Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[CH2:37][N:36]([C:38]4[CH:43]=[C:42]([C:44]5([CH3:48])[CH2:47][O:46][CH2:45]5)[CH:41]=[CH:40][C:39]=4[CH3:49])[CH2:35][CH2:34][C:10]=3[N:11]=[C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[CH:17][N:18]4S(C3C=CC(C)=CC=3)(=O)=O)[N:13]=2)[CH2:6][CH2:5][N:4]([C:50](=[O:52])[CH3:51])[CH2:3]1.[OH-].[NH4+].[OH-].[K+]>CCO>[CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[CH2:37][N:36]([C:38]4[CH:43]=[C:42]([C:44]5([CH3:48])[CH2:45][O:46][CH2:47]5)[CH:41]=[CH:40][C:39]=4[CH3:49])[CH2:35][CH2:34][C:10]=3[N:11]=[C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[CH:17][NH:18]4)[N:13]=2)[CH2:6][CH2:5][N:4]([C:50](=[O:52])[CH3:51])[CH2:3]1
Reactant: CC(=O)N1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2cc(C4(C)COC4)ccc2C)CC3)[C@H](C)C1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCN(c2nc(-c3cccc4[nH]cc(C)c34)nc3c2CN(c2cc(C4(C)COC4)ccc2C)CC3)[C@H](C)C1
Temperature: 100 °C

Procedure:
A mixture of (R)-1-(3-methyl-4-(2-(3-methyl-1-tosyl-1H-indol-4-yl)-6-(2-methyl-5-(3-methyloxetan-3-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)ethanone (0.104 g, 0.145 mmol), 30% ammonium hydroxide (0.854 mL, 21.70 mmol) and KOH (0.073 g, 1.302 mmol) in EtOH (4 mL) was heated in a microwave reactor at 100° C. for 30 min. The mixture was concentrated and partially purified by FCC (0-6% MeOH in DCM). Further purification with HPLC (C18, 15-85% CH3CN in H2O with 0.1% NH4OH) provided (R)-1-(3-methyl-4-(2-(3-methyl-1H-indol-4-yl)-6-(2-methyl-5-(3-methyloxetan-3-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)ethanone. 1H NMR (400 MHz, DMSO-d6 at 120° C.) δ ppm 10.50 (br. s., 1 H) 7.42 (d, J=8.08 Hz, 1 H) 7.25 (d, J=7.20 Hz, 1 H) 7.19 (d, J=7.83 Hz, 1 H) 7.07-7.15 (m, 2 H) 6.97 (s, 1 H) 6.90 (d, J=7.96 Hz, 1 H) 4.79 (d, J=5.43 Hz, 2 H) 4.53 (d, J=5.05 Hz, 2 H) 4.05-4.19 (m, 3 H) 3.91 (br. s., 1 H) 3.75 (br. s., 1 H) 3.56 (d, J=13.26 Hz, 1 H) 3.22-3.48 (m, 5 H) 3.00 (t, J=5.62 Hz, 2 H) 2.29 (s, 3 H) 2.07 (s, 3 H) 1.99-2.04 (m, 3 H) 1.65 (s, 3 H) 1.17 (d, J=6.44 Hz, 3 H); MS (ESI+) m/z 565.4 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[NH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].Br[C:68]1[CH:87]=[CH:86][C:71]([CH2:72][C:73]2[C:74]([CH2:84][CH3:85])=[N:75][N:76]3[C:81]([CH3:82])=[CH:80][C:79]([CH3:83])=[N:78][C:77]=23)=[CH:70][CH:69]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:7](=[N:8][C:68]1[CH:87]=[CH:86][C:71]([CH2:72][C:73]2[C:74]([CH2:84][CH3:85])=[N:75][N:76]3[C:81]([CH3:82])=[CH:80][C:79]([CH3:83])=[N:78][C:77]=23)=[CH:70][CH:69]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Temperature: 105 °C
Reaction time: 0.08 h

Procedure:
Diphenylmethanimine (7.53 g, 39.5 mmol), BINAP (447 mg, 0.718 mmol) and sodium tert-butoxide (6.9 g, 71.8 mmol) were dissolved in 100 ml of toluene. The reaction mixture was heated to 105° C. and stirred for 5 min. Then 3-(4-bromo-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (3) (13 g, 35.9 mmol) and palladium diacetate (81 mg, 0.36 mmol) were added and the reaction mixture was stirred for 12 h at 110° C. The organic layer was extracted two times with EtOAc, washed with water and brine, dried over Na2 SO4 and concentrated under reduced pressure. The precipitate was suspended in cyclohexane and filtered to afford a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Sc1ccc(Cl)cc1
Product: Fc1ccc(Sc2ccc(Cl)cc2)c(Br)c1

Procedure:
Prepared from 4-chloro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [CH3:1][C:2]([NH:36][C:37]([O:39]OCC1C=CC=CC=1)=[O:38])([CH3:35])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]([OH:33])=O)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:8]1=[O:34])=[O:5].[CH3:48][O:49][C:50]1[CH:57]=[CH:56][C:53]([CH2:54][NH2:55])=[CH:52][CH:51]=1>>[CH3:48][O:49][C:50]1[CH:57]=[CH:56][C:53]([CH2:54][NH:55][C:31]([C:26]2[C:25]([C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:9]4[C:10]5[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=5[CH2:12][CH2:13][C@@H:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([NH:36][C:37]([O:39][CH2:12][C:11]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:10]=5)=[O:38])([CH3:35])[CH3:1])[C:8]4=[O:34])=[CH:24][CH:23]=3)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:33])=[CH:52][CH:51]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)O)cc2)C1=O)NC(=O)OOCc1ccccc1
Product: COc1ccc(CNC(=O)c2ccccc2-c2ccc(CN3C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OCc4ccccc4)CCc4ccccc43)cc2)cc1

Procedure:
The title compound was prepared from 4'-[[2,3,4,5-tetrahydro-3(R)-[[3-methyl-1-oxo-3-[[(benzyloxyoxy)carbonyl]amino]butyl]amino]-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylic acid (Example 72, Step B) and 4-methoxybenzylamine by the procedure described in Example 74, Step A. 1H NMR (200 MHz,CD3OD) 1.40 (s,6H), 2.00 (m,1H), 2.31 (m,1H), 2.50-2.75 (m,4H), 3.82 (s,3H), 4.27 (s,2H), 4.43 (dd;7,11 Hz;1H), 4.95 (d,15 Hz,1H), 5.05 (d,12 Hz,1H), 5.15 (d,12 Hz,1H), 5.37 (d,15 Hz,1H), 6.87 (m,3H), 7.03 (d,8 Hz,2H), 7.20-7.57 (m,19H). FAB-MS: calculated for C45H46N4O6 738; found 7.40.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.[CH:10](Cl)([Cl:12])[Cl:11].CC(C)([O-])C.[K+].Cl>CN(C=O)C.C1COCC1>[Br:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[C:5]([CH:10]([Cl:12])[Cl:11])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Br)s1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1sc(Br)cc1C(Cl)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-5-nitrothiophene (29 g, 139 mmol) and chloroform (12.37 mL, 153 mmol) in DMF (110 mL) was added dropwise to a solution of potassium tert-butoxide (62.6 g, 558 mmol) in THF (225 mL)/DMF (180 mL). The internal temperature was monitored and maintained at <−60° C. during the addition. Upon complete addition, the reaction was stirred at −78° C. for 30 minutes. 2 N HCl was added and the products were extracted into EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (0-10% EtOAc-hexanes) gave the title compound as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([OH:19])[CH2:12][C@@H:13]([NH:17][CH3:18])[CH:14]([CH3:16])[CH3:15])[S:9][CH:10]=1)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.[NH:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:31]([C:36](O)=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C@H:11]([O:19][C:36](=[O:37])[C@@H:31]([NH:30][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[C@@H:32]([CH3:33])[CH2:34][CH3:35])[CH2:12][C@@H:13]([NH:17][CH3:18])[CH:14]([CH3:16])[CH3:15])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)c1csc([C@H](O)C[C@@H](NC)C(C)C)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1csc([C@@H](C[C@@H](NC)C(C)C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 0.1 M solution of N-methyl tubuvaline ethyl ester 35 (0.305 g, 1.06 mmol), 1-hydroxybenzotriazole (HOBt) (0.146 g, 1.08 mmol), and Boc-Ile-OH (0.267 g, 1.11 mmol) in CH2Cl2 (10.6 mL) was cooled in a salted ice-water bath. PS-CCD (1.38 mmol/g, 0.920 g, 1.27 mmol) was added with stirring, and the bath was warmed to rt. Stirring was continued for 14 h, the solution was filtered, and the resin was washed with CH2Cl2. The filtrate was then concentrated, diluted with EtOAc, and washed once with sat. NaHCO3 (aq). The aqueous fraction was back-extracted twice with EtOAc, and the combined organic fractions were dried with Na2SO4, filtered, and concentrated to afford intermediate 36, which was taken on without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of compound 305 (670 mg, 2.4 mmol) in dry THF (11 mL) were added phenyl boronic acid 306b (439 mg, 3.6 mmol), palladium acetate (7 mg, 0.03 mmol), triphenyl phosphine (16 mg, 0.06 mmol), and sodium carbonate (4.8 mg). The mixture was stirred at 60° C. for 3 hrs. The solution was then cooled down to room temperature. Water and TBDME were added. Organics were washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to yield compound 307b as a white solid in 95% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 4.11 (s, 3H), 6.71-6.72 (m, 2H), 7.54-8.05 (m, 5H), 8.58 (dd, J=2.78 Hz and J=1.00 Hz, 1H); 19F NMR (CDCl3, 376 MHz) δ (ppm) −62.45 (s, 3F).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][CH3:29])(=[O:4])[CH2:2][CH3:3].C(=O)(O)[O-:31].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26]([CH2:27][CH2:28][CH3:29])=[O:31])(=[O:4])[CH2:2][CH3:3]
Reactant: CCCSCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)CCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
3-Propanoyl-4-(2-methylphenylamino)-8-(2-propylthioethoxy)quinoline (0.5 g, 1.22 mmol) was dissolved in 10 ml methylene chloride. A solution of sodium bicarbonate (250 mg, 3.0 mmol) in 10 ml water was added. The mixture was cooled to 2°-4° C. A solution of 70% m-CPBA (295 mg, 1.20 mmol) in 10 ml methylene chloride was added dropwise during 10 min. The temperature was allowed to rise to room temperature and the mixture was stirred 30 min at this temperature. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by column chromatography (methylene chloride:ethanol 90:10) to give 380 mg (73%) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([NH:15][OH:16])=[NH:14])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=O)=[CH:21][CH:20]=1>C(O)(=O)C>[Cl:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]2[O:16][N:15]=[C:13]([CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]3)[N:14]=2)=[CH:21][CH:20]=1
Reactant: CCC(CC)N1CCC(CC(=N)NO)CC1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CC(=O)O
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc(CCl)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-((1-ethylpropyl)piperidin-4-yl)-N-hydroxyacetamidine (0.50 g, 2.2 mmol, prepared as described in Example 12), glacial acetic acid (15 mL) and 4-(chloromethyl)benzoyl chloride (0.46 g, 2.4 mmol) was stirred overnight at ambient temperature and then heated at reflux for 30 minutes. The mixture was concentrated in vacuo and the residue was dissolved in a mixture of 1 N hydrochloric acid (10 mL), water (50 mL) and diethyl ether (20 mL). The phases were separated and the aqueous phase was washed with diethyl ether (2×10 mL). The organic extracts were discarded and the aqueous phase was made alkaline (pH 10) with 4 N sodium hydroxide and then extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (MgSO4) and the solvent was evaporated. This afforded 0.70 g of 4-[5-(4-(chloromethyl)phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-1-(1-ethylpropyl)piperidine as an oil. 1H NMR (400 MHz, CDCl3) δ 0.87 (t, 6H), 1.22-1.49 (m, 4H), 1.40-1.52 (m, 2H), 1.67-1.74 (m, 2H), 1.78-1.88 (m, 1H), 2.13 (pent., 1H), 2.23-2.31 (m, 2H), 2.68-2.75 (m, 4H), 4.63 (s, 2H), 7.55 (d, 2H), 8.14 (d, 2H). HPLC: Rt=14.22 min.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH-].[Na+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.1 %

Procedure:
To a solution of Boc-L-Trp-OBzl (5.00 g), tetra-n-butylammonium sulfate (43 mg) and NaOH (sodium hydroxide) (1.27 g) in methylene chloride (100 ml) was added a solution of ethyl bromoacetate (5.29 g) in methylene chloride (50 ml) in an ice-bath cooling. After being stirred at room temperature for 2 days, the mixture was washed with 5% aqueous potassium hydrogen sulfate solution, 1M aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo to afford Boc-L-Trp(CH2COOEt)-OBzl (6.10 g) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@@H:15]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=3[CH2:33][CH3:34])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.N[C@H](C1NC=C(C2C=CC(C(N)=O)=CC=2)N=1)CC1C=CC=CC=1>C1COCC1>[NH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C@H:15]([C:12]2[NH:13][CH:14]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH2:2])=[CH:9][CH:8]=3)[N:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:35])=[C:26]([CH2:33][CH3:34])[CH:27]=1
Reactant: CCc1cc(C#N)ccc1C(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccc(C(N)=O)cc2)c[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)c1ccc(-c2c[nH]c([C@@H](N)Cc3ccccc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1cc(CN)ccc1C(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccc(C(N)=O)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Part E: N-{(S)-1-[4-(4-Carbamoyl-phenyl)-1H-imidazol-2-yl]-2-phenyl-ethyl}-4-cyano-2-ethyl-benzamide: The product from Example 143 Part D (90 mg, 0.51 mmol), Bop reagent (265 mg, 0.61 mmol), and triethylamine (0.42 mL, 1.5 mmol) were added together with 5 mL of THF. The mixture was stirred at RT under N2 for 15 minutes and (S)-4-(2-(1-amino-2-phenylethyl)-1H-imidazol-4-yl)benzamide prepared using the methods described in Examples 2 and 28 (365 mg, 0.51 mg) was added. The resulting mixture was heated at 75° C. for 70 minutes. The THF was removed, and the residue was dissolved in EtOAc. It was washed with waster and brine, dried over MgSO4, concentrated, and purified by flash chromatography (silica, EtOAc/hexane) to give 80 mg of the desired product. MS: 464.4 (M+1)+.
Reaction SMILES: C1(P(=C=[CH:21][C:22]([O:24][CH3:25])=[O:23])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[CH:32]=O)[CH3:27]>C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29]1[CH:30]=[C:31](/[CH:32]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[CH3:27]
Reactant: COC(=O)C=C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C=O)cc1OCC
Solvent: Cc1ccccc1
Product: CCOc1ccc(/C=C/C(=O)OC)cc1OCC
Reaction time: 1 h

Procedure:
1.81 g (5.40 mmol) of methyl (triphenylphosphoranylidene)acrylate are added, at room temperature, to a solution of 1.0 g (5.15 mmol) of 3,4-diethoxybenzaldehyde and 10 ml of toluene. The reaction is then allowed to proceed for 1 hour at room temperature, the reaction suspension is clarified by filtration over a silica gel bed and the filtrate is evaporated down. Chromatography of the residue over silica gel using toluene/ethyl acetate gives methyl 3(E)-(3,4-diethoxyphenyl)acrylate.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH:17]1([NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: BrC1CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCc1ccc(NC2CCCCCC2)cc1
Reaction time: 7 h
Yield: 53.2 %

Procedure:
A mixture of 10.0 g of 4-octylaniline, 8.6 g of bromocyclo-heptane, 13.5 g of potassium carbonate and 50 ml of hexamethylphosphoramide (HMPA) was stirred at 90° to 100° C. for 7 hours. After cooling, a saturated saline solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=50:1) to give 7.79 g of N-cycloheptyl-N-(4-octylphenyl)amine (yield: 53%, brown oily product, IR (film): 3390, 2925, 2854, 1617, 1518 cm-1).
Reaction SMILES: [NH2:1][C:2]1([NH:8][C:9](=[O:30])[CH:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[C:22](=[O:28])[C:21]2=[O:29])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]([CH3:6])[NH:4][C:3]1=[O:7].N1C=CC=CC=1.[C:37](OC=O)(=[O:39])C>ClCCl>[CH2:26]([N:23]1[CH2:24][CH2:25][N:20]([C:18]([NH:17][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]([NH:8][C:2]2([NH:1][CH:37]=[O:39])[CH:5]([CH3:6])[NH:4][C:3]2=[O:7])=[O:30])=[O:19])[C:21](=[O:29])[C:22]1=[O:28])[CH3:27]
Reactant: CC(=O)OC=O
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2(N)C(=O)NC2C)c2ccccc2)C(=O)C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CCN(C(=O)NC(C(=O)NC2(NC=O)C(=O)NC2C)c2ccccc2)C(=O)C1=O
Yield: 86.2 %

Procedure:
A solution of the amine (62) (87 mg) and pyridine (33 mg) in dry dichloromethane (2 ml) was treated with formic acetic anhydride (40 mg) for 24 hour after which time the solvent was removed in vacuo. Dry dioxan was added and solution re-evaporated (×3). Silica gel column chromatography of the residue gave the title compound (63) (80 mg) as a white powder, νmax. (Nujol) 3500, 3250, 1770, 1710, 1670, and 1500 cm-1, δ[(CD3)2CO] 0.88, 0.96, 1.00 and 1.03 (each d, J 6.5 Hz, together 3H) (irradiation at 4.00 caused the signals centered at 0.88 and 0.96 to collapse to 2×s), 1.16 (t, J7 Hz, 3H), 3.49(q, J7.Hz, 2H), 3.58-3.68 (m.2H), 3.93-4.23 (complex m, together 3H), 5.59-5.84 (complex m, together 1 H) (collapses to 4×s at 5.65, 5.69, 5.76 and 5.80 upon irradiation at 10.0), 7.25-7.80 (complex m, together 6H) (simplifies on exchange with D2O to a m at 7.25-7.56), 7.97-8.86 (complex m, together 3H) (simplifies to 4×s at 8.03, 8.11, 8.24, and 8.48 on exch.), 9.90-10.05 (m, 1H, exch).
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>C(O)(=O)C.[Fe]>[F:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][CH:11]=1)[N:15]=[C:1]([NH2:2])[C:3]([C:4]([NH2:6])=[O:5])=[CH:7]2
Reactant: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])C(N)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: NC(=O)c1cc2cc(F)ccc2nc1N

Procedure:
Iron powder (8.52 g., 0.152 mole) is gradually added over a 40-minute period to a slurry of α-cyano-β-(2-nitro-5-fluorophenyl)acrylamide (7.97 g., 0.034 mole) in acetic acid (100 ml.) at 85° C. When addition of the iron powder is complete, the mixture is heated to 95°-100° C. for 1.5 hours and then filtered hot through diatomaceous earth. The filtrate is cooled in an ice bath and then filtered to give a tan crystalline solid. The solid is partitioned between ethyl acetate and water, the organic phase separated, dried over anhydrous sodium sulfate and concentrated to yield 6.34 g. (90%) of the title amide as yellow crystals. M.P. 232°-236° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[C:30](=[O:41])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>O1C=COC=C1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:38][CH:39]=2)[C:30](=[O:41])[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)C(=O)C1
Agent: [Pd+2]
Agent: C1=COC=CO1
Agent: CC(=O)[O-]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4=O)cn3)nc2n1C1CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (225 mg, 0.77 mmol), 4-(6-aminopyridin-3-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (204 mg, 0.69 mmol), BINAP (24 mg, 0.038 mmol), palladium(II) acetate (6 mg, 0.027 mmol) and cesium carbonate (340 mg, 1.05 mmol) in dioxin (4 mL) is flushed with nitrogen and heated to 100° C. overnight. Additional palladium(II) acetate (6 mg, 0.027 mmol) and BINAP (24 mg, 0.038) are added and heating is continued at 110° C. for 2 h at which point LCMS and TLC analysis indicates completion of the reaction. The solvent is removed in vacuo and the residue is stirred in water with sonication in an ultrasonic bath. The suspension is filtered and the filter cake is washed with heptane. Drying in vacuo provides 4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester as a tan solid (350 mg, 83%) MS (ESI) m/z=549 [M+H]+.