Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15](CCC3C=C(C=CC=3)N)[CH2:14][CH2:13]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35]([C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=1)=[O:36]>CN(C=O)C.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:34][C:35]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:46])[CH3:45])[CH:40]=[CH:41][CH:42]=3)=[O:36])[CH2:14][CH2:13]2)[N:3]=1
Reactant: CC(=O)Nc1cccc(C(=O)CCl)c1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cccc(C(=O)CN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Reaction time: 1.5 h
Yield: 42 %

Procedure:
To a stirred solution of 2-methyl-5-(1-piperazinyl)quinoline (D6, 0.14 g, 1 eq) in dry DMF (5 mL) were added potassium carbonate (0.11 g, 1.2 eq) and a solution of N-[3-(2-chloroacetyl)phenyl]acetamide (J. Chem. Soc., 1949, 552, 553, 0.17 g, 1.2 eq) in DMF (3 mL) under an inert atmosphere. The reaction was stirred for 1.5 hrs. The mixture was diluted with water (8 mL) and extracted with DCM (3×15 mL). The organic phase was washed with brine (25 mL), dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified on SPE cartridge (Silica) using as eluant DCM-methanol (95:5), affording the title compound in 42% yield (0.104 g).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[N:17]=[CH:18][C:19]([C:22]([O:24]C)=[O:23])=[N:20][CH:21]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].[ClH:30]>CC(C)=O>[ClH:30].[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[N:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[N:20][CH:21]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1cnc(OC2CCN(c3ccc(C(F)(F)F)cc3)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)c1cnc(OC2CCN(c3ccc(C(F)(F)F)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of methyl 5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxylate (0.10 g, 0.26 mmol) and 2N aqueous sodium hydroxide (0.4 mL) in acetone (2 mL) was stirred at room temperature for 0.5 h. The reaction mixture was acidified by concentrated hydrochloric acid and concentrated under reduced pressure to afford 5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxylic acid hydrochloric acid salt as an off-white solid (0.10 g, 96%) which was used next step without further purifications. MS (ESI): 368.4 (M+1).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:16]=2)[CH:11]=[N:10]1>CN(C=O)C>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C@H:18]3[C@@:19]4([C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][C:20]4=[O:28])[CH2:2]3)[CH:16]=2)[CH:11]=[N:10]1
Reactant: C[S+](C)(C)=O
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
To a solution of trimethylsulfoxonium iodide (264 mg, 1.2 mmol) in anhydrous DMF (40 mL) was added sodium hydride (60% dispersion in oil) (140 mg, 3.48 mmol) at 0° C. The mixture was stirred for 15 min after which time (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one (151 mg, 0.58 mmol) was added. The solution was stirred overnight at rt. The reaction was quenched with sat. NH4Cl solution (10 mL), extracted with EtOAc (4×50 mL), dried over MgSO4 and concentrated to dryness. The major diastereomer was isolated by silica gel chromatography (EtOAc/Hex 1:1) as a beige solid (44 mg, 28%). 1H NMR (400 MHz, d6-DMSO) δ 13.01 (s, 1H), 10.61 (d, 1H J=8.3 Hz), 8.01 (s, 1H), 7.63 (d, 1H, J=8.3 Hz), 7.44 (s, 1H), 6.99 (t, 1H, J=7.5 Hz), 6.92 (d, 1H, J=8.0 Hz), 6.84 (d, 1H, J=8.0 Hz), 6.51 (t, 1H, J=7.0 Hz), 5.98 (d, 1H, 8.0 Hz), 3.20-3.17 (m, 1H), 2.30-2.26 (m, 1H), 2.00-1.95 (m, 1H); MS ESI 276.1 [M+H]+, calcd for [C17H13N3O+H]+ 276.3.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][O:10][CH:11]=2)=[CH:6][CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2cocn2)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(-c2cocn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
4-Phenyloxazole (1 g, 6.89 mmol) was dissolved in concentrated sulfuric acid (5 mL) at 0° C. A cold solution of nitrating mixture (prepared by adding 3 mL conc. nitric acid to 5 mL of ice-cold conc. sulfuric acid) was added over 10 minutes. The mixture was allowed to warm to r.t. and stirred for 1 h. The resulting solution was poured into ice-cold water giving a white precipitate, which was filtered and washed thoroughly with water. The solid was dissolved in DCM and washed with water then brine. The organic phase was dried over sodium sulfate and concentrated to yield 4-(4-nitro-phenyl)-oxazole (550 mg, 42%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:44][CH2:43][CH2:42][C@H:18]4[S:19](=[O:41])(=[O:40])[C:20]([CH3:39])([CH3:38])[C:21]([N:23](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:22][C@:17]4([CH3:45])[C:15]=3[CH:16]=2)=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:53][C:54]#[N:55].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O.O.CN(C=O)C>[NH2:23][C:21]1[C:20]([CH3:39])([CH3:38])[S:19](=[O:40])(=[O:41])[C@@H:18]2[CH2:42][CH2:43][O:44][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:5]4[CH:4]=[CH:3][C:2]([O:1][CH2:53][C:54]#[N:55])=[CH:7][N:6]=4)=[CH:16][C:15]=3[C@@:17]2([CH3:45])[N:22]=1
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(NC(=O)c4ccc(O)cn4)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(N)=N[C@]2(C)c3cc(NC(=O)c4ccc(OCC#N)cn4)ccc3OCC[C@H]2S1(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A vial was charged with tert-butyl N-[(4aR,11bR)-10-[(5-hydroxypyridine-2-carbonyl)amino]-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (150 mg, 0.233 mmol), cesium carbonate (152 mg, 0.465 mmol) and DMF (1163 μl). To this slurry was added 2-bromoacetonitrile (19.81 μl, 0.244 mmol), and the reaction was stirred at RT for 3 h. Water and EtOAc were added and the layers were separated. The organic portion was dried, filtered and concentrated. The crude material was dissolved in 1 mL DCM, and TFA (358 μl, 4.65 mmol) was added and the reaction was stirred for 1 h. EtOAc and saturated NaHCO3 were added, and the layers were separated. The organic portion was dried, filtered and concentrated. The crude product was purified by silica gel chromatography, using a gradient 0-50% 90/10 DCM/MeOH in DCM. The product was further purified by reverse phase chromatography on the Isolera using 0-75% 0.1% TFA/ACN in water solvent system followed by isolation using an SCX column to give N-((4aR,11bR)-2-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-(cyanomethoxy)picolinamide. MS m/z=484.1 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH2:28][CH2:29][CH2:30]Br>>[N:1]1([C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: BrCCCBr
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCC1

Procedure:
The title compound, light yellow solid, MS: m/e=425.2 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1,3-dibromopropane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:33])[CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:33])[CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(N)cc1C
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: COC(=O)c1ccc(NC(=O)C(C)n2ccc(-c3cc(Cl)ccc3C#N)cc2=O)cc1C

Procedure:
120 mg (0.39 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of methyl 4-amino-2-methylbenzoate were reacted according to General Method 5A. Following aqueous work-up, the desired product was precipitated using a mixture of a little water, acetonitrile and DMF. Yield: 120 mg (69% of theory)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:25])=[C:11]([CH:22]=[CH:23][CH:24]=1)[CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][C@@H:20]2[C@@H:18]([CH2:19]2)[NH:17]1)=[O:15].[C:26]([C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([CH2:38][C:39](O)=[O:40])[CH:30]=1)(=[O:28])[NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:25])=[C:11]([CH:22]=[CH:23][CH:24]=1)[CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][C@@H:20]2[C@@H:18]([CH2:19]2)[N:17]1[C:39](=[O:40])[CH2:38][N:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([C:26]([NH2:27])=[O:28])=[CH:30]1)=[O:15]
Reactant: NC(=O)c1cn(CC(=O)O)c2ccccc12
Reactant: O=C(NCc1cccc(Cl)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The mixture of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate (70.2 mg, 0.183 mmol), (3-carbamoyl-indol-1-yl)acetic acid [1016689-54-5] (40.0 mg, 0.183 mmol), HBTU (104 mg, 0.275 mmol) and DIPEA (0.128 mL, 0.733 mmol) in CH2Cl2 (8 mL) was stirred at RT over 60 h. The reaction mixture was then diluted with CH2Cl2, and the solution was washed twice with 0.1N HCl. The precipitate formed in the aqueous layer was filtered off, washed with CH2Cl2 and dried in vacuo to afford the title product as a white solid. MS (LC/MS): 469 [M+H]+, 491 [M+Na]+; tR (HPLC conditions b): 3.56 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To DMF (80 mL) solution of the compound obtained in Example 137 (5,7 g) was added potassium carbonate (3.6 g) and iodomethane (1.6 mL) at 0° C., and the mixture was stirred for 17 hours at room temperature. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and thereafter the residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1), to give the captioned compound (4.8 g, 81%) as an oily product.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>>[F:25][C:26]1[N:27]=[CH:28][C:29]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)=[CH:14][CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:30][C:31]=1[CH3:32]
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: Cc1cc(B(O)O)cnc1F
Product: Cc1cc(-c2ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nn23)cnc1F

Procedure:
[7-(6-Fluoro-5-methyl-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine and 2-fluoro-3-methylpyridine-5-boronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (66 mg, 56%). m.p.=210° C.; LCMS (m/e) 418 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 8.61-8.53 (m, 2H), 7.52-7.45 (m, 2H), 6.99-6.92 (m, 3H), 6.82 (d, 1H, J=4.8 Hz), 6.66 (bs, 1H), 3.22-3.16 (m, 4H), 2.63-2.57 (m, 4H), 2.37 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]([S:15]([N:1]([C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])[S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1noc(N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
5-Amino-4-bromo-3-methylisoxazole (0.179 g, 1.0 mmol) was dissolved in dry pyridine (2 ml). 4-Biphenylsulfonyl chloride (0.509 g, 2.2 mmol) was added with stirring at ambient temperature. N,N-dimethylaminopyridine (5 mg) was added, and stirring was continued at 50° C. for 16 h. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (2×50 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography using 8:2, hexanes/ethyl acetate, to give 0.390 g (60% yield) of N-(4-biphenylsulfonyl)-N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[CH2:13]([N:15]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:16]1)[CH3:14]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:20]([C:19]3[N:15]([CH2:13][CH3:14])[N:16]=[C:17]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH:18]=3)=[O:21])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(=O)c1c[nH]c2ncc(Cl)cc12
Reaction time: 0.83 h
Yield: 2.1 %

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine (532, 0.068 g, 0.44 mmol) was combined with methanol (10 mL) and potassium hydroxide (0.16 g, 2.8 mmol). The: mixture was stirred for 50 minutes, then 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.100 g, 0.40 mmol, prepared as described in Example 47, Scheme 162, Step 5) was added and the reaction was stirred overnight at room temperature and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexanes provided the desired compound (0.0033 g, 2%). MS (ESI) [M+H+]+=398.1.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Temperature: 70 °C
Yield: 88.8 %

Procedure:
Using General Procedure D; dibenzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 125, 45.0 mg, 0.11 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.35 g, 3.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5 d. The title compound 40 mg (88%) was isolated by chromatography (hexanes).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]1[CH2:16][O:15]C(C)(C)[O:13]1)=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[C:5]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[Cl:28])=[C:6]([CH:19]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]([OH:13])[CH2:16][OH:15])=[O:8]
Reactant: CC1(C)OCC(CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(NOCC(O)CO)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl

Procedure:
To a stirring solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide (3.7 g, 6.45 mmol) in methanol (20 mL) and water (2 mL) was added p-toluenesulfonic acid (0.12 g, 0.65 mmol). After 20 hours the reaction was concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated NaHCO3 solution and twice with saturated brine solution. The organic layers were collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by crystallization with methanol/water and the solids were dried in a vacuum oven at 40° C. to afford 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-(2,3-dihydroxy-propoxy)-3,4-difluoro-benzamide: m.p.=152-154° C.; 1NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.83 (s, 1H), 7.76 (s, 1H), 7.66 (d, 1H, J=6.8), 7.47 (d, 1H, J=8.5), 6.68 (t, 1H, J=6.6), 4.83 (bs, 1H), 4.60 (bs, 1H), 3.89-3.92 (m, 1H), 3.68-3.76 (m, 2H), 3.30 (2H, partially hidden by HDO); MS(APCI+)=533.0/535.0; Anal.calcd/found for C16H13Cl2F2IN2O4: C, 36.05/36.23; H, 2.46/2.40; N, 5.25/5.03; F, 7.13/7.14.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][O:27][C:28]1[CH:48]=[CH:47][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[CH:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=3)[CH2:35][CH2:34]2)=[CH:30][CH:29]=1>C(Cl)Cl.CO>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[CH:41]=[CH:42][C:43]([NH:46][C:23]([C:20]4[CH:21]=[CH:22][C:13]([C:3]5[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=5[Cl:1])=[C:14]5[C:19]=4[N:18]=[CH:17][CH:16]=[CH:15]5)=[O:25])=[N:44][CH:45]=3)[CH2:35][CH2:34]2)=[CH:47][CH:48]=1
Reactant: COc1ccc(CN2CCN(Cc3ccc(N)nc3)CC2)cc1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)nc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-ylamine (Step 105.1) and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 672.0 [M+H]+; TLC: Rf=0.25 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:18][C:19](=[O:36])[C@@H:20]([CH2:28][S:29]([C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([OH:17])=O)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41].ON1C(=O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:32]([S:29]([CH2:28][C@@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]([NH:18][C@@H:14]([CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=1)[C:15]([NH:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41])=[O:17])=[O:36])(=[O:31])=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1
Yield: 151.3 %

Procedure:
A mixture of 1.98 g (3.06 mmol) of (S)-1-(tert-butoxycarbonyl)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionic acid, 0.58 g (2.55 mmol) of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol, 0.5 g (3.06 mmol) of 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, 0.42 ml (3.07 mmol) of triethylamine and 1.16 g. (3.06 mmol) of HBTU in 30 ml of dimethylformamide is stirred at room temperature under argon for 2 hours. Subsequently, the dimethylformamide is evaporated in a high vacuum and the residue is taken up in 60 ml of ethyl acetate. The ethyl acetate solution is extracted with 30 ml of cold 2N sodium bicarbonate solution and the aqueous phase is back-extracted twice with 60 ml of ethyl acetate. The combined organic phases are washed in sequence with 30 ml of cold, saturated ammonium chloride solution, 30 ml of cold 2N sodium bicarbonate solution and 30 ml of saturated sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated under reduced pressure. There are obtained 2.82 g of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-Boc-imidazole-4-propionamide as a pale yellow foam.