Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:17])[CH2:11][NH:12][C:13](=[O:16])[CH2:14][NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C(Cl)=CC(Cl)=CC=1[O:27][C:28](=O)[C@H:29]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CN1CCOCC1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:17])[CH2:11][NH:12][C:13](=[O:16])[CH2:14][NH:15][C:28](=[O:27])[C@H:29]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1cc(Cl)cc(Cl)c1Cl
Reactant: NCC(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)OCc1ccccc1

Procedure:
A solution of 4.4 parts glycylglycine benzyl ester hydrochloride, 9.1 parts N-t-butoxycarbonyl-L-tyrosine 2,3,5-trichlorophenyl ester and 1.8 parts N-methylmorpholine in 150 parts methylene chloride is stirred overnight at room temperature. The solvent is then removed by evaporation under reduced pressure. The crude material is subjected to low-pressure column chromatography on silica gel to afford N-t-butoxycarbonyl-L-tyrosylglycylglycine benzyl ester.
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.C([Li])CCC.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>C1COCC1.C1(C)C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[Br:18][C:19]([CH3:24])([CH3:23])[C:20]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]=1[CH3:12])=[O:21]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(C)c(C(=O)C(C)(C)Br)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.6 %

Procedure:
To an ice-cooled solution of 5-methoxy-2-methylindole (2.5 g, 15.5 mmol) in THF (30 mL) was added n-butyllithium (2.5M solution in hexanes: 6.25 mL, 16.28 mmol) in a dropwise manner. After 20 minutes, ZnCl2 (1M solution in ether; 15.5 mL, 1.0 eq.) was added and the resulting solution stirred at 0° C. for 2 hrs. The solvent was then removed and the residue dissolved in anhydrous toluene (30 mL) to which 2-bromoisobutyryl bromide (1.93 mL, 16.28 mmol) was added and the mixture stirred at ambient temperature for 24 hrs. The solution was partitioned between 1M HCl (100 mL) and EtOAc (100 mL), the organic phase separated, washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography (0 to 25% EtOAc:hexanes) to afford 2.0 g of 2-bromo-1-(5-methoxy-2-methyl-1H-indol-3-yl)-2-methyl-propan-1-one as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.52 (1H, s), 7.97 (1H, d, J=2.2 Hz), 7.21 (1H, d, J=8.8 Hz), 6.87 (1H, dd, J=8.8, 2.2 Hz), 3.91 (3H, s), 2.67 (3H, s), 2.13 (6H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CCO>[N+:8]([C:7]1[C:2]([NH:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCC1CCN(c2ccncc2)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Reaction time: 17 h
Yield: 59.3 %

Procedure:
A solution of 2-chloro-3-nitropyridine (290 mg, 1.83 mmol), triethylamine (0.26 mL) and 1-(4-pyridyl)-piperidine-4-methylamine (350 mg, 1.83 mmol) in EtOH (10 mL) was heated at reflux. After 17 h, the mixture was concentrated and the residue was purified by chromatography (SiO2, 2 to 4% (2 N NH3 in methanol) in chloroform) yielding 340 mg (60%) of the title compound.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[N:23]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:29]=2)[N:23]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(C(=O)NCc2ccccc2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccc1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 70.2 %

Procedure:
A mixture of methyl thiosalicylate (1.3 g, 7.6 mmol), N-benzyl-6-cyano-2-pyridinecarboxamide (0.88 g, 3.7 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 10 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.97 g, 97%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[CH:12](=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)C>[N:16]1[CH:17]=[CH:18][C:13](/[CH:12]=[N:1]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][O:5][C:6]3=[O:11])=[CH:14][CH:15]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1ccncc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OCc2c(/N=C/c3ccncc3)cccc21
Temperature: 25 °C
Yield: 77 %

Procedure:
A mixture of 4-aminoisobenzofuran-1(3H)-one (894 mg, 6 mmol), isonicotinaldehyde (2.568 g, 24 mmol) and anhydrous sodium sulfate (3.6 g) in anhydrous ethanol (70 mL) was heated to reflux for two days. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to give the crude product. The crude product was washed with petroleum ether to give (E)-4-(pyridin-4-ylmethyleneamino)isobenzofuran-1(3H)-one (1.1 g, yield 77%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.44 (s, 1H), 7.40-7.42 (d, J=7.6 Hz, 1H), 7.59-7.63 (t, J=7.6 Hz, 1H), 7.77-7.79 (d, J=5.6 Hz, 2H), 7.84-7.86 (d, J=7.6 Hz, 1H), 8.54 (s, 1H), 8.81-8.82 (d, J=4.8 Hz, 1H); LC-MS (ESI) m/z: 239(M+1)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(C)=O.[OH:40][CH2:41][C@@H:42]1[CH2:46][C@@H:45]([OH:47])[CH2:44][NH:43]1>C(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:43]3[CH2:44][C@H:45]([OH:47])[CH2:46][C@H:42]3[CH2:41][OH:40])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Br
Reactant: OC[C@@H]1C[C@@H](O)CN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1-c1ccccc1Br
Temperature: 130 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
A mixture of 800 mg (1.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramide, 4 ml dimethyl sulfoxide and 1.15 g (6.9 mmol) (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine was stirred at 130° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with 100 ml ethyl acetate and washed with 200 ml 1 N sodium carbonate solution and 100 ml water. The combined aqueous layers were extracted twice with 100 ml ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. Purification by flash chromatography gave 434 mg (48%) of the title compound as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[OH-].[K+].Cl[CH2:22][C:23]([OH:25])=[O:24]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:12][CH2:13]1)=[O:7]
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Reactant: O=C(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(CC(=O)O)CC2)cc1OC
Temperature: 50 °C

Procedure:
32 Grams of 4-(3,4-dimethoxybenzoyl)piperazine and 13.1 g of potassium hydroxide were dissolved in 300 ml of dimethylformamide (DMF), then under an ice-cooled condition with stirring, 10 g of α-chloroacetic acid was added thereto, next the reaction mixture was heated at 50° C. for 5 hours with stirring. After completion of the reaction, the reaction mixture was concentrated to dryness, the residue obtained was dissolved in water. The solution obtained was washed with chloroform, the aqueous layer was neutralized with concentrated hydrochloric acid, crystals formed were collected by filtration to obtain 9.8 g of α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetic acid.
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([OH:23])=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(=O)(OCC)OCC)#N.C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reactant: Oc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reaction time: 8 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 323, 0.543 g), 0.245 g of phenol, 0.48 ml of triethylamine, and 6 ml of dichloromethane are added 0.42 ml of diethyl cyanophosphonate. After stirring for 1 hr an additional 0.11 g of phenol are added. When the reaction had stirred another 2.5 hr an additional 0.11 g of phenol and 0.26 ml of diethyl cyanophosphonate are added. The reaction is stored overnight in the refrigerator and then stirred with 1 ml of aqueous sodium bicarbonate for about 30 min. The mixture is then partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue chromatographed on silica gel (300 ml) elating with methanol/methylene chloride (2/98), the appropriate fractions are pooled and concentrated to give the title compound, which is crystallized from dichloromethane/hexane, mp 196.5°-199°; MS (m/z) at 388; IR (mineral oil) 1648, 1199, 1723, 1502, 1410 cm-1 ; 1H NMR (CDCl3) 1.81, 3.31, 5.09, 7.15-7.33, 7.42, 7.55, 8.11 δ.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C([Li])CCC.CN(C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([CH2:9][C:17](=[O:19])[CH3:18])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)N(C)C
Reactant: COc1cccnc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccnc1CC(C)=O
Temperature: 0 °C

Procedure:
To a stirred solution of 3-methoxy-2-methylpyridine (844 mg) in tetrahydrofuran (10 ml) was added a solution of n-butyllithium in n-hexane (1.59M, 5.6 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (0.955 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 25% ethyl acetate in n-hexane) to give 1-(3-methoxypyridin-2-yl)propan-2-one (1.12 g).
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O:5][CH2:6][CH3:7])=[O:4].[CH3:23][C:24]1([CH3:37])[C:29]2[CH:30]=[CH:31][C:32]([C:34](=O)[CH3:35])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1.Cl>CS(C)=O>[CH3:23][C:24]1([CH3:37])[C:29]2[CH:30]=[CH:31][C:32]([C:34]([CH3:35])=[CH:12][C:11]3[CH:10]=[CH:9][C:8]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=3)=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Reactant: CC(=O)c1ccc2c(c1)OCCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C=C(C)c2ccc3c(c2)OCCC3(C)C)cc1
Temperature: 40 °C
Yield: 60.3 %

Procedure:
0.5 g of a 50% suspension of sodium hydride in mineral oil were suspended in 15 ml of dimethyl sulfoxide and treated under argon with a solution of 3.2 g of diethyl (4-carbethoxybenzyl)phosphonate in 10 ml of dimethyl sulfoxide. The mixture was subsequently heated to 40° C. for 20 minutes, cooled to room temperature, a solution of 0.87 g of 3,4-dihydro-4,4-dimethyl-7-acetyl-2H-1-benzopyran in 5 ml of dimethyl sulfoxide was added dropwise thereto and the mixture was heated to 40° C. for 1 hour. The reaction mixture obtained was poured on to ice/water, acidified with 1N hydrochloric acid and extracted repeatedly with ether. The organic phase was washed with water, dried and evaporated. There was obtained a yellowish oil which, after filtration over a short column (silica gel, eluting agent hexane/ethyl acetate=9:1), crystallized from hexane and yielded 0.9 g of ethyl p-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-7-yl)propenyl]benzoate, m.p. 48°-50° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:37][CH2:36][C@H:33]1[CH2:32][CH2:31][C@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:35][CH2:34]1
Reactant: C[C@@H](O)C(N)=O
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (42 mg, 0.48 mmol) and triethyloxonium tetrafluoroborate (85 mg, 0.45 mmol) in tetrahydrofuran (0.65 mL) was stirred at room temperature for 2 h. The solvent was removed, and the residue dissolved in ethanol (0.27 mL) and added to a suspension of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanol (41 mg, 0.15 mmol) in ethanol (0.99 mL). The resulting mixture was stirred at 85° C. for 1 h. The solvent was removed and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.3 mg, 4.7%). LCMS calculated for C17H22N3O2S (M+H)+: m/z=332.1. Found: 332.1.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]>CO.[Pd]>[NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Reaction time: 6 h
Yield: 94 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D12, 1.2 g, 3.02 mmol) in methanol (25 ml) was added Pd/C 10% wt (210 mg) and the mixture was stirred under a hydrogen atmosphere (1 atm) for 6 hours. The catalyst was filtered off and the solvent removed under reduced pressure to give the title compound as a white solid (870 mg, 94%); Rt (HPLC): 3.61 min; Rf (cyclohexane:ethyl acetate=1:1): 0.18; MS: (ES/+) m/z: 329 [M+Na+]. C16H22N2O4 requires 306; 1H NMR (300 MHz, d6-DMSO) δ ppm: 9.15 (bs, 1H); 7.40 (bm, 2H); 7.30 (s, 1H); 6.90 (s, 1H); 6.65 (d, 2H); 4.50-4.80 (m, 1H); 4.05-4.28 (m, 1H); 2.07-2.24 (m, 1H); 1.95-2.07 (m, 1H); 1.60-1.89 (m, 2H); 1.00-1.45 (m, 9H).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[NH:28][C:27]([NH2:30])=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:15]1[CH:16]=[CH:17][N:13]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[N:28]=[C:27]([NH:30][C:10]([C:8]3[CH:9]=[C:4]4[CH:3]=[CH:2][S:1][C:5]4=[CH:6][N:7]=3)=[O:12])[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: O=C(O)c1cc2ccsc2cn1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccsc2cn1
Yield: 2.6 %

Procedure:
2.6 mg (3%) of thieno[2,3-c]pyridine-5-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was prepared according to general procedure A using 54 mg (0.3 mmol) thieno[2,3-c]pyridine-5-carboxylic acid, 61 mg (0.25 mmol) intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 114 mg (0.3 mmol) of HBTU, 0.106 mL (0.6 mmol) of DIEA in 1 mL of DMF stirring at 85° C. for 1 h. LCMS: 404 (M+1)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23]>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:27]1[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3c(Cl)cc(O)cc23)cc1
Yield: 94 %

Procedure:
This compound was prepared from 45a using 4-cyanophenylboronic acid according to method P. Yellow solid; Yield: 94%; mp 324° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 6.93 (d, J=2.5 Hz, 1H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.54 (d, J=2.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 8.03 (s, 1H), 8.04 (dd, J=8.5, 1.6 Hz, 1H), 8.09 (d, J=8.4 Hz, 2H), 8.17 (dd, J=12.9, 2.1 Hz, 1H), 10.32 (s, 2H); 19F-NMR (400 MHz, DMSO-d6) δ −136.43 (dd, J=13.0, 9.7 Hz); MS (ESI) m/z 389/391 ([M−H]−), 391/393 ([M+H]+); Anal. Calcd for C22H12ClFN2O2: C, 67.62; H, 3.09; N, 7.17. Found: C, 67.00; H, 3.74; N, 6.64.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:31])[C:9]([CH2:28][CH:29]=O)([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][NH:33]1.CO>ClCCl>[C:1]([O:5][C:6]([N:8]([CH3:31])[C:9]([CH2:28][CH2:29][N:33]1[CH2:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32]1)([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:20][C:21]([CH3:27])([CH3:26])[C:22]([CH3:24])([CH3:25])[O:23]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)C(CC=O)(CCCCB1OC(C)(C)C(C)(C)O1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCN1Cc2ccccc2C1)N(C)C(=O)OC(C)(C)C

Procedure:
Ethyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(2-(isoindolin-2-yl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate was prepared in accordance with the procedure of step 6 in Example 27 except that ethyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(2-oxoethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate was used instead of 3-phenylpropanal and isoindoline was used instead of (R)-2-acetamido-2-((1s,3S)-3-aminocyclobutyl)-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide hydrochloride. Rf 0.32 (10% MeOH in dichloromethane). 1H NMR (CDCl3, 300 MHz) δ 7.20-7.14 (m, 4H), 4.13 (q, J=8.0 Hz, 2H), 3.96 (br s, 4H), 3.00-2.88 (m, 4H), 2.75-2.60 (m, 2H), 2.41-2.31 (m, 1H), 2.15-1.95 (m, 2H), 1.87-1.74 (m, 2H), 1.49-1.08 (m, 26H), 0.79 (t, J=8.5 Hz, 2H). ESI MS found for C30H49B1N2O6 m/z [545.6 (M+1)].
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:26]2[C:31]([CH:32]=O)=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:32]([C:31]3[C:26]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:27][CH:28]=[CH:29][CH:30]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cccnc1N1CCCC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccnc4N4CCCC4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 32.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2-Pyrrolidin-1-yl-pyridine-3-carbaldehyde (28.6 mg, 0.163 mmol) were reacted to produce 24 mg (34%) of the title compound. mp: 190° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 8.21 (m, 1H), 8.02 (s, 1H), 7.71 (d, J=8 Hz, 1H), 6.68 (s, 1H), 7.18 (s, 1H), 7.06 (d, J=8 Hz, 1H), 6.75 (t, 1H), 6.27 (m, 1H), 6.17 (m, 1H), 5.14 (t, J=8 Hz, 1H), 3.32 (s, 3H), 3.29 (s, 2H), 3.08 (m, 2H), 2.85 (s, 1H), 2.71 (s, 1H), 2.55 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.82 (m, 2H), 1.73 (m, 2H), 1.37 (d, J=8 Hz, 1H), 1.09 (t, J=8 Hz, 1H). MS: 494, 496 (M+H), HPLC: 3.19 min (G method).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH:5]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@H:14]([N:25]([CH2:31][C:32]2[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]=2)[C:26]2[N:27]=[N:28][NH:29][N:30]=2)[CH2:13][C@@H:12]1[CH2:46][CH3:47])=[O:10])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH:5]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@@H:14]([N:25]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=2)[C:26]2[N:27]=[N:28][N:29]([CH2:2][CH2:3][OH:4])[N:30]=2)[CH2:13][C@@H:12]1[CH2:46][CH3:47])=[O:10])([CH3:7])[CH3:6]
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCO)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
Add 2-bromoethanol (0.093 mL, 1.25 mmol) to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzyl-(2H-tetrazol-5-yl)amino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (653 mg, 1.045 mmol) and cesium carbonate (749 mg, 2.30 mmol) in dry dimethylformamide under an atmosphere of nitrogen and stir the mixture at 50° C. for 24 h. Cool to room temperature, add water, and extract with ethyl acetate. Dry the organic solvent over sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate/hexanes to afford a mixture of two compounds. Separate by normal phase HPLC eluting with standard hexane/ethanol gradient to afford (+/−)-trans-4-[(3,5-bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1carboxylic acid isopropyl ester (48 mg, 7%). 1H NMR (CDCl3, 300 MHz): δ 0.95 (t, J=7.7 Hz, 3H), 1.33 (d, J=6.3 Hz, 3H), 1.35 (d, J=6.3 Hz, 3H), 1.55-1.69 (m, 2H), 2.31-2.47 (m, 3H), 3.98-4.00 (m, 2H), 4.49-4.73 (m, 5H), 5.09 (septuplet, J=7.5 Hz, 1H), 5.41 (dd, J=11.9, 7.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.81 (s, 2H), 8.39 (d, J=8.6 Hz, 1H). MS (ES+): 670 (M+H).