Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3]Br)#[N:2].[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[C:6]1=[O:15])[CH2:12]2.[Cl-]>C1(C)C=CC=CC=1>[C:6]([O:15][C:6]1([CH2:3][C:1]#[N:2])[CH:7]2[CH2:13][CH:11]3[CH2:10][CH:9]([CH2:14][CH:5]1[CH2:12]3)[CH2:8]2)(=[O:15])[C:5]([CH3:14])=[CH2:12]
Reactant: N#CCBr
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1(CC#N)C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
A three-neck flask under nitrogen is charged with 100 mL toluene and 1 gm of cyanomethylbromide (CNCH2Br) and cooled with an ice bath. A slight molar excess of Mg is added to the toluene and the mixture stirred until completion of formation of the Grignard reagent. A molar equivalent of 2-adamantanone is then added to the reaction mixture and stirring continued for 30 minutes or more while warming to room temperature. The reaction mixture is then again cooled with an ice bath and a slight molar excess of methacrylol chloride is added dropwise. When the acid chloride addition is complete, the ice bath is removed and stirring continued at room temperature until reaction completion. The resulting 2-cyanomethyl-2-adamantyl methacrylate can be isolated and purified by extraction and/or chromatography.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.O.[OH-].[Cs+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]2[CH:28]=[C:29]([C:31]#[CH:32])[S:30][C:21]=12>CN1CCCC1=O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]2[CH:28]=[C:29](/[CH:31]=[CH:32]/[N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[S:30][C:21]=12
Reactant: c1c[nH]nn1
Reactant: C#Cc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2s1
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2c(C#N)cnc3cc(/C=C/n4nccn4)sc23)c(Cl)cc1Cl
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a mixture of 1,2,3-triazole (50 μL, 0.81 mmol) and cesium hydroxide monohydrate (18 mg, 0.11 mmol) in 1-methyl-2-pyrrolidinone (5 mL) is added slowly 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.54 mmol). The mixture is heated to 120° C. for 12 hours, cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of methanol in dichloromethane (0–2%) to provide 90 mg (38%) of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(E)-2-(2H-1,2,3-triazol-2-yl)vinyl]thieno[3,2-b]pyridine-6-carbonitrile as a yelllow solid, mp 315–316° C.; 1H NMR (DMSO-d6-TFA) δ 3.88 (s, 3H), 7.50 (s, 1H), 7.65 (d, J=14 Hz, 1H), 7.85 (s, 1H), 7.88 (s, 1H), 8.15 (s, 2H), 8.32 (d, J=14 Hz, 1H), 9.01 (s, 1H); MS 443.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH2:2][CH3:3].[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1>[CH3:21][O:20][N:19]([CH3:18])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=1[O:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCOc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CNOC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 49.3 %

Procedure:
2-Propoxy-4-(trifluoromethyl)benzoic acid (457 mg, 1.93 mmol) in THF was reacted with N,O-dimethylhydroxy amine (378 mg), NMM (0.65 ml) and DMTMM (947 mg) at room temperature overnight. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with 1 M NaHCO3 (30 ml), 1N HCl (30 ml) and brine (30 ml) and dried over MgSO4. The filterate was purified with column chromatography (Hex/EtOAc=4/1) to yield the title compound (277 mg, 49%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([F:11])([F:10])[C:6](OC)=[O:7])[CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([CH2:4][C:5]([F:11])([F:10])[CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: COC(=O)C(F)(F)CC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)CC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution containing the methyl 3-cyclopropyl-2,2-difluoropropionate from the previous step was diluted with 20 mL of ethanol and cooled to 0° C. under Ar. To this stirred solution was added 605 mg (16 mmol) of sodium borohydride in small portions under Ar. The reaction was stirred in the cold for 1 h and then stored in the freezer for several days. The cold reaction mixture was quenched by the dropwise addition of 2M HCl until no further gas evolution was observed. The reaction was extracted with four portions of ether, the combined organic layers washed with water, brine, dried over Na2SO4 and the solvents removed by distillation at atm. pressure to give a solution of the product in ethanol. This solution was partitioned between pentane and water, the aqueous layer extracted with three portions of pentane, the combined organic layers dried over MgSO4 and the solvents removed by distillation at atm. pressure to give the title compound as a colorless oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].IC.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:16])[CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1O
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C(C)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4'-chloro-2'-hydroxyacetophenone (1.0 g) in dry DMF (5 ml) was added to a stirred mixture of sodium hydride (0.235 g, 60% dispersion) in dry DMF (5 ml) at 5° C. under nitrogen. After the addition the mixture was stirred at 0° C. for 15 minutes and then at ambient temperature for 1 hour. A solution of iodomethane (0.92 g) in dry DMF (5 ml) was added dropwise to the mixture whilst keeping the temperature below 10° C. The reaction mixture was stirred at ambient temperature for 5 hours and then left to stand for 16 hours. Potassium carbonate solution was added to basify the mixture and the product was extracted into dichloromethane. The combined extracts were dried and evaporated. The residue was dissolved in ether, washed with water, then dried and evaporated to give 4'-chloro-2'-methoxyacetophenone which was sufficiently pure for synthetic use in Example 17.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])=[CH:16][CH:15]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:9]([O:8][CH2:7][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: C=CCCCCCCOc1ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCOc1ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Reaction time: 6 h
Yield: 92.5 %

Procedure:
10% Palladium carbon (0.1 g) was added to a solution (30 ml) of 2-acetamido-2-[2-{4-(7-octenyloxy)phenyl}ethyl]-1,3propanediol diacetate (1.27 g) in ethanol and the mixture was stirred at ordinary temperature and at atmospheric pressure for 6 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated. The residue was collected by filtration to give the subject compound (1.18 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.[N:16]([Sn:19]([CH3:22])([CH3:21])[CH3:20])=[N+:17]=[N-:18]>>[C:10]1([C:3]2[CH:4]=[C:5]([C:6]3[N:16]([Sn:19]([CH3:22])([CH3:21])[CH3:20])[N:17]=[N:18][N:7]=3)[CH:8]=[CH:9][C:2]=2[NH2:1])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: N#Cc1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: C[Sn](C)(C)n1nnnc1-c1ccc(N)c(C2=CCCCC2)c1

Procedure:
The title compound was prepared from 4-amino-3-cyclohex-1-enyl-benzonitrile (as prepared in the previous step, 245 mg, 0.123 mmol) and azidotrimethylstannane (267 mg, 1.29 mmol) according to the procedure in Example 52, step (c) (320 mg, 64%). Mass spectrum (ESI, m/z): Calcd. for C13H15N5, 242.1 (M-SnMe3+2H), found 242.2 (M+H).
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#C[C@@H](O)CCCCC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC[C@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (S)-(−)-1-octyn-3-ol (61 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (S)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 101 mg, 68%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[Cl:14]Cl>>[Cl:14][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCCCCC(=O)O
Reactant: ClCl
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCl

Procedure:
155 parts by weight of the caproic acid were added to 1,000 parts by weight of 90% sulfuric acid saturated with chlorine and were reacted for 6 hours at 25° C. to obtain 100 parts by weight of 6-chlorocaproic acid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][C:33]=1[C:40]([F:43])([F:42])[F:41]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:36]([C:35]2[CH:38]=[CH:39][C:32]([S:31][CH3:30])=[C:33]([C:40]([F:43])([F:42])[F:41])[CH:34]=2)[OH:37])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: CSc1ccc(C=O)cc1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C(O)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a −78° C. suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.84 g, 11 mmol) in dry tetrahydrofuran (50 mL) was added n-butyllithium in n-hexane (1.6 M, 6.9 mL, 11 mmol) dropwise. The mixture was stirred at −78° C. for 30 min before adding 4-methylsulfanyl-3-trifluoromethyl-benzaldehyde (2.65 g, 12 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched by adding brine (20 mL). The mixture was extracted with ethyl acetate (300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) afforded (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanol as colorless oil (4.78 g, 91%): LC/MS m/e calcd for C23H20F3N2O4S2 [M+H]+ 479.06, observed 479.0;
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:22][O:23][C:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])([CH3:26])[CH3:25])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]#[N:20])[NH:17][C:16]2=[O:21])=[O:13])[N:10]=1)=[O:4].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:19]([C@H:18]1[NH:17][C:16](=[O:21])[C@H:15]1[NH:14][C:12](=[O:13])[C:11]([C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])[S:7][CH:8]=1)=[N:22][O:23][C:24]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([CH3:26])[CH3:25])(=[O:40])[NH2:20]
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C#N)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C(N)=O)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 2 ml of dimethyl sulfoxide is dissolved 0.38 g of (3S,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-4-cyano-2-azetidinone and, following addition of 0.1 ml of 30% aqueous hydrogen peroxide and 0.1 ml of 1 N sodium hydroxide, the mixture is stirred at approx. 25° C. for 30 minutes. The reaction mixture is chromatographed on an XAD-II column (eluant: 30% ethanol) to give 0.12 of (3S,4S)-4-carbamoyl-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-2-azetidinone.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C([N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)C1C=CC=CC=1>CCO>[N:18]1([CH:21]2[CH2:26][CH2:25][N:24]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH2:22]2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: C=CC(=O)OCC
Reactant: c1ccc(CN2CCN(C3CCNCC3)CC2)cc1
Solvent: CCO
Product: CCOC(=O)CCN1CCC(N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 mL (50.8 mmol) ethyl acrylate were added to a solution of 11.7 g (44.9 mmol) 1-benzyl-4-piperidin-4-yl-piperazine in 120 mL dry EtOH and the reaction mixture was refluxed for 1 h and then stirred overnight at RT. The solvent was eliminated i.vac. and the residue was dried for 1 h under an oil pump vacuum. The crude product was reacted further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[N+:24]([O-])=O)[C:13](=[O:27])[CH2:12]2)=[CH:4][CH:3]=1.O.NN>[Ni].C(O)C>[NH2:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([CH2:10]/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:12][C:13]1=[O:27]
Reactant: O=C1CN(C/C=C/c2ccc(Cl)cc2)CCN1c1cc(F)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Yield: 45.1 %

Procedure:
Raney nickel (50% slurry in water, 200 mg) was added to a solution of the compound obtained in Step C (389 mg) in ethanol (10 ml); hydrazine hydrate (0.5 ml) was added and the reaction mixture was stirred at room temperature until gas evolution ceased (1 hour). The reaction mixture was filtered over Hyflo, the solvent removed in vacuo and the residue purified by column chromatography (2.5% methanol in ethyl acetate) to afford 1-(2-Amino-5-fluoro-phenyl)-4-[(E)-3-(4-chloro-phenyl)-allyl]-piperazin-2-one (162 mg). Retention Time LCMS 2.81 min; MS (ES+) 360/362 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:18])[CH:16]=[CH2:17]>ClCCl>[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])=[O:14])=[CH:8][CH:9]=2)=[O:32])=[CH:29][CH:28]=1)(=[O:18])[CH:16]=[CH2:17]
Reactant: CCOCOC(=O)c1ccc(O)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCOCC)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 42.2 g (0.20 mole) of 4-Hydroxy-benzoic acid ethoxymethyl ester (15) in 520 ml of dichloromethane were added 58.3 g (0.2 mole) of 4-(6-acryloyloxy-hexyloxy)-benzoic acid (5) and 2.4 g (0.02 mole) of 4-N,N-dimethylaminopyridine under N2 atmosphere. The mixture was cooled in an ice-water bath. After few minutes 41.15 g (0.2 mole) of N,N-dicyclohexyl carbodiimide were added. Then the ice-water bath was removed. It was stirred at room temperature under N2 for one night. Then the mixture was filtered and extracted twice with 300 ml of hydrochloric acid (2.4 M).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][Cl:24])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cn2c(CO)nc3ccccc32)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cn2c(CCl)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2.2 g 1-(4-nitrobenzyl)-2-hydroxymethylbenzimidazole in 30 mL of chloroform was added 3.3 mL of thionyl chloride. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was taken up in water, neutralized with K2CO3 to a pH of 10 and extracted into methylene chloride. The organic layer was dried over Na2SO4 and concentrated to give 2 g of 1-(4-nitrobenzyl)-2-chloromethylbenzimidazole as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:16])[C:14]#[CH:15]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH2:13][C:14]#[CH:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: C#CCN
Solvent: CN(C)C=O
Product: C#CCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.8 %

Procedure:
In DMF, 700 mg (3.4 mol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine was dissolved, and then an aqueous solution of 413 mg (7.5 mmol) of 2-propynylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for 1 hour and allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 620 mg (yield: 76.5%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])=[CH:4][CH:3]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[C:37]([OH:41])(=[O:40])[CH:38]=[CH2:39].Cl>C(N(CC)CC)C.O.[Pd](Cl)Cl>[CH3:14][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:39]=[CH:38][C:37]([OH:41])=[O:40])=[CH:3][CH:4]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: C=CC(=O)O
Reactant: Cc1ccc(C)n1-c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1-c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 50.0 g 1-(4-bromophenyl)-2,5-dimethylpyrrole (Meakins et al, J. Chem. Soc., Perkin Trans. I, 1984, 2801-2807) and tri-O-tolylphosphine (2.5 g) in triethylamine (100.0 ml), under a nitrogen atmosphere, is added decolorizing carbon (5.0 g) and palladium chloride (0.35 g). To this stirred slurry is added acrylic acid (20.0 g) followed by triethylamine (39.0 ml). The reaction mixture is refluxed for 4.5 hours, cooled to room temperature and diluted with water (700 ml). The pH of the reaction mixture is adjusted to ca. 2 by the slow addition of concentrated hydrochloric acid (63 ml). The solids are collected by filtration and the filter cake is washed with water until the pH is ca. 7 and then dried. The dried filter cake is suspended in boiling ethanol (350 ml), clarified, cooled to room temperature and diluted with water (450 ml) to induce crystallization. The slurry is cooled to -10° C. and the product collected by filtration. The filter cake is dried in vacuo at 45°. The dried solid is slurried in cold toluene, filtered and to dried to afford 3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-2-propenoic acid, m.p. 184°-185°.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH2:11][C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:21])[NH:14][N:13]=2)=[C:6]([Cl:22])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Cl:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:21])[NH:14][N:13]=1
Reactant: COC(=O)c1cc(Cl)c(Cc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)c1cc(Cc2c(Cl)cc(CO)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 114.1 %

Procedure:
A mixture of 3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-benzoic acid methyl ester (52) (160 mg, 0.45 mmol) in tetrahydrofuran (5 mL) at 25° C. was treated with a 1M solution of diisobutylaluminum hydride in tetrahydrofuran (2.7 mL, 2.7 mmol). The reaction was stirred at room temperature for 24 h. A TLC of the reaction indicated that starting material was still present. An additional amount of the 1M solution of diisobutylaluminum hydride in tetrahydrofuran (1.0 mL) was added to the reaction. After stirring 30 min at room temperature, the reaction was cautiously quenched by addition to a 1:1 mixture of a saturated aqueous sodium chloride solution (30 mL) and a 2N aqueous hydrochloric acid solution (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution (20 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was dried under high vacuum to afford 6-(2,6-dichloro-4-hydroxymethyl-benzyl)-4-isopropyl-pyridazin-3-one (53) (168 mg) as a brown solid that was used without further purification; LRMS-ES(+) for C15H16Cl2N2O2 (M+H) m/z=327. MW=327.2130, Exact Mass=326.0589
Reaction SMILES: [C:1](=[O:25])([O:3][CH:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH:15]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:16][C:10]3=[CH:9][C:8]=2[NH:7][CH:6]([CH3:24])[CH2:5]1)[NH2:2].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33].Cl>ClCCl>[C:1](=[O:25])([O:3][CH:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH:15]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[O:16][C:10]3=[CH:9][C:8]=2[N:7]([C:32](=[O:34])[CH3:33])[CH:6]([CH3:24])[CH2:5]1)[NH2:2]
Reactant: CC1CC(OC(N)=O)c2cc3c(cc2N1)OC(Cc1ccccc1)O3
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2cc3c(cc2C(OC(N)=O)CC1C)OC(Cc1ccccc1)O3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
[Step 3] 675 mg (approx. 1.98 mmol) of the benzyl-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]quinolin-8-yl carbamate were dissolved in 15 mL of dichloromethane followed by adding 313 mg (4.0 mmol) of pyridine. 234 mg (3.0 mmol) of acetyl chloride were further added followed by stirring for 30 minutes at room temperature. Following completion of the reaction, aqueous hydrochloric acid (1 mol/L) was added followed by extraction with chloroform. The organic phase was washed with water and then dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 2:1) to obtain 367 mg of benzyl-5-acetyl-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]quinolin-8-yl carbamate in the form of a pale brown oil (56%, 2 steps).