL) was added 30 mL of TFA. The mixture was stirred at rt for 1 h. Then the solvent were removed in vacuo, the residue was coevaporated 3 times with toluene. The residue was precipitated in Et2O to give the subject compound (2.1 g, yield 100%). Intermediate 32 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 8.45 (sl, 2H), 7.33 (m, 5H), 7.31 (t, 1H), 5.00 (s, 2H), 4.03 (m, 1H), 3.74 (s, 3H), 2.97 (m, 2H), 1.75 (m, 2H), 1.39 (m, 4H).
Reaction SMILES: CN(S(F)(F)[F:5])C.O[C:9]1([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])[CH:14]=[CH:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1>C(Cl)Cl.C(OCC)(=O)C>[F:34][C:18]1[CH:19]=[C:20]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:21]=[CH:22][C:17]=1[C:9]1([F:5])[CH:14]=[CH:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1
Reactant: CN(C)S(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3(O)C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(F)C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
(N,N-Dimethylamino)sulfur trifluoride (2.5 μL, 0.019 mmol) is added to a cooled (−78° C.) solution of the product of Example 12 (6.0 mg, 0.014 mmol) in DCM (0.75 mL). The solution is warmed slowly to room temperature over 4 hours and diluted with ethyl acetate. The organic solution is extracted with satd NaHCO3, H2O, brine and dried (Na2SO4). The crude product is purified by preparative TLC (7% MeOH-DCM) to provide the title compound as a mixture of diastereomers.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)O1.Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([S:33]([NH:36][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][N:38]=4)(=[O:35])=[O:34])=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[C:19]([O:43][CH3:44])[CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:44][O:43][C:19]1[CH:18]=[C:17]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[C:32]2[C:27](=[CH:28][C:29]([S:33]([NH:36][C:37]3[CH:42]=[CH:41][N:40]=[CH:39][N:38]=3)(=[O:34])=[O:35])=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccc(C)o2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 150 °C

Procedure:
A microwave vial charged with Pd(Amphos)2Cl2 (0.012 g, 0.018 mmol), 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (0.073 g, 0.351 mmol), 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (From Example 160; 0.075 g, 0.176 mmol), potassium phosphate (0.149 g, 0.703 mmol), 1.5 mL dioxane and 0.25 mL water was heated to 150° C. in the microwave for 30 minutes. LC/MS showed mostly product. The aqueous layer was removed, and the reaction mixture was treated with HCl (4N in dioxane). Purification of the crude residue by reverse phase column chromatography [RediSep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave the titled compound.