Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(Cl)cc3)sc2Cc2ccccc2)cc1
Yield: 69.4 %

Procedure:
A procedure similar to that in Example 4 was used, 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and p-chlorobenzoyl chloride were used as starting materials, the resulting crude product was recrystallized with acetone to obtain a product as a white solid in a yield of 69.4%, mp: 182-183 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.78 (3H, s, OCH3), 4.21 (2H, s, CH2), 6.75 (2H, d, J=7.56 Hz, ArH), 7.22˜7.35 (9H, m, ArH), 7.60 (2H, d, J=7.56 Hz, ArH), 11.70 (1H, br, CONH); EI-MS m/e (%): 434.2 (M+, 100), 123.0 (83); HREI-MS Calcd. for C24H19ClN2O2S: 434.0856. found: 434.0859. Anal. Calcd. for C24H19ClN2O2S: C, 66.28; H, 4.40; N, 6.44. found: C, 65.91; H, 4.22; N, 6.50.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:25][CH2:26][NH2:27])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C[O-].C([N+](C)(C)C)C1C=CC=CC=1>CN(C=O)C.C(OCC)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:24][CH2:25][CH2:26][NH:27][C:9](=[O:11])[C@@H:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:12]([CH3:14])[CH3:13])=[CH:19][CH:18]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)[C@H](NC1CCCCC1)C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)[C@H](NC1CCCCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
A solution of 335 mg (1.68 mmol) 2-(cyclohexylamino)-3-methylbutyric acid (Example 69, Step A), 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride, 0.29 mL (1.68 mmol) N,N-diisopropylethylamine, and 1.5 mL (3.36 mmol) benzyltrimethylammonium methoxide (40% solution in methanol) in 4 mL dry DMF was cooled to 3° C., and 637° mg (1.68 mmol) O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate was added and the resulting mixture stirred at 3° for 30 minutes, warmed to 25° C., and stirred an additional 30 minutes at which time it was diluted with 20 mL diethyl ether, and washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 4:1 ethyl acetate:hexanes as eluant, followed by conversion to the hydrochloride salt by treating with excess diethyl ether which had been saturated with hydrogen chloride gas to give 29 mg (4%) of titled compound: mp 49-53° C. APCI-MS m/z 443.4 (MH+).
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34]4[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=4[C:36]([OH:38])=O)[CH2:29][CH2:28]3)=[O:26])=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CN>CN(C=O)C.O>[CH3:2][NH:3][C:36]([C:35]1[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=1[O:33][CH:30]1[CH2:31][CH2:32][N:27]([C:25](=[O:26])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:20][N:19]=2)=[O:22])[CH2:28][CH2:29]1)=[O:38]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(NCC(=O)N1CCC(Oc2ccccc2C(=O)O)CC1)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 0.03 h
Yield: 31.1 %

Procedure:
DIPEA (72 mg, 0.56 mmol) was added to a stirred solution of 2-(1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperidin-4-yloxy)-benzoic acid (75 mg, 0.16 mmol) in DMF (2 mL) followed by HOBt (33 mg, 0.24 mmol) and EDCI.HCl (46 mg, 0.24 mmol). After 2 minutes of stirring, methyl amine hydrochloride (11 mg, 0.16 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) afford 23 mg (31.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-methylcarbamoyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 462.2, 96.9%. 1H NMR (300 MHz, DMSO-d6): δ 8.1 (m, 1H), 8.0 (m, 1H), 7.8 (m, 2H), 7.6 (m, 1H), 7.4 (m, 4H), 7.2 (m, 1H), 7.1 (b, 1H), 7.0 (m, 1H), 4.8 (b, 1H), 4.2 (m, 2H), 3.6 (m, 3H), 2.8 (d, 3H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[I:15]Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[I:15][C:7]1[C:8]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:4]2[O:3][CH2:2][O:1][C:5]=2[CH:6]=1
Reactant: ClI
Reactant: CC(=O)NCc1ccc2c(c1)OCO2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1cc2c(cc1I)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide (9.24 g, 47.9 mmol) was added to 1.0 M solution of iodine monochloride in methylene chloride (80 mL). The mixture was stirred at room temperature for 2 hours, and then the mixture was poured into 10% Na2S2O3 and stirred until the red color faded. It was then extracted with CH2Cl2 and the organic layer was washed with water and brine, dried and concentrated to get the crude product which was purified by column chromatography (mobile phase: petroleum/methylene chloride=1/19) to give N-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide compound as a white solid (5.82 g, 38%). LC-MS: 320 [M+1]+. 1H-NMR (DMSO-d6): δ 1.89 (s, 3H), 4.11 (d, 2H, J=6.0 Hz), 6.04 (s, 2H), 7.07 (s, 1H), 7.37 (s, 1H), 8.28 (t, 1H, J=6.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(#N)C.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH:8]=[CH:9][N:10]2[CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25][CH2:24]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: COc1ccc2c(O)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc2c(=O)ccn(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A solution of 7-methoxyquinolin-4-ol (Intermediate 10, 500 mg, 2.85 mmol) in dry DMF (10 mL) was treated at 0° C. with a cooling bath under stirring with sodium hydride (114 mg, 60% in oil, 2.85 mmol). The cooling bath was removed and the mixture was stirred for 30 minutes at room temperature. A solution of 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate in DMF (Intermediate 6, 0.58 mmol/mL, 5 mL, 2.9 mmol) was added and the resulting solution was stirred over night at room temperature. DMF was removed under reduced pressure, the residue was taken up in ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) and the aqueous phase was back extracted three times with ethyl acetate (3×70 mL). The combined organic phases were dried over sodium sulfate. Some starting 7-methoxyquinolin-4-ol was precipitated from dichloromethane (30 mL) with hexanes (20 mL) and removed by filtration. The filtrate was concentrated to dryness under reduced pressure. Chromatography of the residue on silica gel with acetonitrile/water (15:1 to 10:1) gave 373 mg (33% yield) of the product as a colorless solid, mp 207° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCOCC3)c2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCOCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-morpholin-4-yl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K62) (286 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (259 mg, 55%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
To a solution of 2,4-dichloro-6-methoxypyrimidine (5.0 g, 28.0 mmol) and tert-butyl piperidin-4-ylcarbamate (5.6 g, 28.0 mmol) in DMF (50 mL) was added K2CO3 (7.74 g, 56.0 mmol) and the mixture was stirred at RT for 6 h. The reaction was quenched with water and the suspension was filtered, washed with water and dried. The crude was purified with silica gel chromatography (eluting with 20% EtOAc in petroleum ether) to give tert-butyl (1-(4-chloro-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate 276a (6.0 g, 73% yield). MS (ESI, pos. ion) m/z: 342.8 (M+1); 1H-NMR (400 MHz, CDCl3): δ ppm 5.97 (s, 1H), 4.64 (d, 2 H, J=13.2 Hz), 4.49 (brs, 1H), 3.88 (s, 3H), 3.04 (t, 2 H, J=11.6 Hz), 2.03 (d, 2 H, J=10.4 Hz), 1.57 (s, 3H), 1.46 (s, 9H). And tert-butyl (1-(2-chloro-6-methoxypyrimidin-4-yl)piperidin-4-yl)carbamate 276b (1.0 g, 12% yield). MS (ESI, pos. ion) m/z: 343.1 (M+1); 1H-NMR (400 MHz, CDCl3): δ ppm 5.70 (s, 1H), 4.49 (brs, 1H), 4.22 (d, 2 H, J=12.4 Hz), 3.91 (s, 3H), 2.96-3.00 (m, 2H), 2.03 (d, 2 H, J=8.4 Hz), 1.45 (s, 9H), 1.3-1.39 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:34]2[N:39]=[CH:38][C:37]([NH:40][C:41](=[O:54])[CH2:42][NH:43]C(OCC3C=CC=CC=3)=O)=[CH:36][N:35]=2)[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:34]2[N:35]=[CH:36][C:37]([NH:40][C:41](=[O:54])[CH2:42][NH2:43])=[CH:38][N:39]=2)[C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(NC(=O)CNC(=O)OCc3ccccc3)cn2)C[C@H]1CC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(NC(=O)CN)cn2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
(2R*,4S*)-4-({5-[2-(Benzyloxycarbonylamino)acetylamino]pyrimidin-2-yl}-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (631 mg) is dissolved in methanol (10 ml), 10% palladium/carbon (100 mg) is added thereto and then the mixture is stirred at room temperature under hydrogen for 30 minutes. The reaction solution is filtered, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give (2R*,4S*)-4-{[5-(2-aminoacetylamino)pyrimidin-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (463 mg). MS (m/z): 626 [M+H]+
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1>C(OCC)C>[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[N:17]([C:1](=[O:3])[CH3:2])[CH2:16][CH2:15][N:14]=1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)N1CCN=C1COc1cccc(C)c1C
Reaction time: 2 h

Procedure:
A solution of acetic anhydride (3.0 ml; 0.032 moles) in diethyl ether (10 ml) was added dropwise, during 10 minutes, to a stirred suspension of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (6.12 g; 0.030 mole) (prepared from O-ethyl-2,3-dimethylphenoxyacetimidate and ethylene diamine) in diethyl ether (100 ml) cooling the mixture to keep its temperature below 20° C. After stirring for 2 hours the reaction mixture was filtered and the precipitate recrystallised from acetone to yield white crystals of 2-(2,3-dimethylphenoxymethyl)-1-acetyl-2-imidazoline, m.p. 127°-130° C. Analysis: Calculated C 68.27, H 7.37, N 11.37% Found: C 68.13, H 7.44, N 11.13%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:51]1[CH:52]=[N:53][CH:54]=[C:55]([CH:63]=1)[C:56]([NH:58][CH2:59][CH:60]1[CH2:62][CH2:61]1)=[O:57]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.O.CN(C=O)C>[CH:60]1([CH2:59][NH:58][C:56](=[O:57])[C:55]2[CH:63]=[C:51]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=[C:5]4[CH:17]=[O:18])[CH:52]=[N:53][CH:54]=2)[CH2:62][CH2:61]1
Reactant: O=C(NCC1CC1)c1cncc(Br)c1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1nn(C2CCCCO2)c2ccc(-c3cncc(C(=O)NCC4CC4)c3)cc12
Temperature: 80 °C
Yield: 90 %

Procedure:
A solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (I) (1.068 g, 3.0 mmol), bis(pinacolato)diboron (0.914 g, 3.6 mmol), KOAc (0.883 g, 9.0 mmol) and dry DMF (20 mL) was purged with nitrogen. PdCl2(dppf)2 was added to the reaction and purged again with nitrogen. The solution was heated at 80° C. for 2 h. Once TLC showed the disappearance of (I), the solution was cooled to r.t. To this solution was added K3PO4 (0.955 g, 4.5 mmol), 5-bromo-N-(cyclopropylmethyl)nicotinamide (XVII) (0.765 g, 3.0 mmol), Pd(PPh3)4 (104 mg, 0.09 mmol) and water (2 mL). The solution was purged with nitrogen and heated at 90° C. for 3 h. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water and brine, dried over MgSO4 and then evaporated under vacuum. The crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give N-(cyclopropylmethyl)-5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXI) as a yellow solid (1.09 g, 2.7 mmol, 90% yield). 1H NMR (DMSO-d6) δ ppm 0.20-0.31 (m, 2H), 0.35-0.57 (m, 2H), 1.65 (m, 2H), 1.74-1.87 (m, 1H), 2.10 (d, J=12.06 Hz, 2H), 2.35-2.44 (m, 1H), 3.10-3.27 (m, 3H), 3.78-3.99 (m, 2H), 6.14 (d, J=7.35 Hz, 1H), 7.90-8.14 (m, 2H), 8.50 (d, J=12.5, 2H), 9.05 (dd, J=14.60, 1.98 Hz, 2H), 10.25 (s, 1H); ESIMS found C23H24N4O3 m/z 405 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[H][H]>[Pd].CO>[F:11][C:8]([F:9])([F:10])[C:7]1[CH:6]=[C:5]([NH2:12])[CH:4]=[N:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cncc(C(F)(F)F)c1

Procedure:
A mixture of 2-chloro-5-nitro-3-trifluoromethyl-pyridine (30 mg, 0.13 mmol), 10% Pd/C (3 mg, 10% w/w), and MeOH (5 mL) is stirred under 1 atm of hydrogen for 3 h. The mixture is then filtered over Celite® and concentrated in vacuo to give the title compound as an oil. MS (ESI) m/z 162.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:19](O)=[O:20])=[CH:4][CH:3]=1.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:19]([NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:27]=2)=[O:20])=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: Cc1ccc(-c2[nH]c(-c3ccccc3)nc2C(=O)O)cc1
Product: Cc1ccc(-c2[nH]c(-c3ccccc3)nc2C(=O)Nc2nc(-c3ccccc3)cs2)cc1
Yield: 7.7 %

Procedure:
5-(4-Methylphenyl)-2-phenylimidazole-4-carboxylic acid (0.5 g) and 2-amino-4-phenylthiazole (0.55 g) were reacted and treated in the same manner as in Example 1 to give 5-(4-methylphenyl)-2-phenyl-N-(4-phenylthiazol-2-yl)imidazole-4-carboxamide (0.06 g), melting point 274-276° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([O:34]C)=[O:33])[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2([C:32]([OH:34])=[O:33])[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:24][O:25][C:26]([CH3:29])([CH3:30])[O:27][CH2:28]3)=[O:22])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylic acid was prepared following the procedure of Example 40 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylate (335 mg, 0.66 mmol) in 4 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.3 ml, 1.3 mmol) to obtain 315 mg (97%) of the acid. HR-MS: m/z Calculated for C24H31NO8S 494.1843; Found 494.1835.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH3:6][C:7]1[S:8][C:9]([Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(-c2ccccc2)cs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sc(C)nc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
Add n-butyllithium (0.46 mL, 0.74 mmol, 1.6 M in tetrahydrofuran) to a solution of 2-methyl-4-phenylthiazole (0.13 g, 0.74 mmol) in tetrahydrofuran (7 mL) cooled to −78° C. under a nitrogen atmosphere. Stir at −78° C. for 45 minutes, add tributyltin chloride (0.2 mL, 0.74 mmol), and stir for 2 hours as the reaction mixture warms to room temperature. Add aqueous ammonium chloride and then partition the mixture between ethyl acetate and water. Extract the aqueous phase with ethyl acetate. Wash the combined organic layers sequentially with water and saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with hexane containing 10% ethyl acetate to provide the desired compound in 68% yield. MS(ES+): m/z=466.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:49][C@@H:50]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:73])([F:72])[F:71])[CH2:51][N:52]1[C:60](=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53]1=[O:62]>C(Cl)Cl>[O:61]=[C:60]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:62])[N:52]1[CH2:51][C@@H:50]([NH:49][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[CH:8][CH:9]=1)=[O:14])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:72])([F:71])[F:73]
Reactant: Cn1nccc1-c1ccc(C(=O)O)s1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)s1
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (100 mg, 0.48 mmol), PyBrOP (270 mg, 0.58 mmol) and diisopropylethyl amine (420 μL, 2.4 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (168 mg, 0.48 mmol)[from Preparation 6]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (74 mg, 28%) as a white solid: LC-MS (ES) m/z=539 (M+H)+.