Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4](Cl)[N:3]=1.[NH2:13][C@@H:14]1[CH2:18][C@H:17]([CH2:19][OH:20])[CH:16]=[CH:15]1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][C@@H:14]2[CH2:18][C@H:17]([CH2:19][OH:20])[CH:16]=[CH:15]2)[C:5]([NH:9][CH:10]=[O:11])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: N[C@H]1C=C[C@@H](CO)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Yield: 88.1 %

Procedure:
N-(2-Amino-4,6-dichloro-5-pyrimidinyl)formamide (Example 3, 2.07 g, 10.0 mmol) was stirred in refluxing absolute ethanol (40 mL) under nitrogen to achieve partial dissolution. To this stirred mixture was added a solution of freshly prepared (1S,4R)-4-amino-2-cyclopentene-1-methanol (PCT Application 9204015.3, 1.57 g, 12.5 mmol as 90%) in ethanol (15 mL) followed by triethylamine (3.5 mL, 25 mmol, freshly distilled from calcium hydride). After 14 hours of reflux, the resulting dark solution was cooled and 1 N sodium hydroxide (10 mL) was added. The volatiles were evaporated in vacuo. The residual tan solid foam was dissolved in 5% methanol-ethyl acectate, and the solution was washed through a silica gel pad to give the title compound as an off-white solid (2.50 g, 88%), after evaporation of solvents. Recrystallization of the solid from ethyl acetate-methanol (20:1) gave the title compound (Via) as fine white crystals (2.29 g, 81%), m.p. 177-178° C.; mass spectrum (CI/CH4): 286, 284 (M+1), 190, 188 (B+H); 1H-NMR (DMSO-d6) δ: 8.99 and 8.58 (s and d, J=11.1 Hz, total 1, amide NH), 8.11 and 7.80 (s and d, J=11.1 Hz, total 1, amide CH), 6.77 and 6.61 (two d, J=8.0 Hz) overlapping 6.60 and 6.48 (two br s, total 3, NH and NH2), 5.85 and 5.70 (two m, 1 each, CH═CH), 5.15-5.00 (m, 1, NCH), 4.71 (t, J=5.1, 1, OH), 3.45-3.30 (m overlapping H2O, OCH2), 2.80-2.65 (m, 1, CH), 2.45-2.25 and 1.45-1.30 (both m, 1 each, CH2); [α]20589+21.2°, [α]20578+22.2°, [α]20546+25.2°, [α]20436+41.4°, [α]20365+48.3° (c 0.50, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([I:14])[C:11]([CH3:15])=[C:10]([N+:16]([O-])=O)[C:9]2=[O:19])=[CH:5][CH:4]=1>C(O)(=O)C.Cl>[NH2:16][C:10]1[C:9](=[O:19])[N:8]([CH2:7][C:6]2[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:13]=[C:12]([I:14])[C:11]=1[CH3:15]
Reactant: COc1ccc(Cn2cc(I)c(C)c([N+](=O)[O-])c2=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(Cn2cc(I)c(C)c(N)c2=O)cc1
Yield: 28.6 %

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-5-iodo-4-methyl-3-nitro-2-pyridone (1.00 g, 2.5 mmol) in acetic acid (12 mL), cooled on ice, was added a solution of stannous chloride dihydrate (2.85 g, 12.6 mmol) in concentrated HCl (8 mL). After 1 hour the mixture was filtered, and the filtrate was neutralized with solid sodium carbonate (adding water as necessary). The mixture was extracted with methylene chloride, and the organic phase was washed, dried, and evaporated to give 3-amino-1-(4-methoxybenzyl)-5-iodo-4-methyl-2-pyridone (0.265 g, 29%) as an oil.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([I:12])=[CH:7]2.N([O-])=O.[Na+].[NH4+].[OH-].[BrH:21]>O>[Br:21][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([I:12])=[CH:7]2
Reactant: COc1cc(N)c2ncc(I)cc2c1
Reactant: Br
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: COc1cc(Br)c2ncc(I)cc2c1
Temperature: 0 °C

Procedure:
A suspension of 8-amino-3-iodo-6-methoxyquinoline (2.0 g) in HBr (20 ml) cooled to 0° C. is treated with a solution of sodium nitrite (0.48 g) in water (4 ml). The thick cold suspension is then added portionwise to a purple solution of CuBr2 (1.64 g) in 10 ml of conc. HBr preheated at 60° C. After 3 h an aqueous solution of NH4OH is added to the mixture to reach pH 14. After filtration of the mixture the filtrate is purified by flash chromatography (CH2Cl2) providing 8-bromo-3-iodo-6-methoxyquinoline (2.2 g) as a pale yellow solid. 1H NMR (CDCl3) δ ppm: 8.92 (1H, d); 8.32 (1H, d); 7.65 (1H, d); 6.82 (1H, d); 3.87 (3H, s).
Reaction SMILES: [Na].[OH:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>O.CN(C=O)C.N1C=CC=CC=1>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:18](=[O:20])[CH2:17][C:12]1[NH:13][C:14](=[O:16])[CH:15]=[C:10]([N:6]2[CH2:7][CH2:8][O:9][CH:4]([CH2:3][OH:2])[CH2:5]2)[N:11]=1
Reactant: O=C(O)Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1
Reactant: Fc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1)N1CCc2c(F)cccc21
Temperature: 20 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
0.975 g of the sodium salt of (±)-[4-(2-hydroxymethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid (example 25b, step 6b), 0.534 g of 4-fluoroindoline, 0.57 ml of pyridine and 15 ml of DMF are placed in a three-necked flask. 0.9 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added and the mixture is stirred at ambient temperature (20° C.) for 72 hours. The reaction mixture is poured into 50 ml of water, with stirring, and then the insoluble material is filtered off through a VF filter, and washed 3 times with approximately 15 ml of water and then with 10 ml of ethyl acetate and twice approximately 5 ml of diisopropyl ether. The solid is air-dried under a hood. 2-[2-(4-Fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-hydroxymethylmorpholin-4-yl)-3H-pyrimidin-4-one is isolated (0.82 g) and characterized in the form of a pinkish solid, yield 60%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:31]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]2[C:11]3([CH2:31][O:10][C:8]=2[CH:9]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:12]3=[O:29]
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Reactant: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C3(COc4cc(F)c(C#N)cc43)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.7 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (10.50 g, 27.03 mmol) and chloroiodomethane (5.00 mL, 68.7 mmol) in tetrahydrofuran (200 mL) and N,N-dimethylformamide (50 mL) was added cesium carbonate (26.40 g, 81.02 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 20 h and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/3) to afford 6-fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (5.27 g, 48%): mp 142-143° C.; 1H NMR (300 MHz, CDCl3) δ 7.29-7.23 (m, 3H), 7.11-7.02 (m, 2H), 6.89-6.85 (m, 4H), 6.77 (d, J=9.0 Hz, 1H), 5.12-4.75 (m, 4H), 3.78 (s, 3H); MS (ES+) m/z 400.7 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:6][C:5]2=[O:19].[CH:20]1([C:23]([NH2:25])=[O:24])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.[Cl-].[Na+].O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[NH:8][C:9]2[C:4]([C:5](=[O:19])[CH:6]=1)=[CH:3][C:2]([NH:25][C:23]([CH:20]1[CH2:22][CH2:21]1)=[O:24])=[N:11][CH:10]=2
Reactant: NC(=O)C1CC1
Reactant: O=c1cc(-c2ccccc2Cl)[nH]c2cnc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cc2c(=O)cc(-c3ccccc3Cl)[nH]c2cn1)C1CC1
Yield: 6.2 %

Procedure:
A mixture of 6-chloro-2-(2-chlorophenyl)-1,7-naphthyridin-4(1H)-one (29.2 mg, 100 μmol), cyclopropanecarboxamide (17.1 mg, 200 μmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoeth yl)phenyl]palladium(II) (8.0 mg, 10 μmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (5.4 mg, 10 μmol), and cesium carbonate (98.0 mg, 301 μmol) in 1,4-dioxane (5.0 mL) was heated to reflux for 4 hours. Further portions of cyclopropanecarboxamide (17.1 mg, 200 μmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoeth yl)phenyl]palladium(II) (8.0 mg, 10 μmol) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (5.4 mg, 10 μmol) were added and the mixture heated to reflux for 16 hours. The cooled mixture was treated with water and brine and extracted with ethyl acetate, and the separated organic phase washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to afford the title compound as a white solid (2.1 mg, 6.2%). LCMS (Method E): RT=3.715 min, M+H+=340.0 & 342.0.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[CH3:12][O:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([NH:20][C:21](N)=[O:22])=[O:19])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C([O-])(=O)/C=C\C([O-])=O>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:24]=[CH:25][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[O:22])[CH2:5]2
Reactant: COc1ccc(C(=O)NC(N)=O)cc1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])/C=C\C(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NC(=O)NC2CN3CCC2CC3)cc1

Procedure:
The above compound was prepared, following the procedure of Example 14b, from 3-aminoquinuclidine dihydrochloride (1.0 g, 5 mmol), 4-methoxybenzoylurea (0.97 g, 5 mmol) and di-isopropylethylamine (1.29 g, 10 mmol) in pyridine (20 ml). The product (1.12 g) was converted to 1:1 maleate half hydrate, mp 166°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[S:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:39]>C(Cl)Cl>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[S:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (93 mg, 0.17 mmol) in DCM (10 mL) was added HCl (4M, 2 mL). The reaction mixture was stirred at room temperature for 6 hours, and then the solvent was removed to afford (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (76 mg, 100%.) LCMS (APCI+) [M+H]+ 460 and 462.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].[O:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:52]=[C:51]3[NH:53][CH2:54][C:55]4([CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[C:50]3=[CH:49][CH:48]=2)[CH2:43][CH2:42]1.Cl[C:62]1[C:71]2[C:66](=[CH:67][C:68]([F:72])=[CH:69][CH:70]=2)[N:65]=[C:64]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[N:74]=2)[C:63]=1[CH3:81]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:72][C:68]1[CH:67]=[C:66]2[C:71]([C:62]([N:53]3[C:51]4[C:50](=[CH:49][CH:48]=[C:47]([N:44]5[CH2:43][CH2:42][O:41][CH2:46][CH2:45]5)[CH:52]=4)[C:55]4([CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[CH2:54]3)=[C:63]([CH3:81])[C:64]([C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[N:74]=3)=[N:65]2)=[CH:70][CH:69]=1
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: COc1cccc(-c2nc3cc(F)ccc3c(Cl)c2C)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nc3cc(F)ccc3c(N3CC4(CCOCC4)c4ccc(N5CCOCC5)cc43)c2C)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (26.9 mg, 0.056 mmol), Pd2dba3 (25.9 mg, 0.028 mmol), sodium tert-butoxide (45.4 mg, 0.47 mmol), 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (50 mg, 0.18 mmol) (described herein), and 4-chloro-7-fluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline (57 mg, 0.19 mmol) (described herein) in toluene (2 mL) was stirred at 100° C. for 18 h, then cooled to rt and concentrated. The resulting residue was taken up in EtOAc, washed with saturated aqueous sodium bicarbonate solution, 1 M NaOH, and brine, and the organic layer dried (MgSO4) and concentrated. Column chromatography afforded 1-(7-fluoro-2-(6-methoxy-2-pyridinyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.75-7.90 (3H, m), 7.55 (1H, dd, J=7.2, 0.8 Hz), 7.22-7.27 (1H, m), 7.11-7.19 (1H, m), 6.85 (1H, dd, J=8.3, 0.9 Hz), 6.30-6.39 (1H, m), 5.64 (1H, d, J=2.2 Hz), 3.93-4.09 (7H, m), 3.67-3.79 (4H, m), 3.48-3.64 (2H, m), 2.91-3.05 (4H, m), 2.39-2.48 (3H, m), 2.09-2.24 (2H, m), 1.90 (1H, dt, J=13.8, 1.1 Hz), 1.76-1.86 (1H, m). Mass Spectrum (ESI) m/e=541 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]3[CH2:33][CH2:32]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]3[CH2:33][CH2:32]3)[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CC4)c23)ccc1OCc1ccccn1
Reactant: CC(=O)Cl
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CC1
Yield: 38 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(cyclopropylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 38% yield; NMR spectrum (DMSO-d6) 0.76-0.82 (m, 4H), 2.06 (s, 3H), 2.76-2.83 (m, 1H), 3.87 (t, 2H), 4.42 (t, 2H), 5.31 (s, 2H), 7.19 (d, 1H), 7.26 (d, 1H), 7.32-7.40 (m, 2H), 7.56-7.61 (m, 2H), 7.70-7.75 (m, 1H), 7.86-7.92 (m, 1H), 7.94-7.96 (m, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.76 (s, 1H); Mass spectrum MH+ 504.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:37])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:79]1[CH:83]=[CH:82][CH:81]=[C:80]1[C:84](O)=[O:85]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:37])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:12][NH:13][C:84]([C:80]1[S:79][CH:83]=[CH:82][CH:81]=1)=[O:85]
Reactant: O=C(O)c1cccs1
Reactant: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CN)C(=O)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.1 %

Procedure:
To a solution of (S)-3-Amino-2-({3-ethyl-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester trifluoro-acetic acid salt (0.14 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.06 ml, 0.42 mmol), HBTU (0.080 g, 0.21 mmol), HOBt (0.023 g, 0.17 mmol), and 2-Thiophenecarboxylic acid (0.022 g, 0.17 mmol). The mixture was stirred at room temperature 15 h, treated with EtOAc (30 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (30-100% EtOAc in hexane) to give 0.0280 g (37%) white foam. MS m/e 540.0 (M+H+).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pt]=O>[CH2:8]([C:9]1[NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=1[C:16]=23)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCc2c(C#Cc3ccccc3)[nH]c3cccc1c23
Agent: O=[Pt]
Solvent: CO
Product: O=C1NCCc2c(CCc3ccccc3)[nH]c3cccc1c23
Temperature: 24 °C
Reaction time: 20 h

Procedure:
2-Phenylethynyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (Compound 17) (37 mg, 0.13 mmol) and platinum oxide (1.5 mg, 0.05 mmol) were suspended in 2 mL MeOH under an argon atmosphere. The flask was flushed with hydrogen gas and the resulting mixture stirred at 24° C. under 1 atmosphere of hydrogen for 20 h. The catalyst was filtered off and the resulting solution concentrated, leaving a pale-yellow crystalline solid. Purification by radial chromatography (5% MeOH in CHCl3) followed by recrystallization (MeOH/CHCl3/hexanes) yielded 2-phenethyl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 14 mg (37%), as a pale-yellow solid. mp 207-208° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.60 (m, 2H), 2.95 (m, 4H), 3.26 (m, 2H), 7.17 (m, 6H), 7.46 (dd, 1H, J=7.8, 0.6 Hz), 7.61 (dd, 1H, J=7.5, 0.6 Hz), 7.90 (br t, 1H), 11.16 (br s, 1H); MS (FAB, MH+) 291; Anal. (C19H18N2O) C, H, N.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:15]([OH:17])=O)[CH2:11][CH2:12][S:13][CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(NC(C(O)=O)C(C)C)(=O)C1C=CC=CC=1.Cl.ClC1C=CC(C2CCNCC2)=CC=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([C:15](=[O:17])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][S:13][CH3:14])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CSCCC(NC(=O)c1ccccc1)C(=O)O
Agent: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Agent: Clc1ccc(C2CCNCC2)cc1
Product: CSCCC(NC(=O)c1ccccc1)C(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
Example 217 was prepared in a similar manner as described for the preparation of Example 208 with the exceptions that benzoyl-DL-methionine and 4-(4-chlorophenyl)-4-hydroxypiperidine were substituted for benzoyl-DL-valine and 4-(4-chlorophenyl)piperidine hydrochloride, respectively. MS found: (M+H)+=448.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]>>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([NH:30][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)([CH3:28])[CH3:29])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCC(C)(C)N)cc1
Product: COC(=O)c1ccc(CCC(C)(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared as in Example 1a from 3-trifluoromethylphenyl glyoxal (2.0 g) and 3-(4-carbomethoxyphenyl)-1,1-dimethylpropylamine (2.6 g) and isolated as the hydrochloride salt monohydrate m.p. 214°-219°. (methanol-ether). τ(DMSO d6) 8.6 (6H,s), 7.8-8.2 (2H,m), 6.6-7.4 (4H,m), 6.1 (3H,s), 5.8 (3H, broad, replaceable by D2O), 4.8 (1H,m), 2.55 (2H,d,J=8 Hz), 2.1-2.4 (4H,m), 2.07 (2H,d,J=8 Hz), 1.3 (1H, broad, replaceable by D2O), 0.33 (1H, broad, replaceable by D2O).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7]P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=O)[S:29][C:30]=1[Br:31]>C1COCC1.CO>[C:1]([O:5][C:6](=[O:24])/[CH:7]=[CH:32]\[C:28]1[S:29][C:30]([Br:31])=[C:26]([Br:25])[CH:27]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1cc(Br)c(Br)s1
Reactant: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C\c1cc(Br)c(Br)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(Diphenoxy-phosphoryl)-acetic acid tert-butyl ester (8.49 g, 24.4 mmol) was dissolved in THF (519 ml) and cooled to −78° C. followed by the addition of triton B (13.3 ml, 40% by wt. in MeOH). After 15 minutes a solution of 4,5-Dibromo-thiophene-2-carbaldehyde (7.0 g, 25.9 mmol) in THF (20 ml) was added and the reaction was stirred for 1 hour. Next, the reaction mixture was quenched with sat. NH4Cl (250 ml), diluted with H2O (500 ml), and extracted with EtOAc (2×300 ml). The organic layers were washed with water (2×200 ml), brine (100 ml), and dried (MgSO4). The crude was passed through a plug of silica gel with EtOAc providing the desired product 9.2 g (96%) as a 4:1 mixture of cis:trans. MS calculated for C10H12BrNS−H 367, observed M-tBu 309, 311, 313.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Li])CCC.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>O1CCCC1>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([B:25]([OH:26])[OH:24])=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCNc1ccc2ncc(B(O)O)n2n1
Temperature: -78 °C
Yield: 57.7 %

Procedure:
A precooled (−78° C.) solution of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (200 mg, 0.74 mmol) and tetrahydrofuran (4 mL) was treated dropwise with n-butyllithium (1.2 mL, 1.6 M, 1.9 mmol). The resulting reaction mixture was maintained at −78° C. for 5 min, then treated dropwise with tris(isopropyl)borate (0.21 mL, 0.89 mmol) and maintained at −78° C. for 2.5 h. The reaction was quenched with H2O (1 mL) and allowed to warm to RT. The organic volatiles were removed under reduced pressure, and the aqueous layer was acidified with 1 N HCl until a white precipitate formed. The solid was collected by filtration to afford (6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)boronic acid (100 mg, 58%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.56 (d, J=9.9 Hz, 1H), 7.39 (s, 1H), 6.66 (d, J=9.9 Hz, 1H), 3.25-3.35 (m, 2H), 1.60-1.75 (m, 1H), 1.37-1.58 (m, 1H), 0.94-1.08 (m, 1H); LCMS (ESI) m/e 235.2 [(M+H)+, calcd for C10H15BN4O2 235.1].