Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7](C)[CH2:8][CH:9]=O.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13]>C(O)(=O)C.N1CCCCC1>[C:12](/[C:14](=[CH:9]\[CH2:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)/[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: COC(=O)CC#N
Reactant: CC(CC=O)c1cnccn1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C/CCc1cnccn1
Yield: 35.5 %

Procedure:
A solution of 13e (0.191 g, 1.27 mmol) in 0.17 mL glacial acetic acid was treated with NCCH2CO2CH3 (0.115 g, 1.27 mmol, 0.1 mL, 1.0 equiv), then a premixed solution of piperidine (0.0038 g, 0.04318 mmol, 4.4 mL, 3.4 mol %) and 50 mL of acetic acid at room temperature (24 h). The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (15 mL, pH>7) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. SGC chromatotron (SiO2, 1 mm, 25-65% EtOAc/hexanes) afforded 15e (0.098 g, 0.282 g theoretical, 35%). For 15e: 1H NMR (CDCl3, 400 MHz) d 8.52 (dd, 1H, J=1.6, 2.5 Hz, Pyr C5-H), 8.46 (d, 1H, J=1.6 Hz, Pyr C3-H), 8.44 (d, 1H, J=2.5 Hz, Pyr C6-H), 7.59 (dd, 1H, J=7.8, 7.8 Hz, CH=C), 3.82 (s, 3H, OCH3), 3.23 (ddq, 1H, J=6.4, 7.0, 7.2 Hz, PyrCH), 3.07 (ddd, 1H, J=7.2, 7.8, 14.9 Hz, CHH), 2.91 (ddd, 1H, J=6.4, 7.8, 14.6 Hz, CHH), 1.39 (d, 3H, J=7.0 Hz, CH3); IR (neat) nmax 2967, 2360, 2341, 1737, 1626, 1437, 1407, 1282, 1259, 1060, 1017, 850, 761, 668 cm-. See FIG. 19d.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([CH3:31])[C:21]=1[CH2:22][OH:23].N1C=CN=C1.O>CN(C)C=O>[Si:1]([O:23][CH2:22][C:21]1[C:24]([CH3:31])=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:20]=1[CH3:19])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.5 %

Procedure:
To a solution of tert-butyldiphenylsilyl chloride (30.7 g) in N,N-dimethylformamide (90 ml) were added 2,6-dimethyl-3-nitrobenzyl alcohol (18.4 g) and imidazole (8.99 g) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 3 hours at ambient temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-nitrobenzene (46.67 g) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[O:45][C:41]=2[C:40]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:46][C:44]2[O:45][C:41]3[C:40]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=3[N:43]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCOCC2)c2oc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2oc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluorobenzoic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-morpholin-4-yl-benzooxazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 372 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([O:33][CH2:34][CH3:35])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([C@@:10]1([CH:15]2[CH2:17][CH2:16]2)[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[C:22]([O:33][CH2:34][CH3:35])[CH:21]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: CCOc1cc(N)ccc1C(=O)OC(C)(C)C
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOc1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)ccc1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
To a solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (100 mg) obtained in Step E of Example 103, tert-butyl 4-amino-2-ethoxybenzoate (110 mg) obtained in Step C of Example 139, cesium carbonate (250 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (35 mg) in tetrahydrofuran (3.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (34 mg) under argon atmosphere, and the mixture was stirred overnight at 90° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (41 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)[CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([N:8]3[C:6]4=[N:7][C:2]([C:24]5[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=5)=[CH:3][N:4]=[C:5]4[N:10]=[CH:9]3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Brc1cnc2ncn(-c3ccc4[nH]ccc4c3)c2n1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3ncn(-c4ccc5[nH]ccc5c4)c3n2)cc(OC)c1OC
Temperature: 150 °C

Procedure:
Following a method described in Pteridines, 2002, Vol. 13, 65-72, Intermediate BB was heated in anhydrous DMF at 175° C. for 15 min in a Personal Chemistry Optimizer. To the resulting 6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazine 1 in CH3CN (1 mL) in a microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The resulting mixture was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue that was purified via preparatory HPLC to give 4.7 mg of the title compound. HPLC retention time: 2.43 minutes; MS ESI (m/z): 402.8 (M+1)+, calc. 401.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:20][C:21]2[NH:25][N:24]=[C:23]([CH2:33][CH2:34][C:35]3[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=3)[CH:22]=2)=[O:16])=[CH:18][CH:19]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCN3CCCC3C2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN5CCCC5C4)cc3)[nH]n2)cc(OC)c1
Yield: 10.2 %

Procedure:
4-(3,4,6,7,8,8a-Hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared as for Example 94, but starting from methyl 4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (193 mg, 0.7 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (292 mg, 0.84 mmol) and 1M NaHMDS (1.23 ml, 1.23 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 33-53% gradient of acetonitrile in water, containing 1% 0.880 ammonia. The clean fractions were combined and evaporated to afford the title compound (34 mg, 10%); 1H NMR (399.9 MHz, DMSO-d6) δ 1.37-1.41 (1H, m), 1.67-1.77 (2H, m), 1.84-1.88 (1H, m), 1.99-2.06 (1H, m), 2.09 (1H, t), 2.18-2.25 (1H, m), 2.80-2.84 (1H, m), 2.87 (4H, s), 3.01-3.06 (2H, m), 3.73 (6H, s), 3.80-3.83 (1H, m), 3.96-3.98 (1H, m), 6.33 (1H, t), 6.42-6.45 (3H, m), 6.97 (2H, d), 7.90 (2H, d), 10.28 (1H, s), 12.07 (1H, s)
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH:26]=O.[C:28]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)(=[O:30])[CH3:29].[OH-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][C:2]1[N:6]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[N:4][C:3]=1/[CH:26]=[CH:29]/[C:28]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:30]
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(/C=C/C(=O)c2c[nH]c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 94.7 %

Procedure:
A mixture of 5-methyl-1-(triphenylmethyl)-1H-imidazol-4-carboxaldehyde (4.90 g), 3-acetylindole (2.24 g) and potassium hydroxide (6.08 g) in absolute ethanol (100 ml) and water (50 ml) was heated at 80° for 24 h. The suspension was poured into 2N sodium carbonate solution (300 ml) and extracted with dichloromethane (3×150 ml). The combined extracts were dried, filtered and evaporated to give an orange solid (6.5 g) which was triturated with ethyl acetate (50 ml) to give the title compound (2.42 g) as a yellow solid, m.p. 240°-242°.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([N+:17]([O-:19])=[O:18])=[C:7]([CH:16]=1)[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1.C([O:22][C:23](=O)[C:24]([F:27])([F:26])[F:25])C.C(N(CC)CC)C>CO>[N+:17]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:16][C:7]=1[O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:23](=[O:22])[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:14]1)([O-:19])=[O:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1)C(F)(F)F
Reaction time: 8 h

Procedure:
A reaction mixture of 0.071 g trans-4-(5-fluoro-2-nitro-phenoxy)-cyclohexylamine hydrochlorid, 0.05 g ethyltrifluoroacetate and 0.075 g triethylamine in 2 ml methanol was stirred overnight. The mixture was concentrated and partitioned between 5 ml EtOAc and 5 ml water. The organic phase was washed with water, HCl solution (2M) and water. The organic phase was dried and the solvent evaporated.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:13])[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH:3]([O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH2:4][P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: CCOP(=O)(CC(O)CBr)OCC
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(CC(CBr)OC1CCCCO1)OCC
Yield: 128.1 %

Procedure:
To a mixture of diethyl 3-bromo-2-hydroxypropylphosphonate (82.5 g) and p-toluenesulfonic acid (1.03 g) was added dropwise 3,4-dihydro-2H-pyrane (250 g) under ice-cooling and with stirring. After the reaction mixture was stirred at the same temperature for 10 minutes and at ambient temperature for 1.5 hours, the dihydropyrane was removed off by evaporation under reduced pressure to give a residue, which was dissolved in ethyl acetate (500 ml). The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate solution (100 ml) and with saturated aqueous sodium chloride solution (100 ml) dried over magnesium sulfate and evaporated to dryness under reduced pressure to give oily diethyl 3-bromo-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (138 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[O:21][CH3:22].[C:23]([O-])([O-])=O.[K+].[K+].CO.[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CCOCC>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[CH:23])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[O:21][CH3:22]
Reactant: COC(=O)c1nc(-c2ccc(C=O)cc2)c(F)c(N)c1OC
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(OC)c(N)c2F)cc1
Reaction time: 4 h
Yield: 73.4 %

Procedure:
To a 20 mL reaction vial were added methyl 4-amino-5-fluoro-6-(4-formylphenyl)-3-methoxypicolinate (0.41 g, 1.347 mmol), K2CO3 (0.372 g, 2.69 mmol), and CH3OH (20 mL). Dimethyl 1-diazo-2-oxopropylphosphonate (0.311 g, 1.617 mmol) was added in one portion. After stirring for 4 h, the reaction mixture was diluted with Et2O (50 mL) and washed with 5% NaHCO3 (25 mL). The organic layer was dried over MgSO4 (5 g), filtered, and concentrated on a rotary evaporator. The resulting residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as an off-white solid (297 mg, 73%): 1H NMR (400 MHz, CDCl3) δ 7.93-7.85 (m, 2H), 7.62-7.53 (m, 2H), 4.57 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.15 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −139.97; ESIMS m/z 301 ([M+H]+), 299 ([M−H]−).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51](O)=[O:52])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1.CN1CCOCC1.[NH2:63][CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66].Cl.OP([O-])(O)=O.[K+]>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([NH:63][CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66])=[O:52])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1
Reactant: CCOC(=O)CN
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CNC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12
Reaction time: 0.08 h

Procedure:
HATU (180 mg, 0.47 mmol) was added to a solution of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (187 mg, 0.4 mmol, Example 44), 4-methylmorpholine (0.2 mL, 1.8 mmol), and DMF (2 mL). After 5 min, this solution was added to Gly-OEt•HCl (65 mg, 0.47 mmol). After 75 min, the reaction was poured into 1M KH2PO4 (30 mL) and extracted with ethyl acetate (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (1:4→0:1; hexanes:ethyl acetate) to give ethyl 2-(6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanamido)acetate: 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 8.21 (t, 1H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 4.05 (q, 2H), 3.97 (t, 2H), 3.92 (s, 3H), 3.77 (d, 2H), 2.14 (t, 2H), 1.68 (m, 2H), 1.55 (m, 2H), 1.44 (m, 2H), 1.16 (t, 3H); MS (ESI): 552.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:23][C@H:24]1[CH2:28][NH:27][C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH2:14][CH3:15])[C:10]([N:27]1[CH2:28][C@H:24]([OH:23])[CH2:25][C@H:26]1[C:29]([O:31][CH3:32])=[O:30])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)O
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: ClCCl
Product: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.5 %

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoic acid (all material from step 1, 1.00 g, 3.32 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate-HCl salt (0.663 g, 3.65 mmol), HATU (1.26 g, 3.32 mmol) and CH2Cl2 (30 mL). To the mixture was added N,N-diisopropylethylamine (1.75 mL, 9.95 mmol). The mixture was stirred at room temperature for 16 h. The mixture was transferred to a separatory funnel and was thrice washed with aq. HCl (1M); then brine. The organic solution was dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,4R)-methyl 1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylate as a yellow oil (1.53 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][N:6]=[CH:5]2.C([Sn](CCCC)(CCCC)[C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:19][CH:18]=1)CCC.CN(C=O)C.[F-].[Cs+]>C(Cl)Cl.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:17]3[S:21][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[N:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: Brc1ccc2cnncc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc3cnncc3c2)s1
Temperature: 100 °C
Yield: 72.5 %

Procedure:
A glass microwave reaction vessel was charged with 6-bromophthalazine (1.0 g, 5 mmol), tert-butyl 5-(tributylstannyl)thiazol-2-ylcarbamate (4.0 g, 7 mmol), DMF (4 mL), cesium fluoride (1.0 g, 10 mmol), copper(I) iodide (0.2 g, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.2 mmol). The reaction mixture was stirred and heated at 100° C. overnight. The mixture was diluted with DCM (20 mL) and water (5 mL) and filtered through Celite. The organic solution was evaporated under reduced pressure, and the residue was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 10% MeOH in DCM to provide the title compound (1.19 g, 76%). LCMS (M+H+) 329.3 calc. for C16H16N4O2S 329.3; 1H NMR (400 MHz, CDCl3) δ ppm 9.50 (s, J=13.69 Hz 1H), 9.46 (s, 1H), 8.01 (d, J=1.37, Hz 1H), 7.92 (d, J=8.41 Hz, 1H), 7.81 (s, 1H), 7.58 (s, 1H) 1.40 (s, 9H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:32])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[Cl:32][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH3:33])[CH2:17][C:16]=2[CH:18]=1
Reactant: COc1ccc(-c2cc(Cl)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c(OC)c1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3ccc(OC)cc3OC)c2O1

Procedure:
The title compound was prepared (0.052 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.099 g, 0.21 mmol) and methylamine (0.065 g, 2.1 mmol). mp 206-208° C.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:9][N:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:11]2[C:20]([N+:21]([O-])=O)=[C:19]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.C(Cl)Cl.O.[Ni](Cl)Cl>[C:33]1([CH2:32][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11]2[C:20]([NH2:21])=[C:19]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=[N+]([O-])c1c(N(Cc2ccccc2)Cc2ccccc2)nc2c(c1NCc1ccccc1)CCCC2
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1c(N(Cc2ccccc2)Cc2ccccc2)nc2c(c1NCc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Sodium borohydride (0.82 g, 22 mmole) was added to a solution of nickel(II) chloride hydrate (1.43 g, 6 mmole) in methanol (300 mL). The addition caused a black solid to form along with gas evolution. The resulting heterogeneous mixture was stirred at ambient temperature for about 30 minutes. A solution containing N2,N2,N4 -Tris(phenylmethyl)-5,6,7,8-tetrahydro-3-nitroquinolin-2,4-diamine (5.73 g, 12 mmole) in methylene chloride (20 mL) was added followed by 5 successive additions of sodium borohydride (0.38 g, 10 mmole each addition). The reaction mixture was stirred at ambient temperature for about 15 minutes then filtered through a layer of silica gel. The filtrate was evaporated. The residue was taken up in a minimum amount of methylene chloride then placed on a layer of silica gel. The silica gel was eluted with hexane:ethyl acetate 80:20. The organic phase was collected then evaporated to provide 5.0 g of the desired product as a green oil.