Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:37])[C:35]=1[OH:36].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:31]=[C:30]([F:29])[C:35]([OH:36])=[C:34]([F:37])[CH:33]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(F)c(O)c(F)c3)n(-c3ccccc3)c(=O)c12
Yield: 15.2 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (260 mg, 0.59 mmol) was treated with (3,5-difluoro-4-hydroxyphenyl)boronic acid (154 mg, 0.89 mmol), sodium carbonate (2 M, 1.33 mL, 2.66 mmol) and 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (17 mg, 0.03 mmol) according to the method described in the Preparation 17. The residue was purified using SP1® Purification System (0% to 60%, hexane-ethyl acetate) to give 44 mg (15% yield) of the title compound as a white solid. Purity 95%.
Reaction SMILES: C([O:8][CH2:9][CH:10]([CH2:26][O:27]CC1C=CC=CC=1)[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([NH:23]C=O)=[N:17][C:18]=2Cl)C1C=CC=CC=1.C(O)=[O:36].N>[Pd].O>[OH:8][CH2:9][CH:10]([CH2:26][OH:27])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:36])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2
Reactant: O=CO
Reactant: O=CNc1nc(Cl)c2ncn(OCC(COCc3ccccc3)COCc3ccccc3)c2n1
Agent: [Pd]
Agent: N
Solvent: O
Product: Nc1nc2c(ncn2OCC(CO)CO)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 9-(3-benzyloxy-2-benzyloxymethylprop-1-oxy)-2-formamido-6-chloropurine (2.5 g, 5.2 mmol) and 80% formic acid (100 ml) was stirred at 100° C. for 1 hour, cooled and 10% palladium on charcoal (2.0 g) added. The mixture was then stirred under an atmosphere of hydrogen for 45 minutes. The catalyst was removed and the solution evaporated under reduced pressure. The residue obtained was heated in water (100 ml) until boiling commenced. Concentrated aqueous ammonia (4 ml) was added and the solution was then heated for a further 15 minutes, cooled and evaporated under reduced pressure. Recrystallisation from water (charcoal) afforded 9-(3-hydroxy-2-hydroxymethylprop-1-oxy)guanine (430 mg, 32%). IR: υmax (KBr) 3380, 3183, 1679, 1637, 1605, 1541, 1479, 1395 cm-1. 1H NMR: δH [(CD3)2SO] 1.94 (1H, m, CH), 3.53 (4H, m, 2×CH2OH), 4.26 (2H, d, J=6.3 Hz), 4.57 (2H, t, J=5.2 Hz, D2O exchangeable, 2×OH), 6.58 (2H, br.s, NH2), 7.92 (1H, s, H-8), 10.64 (1H, br.s, D2O exchangeable, H-1). Found: C, 42.08; H, 5.15; N, 27.41%. C9H13N5O4 requires: C, 42.34; H, 5.14; N, 27.44%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([NH2:19])=[N:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:48])[C:39]1[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:41](Cl)=[O:42]>ClCCl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([N:19]2[C:41](=[O:42])[C:40]4[C:39](=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:38]2=[O:48])=[N:14][CH:13]=[CH:12]3)=[CH:22][CH:23]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N)c3cn2)cc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N4C(=O)c5ccccc5C4=O)c3cn2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of crude 4-5 (10.9 g, <19.3 mmol), triethylamine (8.05 mL, 57.8 mmol), and dichloromethane (75.0 mL) at 0° C. under an atmosphere of nitrogen gas was added phthaloyl dichloride (90%; 3.75 mL, 23.4 mmol). The resulting mixture was stirred at ambient temperature for 15 hours under an atmosphere of nitrogen gas. The reaction mixture was quenched with saturated aqueous NH4Cl (200 mL) and the resulting mixture was extracted with dichloromethane (1000 mL, 500 mL×2). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 200 g, step gradient eluting with 50:1, 40:1, 30:1, 20:1, 10:1, and 5:1 dichloromethane/ethyl acetate) followed by recrystallization from dichloromethane to give 3.94 g (39% in 3 steps) of 4-6 as yellow crystals: 1H NMR (400 MHz, CDCl3) δ 8.94 (1H, br s), 8.33 (1H, d, J=6.0 Hz), 8.02 (2H, m), 7.84 (2H, m), 7.31 (1H, dd, J=6.0, 0.8 Hz), 7.15 (4H, m), 6.85 (4H, m), 6.52 (1H, br s), 4.81 (4H, br s), 3.79 (6H, s); ESI-MS m/z 531 [C32H26N4O4+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29].C(OCC)C>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]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2Cl)CC1
Temperature: 100 °C
Yield: 42.3 %

Procedure:
To a solution of [1,4]diazepane-1-carboxylic acid tert-butyl ester (0.36 g, 1.77 mmol) in toluene (5 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.040 g, 0.044 mmol), R(+)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.027 g, 0.044 mmol), sodium t-butoxide (0.13 g, 1.33 mmol), and 1-bromo-2,4-dichlorobenzene (0.20 g, 0.89 mmol). The solution was heated to 100° C. for 2 h. The reaction was cooled to room temperature, diethylether (5 mL) was added and the resulting mixture filtered through a bed of diatomaceous earth. The residue was chromatographed on silica gel using hexane/ethyl acetate from 100% to 95% hexane in a gradient fashion, to give the title compound as a gum (0.13 g, 43%). The residue was used as is without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@@:8]1([C:18]([OH:20])=[O:19])[C@@H:13]([F:14])[CH2:12][C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([OH:17])=[O:16])=[O:6])[CH:2]=[CH2:3].[CH2:21](O)[CH:22]=[CH2:23].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl>[CH2:23]([O:16][C:15]([C@@H:10]1[C@@H:9]2[C@H:11]1[CH2:12][C@H:13]([F:14])[C@@:8]2([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C:18]([OH:20])=[O:19])=[O:17])[CH:22]=[CH2:21]
Reactant: C=CCO
Reactant: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)OCC=C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A solution of a mixture of (1S,2S,3S,5R,6S)-2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (A-1-1, 1.41 g), allyl alcohol (336 μL), N,N-diisopropylethylamine (837 μL) and N,N-dimethylaminopyridine (60 mg) in chloroform (30 mL) was cooled to 0° C. To this solution, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (837 mg) was added, and then the mixture was heated to room temperature and stirred for 2 days. To the reaction solution, chloroform was added, and the organic layer was washed twice with 0.25 mol/L hydrochloric acid, once with water, and once with brine, sequentially. After the organic layer was dried over anhydrous magnesium sulfate, the insoluble was filtered and the filtrate was concentrated under reduced pressure to give (1S,2S,3S,5R,6S)-6-((allyloxy)carbonyl) 2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2-carboxylic acid (B-1-1, 1.30 g) as a colorless amorphous.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1[C:29]([C:30]([NH:32][CH2:33][C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:31])=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.CCCCCC>CN(C=O)C>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[C:29]([C:30]([NH:32][CH2:33][C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[O:31])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(CCS)c1ccccc1
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(NCc1cccs1)c1cc2ccccc2nc1SCCS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
112 mg (1.0 mmol) potassium tert-butylate were added to a solution of 202 mg (1.0 mmol) 2-(phenylsulfonyl)ethanethiol in DMF (6 ml) at 0° C. and the mixture was stirred for 10 min at 0° C. Then 303 mg (1.0 mmol) 2-chloro-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV01) were added at 0° C. and the reaction solution was heated slowly to 50° C. and stirred for 16 h at this temperature. After cooling to RT it was diluted with EE and washed with a saturated aqueous NH4Cl solution. The aqueous phase was extracted with EE. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) with the residue yielded 326 mg (0.7 mmol, 70%) 2-[2-(phenylsulfonyl)ethylthio]-N-(2-thienyl-methyl)-3-quinoline carboxamide. MS: m/z 469.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:14][CH:13]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24]O>S(=O)(=O)(O)O>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1ccc(C(=O)CCCc2ccccc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccc(C(=O)CCCc2ccccc2)cc1

Procedure:
To a suspension of 2.10 g of 4-[4-(4-phenylbutyryl)phenyl]butyric acid in 15 ml of methanol, 0.1 ml of sulfuric acid was added, and the mixture was heated under reflux for 4 hours. After the reaction solution was removed under reduced pressure, the residue was dissolved in ethyl acetate and then washed successively with water, aqueous potassium carbonate and water. After the ethyl acetate layer was dried, the solvent was removed under reduced pressure. The residue was washed with isopropyl ether to yield 1.87 g of colorless crystals. Recrystallization from methanol gave colorless flakes, mp 61°~62° C.
Reaction SMILES: COC(=O)C1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[CH:12]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][C:21]2=[O:34])[CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:6]C=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.NC1C=C[N:61]([CH2:64][C:65]([CH3:68])([OH:67])[CH3:66])N=1>ClCCl>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[O:25][C:23]1[CH2:24][N:20]([CH:12]([CH2:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][N:61]([CH2:64][C:65]([OH:67])([CH3:68])[CH3:66])[N:6]=2)=[O:35])[C:21](=[O:34])[CH:22]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCOCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (as prepared in Example 40, 200 mg, 0.54 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (85 mg, 0.55 mmol) and 1-hydroxybenzotriazole (80 mg, 0.57 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 101 mg, 0.65 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (186 mg, 68%) as a white solid: LR-ES-MS m/z calculated for C25H30F2N4O5 [M]+ 504, observed [M+H]+ 505; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H) 1.06 (s, 3H) 1.11-1.52 (m, 3H) 1.52-1.74 (m, 3H) 1.74-1.88 (m, 1H) 3.07-3.32 (m, 2H) 3.75-3.87 (m, 2H) 3.89 (s, 2H) 4.33 (d, J=19.0 Hz, 1H) 4.65 (d, J=19.0 Hz, 1H) 4.68 (s, 1H) 4.91 (dd, J=10.6, 4.5 Hz, 1H) 5.04 (s, 1H) 6.45 (d, J=2.2 Hz, 1H) 7.26-7.51 (m, 3H) 7.54 (d, J=2.2 Hz, 1H) 10.83 (s, 1H).
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:4]2[CH2:3][NH:2]1.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.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:72]1[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([F:81])([F:80])[F:79])[CH:73]=1>C1(C)C=CC=CC=1>[F:79][C:78]([F:81])([F:80])[C:74]1[CH:73]=[C:72]([N:2]2[CH2:3][C@@H:4]3[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)[CH:77]=[CH:76][CH:75]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)c3)C[C@@H]21
Temperature: 80 °C

Procedure:
tert-Butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate from Example 252 Step B (50.3 mg, 0.222 mmol), tris(dibenzylidineacetone)dipalladium(0) (4.07 mg, 4.45 μmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (8.30 mg, 0.013 mmol), potassium phosphate, tribasic (54.2 mg, 0.311 mmol) and 1-bromo-3-(trifluoromethyl)benzene (0.032 mL, 0.233 mmol) were combined in toluene (2 mL) and put under nitrogen. The reaction mixture was heated at 80° C. overnight. The reaction was quenched with water (1 mL), the phases were separated, and the organic phase was applied to a 4 g silica gel cartridge and purified using a gradient of 1-20% ethyl acetate/hexanes over 15 minutes to give tert-butyl(3aR,4S,6aS)-2-(3-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.73 (d, J=6.3, 1H), 7.33 (t, J=7.8, 1H), 7.06 (d, J=7.4, 1H), 6.91 (s, 1H), 6.76 (d, J=7.9, 1H), 4.13-4.02 (m, 1H), 3.44 (d, J=10.0, 1H), 3.34-3.27 (m, 1H), 3.21-3.12 (m, 1H), 2.99 (d, J=10.1, 1H), 2.81-2.70 (m, 2H), 2.12 (td, J=12.6, 6.4, 1H), 2.06-1.95 (m, 1H), 1.73 (dq, J=15.0, 7.5, 1H), 1.55 (s, 9H), 1.44-1.34 (m, 1H); MS (ESI+) m/z 371 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[C:12]([CH:18]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1
Reactant: CCOC(=O)c1cc(Br)cc(C(=O)OCC)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ccccc2)c1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
A mixture of Na2CO3 (776 mg, 7.32 mmol), Pd (OAc)2 (4.5 mg, 0.02 mmol), diethyl 5-bromoisophthalate (1 g, 3.66 mmol), phenyl boronic acid (670 mg, 5.49 mmol), distilled water (14 mL) and acetone (12 mL) was stirred at 35° C. for 0.5 h. The reaction solution was then extracted four times with diethyl ether (4×20 mL). The combined organic phase washed with brine, dried over sodium sulfate and then filtered. The solvent was removed under vacuum, and the crude diethyl biphenyl-3,5-dicarboxylate was taken to the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH2:21](Br)[C:22]#C>O.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:21]#[CH:22])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: C#CCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: C#CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is treated, under nitrogen, with 1.14 g. sodium borohydride at 20°-30° C. After 1 1/2 hours 5 ml. of propargyl bromide is added. The mixture is stirred for three hours at 20°-30° C, then diluted with water. The product, a red solid, is isolated by extraction into chloroform yielding 1-amino-2-nitro-4-propargylthiobenzene.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([O:21][CH3:22])[C:3]=1[O:23][CH3:24].C1(C)C=CC=CC=1.C([Li])CCC.[OH-].[Na+].CN(C)[CH:41]=[O:42]>CCCCCC>[CH3:22][O:21][C:4]1[C:3]([O:23][CH3:24])=[C:2]([CH:41]=[O:42])[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]=1[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: COc1c(Br)c2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1c(C=O)c2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Reaction time: 0.33 h

Procedure:
To a solution of 18.21 g. (0.0446 mole) of 9-bromo-7,8-dimethoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared as in Example 20) in 200 ml. of toluene, cooled to -78° C., is slowly added 26.0 ml. of 2.1 M n-butyl lithium in hexane. After 20 minutes at this temperature 23.1 ml. of dimethylformamide is added and the mixture is stirred for 1/2 hour. The reaction mixture, at room temperature, is poured into 10% sodium hydroxide solution and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give 7,8-dimethoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine-9-carboxaldehyde.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCCCN
Product: CCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 96° C. and MS: m/e=268.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and butylamine.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][CH2:19][C:18]([OH:29])=[O:17])=[CH:27][CH:26]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCCc1ccc(O)cc1
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)CCCc1ccc(OCc2cccnc2SC2CCCC2)cc1
Yield: 92.7 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.020 g, 0.09 mmol) obtained in Step C of Preparation Example 8 and 4-(4-hydroxy-phenyl)-butyric acid ethyl ester (0.018 g, 0.09 mmol) obtained in Step E of Preparation Example 13 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.031 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:3]=1.[CH2:26]([O:28][C:29](=[O:35])[CH2:30][CH2:31][C:32](O)=[O:33])[CH3:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH:15]1([NH:14][C:7]2[CH:6]=[C:5]3[C:10]([C:11](=[O:12])[C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:35])=[CH:3][N:4]3[CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:9][C:8]=2[F:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)CCC(=O)O
Reactant: Nc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)Nc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
250 mg of 3-amino-7-(cyclohexylamino)-1-cyclopentyl-6-fluoroquinoline-4(1H)-one and 127 mg of 4-ethoxy-4-oxobutanoic acid were dissolved in 20 ml of DMF, and 170 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 160 mg of 1-hydroxybenzotriazole were added, followed by overnight stirring at room temperature. By adding water to the reaction mixture and collecting the insoluble materials by filtration, 220 mg of ethyl 4-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}-4-oxobutanoate was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:33])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([C:41](O)=[O:42])=[N:39][CH:40]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(#N)C.CO>[F:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([NH:1][C:2]2[C:3]([CH3:33])=[C:4]([C:8]3[C:20]4[C:19]5[C:14](=[CH:15][C:16]([C:21]([N:23]6[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]6)=[O:22])=[CH:17][CH:18]=5)[NH:13][C:12]=4[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:42])=[N:39][CH:40]=1
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Reactant: O=C(O)c1ccc(F)cn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)c2ccc(F)cn2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-2, 100 mg, 0.204 mmol), 5-fluoropicolinic acid (43.1 mg, 0.306 mmol), and HOAT (41.6 mg, 0.306 mmol) in acetonitrile (2 mL) was treated with DIEA (0.053 mL, 0.306 mmol) and EDC (78 mg, 0.408 mmol) and the mixture was stirred at rt. After 18 h, the mixture was diluted with methanol and purified by preparative HPLC. The aqueous residue from concentration of the appropriate effluent fractions was made basic with NaHCO3 (aq) and extracted three times with EtOAc. The combined organic phases were dried and concentrated to provide 4-(3-(5-fluoropicolinamido)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a light gray powder (111.5 mg, 92%). 1H NMR (400 MHz, methanol-d4) δ 8.58 (d, J=3.1 Hz, 1H) 8.31 (dd, J=8.8, 4.8 Hz, 1H) 7.96-8.03 (m, 2H) 7.82 (td, J=8.6, 2.6 Hz, 1H) 7.68 (d, J=0.9 Hz, 1H) 7.45 (t, J=7.9 Hz, 1H) 7.23 (dd, J=7.5, 0.9 Hz, 1H) 7.09 (d, J=7.9 Hz, 1H) 7.03-7.08 (m, 1H) 6.95-7.00 (m, 1H) 3.78 (br. s., 2H) 3.49 (br. s., 2H) 2.52 (br. s., 2H) 2.40 (br. s., 2H) 2.31 (s, 3H) 2.04 (s, 3H). Mass spectrum m/z 565.2 (M+H)+.