Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[C:21]([C:28]3[NH:36][C:35]4[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=4[CH:29]=3)[CH:22]=[CH:23][CH:24]=2)[N:19]=1>C1COCC1>[O:37]=[C:31]1[C:30]2[CH:29]=[C:28]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[N:19]=[C:18]([O:1][C@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[CH:27]=[CH:26]4)[NH:36][C:35]=2[CH2:34][CH2:33][NH:32]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-tert-Butyl 3-hydroxypiperidine-1-carboxylate (Astatech Inc., Bristol, Pa.; 406 mg, 2.02 mmol) was added to a suspension of NaH (81 mg, 2.02 mmol) in THF (2.5 mL) and the resulting suspension was stirred at RT for 10 min. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 75 mg, 0.25 mmol) was then added and the resulting suspension was stirred at RT for 5 min, then heated at 70° C. for 1.25 h. The mixture was cooled to RT and partitioned between EtOAc (60 mL) and saturated aq. NH4Cl (20 mL). The organic layer was separated, sequentially washed with water (20 mL) then brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give (S)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate as a light yellow solid: m/z (ESI, +ve ion) 463.1 (M+H)+. The material was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: OCCC1CCNCC1
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CCO)CC1)c1cccc(Cl)c1
Temperature: 180 °C
Yield: 99.9 %

Procedure:
A mixture of 1.06 g (5.00 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide and 0.646 g (5.00 mmol) of 4-piperidine ethanol in acetonitrile (25 mL) is heated in a microwave reactor at 180° C. for 4 hours. Upon standing at room temperature a solid precipitates from solution. The solid is collected by filtration, washed with cold acetonitrile, and dried on the filter pad to provide 1.97 g (76%) of 3-chloro-N-[5′-chloro-4-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide as a clear solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([O:17][CH3:18])[CH:11]=1.[C:19](Cl)(Cl)=[O:20]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=2[N:1]=[C:19]=[O:20])=[CH:11][C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2ccc(C#N)cc2N)ccc1Br
Reactant: O=C(Cl)Cl
Product: COc1cc(-c2ccc(C#N)cc2N=C=O)ccc1Br
Yield: 100 %

Procedure:
To the product from Step 2 (363 mg, 1.2 mmol) was added phosgene (20% solution in PhMe, 5.9 g, 11.97 mmol), and the mixture was heated to reflux for 2 hours. The solvent was then removed in vacuo to give crude 4′-bromo-2-isocyanato-3′-methoxybiphenyl-4-carbonitrile (394 mg, 1.2 mmol), which was then taken up in chlorobenzene (4 mL). To this mixture, AlCl3 (319 mg, 2.4 mmol) was added at RT. 1 N HCl (30 mL) was then added, which caused a grey precipitate to form. This was isolated by filtration and washed with DCM and MeOH to give the title compound. LRMS (M+H)+=329.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:27]4[C:22](=[N:23][C:24]([NH:28]CC5C=CC(OC)=CC=5)=[CH:25][CH:26]=4)[NH:21][N:20]=3)[CH:14]=[CH:13][C:12]=2[Cl:38])[CH:9]=1)[C:5]#[N:6].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>>[NH2:28][C:24]1[N:23]=[C:22]2[NH:21][N:20]=[C:19]([CH2:18][O:17][C:15]3[CH:14]=[CH:13][C:12]([Cl:38])=[C:11]([CH:16]=3)[O:10][C:8]3[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=3)[C:5]#[N:6])[C:27]2=[CH:26][CH:25]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: COc1ccc(CNc2ccc3c(COc4ccc(Cl)c(Oc5cc(Cl)cc(C#N)c5)c4)n[nH]c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2cc(OCc3n[nH]c4nc(N)ccc34)ccc2Cl)c1
Temperature: 60 °C

Procedure:
3-chloro-5-[2-chloro-5-({6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridin-3-yl}methoxy)phenoxy]benzonitrile (37-8) was dissolved in 6 mL of TFA and heated to 60° C. for 7 hours until reaction was complete as determined by LC/MS analysis. After removal of all volatile material the crude residue was purified via prep HPLC (20%-70% acetonitrile in H2O: C18 Phenomenex Gemini) and lyophilzed from dioxane to yield the title compound in the form of a TFA salt. H1 NMR (CD3OD): 5.40 (s 2H), 6.58 (d, 1H), 6.96 (d, 1H), 7.04 (d, 1H), 7.16 (s, 1H), 7.18 (s, 1H), 7.58 (d, 1H), 7.52 (s, 1H), 8.10 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][C:25]4[CH:30]=CC([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:44]([C:47]1[N:48]=C(CO)[O:50][CH:51]=1)(=[O:46])[NH2:45]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][CH2:25][C:30]4[O:50][CH:51]=[C:47]([C:44](=[O:46])[NH2:45])[N:48]=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1coc(CO)n1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1coc(COC(=O)NCCC2CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)n1
Yield: 64.2 %

Procedure:
The process is performed according to the procedure described in Example 4. Starting with 0.25 g (0.54 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylcarbamate, described in Example 1 (step 1.5.), 0.139 g (1.08 mmol) of N,N-diisopropylethylamine, 0.033 g (0.27 mmol) of N,N-dimethylaminopyridine and 0.084 g (0.59 mmol) of 4-carbamoyloxazol-2-ylmethanol, prepared in step 5.2., 0.162 g of pure product is obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[OH-:28].[K+]>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:28]
Reactant: [OH-]
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1C#N
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1C(N)=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
To a solution of 5-chloro-2-[8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl]benzonitrile (55.0 mg, 0.138 mmol) in tert-butyl alcohol (1.5 mL) was added potassium hydroxide (30.9 mg, 0.551 mmol). The reaction mixture was stirred at 80° C. for 15 min. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-60% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from methanol to give the title compound as a colorless powder (24.6 mg, 0.0872 mmol, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N:15]([C:24](=[O:36])[NH:25][C:26](=O)[C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=1[F:34])[NH:16]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N:15]1[C:24](=[O:36])[NH:25][C:26]([C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[N:16]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)NC(=O)c1ccc(I)cc1F)c1cc(CNC(=O)C2CC2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.2 %

Procedure:
To a solution of tert-butyl 2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)-2-((2-fluoro-4-iodobenzoyl)carbamoyl)hydrazinecarboxylate (0.200 g, 0.31 mmol) in DCM (10 mL) was added trifluoro acetic acid (1.0 mL). The reaction mass was stirred at RT for 12 h and refluxed for 15 h. The reaction mass was cooled to RT, basified with NaHCO3 (pH=8), extracted with DCM and concentrated to afford 0.110 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (m, 4H), 1.59 (m, 1H), 4.32 (d, J=5.7 Hz, 2H), 7.38 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.51-7.63 (m, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.88 (d, J=10.2 Hz, 1H), 8.68 (m, 1H), 12.43 (br s, 1H); MS (m/z): 513.01 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:13]1[CH:18]=[C:17]([O:19][C@H:20]([CH3:42])[CH2:21][O:22][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=[C:15]([S:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=2[F:52])[N:14]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(C2C=CN=CC=2)(=O)=O)C=C(O[C@H](C)CO)N=1>>[C:1]([C:3]1[O:7][C:6]([S:8]([NH:11][C:13]2[CH:18]=[C:17]([O:19][C@H:20]([CH3:42])[CH2:21][O:22][C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:16]=[C:15]([S:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[F:52])[N:14]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(N)(=O)=O)o1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccncc2)nc(SCc2cccc(F)c2F)n1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C#N)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared from 5-cyanofuran-2-sulfonamide (the product of step i) (0.29 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-pyrimidine (the product of Example 13, step (0.15 g) according to the procedure outlined in Example 1, step iv). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:4 to 2:3 gradient) to give the subtitle compound as a pale yellow solid. Yield: 0.25 g
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][C:18]=1[CH:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:33].CN(C1C=CC=CN=1)C.CCOCC>CN(C=O)C>[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][C:18]=1/[CH:23]=[C:24]1\[C:25](=[O:33])[N:26]([C:13](=[O:15])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:27]2[C:32]\1=[CH:31][CH:30]=[CH:29][CH:28]=2
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)CNC(=O)OCc3ccccc3)c3ccccc32)[nH]1
Temperature: 55 °C

Procedure:
A mixture of N-(benzyloxycarbonyl)glycine (4.9 g, 23 mmol), 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one (2.38 g, 10 mmol), dimethylaminopyridine (1.28 g, 10 mmol) in DMF (20 mL) was heated at 55° C. for 2 h. The solution was cooled, ether (10 mL) was added and the precipitate of the title compound was filtered off and dried to give 2.35 g, mp 193–196° C. HPLC Rt 7.04 min. 1H NMR (CDCl3) δ 2.34 (s, 3H), 2.42 (s, 3H), 4.87 (d, 2H), 5.18 (s, 2H), 5.74 (t, 1H), 6.06 (d, 1H), 7.2 (m, 3H), 7.3–7.65 (m, 7H), 7.49 (m, 1H), and 8.23 (m, 1H). Anal Calcd for C25H23N3O: C, 69.92; H, 5.40; N, 9.78. Found: C, 69.91; H, 5.50; N, 9.86.
Reaction SMILES: CN1C(C)=[C:9]2[C:4]([N:5]([CH3:15])[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])=N1.Br[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:28]([F:38])[CH:27]=2)[N:25]=1)=[O:19].[H-].[Na+]>CN(C=O)C>[CH3:35][C:34]([CH3:37])([CH3:36])[CH2:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:25]=[C:21]([NH:20][C:18](=[O:19])[CH2:17][N:25]3[C:9]4[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=4[CH:23]=[C:24]3[CH3:26])[S:22][CH:23]=2)=[CH:27][C:28]=1[F:38]
Reactant: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Reactant: CC(C)(C)COc1ccc(-c2csc(NC(=O)CBr)n2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c(=O)n(C)c(=O)n2C)n1CC(=O)Nc1nc(-c2ccc(OCC(C)(C)C)c(F)c2)cs1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 2 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[4-(2,2-dimethylpropoxy)-3-fluorophenyl]-1,3-thiazol-2-yl}acetamide (124 mg, 0.310 mmol) in the presence of NaH (15 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 55 mg of the product as a white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz) 1.06 (s, 9H), 2.26 (s, 3H), 3.17 (s, 3H), 3.36 (s, 3H), 3.75 (s, 2H), 5.32 (s, 2H), 6.07 (s, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.65-7.75 (m, 2H), 12.77 (br s, 1H, exchangeable with D2O); APCI-MS (m/z) 514.16 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5](OS(C(F)(F)F)(=O)=O)[N:6]=[CH:7]2.CC1(C)C(C)(C)OB([C:29]2[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)[N:6]=[CH:7]2
Reactant: CC1(C)OB(c2cccnc2N)OC1(C)C
Reactant: O=S(=O)(Oc1cc2c(Cl)ccc(F)c2cn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncccc1-c1cc2c(Cl)ccc(F)c2cn1
Temperature: 100 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 5-chloro-8-fluoroisoquinolin-3-yl ester (9.00 g, 27.4 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (8.42 g, 38.3 mmol), Pd(PPh3)4 (0.63 g, 2 mol %), and Cs2CO3 (20.5 g, 62.9 mmol) in dioxane/H2O (4:1, 300 mL) were heated under nitrogen at 100° C. for 16 h. Solvents were evaporated in vacuo, water (100 mL) was added to the residue, and the mixture was extracted with EtOAc (3×75 mL). The EtOAc extract was dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. It was purified by column chromatography on silica gel using EtOAc/Hexanes (1:3) to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=6.87 (brs, 2H), 6.81 (dd, J=8.7, 4.8 Hz, 1H), 7.18 (dd, J=9.3, 9.0 Hz, 1H), 7.22 (dd, J=8.1, 4.2 Hz, 1H), 7.99 (dd, J=7.5, 2.1 Hz, 1H), 8.15 (dd, J=6.8, 1.8 Hz, 1H), 8.13 (t, J=1.2 Hz, 1H), 9.56 (d, J=1.2 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:20]=[N:19][C:5]2[NH:6][CH2:7][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1>O1CCOCC1.O.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]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:38]4[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:30]5[O:29][C:28]([C:25]6[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=6)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:31]=5[CH:37]=4)[CH:20]=[N:19][C:5]=3[NH:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C1c2cc(Br)cnc2NCN1Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4c(c3)C(=O)N(Cc3ccc(F)cc3)CN4)cc12
Temperature: 100 °C
Yield: 42.2 %

Procedure:
To a solution of 6-bromo-3-(4-fluorobenzyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (110 mg, 0.33 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (150 mg, 0.30 mmol) and K3PO4.3H2O (159 mg, 0.60 mmol) in dioxane/water (2 mL/0.2 mL) was added Pd(dppf)Cl2 (10 mg) under nitrogen. The mixture was heated at 100° C. for 5 h, and after being concentrated in vacuo, the residue was suspended in water. The suspension was extracted with EtOAc and the organic phase was washed with brine and dried over sodium sulfate. Finally, 5-(3-(4-fluorobenzyl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, yield: 42%) was obtained by the prep-HPLC. 1H-NMR (CDCl3, 400 MHz) δ 8.27˜9.00 (m, 2H), 7.93˜7.96 (m, 2H), 7.80 (s, 1H), 7.64 (s, 1H), 7.33˜7.36 (m, 2H), 7.20 (t, J=8.8 Hz, 2H), 7.05 (t, J=8.4 Hz, 2H), 5.85 (br s, 1H), 5.26 (br s, 1H), 4.72 (s, 4H), 3.19 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.87 (s, 3H). MS (M+H)+: 632.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:24])[CH3:25])[NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.9 %

Procedure:
A stirred solution of 1.29 g of the ester from Example 20 (step A) in 3.5 ml of methylene chloride was treated with 3.5 ml of trifluoroacetic acid and the solution stirred 2.5 hours at ambient temperature. The solution was then concentrated under a stream of nitrogen and the residue dissolved in methylene chloride/diethyl ether. The solution was washed 2 times with saturated aqueous sodium carbonate solution and the organic phase was then dried with sodium sulfate and filtered. Concentration under vacuum provided 919 mg of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].C1CCC(N=C=NC2CCCCC2)CC1.[C:31](=S)=[S:32]>C(OCC)C>[F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:12]=[C:31]=[S:32])=[CH:9][CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: NCc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: FC(F)(F)C(F)(F)c1ccc(CN=C=S)cc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
4.7 g of 4-pentafluoroethylbenzylamine was added dropwise to a mixture of 4.8 g of DCC, 20 ml of carbon disulfide and 50 ml of diethyl ether with stirring at -10° C. The temperature of the mixture was returned to room temperature, and it was left to stand for 12 hours.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(Cc3ccccc3)C2)cc1
Solvent: CCO
Product: c1ccc(CN2CC[C@H](N3CCCC3)C2)cc1
Temperature: 140 °C
Reaction time: 20 h
Yield: 69.8 %

Procedure:
2.00 g of (R)-1-benzyl-3-(p-toluenesulfonyloxy)pyrrolidine (J. Med. Chem., 1992, 35, 4205-4208) was dissolved in 12 ml of ethanol, 1.63 g of pyrrolidine was added, and then the mixture was stirred at 140° C. for 20 hours in a sealed tube. The reaction solution was concentrated under reduced pressure, mixed with water, followed by extraction with ethyl acetate, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.97 g of the objective compound as a brown oily product.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:24])=[O:11])[CH2:2]1.F[C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[S:16][C:12]([C:10]([NH:9][CH2:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][N:1]([C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([O:30][CH3:31])=[O:29])[CH2:2]3)=[O:11])=[C:13]([CH3:24])[N:14]=2)=[CH:18][CH:19]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCCNC1
Reactant: COC(=O)c1ccccc1F
Product: COC(=O)c1ccccc1N1CCCCC(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2C)C1
Yield: 19.2 %

Procedure:
Using N-(perhydroazepin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (200 mg, 0.550 mmol) and methyl 2-fluorobenzoate (0.140 mL, 1.10 mmol), the same procedure was followed as in Step 9c of Example 9 to give 52.7 mg (19%) of the desired compound as a colorless oil.