Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9][CH2:8]1>[OH-].[Pd+2].[OH-].CO>[O:20]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: O=S1(=O)CCCN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=S1(=O)CCCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
20% Palladium hydroxide (100 mg) was added to the methanol solution (5 mL) containing 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-benzylpiperidine (252 mg) at 0° C., followed by stirring at room temperature for 5 hrs. under a hydrogen atmosphere. The reaction mixture was filtered to remove the palladium catalyst, followed by concentration under reduced pressure to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[NH:11][C:10]2=[O:16].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32]I)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.CCOC(C)=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][N:11]2[C:10](=[O:16])[C:9]3[C:14](=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][CH:8]=3)[N:13]=[C:12]2[CH3:15])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Reactant: COc1cccc2c(=O)[nH]c(C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C)nc12
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (91 mg, 2.37 mmol) was added to a solution of 8-methoxy-2-methyl-3H-quinazolin-4-one (300 mg, 1.58 mmol) in DMF (30 mL). The reaction mixture was stirred at 80° C. for 0.75 h and cooled to room temperature, then a solution of 4-(3-iodo-propyl)-piperidine-1-carboxylic acid tert-butyl ester (837 mg, 2.37 mmol) in DMF (1 mL) was added. The reaction mixture was heated at 85° C. for 17 h and diluted with EtOAc. The organic solution was washed with water and sat'd aq NaCl, dried and concentrated. Purification on SiO2-gel chromatography (50% EtOAc/hexanes) provided the desired product as a yellow oil. API-MS: 416 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=2)[CH2:2]1.[C:17]1([C:23]2[O:27][C:26]([C:28](OCC)=[O:29])=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:14][N:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH:3]2[CH2:2][N:1]([C:28]([C:26]3[O:27][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[N:24][N:25]=3)=[O:29])[CH2:4]2)=[CH:7][C:8]=1[CH3:16])[CH3:15]
Reactant: Cc1cc(OC2CNC2)ccc1CN(C)C
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Product: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1CN(C)C
Temperature: 120 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Intermediate 20C (0.16 g, 0.73 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.17 g, 0.80 mmol) were mixed together in a microwave vial. The vial was sealed and the mixture was then stirred at 120° C. for 2 hours using an oil bath. The mixture was cooled to room temperature. The product was purified by column chromatography eluting with DCM and MeOH (saturated with ammonia)/DCM (gradient, 0.5-2%). The solvent was removed by evaporation and the semi solid residue was triturated with Et2O. There was obtained 0.27 g (93%) of the product as a crystalline solid m.p. 135° C. 1H NMR (600 MHz, CDCl3): δ 2.21 (s, 6H), 2.34 (s, 3H), 3.31 (s, 2H), 4.28-4.35 (m, 1H), 4.59-4.67 (m, 1H), 4.70-4.78 (m, 1H), 5.01-5.15 (m, 2H), 6.54 (d, 1H), 6.60 (s, 1H), 7.15 (d, 1H), 7.49-7.62 (m, 3H), 8.16 (d, 2H), MS (APCI+) m/z 393 [M+H]+, LC purity: 99%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C@H:11]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:12]([N:14]1[CH2:19][CH2:18][S:17][CH2:16][C@H:15]1[C:20](=[O:39])[NH:21][CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][NH:31]C(OC(C)(C)C)=O)=[O:13])(=O)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>CO.CCOC(C)=O.C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[NH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=1[CH2:22][NH:21][C:20]([C@@H:15]1[CH2:16][S:17][CH2:18][CH2:19][N:14]1[C:12](=[O:13])[C@H:11]([OH:10])[C:40]([CH3:43])([CH3:42])[CH3:41])=[O:39]
Reactant: CC(=O)O[C@@H](C(=O)N1CCSC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](O)C(=O)N1CCSC[C@H]1C(=O)NCc1cc(Cl)ccc1CN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Solid K2CO3 (5.8 mg, 0.042 mmol) was added to the solution of (R)-1-{(R)-3-[2-{(tert-Butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]thiomorpholino)-3,3-dimethyl-1-oxo-butan-2-yl acetate (0.12 g, 0.21 mmol) in MeOH (5 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with 0.1M aqueous HCl (20 mL), water (2×20 mL), and brine solution (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile/water) to afford the intermediate BOC-protected alcohol as an off-white solid (0.092 g, crude). The crude intermediate was dissolved in CH2Cl2 (3 mL) then trifluoroacetic acid (1.0 mL, 13.42 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. Volatile byproducts were removed under vacuum and the residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound as a white solid. 1H NMR (MeOD 400 MHZ) (δ) ppm: 7.41 (s, 1H); 7.39-7.35 (m, 2H); 5.28 (t, J=4.4 Hz, 1H); 4.54-4.38 (m, 3H); 4.28-4.21 (m, 3H); 3.61-3.54 (m, 1H); 3.18-3.12 (m, 1H); 2.93-2.88 (m, 1H); 2.82-2.75 (m, 1H); 2.62-2.59 (m, 1H), 0.98 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([OH:7])=O.[NH2:29][CH:30]([CH3:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[NH:29][CH:30]([CH3:33])[CH2:31][OH:32])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and 2-aminopropan-1-ol were reacted by a procedure similar to that to prepare 137 in Example 47 to give 228. MS: (ESI+) 471.0
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44](Br)[CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:39][C:40]1[CH:45]=[C:44]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([CH3:38])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH:43]=[N:42][CH:41]=1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Brc1cncc(Br)c1
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: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cncc(Br)c5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3,5-dibromopyridine (947 mg, 4 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (534 mg, 91%) as a brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].Cl[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:45][CH3:46])[N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.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.O.CN(C=O)C>[CH3:46][O:45][C:27]1[CH:28]=[C:29]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH:30]=[CH:31][C:26]=1[NH:25][C:17]1[N:18]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:20]([C:21]([F:23])([F:24])[F:22])=[CH:15][N:16]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 98 %

Procedure:
A mixture of methyl 2-(2-ethynylphenyl)acetate (I4) (0.472 g, 2.71 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I27) (1.10 g, 2.26 mmol), triphenylphosphine (59 mg, 10 mol %), copper(I) iodide (43 mg, 10 mol %), bis(triphenylphosphine)palladium(II) chloride (79 mg, 5 mol %), DMF (12 mL) and triethylamine (1.26 mL, 9.04 mmol) was degassed with nitrogen in a microwave tube then heated under microwave irradiation at 120° C. for 15 minutes. Three additional tubes were prepared and heated as described above (i.e. a total of 4.40 g of I27). The cooled mixtures were combined, and poured into water (600 mL). The resulting mixture was extracted with dichloromethane (3×250 mL) then the combined organic phases were washed with water (2×300 mL), brine (300 mL), dried over sodium sulfate and evaporated to dryness. The residue was chromatographed (120 g silica cartridge, 0-50% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I28) (5.52 g, 98% yield) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.00 (s, 1H), 7.69 (dd, J=7.7, 0.9 Hz, 1H), 7.43 (td, J=7.6, 1.4 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.32 (dd, J=7.5, 1.4 Hz, 1H), 6.87 (dd, J=8.4, 1.8 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.26 (s, 2H), 3.97 (s, 2H), 3.91 (s, 3H), 3.71 (s, 3H), 2.81 (t, J=12.6 Hz, 2H), 2.64 (tt, J=12.2, 3.6 Hz, 1H), 1.84 (d, J=12.6 Hz, 2H), 1.69-1.55 (m, overlaps with water), 1.49 (s, 9H). LCMS Method C: rt 7.05 min; m/z (625.1 [M+H]+, 569.1 [M-tBu+2H]+; m/z 623.2 [M−H]−.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:16][CH2:15][CH2:14][CH2:13][S:12][CH:11]([CH3:17])[C:10]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([N:16]1[C:9]2[CH:8]=[CH:7][C:6]([Cl:5])=[CH:18][C:10]=2[CH:11]([CH3:17])[S:12][CH2:13][CH2:14][CH2:15]1)(=[O:3])[CH3:2]
Reactant: CC1SCCCNc2ccc(Cl)cc21
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)N1CCCSC(C)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
4 g of acetyl chloride were added dropwise to a suspension of 11.4 g of 8-chloro-1,3,4,6-tetrahydro-6-methyl-2H-5,1-benzothiazocine and 10 g of potassium carbonate in 100 ml of acetone, whilst keeping the temperature of the mixture below 10° C. The mixture was stirred for 30 minutes, after which it was poured into ice-water and extracted with chloroform. The solvent was evaporated from the extract and the residue was recrystallized from a 3:2 by volume mixture of methylene chloride and n-hexane to give 5 g of 1-acetyl-8-chloro-1,3,4,6-tetrahydro-6-methyl-2H-5,1-benzothiazocine in the form of crystals melting at 132°-135° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:23][OH:24])=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:21])([CH3:20])[CH3:19])[CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:21])([CH3:19])[CH3:20])[CH:14]=3)[C:9]2=[O:22])[C:3]=1[CH2:23][O:24][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)c1ccc2c(c1)CCN(c1cccc(Br)c1CO)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1c(Br)cccc1N1CCc2cc(C(C)(C)O)ccc2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Intermediate 43 (238 mg, 0.610 mmol) in DCM (6 ml) were added TEA (0.085 ml, 0.610 mmol), DMAP (7.5 mg, 0.061 mmol), and acetic anhydride (62 mg, 0.610 mmol). The resulting mixture was stirred for 24 hrs at r.t. The solvents were removed in vacuo and the crude product was purified by flash chromatography (silica gel, cyclohexane/EtOAC gradient) to yield Intermediate 44.
Reaction SMILES: [N:1]([CH2:4][C:5]1[NH:6][CH:7]=[C:8]([O:12]CC2C=CC=CC=2)[C:9](=[O:11])[CH:10]=1)=[N+]=[N-].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H].C(N(C(C)C)CC)(C)C>CN(C)C=O.[Pd]>[NH2:1][CH2:4][C:5]1[NH:6][CH:7]=[C:8]([OH:12])[C:9](=[O:11])[CH:10]=1
Reactant: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NCc1cc(=O)c(O)c[nH]1

Procedure:
A suspension of 2-(azidomethyl)-5-[(phenylmethyloxy)]-4-oxo-1,4-dihydropyridine (641 mg, 2.5 mmole) in 7 ml of dimethylformamide was treated with p-toluenesulfonic acid monohydrate (951 mg, 5 mmole), and the resulting solution was treated with 10% palladium on charcoal (641 mg). The mixture was stirred under 1 atmosphere of hydrogen for 75 minutes. The hydrogen was purged with argon, and diisopropylethylamine (871 μl, 5 mmole) was added. The resulting mixture was used immediately in the following reaction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[C:24]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[NH:14][S:13](=[O:26])(=[O:25])[N:12]2[CH3:27])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH:54][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([CH:11]2[C:24]3[CH:23]=[CH:22][C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[NH:14][S:13](=[O:26])(=[O:25])[N:12]2[CH3:27])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: CN1C(c2ccc(F)c(C(=O)O)c2)c2ccc3cccnc3c2NS1(=O)=O
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1cc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)ccc1F
Yield: 14.6 %

Procedure:
In a similar fashion, using route 37 general procedure 90, 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzoic acid 424 (60 mg, 0.15 mmol), TBTU (50 mg, 0.15 mmol), N,N-dimethylethane-1,2-diamine (16.9 μl, 0.15 mmol) and DIPEA (25.6 μl, 0.15 mmol) in DCM (1 ml) gave the title compound (10 mg, 14%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:20]=[C:19]1[CH3:40])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH2:1]([O:4][N:5]([C@@H:18]1[C:19]([CH3:40])=[CH:20][C@@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[NH:22][CH2:23]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C=CCON([C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 10, 13.38 g, 22.38 mmol) in DCM (200 mL) at room temperature was added zinc bromide (3.36 mL, 67.15 mmol). The reaction mixture was stirred at room temperature overnight then diluted with DCM and washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the desired product as an orange oil (11.14 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH:8]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: COC(=O)C1CC(Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C1CC(n2cc(Br)cn2)C1
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-1H-pyrazole (500 mg, 3.40 mmol), methyl 3-chlorocyclobutanecarboxylate (607 mg, 4.08 mmol), and potassium carbonate (1.18 g, 8.50 mmol) in DMF (5 mL) was heated to 70° C. for 24 hours. The reaction mixture was cooled to ambient temperature and diluted with diethyl ether (200 mL). The mixture was washed with water (2×50 mL) and then brine (25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% diethyl ether/hexanes) to afford methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1) and methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 2). Methyl 3-(4-bromo-1H-pyrazol-1-yl)cyclobutanecarboxylate (Isomer 1): MS ESI calc'd. for C9H12BrN2O2 [M+H]+ 259 and 261. found 259 and 261. 1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.59 (s, 1H), 5.02-4.95 (m, 1H), 3.65 (s, 3H), 3.20-3.14 (m, 1H), 2.75-2.66 (m, 2H), 2.64-2.56 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N)C1=O
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccco2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.30 g of t-butyl α-[6-amino-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [obtained as described in Example 56(f)] was N-alkylated using 0.50 g of butyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to isolate two isomers, A and B, (ascribed to the asymmetric carbon atom, to which the phenethyl group is attached).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=3)=[O:14])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36]>ClCCl>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35](=[O:36])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13](=[O:14])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=3)=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of the product of Example 364B (27.5 g, 0.0618 mol) and pyridine (7.73 g, 7.50 mL, 0.0927 mol, 1.5 equiv.) in dichloromethane (500 mL) was stirred at room temperature. To this mixture was added slowly, dropwise 2,2,2-trichloroethyl chloroformate (17.0 g, 10.8 mL, 0.0803 mol, 1.3 equiv.) over 30 minutes. The reaction mixture was stirred at room temperature for 2 hours, during which time the product precipitated as a yellow solid. The mixture was filtered and the filter cake was rinsed with dichloromethane (100 mL) and dried in vacuo to give the title compound (35.3 g, 92%) as a yellow solid.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[N:40]1([C:44](=O)[CH2:45]Cl)[CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:44][CH2:45][O:10][C:8]2[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:35][CH:34]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCC1
Product: COc1cc(NCCCc2ccc(OCCN3CCC3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 9.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 1-azetidin-1-yl-2-chloroethanone (9.4 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (0.9 mg) was obtained.