Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=CC=1.[OH-].[Na+].[C:21]1(C)C=CC=CC=1>C(OC(=O)C)C>[CH3:21][N:9]1[N:8]=[CH:7][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: Cc1ccc(-c2n[nH]c(=O)c3ccccc23)cc1
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1ncc2ccccc2c1=O
Temperature: 85 °C
Reaction time: 12 h

Procedure:
To a suspension of 4-p-toluyl-phthalazin-1-(2H)-one [compound 2D] (2.36 g, 10 mMol) in toluene (50 mL) were added 2:5 N aqueous NaOH (4 mL) and Triton B (1 mL) followed by 2-(4'-bromomethylbiphenyl)-t-butylsulfonamide [prepared according to the procedure described in U.S. Pat. No. 5,126,342] (4.2 g, 11 mMol). The mixture was stirred at 85° C. for 12 h and then cooled to room temperature. The reaction was diluted with ethylacetate (100 mL), and the organic phase was washed with water (3×50 mL), and then dried over MgSO4. The ethylacetate layer was filtered and concentrated in vacuo to a small volume (~10 mL). Dry ether (100 mL) was added and the precipitate formed was filtered and dried. The crude product was then recrystallized from hot ethylacetate to give the desired product 4-p-toluyl-2-(2'-t-butylaminosulfonyl)-biphen-4-yl)methyl-phthalazin-1-(2H)-one as white crystalline solid (4.3 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:9][CH:8]=1)(=O)=O.C[Sn](C)(C)[C:28]1[CH:29]=[N:30][CH:31]=[N:32][CH:33]=1.C(N(CC)CC)C.[Cl-].[Li+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C)C=O>[CH3:23][N:20]1[CH2:21][CH2:22][N:17]([C:14]2[C:15]3[C:10](=[CH:9][CH:8]=[C:7]([C:28]4[CH:29]=[N:30][CH:31]=[N:32][CH:33]=4)[CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: C[Sn](C)(C)c1cncnc1
Reactant: CN1CCN(c2cccc3ccc(OS(=O)(=O)C(F)(F)F)cc23)CC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3ccc(-c4cncnc4)cc23)CC1
Yield: 29.9 %

Procedure:
A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (0.250 g, 0.67 mmol), bis(triphenylphosphine)palladium[11]chloride (0.025 g, 0.036 mmol), 5-trimethylstannylpyrimidine (0.178 g, 0.74 mmol, from Preparation 6), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), 2,6-di-tert-butyl-4-methylphenol (approximately 0.01 g), and N, N-dimethylformamide (12.5 mL) was heated between 100° C. to 115° C. under nitrogen for 45 minutes. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica gel (approximately 25 g) and elution with 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]to afford the title compound (0.060 g, 0.20 mmol, 29%) as a pale yellow foam: Rf =0.15 in 20% methanol in ethyl acetate; 13C NMR (CDCl3) δ 157.3, 155.0, 149.8, 134.6, 134.5, 130.8, 129.9, 129.0, 127.1, 124.0, 123.4, 122.1, 116.0, 55.4, 52.7, 45.9; LRMS (m/z, relative intensity) 304 (M+, 7), 240 (100), 225 (15), 196 (16), 169 (44), 155 (33), 141 (16); HRMS m/e calculated for C19H20N4 304.1690. Observed m/e 304.1689.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[C:35]([F:41])[CH:34]=1>>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:11]([CH2:12][C:13]2[CH:31]=[CH:30][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[CH3:1])=[C:35]([F:41])[CH:34]=1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Reactant: Fc1cc(Cl)ccc1CBr
Product: COC(=O)CCc1ccc(Oc2ccc(CN(Cc3ccc(Cl)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 76C and 4-chloro-2-fluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:11][NH:10][C:9]1=S)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C@H:12]1[CH2:11][NH:10][C:9](=[N:24][CH2:25][CH:26]([OH:32])[CH2:27][C:28]([F:31])([F:30])[F:29])[C@@H:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13]1
Reactant: NCC(O)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Agent: Cl[Hg]Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=NCC(O)CC(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl[(3S,5S)-5-(2,3-difluorophenyl)-2-thioxopiperidin-3-yl]carbamate (75.0 mg, 0.219 mmol) in ethanol (2.19 mL) was added the hydrochloride salt of 1-amino-4,4,4-trifluorobutan-2-ol (98.0 mg, 0.548 mmol), mercury(II) chloride (77.0 mg, 0.285 mmol), and triethylamine (73.3 uL, 0.526 mmol). The mixture was stirred 10 min, filtered, and concentrated giving the crude title compound. MS 452.17 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([CH:16]=[CH2:17])=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.C1CCN2C(=NCCC2)CC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:17][CH2:16][CH2:14][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: C=CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: c1ccc(CC2CCN(CCCNc3ccccc3)CC2)cc1
Yield: 66 %

Procedure:
To a solution of 4-benzylpiperidine (52.58 g, 300 mmol), DBU (0.449 ml, 3.0 mmol) in THF (600 ml) was added dropwise a solution of acrolein (90%, 18.69 g, 300 mmol) in THF (60 ml) over a period of 10 minutes at −20° C. under stirring. While a temperature of the solution was elevated from −20° C. to −10° C., the solution was stirred 1 hour. To the solution were added at −10° C. aniline (27.94 g, 300 mmol) and sodium triacetoxyborohydride (127.16 g, 600 mmol), successively, and the mixture was stirred for 19 hours while the temperature of the mixture was elevated to room temperature. To the mixture was added an aqueous solution of 2N-sodium hydroxide (900 ml) under ice cooling, and the mixture was stirred for 30 minutes and extracted with diethyl ether (400 ml, 200 ml×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was dissolved in 2-propanol (400 ml), and to the solution was added 4N-hydrogen chloride in ethyl acetate (200 ml) with stirring. The resulting precipitates were collected by filtration. The precipitates were washed with 2-propanol (100 ml×3), and dried under reduced pressure to give the titled compound (75.66 g, 198 mmol, Yield 66%) as white crystals. mp 217° C. (dec.)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][C@H:11]([C:13]([O:15][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(=O)O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of trans-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (0.5 g, 2.323 mmol) and potassium carbonate (0.321 g, 2.323 mmol) in dimethylformamide (2.323 ml) was treated with (bromomethyl)benzene (0.401 g, 2.346 mmol) added from a syringe over 3 minutes. The reaction mixture was stirred at room temperature for 17 hours and water was added. The suspension was filtered and the solid collected was washed with water and dried under vacuum to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:19]([N:38]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[CH:56]=[CH:55][C:52]([CH2:53]Br)=[CH:51][CH:50]=2)=[N:41][N:40]=[N:39]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([C:5]1[N:6]([CH2:53][C:52]2[CH:51]=[CH:50][C:49]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[C:42]3[N:38]([C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:39]=[N:40][N:41]=3)=[CH:56][CH:55]=2)[C:7]([C:15]#[N:16])=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(C(C)(O)CC)c(C#N)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc(C(C)(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 72 %

Procedure:
Following a procedure similar to that described in Example 18(a), but using 465 mg of 2-butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)imidazole (prepared as described in Preparation 19), 92 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 1.11 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 1.00 g of the title compound was obtained as a gum.
Reaction SMILES: II.[CH3:3][C@@:4]12[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C@@H:8]1[CH2:14][CH2:15][C:16]3[C@@H:22]([C@H:7]1[CH2:6][CH2:5]2)[CH2:21][CH2:20][C:18](=[O:19])[CH:17]=3.O=O.S([O-])([O-])(=[O:27])=S.[Na+].[Na+].[CH:32]([OH:35])([CH3:34])[CH3:33]>C(#N)C>[CH3:3][C@@:4]12[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C@@H:8]1[CH2:14][C:15]([C:16]3[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:22]=3[C@H:7]1[CH2:6][CH2:5]2)=[O:27].[CH:32]([O:35][CH:4]([CH3:5])[CH3:3])([CH3:34])[CH3:33]
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: II
Agent: O=O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)OC(C)C
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C(=O)C[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
Iodine (7.61 g, 30 mmol) and 19-nor-4-androstene-3,17-dione (2.72 g, 10 mmol) were dissolved in a mixture of acetonitrile (75 mL) and isopropanol (75 mL), to thereby form a reaction mixture. The reaction mixture was stirred for two hours while oxygen was introduced (50 mL/min) thereto under cooling in an ice-bath. The resultant mixture was maintained at room temperature, and after stirring of the mixture for a further 1.5 hours, introduction of oxygen was stopped and the mixture was refluxed for one hour. The reaction mixture was cooled to room temperature, and an aqueous solution of sodium thiosulfate was added to the mixture. The mixture was extracted with chloroform, and the organic phase was washed sequentially with an aqueous solution of sodium bicarbonate and saturated brine. The washed matter was dried over magnesium sulfate anhydrate, filtered, and evaporated under reduced pressure. The formed precipitates were recrystallized from acetone, to thereby yield 1.3 g of the title compound (yield 40%). The remaining mother liquor was purified through silica gel column chromatography (chloroform), to thereby further obtain 1.3 g of the title compound (overall yield: 80%).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10](N)(=O)=O)(=[O:3])[CH3:2].[Cl:14]Cl>>[C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10][Cl:14])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)sc1S(N)(=O)=O
Reactant: ClCl
Product: CC(=O)c1cc(Cl)sc1SCl

Procedure:
The process comprises displacing the C(2)-chloro of 3-acetyl-2,5-dichlorothiophene (1) with benzyl mercaptide to form the thioether of structure (2), which is then converted to 3-acetyl-5-chloro-2-thiophenesulfonamide (3) by reaction with chlorine to form 3-acetyl-5-chloro-2-thiophenesulfenyl chloride, followed by reaction with ammonia to form 3-acetyl-5-chloro-2-thiophenesulfenamide, and finally oxidation. Bromination provides 3-bromoacetyl-5-chloro-2-thiophenesulfonamide (4), which is converted to (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (5) by reduction with (+)-β-chlorodiisopinocampheylborane followed by treatment with aqueous base. Alkylation at N(2) provides the (S)-3,4-dihydro-6-chloro-4-hydroxy-2-substituted-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide of structure (6) Formation of the C(6) anion is accomplished by halogen-metal exchange, and the anion is reacted with sulfur dioxide to form a lithium sulfinate, which upon reaction with hydroxylamine-O-sulfonic acid provides the (S)-3,4-dihydro-4-hydroxy-2-substituted-2H-thieno[3,2-e] -1,2-thiazine-6-sulfonamide-1,1-dioxide of structure (7). Protection of the C(6)-sulfonamide functionality, followed by activation of the C(4)-hydroxyl and displacement with an appropriate amine provides the (R)-3,4-dihydro-4-alkylamino-2-substituted-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide of structure I.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[OH2:16]>O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:6]([C:5]3[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][C:9](=[O:16])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc(-c2ccc(F)cc2)cc1=O

Procedure:
25 gms of ethyl 4-fluorobenzoylacetate was dissolved in 250 gms of 1:10 P2O5 /methanesulfonic acid and heated at 45° for 4 days. The mixture was cooled, poured into 1200 mls of water and extracted with (3×100 mls) methylene chloride. Evaporation of the solvent and chromatography of the resulting oil (silica gel/ether) provided 12.9 gms of crystalline 2,6-di(4'-fluorophenyl)-3-ethoxycarbonyl-pyr-4-one. mp=113-4.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:22][CH2:21]2)[CH2:16][CH2:15]1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[CH:33]([NH:35][C:36]1[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:46])[CH:42]=3)[N:37]=1)[CH2:32][CH2:31][CH2:30]2>>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:14]([NH:13][C:1]([NH:46][C:41]3[CH:42]=[C:43]4[C:38](=[CH:39][CH:40]=3)[N:37]=[C:36]([NH:35][CH:33]3[C:34]5[C:29](=[CH:28][CH:27]=[CH:26][C:25]=5[O:24][CH3:23])[CH2:30][CH2:31][CH2:32]3)[CH:45]=[CH:44]4)=[O:2])[CH2:15][CH2:16]2)[CH2:22][CH2:21]1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCN(C2CC2)CC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C5CC5)CC4)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 4-amino-1-cyclopropylpiperidine (CAS no. 62813-02-9) and rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine MS: m/e=486.1 (M+H+).
Reaction SMILES: C[C:2]1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H:3]1[C:11]([OH:13])=[O:12].C(N(C(C)C)CC)(C)C.COC(OC)N1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(Cl)(Cl)[Cl:36]>>[ClH:36].[CH3:2][CH:3]([C:11]([OH:13])=[O:12])[CH2:32][CH2:31][CH2:30][CH2:29][CH3:28]
Reactant: ClC(Cl)Cl
Reactant: COC(OC)N1CCCCC1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCC(C)C(=O)O
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
The dihydrochloride salt of 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-S2-yl)ethyl]-piperidine (1.6 g, 5.8 mM) in methanol (12 ml) which contained MeONa (12 mM) and dimethylformamide dimethyl acetal (20 ml) was heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed in vacuo to give the 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl] 1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.1 g, 5 mM) and diisopropylethylamine (0.96 ml) in 20 ml dry CHCl3 was added the solution (CHCl3 8 ml: MeOH 1 ml) of the above piperidine-carboxaldehyde dimetylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr and then at room temperature for 3 hrs. The solvent was then removed, and water added (30 ml). The aqueous solution, washed with ethylacetate, was acidified to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 column to yield [2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabocyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.85 g, 38% yield)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[C:32]1(=O)[CH2:37]CCC[CH2:33]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C.C(N(CC)CC)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:37][CH2:32][CH2:33][CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:20]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCCN1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)N1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
The compound (57.7 mg) obtained in Example 32-3 was dissolved in methanol (1.73 ml) and then added with cyclohexanone (21.6 mg), sodium cyanoborohydride (13.8 mg), and triethylamine (76.5 μl). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 7 days. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then the whole was separated and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (7.9 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C1C(=O)N([Br:18])C(=O)C1.C(O)(C(F)(F)F)=O>C(#N)C>[Br:18][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2nccn2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2ncc(Br)n2n1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (5 g, 32.6 mmol) in acetonitrile (300 mL) was added NBS (6.37 g, 35.8 mmol) and TFA (0.75 mL). The resulting solution was allowed to stir at it overnight. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc, washed with NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo to afford 7.2 g (92%) of the title compound as a light yellow solid. 1H-NMR (400 MHz, CDCl3) ppm 7.91 (d, 1H), 7.79 (s, 1H), 7.12 (d, 1H). LCMS (method A): [MH]+=232/234, tR=4.48 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[O:37]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:38][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)C(N)=O
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)C(C)(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and 2,2-dimethylpropanamide, the title compound was obtained as crystals, melting at 170-172° C. (from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH3:36][C:37]1[CH:49]=[CH:48][CH:47]=[CH:46][C:38]=1[CH2:39][N:40]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28]([NH:45][CH:42]1[CH2:43][CH2:44][N:40]([CH2:39][C:38]2[CH:46]=[CH:47][CH:48]=[CH:49][C:37]=2[CH3:36])[CH2:41]1)=[O:34]
Reactant: Cc1ccccc1CN1CCC(N)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5C)C4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (99 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-(2-Methylbenzyl)-3-pyrrolidinamine (86 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (82 mg, yield 50%).