Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH3:27].O>CN(C)C=O>[Cl:18][C:14]1[C:15]([O:17][CH2:26][CH3:27])=[CH:16][C:11]([N:3]2[CH:2]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)=[C:12]([F:19])[CH:13]=1
Reactant: CCI
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-n2cc3c(n2)CCCC3)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Into a solution of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (0.9 g) in dimethylformamide (10 ml), there were added potassium carbonate (0.25 g) and ethyl iodide (1 g), and the mixture was stirred at 60° C. for 3 hours. After cooling, water was added to the reaction mixture, followed by extraction with ether. The ether layer was washed with water twice, dried and concentrated. The residue was crystallized from hexane to give 0.2 g of 3-chloro-2-(4-chloro-2-fluoro-5-ethoxyphenyl-4,5,6,7-tetrahydro-2H-indazole (Compound No. 1). m.p., 85.1° C.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[C:27]([Cl:40])[CH:26]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[C:16]1[CH3:41])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>CO>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[C:16]([CH3:41])=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: Cc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2n1CCOCCOC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2n1CCOCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
2-{2-[4-({3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl benzoate (90.0 mg) was dissolved in methanol (1 mL), 1N aqueous sodium hydroxide solution (0.3 mL) was added, and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=33:67→0:100) to give the title compound (43.9 mg) as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[NH2:27])=[CH:22][CH:21]=1)=[O:18].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1C=CC=CC=1>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][C:17](=[O:18])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[CH:21][CH:22]=1)(=[S:38])[NH2:27]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc(OC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1
Solvent: c1ccccc1
Product: NC(=S)c1ccc(OC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.7 %

Procedure:
4-Carbamoylphenyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate (5, 480 mg, 1.14 mmol) and Lawesson reagent (460 mg, 1.14 mmol) were dissolved in 20 ml of anhydrous benzene. The reaction was warmed to 50° C. and stirred for 6 h. The solvent was removed under reduced pressure; the crude residue was purified by silica gel column (dichloromethane/methyl alcohol 9.5/0.5) to furnish the pure compound 6 (446 mg, 91% yield).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)[N:4]=1.[OH-].[Na+].Cl>C(O)C.[Cl-].[Na+].O>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]3)[S:16][CH:17]=2)[N:4]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3nc(C(F)(F)F)cc(C(F)(F)F)n3)cs2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(Cc2nc(-c3nc(C(F)(F)F)cc(C(F)(F)F)n3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
The crude compound (100 mg) obtained in Example 33d was dissolved in ethanol (2 mL), 2N aqueous sodium hydroxide solution (0.44 mL, 0.88 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography and then recrystallization (ethyl acetate-hexane) to give the title compound (6 mg, 7% in 2 steps) as colorless crystals.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[O-:10][C:11]#[N:12].[K+].Cl.[OH-].[K+]>O1CCCC1.O>[C:11]([N:4]1[CH:5]2[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]2)[CH2:2][CH2:3]1)(=[O:10])[NH2:12]
Reactant: N#C[O-]
Reactant: C1CN2CCC(CC2)N1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)N1CCN2CCC1CC2
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 24.4 %

Procedure:
To a solution of 1,4-diazabicyclo[3.2.2]nonane (2.75 g) in a mixture of tetrahydrofuran (40 ml) and water (20 ml) was added potassium cyanate (2.65 g) at ambient temperature. The mixture was adjusted to pH 5.0 with concentrated hydrochloric acid and stirred at 50° C. for 40 minutes. The mixture was poured into 50% aqueous solution of potassium hydroxide. The resulted aqueous solution was extracted with chloroform. The extract was dried over anhydrous potassium carbonate and evaporated to dryness in vacuo. The crystalline residue was recrystallized from diethyl ether to give 4-carbamoyl-1,4-diazabicyclo[3.2.2]nonane (898.5 mg).
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([OH:17])=O)[CH:8]=[CH:7][CH:6]=1.N1C2C(=CC=CC=2C(Cl)=O)C=CC=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:34][CH:33]=1>C1COCC1.ClCCl.CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][N:43]([C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:14]=3[N:5]=[CH:6][CH:7]=[CH:8]4)=[O:17])[CH2:44][CH2:45]2)=[CH:34][CH:33]=1
Reactant: Fc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(O)c1cccc2cccnc12
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1cccc2cccnc12
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cccc2cccnc12)N1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
0.34 ml of thionyl chloride is added to a suspension of 0.4 g of quinoline-8-carboxylic acid in THF, and the mixture is refluxed for 1 hour. The mixture is then freed from solvent, and the residue (quinoline-8-carbonyl chloride) is taken up in 50 ml of dichloromethane. 2.1 g of polymeric DMAP (Aldrich, Article No. 35,998-2), 0.6 ml of triethylamine and 0.6 g of 1-[2-(4-fluoro-phenyl)ethyl]piperazine are added to this solution, and the mixture is stirred at room temperature for 5 days. Conventional work-up gives {4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}quinolin-8-ylmethanone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].C(OC([N:17]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=[CH:18]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[N:20]1[CH:21]=[CH:22][CH:23]=[N:17][CH:18]=[CH:19]1
Reactant: CC(C)(C)OC(=O)N1C=CC=NC=C1
Reactant: Clc1cccc(Br)c1Cl
Agent: [Pd]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cccc(N2C=CC=NC=C2)c1Cl

Procedure:
2.25 g (10 mmol) 1-bromo-2,3-dichloro-benzene was dissolved in dry toluene (50 ml), 2.3 (11 mmol) of [1,4]diazepine-1-carboxylic acid tert-butylester was added followed by 0.2 g BINAP (2,2-bis(diphenylphosphino)-1,1′-binaphtyl), 85 mg tris(dibenzylideneacetone)dipalladium(0) and 1.2 g (12 mmol) sodium-tert-butoxyde. The reaction mixture was refluxed for eight hours and filtered. The organic layer was washed with water, dried and evaporated in vacuo. The residue was purified by chromatography and deprotected at 10° C. using 20 ml ethylacetate saturated with gaseous hydrochloric acid, the precipitate was filtered giving 2.1 g (yield: 75%) hydrochloride salt of the title compound, melting at 182-3° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1.FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.Cl>CN(C)C=O>[CH3:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:5]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)nn1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 22.8 %

Procedure:
To a suspension of sodium hydride (1.62 g, 40.4 mmol) in N,N-dimethylformamide (250 mL) was added dropwise a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (5660 mg, 36.8 mmol) in N,N-dimethylformamide (50 mL) over 10 min under ice-cooling. After the completion of the dropwise addition, the reaction mixture was stirred at 0° C. for 10 min and at room temperature for 40 min. To the mixture was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.87 g, 40.4 mmol), and the mixture was stirred at room temperature for 3 hr. Under ice-cooling, 1N hydrochloric acid (36 mL) was added to the mixture, and the solvent was evaporated under reduced pressure. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→60/40), and recrystallized from ethyl acetate/hexane to give ethyl 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylate (1.98 g, 23%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(Cl)Cl.CCOC(C)=O>CCO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc2nc(-c3ccc(C=Cc4cccc([N+](=O)[O-])c4)cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3ccc(C=Cc4cccc(N)c4)cc3)sc2c1
Yield: 70.7 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-{4-[2-(3-nitrophenyl)-vinyl]-phenyl}-6-methylbenzothiazole (0.12 g, 0.322 mmol) and tin (II) chloride dihydrate (0.58 g, 2.58 mmol) in EtOH (3 ml) to give the title compound (0.078 g, 71%) as a pale yellow solid after work-up and flash chromatography (20:1 DCM/EtOAc).
Reaction SMILES: C([O:14][NH:15][C:16]([CH:18]1[CH:24]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[S:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)(=[O:36])=[O:35])=[O:17])(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[OH:14][NH:15][C:16]([CH:18]1[CH:24]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[S:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)(=[O:36])=[O:35])=[O:17]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)NO)cc1

Procedure:
To a solution of 3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid benzhydryloxy-amide (10 mg, 0.016 mmoL) in 0.25 mL of dichloromethane at 0° C. was added 0.25 mL of trifluoroacetic acid followed by triethyl silane (3.7 mg, 0.032 mmoL). After 50 minutes the solvent was removed under reduced pressure and the residue was azeotroped twice with toluene. The residue was then purified by column chromatography (silica: 1.5% to 3% methanol in dichloromethane) to yield 3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid hydroxyamide; MS: (M-H)- =447.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[C:4]([F:18])[C:3]=1[O:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([Cl:28])[CH:21]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1>ClCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]([C:10]2[N+:11]([O-:37])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:4]([F:18])[C:3]=1[O:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([Cl:28])[CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3ccccn3)c2F)c1
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cccc[n+]3[O-])c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of N-[4-Chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl]pyridine-2-carboxamide (0.064 g, 0.154 mmol) in 4 mL of dichloromethane was added mCPBA (0.026 g, 0.154 mmol). The resulting mixture was stirred overnight at RT. The reaction mixture was washed with 15% Na2CO3 and the organic layer separated and evaporated. The solid was dissolved in DMF and diluted with MeOH to a volume of 2 mL. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.006 g, 9%) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.74-11.85 (m, 1H), 8.44 (dd, 1H), 8.26-8.30 (m, 1H), 7.46-7.52 (m, 1H), 7.40-7.45 (m, 1H), 7.32-7.38 (m, 2H), 7.24-7.29 (m, 1H), 7.16 (t, 1H), 7.01-7.04 (m, 1H), 4.74 (d, 2H). LCMS: m/z 431.9 (M+1).
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][C@H:5]([OH:18])[CH2:6]OS(C1C=CC(C)=CC=1)(=O)=O.C(OC(=O)C[C@H](O)CI)C.C(OC(=O)CC1CO1)C.C(O)(=O)[C@H](CC(O)=O)O.[CH2:48]([NH2:51])[C:49]#[CH:50]>>[OH:18][C@@H:5]1[CH2:6][N:51]([CH2:48][C:49]#[CH:50])[C:3](=[O:19])[CH2:4]1
Reactant: C#CCN
Reactant: COC(=O)C[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)CC1CO1
Agent: CCOC(=O)C[C@H](O)CI
Agent: O=C(O)C[C@H](O)C(=O)O
Product: C#CCN1C[C@@H](O)CC1=O

Procedure:
In accordance with Scheme I, (S)-3-hydroxy-4-[[(4-methylphenyl)sulfonyl]oxy]butanoic acid methyl ester 2, (S)-3-hydroxy-4-iodobutanoic acid ethyl ester 3 and (S)=oxiraneacetic acid ethyl ester 4 are prepared from (S)-malic acid 1 using previously described methods [S. Saito et. al. Chem. Lett. 1389, (1984) and M. Larcheveque et. al. Tetrahedron Lett. 1781, 28 (1987)]. The esters 2, 3 and 4 are individually reacted with propargylamine in an alcohol solvent at temperatures ranging from room temperature to the reflux temperature of the solvent, preferably in the presence of an alkali metal carbonate, to produce (S)-4-hydroxy-1-(2-propynyl)-2-pyrrolidinone 5. Compound 5 is then reacted with an aryl or a (C1 -C6) carboxylic acid anhydride such as acetic anhydride in the presence of pyridine and preferably dimethylaminopyridine in an ether or a chlorohydrocarbon solvent, such as dichloromethane, to give the intermediate of general formula 6, for example, (S)-4-(acetyloxy)-1-(2-propynyl)- 2-pyrrolidinone.
Reaction SMILES: [CH2:1]([C:4]([CH2:35][CH:36]=C)([CH:8]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:9]([NH:11][CH:12]1[C:18](=[O:19])[N:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:13]1)=[O:10])[C:5]([NH2:7])=[O:6])[CH:2]=C.C>C1(C)C=CC=CC=1.C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[CH3:34][CH:32]([CH3:33])[CH2:31][C@H:8]([C:4]1([C:5]([NH2:7])=[O:6])[CH2:35][CH:36]=[CH:2][CH2:1]1)[C:9](=[O:10])[NH:11][CH:12]1[N:13]=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[N:17]([CH3:20])[C:18]1=[O:19]
Reactant: C=CCC(CC=C)(C(N)=O)C(CC(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O)C1(C(N)=O)CC=CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.2 %

Procedure:
To a solution of 31 (110 mg, 0.22 mmol) in 20 ml of toluene and CH2Cl2 (1:1) at 100 degree was added (bis(tricyclohexylphosphine)-benzylidine ruthenium (IV) dichloride) (24 mg, 0.029 mmol). The mixture was stirred at 100 degree for 4 hrs and another 24 mg Grubbs' catalyst was added. The mixture was then stirred at 100 degree for another 4 hrs. Then the solution was cooled to RT, after which 100 mg of charcoal was added. The mixture was filtered through ceslite to provide a slightly yellow solution, then concentrated. The residue was purified in silica gel chromatography with CH2Cl2/methanol (10:0.5) to give 48 mg of 32 (46%). 1H NMR (CDCl3) 0.97-0.90 (dd, 6H), 1.30-1.25 (m, 1H), 1.65-1.57 (m, 1H), 2.00-1.85 (m, 1H), 2.40-2.30 (d, 1H), 2.80-2.65 (m, 2H), 3.00-2.80 (d, 1H), 3.40-3.20 (m, 1H), 3.47 (s, 3H), 5.40-5.20 (s, 1H), 5.52-5.49 (d, 1H), 5.80-5.71 (m, 2H), 7.63-7.20 (m, 9H), 7.90 (s, 1H). API AP+ 473.1 (M+1).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH:18]=[C:19]4[S:23][C:22](=[S:24])[NH:21][C:20]4=[O:25])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:26])=[CH:3][CH:2]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C1(C)C=CC=CC=1>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH2:18][CH:19]4[S:23][C:22](=[S:24])[NH:21][C:20]4=[O:25])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:26])=[CH:5][CH:6]=1
Reactant: O=C1NC(=S)SC1=Cc1cccc2c1CCC(=O)N2Cc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: Cc1ccccc1
Product: O=C1NC(=S)SC1Cc1cccc2c1CCC(=O)N2Cc1ccc(-c2ccccc2)cc1
Yield: 59.7 %

Procedure:
To 20 ml of toluene were added 1.4 g of 1-(biphenyl-4-ylmethyl)-5-(4-oxo-2-thioxothiazolidine-5-ylidenemethyl)-3,4-dihydro-1H-quinolin-2-one, 1.01 g of diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate, and 1.4 g of silica gel, followed by heating and refluxing overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→2:1). The purified product was recrystallized from toluene, giving 0.84 g (60% yield) of 1-(biphenyl-4-ylmethyl)-5-(4-oxo-2-thioxothiazolidin-5-ylmethyl)-3,4-dihydro-1H-quinolin-2-one as a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8](OS(C(F)(F)F)(=O)=O)[C:4]2([CH2:7][CH2:6][CH2:5]2)[O:3]1.[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>C1COCC1.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>[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29]([C:8]2[C:4]3([CH2:5][CH2:6][CH2:7]3)[O:3][C:2](=[O:1])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:28][CH:27]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=C1OC2(CCC2)C(OS(=O)(=O)C(F)(F)F)=C1c1ccccc1
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: [Cl-]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)OC23CCC3)cc1
Temperature: 70 °C
Yield: 90.3 %

Procedure:
To a solution of the triflate (550 mg, 1.58 mmol) from step 2 in THF (10 ml) and boronic acid from step 3 (318 mg, 1.90 mmol) was added an aq. solution of Na2CO3 (2.0M, 3.16 mmol, 1.60 ml) and Pd(PPh3)4 (91 mg, 0.079 mmol). The mixture was heated for 2 h at 70° C., cooled and poured into sat. aq. NH4Cl. The aq. layer was extracted with Et2O and the combined org. layers were dried over MgSO4. Purification via flash chromatography (20% EtOAc in hexane) gave 460 mg of the title compound as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][CH:16]1[CH2:30][CH:19]2[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH:18]2[CH:17]1[CH3:31].C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]3[CH2:30][C@@H:19]4[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:22][C@@H:18]4[C@H:17]3[CH3:31])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC1C(N)CC2CN(C(=O)OC(C)(C)C)CC21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 95 °C

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 5.05 g, 18.40 mmol), crude tert-butyl 5-amino-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Intermediate 7, 7.07 g) and N,N-diisopropylethylamine (12.85 mL, 73.6 mmol) in N-methylpyrrolidinone (80 mL) was heated to 95° C. for 5 h. The mixture was diluted with ethyl acetate (600 mL), washed with water, brine, dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, gave the desired product as a racemic mixture (3.1 g). This mixture was resolved using preparative SFC using the following conditions: Column: ChiralPak AD-H 25×3 cm, 5 μm; Column Temp: 40° C.; Flow rate: 130 mL/min; Mobile Phase: CO2/methanol=50/50; Injection Volume: 5 mL (22.2 mg/mL, 3 g solid in 75 mL methanol and 60 mL chloroform); Detector Wavelength: 263 nm. The first eluted enantiomer was the desired (3aS,4R,5R,6aS)-tert-butyl 5-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.35 g). 1H NMR (400 MHz, chloroform-d) δ ppm 10.40 (1 H, d, J=8.36 Hz), 7.88 (1 H, s), 7.58 (1 H, d, J=1.76 Hz), 6.83 (1 H, d, J=1.76 Hz), 5.64 (2 H, br. s.), 3.86-4.08 (1 H, m), 3.49-3.67 (1 H, m), 3.38-3.50 (2 H, m), 3.14-3.34 (1 H, m), 2.74-2.82 (1 H, m), 2.55-2.68 (1 H, m), 2.18-2.40 (1 H, m), 1.59-1.90 (2 H, m), 1.51 (9 H, s), 1.08-1.19 (3 H, m); MS (ES+) m/z: 478.2, 480.2 (M+H).