Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1.CCN=C=NCCCN(C)C.[C:30]([NH:37][C:38](=[NH:41])[S:39][CH3:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:41]=[C:38]([S:39][CH3:40])[NH:37][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[O:17])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CSC(=NC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid (10.0 g, 30.3 mmol), EDCI (7.5 g, 36.4 mmol) in DCM (200 mL) was stirred at room temperature for 10 min, then DMAP (7.39 g, 60.6 mmol) was added by one portion. 10 minutes later, N-Boc-2-Methyl-isothiourea (6.9 g, 36.4 mmol) was added. The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was treated with methanol/water (20 mL, 1:1) to afford 10.2 g of methyl N′-8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl-N-Boc-carbamimidothioate. Yield: 67%. 1H NMR (CDCl3, 400 MHz): δ12.33 (s, 1H), 7.95-7.51 (m, 2H), 7.35-6.94 (m, 2H), 4.28-4.25 (m, 2H), 3.15-3.30 (m, 2H), 2.52 (s, 3H), 1.51-1.45 (s, 9H). LC-MS: m/z=497 [M+H+]
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:25]3[CH:40]=[CH:39][C:38]([O:41]C)=[CH:37][C:26]=3[S:27][C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=2)=[O:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([C:24]2[C:25]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:26]=3[S:27][C:28]=2[C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=2)=[O:23])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC3CCCCN3Cc3ccccc3)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(OCC2CCCCN2Cc2ccccc2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12

Procedure:
The product from Step 3 (295 mg, 0.5 mmol) was combined with boron tribromide (2.50 mL, 1M in dichloromethane, 2.5 mmol) in 4 mL of methylene chloride at room temperature. After 2 hours the reaction was quenched with saturated sodium bicarbonate solution and extracted into chloroform-methanol (10: 1). The combined organic layers was washed with brine and dried over anhydrous magnesium sulfate. After filtration, concentration and silica gel column chromatography with 40% ethyl acetate-hexanes as eluant the title compound (169 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1I)[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[C:27]([F:28])=[CH:26][C:25](B(O)O)=[C:24]([O:32][CH3:33])[CH:23]=1>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:25]1[CH:26]=[C:27]([F:28])[C:22]([F:21])=[CH:23][C:24]=1[O:32][CH3:33])[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1I
Reactant: COc1cc(F)c(F)cc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-carbamic acid tert-butyl ester and (example 85, intermediate c) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (79%). MS (ESI): m/z=419.139 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)Cl.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:32][CH2:31][N:30]([CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:29][CH2:28]1>N1C=CC=CC=1>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:28][CH2:29][N:30]([CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37]([NH:1][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:38])[CH2:31][CH2:32]1
Reactant: CCOC(=O)C1=C(N)CCCC1
Reactant: CC(CCCC(=O)O)N1CCN(c2ccc3ccccc3n2)CC1
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(NC(=O)CCCC(C)N2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
To a solution of 170 mg of ethyl 2-aminocyclohex-1-enecarboxylate as synthesized in Step 7-1-B in 5 ml of pyridine, 70 mg of phosphorus trichloride was added under cooling with ice, followed by 15 minutes' stirring. Raising the temperature to room temperature, 327 mg of 5-(4-quinoline-2-ylpiperazin-1-yl)hexanoic acid as synthesized in above Step 7-14-C was added to the solution and stirred for 3 hours. Distilling the pyridine off under reduced pressure, the residue was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate) to provide 182 mg (38%) of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)hexanoylamino]cyclohex-1-enecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][C:12]([C:16]([O:18]C)=[O:17])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][C:12]([C:16]([OH:18])=[O:17])([CH2:11][CH2:10]1)[CH2:13][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C12CCC(NC(=O)OC(C)(C)C)(CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a solution of methyl 4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylate (2.21 g, 8.20 mmol) in THF (27 mL) and MeOH (14 mL) was added aqueous NaOH (1 N, 20.0 mL, 20.0 mmol). The mixture was stirred at room temperature for about 16 h and concentrated to dryness under reduced pressure. Water (25 mL) was added to the remaining residue and the mixture was extracted with Et2O (2×25 mL) and the Et2O extracts were discarded. The aqueous layer was acidified to about pH 4 using aqueous 6 N HCl and extracted with Et2O (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to provide 4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid as an off-white solid (1.69 g, 81%): 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.00 (s, 1H), 2.00-1.69 (m, 6H), 1.67-1.45 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[S:14])[NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:16][CH:17]=O>C(O)(C)(C)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[S:14][CH:16]=[CH:17][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=S)CCc1ccc([N+](=O)[O-])cc1
Reactant: O=CCCl
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccc(CCc2nccs2)cc1
Yield: 27.8 %

Procedure:
A mixture of 3-(4-nitrophenyl)propanethioamide (1.0 g), chloroacetaldehyde (40% aqueous solution, 2.83 g) and tert-butanol (20 mL) was heated under reflux for 2 hrs. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-[2-(4-nitrophenyl)ethyl]-1,3-thiazole as pale-yellow crystals (0.31 g, yield 28%) from a fraction eluted with hexane-ethyl acetate (3:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 92-93° C.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[O:11][C:10]=2[CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[O:11][C:10]=1[CH3:20]
Reactant: Cc1oc(-c2cccnc2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2cccnc2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl[2-methyl-5-(pyridin-3-yl)furan-3-yl]methanol (1.6 g) in toluene (20 mL) was added thionyl chloride (1.3 mL), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure to give the title compound (1.7 g, 100%) as an amorphous compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][CH:11]([O:22][CH3:23])[CH2:12][N:13]1[CH2:16][CH2:15][CH:14]1C(OCC)=O.[O:24]=O>O1CCCC1.ClCCl.[Zn]>[CH3:9][O:10][CH:11]([O:22][CH3:23])[CH2:12][N:13]1[CH2:16][CH2:15][C:14]1=[O:24]
Reactant: O=O
Reactant: CCOC(=O)C1CCN1CC(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(CN1CCC1=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 2.2 mmol of lithium diisopropylamide in 15 ml tetrahydrofuran at -78° was added dropwise 0.43 g (2 mmol) of N-(2,2-dimethoxyethyl)-2-carbethoxy azetidine in 3 ml of tetrahydrofuran. After stirring at -78° for 30 minutes, the deep yellow anion was silylated in the usual way and warmed to room temperature. Removal of all volatiles by rotary evaporation with a high vacuum pump gave a purple residue which was redissolved in dichloromethane. Internal photooxidation using 5 g of Photox (trademark for photoconductive lead-free zinc oxides available from The New Jersey Zinc Co.) as the sensitizer required less than 5 minutes for oxygen uptake. The mixture was then filtered free of sensitizer and worked up by aqueous extraction in the usual manner. The pink residue obtained was applied to a 17×2 cm neutral alumina column. Elution with 10:3 ethyl acetate-hexane yielded 0.18 g (56%) of pale yellow liquid, which by NMR analysis was greater than 90% pure. Comparison of its spectral properties (IR, NMR) with those of an authentic known sample confirmed the identity of the product as the expected beta-lactam.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)[N:11]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)=[C:30]([Cl:40])[CH:29]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)=[C:30]([Cl:40])[CH:29]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(-c3noc(=O)[nH]3)c(Cl)c2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2ccc(-c3noc(=O)[nH]3)c(Cl)c2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
560 mg [1-[3-Chloro-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-6-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid tert-butyl ester were dissolved in 7 ml dichloromethane. 1 ml trifluoroacetic acid were added and the reaction mixture stirred at room temperature for one hour. The solvents were removed in vacuo and the residue purified by chromatography on reversed has to obtain 7 mg 3-{4-[4-Amino-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-2-chloro-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][S:9][CH2:10][CH2:11][OH:12].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][S:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCSCCc1ccccn1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCSCCc1ccccn1
Reaction time: 6 h
Yield: 63.5 %

Procedure:
A mixture of 2-[[2-(2-pyridinyl)ethyl]thio]ethanol (0.50 g), 1,6-dibromohexane (2.13 g), TAB (0.4 g) and 50% aqueous sodium hydroxide (6 ml) was stirred under nitrogen for 6 h, then diluted with water (75 ml) and extracted with diethyl ether (2×150 ml). The organic extracts were evaporated in vacuo to give an oil, which was partitioned between 2N hydrochloric acid (100 ml) and hexane (2×100 ml). The aqueous phase was basified to pH 12 with 50% aqueous sodium hydroxide and extracted with diethyl ether (2×150 ml), the dried organic extracts were evaporated in vacuo to give an oil. Purification by FCC eluting with System F (1:1) gave the title compound (0.60 g) as a colourless oil. T.l.c. (diethyl ether) Rf 0.64
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])[CH:5]=[C:6]([F:12])[C:7]=1[S:8]([CH3:11])(=O)=O.[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>C(OC(=O)C)(=O)C>[C:25]([O:28][CH2:11][S:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:5][C:6]=1[F:12])(=[O:27])[CH3:26]
Reactant: CC(=O)[O-]
Reactant: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(C)(=O)=O)c(F)c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCSc1c(F)cc(-c2c(-c3ccccc3)noc2C)cc1F
Yield: 82.3 %

Procedure:
A slurry of 4-[3,5-difluoro-4-(methylsulfinyl)phenyl]-5-methyl-3-phenylisoxazole (2.3 g, 6.8 mmol) (step 9 example 14), sodium acetate (3.4 g, 41 mmol) in acetic anhydride (30 mL) was heated and held at reflux for 9 hours. The mixture was concentrated on at reduced pressure and the residue was treated with dilute aqueous sodium bicarbonate and extracted with dichloromethane (1×200 mL, 2×75 mL). The combined extracts were washed with dilute sodium bicarbonate, dilute ammonium chloride, dried with magnesium sulfate and concentrated. The product was purified by silica gel chromatography using 1% ethyl acetate/50% dichloromethane in hexanes to give {[2,6-difluoro-4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]thio}methyl acetate as a white solid (2.1 g, 82%), MP 130.3-130.3° C. 1H NMR (CDCl3/400 MHz) 7.34-7.43 (m, 5H), 6.73-6.79 (m, 2H), 5.29 (s, 2H), 2.49 (s, 3H) 2.05 (s, 3H). HRMS m/z 376.0822 (M+H+, Calcd 376.0819). Anal. Calcd for C19H15F2NO3S: C, 60.79; H, 4.03; N, 3.73. Found: C, 60.44; H, 4.09; N, 3.66.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[N:12]2[N:16]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[N:18]=[C:11]2[CH:10]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[N:12]2[N:16]=[C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:18]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCNCC3)nn12
Reaction time: 0.03 h

Procedure:
8.47 g (18.2 mmol) of tert-butyl 4-[7-(2,4-dichlorophenyl)-5-oxo-5,6-dihydro[1,2,4]triazolo[1,5-c]-pyrimidin-2-yl]piperidine-1-carboxylate (Example 42A) and hydrogen chloride in dioxane (4M, 90 ml) were stirred at RT for 3 h, the solvent was then concentrated to half of its original volume, diethyl ether (50 ml) was added and the reaction mixture was stirred for another 2 min. The solid was filtered off and dried. This gave 7.22 g (99% of theory) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=1>[Pd].CCO>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:4][C:3]=2[O:2][CH3:1])=[N:11][CH:12]=1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1Oc1ccc(N)cn1
Temperature: 40 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A mixture of tert-butyl {3-methoxy-4-[(5-nitropyridin-2-yl)oxy]phenyl}methylcarbamate (4.80 g) and palladium on carbon (5% wt., 1.36 g) in EtOH (100 mL) was stirred at 40° C. for 2 hours under a hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/2 to 3/7) to afford the title compound (3.58 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:7]2)[N:6]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]#[N:28])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3cccc(F)c3F)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 31.6 %

Procedure:
A mixture of 2′-amino-6-bromo-2-(2,3-difluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (25 mg, 0.05 mmol), 3-cyanophenylboronic acid (19.7 mg, 0.104 mmol), Pd(PPh3)2Cl2 (10 mg, 50%), aqueous cesium carbonate solution (2 M, 0.3 mL) in dry 1,4-dioxane (1 mL) was heated at 120° C. under microwave reactor for 30 minutes. The mixture was concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-(2,3-difluorophenyl)-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (7.02 mg, 27%). 1H-NMR (CDCl3): 2.20 (m, 2H), 3.12 (s, 3H), 6.25 (d, 1H), 6.77 (d, 1H), 7.13 (m, 3H), 7.29 (m, 1H), 7.34 (d, 1H), 7.43 (m, 1H), 7.48 (m, 2H), 7.51 (m, 1H), 7.61 (d, 1H), 7.68 (s, 1H), 7.78 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]1([C:13]([F:16])([F:15])[F:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Br:19][C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:3][C:2]([F:1])([F:17])[F:18])([C:13]([F:15])([F:14])[F:16])[O:5][C:6]=2[CH:12]=1
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Reactant: BrBr
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccc(Br)cc2O1

Procedure:
54.4 g of 2-(2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole were dissolved in 300 ml of carbon tetrachloride, and 0.4 g of anhydrous iron(III) chloride was added. 32 g of bromine were then added dropwise at the reflux temperature and the mixture was subsequently stirred until the reaction was complete (monitoring by gas chromatography). The mixture was then allowed to cool, and was washed with 10% strength by weight aqueous sodium hydrogen sulphide solution and water, dried with magnesium sulphate and concentrated. The residue was distilled in vacuo. The yield was 58 g (83% of theory), and the boiling point was 80° C. under 14 mbar. The characteristic absorptions in the NMR spectra were as follows: 19F-NMR: -59.2 and -84.9 ppm. 1H-NMR: 3.02 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].O1CCCC1.C(Cl)(=O)C([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:21])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A stirred solution of 0.22 gram (0.0012 mole) of 3-chloro-4-methoxybenzoic acid in a small amount of tetrahydrofuran and chloroform was cooled to 0° C., and 0.12 mL (0.0014 mole) of oxalyl chloride was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for about 3.5 hours. After this time the reaction mixture was concentrated under reduced pressure, yielding 3-chloro-4-methoxybenzoyl chloride, which was dissolved in a small amount of tetrahydrofuran for later use.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=2[O:24]1>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.C(#N)C>[O:24]1[C:25]2[CH:26]=[CH:27][C:28]([C:2]3[N:3]=[N:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]([CH:14]5[CH2:16][CH2:15]5)[CH2:10][CH2:9]4)=[CH:6][CH:7]=3)=[CH:29][C:30]=2[O:31][CH2:23]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1cc2c(cc1-c1ccc(N3CCN(C4CC4)CC3)nn1)OCO2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-Chloro-6-(4-cyclopropylpiperazin-1-yl)pyridazine (8.0 g, 33.5 mmol), acetonitrile (100 mL), 1 M sodium carbonate solution (100.5 mL, 100.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.17 g, 1.67 mmol) were mixed and degassed in vacuo under nitrogen. 3,4-Methylenedioxybenzeneboronic acid (8.34 g, 50.3 mmol) was added and the mixture was heated to 80° C. for 16 h. The precipitated product was filtered and washed with acetonitrile and water, and dried in vacuo. The solid was suspended in methanol (500 mL) and 2,2 equivalents of a 4M HCl in dioxane solution was added. The formed solution was filtered, concentrated in vacuo and acetonitrile (100 mL) was added. The suspension was stirred for 1 h, filtered and the solid dried in vacuo to yield 3-(1,3-benzodioxol-5-yl)-6-(4-cyclopropylpiperazin-1-yl)pyridazine as a yellow powder, 11.4 g, 86%.
Reaction SMILES: [OH:1]C(CCCCC)CCC1N(CCCCCCC(O)=O)C(=O)CS1.[OH:25][CH:26]([CH2:44][O:45][CH2:46][CH2:47][CH3:48])[CH2:27][CH2:28][CH:29]1[N:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:32](=[O:43])[CH2:31][S:30]1>>[OH:25][CH:26]([CH2:44][O:45][CH2:46][CH2:47][CH3:48])[CH2:27][CH2:28][CH:29]1[N:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:32](=[O:43])[CH2:31][S:30]1=[O:1]
Reactant: CCCCCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Reactant: CCCOCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Product: CCCOCC(O)CCC1N(CCCCCCC(=O)O)C(=O)CS1=O

Procedure:
This compound is prepared essentially by the method described in Example 2 except that the 7-[2-(3-hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid is replaced by 7-[2-(3-hydroxy-4-propoxybutyl)-4-oxo-3-thiazolidinyl]heptanoic acid. Column chromatography of the resulting product provides the title compound as a t.l.c. homogeneous oil.