Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([C:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])[N:11]([CH3:13])[N:12]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].[CH3:23]I>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:9]=[C:10]([C:14]([O:20][CH3:23])([CH3:19])[C:15]([F:18])([F:17])[F:16])[N:11]([CH3:13])[N:12]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1cc(C(C)(O)C(F)(F)F)n(C)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(c1cc(-n2c(C)ccc2C)nn1C)C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 2-[5-(2,5-dimethyl-pyrrol-1-yl)-2-methyl-2H-pyrazol-3-yl]-1,1,1-trifluoro-propan-2-ol (0.5 g, 1.7 mmol) in THF (10 mL) at 0° C., sodium hydride (0.21 g, 60%, 5.2 mmol) is added, and the mixture is stirred for 10 min followed by the addition of methyl iodide (0.22 mL, 3.5 mmol). The ice bath is removed and the reaction mixture is stirred at room temperature for 5 hour, poured into water, separated, and the water layer is extracted with DCM. The organic layers are combined and concentrated. The residue is purified by FCC to give the title compound. MS (ESI) m/z 302.0 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCC[C@@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (R)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 121.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.28 min, m/z=473.1 [M+H]+, m/z=471.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.39 (m, 2H) 1.53-1.62 (m, 1H) 1.77-1.86 (m, 1H) 2.54 (s, 3H) 2.55-2.62 (m, 1H) 2.68-2.77 (m, 1H) 3.42-3.51 (m, 2H) 3.55-3.63 (m, 1H) 4.72 (s, 1H) 7.36 (d, J=9.05 Hz, 2H) 7.40 (d, J=8.07 Hz, 1H) 7.83-7.88 (m, 2H) 7.92-7.98 (m, 1H) 8.07 (d, J=1.96 Hz, 1H) 8.67-8.72 (m, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [N:1]1([C:10](=[N:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:11]2[C:16](=[O:17])[CH:15]=[CH:14][N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:12]=2)C2C=CC=CC=2[N:3]=[N:2]1.[N-]=[N+]=[N-].[Na+].FC(F)(F)C(O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[C:29]1([N:28]2[C:10]([C:11]3[C:16](=[O:17])[CH:15]=[CH:14][N:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[N:12]=3)=[N:1][N:2]=[N:3]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1C(=Nc1ccccc1)n1nnc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
A solution of 3-[1H-benzotriazol-1-yl(phenylimino)methyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.094 g, 0.20 mmol), sodium azide (0.030 g, 0.46 mmol), and tetrabutylammonium bromide (0.015 g, 0.047 mmol) in methylene chloride (5 mL) and water (5 mL) was treated with trifluoroacetic acid (0.040 mL, 0.52 mmol) and stirred 24 h at room temperature. After that time, the organic layer was separated and the aqueous layer was extracted with methylene chloride (3×25 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (50 mL), dried (MgSO4), and concentrated. The crude product purified by flash column chromatography (silica gel, 80:20 hexanes/ethyl acetate to ethyl acetate) to give an off-white solid that was recrystallized from ethyl acetate/hexanes to give 0.034 g (56%) of 3-(1-phenyl-1H-tetrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1.[Na+].[I-].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:33][CH2:32][CH2:31][N:30](CCCCOC2C=C3C(CCC(=O)N3)=CC=2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][NH:12][C:13]3=[O:16])=[CH:8][CH:7]=2)[CH2:29][CH2:28]1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: O=C1NCCc2ccc(OCCCBr)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1NCCc2ccc(OCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of intermediate 20 (110 mg, 0.39 mmol) and NaI (117 mg, 0.78 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 2 (165 mg, 0.58 mmol) and anhydrous K2CO3 (216 mg, 1.56 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. The reaction solution was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(3-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)propoxy)-3,4-dihydroisoquinolin-1(2H)-one (compound 5) (125 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=2.1 Hz, 1H), 7.14-7.08 (m, 3H), 7.02-7.00 (m, 2H), 6.02 (br., 1H), 4.10 (t, J=6.3 Hz, 2H), 3.56-3.53 (m, 2H), 3.31-3.27 (m, 4H), 2.96-2.88 (m, 6H), 2.77-2.72 (m, 2H), 2.01 (m, 4H). HPLC: 99%, RT 2.578 min. MS (ESI) m/z 448.1 [M+H]+. mp: 116-117° C.
Reaction SMILES: [CH3:1][CH:2]1[C@H:19]([C:20]([CH3:22])=[O:21])[C@:18]2([CH3:23])[C@H:4]([C@H:5]3[C@H:15]([CH2:16][CH2:17]2)[C@:14]2([CH3:24])[C:8](=[CH:9][C:10]([CH2:12][CH2:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[CH3:1][C@@H:2]1[CH2:3][C@@H:4]2[C@:18]([CH3:23])([CH2:17][CH2:16][C@H:15]3[C@H:5]2[CH2:6][CH2:7][C:8]2[C@:14]3([CH3:24])[CH:13]=[CH:12][C:10](=[O:11])[CH:9]=2)[C@H:19]1[C:20](=[O:21])[CH3:22]
Reactant: CC(=O)[C@H]1C(C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
A mixture of 16α-methylprogesterone (792 mg), DDQ (575 mg) and benzene are heated at reflux for 28 hr, after 20 hr additional DDQ (70 mg) is added. After refluxing, the mixture is cooled to 20°-25°, filtered followed by basic workup (ether--potassium carbonate--magnesium sulfate) to give 16α-methylpregna-1,4-diene-3,20-dione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([NH2:33])=[O:32])[CH:29]=4)[NH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[C:7]1=[O:34].F[C:40]1[CH:41]=C(C=C[C:75]=1F)CN1C=CC=C(C(NCC2C=C(C3C4C(=NC=C(C(O)=O)C=4)NC=3)C=CC=2)=O)C1=O.C(N)CC>>[CH2:75]([NH:33][C:31]([C:28]1[CH:29]=[C:30]2[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][C:12]([C:8]4[C:7](=[O:34])[N:6]([CH2:5][C:4]5[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=5)[CH:11]=[CH:10][CH:9]=4)=[O:13])[CH:17]=3)=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1)=[O:32])[CH2:40][CH3:41]
Reactant: O=C(O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: NC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Solvent: CCCN
Product: CCCNC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
Except where indicated, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid propylamide was synthesized as per Example 81, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid amide using 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (53 mg, 0.00010 mol) as carboxylic acid and 1-Propanamine (20 mg, 0.00034 mol; Aldrich) as amine, to yield the product. 1H NMR (400 MHz, CDCl3) d ppm 12.514 (s, 1H) 10.791 (m, 1H) 9.331 (s, 1H) 9.039 (s, 1H) 8.617 (m, 1H) 8.274 (m, 1H) 7.881-7.566 (m, 3H) 7.566-7.320 (m, 3H) 7.196-7.088 (m, 2H) 7.055-6.991 (m, 1H) 6.534 (t, J=6.5 Hz, 1H) 5.164 (s, 2H) 4.757 (d, J=5.3 Hz, 2H) 3.503 (m, 2H) 1.736 (m, 2H) 0.999 (t, J=7.4 Hz, 3H); MS m/z=556.36 M+H.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][C:11]2([CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15]2)[CH2:10]1)=[O:7])([CH3:4])[CH3:3]>CCO.[OH-].[OH-].[Pd+2]>[OH:14][CH:13]1[CH2:12][C:11]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[NH:8][C:6](=[O:7])[O:5][C:2]([CH3:3])([CH3:1])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CC2(CCN(C(=O)OCc3ccccc3)CC2)CC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CC2(CCNCC2)CC1O
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To a solution of phenylmethyl 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (˜3.1 g, 7.65 mmol) in EtOH (38 mL) was added Pd(OH)2 (1.5 g, 50 wt %). The solution was hydrogenated using a Parr Shaker at 50 psi. After 2 h, the solution was filtered through Celite®, concentrated and purified by column chromatography (silica, 15% MeOH in DCM (1% NH4OH)) yielding the title compound (618 mg, 31%-2 steps) as a yellow oil: LCMS (ES) m/e 272 (M+H)+.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH:26]([NH:29]N)([CH3:28])[CH3:27].CCN(CC)CC>C(O)C.Cl>[CH3:27][CH:26]([N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1)[CH3:28]
Reactant: CC(C)NN
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)n1nccc1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 61.8 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (500 mg, 1.5 mmol) in ethanol (10 mL) were added isopropylhydrazine hydrochloride (246 mg, 2.2 mmol) and Et3N (0.41 mL, 3.0 mmol). The mixture was stirred at 100° C. for 5 h. The mixture was diluted with 1N HCl aqueous solution, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=10/90 to 0/100) and recrystallized with AcOEt/i-Pr2O to yield the title compound as a pale yellow solid (323 mg, 63%).
Reaction SMILES: [C:1]([CH2:3][N:4]([C:16]1[CH:21]=[CH:20][N:19]=[C:18](F)[N:17]=1)[C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])#[N:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:18]3[N:17]=[C:16]([N:4]([CH2:3][C:1]#[N:2])[C:5](=[O:15])[C@H:6]([CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[NH2:7])[CH:21]=[CH:20][N:19]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: N#CCN(C(=O)[C@@H](N)Cc1ccccc1)c1ccnc(F)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: N#CCN(C(=O)[C@@H](N)Cc1ccccc1)c1ccnc(N2CCN(c3ccc(Cl)cc3)CC2)n1

Procedure:
The title compound was prepared from the product of example 5 step (ii) (0.2 g) and 4(4-chlorophenyl)piperazine by the method of example 1 step (iv). Yield 0.18 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[CH:15][C:16]#[N:17])[CH2:9][C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[NH2:17][C:16]1[N:21]([CH:18]2[CH2:20][CH2:19]2)[C:10](=[O:11])[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=1
Reactant: NC1CC1
Reactant: CCOC(=O)CC(=CC#N)c1cccc(Cl)c1
Product: Nc1cc(-c2cccc(Cl)c2)cc(=O)n1C1CC1

Procedure:
Starting compounds: ethyl 3-(3-chlorophenyl)-4-cyano-3-butenoate and cyclopropylamine
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[C:10]([F:20])[C:9]([OH:21])=[C:8]([CH:22]=[O:23])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[C:10]([F:20])[C:9]([O:21][CH:2]([CH3:4])[CH3:3])=[C:8]([CH:22]=[O:23])[CH:7]=1
Reactant: CC(C)I
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Reaction time: 3 h
Yield: 94.5 %

Procedure:
2-Iodopropane (461 mg) was added at room temperature to a mixture of 6-bromo-2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (598 mg), potassium carbonate (499 mg), and DMF (10 mL), and the mixture was stirred at 60 C for 3 hours in a nitrogen atmosphere. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated, then washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (637 mg).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]2)=[CH:9][CH:8]=1)C>CCO.[OH-].[Na+]>[O:18]=[C:15]1[CH2:16][CH2:17][C@@H:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:19])=[O:3])=[CH:8][CH:9]=2)[CH2:14]1
Reactant: CCOC(=O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Yield: 88.2 %

Procedure:
(R)-[4-(3-Oxo-cyclopentyl)-phenoxy]-acetic acid ethyl ester (preparation 30) (6.0 mmol, 1.57 g) was taken up in EtOH (6 mL) and NaOH (2N, 6 mL), the reaction mixture stirred at r.t. for 2 h. Then the EtOH was evaporated and the reaction mixture diluted with water, then neutralized with HCl (2N) to pH 5 and extracted with DCM. Dried over Na2SO4 and concentrated in vacuo to yield the title compound (1.24 g, 89%). 1H NMR (300 MHz, CDCl3) δ 7.23-7.06 (m, 2H), 6.98-6.72 (m, 2H), 4.66 (s, 2H), 3.53-3.13 (m, 1H), 2.64 (dd, J=7.5, 18.2, 1H), 2.56-2.17 (m, 4H), 2.14-1.69 (m, 1H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[CH2:30])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[CH:32]=[CH:31][C:28]([CH:29]=[CH2:30])=[CH:27][CH:26]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: C=Cc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: C=Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 20 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminostyrene (46.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-vinylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (13.1 mg).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:32]=[CH:31][S:30][N:29]=1)[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:32]=[CH:31][S:30][N:29]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1ncsn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ncsn1
Reaction time: 0.42 h
Yield: 53.4 %

Procedure:
To a solution of benzhydryl 2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetate (syn isomer) (6.5 g) and anisole (6.5 ml) in methylene chloride (60 ml) was added trifluoroacetic acid (13 ml) at ambient temperature, and the mixture was stirred at the same temperature for 25 minutes. To the reaction mixture was added ethyl acetate and the solution was washed with water. To the separated organic layer was added water and the mixture was adjusted to pH 7.5 with 20% aqueous sodium carbonate. The separated aqueous layer was acidified to pH 2.0 with 10% hydrochloric acid. The acidified solution was saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium chloride, and dried over magnesium sulfate. The solution was evaporated and the residue was pulverized with diisopropyl ether and n-hexane to give 2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (2.2 g), mp. 137° C. (dec.).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[C:32]4[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=4[N:26]=[C:25]([N:33]4[CH2:37][CH2:36][CH2:35][CH:34]4[C:38](OC)=[O:39])[N:24]=3)[NH:19][N:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:18][N:19]=[C:20]([NH:22][C:23]3[C:32]4[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=4[N:26]=[C:25]([N:33]4[CH2:37][CH2:36][CH2:35][C@@H:34]4[C:38]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:39])[N:24]=3)[CH:21]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCCC2
Reactant: Nc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)nc1)[C@H]1CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCCC2
Reaction time: 0.33 h
Yield: 4.9 %

Procedure:
To a stirred solution of 6-fluoropyridin-3-amine (2.58 g, 23.01 mmol) in THF (40 mL) was added a 2M solution of isopropylmagnesium chloride in THF (11.5 mL, 23 mmol) at 0° C. After 20 min of stirring, to this was added a solution of methyl 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxylate (2.2 g, 5.75 mmol) in THF (10 mL) at 0° C. The reaction mixture was further stirred at RT for 2 h. After completion of reaction it was quenched with saturated ammonium chloride and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layer was treated with brine, dried over Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography on 100-200 mesh silica gel using MeOH-DCM (1:10) as eluent to obtain as racemate (0.6 g, 23% yield). The enantiomers were separated by chiral HPLC to afford (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide (130 mg), and its (S) enantiomer. 1H NMR (400 MHz, CDCl3, freebase) δ (ppm): 0.60-0.77 (m, 2H), 0.85-0.98 (m, 2H), 1.77-1.90 (m, 6H), 1.91-2.20 (m, 3H), 2.38-2.43 (m, 2H), 2.60-2.80 (m, 3H), 3.59-3.78 (m, 2H), 4.71 (d, 1H), 6.17 (s, 1H), 6.80-6.83 (m, 1H), 6.91 (s, 1H), 7.95 (s, 1H), 8.20 (brs, 1H), 10.90 (brs, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.N[NH:14][C@@H:15]([CH2:20][OH:21])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[OH:21][CH2:20][C@H:15]([NH:14][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C[C@H](CO)NN
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: CC(C)C[C@H](CO)NC(=O)c1ccc2c(c1)OCO2

Procedure:
Prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxylic acid and (R)-aminoleucinol. MS (M+H, 266.1)
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1.Cl([O-])(=O)(=O)=O.[CH2:26]1[C:33]2[CH2:32][CH2:31][CH2:30][N+:29]=2[CH2:28][CH2:27]1.Cl>C1COCC1.CCOC(C)=O>[Cl:13][C:14]1[C:19]([C:33]23[CH2:32][CH2:31][CH2:30][N:29]2[CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1
Reactant: Clc1cccc(Cl)n1
Reactant: C1CC2=[N+](C1)CCC2
Agent: Cl
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Clc1ccc(C23CCCN2CCC3)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17.2 %

Procedure:
A solution of 2.5M nBuLi (675 μL, 1.7 mmol) in hexanes was added to diisopropylamine (220 μL, 1.7 mmol) in THF (4.5 mL) at ambient temperature. After 10 minutes of stirring, the reaction mixture was cooled to -78° C., 2,6-dichloropyridine (237 μL, 1.60 mmol) was added neat, and stirring was continued for 1 hour at -78° C. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (500 mg, 2.40 mmol) was added, and the reaction mixture was allowed to stir for 2 hours at -78° C. then warm to ambient temperature. A solution of 2N HCl was added, and the mixture was then poured over EtOAc. The phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (70.6 mg, 17%). MS (CI/NH3) m/e: 257/259 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.47-1.61 (m, 2H), 1.77-1.90 (m, 2H), 2.10-2.25 (m, 4H), 2.67-2.75 (m, 2H), 3.03-3.11 (m, 2H), 7.19 (d, J=8.5 Hz, 1H), 8.37 (d, J=8.5 Hz, 1H).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:5]=[C:6]2[C:36](=[CH:37][CH:38]=1)[C:14]1[N:15]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:16]([C:18]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[N:17][C:13]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:39][C:40](=[O:42])[CH3:41])=[CH:8][C:7]2=1>C(OCC)C.Cl[Ti](Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]2[C:36](=[CH:37][CH:38]=1)[C:14]1[N:15]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:16]([C:18]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[N:17][C:13]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:39][C:40]([OH:42])([CH3:1])[CH3:41])=[CH:8][C:7]2=1
Reactant: [Li]C
Reactant: CC(=O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a round bottomed flask at −78° C. charged with TiCl4 (1 M in CH2Cl2, 20 mL), was added methyllithium (1.6 M in diethyl ether, 12.5 mL). The resulting deep red solution was stirred at −78° C. for 15 minutes and then added via cannula to a 0° C. solution of 2-(9-chloro-6-(2-oxopropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl)-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (2.8 g, 5.0 mmol) from Step 2 above, in diethyl ether (10 mL). The resulting mixture was stirred at 0° C. for 3 h, then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography on silica (50% ethyl acetate in hexanes) to provide 2-(9-chloro-6-(2 -hydroxy-2-methylpropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (1.94 g),