Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C@@H:27]1[CH2:36][C@@H:35]2[N:30]([C:31](=[O:52])/[C:32](=[CH:37]/[C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=3)/[CH2:33][CH2:34]2)[C@H:29]([C:53]2[CH:58]=[C:57]([F:59])[C:56]([F:60])=[C:55]([F:61])[CH:54]=2)[CH2:28]1)(C(C)(C)C)(C)C.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[F:59][C:57]1[CH:58]=[C:53]([C@@H:29]2[CH2:28][C@H:27]([OH:26])[CH2:36][C@@H:35]3[N:30]2[C:31](=[O:52])/[C:32](=[CH:37]/[C:38]2[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=2)/[CH2:33][CH2:34]3)[CH:54]=[C:55]([F:61])[C:56]=1[F:60]
Reactant: COc1cc(/C=C2\CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CC[C@@H]3C[C@@H](O)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
TBAF (1.0 M solution in THF, 68.6 μL) was added to a solution of (E)-(6S*,8R*,9aR*)-8-(tert-butyldimethylsilanyloxy)-6-(3,4,5-trifluorophenyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]octahydroquinolizin-4-one (21.0 mg) in THF (1.0 mL), and the reaction solution was stirred at room temperature overnight. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 11.5 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[F:32])[C:24]([NH:26][O:27][CH3:28])=[O:25]>CN(C)C=O.C(OCC)(=O)C>[F:32][C:31]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][O:27][CH3:28])=[O:25])=[CH:22][C:21]=1[NH:20][C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Cc1cnc(-c2cn3ncnc(Cl)c3c2C(C)C)o1
Reactant: CONC(=O)c1ccc(F)c(N)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CONC(=O)c1ccc(F)c(Nc2ncnn3cc(-c4ncc(C)o4)c(C(C)C)c23)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 47.1 %

Procedure:
To a solution of Example 58 (30 mg, 0.11 mmol) in dimethyl formamide (0.7 mL) at RT was added 3-amino-4-fluoro-N-methoxy-benzamide (30 mg, 0.16 mmol). After stirring at ambient temperature for 19 h, the mixture was dissolved in ethyl acetate and washed with 10% LiCl solution. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5% methanol in chloroform to afford the title compound (22 mg, 48%) as an off-white solid. LC/MS; (M+H)+=425.1.
Reaction SMILES: [N:1](OCCCC)=[O:2].C[O-].[Na+].[CH3:11][O:12][N:13]=[C:14]([C:16](=[O:19])[CH2:17][CH3:18])[CH3:15].Cl>CO>[CH3:11][O:12][N:13]=[C:14]([CH3:15])[C:16](=[O:19])[C:17](=[N:1][OH:2])[CH3:18]
Reactant: CCCCON=O
Reactant: CCC(=O)C(C)=NOC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(C)C(=O)C(C)=NO
Reaction time: 12 h

Procedure:
10.3 g (0.1 mol) of n-butyl nitrite and then 54 g of a 30% strength solution of sodium methylate in methanol are carefully added dropwise at 10° C. to a solution of 12.9 g (0.1 mol) of pentane-2,3-dione 2-(O-methyl oxime) in 120 ml of methanol. The mixture is allowed to come to room temperature and is stirred for 12 hours at this temperature. The mixture is worked up by adding dilute hydrochloric acid to a pH of 7 and subsequent evaporation in vacuo. The residue is taken up in 100 ml of water and extracted twice using in each case 100 ml of diethyl ether. The organic phase is dried over sodium sulfate and evaporated in vacuo. This gives 7.7 g (49%) of an oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH:19](=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:20].[CH3:26][O:27][C:28]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[C:29]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CCOCC.O.C1COCC1>[CH3:43][O:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:28]([O:27][CH3:26])[C:29]=1[C:30]([OH:31])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:20][CH:19]=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC=NC(C)(C)C
Reactant: COc1cccc(OC)c1C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(OC)c1C(O)(CC=NC(C)(C)C)c1ccccc1
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
A solution of diisopropylamine (10.1 g, 0.1 mol) in dry ether (100 ml) was cooled to -10°. A solution of butyl lithium in hexane (65 ml, 0.1 mol) was added, and the mixture was stirred at -10° for 20 min. A solution of N-ethylidene-tert.butylamine (10 g, 0.1 mol) in dry ether (100 ml) was added and the solution was stirred at 0° for 20 min. After cooling to -30° a solution of 2,6-dimethoxybenzophenone (24.1 g, 0.1 mol) in dry ether (100 ml), containing 30 ml THF, was added. The mixture was then stirred at ambient temperature for 20 h and hydrolized with water. The organic phase was washed with water, dried and evaporated, giving 32 g (94%) of N-(3-(2,6-dimethoxyphenyl)-3-hydroxy-3phenylpropylidene)tert.butylamine as an oil.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[CH2:11][CH:10]1[CH2:12][CH2:13]O)=[S:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl.[Cl-].[Na+].O.O>[C:1]([NH:5][C:6]1[S:7][CH2:13][CH2:12][CH:10]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)([CH2:11]2)[N:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=S)NC1(c2cccc([N+](=O)[O-])c2)CC1CCO
Agent: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NC1=NC2(c3cccc([N+](=O)[O-])c3)CC2CCS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
tert-Butyl-3-((1SR,2SR)-2-(2-hydroxyethyl)-1-(3-nitrophenyl)cyclopropyl)thiourea (intermediate A3c) (1.47 g, 4.36 mmol, Eq: 1.00) was dissolved in dichloromethane (50 ml), then at 0° C. triphenylphosphine (2.06 g, 7.84 mmol, Eq: 1.8) and carbon tetrabromide (2.6 g, 7.84 mmol, Eq: 1.8) were added. The reaction mixture was stirred at 0° C. for 2 hours. To the reaction mixture was added 60 ml of sat. NaHCO3 solution and stirred for 15 min. Then more dichloromethane, water and brine were added and extracted. The organic layer was separated and washed with brine and then dried over Na2SO4. Removal of the solvent in vacuum left a brown oil which was chromatographed on 50 g SiO2 with 0-50% ethyl acetate in heptane to give the (1SR,7SR)—N-tert-butyl-1-(3-nitrophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-amine (995 mg, 3.12 mmol, 71.5% yield) as a light yellow oil. MS (ISP): m/z=320.1 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](Br)=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[SH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][S:14][C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)[CH3:21]
Reactant: CCOC(=O)CCS
Reactant: Nc1ncc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1cnc(N)s1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 2-amino-5-bromothiazole (50 g, 192 mmol) in DMF (300 mL) were added potassium carbonate (53 g, 384 mmol) and ethyl 3-mercaptopropionate (25.8 g, 192 mmol). The reaction mixture was stirred at room temperature for 36 h. The mixture was partitioned between water (500 mL) and ethyl acetate (500 mL) and the isolated water phase was extracted with ethyl acetate (250 mL). The combinde organic phases were washed with water (250 mL) and 10% aqueous sodium hydrogencarbonate (250 mL), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo to give 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. Yield: 19.6 g (44%). 1H-NMR (CDCl3): δ 7.07 (s, 1H); 4.15 (q, 2H); 2.88 (t, 2H); 2.61 (t, 2H); 1.26 (t, 3H); HPLC-MS: m/z: 233 (M+1).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH:20]([CH3:22])[CH3:21])=[N:7][C:8]3[C:9]([C:15]#[C:16][C:17]([NH2:19])=[O:18])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd]Cl.CN(C=O)C>[CH:20]([C:6]1[C:5]2[CH:23]=[CH:24][C:2]([C:29]3[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=3)=[CH:3][C:4]=2[C:13]2[C:12](=[O:14])[NH:11][CH:10]=[C:9]([C:15]#[C:16][C:17]([NH2:19])=[O:18])[C:8]=2[N:7]=1)([CH3:21])[CH3:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)c1nc2c(C#CC(N)=O)c[nH]c(=O)c2c2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1nc2c(C#CC(N)=O)c[nH]c(=O)c2c2cc(-c3cnn(C)c3)ccc12
Temperature: 100 °C

Procedure:
3-(9-bromo-6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-4-yl)prop-2-ynamide (57 mg, 0.15 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62 mg, 0.30 mmol), and PdCl2(dppp-CH2Cl2 adduct (24 mg, 0.030 mmol) were added to a vial, followed by DMF (1.8 ml) and aqueous sodium carbonate (2M) (0.15 ml, 0.30 mmol). The resulting suspension was purged with argon (subsurface bubbling) for 10 min, then heated in a microwave reactor at 100° C. for 30 min. The mixture was cooled, diluted with DMF, and filtered to remove salts. The solution was purified directly by preparative reverse phase HPLC eluting with an acetonitrile/water (with 0.05% TFA as a modifier) gradient, to afford 3-[6-isopropyl-9-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-4-yl]prop-2-ynamide. 1H NMR (500 MHz, DMSO-D6) δ 12.15 (br s, 1H), 10.15 (s, 1H), 8.46 (d, 1H), 8.34 (s, 1H), 8.01-7.98 (overlapping m, 3H), 7.89 (br s, 1H), 7.56 (br s, 1H), 4.08 (septet, 1H), 3.92 (s, 3H), 1.41 (d, 6H). LRMS (ESI) calc'd for (C22H19N5O2) [M+H]+, 386.2; found 386.1.
Reaction SMILES: C(C1CCCCC1)(C)(C)C.[C:11]([C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][C:22]2[C:23](C(F)(F)F)=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([C@:32]2([CH3:38])[CH2:36][O:35]C(=O)[NH:33]2)[N:26]=[CH:25]3)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].OC1C=C2C(=CC=1)N=C([C@]1(C)COC(=O)N1)N=C2.N[C@@](C1N=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C(F)(F)F)N=1)(C)CO>>[NH2:33][C@@:32]([C:27]1[N:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[C:22]([O:21][C@H:18]3[CH2:17][CH2:16][C@H:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:20][CH2:19]3)[CH:23]=2)[N:28]=1)([CH3:38])[CH2:36][OH:35]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc([C@]4(C)COC(=O)N4)ncc3c2C(F)(F)F)CC1
Agent: CC(C)(C)C1CCCCC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc([C@@](C)(N)CO)ncc3c2C(F)(F)F)CC1
Agent: C[C@@]1(c2ncc3cc(O)ccc3n2)COC(=O)N1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc([C@@](C)(N)CO)ncc3c2)CC1

Procedure:
Coupling of t-butyl cyclohexane to the core was performed similar to that described for (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-iodoquinazolin-2-yl)-4-methyloxazolidin-2-one (Example 60) utilizing (R)-4-(6-hydroxyquinazolin-2-yl)-4-methyloxazolidin-2-one as the starting material. Deprotection was then performed similar to that described for (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)quinazolin-2-yl)propan-1-01 (Example 61) to give the title compound. 1H NMR (MeOD) δ: 9.37 (s, 1H), 7.92 (d, J=9.3 Hz, 1H), 7.57 (dd, J=9.2, 2.6 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 4.34-4.49 (m, 1H), 4.05 (d, J=10.8 Hz, 1H), 3.79 (d, J=10.8 Hz, 1H), 2.29 (d, J=10.8 Hz, 2H), 1.93 (d, J=12.8 Hz, 2H), 1.54 (s, 3H), 1.38-1.51 (m, 2H), 1.21-1.35 (m, 2H), 1.08-1.19 (m, 1H), 0.93 (s, 9H). MS (M+1): 358.20.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Cl.N[C@@H]1CCCC[C@H]1O.C[Si](C)(C)N[Si](C)(C)C.[Na].I[CH:32]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]1>[Ni](I)I>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:32]2[CH2:33][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: I[Ni]I
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A modified procedure to that described in Org. Lett. 2008, 10, 3259 was performed as follows. To a 20-mL vial was added (4-cyanophenyl)boronic acid (1.01 g, 6.87 mmol), trans-2-aminocyclohexanol hydrochloride (32 mg, 0.21 mmol), nickel (II) iodide (66 mg, 0.21 mmol) and sodium hexamethyldisilazane (1.29 g, 7.06 mmol). The system was purged with nitrogen and charged with isopropyl alcohol (7 mL). The mixture was stirred at room temperature for 10 minutes then sonicated for 1 min. While stirring, tert-butyl 3-iodoazetidine-1-carboxylate (1.00 g, 3.53 mmol) was added and the syringe rinsed with isopropyl alcohol (2×500 μL). The suspension was stirred at 80° C. for 1 hour then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes to 25% ethyl acetate) to yield the title compound as a pale yellow oil which solidified upon standing (0.832 g, 46%). m/z (ES+) 203 (M-C4H8+H)+. 1H NMR (400 MHz, CDCl3): δ 7.65 (d with fine str., J=8.4 Hz, 2H), 7.43 (d with fine str., J=8.4 Hz, 2H), 4.37 (app t, J=8.8 Hz, 2H), 3.98-3.91 (m, 2H), 3.81-7.73 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]2[NH:24][C:10]([CH2:9][N:8]([CH3:13])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:25][C:20]=2[CH:19]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(CN(C)C(=O)OC(C)(C)C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-N-methylglycine (1.00 g), 4-methoxybenzene-1,2-diamine dihydrochloride (1.16 g) and DMF (25 mL) were added HATU (2.41 g) and DIPEA (4.5 mL), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with water and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. To the residue was added acetic acid (20 mL), followed by heating and stirring at 80° C. for 3 hours, and then concentrating under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: Hex/EtOAc=80/20-20/80) to obtain tert-butyl [(5-methoxy-1H-benzimidazol-2-yl)methyl]methylcarbamate (1.22 g).
Reaction SMILES: [C:1]1([C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CC3C=NC=CC=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([O-])(=O)/[CH:35]=[CH:36]/[C:37]([O-])=O>>[C:28]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:34][CH2:35][C:36]3[CH:37]=[N:12][CH:11]=[CH:10][CH:9]=3)[CH2:11][CH2:10]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCc2cccnc2)CC1
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCc2cccnc2)CC1

Procedure:
3-[7-[4-(2,2-diphenylethenyl)-1-piperidinyl]heptyl]pyridine (1:1)-(E)-2-butenedioate salt hemihydrate;
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([CH:7]=[CH:8][C:9]3[O:10][C:11](=[O:18])[C:12]([CH3:17])([CH3:16])[C:13]=32)=[CH:5][CH:4]=1.[CH3:19][C:20]1[N:21]=[CH:22][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:24]=1>C(#N)C>[CH3:16][C:12]1([CH3:17])[C:11](=[O:18])[O:10][C:9]2[CH:8]=[CH:7][C:6]3[C:14]([C:13]1=2)=[CH:15][C:3]([CH2:2][N:21]1[C:20]([CH3:19])=[CH:24][N:23]=[CH:22]1)=[CH:4][CH:5]=3
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC1(C)C(=O)Oc2ccc3ccc(CBr)cc3c21
Solvent: CC#N
Product: Cc1cncn1Cc1ccc2ccc3c(c2c1)C(C)(C)C(=O)O3

Procedure:
A mixture of 8-bromomethyl-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone (0.46 g), 4-methyl-1-tritylimidazole (0.49 g) and acetonitrile (2 ml) was heated under reflux for 18 h, then evaporated to dryness. The residue was treated with glacial acetic acid (4 ml) and water (1 ml), and the mixture was heated at 90° for 0.5 h. The mixture was diluted with water (20 ml) and washed with diethyl ether. The aqueous phase was separated, basified with potassium hydrogen carbonate and extracted twice with ethyl acetate. The extracts were combined, dried and evaporated to dryness, and the residue was purified by flash chromatography, eluting with methanol:ethyl acetate, 1:99 v/v, to give 1,1-dimethyl-8-(5-methylimidazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone, m.p. 88°-91°.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:40][C:41]1[C:48]2[C:47]([CH3:49])=[CH:46][S:45][C:44]=2[S:43][C:42]=1[CH2:50][NH:51][CH3:52].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:51]([CH2:50][C:42]2[S:43][C:44]3[S:45][CH:46]=[C:47]([CH3:49])[C:48]=3[C:41]=2[CH3:40])[CH3:52])=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CNCc1sc2scc(C)c2c1C
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCOCC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1csc2sc(CN(C)C(=O)/C=C/c3cnc(N)c(CN4CCOCC4)c3)c(C)c12

Procedure:
According the procedure of Example 1, except substituting (E)-3-(6-amino-5-morpholin-4-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting (3,4-dimethyl-thieno[2,3-b]thiophen-2-ylmethyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound was prepared (70 mg, 13%) as a light, yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.40 (s, 1H), 7.51 (d, J=15.1 Hz, 1H), 7.20-7.12 (m, 2H), 5.00-4.77 (m, 2H), 4.40-4.32 (m, 2H), 3.95-3.15 (m, 10H), 3.13 (s, 3H), 2.90 (s, 1H), 2.46 (s, 3H), 2.45 (s, 3H); MS (ESI) m/e 457 (M+H)+.
Reaction SMILES: FC1C=CC([N:8]2C3C(=CC(C(C4C=CC=CC=4)C(CC)C(O)=O)=CC=3)C=N2)=CC=1.FC1C=CC(N2C3C(=CC(C(C4C=CC=CC=4)C(C)(C)CN)=CC=3)C=N2)=CC=1.[F:58][C:59]1[CH:64]=[CH:63][C:62]([N:65]2[C:73]3[C:68](=[CH:69][C:70]([CH:74]([C:81]4[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=4)[CH:75]([CH2:79][CH3:80])[C:76](F)=[O:77])=[CH:71][CH:72]=3)[CH:67]=[N:66]2)=[CH:61][CH:60]=1.N>C1COCC1.O>[F:58][C:59]1[CH:64]=[CH:63][C:62]([N:65]2[C:73]3[C:68](=[CH:69][C:70]([CH:74]([C:81]4[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=4)[CH:75]([CH2:79][CH3:80])[C:76]([NH2:8])=[O:77])=[CH:71][CH:72]=3)[CH:67]=[N:66]2)=[CH:61][CH:60]=1
Reactant: CCC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CCC(C(=O)F)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CC(C)(CN)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CCC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(c)(d) 2-((1-(4-Fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoic acid (60, mg, 0.154 mmol) was converted into the acid fluoride using the identical procedure to that for Synthetic Intermediate I above. A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-ethyl-3-phenylpropanoyl fluoride (0.32 mmol) in anhydrous THF (5 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-ethyl-3-phenylpropanamide.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)=O.[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:35].O>O1CCCC1>[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:35][C:25](=[O:27])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Solid carbonyldiimidazole (79.10 g, 0.488 mol) was added to a room temperature solution of N-benzyloxycarbonyl-glycine (117.11 g, 0.560 mol) in anhydrous tetrahydrofuran (THF, 600 mL). The resulting solution was stirred for 45 minutes until CO2 evolution had ceased. A solution of L-phenylalanine methyl ester (79.65 g, 0.444 mol) in anhydrous THF (~200 mL) was then added. The reaction temperature was maintained below 40° C. by application of a water bath to the exterior of the reaction vessel. After two hours, a small portion of water (1.5 mL, ~0.08 mol) was added to the reaction mixture to hydrolyze any remaining acylimidazolides and the resulting solution was left to stir overnight. The reaction mixture was concentrated in vacuo and the residual oil was dissolved in ethyl acetate (~1 L). This ethyl acetate solution was extracted with 1 N HCI (2×300 mL--the first aqueous extract was acidified a pH of 1 by addition of 6 N HCl), water (300 mL), saturated aqueous sodium carbonate (300 mL), half-saturated aqueous sodium carbonate (250 mL), and brine (250 mL). The organic phase was dried by filtration through magnesium sulfate and sodium sulfate and concentrated in vacuo to constant weight. Field desorption mass spectrometry (FDMS) of the resulting oil (160.88 g, ~0.434 mol, 98%) indicated the presence of a single component (M+=370). This material was not further purified, but was instead converted directly into cyclo-glycyl-L-phenylalanine (8) by catalytic hydrogenation (vide infra).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=O.[CH3:22][CH:23]([CH3:39])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1)=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH2:17][N:36]1[CH2:37][CH2:38][CH:33]([C:29]2[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH:23]([CH3:22])[CH3:39])[CH:32]=[CH:31][CH:30]=2)[CH2:34][CH2:35]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1c(OCc2cccc(Cl)c2)ccc2ccccc12
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c(OCc4cccc(Cl)c4)ccc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-[(3-chlorobenzyl)oxy]-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 527.2 (M+H)+.