Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]([N:8]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](Cl)=[O:17])[C:11]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:10]1=2)(=[O:7])[CH3:6]>ClCCl>[CH:1]([NH:4][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:9]([N:8]([C:5](=[O:7])[CH3:6])[CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:26]=2)[C:10]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:11]1=2)=[O:17])([CH3:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)Cl)c2cc(Cl)ccc21
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)NC(C)C)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 86 %

Procedure:
Add isopropyl amine (0.3 mmol) to a dichloromethane solution of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl chloride (0.050 g, 0.11 mmol) at room temperature under nitrogen. After stirring for 1 h remove solvent under vacuum and chromatograph the crude product over silica gel using ethyl acetate/hexane (30-40%) to elute. This provides the title compound (0.052 g, 87%) as a colorless solid: MS (ES+): 550 (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N+:13]([O-])([OH:15])=[O:14].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]([F:11])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1cccc([N+](=O)[O-])c1)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
20.0 g (114.9 mmol) of 2,2,2-trifluoroacetophenone were initially charged in 80 ml of conc. sulphuric acid, and the mixture was cooled to −10° C. A solution, prepared beforehand at −10° C., of 4.8 ml (114.8 mmol) of nitric acid in 20 ml of conc. sulphuric acid was added dropwise to this mixture such that the reaction temperature did not exceed −5° C. After the addition had ended, the reaction mixture was stirred between −10° C. and 0° C. for 1 h and then added carefully to ice-water. By addition of 50% strength aqueous sodium hydroxide solution, the pH of the mixture was adjusted to about 9-10. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase initially cyclohexane/dichloromethane 2:1 to 1:1, finally pure dichloromethane). This gave 19.2 g of the target product (76.2% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9][N:8]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1n[nH]c2ncc(Br)cc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To a solution of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (2.92 Kg, 11.4 mol) in anhydrous DCM (88 L) was added TEA (2.38 L, 17.1 mol). The solution was cooled to 0° C. before adding dropwise a solution of TrCl (4.0 Kg, 14.3 mol) in anhydrous DCM (51 L). The solution was warmed to room temperature and stirred for 20 hours. The reaction was then washed once with water (29 L), once with aqueous 25% NaCl (29 L), dried over Na2SO4 and concentrated to a volume of 3.0 L to give methyl 5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XXII) (5.69 Kg, 11.4 mol, 77.3% purity, 99.5% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 3.91 (s, 3H), 7.19 (d, J=8.4 Hz, 5H), 7.21-7.32 (m, 10H), 8.45 (d, J=2.4 Hz, 1H), 8.61 (d, J=2 Hz, 1H); ESIMS found C27H20BrN3O2 m/z 520.0 (M+Na).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[CH:15]([C:21]([O:23][CH3:24])=[O:22])[C:16]([CH3:20])(Br)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+]>C(#N)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:25](=[O:26])[N:14]2[C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([CH3:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C1=C(C)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Yield: 23.3 %

Procedure:
A mixture of methyl 7-(2-phenoxyacetamido)-3-methyl-3-bromocepham-4-carboxylate (210 mg.) in acetonitrile (5 cc) and anhydrous sodium acetate (100 mg.) was heated under reflux for 6.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution washed with water, dried and then concentrated. The residue was crystallized from a mixture of ether and methanol to yield crystals (40 mg.) of methyl 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 124° - 125° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][CH:4]=1.[CH2:13]([NH2:15])[CH3:14]>C1COCC1>[CH2:13]([NH:15][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[N:8]=1)[CH3:14]
Reactant: O=Cc1cccc(C(F)(F)F)n1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cccc(C(F)(F)F)n1

Procedure:
prepared by reaction of 6-trifluoromethyl-pyridin-2-carbaldehyde (Ashimori A. Chem. Pharm. Bull. 1990, 38, 9, 2446-2458) with 2M ethylamine in THF.
Reaction SMILES: NC1C=C([Cl:8])C(OC)=CC=1C(=O)C.C(C1N=C(C(Cl)=O)SC=1)(C)C.[C:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[NH:36][C:37]([C:39]1[S:40][CH:41]=[C:42]([CH:44]([CH3:46])[CH3:45])[N:43]=1)=[O:38])(=[O:27])[CH3:26]>>[C:25]([C:28]1[C:29]([NH:36][C:37]([C:39]2[S:40][CH:41]=[C:42]([CH:44]([CH3:46])[CH3:45])[N:43]=2)=[O:38])=[C:30]([Cl:8])[C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)(=[O:27])[CH3:26]
Reactant: COc1cc(C(C)=O)c(N)cc1Cl
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Agent: CC(C)c1csc(C(=O)Cl)n1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl
Yield: 69 %

Procedure:
Compound 217d was synthesized from compounds 201g and 214 as a beige solid in 69% yield, according to the procedure as described for compound 217a. MS (ESI, EI+): m/z=354 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:20][C:21]4[N:22]([C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34](=[O:36])[NH2:35])[CH:29]=5)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:20][C:21]4[N:22]([C:24]([C:28]5[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=5)[C:34]([NH2:35])=[O:36])=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1-c1cccc(C(N)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn2c1-c1cccc(C(N)=O)c1
Reaction time: 1 h
Yield: 22.7 %

Procedure:
210 mg Crude (1-{4-[3-(3-carbamoyl-phenyl)-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, intermediate example Int-4-0, were stirred with 15 mL 4M hydrogen chloride in dioxane over night at room temperature. The solvent was evaporated and the residue was dissolved in methanol/dichloromethane. Methyl-tert.butylether was added until the product precipitated. The reaction mixture was stirred for one hour and the precipitate was sucked off. The crystals were dissolved in methanol and given on a ForaPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH3. After evaporation of the solvents the residue was purified by HPLC to yield 39.3 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:18])[CH:3]=1.Cl.N1C2=NC=CC(OC3C=CC(N[C:37]4[N:53]=[CH:52][CH:51]=[CH:50][C:38]=4[C:39]([NH:41][C:42]4[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=4[F:49])=[O:40])=CC=3F)=C2C=C1>>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:37]3[N:53]=[CH:52][CH:51]=[CH:50][C:38]=3[C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=3[F:49])=[O:40])=[CH:3][C:4]=2[F:18])[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: O=C(Nc1ccc(F)cc1F)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Agent: Cl
Product: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Yield: 37 %

Procedure:
4-(4-Amino-2-fluorophenoxy)picolinamide (0.12 g, 0.50 mmol) was converted to the desired compound (0.088 g, 37%) in a manner similar to the preparation of 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-nicotinamide (Example 2). HRMS(ESI+), 480.1283 (M+H)+ calc, 480.1281 (M+H)+ found.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:20][C:21]1[O:25][C:24]([C:26]([NH2:33])([CH3:32])[CH2:27][CH:28]2[CH2:31][O:30][CH2:29]2)=[N:23][N:22]=1>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:33][C:26]([C:24]3[O:25][C:21]([CH3:20])=[N:22][N:23]=3)([CH3:32])[CH2:27][CH:28]3[CH2:31][O:30][CH2:29]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnc(C(C)(N)CC2COC2)o1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: Cc1nnc(C(C)(CC2COC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(oxetan-3-yl)propan-2-amine (example 190c) as starting materials and isolated (36 mg, 22%); MS (ESI, m/z): 441.5 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:64]([SH:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=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].O1CCOCC1>[CH2:64]([S:71][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Br:1])=[CH:3][N:4]=[CH:5]2)=[CH:10][CH:9]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: Brc1ccc2c(Br)cncc2c1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cncc2cc(SCc3ccccc3)ccc12
Temperature: 60 °C

Procedure:
To a vial charged with 4,7-dibromoisoquinoline (Pharmabridge, Inc., Doylestown, Pa.) (0.783 g, 2.73 mmol) was added dioxane (10.91 ml), DIEA (0.953 ml, 5.46 mmol), Xantphos (0.316 g, 0.546 mmol), Pd2(dba)3 (0.250 g, 0.273 mmol) and benzyl mercaptan (0.323 ml, 2.73 mmol). The vessel was sealed and heated to 60° C. for 4 hrs affording conversion to desired product as the primary species. The mixture was dried under reduced pressure and the crude material purified with a 40 HP silicycle column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 25%, then isocratic at 25%, with 10% DCM isocratic throughout) providing product 7-(benzylthio)-4-bromoisoquinoline (0.573 g, 1.735 mmol, 63.6% yield), obtained as an orange solid. m/z (ESI) 330.2 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH:7]1C2O[CH:15]3[CH:8]1OC(=O)[CH:11]3C2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(O[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](O)[C:24]=1[CH3:30])(=O)C(C)=C>>[C:1]([O:6][CH:7]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:23][C:24]=2[CH2:30][CH2:11][CH2:15][CH2:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Oc1cccc(O)c1C
Reactant: C=C(C)C(=O)OC1C2CC3C(=O)OC1C3O2
Product: C=C(C)C(=O)OC1CCCCc2ccccc21

Procedure:
3-oxo-2,7-dioxatricyclo[4.2.1.04,8]nonan-9-yl methacrylate:PAG Monomer 1=0.30:0.30:0.30:0.10
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[N:17]=[N:16][C:15]([C:18](=[S:20])[NH2:19])=[CH:14][CH:13]=1.CO[C:28](OC)([N:30]([CH3:32])[CH3:31])[CH3:29]>C1(C)C=CC=CC=1>[CH3:31][N:30]([CH3:32])[C:28](=[N:19][C:18]([C:15]1[N:16]=[N:17][C:12]([S:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)=[CH:13][CH:14]=1)=[S:20])[CH3:29]
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=S)c1ccc(SCCCCOc2cccc(C(F)(F)F)c2)nn1
Solvent: Cc1ccccc1
Product: CC(=NC(=S)c1ccc(SCCCCOc2cccc(C(F)(F)F)c2)nn1)N(C)C
Yield: 99.8 %

Procedure:
A mixture of intermediate 12 (0.009 mol) and N,N-dimethylacetamide dimethyl acetal (0.015 mol) in toluene (100 ml) was stirred and refluxed for 3 hours. The solvent was evaporated, yielding 4.1 g (100%) of N-[1-(dimethylamino)ethylidene]-6-[[4-[3-(trifluoromethyl)phenoxy]butyl]thio]-3-pyridazinecarbothioamide (intermediate 13).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O>CCCCCC.C(OCC)(=O)C>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]([OH:38])=[O:17])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: COC(=O)CCc1ccccc1CCCCCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCc2ccccc2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 11 and starting with 0.2 g (1 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.32 g (1 mmol) of 2-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester (from example 36), 2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid was obtained in 45.6% overall yield, as a colorless solid, mp 98°-99° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])[C:22]=1[CH2:34][CH3:35])(=[O:20])=[O:19])[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[O:8][N:7]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[Cl:16][C:13]1[S:12][C:11]([C:9]2[O:8][N:7]=[C:6]([CH2:5][C@H:4]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][C:28]4=[O:33])[C:22]=3[CH2:34][CH3:35])(=[O:20])=[O:19])[C:3]([OH:36])=[O:2])[CH:10]=2)=[CH:15][CH:14]=1
Reactant: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](Cc1cc(-c2ccc(Cl)s2)on1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](Cc1cc(-c2ccc(Cl)s2)on1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 7 (1.5 g, 2.71 mmol) in THF (15 ml), MeOH (5 ml) and water (5 ml) was treated with LiOH (194 mg, 8.12 mmol) and stirred at RT overnight. The mixture was acidified with HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with MgSO4, filtered and evaporated to dryness. The crude product (1.3 g) was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Yield: 85.2 %

Procedure:
The title compound was synthesized by triturating aniline (0.5 g, 5.36 mmol), powdered sodium bicarbonate (0.9 g, 1.07 mmol) and powdered p-toluene sulfonyl chloride (1.02 g, 5.36 mmol) for 5 min at rt. The reaction mixture was stirred with water, filtered, washed with water and dried to give 16 (1.13 g, 84.9%). Product was purified by FCC by using eluent as in 15 to give 16 as white powder (0.9 g), mp-95-97° C. (lit32A 96° C.); IR(CHCl3) 3255, 1599, 1342, 1160, cm−1; 1H NMR (500 MHz, DMSOD6) δ 2.37 (s, 3H, CH3), 6.53 (br, 1H, NH), and 7.04-7.65 (m, 9H, aromatic). HRMS calcd 270.05592 (C13H13NO2S.Na+), found 270.05589.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([NH2:40])[CH:37]=[CH:36][N:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:37]=[CH:36][N:35]=1
Reactant: COc1cc(N)ccn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)ccn1
Yield: 46.5 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.4 g, 0.75 mmol) was reacted with 2-methoxy-pyridin-4-ylamine (Oakwood) (0.1 g, 0.9 mmol), HATU (0.51 g, 1.35 mmol) and iPr2NEt (0.33 mL, 1.9 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methoxy-pyridin-4-yl)-amide as a white solid (0.2 g, 47%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:24]1[C:25]2[C:32]([CH3:33])=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:15][CH2:16][N:17]([C:24]3[C:25]4[C:32]([CH3:33])=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:18][CH2:19]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(C)CCNCC2)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 100 °C
Yield: 53 %

Procedure:
3-(4-methylpiperidine-4-carboxamido)phenyl dimethylcarbamate from step B (47 mg, 0. 14 mmol) 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (23 mg, 0.138 mmol), N,N-diisopropylethylamine (54 mg, 0.41 mmol), and isopropanol (1.0 mL) were combined in a pressure rated sealed tube and heated at 100° C. for 18 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound in 53% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH2:15][C@H:14]3[C@H:11]([NH:12][CH2:13]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[C:19]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[CH2:16][CH2:15][C@H:14]3[C@H:11]([N:12]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[C:19]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:22])[CH2:13]3)[CH2:10]2)[N:5]=1
Reactant: Cc1cc(C)nc(N2CC[C@@H]3CN[C@@H]3C2)n1
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC[C@@H]3CN(C(=O)c4cccc(F)c4-c4ncccn4)[C@@H]3C2)n1
Yield: 38.2 %

Procedure:
To a mixture of (1S,6R)-3-(4,6-dimethylpyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 34, 30 mg, 0.14 mmol), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (Intermediate 35, 30 mg, 0.14 mmol), and TEA (29 μL, 0.21 mmol) in DMF (1.3 mL) was added HATU (58 mg, 0.15 mmol) After 15 h, the reaction mixture was purified using prep HPLC (agilent, basic) to give 22.4 mg (39%) of the title compound as a clear oil. MS (ESI) mass calcd. For C23H23FN6O, 418.48; m/z found 419.2 [M+H]+. 1H NMR (CDCl3): 8.89-8.57 (m, 2H), 7.50-7.32 (m, 1H), 7.28-7.04 (m, 3H), 6.37-6.23 (m, 1H), 4.76-4.50 (m, 2H), 4.15-3.45 (m, 4H), 3.25-2.73 (m, 2H), 2.43-2.24 (m, 6H), 2.20-1.69 (m, 2H).
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].[CH3:34][N:35](C=O)C>O.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].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.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[C:34]([C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14])#[N:35]
Reactant: CN(C)C=O
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(C#N)cc21
Temperature: 130 °C
Yield: 88 %

Procedure:
A suspension of (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (2.4 g, 4.63 mmol), prepared as described in Example 3, Part A, Pd2(dba)3 (0.212 g, 0.231 mmol), DPPF (0.257 g, 0.463 mmol) and zinc(II) cyanide (0.544 g, 4.63 mmol) in DMF (20 mL) and water (1 mL) was degassed with nitrogen and heated to 130° C. overnight. Ater cooling to room temperature, the volatiles were concentrated under reduced pressure. The residue was reconstituted in ethyl acetate and filtered through diatomaceous earth (Celite®). The organic layer was washed with H2O, followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether and ethyl acetate) to afford (S)-tert-butyl 1-(9-cyano-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)-4-methylpentan-2-ylcarbamate (1.9 g, 4.09 mmol, 88% yield) as a yellow solid. LC/MS (ESI) m/e 465.2 [(M+H)+, calcd for C26H33N4O4, 465.2]; LC/MS retention time (method C): tR=2.74 min.