Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH2:8][S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](N3CCC[C@H]3CN3CCCC3)=[O:20])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C(Cl)(=O)C(Cl)=O.CN1CCOCC1.[NH:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50][N:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1>CN(C)C=O.ClCCl.C(#N)C>[CH3:8][S:9]([C:6]1[CH:5]=[CH:4][C:8]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([N:45]3[CH2:49][CH2:48][CH2:47][C@H:46]3[CH2:50][N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[O:20])=[CH:17][CH:18]=2)(=[O:10])=[O:11])=[CH:2][CH:7]=1)(=[O:11])=[O:10]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(c1ccc(NS(=O)(=O)Cc2ccccc2)cc1)N1CCC[C@H]1CN1CCCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1
Yield: 90 %

Procedure:
The title compound is prepared substantially in accordance with the procedure for the free base of C-Phenyl-N-[4-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-methanesulfonamide hydrochloride (Example 21) using the title compound of Intermediate 8 (4-(4-methanesulfonyl-benzenesulfonylamino)-benzoic acid) (0.270 g, 0.761 mmol), oxalyl chloride (0.145 g, 1.14 mmol), 1 drop N,N-dimethylformamide, N-methylmorpholine (0.081 g, 0.8 mmol), and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.115 g, 0.75 mmol) in a 1:1 mixture of dichloromethane/acetonitrile. The reaction is purified by radial chromatography to provide 0.338 g (90%) of the title compound as a white solid. MS (ES+) m/e 492.1 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:30][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:5][CH2:6]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(C)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.13 g) and a 37% aqueous solution of formaldehyde (0.04 ml) suspended in 1,2-dichloroethane (5 ml) was added under ice cooling sodium triacetoxyborohydride (0.11 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was then neutralized with a 1 N aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-methylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 61) (0.11 g) as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[F:21][C:22]([F:32])([F:31])[C@H:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[NH2:24]>>[F:32][C:22]([F:21])([F:31])[C@@H:23]([NH:24][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc(OCc2ccc(F)cc2)c(Cl)cn1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Agent: Cl
Product: O=C(N[C@@H](c1cccnc1)C(F)(F)F)c1cc(OCc2ccc(F)cc2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-(4-fluoro-benzyloxy)-pyridine-2-carboxylic acid and (αS)-α-(trifluoromethyl)-3-pyridinemethanamine hydrochloride (1:1) (CAN 749839-26-7) as starting materials and isolated (26 mg, 83%) as colorless oil; MS (ESI, m/z): 440.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[CH3:17])[CH:5]=[CH:4][N:3]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN1CCCC1=O.O>[CH:25]1([NH:28][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:10][N:11]4[C:16]=3[CH2:15][CH2:14][CH2:13][N:12]4[CH3:17])[CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CN1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21

Procedure:
A solution of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-7-methylpyrazolo[1,5-b]pyridazine (i.e. the product of Step B) (30.0 mg, 0.087 mmol) and cyclopropylamine (0.31 mL, 4.36 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was heated under microwave irradiation at 150° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-80% ethyl acetate in hexanes as eluant to give 27 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](B(O)O)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=1)[CH2:24][N:25]1[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]1>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:21]3[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=3)[CH2:24][N:25]3[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]3)=[CH:13][C:12]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc2cc(Cc3ccccc3)ccc2o1
Reactant: COC(=O)C1CN(Cc2cccc(Br)c2)C1
Product: COC(=O)C1CN(Cc2cccc(-c3cc4cc(Cc5ccccc5)ccc4o3)c2)C1

Procedure:
Synthesized according to Scheme B2, Step 2 and general procedure F from 5-benzylbenzofuran-2-ylboronic acid and methyl 1-(3-bromobenzyl)azetidine-3-carboxylate to give methyl 1-(3-(5-benzylbenzofuran-2-yl)benzyl)azetidine-3-carboxylate as a light yellow oil. MS (ESI) m/z: Calculated: 411.2; Observed: 412 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([I:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:18])=[O:10])=[C:4]([I:12])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)cc1I
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)cc1I
Yield: 95 %

Procedure:
A solution of the acid 324 (3.95 g, 14.1 mmol) and sulfuric acid (0.5 mL) in methanol (50 mL) was heated under reflux for 18 h, then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water; the organic phase was collected, dried (anhydrous MgSO4), filtered and concentrated to afford pure 325 (3.93 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.57 (dd, J=8.2, 2.7 Hz, 1H); 7.25 (dd, J=8.6, 5.9 Hz, 1H); 7.05 (dt, J=8.2, 2.7 Hz, 1H); 3.78 (s, 2H); 3.72 (s, 3H). LCMS: (M+H) 295.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[O:26]=[C:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:33](=[O:34])[CH2:32][N:28]4[CH2:29][CH2:30][CH2:31][C:27]4=[O:26])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)CN1CCCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4CCCC4=O)CC3)C(=O)C2(C)C)cc1OC
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1), 0.24 g of (2-oxo-pyrrolidin-1-yl)acetyl chloride and 0.5 ml of triethyl amine in 50 ml of dichloromethane is stirred for 30 min and washed subsequently with aqueous sodium carbonate. After drying over magnesium sulphate the solvent is evaporated and the residue purified by column chromatography [silica, ethyl acetate/methanol: 6:1(Vol/Vol)]. Crystallized from diethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][OH:11])[CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=1>C1COCC1>[CH3:24][O:23][C:17]1[CH:18]=[C:19]([O:21][CH3:22])[N:20]=[C:15]([O:11][CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)[N:16]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: O=[N+]([O-])c1cnn(CCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(OCCn2cc([N+](=O)[O-])cn2)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanol (1.90 g, 12.02 mmol) in THF (60 mL), NaH (673 mg, 16.82 mmol, 60%) was added and the solution was stirred for 5 min at 0° C., then the ice bath was removed and the reaction mixture was stirred at rt for 30 min, before 2-chloro-4,6-dimethoxypyrimidine (2.31 g, 13.22 mmol) was added. After 40 min at rt, the reaction mixture was quenched with water and the org. solvent was removed in vacuo. The aq. layer was extracted with DCM (1×), then acidified with 1 N HCl-solution to pH 2, and extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification by crystallization (DCM-hept-mixture) yielded 4,6-dimethoxy-2-(2-(4-nitro-1H-pyrazol-1-yl)ethoxy)pyrimidine as a beige solid. LC-MS conditions A: tR=0.88 min, [M+H]+=295.98.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][C:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:13]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([N:15]1[C:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([Br:9])[CH:11]=2)[C:16]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
Benzyl bromide (152 mg, 0.887 mmol, 1.50 equiv.) was added to a stirred mixture of methyl 5-(6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (200 mg, 0.591 mmol) and Cs2CO3 (289 mg, 0.887 mmol, 1.50 equiv.) in DMF (1 mL) and the mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was diluted with water, extracted with EtOAc (2×5 mL), washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with 0-20% EtOAc/hexanes to give 147 mg of methyl 5-(2-benzyl-6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate as a pink solid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1
Reactant: [H][H]
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(N)c(Oc2ccccc2)c1
Yield: 100.1 %

Procedure:
A mixture dimethyl-[2-(4-nitro-3-phenoxy-phenoxy)-ethyl]-amine (3.0 g, 9.9 mmol) and 5% Pd—C (0.6 g) in ethyl acetate (100 mL) was shaken under 50 psi of hydrogen for 20 hours. The mixture was filtered through Celite and evaporated, providing 2.7 g of the product, in quantitative yield; 1H NMR (CDCl3) δ 2.30 (s, 6H), 2.65 (t, J=5.7 Hz, 2H), 3.93 (t, J=5.7 Hz, 2H), 6.51 (d, J=2.6 Hz, 1H), 6.60 (dd, J=8.6 Hz, J=2.9 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 6.95-7.00 (m, 2H), 7.06 (t, J=7.3 Hz, 1H), 7.28-7.34 (m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:31])[C:11](=[O:12])[N:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:9](=[O:25])[N:8]1[CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][S:2]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][N:8]1[C:7]([CH3:31])([CH3:6])[C:11](=[O:12])[N:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:14]=2)[C:9]1=[O:25])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCOS(C)(=O)=O

Procedure:
0.17 ml of methanesulfonyl chloride were added to 740 mg of the product of Example 58 in solution in 7.4 ml of pyridine and 24 mg of 4-dimethylamino-pyridine and the mixture was stirred for one hour. The mixture was poured into ice-cooled water and extraction was carried out with methylene chloride. The extracts were washed with water and the residual pyridine was eliminated by distillation. The residue was chromatographed on silica (eluant: methylene chloride-ethyl acetate 8-2) to obtain 771 mg of the expected product.
Reaction SMILES: [N:1](CCCCCNCCCCCN=[N+]=[N-])=[N+:2]=[N-:3].[OH:18][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]1[C@@H:33]2[C@@H:28]([NH:29][C:30]([NH:32]2)=[O:31])[CH2:27][S:26]1)=[O:20].C1CN([P+](O[N:51]2[N:59]=[N:58]C3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[N-:1]=[N+:2]=[N-:3].[N-:58]=[N+:59]=[N-:51].[OH:20][C:19]([CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]1[C@@H:33]2[C@@H:28]([NH:29][C:30]([NH:32]2)=[O:31])[CH2:27][S:26]1)=[O:18]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: [N-]=[N+]=NCCCCCNCCCCCN=[N+]=[N-]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=[N-]
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of di(5-azidopentyl)amine (0.12 g, 0.49 mmol) in anhydrous DMF (5 mL) of were added biotin (0.12 g, 0.41 mmol), PyBOP (0.25 g, 0.49 mmol) and Et3N (0.23 mL, 1.64 mmol). The mixture was stirred for 22 h at room temperature under argon, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CH2Cl2/MeOH=13:1) to give biotin-diazide compound 25 (0.15 g, 79%). C20H35N9O2S; pale yellow oil; 1H NMR (CDCl3, 600 MHz) δ 4.48 (dd, J=7, 5 Hz, 1 H), 4.29 (dd, J=7, 5 Hz, 1 H), 3.28 (t, J=7 Hz, 4 H), 3.25 (t, J=7 Hz, 4 H), 3.20 (t, J=7 Hz, 2 H), 2.89 (dd, J=12, 5 Hz, 1 H), 2.71 (d, J=12 Hz, 1 H), 2.29 (t, J=7 Hz, 2H), 1.84 (br s, 3 H), 1.50-1.67 (m, 8 H), 1.43-1.44 (m, 2 H), 1.32-1.38 (m, 4 H); 13C NMR (CDCl3, 150 MHz) δ 172.4, 163.2, 61.8, 60.1, 55.3, 51.2, 47.0, 46.2, 45.6, 40.5, 32.5, 28.7, 28.6, 28.3, 27.3, 26.4, 25.1, 24.1. ESI-HRMS calcd for C20H36N9O2S: 466.2707, found: m/z 466.2703 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:34])[C@H:17]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][C@H:18]2[F:33])=[O:15])[C@:11]([CH2:41][OH:42])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:10]=1.C1CC=CCC=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([C@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[F:33])[CH3:34])=[O:15])[C@:11]([CH2:41][OH:42])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:10]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1F
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)[C@H]1CCNC[C@H]1F
Reaction time: 8 h

Procedure:
To a solution of 405 mg (0.58 mmol) of 10-1 in 4 mL of EtOH was added 1.38 mL (14.6 mmol) of 1,4-cyclohexadiene, 100 mg of 10% palladium on carbon, and then stirred overnight. The reaction was filtered through Celite, concentrated, and the residue was dissolved in 3 mL of CH2Cl2. To this was added 3 mL of trifluoroacetic acid, stirring was maintained for 1 h, and then the mixture was partitioned between EtOAc and saturated aqueous NaHCO3 plus 25 mL of 5% aqueous Na2CO3, the organic phase was washed with NaHCO3 again, H2O, brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was loaded onto a silica gel column and eluted with EtOAc—20:1:1 EtOH/NH4OH/H2O to provide 10-2 as a white solid. There was an impurity of 5% subsequently removed by reverse phase chromatography with 95:5 to 5:95 H2O/CH3CN (both with 0.1% TFA). The fractions were basified with NaHCO3 to provide pure B-2 as a white solid. Data for 10-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (mn, 3H), 6.3 (s, 1H), 5.2 (bs, 1H), 4.9 (m, 1H), 4.8-4.6 (m, 2H), 4.45 (m, 1H), 4.2-4.1 (m, 1H), 4.0 (m, 1H), 3.3-3.2 (mn, 2H), 3.1 (s, 3H), 2.85-2.7 (m, 2H), 2.1 (m, 1H), 1.7 (m, 2H) ppm. HRMS (ES) calc'd M+H for C24H26F3N3O2: 446.2050. Found: 446.2059.
Reaction SMILES: P(Cl)(Cl)Cl.[ClH:5].[CH3:6][O:7][C:8](=[O:23])[C:9](Cl)([C:20]#[N:21])[CH2:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:12]=O>CN(C=O)C>[Cl:5][C:20]1[C:9]([C:8]([O:7][CH3:6])=[O:23])=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][N:21]=1
Reactant: Cl
Reactant: COC(=O)C(Cl)(C#N)CC(C=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: COC(=O)c1cc(-c2ccccc2)cnc1Cl
Temperature: 90 °C

Procedure:
5 g of PCl3 were added to 25 mL of DMF at room temperature. The resulting yellow solution was saturated with anhydrous HCl while keeping the temperature below 90° C. 5 g (18 mmol) of methyl-2-chloro-2-cyano-4-phenyl-5-oxopentanoate in 5 mL DMF were added at 80° C. and the resulting solution heated at 90° C. for 90 min. The reaction mixture was cooled to room temperature, quenched with water, extracted with toluene, dried and distilled to give methyl 2-chloro-5-phenyl-3-pyridine carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].C(#N)C.O.Cl[C:25]([F:35])([F:34])C(C1C=CC=CC=1)=O>>[F:34][CH:25]([F:35])[O:12][C:10]1[CH:11]=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc2cc(F)cc(OC(F)F)c2n1
Temperature: 80 °C

Procedure:
To a mixture of 6-fluoro-2-methylquinolin-8-ol (0.15 g, 0.85 mmol) and potassium carbonate (4.2 g, 30 mmol) in acetonitrile (3.4 mL, 0.85 mmol) and water (3.4 mL, 0.85 mmol) was added 2-chloro-2,2-difluoroacetophenone (0.62 mL, 4.2 mmol). The vessel was sealed and the mixture was heated at 80° C. for 4 hours. The cooled reaction mixture was extracted with diethyl ether (2×30 mL), and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure at ambient temperature The resulting residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water). Aqueous fractions containing the product were combined and extracted with diethyl ether (2×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure at ambient temperature providing the title compound. Presence of water was noted and the material taken on as is assuming theoretical yield obtained (0.19 g, 100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:24][C:25]1[C:26]([C:32](O)=[O:33])=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:26]3[C:25]([Cl:24])=[CH:30][C:29]([Cl:31])=[CH:28][N:27]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 3,5-dichloro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:12]=1[C:13]([NH:15][C:16]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])(=O)C>CO.O1CCOCC1>[Cl:39][C:37]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:14])=[C:11]([OH:10])[CH:38]=1
Reactant: CC(=O)Oc1cc(Cl)ccc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (0.12 g) was added to a solution mixture of the obtained tert-butyl 2-(2-acetoxy-4-chlorobenzamido)-4-phenylbenzoate (0.13 g) in methanol (2.5 mL) and dioxane (2.5 mL), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of citric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 0.11 of tert-butyl 2-(4-chloro-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:8][C:7]2[CH:9]=[CH:10][C:11]([C:13](Cl)=[O:14])=[CH:12][C:6]=2[N:5]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:4][CH2:3]1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:26]([NH:30][C:13]([C:11]1[CH:10]=[CH:9][C:7]2[S:8][C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4][N:5]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:6]=2[CH:12]=1)=[O:14])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC1(C)CCN(S(=O)(=O)c2ccccc2)c2cc(C(=O)Cl)ccc2S1
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccccc1)CCC(C)(C)S2
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.4 %

Procedure:
To a biphasic mixture of 2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carbonyl chloride (30 mg, 0.076 mmol) in DCM (2 mL) and saturated aqueous NaHCO3 (2 mL) was added tert-butylamine (25 μL, 0.236 mmol). The reaction was stirred at room temperature for 72 hours. TLC analysis of the reaction mixture indicated consumption of starting material. The biphasic mixture was extracted with DCM (3×2 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of Hexanes with 5-50% EtOAc to provide N-tert-butyl-2,2-dimethyl-5-(phenylsulfonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-7-carboxamide (26.3 mg, 0.052 mmol, 68.2% yield) as an off white solid. LCMS (+ESI) m/z=432.9 [M+H]+; 1H-NMR (CDCl3) δ 7.73-7.70 (m, 2H), 7.68-7.63 (m, 2H), 7.55 (tt, 1H), 7.49 (d, 1H), 7.47-7.41 (m, 2H), 5.89 (s, 1H), 3.77 (br s, 1H), 1.88 (br s, 2H), 1.46 (s, 9H), 1.12 (br s, 6H).