Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:17])=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1
Reactant: CON(C)C(=O)c1ccc(Cl)c(-n2cccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)c(-n2cccc2)c1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
A solution of 1.5 g of N-methoxy-N-methyl-4-chloro-3-(1H-pyrrol-1-yl)benzamide in 30 ml of anhydrous tetrahydrofuran was added drop-wise over a period of 30 minutes to a solution, pre-cooled to 0-5° C., of 237 mg of lithium aluminium hydride (98%) in 30 ml of anhydrous tetrahydrofuran. The mixture was stirred at 0-5° C. for a further 45 minutes and ther reaction was then quenched by the adition of 25 ml of saturated aqueous ammonium chloride solution and 25 ml of 50% aqueous hydro-chloric acid. The mixture was then extracted with three 100 ml portions of diethyl ether and the combined extracts were dried over anhydrous magnesium sulphate. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate (90:10) as the eluent to give 0.84 g of 4-chloro-3-(1H-pyrrol-1-yl)benzaldehyde as a yellow oil; nmr (CDC13, 250 Mhz) dH 10.00 (CHO).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([N:17]=[C:18]=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Si]([O:27][C:28]1[CH:33]=[C:32]([O:34][Si](C(C)(C)C)(C)C)[CH:31]=[CH:30][C:29]=1[C@H:42]1[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]1)(C(C)(C)C)(C)C>CN(C)C=O>[CH2:10]([NH:17][C:18](=[O:19])[O:48][C@H:45]1[CH2:44][CH2:43][C@H:42]([C:29]2[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=2[OH:27])[CH2:47][CH2:46]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Diisopropylethylamine (398 μl) and benzylisocyanate (154 μl) was added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (200 mg) in anhydrous dimethylformamide (1 ml). After 16 hr at 50° C., the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml) and stirred for 16 hr at room temperature. The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to give the title compound (20 mg, 13%) as a pale yellow gum. δH (CD3OD) 1.40-1.60 (4H, m), 1.80-1.90 (2H, m), 1.00-1.20 (2H, m), 2.70-2.82 (1H, m), 4.20-4.30 (2H, s), 4.55-4.65 (1H, m), 6.20-6.30 (2H, m), 6.86 (1H, d), 7.15-7.40 (5H, m); m/z (ES+) 342 (M+H+).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC[C@H](C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)nc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC[C@H](C)NC(=O)c1ccc(-c2cc(C(=O)NC3CC3)cc(F)c2C)[n+]([O-])c1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1-methyl-2-(methyloxy)ethyl]-3-pyridinecarboxamide (Intermediate 13, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1-methyl-2-(methyloxy)ethyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH3:11])[CH2:7][C:8](O)=[O:9])=[O:4].Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]([CH3:11])[CH2:7][C:8]([N:32]1[CH2:31][CH2:30][C:29]2[C:34](=[CH:35][C:26]([C:24]3[CH:25]=[C:20]([N:17]4[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]4)[N:21]=[C:22]([NH2:36])[N:23]=3)=[CH:27][CH:28]=2)[CH2:33]1)=[O:9]
Reactant: COC(=O)NC(C)CC(=O)O
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: COC(=O)NC(C)CC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from 3-[(methoxycarbonyl)amino]butanoic acid and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=468.2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>C1COCC1>[C:12]([NH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1)(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Cl
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Temperature: 25 °C

Procedure:
100.0 mg (0.77 mmol) (1R,3S)-3-Aminocyclopentane carboxylic acid is stirred in 2.0 mL THF and 0.77 mL (1.55 mmol) sodium hydroxide solution (2 mol/l). 74.0 μL (0.85 mmol) Propionyl chloride is added drop wise and the mixture is stirred at RT over night. The solvent is evaporated. The mixture is stirred at RT over night. The product is purified by RP-HPLC (water+5-95% acetonitrile (with addition of 0.1% TFA)) and lyophilized.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1
Reactant: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Cl)cc2n1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(-c3ccc(Cl)cc3Cl)cc2n1

Procedure:
In analogy to the procedure described for Example 7, 9.3 mg (13% of theory) of the product are obtained starting from 60 mg (0.15 mmol) of N6-{2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 23A) by coupling with 29.3 mg (0.15 mmol) of (2,4-dichlorophenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([CH2:11][NH2:12])[OH:10].C(N(CC)CC)C>ClCCl>[Si:1]([O:10][CH2:9][CH2:11][NH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyldimethylsilylchloride (24.87 g, 165 mmol) was added portion wise to a solution of ethanolamine (11.84 mL, 150 mmol) in triethylamine (46.0 mL, 330 mmol) and dichloromethane (100 mL) at 0° C. The reaction was stirred at this temperature for 1 hour and then allowed to warm to room temperature. After 16 hours, the reaction mixture was washed with sodium hydrogen carbonate solution (2×50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo to give 2-(tert-butyldimethylsilyloxy)ethylamine as a colourless oil. Yield: 24.1 g, 137 mmol, 92%. 1H NMR (400 MHz, CDCl3) δ: 3.63 (2H, t), 2.78 (2H, t), 0.91 (9H, t), 0.07 (6H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[C:66]([O:74][CH3:75])[CH:65]=1>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][C:66]=1[O:74][CH3:75]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1OC
Yield: 5.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.25 g, 1.1 mmol), then reacted with methyl 4-amino-2-methoxybenzoate (Acros) (0.077 g, 0.43 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-2-methoxy-benzoic acid methyl ester as a white solid (Yield 0.012 g, 54%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][CH:18]([F:28])[C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1.O>CN(C)C=O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=[C:19]2[CH:18]([F:17])[F:28])[CH:7]=1
Reactant: FC(F)c1nc2ccccc2[nH]1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(Cl)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
To a solution of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (5 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (5.3 g) and 2-(difluoromethyl)-1H-benzimidazole (3.9 g), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (5.49 g) as a white powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([Cl:3])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CC(=O)O)cc1OC
Solvent: ClCCl
Product: COc1ccc(CC(=O)Cl)cc1OC

Procedure:
First, thionyl chloride (600 ml) is added dropwise with stirring over a period of 2 hours to a suspension of 3,4-dimethoxy-phenylacetic acid (549.4 g) in methylene chloride (600 ml). After the evolution of gas has ended (16 hours) the mixture is refluxed for a further hour. After the volatile components have been eluminated the residue is distilled in vacuo.
Reaction SMILES: O=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]1([C:10]([O:12]C)=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH2:26])[CH3:22].CC(O)=O.[BH3-]C#N.[Na+]>CCO>[O:12]=[C:10]1[C:5]2([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][C@@H:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:26]1[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:27]
Reactant: CCOC(=O)CN
Reactant: COC(=O)C1(NCC(=O)c2ccccc2)CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)C2(CCCC2)NC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred mixture of methyl 1-[(2-oxo-2-phenylethyl)amino]cyclopentanecarboxylate from Step A (1.10 g, 2.67 mmol) and glycine ethyl ester hydrochloride (881 mg, 6.31 mmol) in EtOH (10 mL) was added AcOH (0.72 mL, 12.6 mmol). The resulting mixture was stirred at ambient temperature for 5 min, then NaCNBH3 (397 mg, 6.31 mmol) was added. The reaction mixture was heated to 70° C. for 3 h then allowed to cool. The reaction mixture was quenched with saturated aqueous NaHCO3 and then extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the racemic product. The enantiomers were separated by HPLC, using a Chiralcel OD column and eluting with hexane:EtOH—60:40. The first major peak to elute was ethyl [(8S)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate and the second major peak to elute was ethyl [(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate, the title compound. MS: m/z=317 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:4]=1[N:11]=[CH:12][N:13](C)C)#[N:2].Cl.[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][CH2:22]N.C(O)C>C(O)(=O)C>[F:9][C:8]1[CH:7]=[CH:6][C:5]([F:10])=[C:4]2[C:3]=1[C:1]([NH:2][CH2:22][CH2:21][C:20]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([CH3:17])[CH:19]=1)=[N:13][CH:12]=[N:11]2
Reactant: CN(C)C=Nc1c(F)ccc(F)c1C#N
Reactant: COc1ccc(CCN)cc1C
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CCNc2ncnc3c(F)ccc(F)c23)cc1C
Yield: 58 %

Procedure:
N′-(2-Cyano-3,6-difluorophenyl)-N,N-dimethylformamidine (1.65 g, 7.9 mmol) and 3-methyl-4-methoxyphenethylamine hydrochloride (2.4 g, 11.8 mmol) were combined in acetic acid (2.55 mL) and absolute ethanol (15 mL) and heated to reflux for 16 h. Upon cooling, the solvent was removed under reduced pressure and the remaining solid was slurried with water, suction filtered and washed with water, dried in vacuum at 45° C. to give 1.51 g (58%) of (5,8-difluoroquinazolin-4-yl)-[2-(4-methoxy-3-methylphenyl)-ethyl]-amine as an off-white solid. LC/MS: 330.18 (M++1). 1H NMR (CDCl3): δ 8.67 (s, 1H), 7.35 (m, 1H), 6.94-7.09 (m, 3H), 6.79 (d, J=9.0 Hz, 1H), 6.65-6.80 (br, 1H), 3.87 (q, J=6.9 Hz, 2H), 3.83 (s, 3H), 2.93 (t, J=6.9 Hz, 2H), 2.22 (s, 3H). M.P. 162-169° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: Sc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(Br)cc1

Procedure:
4-Bromothiophenol (100 g) and tert-butyl 2-bromoisobutyrate (118 g) are dissolved in 1 l of ethanol and treated with 29 g of KOH. The mixture is stirred under reflux for 2 h and cooled, and the KBr is filtered off. The filtrate is concentrated and the residue is recrystallized from n-hexane. This gives 93.6 g of a colourless solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14].[I-].[Na+].O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)COC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-hydroxybenzoic acid (1.38 g, 0.01 mol), 2-chloro-N,N-diethylacetamide (1.4 g, 0.01 mol) triethylamine (1.44 ml. 0.01 mol) and sodium iodide (150 mg, 0.001 mol) in N,N-dimethylformamide (6 ml) was stirred at room temperature for 18 h. Water (100 ml) was added and the mixture allowed to stand at 4° C. for 5 h. The title compound was isolated by filtration, washed with water and recrystallized from ethanol-water to give 1.8 g. Mp 148°-149° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: C1CCNNC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(N2CCCCN2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (2.36 g, 13.6 mmol), the hydrochloride salt of the hexahydro-pyridazine (5.0 g, 41 mmol) and anhydrous potassium carbonate (11.3 g, 82 mmol) in N,N-dimethylacetamide (20 ml) was stirred at 115-120° C. under nitrogen for 3 days. A sample was analyzed by NMR showed complete conversion of the starting material. The resultant mixture was cooled to room temperature, poured onto cold water (200 mL), stirred vigorously and incubated at 4° C. overnight. The resulting brown precipitate was collected by filtration, washed well with water and dried on the filter funnel. This was then slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 2-Nitro-5-(tetrahydro-pyridazin-1-yl)-phenylamine (1.9 g, 62.5%). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]([CH3:61])[C:55]([CH3:60])([C:57](O)=[O:58])[CH3:56])=[O:53])([CH3:50])([CH3:49])[CH3:48].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:47]([O:51][C:52]([N:54]([CH3:61])[C:55]([CH3:60])([C:57]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:58])[CH3:56])=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OC(C)(C)C)C(C)C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a mixture of #86 (80.3 mg, 0.122 mmol, 1 eq.) in dichloromethane (4 mL, 0.03 M) was added N-(tert-butoxycarbonyl)-N,2-dimethylalanine (29.1 mg, 0.134 mmol, 1.1 eq.) followed by diisopropylethylamine (64 μL, 0.365 mmol, 3 eq.) and HATU (71.7 mg, 0.183 mmol, 1.5 eq.) After stirring overnight, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (6 mL) and washed with 1 M aqueous hydrochloric acid solution (2×2 mL) and with brine. The organic solvent was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in dichloromethane and filtered; the filtrate was concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane) to afford #87 (58 mg, 50%) as a white solid. LC-MS: m/z 857.7 [M+H+], 879.7 [M+Na+], retention time=0.99 minute; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8 Hz) and 8.87 (br d, J=9 Hz), total 1H], [7.77 (d, J=3.3 Hz) and 7.80 (d, J=3.3 Hz), total 1H], [7.63 (d, J=3.2 Hz) and 7.66 (d, J=3.2 Hz), total 1H], 7.13-7.31 (m, 5H), [6.95 (br d, J=8 Hz) and 7.06 (br d, J=8 Hz), total 1H], 5.35-5.42 and 5.51-5.58 (2 m, total 1H), 3.15, 3.19, 3.20 and 3.26 (4 s, total 6H), 2.94 and 3.03 (2 br s, total 3H), 2.83 and 2.84 (2 s, total 3H), [1.05 (d, J=6.7 Hz) and 1.11 (d, J=6.7 Hz), total 3H].
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([F:13])[CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([F:13])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cc(F)cc(Br)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Yield: 66.3 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol (11.5 g, 0.047 mol) with p-toluenesulfonyl chloride (9.76 g, 0.051 mol) generally according to the procedure described for Intermediate 10 gave 12.50 g (66%) (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.44 (silica, ethyl acetate:hexanes 1:4); mp 84-86° C.; Anal. calcd. for C16H14BrFO4S: C, 47.89; H, 3.52. Found: C, 47.65; H, 3.63.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].C([Li])CCC.[Br-].[Mg+2].[Br-].[C:16]([O:20]OC(=O)C1C=CC=CC=1)([CH3:19])([CH3:18])[CH3:17]>C(OCC)C>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[O:20][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Reactant: Brc1ccsc1Br
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)(C)Oc1sccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A -78° C. solution of 2,3-dibromothiophene (Aldrich, 10.0 g, 41.3 mmol) in 150 mL of diethyl ether was treated with n-butyl lithium (2.5 M, 16.5 mL) over a 20 min period. The mixture was stirred 1h at -78° C. Magnesium bromide (13.0 g, 49.6 mmol) was added as a solid in two portions. The mixture was stirred at -780° C. for 1h and rt for 2h. t-Butylperbenzoate was added at 0° C. and the reaction was allowed to stir at ambient temperature overnight. The mixture was quenched with ice water (50 mL) and 2N HCl (25 mi). The organic layer was separated and washed once with ice cold 1 N NAOH, water and brine. The organic layer was dried over magnesium sulfate and concentrated to give 10.5 g (98%) of the title compound: MS: m/z 236 MH+); 1H NMR(CDCl3): d 1.36 (s, 9H), 6.61 (d, j=6.1 Hz, 1H) and 7.23 (d, J=6.1 Hz, 1H).