Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2=[N:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][NH2:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][NH:24][C:14]([C:3]1[N:4]=[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:6]2[C:7](=[O:8])[C:2]=1[OH:1])=[O:16]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Product: CN1C(=O)Cn2c1nc(C(=O)NCc1ccc(Cl)c(Cl)c1)c(O)c2=O
Yield: 59.6 %

Procedure:
Reaction of intermediate 13, ethyl 6-hydroxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate, (0.050 g, 0.197 mmol) with 3,4-dichlorobenzylamine (0.11 g, 0.57 mmol) as described in the preparation of example 1 gave 0.045 g (59% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.15 (3H, s, NCH3), 4.48 (2H, s, CH2), 4.50 (2H, d, J=6.9 Hz, NCH2), 7.32 (1H, dd, J=1.4 Hz and J=8.3 Hz, aromatic), 7.58 (1H, d, J=1.4 Hz, aromatic), 7.62 (1H, d, J=8.3 Hz, aromatic), 9.52 (1H, broad t, NH), 12.13 (1H, s, OH). MS (ESI+) m/z 383 [M+H+].
Reaction SMILES: [C:1]([CH:8]([NH2:28])[CH2:9][N:10]([C:17](=[O:27])[CH2:18][C:19]1[C:20](=[O:26])[NH:21][C:22](=[O:25])[NH:23][CH:24]=1)[CH2:11][C:12]([O:14]CC)=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl>[OH-].[Na+]>[C:1]([CH:8]([NH2:28])[CH2:9][N:10]([C:17](=[O:27])[CH2:18][C:19]1[C:20](=[O:26])[NH:21][C:22](=[O:25])[NH:23][CH:24]=1)[CH2:11][C:12]([OH:14])=[O:13])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)Cc1c[nH]c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)C(N)CN(CC(=O)O)C(=O)Cc1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
Ethyl N-(2-BOC-aminoethyl)-N-(uracil-5-ylacetyl)glycinate (35, 1.00 g, 2.5 mmol) was dissolved in 1 M aqueous sodium hydroxide (50 ml) and the mixture was stirred for 15 min at room temperature. The reaction mixture was cooled to 0° C. and the pH was adjusted to 1.5 by the addition of 2 M hydrochloric acid. After 30 min the aqueous solution was extracted with n-butanol (4×80 ml). The n-butanol of the combined organic phases was evaporated under reduced pressure. Residual n-butanol was removed azeotropically with water (5×50 ml). The resultant aqueous solution was freeze-dried to yield 0.93 g (100%) of the title compound as a white solid. Due to hindered rotation around the amide bond several of the NMR signals are comprised of a major (ma) and minor (mi) component. 1H-NMR (DMSO-d6/TMS): δ=1.44 (s, 9H, BOC); 3.07-3.48 (m, CH2CON, NCH2, CH2N and water); 4.00 (ma), 4.26 (mi) (s, 2H, CH2COO); 6.75 (mi), 6.94 (ma) (br, 1H, BOC-NH); 7.28 (mi), 7.32 (ma) (d, 1H, J=5.5 Hz, H-6); 10.87 (br, 1H, H-1); 11.12 (br, 1H, H-3). MS (FAB+) m/z (%): 371 (26, M+H). Calcd. for C15H22N4O7: C, 48.65; H, 5.99; N, 15.13; C/N, 3.22. Found: C, 35.13; H, 4.66; N, 10.48; C/N, 3.35.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.C([O-])(O)=O.[Na+].[CH2:17](O)[CH3:18]>OS(O)(=O)=O>[CH2:17]([O:9][C:8]([C:5]1[CH:4]=[C:3]([CH3:11])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])[CH3:18]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)ncc1Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(C)c(Br)cn1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a suspension of crude 5-bromo-4-methyl-pyridine-2-carboxylic acid (10.9 g, as potassium salt, approximately 35.5 mmol) in ethanol (120 mL), H2SO4 (0.5 mL) is added. The mixture is stirred at 70° C. for 18 h. The pH of the clear solution is adjusted to pH 9 by adding sat. aq. NaHCO3-solution and the mixture was extracted with diethyl ether (3×300 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated to give 5-bromo-4-methyl-pyridine-2-carboxylic acid ethyl ester (8.20 g) as a green oil; LC-MS: tR=0.87 min, [M+1]+=243.91.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)=[N:5][N:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>ClCCl.CO>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[N:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: Clc1nnc(Cc2ccncn2)c2ccccc12
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Clc1ccc(Nc2nnc(Cc3ccncn3)c3ccccc23)cc1

Procedure:
A mixture of 100 mg (0.45 mmol) 1-chloro-4-(4-pyrimidinylmethyl)phthalazine hydrochloride and 149 mg (1.17 mmol) 4-chloroaniline is heated for 1.5 h to 100° C. The reaction mixture is distributed between dichloromethane/CH3OH, 19:1 and sat. NaHCO3solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4), and concentrated by evaporation. Chromatography (SiO2; ethyl acetate/CH3OH, 19:1) and crystallization from ethyl acetate/ether yield the title compound: m.p.: 174-176° C.; FAB MS (M+H)+=348. The starting material is prepared as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].CCN(CC)CC>C1COCC1>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:3][C:2]([NH:1][C:25](=[O:27])[CH3:26])=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(N)ccc3[nH]c2=O)on1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A flask charged with 6-amino-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (0.027 mg, 0.085 mmol)(Example 52), acetic anhydride (0.01 mL, 0.100 mmol), NEt3 (0.018 mL, 0.13 mmol) and 1 mL of THF was stirred for 6 hrs at 25° C. The title compound was eluted from a 5 g SPE with 100% EtAc to give 0.015 g (50%) of a white solid. 1H NMR (400 MHz, CDCl3) 12.30 (s, 1H), 8.06 (s, 1H), 7.72 (m, 1H), 7.36 (m, 5H), 7.14 (m, 2H), 6.36 (s, 1H), 2.22 (s, 3H), 2.02 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C21H17N3O3 359.1, found 360.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1

Procedure:
Acetanilide is prepared by the method of Example 5 using 5.0 mls (0.05 mole) of aniline, 7.5 grams of 3A molecular sieves and 6.6 g (0.065 mole) of acetic anhydride in 100 mls of methylene chloride. The crude product (6.23 grams; 86% of theoretical) is recrystallized from toluene to obtain pure acetanilide, m.p. 112°-114° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH3:17])=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35]C(N(C)C)N(C)C)(C)(C)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:19](=[O:28])[C:20]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[CH:31][OH:35])[CH3:17])=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1cc(CC(C)NC(=O)Cc2ccc(C)cc2)ccc1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CC(C)NC(=O)C(=CO)c2ccc(C)cc2)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2.40 g (5.95 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)-1-methylethyl]-2-(4-methylphenyl)acetamide and 3.10 g (17.8 mmol) of t-butoxybis(dimethylamino) methane were mixed and stirred at 80° C. for 2 hours. The reaction mixture was cooled and tetrahydrofuran was added thereto. The reaction mixture was acidified with hydrochloric acid and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with chloroform washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=3:2) and dried to give 1.90 g of N-[2-(4-benzyloxy-3-methoxyphenyl)-1-methylethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide.
Reaction SMILES: C[O-].[Na+].[CH2:4]([OH:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH2:11]Br>O>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH2:11][O:6][CH2:5][CH2:4][OH:7]
Reactant: OCCO
Reactant: Clc1cccc(Cl)c1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: OCCOCc1c(Cl)cccc1Cl
Temperature: 57.5 °C
Reaction time: 1.5 h

Procedure:
Sodium methoxide (104.4 g, 1.93 mol) was added portionwise to ethylene glycol (3.74 L) under N2, keeping the temperature below 35° C. After 1-2 h, 2,6-dichlorobenzylbromide (400 g, 1.67 mol) was added and the mixture heated to 55-60° C. for 1 h. On cooling to 20° C. water (2.14 L) was added and the mixture extracted with ethyl acetate (2.14 L). The aqueous layer was separated and extracted twice with ethyl acetate (2.14 L, 1.28 L). The combined organic extracts were washed with water (2.14 L) then evaporated to dryness to afford a colourless oil (371.8 g)-LC RT=4 min. This may be chromatographed on silica (Biotage) eluting with 10% ethyl acetate in 60/80 petrol to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]([N:16]=CN(C)C)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1>CCO>[NH2:16][C:4]1[N:3]=[C:2]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)[C:7]([S:8]([NH:11][C:12]([CH3:13])([CH3:14])[CH3:15])(=[O:9])=[O:10])=[CH:6][N:5]=1
Reactant: Cc1cccc(N)c1
Reactant: CN(C)C=Nc1ncc(S(=O)(=O)NC(C)(C)C)c(Cl)n1
Solvent: CCO
Product: Cc1cccc(Nc2nc(N)ncc2S(=O)(=O)NC(C)(C)C)c1
Yield: 85 %

Procedure:
To a mixture of 4-chloro-2-[[(dimethylamino)methylene]amino]-N-(1,1-dimethylethyl)-5-pyrimidinesulfonamide, prepared according to the process of Example 1, Step 6 (44.62 g, 0.139 mol) in EtOH (1800 mL) was added metatoluidine (59.8 g, 0.558 mol) and heated to reflux for 10 hours. After cooling, the solvent was removed in vacuo and the residue extracted into EtOAc (1 liter). The solution was twice washed with 1N HCl washed with water and then with saturated NaCl. The organics were dried over MgSO4 and evaporated in vacuo to give a colorless solid, m.p. 174°-178° C. in 85% yield. Used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[C-:13]#[N:14].[Na+]>C(O)C>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][C:13]#[N:14])=[CH:12][CH:11]=2)[N:6]=[CH:7][CH:8]=1
Reactant: BrCc1ccc2nccnc2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc2nccnc2c1
Temperature: 50 °C
Yield: 28.9 %

Procedure:
To a solution of crude 6-bromomethylquinoxaline (36.0 g) in 95% ethanol (200 mL) was added NaCN (30.9 g, 0.63 mol) at room temperature. The mixture was heated at 50° C. for 3 hours and then concentrated under vacuum. Water (100 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column (Petroleum Ether/EtOAc 10:1) to give 2-(quinoxalin-6-yl)acetonitrile (7.9 g, 23% over two steps). 1H NMR (300 MHz, CDCl3) δ 8.88-8.90 (m, 2H), 8.12-8.18 (m, 2H), 7.74 (dd, J=2.1, 8.7 Hz, 1H), 4.02 (s, 2H). MS (ESI) m/z (M+H)+ 170.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([Br:11])[CH2:9]Br)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([Br:11])=[CH2:9]
Reactant: Clc1cccc(C(Br)CBr)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=C(Br)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In 50 ml of ethanol was suspended 20.8 g (69.7 mmol) of 3-chloro-α,β-dibromoethylbenzene. To the suspension was added 100 ml of an ethanol solution containing 5.8 g (103.4 mmol) of potassium hydroxide at room temperature, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into 150 ml of ice-water and extracted with 300 ml of diethyl ether. The extract was dried over anhydrous sodium sulfate and concentrated to give 15.0 g (purity: 99%) of 3-chloro-α-bromostyrene. 1H-NMR (CDC13, 8): 5.82 (1H, d), 6.14 (1H, d), 7.26-7.33 (2H, m), 7.45-7.49 (1H, m), 7.57-7.58 (1H, m)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].C([O-])(O)=O.[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH4-].[Na+]>CO>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)NCCN
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCCNCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-amino-ethyl)-acetamide (1.2 eq.) in MeOH were added NaHCO3 (1.5 eq.) and 4-chlorobenzaldehyde (1 eq.). The reaction was refluxed for 4 h, then cooled to 0° C. NaBH4 (1.2 eq.) was added portionwise. The reaction was stirred for 1 h at 0° C., then 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and DCM. The aqueous layer was then extracted twice with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 0/1) to afford N-[2-(4-chloro-benzylamino)-ethyl]-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([CH3:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1cc2c(s1)CCNC2C
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: Cc1cc2c(s1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C
Yield: 46 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,4-dimethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[CH2:11]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([N:30](CC)CC)C>>[CH2:11]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:30])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 3R-carboxylate-6-nitro-2H-3,4-dihydro-[2-1b]imidazopyran (Example 21, 1 eq.), triethylamine (1 eq.), diphenylphosphoryl azide (1 eq.) in toluene is heated at 80° C. for 4 h, cooled and t-butanol is added. The reaction is warmed to 70° C. for an additional 1 h. Workup in the standard fashion gives the Boc amine. Deprotection of the Boc group (trifluoroacetic acid:dichloromethane, 1:1) and addition of 4-benzyloxybenzoyl chloride and triethylamine gives the 4-benzyloxybenzamide of 3R-amino-6-nitro-2H-3,4-dihydro-[2-1b]imidazopyran.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[CH2:36][CH2:35][CH2:34][CH2:33][N:11]2[C:12](=[O:32])[C:13]([O:30]C)=[C:14]3[C:19]([CH2:18][CH2:17][N:16]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=4)[C:15]3=[O:29])=[C:10]2[C:9]1=[O:37])(C)(C)C.Br>C(O)(=O)C.O1CCOCC1>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:16]1[CH2:17][CH2:18][C:19]2[C:14](=[C:13]([OH:30])[C:12](=[O:32])[N:11]3[CH2:33][CH2:34][CH2:35][CH2:36][N:8]([CH2:7][C:6]([OH:38])=[O:5])[C:9](=[O:37])[C:10]3=2)[C:15]1=[O:29]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CC(=O)OC(C)(C)C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)CN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl[11-(3-chloro-4-fluorobenzyl)-9-methoxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-decahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]acetate (50 mg, 0.09 mmol) and 33% hydrogen bromide in acetic acid (1 mL) in dioxane (1 mL) was stirred at room temperature for 1 hour. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and Iyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)([O-])O.[Na+]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][CH2:3][C:4]1([CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10])(=[O:23])=[O:22]
Reactant: O=C1NCCCC1(CO)CCO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(COS(C)(=O)=O)CCCNC1=O
Temperature: 0 °C

Procedure:
A solution of 1 mmol of 3-(2-hydroxy-ethyl)-3-hydroxymethyl-piperidin-2-one in 3 ml of dichloromethane is admixed at 0° C. with 3 mmol of triethylamine, followed by 2.2 mmol of methanesulphonyl chloride. The reaction mixture is stirred at 0° C. for an hour and then at room temperature for an hour. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (2×). The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[CH2:25][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[C:1]([NH:20][C@@H:21]1[CH2:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH2:22]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C=C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 40 °C
Reaction time: 19 h

Procedure:
A reactor was charged with a solution of methyl (1S,4R)-4-(tritylamino)cyclopent-2-ene-1-carboxylate (4.75 kg, 12.4 mol) in methylene chloride. The reactor was charged with additional methylene chloride (15 L) to bring the total volume to 23.8 L. To the stirred solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.82 L, 32.2 mol). The reaction mixture was warmed to 40° C., with stirring for 16 to 22 h. 1H NMR (CDCl3) analysis of a small sample of the reaction mixture confirmed the formation of the product. The reaction was washed with 10% aqueous citric acid solution (2×7 L). The organic phase was concentrated under reduced pressure to afford the title compound as an oil. The oil was diluted with anhydrous toluene and concentrated to remove residual water and used without further purification. 1H NMR (300 MHz, CDCl3, δ): 7.60-7.54 (m, 5H), 7.34-7.17 (m, 10H), 6.53-6.50 (m, 1H), 3.70 (s, 3H), 3.50-3.40 (m, 1H), 2.60-2.52 (dd, J=16.6, 8.3 Hz, 1H), 2.24-2.20 (m, 1H), 2.16-2.05 (m, 1H) and 1.91-1.80 (m, 1H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[CH2:18]Br>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[CH2:18][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:2](=[O:11])[CH2:3]1
Reactant: O=C1CCc2ccccc2N1
Reactant: COc1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(CC2CC(=O)Nc3ccccc32)c1
Reaction time: 1 h

Procedure:
3,4-Dihydro-2(1H)-quinolinone was purchased from Aldrich Chemical Co. (Cat. No. 41,593-6) and used without purification in this step. 0.45 grams of 3,4-dihydro-2(1H)-quinolinone (3.0 mmole) was dissolved in 15 ml dimethylformamide and cooled in an ice bath. 0.2 grams (4.5 mmole) of sodium hydride (60% wt. in oil ) was added to this solution, and after 5 minutes 0.84 grams 3-bromo-5-methoxy-benzylbromide (3 mmol) was added thereto all at once. The mixture was stirred at ice bath temperature for 1 hour and then quenched by addition of 1% hydrochloric acid. The reaction mix was extracted with ethyl acetate, which was evaporated under reduced pressure to give an oil, which was chromatographed with medium pressure eluting using 10% ethyl acetate in hexanes to yield 0.8 grams of solid 4-(3-bromo-5-methoxy-benzyl)-3,4-dihydro-1H-quinoline-2-one.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:12][N:11]([CH3:13])[S:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[C:6]#[N:7])(=[O:15])=[O:14]
Reactant: CN(C)S(=O)(=O)c1cc(C#N)ccc1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(C#N)cc2S(=O)(=O)N(C)C)CC1

Procedure:
In a manner analogous to that of Example 22, 49 g of 4-chloro-3-dimethylsulfamoylbenzonitrile (0.2 mole) were reacted with N-methylpiperazine, and the final product was recrystallized from ethanol.
Reaction SMILES: [O-]S([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[C:18]([CH3:20])[CH:19]=1.Cl[CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32]>O.CN(C=O)C>[CH3:13][C:14]1[CH:15]=[C:16]([S:21]([CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])(=[O:23])=[O:22])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3cc(C)cc(C)c3)c(C)o2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A solution of Na2SO3 (308 mg, 2.4 mmol) and Na2CO3 (259 mg, 2.4 mmol) in water (5 mL) was added to a suspension of 3,5-dimethylbenzenesulfonyl chloride (500 mg, 2.4 mmol) in water (5 mL) and the mixture was stirred at 100° C. for 2 h. The mixture was cooled, filtered, and the filtrate was made acidic with 1 M HCl and chilled at 0° C. for 2 h. The precipitate was filtered, washed with water (1 mL) and dried. A mixture of chloride 2 (289 mg, 1.08 mmol) and crude sulfinic acid (184 mg, 1.08 mmol) in dry DMF (10 mL) was stirred at 100° C. for 16 h. The mixture was cooled and diluted with ice/water (50 mL) and stirred for 15 min. The precipitate was filtered, washed with water (5 mL). The residue purified by column chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give benzoate 25 (388 mg, 90%) as a white powder: mp (EtOAc) 141-143° C.; 1H NMR (CDCl3) δ 8.03 (ddd, J=8.6, 1.8, 1.5Hz, 2 H, H-2, H-6), 7.94 (ddd, J=8.6, 1.8, 1.5Hz, 2 H, H-3, H-5), 7.42 (br s, 2 H, H-2′, H-6′), 7.25 (br s, 1 H, H-4′), 4.28 (s, 2 H, CH2SO2), 3.94 (s, 3 H, OCH3), 2.35 (s, 3 H, CH3), 2.33 (s, 6 H, 2×CH3); MS m/z 400.5 (MH+, 100%). Anal. calcd for C21H21NO5S: C, 63.14; H, 5.30; N, 3.51. Found: C, 63.23; H, 5.28; N, 3.46%.