Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]([Cl:28])([Cl:27])[CH2:25]O.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:23][C:24]([Cl:28])([Cl:27])[CH2:25][O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In 30 ml of tetrahydrofuran were dissolved 1.53 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and 1 ml of 2,2,2-trichloroethanol and under cooling at 0°-5° C., 0.8 ml of pyridine was added. Then, 1.2 g of dicyclohexylcarbodiimide was added and the mixture was stirred at the same temperature as above for 2 hours and at room temperature for 18 hours. The precipitated dicyclohexylurea separating out was filtered off and the filtrate was concentrated under reduced pressure. The residue was added to a mixture of 2 N hydrochloric acid and ethyl acetates and the ethyl acetate layer was separated, washed with 2 N hydrochloric acid, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-ethyl acetate (3:1). The eluate was concentrated under reduced pressure and the residue was crystallized from ethyl ether-petroleum ether. Yield 0.7 g.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:30])[NH:13][C:14]([CH3:29])([CH3:28])[CH2:15][N:16]([C:24](=[O:27])[CH2:25]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])([CH3:10])([CH3:9])[CH3:8].[Cl-].[NH4+]>O1CCCC1.O>[C:7]([O:11][C:12]([N:13]1[CH2:25][C:24](=[O:27])[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][C:14]1([CH3:29])[CH3:28])=[O:30])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(CN(C(=O)CBr)c1ccccc1Cl)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2Cl)CC1(C)C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
A solution of 1.87 g of potassium t-butoxide (16.7 mmol) in tetrahydrofuran (110 ml) was added to a solution of 4.68 g of {2-[(2-bromoacetyl)-(2-chlorophenyl)amino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in Example (1i) (11.2 mmol) in tetrahydrofuran (110 ml) under a nitrogen atmosphere and under cooling in a dry ice-acetone bath over 30 minutes, and the mixture was stirred at the same temperature for 10 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture. The mixture was returned to room temperature and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=2/1) to obtain 3.07 g of the title compound (yield: 81%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](O)=[O:11])[N:7]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:6]=1)=[O:4].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[CH:41]([N:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)([CH3:43])[CH3:42]>C(Cl)Cl.CCN(CC)CC>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:11])[NH:50][CH:47]2[CH2:48][CH2:49][N:44]([CH:41]([CH3:43])[CH3:42])[CH2:45][CH2:46]2)[N:7]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:6]=1)=[O:4]
Reactant: CC(C)N1CCC(N)CC1
Reactant: COC(=O)c1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)NC2CCN(C(C)C)CC2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 0.5 h

Procedure:
To 1 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrazole-3,5-dicarboxylic acid 3-methyl ester in 10 ml DCM and 1.4 ml NEt3, 667 mg BOP-Cl were added at RT and the mixture was stirred for 30 min. After addition of 563 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride the mixture was stirred for 16 h. After removal of the solvent under reduced pressure the residue was purified by silica gel chromatography eluting with DCM/MeOH/AcOH/H2O 20:10:1:1 to yield a white solid. Yield: 800 mg MS (ES+): m/e=492, chloro pattern.
Reaction SMILES: C([Mg]Br)C.[CH2:5]([OH:8])[C:6]#[CH:7].[Cl:9][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=[O:12].P(O)(O)([O-])=O.[Na+]>O1CCCC1>[Cl:9][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]([OH:12])[C:7]#[C:6][CH2:5][OH:8]
Reactant: C#CCO
Reactant: CCCCCC(Cl)C=O
Agent: CC[Mg]Br
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(Cl)C(O)C#CCO
Reaction time: 2 h
Yield: 50.5 %

Procedure:
460 ml of a solution of ethyl magnesium bromide in tetrahydrofuran titrating 0.71 moles per liter were added dropwise to a solution of 9 g of propargyl alcohol in 100 ml of tetrahydrofuran and after stirring the mixture for 11/2 hours, a solution of 35.6 g of α-chloro-heptanal in 100 ml of tetrahydrofuran was added thereto. The mixture was stirred for one hour and was then poured into a saturated aqueous monosodium phosphate solution. The mixture was extracted with ether and the organic phase was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure at 100°C. The residue was chromatographed over silica gel and was eluted with a 4-1 benzene-ethyl acetate mixture to obtain 16.6 g of 5-chloro-4-hydroxy-2-decynol in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].C([Mg]Cl)(C)C.[C:31]([CH:39]1[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:38][C:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:13])([F:15])[F:14])[C:6]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:5]2[C:22]([F:23])([F:24])[F:25])[CH:39]1[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]1
Reactant: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(O)(c2ccccc2)c2ccc3nc(C(F)(F)F)c(-c4ccccc4)c(C(F)(F)F)c3c2)CC1
Reaction time: 0.15 h

Procedure:
A ˜−70° C. solution of 6-iodo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (754 mg, 1.61 mmol, Intermediate 8, step d) in THF (1.4 mL) was treated with iPrMgCl (0.784 mL, 2.06 M in THF, 1.61 mmol) dropwise via syringe under argon over the course of 3 min to provide a light amber solution. After 9 min, the opaque yellow slurry was removed from the cold bath and stirred under ambient conditions for 4 min. A solution of 1-(4-benzoylpiperidin-1-yl)ethanone (442 mg, 1.91 mmol, Intermediate 27) in THF (0.3 mL) was added to the olive drab slurry rapidly dropwise over ˜15 sec, and the homogeneous brown solution was stirred at room temperature overnight. The light amber solution was then quenched with 5 M NH4Cl (1 mL) and extracted with 2-methoxy-2-methylpropane (1×10 mL, 1×2 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was flash chromatographed using 50% acetone/heptane (isocratic elution), and impure fractions were additionally flash chromatographed using 90% EtOAc/heptanes (isocratic elution) to afford the title compound as an off-white foam. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=10.11 Hz, 1H), 8.24 (dd, J=5.56, 9.09 Hz, 1H), 7.94 (t, J=8.84 Hz, 1H), 7.54 (t, J=7.33 Hz, 2H), 7.41-7.51 (m, 3H), 7.33-7.41 (m, 2H), 7.28 (br. s., 3H), 4.71 (d, J=7.58 Hz, 1H), 3.86 (br. s., 1H), 3.00-3.21 (m, 1H), 2.74-2.89 (m, 1H), 2.52-2.69 (m, 1H), 2.44-2.52 (m, 1H; D2O-exch), 2.05 (d, J=2.02 Hz, 3H), 1.69-1.84 (m, 1H), 1.31-1.55 (m, 3H); MS m/e 573.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(Cl)(Cl)=O.[CH3:19]O>C(=O)(O)[O-].[Na+]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CO
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,5-dimethoxyphenyl)acetic acid (5) (600 mg, 3.06 mmol) in MeOH (30 mL) was added dropwise thionyl chloride (3 mL) at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The mixture was diluted with saturated sodium bicarbonate (aq., 20 mL) and extracted by EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give methyl 2-(3,5-dimethoxyphenyl)acetate (crude, 700 mg) as a yellow oil. MS (ES+) C11H14O4 requires: 210. found: 211 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:12]([N:17]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:6]=[CH:7][CH:8]=1)#[N:2]>O=[Pt]=O.C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:12]([N:17]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(-c2nc3ncccc3o2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: NCc1cccc(-c2nc3ncccc3o2)c1

Procedure:
A mixture of 2-(3-cyanophenyl)oxazolo[4,5-b]-pyridine (2.2 g., 0.01 m.), 200 ml. of glacial acetic acid and 1.0 g. of PtO2 catalyst is reacted in a 40 p.s.i. hydrogen atmosphere at room temperature until the theoretical amount of hydrogen has been absorbed. The mixture is filtered, the acetic acid removed in vacuo to yield 2-[3-(aminomethyl)phenyl]oxazolo[4,5-b]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]=[S:39]1(=[O:45])[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40]1>>[O:38]=[S:39]1(=[O:45])[CH2:43][CH2:42][CH:41]([NH:44][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CCS(=O)(=O)C3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 1,1-Dioxo-tetrahydro-1λ6-thiophen-3-ylamine according to conditions described in general procedure C. Mp: 150-151° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.04 (s, 2 H), 2.30 (s, 1 H), 2.88 (s, 2 H), 3.07 (s, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.77 (t, J=4.8 Hz, 4 H), 4.56 (s, 1 H), 6.49 (s, 1 H), 7.04 (d, J=12.4 Hz, 1 H), 7.26 (d, J=8.8 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.56-7.61 (m, 3 H), 7.81-7.84 (m, 1 H), 7.99 (d, J=7.6 Hz, H), 8.30 (d, J=4.0 Hz, 1H), 10.46 (s, 1 H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].Br[CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[C:1]([NH:4][C:5]([CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COC(=O)CCCC#CCBr
Product: CCOC(=O)C(CC#CCCCC(=O)OC)(NC(C)=O)C(=O)OCC

Procedure:
Under the reaction conditions described in Example 1A diethyl acetamidomalonate and methyl 7-bromohept-5-ynoate reacted to give diethyl acetamido-(6-methoxycarbonylhex-2-ynyl)malonate as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
3-Bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 7.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (66.6 mg, 0.325 mmol), Pd(PPh3)2Cl2 (9.13 mg, 0.013 mmol) and Na2CO3 (68.9 mg, 0.650 mmol) were added to a MW vial. The vial was sealed, evacuated/purged with argon, and DME (552 μL), water (158 μL), EtOH (79 μL) were added. The RM was then subjected to MW irradiation at 120° C. for 10 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 102 mg, 0.130 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, from 20% to 50% in 18 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.10 min, m/z=461.0 [M+H]+, m/z=459.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.75 (d, J=10.27 Hz, 2H) 3.27 (dd, J=10.39, 3.55 Hz, 2H) 3.88 (br. s, 2H) 5.07 (d, J=3.42 Hz, 2H) 6.97 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.82-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.45 Hz, 1H) 8.85 (s, 2H) 9.17 (s, 1H) 10.10 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:28]4[CH2:30][CH2:29]4)=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4]
Reactant: OB(O)C1CC1
Reactant: C=CCN1CCN(c2ccc(NS(=O)(=O)c3ccc(Br)cc3)cn2)CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCN1CCN(c2ccc(NS(=O)(=O)c3ccc(C4CC4)cc3)cn2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
398 mg (0.84 mmol) of N-[6-(4-allylpiperazin-1-yl)pyridin-3-yl]-4-bromobenzenesulfonamide from Example 19, 101 mg (1.18 mmol) of cylcopropylboronic acid, 676 mg (3.19 mmol) of K3PO4 and 26 mg (0.09 mmol) of tricyclohexylphosphine were dissolved in 4 ml of toluene and 0.2 ml of water under a nitrogen atmosphere. 10 mg (0.04 mmol) of palladium(II) acetate were then added and the mixture was stirred at 100° C., in a microwave oven, for one hour. After the solvent had been evaporated down to dryness, the resulting residue was treated with water and the mixture was then extracted with ethyl acetate. Because the phases only separated poorly, the finely divided solid was filtered off. The aqueous phase was extracted twice with ethyl acetate. After the combined organic phases had been dried over sodium sulfate and the solvent had been filtered and evaporated down to dryness, the resulting residue was purified by column chromatography.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[CH:11]=[C:10]([N:19]([C:21]2[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27]([OH:29])=O)=[CH:23][CH:22]=2)[CH3:20])[N:9]=1>ClCCl>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[CH:11]=[C:10]([N:19]([C:21]2[CH:22]=[CH:23][C:24]([O:25][CH:26]([CH3:30])[C:27]([Cl:2])=[O:29])=[CH:31][CH:32]=2)[CH3:20])[N:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1)C(=O)O
Solvent: ClCCl
Product: CC(Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1)C(=O)Cl
Reaction time: 12 h

Procedure:
2-{4-[N-(1,7-Dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionyl chloride was prepared by adding phosphorus pentachloride (1.07 g) portionwise to a solution of 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionic acid (2.0 g) in dichloromethane at room temperature and stirring the reaction mixture for a period of 12 hours.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:8][CH2:7]1.C(=O)([O-])O.[Na+].[Cl-].[NH4+]>Cl.C(OCC)(=O)C>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
A reaction mixture of tert-butyl N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycinate (4.8 g) and 4N hydrogen chloride/ethyl acetate (20 mL) was stirred at room temperature for 2 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from methanol/ethyl acetate to give the title compound (3.00 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH2:22][CH3:23])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(Cl)Cl.O.O.[NH2:31][NH2:32]>>[NH:31]([C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH2:22][CH3:23])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[NH2:32]
Reactant: CCOc1cc2cc(CO)cc(-c3ccnc(Cl)c3)c2cc1OCC
Reactant: NN
Solvent: ClCCl
Solvent: O
Product: CCOc1cc2cc(CO)cc(-c3ccnc(NN)c3)c2cc1OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1-(2-chloro-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (3.90 g) in hydrazine hydrate (17.8 ml) is refluxed for 9 hours. The mixture is stirred at room temperature for 10 minutes, and further stirred under ice-cooling for 10 minutes. To the mixture are added methylene chloride and water, and the methylene chloride layer is separated, washed, dried, and concentrated under reduced pressure to remove the solvent. The residue is dissolved in hot ethanol (20 ml), and allowed to cool overnight to give 1-(2-hydrazino-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (3.19 g).
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH2:15][C:16]#[N:17])[C:10](OCC)=[O:11])=[CH:5][CH:4]=1.N.CO>[Ni].CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:15][CH2:16][NH:17][C:10]2=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CC#N)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: O=C1NCCC1(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL stainless steel pressure bottle was charged with a Raney®-nickel 2800/water slurry (23.60 g, 402 mmol), followed by addition of the product from Example 25A (5.90 g, 16.9 mmol) and a solution of 7M NH3—CH3OH (30 mL)/CH3OH (120 mL). The reaction mixture was stirred at ambient temperature under an atmosphere of 30 psi H2 for 4 hours. The mixture was filtered through a nylon membrane and concentrated in vacuo. The crude product was slurried in 5% ethyl acetate/hexane, and the solid was collected by filtration to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.13 (s, 1H), 7.41-7.35 (m, 4H), 7.35-7.30 (m, 4H), 3.18 (t, J=6.4, 2H), 2.72 (t, J=6.4, 2H); MS (DCI+) m/z 323 (M+NH4)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.Cl.CN(C)CCCN=C=NCC.ON1C(=O)C2C=CC=CC=2N=N1.Cl.[CH3:43][O:44][C:45](=[O:52])[C@H:46]([CH2:48][CH2:49][S:50][CH3:51])[NH2:47].CN1CCOCC1>C(OCC)(=O)C.CN(C=O)C.ClCCl>[CH3:43][O:44][C:45](=[O:52])[C@H:46]([CH2:48][CH2:49][S:50][CH3:51])[NH:47][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][OH:1])=[CH:4][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc(CO)cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution in 1:3 DMF-dichloromethane (100 mL) of 4-hydroxymethyl-2-phenylbenzoic acid (5.2 g, 23 mmol), prepared as in Example 158D, at 5-10° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.8 g, 25 mmol), 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (4.1 g, 25 mmol), methionine methyl ester hydrochloride (5.0 g, 25 mmol) and 4-methylmorpholine (2.8 mL, 25 mmol). The reaction was warmed slowly to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with aqueous 1M H3PO4. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (65% ethyl acetate-hexanes) gave [4-hydroxymethyl-2-phenylbenzoyl]methionine methyl ester (5.15 g, 60%).