Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.Br[CH2:12][CH2:13][CH2:14][C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:3][O:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: COCC1CCCN1
Reactant: N#CCCCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1CCCN1CCCCN
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-(methoxymethyl)pyrrolidine (300 mg, 2.61 mmol) and 4-bromobutyronitrile (0.31 mL, 2.99 mmol) in dry CH3CN (13 mL) was added K2CO3 (1.51 g, 10.94 mmol) at rt followed by KI (43 mg, 0.26 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (21 mL) and treated with LiALH4 (192 mg, 5.07 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Sat. aq. Rochelle's salt solution and EA were then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(2-(methoxymethyl)pyrrolidin-1-yl)butan-1-amine as a pale yellow oil. GC-MS-conditions 01: tR=2.1 min; [M+H]+=187.20.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1[C:41]([F:44])([F:43])[F:42])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.O>[F:42][C:41]([F:43])([F:44])[C:32]1[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:31]=1[N:30]1[C:18](=[O:19])[C:11]2[C@@H:12]3[C:15]([CH3:17])([CH3:16])[C@@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CN(Nc1ccc(C(F)(F)F)cc1C(F)(F)F)C(=O)OC(C)(C)C
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: Cn1c2c(c(=O)n1-c1ccc(C(F)(F)F)cc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 66.5 %

Procedure:
Triethylamine (840 μL, 6.0 mmol) was added to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 612 mg, 2.9 mmol) in 1,2-dichloroethane (8 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of N′-(2,4-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (646 mg, 1.8 mmol) in 1,2-dichloroethane (14 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 30 min, and then in an oil bath at 50° C. for 30 min. An additional portion of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 0.6 g, 2.8 mmol) in 1,2-dichloroethane (6 mL) was added and the mixture was heated at 50° C. for 45 min. The reaction mixture was allowed to cool. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the reaction mixture was heated at reflux for 1 h, allowed to cool, poured into water (200 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (magnesium sulfate), filtered, evaporated, and chromatographed, eluting with 40% ethyl acetate/hexanes) to give (4S,7R)-2-(2,4-bis-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (501 mg, 66%) as an off-white solid. APCI(+)-MS (M+H) 419.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[CH:13][O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>N1C=CC=CC=1>[F:26][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:24])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:19][CH:18]=3)=[CH:13][O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2=O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(-c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a suspension of 3-(4-aminophenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (2.2 g, 7.12 mmol) in pyridine (10 mL) at 0° C. was added methanesulfonyl chloride (1.1 mL, 14.24 mmol) over 5 minutes, and then warmed up to room temperature under stirring conditions. After 2 hours the reaction was complete, and water was added in portions under vigorous stirring. The organic phase was then separated and concentrated and the resulting solids were filtered and dried under high vacuum. The solids were heated in acetonitrile, stirred until room temperature was achieved, then filtered off to give 3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (2.49 g). 1H NMR (DMSO, 400 MHz) δ 9.87 (s, 1H); 8.60 (s, 1H); 8.31 (d, J=8.0 Hz, 1H); 8.09 (s, 1H); 7.65 (d, J=8.0 Hz, 1H); 7.57 (d, J=8.4 Hz, 2H); 7.27 (d, J=8.4 Hz, 2H); 3.01 (s, 3 H).
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[C@H:10]1[OH:23])#[N:2].[C:24](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[C:1]([N:3]=[C:4]1[N:8]([CH3:24])[CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:21])([CH3:22])[C@H:10]1[OH:23])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1=NC#N
Temperature: 80 °C
Reaction time: 5 h
Yield: 19.1 %

Procedure:
To a mixture of trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.50 g) and potassium carbonate (0.66 g) in N,N-dimethylformamide (5 ml) was added methyl iodide (0.30 ml). The reaction mixture was stirred at 80° C. for 5 hours, poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic layer was washed successively with aqueous sodium bisulfite (25 ml) and brine (25 ml), dried over magnesium sulfate, and then evaporated in vacuo. The residue was subjected to column chromatography on silica gel (15 g) and eluted with chloroform and then a mixture of chloroform and methanol (50:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from isopropyl alcohol to give trans-4-(2-cyanoimino-3-methylimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.10 g).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:9][O:8][C:6](=[O:7])/[CH:5]=[CH:4]/[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[O:1][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: COC(=O)C=Cc1ccccc1O
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)/C=C/c1ccccc1OCCCCCBr

Procedure:
A mixture of 0.64 g (3.59 mmol) of methyl 2-hydroxycinnamate, 6.6. g (28.7 mmol) of 1,5-dibromopentane, 2 g (14.5 mmol) of anhydrous, granular potassium carbonate, and 25 mL of acetonitrile was stirred and refluxed for 24 hr. The resulting slurry was cooled, diluted with ether, and filtered with suction. The solids were washed well with ether. The filtrate and washes were combined and concentrated under reduced pressure. The oily residue was flash chromatographed on silica gel, eluting with 5:1 hexane-ether giving 1 g (85%) of (E)-3-[2-[(5-bromopentyl)oxy]phenyl]-2-propenoic acid methyl ester as a solid.
Reaction SMILES: [O-:1]Cl=O.[Na+].[N:5]([C:8]1[N:9]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]([CH:14]=[O:15])=[C:11]([Cl:13])[N:12]=1)=[N+:6]=[N-:7].CC(=CC)C>O.C1COCC1.CC(O)(C)C>[N:5]([C:8]1[N:9]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]([C:14]([OH:1])=[O:15])=[C:11]([Cl:13])[N:12]=1)=[N+:6]=[N-:7]
Reactant: C[Si](C)(C)CCOCn1c(N=[N+]=[N-])nc(Cl)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(N=[N+]=[N-])nc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaClO2 (21.7 g, 240 mmol) and NaH2PO4.2H2O (19.9 g, 144 mmol) in H2O (51 mL) was added to a stirred solution of 2-azido-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carbaldehyde (7.2 g, 24.0 mmol) and 2-methyl-2-butene (144 mL of a 2M solution in THF, 2887 mmol) in THF (72 mL) and t-BuOH (17 mL). The reaction mixture was stirred at RT for 1 h and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and dried to provide 2-azido-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid as a clear oil that was assumed to be quantitative and used without further purification. The above acid (1.40 mmol) was stirred in a solution of TFA (2.15 mL, 27.9 mmol) in CH2Cl2 (2 mL) for 1 h at RT. Sat'd NaHCO3 was added and the mixture was washed with EtOAc. The aqueous layer was isolated, acidified with 1N HCl and extracted thoroughly with EtOAc. The organic layer was dried (Na2SO4), filtered, concentrated, and triturated with hexanes and again with diethyl ether to provide the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.33 (br. s., 1H), 12.77 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])=[O:5])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:32]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[O:9][C:10]=1[CH2:11][Br:32])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1CBr
Yield: 135.7 %

Procedure:
To a boiling solution of 6.0 g 2-(4-methoxy-phenyl)-5-methyl-oxazole-4-carboxylic acid ethyl ester in 100 ml tetrachloro-methane were added portionwise a mixture of 1.51 g 2,2′-azobis(2-methylpropionitrile) and 4.9 g N-bromosuccinimide. The reaction mixture was refluxed for three hours. The cooled reaction mixture was filtered over a celite pad and the solvent removed in vacuo to obtain 10.6 g of crude 5-bromomethyl-2-(4-methoxy-phenyl)-oxazole-4-carboxylic acid ethyl ester, which contains to some extend the dibrominated byproduct. The material was used without further purification in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([NH:15][CH:16]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:22]=[N:23][C:24]([NH2:28])=[C:25]([CH3:27])[CH:26]=1)[CH3:17])=O)(C)(C)C>C1(OC)C=CC=CC=1>[CH3:13][NH:15][CH:16]([CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:22]=[N:23][C:24]([NH2:28])=[C:25]([CH3:27])[CH:26]=1)[CH3:17]
Reactant: Cc1cc(/C=C/CC(C)NC(=O)OC(C)(C)C)cnc1N
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1cnc(N)c(C)c1
Reaction time: 0.75 h
Yield: 12.2 %

Procedure:
Under a nitrogen atmosphere, trifluoroacetic acid (17.76 g, 155.76 mmol) was added dropwise, via addition funnel, over 30 min to a cold (0–5° C.), stirring solution of (4E)-N-(tert-butoxycarbonyl)-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine (1.11 g, 3.47 mmol) in anisole (15 mL). The resulting solution was stirred for 45 min at 0–5° C. and was then concentrated by rotary evaporation. The viscous, brown oil was further dried under high vacuum for 18 h. The crude product was cooled (0–5° C.), basified with 10% NaOH solution (10 mL), treated with saturated NaCl solution (10 mL), and extracted with CHCl3 (5×10 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying under high vacuum yielding a dark-brown oil. The crude product was purified by column chromatography on silica gel (50 g), eluting with CHCl3—CH3OH-Et3N (4:1:1, v/v/v). Selected fractions containing the product (Rf 0.13) were combined and concentrated by rotary evaporation, and the residue was re-chromatographed on silica gel (50 g) eluting with CHCl3—CH3OH (7:3, v/v). Fractions containing the product (Rf 0.12) were combined and concentrated by rotary evaporation. The residue was dissolved in CHCl3, and the CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried affording a yellow oil (0.087 g) which tended to crystallize. The semi-crystalline material was dissolved in a warm solution of hexane containing a small amount of ethyl acetate. The warm solution was decanted from an insoluble gum. The solution was allowed to cool to ambient temperature and was further cooled at 5° C. for 18 h. The resulting crystalline solids were collected, washed with hexane, and vacuum dried at 40° C. for 16 h. The yield was 30.8 mg (4.3%) of a light-yellow powder, mp 78–81° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:17])=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:17])=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=1)=[O:4]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
To a round bottom flask was added chloroacetyl chloride (2.0 mL, 25.0 mmol, 1.0 eq.) and CH2Cl2 (100 mL). The solution was cooled to 0° C. before a mixture of 5-amino-2-chloro-benzotrifluoride (4.88 g, 25.0 mmol, 1.0 eq.) and triethyl amine (3.56 mL, 27.5 mmol, 1.1 eq.) in CH2Cl2 (5.0 mL) was added dropwise. The reaction was then stirred at 0° C. for 1.5 h before quenching with H2O (50 mL). The organic layer was then separated, washed with brine, and dried with Na2SO4. Concentration via rotary evaporation gave acetamide 21 as a yellow solid (5.72 g, 84.7% yield). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.79 (br s, 1H), 8.20 (d, 1H), 7.87 (dd, 1H), 7.75 (d, 1H), 4.36 (s, 2H) ppm.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.O.[NH2:12][NH2:13].O>C(O)C>[NH:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1)[NH2:13]
Reactant: NN
Reactant: Cc1nc(Cl)ccc1C#N
Solvent: CCO
Solvent: O
Product: Cc1nc(NN)ccc1C#N
Temperature: 80 °C
Yield: 59.9 %

Procedure:
To a suspension of 6-chloro-2-methylnicotinonitrile (6.2 mmol) in 6.2 mL of ethanol, hydrazine monohydrate (9.3 mmol) was added. The resulting mixture was then heated to 80° C. overnight. The mixture was cooled to room temperature and 2 mL of water was added. It was heated to 80° C. again to a clear solution and then allowed to cool down to room temperature and finally in an ice-bath. The solid was collected by filtration, washed with cold 50% ethanol, and dried under vacuum to give 550 mg of the desired solid product. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.41 (s, 3H), 4.41 (s, 2H), 6.60 (br. s., 1H), 7.66 (d, J=8.59 Hz, 1H), 8.47 (s, 1H); ES-MS m/z 149 (M+H).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH3:15])=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH:20]=[N:19]1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu](I)I>[CH3:15][C@@H:11]1[CH2:12][CH2:13][CH2:14][N:10]1[CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:16]=[CH:17][C:2]([N:18]2[CH:22]=[C:21]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])[CH:20]=[N:19]2)=[CH:3][CH:4]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(I)cc1
Reactant: O=C(c1cn[nH]c1)N1CCOCC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N3CCOCC3)cn2)cc1
Temperature: 25 °C

Procedure:
A suspension of (2R)-1-[3-(4-iodophenoxy)propyl]-2-methylpyrrolidine obtained in Example 1-(2) (0.30 g), 4-(1H-pyrazol-4-ylcarbonyl)morpholine obtained in Example 6-(1) (0.19 g), (rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.049 g), copper iodide (0.017 g) and cesium carbonate (0.57 g) in N,N-dimethylformamide (0.5 mL) was stirred at 120° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=2:1 to 1:1). The resulting crystal was washed with isopropyl ether to give the titled compound (0.20 g) as a white solid.
Reaction SMILES: [Na].[S:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:4]=[N:3]1.[N:12](OCCC(C)C)=[O:13]>CO>[OH:13][N:12]=[C:7]([C:5]1[CH:4]=[N:3][S:2][CH:6]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(C)CCON=O
Reactant: COC(=O)Cc1cnsc1
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=NO)c1cnsc1
Yield: 61 %

Procedure:
A solution of sodium (1.01 g.) in absolute methanol (10 ml.) was dropwise added over 15 minutes with stirring and ice-cooling to a solution of methyl 2-(isothiazol-4-yl)acetate (6.30 g.) and isopentyl nitrite (10.6 g.) in absolute methanol (63 ml.). The mixture was stirred for 30 minutes at the same temperature and for 3 hours at ambient temperature. The reaction mixture was concentrated and the residue was poured into a mixture of ethyl acetate (50 ml.) and water (50 ml.). The aqueous layer was separated and the ethyl acetate layer was extracted twice with 1 N aqueous solution of sodium hydroxide (20 ml. and 10 ml.). The extracts and the aqueous layer separated above were combined, adjusted to pH 1 with 10% hydrochloric acid and extracted twice with ethyl acetate (70 ml. and 50 ml.). The extracts were washed with a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 2-hydroxyimino-2-(isothiazol-4-yl)acetate (anti isomer) (4.55 g.), mp 110° to 112° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[CH:18].N1CCCCC1>O.[Cu](I)I>[CH3:15][C:16]([CH3:20])([CH3:19])[C:17]#[C:18][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: C#CC(C)(C)C
Agent: I[Cu]I
Solvent: C1CCNCC1
Solvent: O
Product: CC(C)(C)C#Cc1ccc(S(=O)(=O)n2cccc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
A mixture of N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol), 3,3-dimethyl-1-butyne (338 mg, 4.1 mmol), copper iodide (39 mg, 0.21 mmol), tetrakistriphenylphosphine palladium [Pd(PPh3)4] (118 mg, 0.1 mmol) and piperidine (5 ml) was stirred at room temperature for a period of 24 hours under a nitrogen atmosphere. The mixture was then diluted with water (10 ml) and extracted with 3×25 ml portions of ether. The combined ether extracts are washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and crude product purified by column chromatography using 2% ethyl acetate/hexanes to give 423 mg N-[5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonyl]pyrrole as a yellow powder (70% yield).
Reaction SMILES: [S:1]1[C:5]2[C:6](=O)[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1Nc2ccccc2Cc2ccsc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1ccsc1CN2
Yield: 64.2 %

Procedure:
A stirred solution of 2.0 g of the product of Example 6 and 500 mg of lithium aluminum hydride in 200 ml of tetrahydrofuran is refluxed for 4 hours. The reaction mixture is carefully quenched with ice cold water and extracted with chloroform. The organic layer is washed well with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a residue. The residue is purified by column chromatography on silica gel by elution with 30% ethyl acetatehexane to give 1.2 g of the desired product as a bright yellow solid, M+ =202.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:4][OH:5].[OH-].[K+].C1C[O:18][CH2:17]C1.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl>O.C(OCC)(=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C@H:3]2[CH2:4][O:5][C:17](=[O:18])[NH:2]2)=[CH:7][CH:8]=1
Reactant: N[C@H](CO)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1N[C@@H](c2ccc(F)cc2)CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of (S)-2-amino-2-(4-fluorophenyl)ethanol hydrochloride (2.0 g, 10 mmol) in water (50 mL) cooled to 0° C. was added potassium hydroxide (3.5 g, 63 mmol) followed by THF (50 mL) and the reaction was stirred for 20 minutes at 0° C. Bis(trichloromethyl) carbonate (3.1 g, 10 mmol) was added as a solid and the reaction was stirred at 0° C. for 2 hours. The reaction was poured into ethyl acetate (200 mL) and the organic layer was washed with HCl (1N, 30 mL), NaOH (1N, 30 mL) and brine (30 mL), dried over MgSO4 and concentrated under vacuum to give (S)-4-(4-fluorophenyl)oxazolidin-2-one (1 g, 53%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:27]=[C:26]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([NH:14][C:15]2[CH:27]=[C:26]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:25]=[CH:24][C:16]=2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To toluene 1.0 mL solution of 4-bromobiphenyl 0.12 g were added 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 4.8 mg, tert-butyl 2-amino-4-phenethylbenzoate 60 mg, cesium carbonate 0.13 g, palladium acetate 0.50 mg and tris(dibenzylideneacetone)dipalladium(0) 1.8 mg at room temperature, and it was heated and refluxed for 5 hours and 30 minutes. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 4.8 mg, palladium acetate 0.50 mg and tris(dibenzylideneacetone)dipalladium(0) 1.8 mg were added to it, and it was heated and refluxed for 7 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=200:1] to give tert-butyl 2-((biphenyl-4-yl)amino)-4-phenethylbenzoate 50 mg of a yellow oil.