Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH2:3][CH2:2]1.[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O)(=O)C>C1COCC1.CO>[O:17]1[CH2:22][CH2:21][CH:20]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10]4)[CH2:5][CH2:6]2)[CH2:19][CH2:18]1
Reactant: O=C1CCOCC1
Reactant: O=C1Cc2cc(C3CCNCC3)ccc2N1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Cc2cc(C3CCN(C4CCOCC4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 96 h
Yield: 94.5 %

Procedure:
To a solution of 5-(piperidin-4-yl)indolin-2-one (64.6 mg, 0.299 mmol) in THF (1.5 ml) and MeOH (3 ml) were added dihydro-2H-pyran-4 (3H)-one (0.132 ml, 1.34 mmol), acetic acid (0.170 ml, 29.5 mmol) and NaBH3(CN) (61.6 mg, 0.931 mmol). After stirring at room temperature for 4 days, the reaction mixture was concentrated. The residue was diluted with sat. NaHCO3 aq. and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (CHCl3/MeOH) to give 5-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)indolin-2-one (84.9 mg, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:17])[N:9]3[CH2:16][CH2:15][CH2:14][C:10]3=[N:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+]>CO>[CH:18](=[C:14]1[C:10]2=[N:11][C:12]3[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[C:8](=[O:17])[N:9]2[CH2:16][CH2:15]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1c2ccc([N+](=O)[O-])cc2nc2n1CCC2
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1c2ccc([N+](=O)[O-])cc2nc2n1CCC2=Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-nitro-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one, m.p. 196°-197° C. (3.7 g), prepared according to the Example 2, was reacted with benzaldehyde (2 g) in methanol (100 ml) in the presence of sodium methoxide (1.74 g) under stirring at room temperature for 16 hours and then at 60° C. for 4 hours. After concentration in vacuo of the suspension, the precipitate was filtered and washed with water until neutral: crystallization from CH2Cl2 -methanol gave 3-benzylidene-6-nitro-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one, m.p. 255°-257° C. (3.5 g), which was reacted with SnCl2.2H2O (25 g) in 37% HCl (15 ml) and acetic acid (45 ml) under stirring at 60° C. for 3 hours. After cooling the precipitate was filtered and washed with water and then suspended under stirring in 2.5% aqueous NaHCO3 : the product was filtered, washed with water until neutral and then crystallized from ethanol to give 1.6 g of 6-amino-3-benzylidene-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one, m.p. 268°-270° C., NMR (DMSO-d6) δppm: 3.23 (bt) (2H, C-2 protons), 4.11 (t) (2H, C-1 protons), 6.07 (bs) (2H, --NH2), 6.73 (m), (2H, C-5 and C-7 protons), 7.33-7.76 (m) (5H, phenyl protons), 7.68 (bs) (1H, =CH--), 7.83 (d) (1H, C-8 proton).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:52]([C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1)#[N:53]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: N#Cc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C#N)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) was added toluene/ethanol/water (20/5/2, 21.6 ml) and then were added 4-cyanophenyl borate (147 mg) and potassium carbonate (147 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (46 mg), and the mixture was refluxed for 6 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-cyanophenyl)-N-(4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 92) (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11].C(N(CC)CC)C.CCCCCC>C(Cl)(Cl)Cl.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][OH:12])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: OCC#Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of 6 g of 1-chloro-4-iodo-benzene, 1.8 ml of propargyl alcohol and 5.2 ml of triethylamine in 30 ml of chloroform is placed under a nitrogen atmosphere. 208 mg of bis(triphenylphosphine)palladium(II) dichloride and 98 mg of copper(I) iodide are added thereto. The reaction mixture is stirred for one hour at 40° C. 300 ml of hot n-hexane are then added. The n-hexane phase is decanted off. The residue is again digested with 200 ml of hot n-hexane, and the n-hexane phase is decanted off. The n-hexane phases are concentrated and the residue is subjected to flash chromatography on silica gel with ethyl acetate/n-hexane (1:4), yielding 3-(4-chloro-phenyl)-2-propyn-1-ol, which can be recrystallised from n-hexane, m.p. 78-80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([O:16][CH3:17])[C:13]([OH:15])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:13](=[O:15])[CH:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[F:1])[O:16][CH3:17])=[CH:22][CH:21]=1)#[N:18]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(C(F)(F)F)cc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(C(F)(F)F)cc1F

Procedure:
(RS)-(2-Fluoro-4-trifluoromethyl-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-trifluoromethyl-phenyl)-2-methoxy-acetamide. Light yellow gum.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[Cl:31])[C:22]3[CH2:21][CH2:20][N:19]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:18](=[O:38])[C:17]=3[C:16]=2[CH3:39])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:23]1[C:22]2[CH2:21][CH2:20][N:19]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:18](=[O:38])[C:17]=2[C:16]([CH3:39])=[C:15]1[C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(O[Si](C)(C)C(C)(C)C)cc1)CCN(N1CCCCC1)C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
2-[4-(tert-Butyldimethylsilanyloxy)phenyl]-1-(2-chloro-4-fluorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (0.929 g, 1.63 mmol) was suspended in THF (10 ml) and TBAF (1 M in THF, 1.64 ml) was added. The reaction mixture was stirred at rt for 1 h whereafter the solvent was evaporated and ethyl acetate/water added. The phases were separated and the organic phase dried and evaporated. The crude product was recrystallised from ethyl acetate/toluene to yield the product as an orange solid (0.223 g, 23% over 3 steps).
Reaction SMILES: C([NH:14][CH:15]([P:22]([OH:24])[OH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([P:22]([OH:24])[OH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(NC(c1ccccc1)c1ccccc1)P(O)O
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: CCCCCCC(N)P(O)O

Procedure:
The procedure described in Example 1C was repeated using DL-1-benzhydrylaminoheptanephosphonous acid as starting material instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-n-heptanephosphonous acid of melting point 208°-210° (dec.).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:36][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.2 g) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.1 g, 14%). MS (ISP) 580.2 [(M+H)+]; mp 204.5° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH3:28]I>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH3:28])[C:8]1=[O:21]
Reactant: CI
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Product: Cn1c(=O)n(O)c(=O)c2sc3ccccc3c21

Procedure:
3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with methyl iodide according to procedure B2. The crude intermediate was deprotected via general procedure D1 to give the title compound which was purified by mass-triggered preparative HPLC. 1H NMR (d6-DMSO, 300 MHz) δ 3.76 (s, 3H); 7.33 (dd, J=7 Hz, 1H); 7.42 (dd, J=7 Hz, 1H); 7.93 (d, J=8 Hz, 1H); 8.27 (d, J=8 Hz, 1H); Retention time=1.81 min., m/z=249.0.
Reaction SMILES: CON(C)[C:4](=[O:21])[CH:5]([O:19][CH3:20])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1.[Br:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][C:25]=1[O:37][CH3:38]>CCOC(C)=O>[Br:23][C:24]1[C:25]([O:37][CH3:38])=[CH:26][C:27]([C:32]2[O:33][C:34]([C:4](=[O:21])[CH:5]([O:19][CH3:20])[C:6]3[CH:7]=[CH:8][C:9]([CH2:12][N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[CH:10][CH:11]=3)=[CH:35][CH:36]=2)=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(CN2CCOCC2)cc1
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(CN4CCOCC4)cc3)o2)cc(OC)c1Br
Temperature: 25 °C
Yield: 13 %

Procedure:
N,2-Dimethoxy-N-methyl-2-(4-(morpholinomethyl)phenyl)acetamide was coupled with 2-(4-bromo-3,5-dimethoxyphenyl)furan following the procedure of Example 12. Purification by chromatography (0-9% NH3-MeOH in CH2Cl2; 0.7 M NH3-MeOH used) gave a mixture which was digested with EtOAc at 30-40° C. After cooling to room temperature, the crystals were collected on a Büchner, rinsed with EtOAc and dried in vacuo to give 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(morpholinomethyl)phenyl)ethanone as a white solid. A second batch was also isolated (0.125 g for two batches, 13% yield). MS: m/z 530.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: N[C@H]1CC[C@H](Oc2nccnc2C2CCOCC2)CC1
Reactant: Fc1ccccn1
Product: c1ccc(N[C@H]2CC[C@H](Oc3nccnc3C3CCOCC3)CC2)nc1
Temperature: 160 °C
Reaction time: 72 h

Procedure:
trans-4-(3-(Tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexanamine (0.053 g, 0.19 mmol) and 2-fluoropyridine (0.033 mL, 0.38 mmol) were mixed in a microwave tube. The tube was sealed, and the mixture was stirred neat at 160° C. for 3 d. The crude mixture was purified via silica gel column chromatography to give N-(trans-4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)pyridin-2-amine as a brown solid. [M+1] 355.2. IC50 (uM): 2.665.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10].[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([O:32][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])[CH2:28][NH:27][C:26]1=[O:33])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Reactant: CCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCOC(=O)O[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Triethylamine (2 mL, 15 mmol) is added to a solution of pentyl chloroformate (1.8 g, 12.2 mmol), (3S 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (1.5 g, 6.1 mmol) and 20 mL of CH2Cl2 at 5° C. The reaction mixture is stirred at room temperature overnight. The reaction mixture is then partitioned with water, and the organic layer is dried (Na2SO4), and concentrated by rotary evaporation. The resulting residue is chromatographed (5% EtOAc-CH2Cl2) to give 1.3 g (60%) of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-([[pentyloxy]carbonyl]oxy)-2H-azepin-2-one as a pale yellow solid: 1H NMR (CDCl3): δ 5.90 (d, J=6 Hz, 1H), 5.77 (t, J=6 Hz, 1H), 4.79 (m, 1H), 4.30 (m, 1H), 4.12 (m, 3H), 3.53 (m, 2H), 2.24 (m, 1H), 1.92 (m, 2H), 1.66 (m, 1H), 1.44 (s, 9H), 1.34 (m, 5H), 0.91 (m, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1.I[CH3:20].O>CN(C=O)C>[Br:3][C:4]1[C:13]([O:14][CH3:20])=[CH:12][C:11]2[C:10]([CH3:16])([CH3:15])[CH2:9][CH2:8][C:7]([CH3:18])([CH3:17])[C:6]=2[CH:5]=1
Reactant: CI
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reaction time: 2 h

Procedure:
720 mg (24 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 5.7 g (20 mmol) of 2-bromo-3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene in 75 ml of DMF was added dropwise and stirring was carried out until gas evolution had ceased. 1.5 ml (24 mmol) of iodomethane was then added and stirring was carried out at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was triturated in heptane and filtered. 5.5 g (93%) of 2-bromo-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, with a melting point of 70°-71° C., were recovered.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:24])[C:14]([C:25]([OH:27])=O)=[CH:13]1)[CH3:11].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[C:63]([NH2:78])=[N:64][CH:65]=[C:66]([C:68]3[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[C:70]([O:76][CH3:77])[CH:69]=3)[CH:67]=2)=[CH:58][CH:57]=1>CN(C=O)C.O>[NH2:78][C:63]1[C:62]([C:59]2[CH:58]=[CH:57][C:56]([NH:55][C:25]([C:14]3[C:15](=[O:24])[C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:17][N:12]([CH2:10][CH3:11])[CH:13]=3)=[O:27])=[CH:61][CH:60]=2)=[CH:67][C:66]([C:68]2[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[C:70]([O:76][CH3:77])[CH:69]=2)=[CH:65][N:64]=1
Reactant: CCn1cc(C(=O)O)c(=O)c(-c2ccccc2)c1
Reactant: COc1ccc(-c2cnc(N)c(-c3ccc(N)cc3)c2)cc1OC
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2ccc(-c3cc(-c4ccc(OC)c(OC)c4)cnc3N)cc2)c(=O)c(-c2ccccc2)c1
Reaction time: 0.33 h
Yield: 74.2 %

Procedure:
DIPEA (601 μl) was added to a solution of 1-ethyl-4-oxo-5-phenyl-1,4-dihydropyridine-3-carboxylic acid (420 mg) and COMU (961 mg) in DMF (5.0 ml) at room temperature, and the mixture was stirred for 20 minutes. The compound obtained in Step 2 of Example 1 (610 mg) was added at room temperature. The mixture was stirred for 15 hours, followed by the addition of water. The organic layer was extracted with ethyl acetate, and then washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->60:1 (v/v)] to give 700 mg of the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Mg].[C:17]([N:25]1[CH2:34][CH2:33][C@H:32]2[C@@H:27]([CH2:28][CH2:29][C:30](=[O:35])[CH2:31]2)[CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+].[OH-].[Na+]>C1COCC1>[C:17]([N:25]1[CH2:34][CH2:33][C@H:32]2[C@@H:27]([CH2:28][CH2:29][C:30]([OH:35])([C:2]3[CH:7]=[CH:6][C:5]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=3)[CH2:31]2)[CH2:26]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CC[C@H]2CN(C(=O)c3ccccc3)CC[C@@H]2C1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(O)CC[C@H]3CN(C(=O)c4ccccc4)CC[C@@H]3C2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-bromo-4-t-butyldimethylsilyloxy-benzene (1.7 g, 3.9 mmol), magnesium mesh (0.1 g, 3.9 mmol) and anhydrous THF were stirred at reflux temperature under a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and transferred via syringe to a stirred semi-solution of trans-2-benzoyl-6-oxodecahydroisoquinoline (1.0 g, 3.9 mmol) in anhydrous THF at -78° C. The reaction mixture was warmed gradually to ambient temperature over 17.5 h. The reaction mixture was poured onto a saturated ammonium chloride solution, mixed, basified with a 1N NaOH solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography (ethyl acetate) gave the product, a solid (747 mg): mp 103°-104° C.; NMR (CDCl3, 300 MHz): 7.5-7.3 (m, 7H), 6.85 (dd, 2H, J=8, 6), 4.9-4.6 (m, 1H), 3.9-3.55 (m, 1H), 3.1-2.4 (m, 2H), 1.9-1.0 (m, 9H), 0.95 (s, 9H), 0.25 (s, 3H), 0.2 (s, 3H); HRMS: Calcd: 465.2700, Found: 465.2689; Anal. Calcd for C28H39NO3Si: C, 72.23, H, 8.44, N, 3.01; Found: C, 71.99, H, 8.61, N, 2.87.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CCO>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1
Reactant: NCC1CCNCC1
Reactant: Clc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: NCC1CCN(c2ccccn2)CC1
Yield: 23.7 %

Procedure:
A mixture of 2-chloropyridine (19.4 g), 1-(piperid-4-yl)methylamine (14.25 g), sodium carbonate (11.4 g) and 3-methyl-1-butanol (100 ml), was stirred and heated under reflux for 16 hours, then filtered. The solvent was removed in vacuo to leave an oil which was distilled to give 1-[1-(pyrid-2-yl)piperid-4-yl]methylamine as a pale yellow oil (5.65 g), b.p. 126°-130° C. at 0.6 mbar.
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[N:29][C:28]([CH3:31])=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[O:14])[N:33]=1
Reactant: Cc1ncn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 65 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((3-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (100 mg, 0.149 mmol), DCM (4.0 mL) and TFA (1.0 mL, 13.0 mmol) for 3 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (50 mg, 65%) as a white powder. LCMS: m/z=514.7 (M−1); 1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J=8.4 Hz, 1H), 8.72 (br s, 1H), 6.78 (s, 1H), 5.25 (dd, J=8.8, 5.6 Hz, 1H), 4.61 (dd, J=14.4, 5.2 Hz, 1H), 4.47 (dd, J=14.4, 6.0 Hz, 1H), 4.33 (dd, J=6.0, 5.2 Hz, 1H), 2.30 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H).