Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[C:33]([Cl:35])[C:32](Cl)=[N:31][CH:30]=1.N12CCN(CC1)CC2>C(N(CC)CC)C>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[N:31][CH:30]=1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
In analogy to Example 163, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with methyl-5,6-dichloronicotinate in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as a colorless solid. MS (m/e)=545.2 [M+H+].
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:7][CH:3]([C:2]#[CH:1])[CH2:4][CH2:5][CH3:6])[CH3:15]
Reactant: C#CC(O)CCC
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCCCCCC
Product: C#CC(CCC)OCC(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.3 %

Procedure:
To a solution of 1-hexyn-3-ol (981 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (1.0 mL, 9.0 mmol). The reaction mixture is stirred at rt for 6 h. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel: elution with EtOAc:heptane (25:75) gives 900 mg of the product 446. 1H NMR (CDCl3) δ 4.35-4.10 (m, 5H), 2.43 (s, 1H), 1.90-1.65 (m, 2H), 1.65-1.40 (m, 2H), 1.40-1.20 (m, 3H), 0.95 (t, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.CCN(CC)CC.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:22][CH:19]2[CH2:21][CH2:20]2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: NC1CC1
Reactant: Clc1cc(Cl)n2nccc2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1cc(NC2CC2)n2nccc2n1
Temperature: 80 °C
Yield: 70.5 %

Procedure:
To 5,7-dichloropyrazolo[1,5-a]pyrimidine (200 mg, 1.06 mmol) in acetonitrile was added Et3N (148 μl, 1.06 mmol) and cyclopropylamine (75 μl, 1.06 mmol). The reaction was heated at 80° C. overnight. The mixture was concentrated under reduced pressure, dissolved in dichloromethane, and washed with water. The resulting organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 156 mg of 5-chloro-N-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (70% yield). LCMS (M+1=209)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][CH2:22][C:21]([C:28]([O:30]C)=[O:29])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][CH2:22][C:21]([C:28]([OH:30])=[O:29])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3C=O)cc1
Temperature: 90 °C
Reaction time: 19 h
Yield: 50.7 %

Procedure:
To methyl 8-(4-(2-butoxyethoxy)phenyl)-1-formyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (4.5 g) were added tetrahydrofuran (66 ml) and methanol (66 ml), followed by adding aqueous 1N sodium hydroxide solution (22 ml). The mixture was stirred at 90° C. for 19 hours. After cooling to 0° C., water was added and the mixture was neutralized with 1N hydrochloric acid. After extracting with ethyl acetate, the organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the reaction material was re-crystallized from hexane-ethyl acetate to give 8-(4-(2-butoxyethoxy)phenyl)-1-formyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (2.21 g) as yellow crystals.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH2:10].[O:11]=[C:12]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][N:13]1[CH2:29][C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:30](=[O:31])[CH2:29][N:13]1[CH2:14][CH2:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1=[O:11]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NC1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NC1Cc2ccccc2C1
Reaction time: 8 h

Procedure:
A solution of 2,3-dihydro-1H-inden-2-amine (0.020 g, 0.149 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.040 g, 0.135 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.039 g, 0.203 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.18-7.32 (m, 14H), 6.05 (d, J=7.5 Hz, 1H), 4.60 (qt, J=7.5, 5.7 Hz, 1H), 3.99 (s, 2H), 3.49 (t, J=6.5 Hz, 2H), 3.20 (dd, J=15.9, 7.5 Hz, 2H), 2.78 (t, J=6.5 Hz, 2H), 2.52 (dd, J=15.9, 5.8 Hz, 2H); MS (ESI−) m/z 409 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.C(=O)(O)[O-].[Na+].[CH2:17](O)[CH3:18]>>[CH2:17]([O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2](=[O:1])[NH:3][CH:4]=1)=[O:8])[CH3:18]
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccc(=O)[nH]c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a suspension of 6-hydroxy-nicotinic acid (5.00 g, 35.9 mmol) in ethanol (60 mL) was added 1N hydrochloric acid (20 mL), which was then stirred at 110° C. for 3 hours. The reaction solution was cooled to 0° C., then, an aqueous solution of saturated sodium bicarbonate was added, the solution was extracted with ethyl acetate and tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (ethyl acetate), and the title compound (3.90 g, 23.3 mmol, 65%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]([NH:15][NH2:16])=[O:14])[O:4]1.[CH2:17]([N:24]=[C:25]=[S:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]([NH:15][NH:16][C:25](=[S:26])[NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[O:4]1
Reactant: CO[C@@H]1O[C@H](C(=O)NN)[C@H]2OC(C)(C)O[C@@H]12
Reactant: S=C=NCc1ccccc1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](C(=O)NNC(=S)NCc2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Yield: 89.9 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbohydrazide (Preparation 16) (4 g, 17.2 mmol) and benzyl isothiocyanate (2.38 ml, 18 mmol) in dichloromethane (50 ml) was stirred at room temperature for 12 hours. The solvent was removed by evaporation under reduced pressure and the residue was partioned between dichloromethane (100 ml) and water (100 ml). The organic layer was separated, dried (anhydrous magnesium sulphate) and evaporated under reduced pressure to give the title compound (5.90 g) which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2CCCc3cncn32)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)C1(c2ccc(C#N)cc2)CCCc2cncn21

Procedure:
In a manner analogous to that described in example 11, reaction of 5-p-cyanophenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with ethyl chloroformate yields the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:38])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:7]1[C:2]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:39]=[O:40])[CH:46]=2)=[CH:3][C:4]([CH2:9][NH:10][C:11](=[O:38])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])=[CH:5][CH:6]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(Br)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(-c2cccc(C=O)c2)c1
Yield: 82.7 %

Procedure:
A solution of N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.0 g, 1.650 mmol), (3-formylphenyl)boronic acid (0.300 g, 2.00 mmol), tetrakis (triphenylphosphine) palladium (0) (0.092 g, 0.08 mmol) and sodium carbonate (0.509 g, 4.8 mmol) in 1,4-dioxane (12 mL) and water (4.00 mL) was microwaved at 140° C. for 30 min. The reaction was diluted with water and EtOAc and the organic layer taken off. The aqueous phase was re-extracted with EtOAc. The combined organic layers were dried over Na2SO4 and solvent was evaporated giving a residue. The crude material was purified on the Chromatotron on silica gel (2000u) eluting with CH2Cl2 (3-6% MeOH) to give N-[(6-chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (861 mg, 83%) as a glassy solid. LC-MS m/z 631.4 (M+H)+, 0.86 min (ret time).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:13][CH2:14][CH3:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:13][CH2:14][CH3:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[F:30][C:29]([C:27]([OH:33])=[O:28])([F:32])[F:31]
Reactant: CCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](NC(=O)[C@@H](N)CCC(N)=O)C(=O)OC
Reaction time: 0.17 h

Procedure:
The protected dipeptide ester (XI) (4.8 g, 13 mmol) was dissolved in cold TFA (40 ml). After 10 minutes, the TFA was removed in vacuo and dry ether (200 ml) was added. The ether was decanted and the residue was washed with more ether (100 ml). The oily material was dried over KOH to give (XII) as a white foam that was used immediately, T.l.c. RfA3 =0.42.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[S:22][C:15]=12.[CH3:28][C:29]([CH3:31])=[O:30]>O1CCCC1.O>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]3[S:24][C:25]([C:29]([OH:30])([CH3:31])[CH3:28])=[CH:26][N:27]=3)[S:22][C:15]=12
Reactant: CC(C)=O
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1cnc(-c2cc3nccc(Cl)c3s2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
In a 25 mL round-bottomed flask 2 mL of tetrahydrofuran and diisopropyl amine (0.14 mL, 1.0 mmol) were cooled to −78° C. and n-butyllithium (0.38 mL, 0.95 mmol) was added. The solution was warmed to 0° C. for 10 minutes then recooled to −78° C. A solution of 7-chloro-2-thiazol-2-yl-thieno[3,2-b]pyridine (200 mg, 0.79 mmol) in 2 mL of tetrahydrofuran was added dropwise and the resulting solution was stirred 30 minutes. Acetone (0.88 mL, 1.19 mmol) was added to the anion and the reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with water and extracted with chloroform (3×50 mL). The combined extracts were dried over NaSO4, filtered, and concentrated. Chromatography on 50 g of silica gel with 30% ethyl acetate:methylene chloride afforded 129 mg (52%) 2-[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-5-yl]-propan-2-ol. 1H NMR (400 MHz, CD3OD) δ8.56 (d, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.50 (d, 1H), 1.66 (s, 6H). LC-MS: 308.1, 311 (MH+); HPLC RT: 5.32 min.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.[CH3:38][Li]>C1COCC1>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][C:34]([OH:37])([CH3:38])[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(=O)CC4)c3)cc2n1
Reactant: [Li]C
Solvent: C1CCOC1
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(C)(O)CC4)c3)cc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
4-oxo-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (50 mg, 0.1 mmol) in dry THF under argon, at −78° C. was treated dropwise with methyllithium (1.5M in diethylether, 0.2 mL, 0.3 mmol). The reaction was stirred for 30 minutes at −78° C. before warming to rt. The reaction was stirred overnight before partitioning between EtOAc and saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:2) to give 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (12 mg, 23%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.13 (1H, s), 9.02 (1H, s), 8.25 (1H, s), 8.13 (1H, d), 8.10 (1H, s), 7.94 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.64 (1H, d), 7.23-7.32 (2H, m), 6.92 (1H, d), 6.66 (1H, t), 6.54 (1H, d), 4.43 (2H, d), 4.31 (1H, s), 4.13 (3H, s), 3.68-3.74 (2H, m), 3.16-3.25 (2H, m), 1.35-1.46 (4H, m), 1.12 (3H, s); m/z (ES+) 514 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=2)[NH:10][C@@H:11]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][C@@H:11]([C:13]2[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=2)[CH3:12])[C:22]2[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N[C@H](C)c2cc(F)c(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(N[C@H](C)c2cc(F)c(F)c(F)c2)c2cccc(N)c2)cc1
Yield: 96.2 %

Procedure:
Following a similar procedure to that described in Example (1b), 2.61 g of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(3,4,5-trifluorophenyl)ethyl]amine [prepared as described in step (a) above], 3.00 g of nickel chloride hexahydrate and 958 mg of sodium borohydride were reacted, to obtain 2.33 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:33][C@@H:34]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:35][NH:36][C@H:37]([C:39]([NH:41][C@H:42]([C:46]([NH:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH3:38]>CN(C=O)C>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:33][C@@H:34]([CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH2:35][NH:36][C@H:37]([C:39]([NH:41][C@H:42]([C:46]([NH:48][CH2:49][CH:50]([CH3:51])[CH3:52])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH3:38])=[O:12])=[O:6])[CH2:17][CH3:18]
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)CNC(=O)[C@@H](NC(=O)[C@H](C)NC[C@@H](N)Cc1ccccc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@H](CN[C@@H](C)C(=O)N[C@H](C(=O)NCC(C)C)C(C)C)Cc2ccccc2)c1
Reaction time: 1 h
Yield: 51.2 %

Procedure:
3-[(Dipropylamino)carbonyl]benzoic acid, (52 mg, 0.21 mmol) is combined with EDC(40 mg, 0.21 mmol) and HOBT (30 mg, 0.22 mmol) in 2.5 mL of DMF and stirred under nitrogen for 1 h. This solution is then added to a solution of N-[(2S)-2-amino-3-phenylpropyl]-L-alanyl-N1-isobutyl-L-valinamide (0.17 mmol) in 1 mL of DMF. The reaction is continued for 3 days at ambient temperature. It is then quenched with 1 N KH2PO4 and diluted with ethyl acetate. The organic phase is washed with water, 1 N NaHCO3, and brine, and dried over Na2SO4. Concentration and chromatography over silica gel, eluting with 5% methanol in dichloromethane, affords 53 mg (0.087 mmol, 51%) of the title compound. Addition of several drops of deuterated methanol to the compound in deuterated chloroform is necessary. NMR (CDCl3+MeOD) δ 7.79 (br d, 1H), 7.69 (s, 1H), 7.44 (m, 2H), 7.30 (m, 4H), 7.26 (m, obscured by CHCl3), 7.19 (m, 2H), 4.33 (m, 1H), 4.03 (d, J=8 Hz, 1H), 3.5-3.4 (m, 3H), 3.13-3.0 (m, 6H), 2.90 (m, 1H), 2.68 (dd, 1H), 2.0 (m, 1H), 1.8-1.7 (m, 3H), 1.5 (m, 2H), 1.31 (d, J=7 Hz, 3H), 0.99 (t, J=7 Hz, 3H), 0.93-0.86 (overlapping d, 12H), 0.72 (t, J=7 Hz, 3H). MS (FAB) m/z 608 (MH+).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[C:32]([Cl:37])[C:31]=1[C:38](=O)[CH3:39]>>[Cl:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[C:32]([Cl:37])[C:31]=1[CH:38]([NH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1)[CH3:39]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(N)c4c3)cn2)CC1
Product: CC(Nn1ccc2ncc(-c3cnn(C4CCNCC4)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared as described in example 27 by condensing tert-butyl 4-[4-(1-amino-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (prepared in example 18:100 mg, 0.26 mmol) with 1-(2,6-dichloro-3-fluorophenyl)ethanone (excess). The reduction of imine and BOC-deprotection were also carried out as described in Example 27.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[O-]CC.[Na+].[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(O)C>[C:10]([C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[C:28]1[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]1)#[N:11]
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To the solution of 4-(trifluoromethyl)phenylacetonitrile (2560.9 mg; 13.83 mmol; 1.06 eq.) in ethanol (50 mL), 21% sodium ethoxide (5.70 ml; 15.27 mmol; 1.17 eq.) in ethanol was added dropwise at RT. After stirred for 30 min, a solution of 1-boc-4-piperidone (2600.00 mg; 13.05 mmol; 1.00 eq.) in ethanol (10 mL) was added slowly. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with 50 mL of saturated aqueous NH4Cl and concentrated to half volume. The aqueous solution was extracted with ether three times. The combined organic extracts were washed with brine, dried and then concentrated to give the crude product, which was purified by Biotage chromatography with EtOAc/Hexane (5-30%) to yield the desired product as light yellow solid (3200.00 mg, yield 66.9%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[I:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[C:66]([O:71][C:72]([F:75])([F:74])[F:73])[CH:65]=1>C(Cl)Cl>[I:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17]2)=[O:36])=[C:66]([O:71][C:72]([F:73])([F:74])[F:75])[CH:65]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(I)cc1OC(F)(F)F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(I)cc2OC(F)(F)F)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (200 mg, 344 μmol, Eq: 1.00), was combined with CH2Cl2 (5 ml) to give a clear solution. DIPEA (178 mg, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 30 minutes. 4-Iodo-2-(trifluoromethoxy) aniline (136 mg, 447 μmol, Eq: 1.3) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc/Hexanes) to give the desired product as a white solid. 255 mg. (ES+) m/z Calcd: [(M+)+]: 752. found: 752.