Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][CH:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:3]([O:5][CH3:18])=[O:4]
Reactant: CO
Reactant: NC(Cc1ccc(Br)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-3-(4-bromophenyl)propanoic acid (2.0 g, 8.2 mmol, Chem-Impex, Cat. No. 06163) in methanol (10 mL) was added thionyl chloride (1.2 mL, 16 mmol) dropwise. The mixture was stirred at r.t. overnight and then concentrated under reduced pressure. The residue was washed with ether and dried under vacuum to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=258.2.
Reaction SMILES: C([O:8][C:9](=[O:19])[CH2:10][C:11]1([C:17]#[N:18])[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]1)C1C=CC=CC=1>[Pd].[O-]S([O-])(=O)=O.[Ba+2].CO>[C:17]([C:11]1([CH2:10][C:9]([OH:19])=[O:8])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:18]
Reactant: N#CC1(CC(=O)OCc2ccccc2)C=CCC=C1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: N#CC1(CC(=O)O)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
Added 5% Pd/BaSO4 catalyst (9.0 mg, 4.2 μmol) to a solution of (1-cyanocyclohexa-2,5-dienyl)acetic acid benzyl ester (1.00 g, 3.95 mmol) in MeOH (20 mL). After stirring the reaction mixture under an atmosphere of H2 at 0° C. for 0.5 hour and room temperature for 1.5 hours, additional 5% Pd/BaSO4 (75.8 mg, 35.6 μmol) was added. After stirring the reaction mixture under an atmosphere of H2 at 0° C. for 1 hour and room temperature for 19.5 hours, the reaction was filtered and concentrated under reduced pressure to afford 0.56 g (87%) of crude oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]([O:21][CH2:22][CH3:23])[C:17](Cl)=[N:18][CH:19]=1>CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]([O:21][CH2:22][CH3:23])[C:17]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:18][CH:19]=1
Reactant: CCOc1cc(Br)cnc1Cl
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(Br)cnc1OCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a mixture of (4-methoxyphenyl)methanol (16.71 g, 121 mmol) in DMF (200 mL) was added NaH (3.96 g, 165 mmol) at 0° C. After the mixture was stirred for 30 min, 5-bromo-2-chloro-3-ethoxypyridine (26 g, 110 mmol) was added to above mixture; the mixture was stirred for 12 h at 80-90° C. The mixture was quenched by H2O (20 mL), extracted with DCM (2×200 mL), dried over Na2SO4, filtered, and concentrated to give the residue which was purified by column chromatography (10% EA/90% PE, 360 g silica column). All fractions found to contain product by TLC (EA/PE=5:1, Rf=0.5) were combined and concentrated to yield a white solid of 5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (36 g, 74.5 mmol, 67.8% yield): 1H NMR (400 MHz, CD3OD) δ 7.71 (d, J=2.0 Hz, 1H), 7.36-7.31 (m, 3H), 6.89-6.87 (m, 2H), 5.27 (s, 2H), 4.05-4.00 (m, 2H) 3.77 (s, 3H), 2.37 (d, J=7.0 Hz, 3H); ES-LCMS m/z 338 (M+H).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1.Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[B:22](OC)([O:25]C)[O:23]C>C1COCC1.OS(O)(=O)=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([B:22]([OH:25])[OH:23])=[CH:15][CH:16]=1
Reactant: COc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: O=S(=O)(O)O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1

Procedure:
Intermediate 9H-Carbazole-9-akylamines 3 and 4 (Scheme 1). Both starting biphenyl derivatives 1a and 1b were synthesized by Suzuki coupling methodology [Martin, et al, Acta Chem. Scand. 47, 221-230 (1993); and Miyaura, et al, Syn. Commun., 11, 513 (1981)]. A Grignard reagent was prepared from 4-bromoanisole which was subsequently reacted with trimethyl borate in THF. Hydrolysis of the product in aqueous H2SO4 gave 4-methoxyphenylboronic acid. This was then coupled to 1-bromo-2-nitrobenzene or 4-bromo-3-nitroanisole in a mixture of (Ph3P)4Pd, aqueous Na2CO3, EtOH, and benzene to give 1a or 1b, respectively. The biphenyls 1a and 1b were subsequently refluxed in triethyl phosphite to give the carbazoles 2a and 2b. These were then alkylated with bromoacetonitrile in NaH/DMF to afford the respective carbazole-9-acetonitriles. The reduction of the nitriles was accomplished with Raney nickel and aqueous ammonia in 2-methoxyethanol to give the 9H-carbazole-9-ethanamines 3a and 3b. The propanamine 4 was prepared by conjugate addition of 2b to acrylonitrile in NaH/DMF, followed by reduction of the resulting propionitrile with Raney nickel in Ac20 to yield the propyl acetamide. Subsequent hydrolysis in 20% NaOH and EtOH gave the 9H-carbazole-9-propanamine 4. ##STR7##
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)(=O)C.[CH3:12][N:13]([CH3:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:16][CH:15]=1.[OH-].[NH4+]>C1(C)C=CC=CC=1.N1C=CC=CC=1.CO>[CH3:1][O:21][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([N:13]([CH3:34])[CH3:12])=[CH:19][CH:18]=2)[C:22]2[C:23](=[CH:27][C:28]([N:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)[C:24](=[O:26])[O:25]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: COC1(c2ccc(N(C)C)cc2)OC(=O)c2cc(N(C)C)ccc21
Temperature: 47 °C

Procedure:
To a stirred mixture of 30.0 ml of acetic anhydride and 15.0 ml of glacial acetic acid there was added gradually 5.0 g of 2-(4-dimethylaminophenyl)carbonyl-5-dimethylaminobenzoic acid. The reaction mixture was heated slowly to approximately 47° C. and maintained at a temperature in the range of 45° to 50° C. for approximately thirty minutes. The resultant mixture was cooled to ambient temperature, stirred approximately forty-five minutes and then cooled to approximately 0° C. A solution of 15.0 ml of methyl alcohol and 19.4 ml of pyridine was added dropwise to the reaction mixture while maintaining a temperature of approximately 0° C. The resulting mixture was allowed to stir at ambient temperature for approximately two hours. After adding toluene to the reaction mixture, five percent aqueous ammonium hydroxide was added slowly until the resulting mixture was slightly alkaline. The toluene layer was separated from the alkaline water layer and toluene was removed under reduced pressure to obtain 4.67 g of 3-methoxy-3-(4-dimethylaminophenyl)- 6-dimethylaminophthalide (Formula II: R0 =R=R2 =R5 =H; R1 =N(CH3)2 ; R4 =R4' =Y=CH3 ; X=O), a pale green-colored solid which melted at 140° to 147° C. A significant infrared maximum appeared at 1760 cm-1 (C=O;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure. A toluene solution of the product spotted on an acid-clay coated paper developed a turquoise-colored image.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+].[Sn](Cl)Cl>Cl>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: NNc1ccc(F)c(F)c1F
Yield: 33.8 %

Procedure:
2,3,4-Trifluoroaniline (25 g) was added to concentrated hydrochloric acid (125 ml), and an aqueous solution (20 ml) of sodium nitrite (12.9 g) was added dropwise under ice-cooling. A solution of tin (II) chloride (114.6 g) in concentrated hydrochloric acid (50 ml) was separately prepared and it was added dropwise to the reaction solution. The precipitated solid was collected by filtration, added to an aqueous solution of sodium hydroxide and the aqueous solution was extracted with toluene to give 2,3,4-trifluorophenylhydrazine (9.3 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[F:36])[C:30](Cl)=[O:31]>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([F:36])=[C:27]([F:26])[CH:28]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: COC(=O)c1c(CNC(=O)c2ccc(F)c(F)c2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
7-Methoxy-3-[(3,4-difluoro-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester was prepared starting from intermediate K and 3,4-difluorobenzoyl chloride. MS calcd. for C26H20F2N2O5 [(M+H)+] 479.1, obsd. 479.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[C:21]([Cl:22])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[Cl:23].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[C:14]([Cl:23])=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][C:21]=1[Cl:22])=[O:11]
Reactant: O=C(O)c1cc(Cl)c(CO)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1c(Cl)cc(C(=O)O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In a 1 liter 4-necked round-bottomed flask were place 300 ml of methylene chloride and cooled down to -78° C. 26.0 g (0.20 mole) of oxalyl chloride were added slowly, followed by dropwise addition of 35.4 g (0.452 mole) of dry dimethylsulfoxide in 25 ml of methylene chloride, keeping the temperature below -70° C. After the addition was completed the reaction mixture was stirred at -78° C. for 30 minutes and 50.0 g (0.226 mole) of 4-hydroxymethyl-3,5-dichlorobenzoic acid were added in 1 portion 82.5 g (0.817 mole) of triethylamine in 25 ml of methylene chloride were added dropwise, keeping the temperature below -65° C. The reaction mixture was warmed up slowly to room temperature and stirred during 90 minutes, washed with 2% aqueous sodium hydroxide (3×300 ml). The combined basic layers were washed with hexane (2×250 ml) then acidified with concentrated hydrochloric acid and then extracted with ethyl acetate (4×200 ml). The combined organic layers were washed with water (1×500 ml), and then with brine (1×300 ml) and dried over anhydrous magnesium sulfate. The solvent was then eliminated in a rotavap. The resulted oily product was triturated with hexane and filtered yielding 39.6 g (80% purity) 4-formyl-3,5-dichloro benzoic acid as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12](Cl)(Cl)=[O:13]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:12](=[O:13])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a mixture of 10.0 g (66.0 mmol) of 5-methylanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight at room temperature, followed by concentration in vacuo to a small volume. The concentrated reaction mixture was filtered through silica and the filter cake was washed with hexane to give 9.81 g (83.7%) of the 5-methylisatoic anhydride as a light yellow solid. MS (Cl mode) m/z 160 (M-18, 100%), 178 (M+H, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1
Reactant: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](COc1ccc(CC2SC(=O)NC2=O)cc1)N1C[C@@H](COc2cccc(Cl)c2)OC1=O
Yield: 80.9 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 0.96 g of 5-[4-{2(R)-[5(S)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 29), 4 ml of methylene chloride and 4 ml of trifluoroacetic acid were used, to give 0.52 g of the title compound having a melting point of 48° C. to 53° C. (softening) and having [α]D =+54.0° (methanol, c=1.000).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:14]([CH3:17])([CH3:16])[CH3:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[OH-].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:3]1[CH:4]=[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cc(C(C)(C)C)cc(C(C)(C)C)c1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COc1cc(C(C)(C)C)cc(C(C)(C)C)c1-c1ccc(Cl)cc1
Temperature: 75 °C

Procedure:
A solution of 9.0 g (30.1 mmol) of 2-bromo-1,5-di-tert-butyl-3-methoxybenzene (Zhang, H.; Kwong, F. Y.; Tian, Y.; Chan, K. S. J. Org. Chem. 1998, 63, 6886-6890) in 100 mL of DME was purged with nitrogen for 15 min and 1.5 g (0.13 mmol) of tetrakis(triphenylphosphine)palladium(0) was added. After stirring 20 min 5.0 g (31.9 mmol) of 4-chlorobenzeneboronic acid was added. The reaction mixture was stirred at 75° C. and 15 mL of 5 N sodium hydroxide was added dropwise. The resulting mixture was then stirred overnight at 80° C. The reaction mixture was then cooled to room temperature and the DME was removed in vacuo. The residue was partitioned between water and hexane containing 10% EtOAc and extracted. The organic layer was dried, filtered and evaporated to afford the title compound suitable for use in the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Ca].[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1>[NH4+].[Cl-]>[CH2:2]([CH:13]1[CH2:14][CH2:15][CH2:16][C:11](=[O:17])[CH2:12]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCl
Reactant: O=C1C=CCCC1
Agent: [Ca]
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCCCC1CCCC(=O)C1
Temperature: -35 °C
Yield: 87 %

Procedure:
The following experimental procedure is representative of the reactions set forth below in Table III. The organocalcium reagent (2.66 mmol) was prepared from 1-chlorooctane (395 mg, 2.66 mmol) and highly reactive calcium (3.10 mmol) as described above. An organocalcium cuprate reagent was prepared by adding lithium 2-thienylcyanocuprate (Aldrich Chemical Co., Milwaukee, Wis., 0.25M in THF, 14 mL, 3.50 mmol) to the calcium reagent via a syringe at -50° C. The reaction mixture was gradually warmed to -35° C. over a 30 minute period. The reaction mixture was cooled to -50° C. and 2-cyclohexen-1-one (210 mg, 2.18 mmol) was added via a disposable syringe. The resulting mixture was gradually warmed to room temperature. Saturated aqueous NH4Cl solution (20 mL) was added at room temperature. The reaction mixture was then filtered through a small pad of Celite™ filter agent and was washed with Et2O (50 mL). The aqueous layer was extracted with Et2O (2×30 mL). The combined organic phases were washed with H2O (3×15 mL) and dried over anhydrous MgSO4. Removal of solvent and flash-column chromatography on silica gel (70 g, 230-400 mesh, eluted sequentially with 50:1 hexanes/EtOAc and 10:1 hexanes/EtOAc) gave 3-octylcyclohexanone (401 mg, 87% yield): IR (neat) 2954, 2925, 2854, 1714, 1458, 1225 cm-1 ; 1H NMR (200 MHz, CDCl3) δ 1.10-2.50 (m, 23 H), 0.88 t, J=6.4 Hz, 3 H); 13C NMR (50 MHz, CDCl3) δ 212.0, 48.2, 41.5, 39.1, 36.6, 31.8, 31.3, 29.7, 29.5, 29.2, 26.6, 25.3, 22.6, 14.1.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:29])[O:15][C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]2[CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:23]1([C:16]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]3[CH2:9][NH:8][CH2:13][CH2:12][N:11]3[C:14](=[O:29])[O:15]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of (1,1-dimethylethyl)tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (2.3 g, 5.5 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added an aqueous saturated sodium hydrogen carbonate solution (10 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to obtain the title compound (1.6 g, yield 99%).
Reaction SMILES: [N:1]([CH:4]([C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[CH3:16][C:13]1[O:12][C:11]([CH:4]([NH2:1])[CH:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(N=[N+]=[N-])C2CCOCC2)o1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(N)C2CCOCC2)o1
Yield: 99.3 %

Procedure:
A solution of 3.09 g (14 mmol, 1 eq) of 4-[azido-(5-methylfuran-2-yl)methyl]tetrahydropyran in 60 ml of ethanol in the presence of 470 mg (15% by weight) of palladium on carbon at 10% was stirred at hydrogen atmospheric pressure for 17 hours. The reaction medium was filtered and the filtrate was evaporated. 2.715 g of C-(5-methylfuran-2-yl)-C-(tetrahydropyran-4-yl)methylamine were obtained. Yield=99%.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:15]1[S:16][C:17]3[C:18]([N:23]=1)=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=O.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C(Cl)Cl>[S:16]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:23]=[C:15]1[O:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([CH2:3][OH:2])[NH:6]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: OCc1cc2ccc(Oc3nc4ncccc4s3)cc2[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a cooled (0° C.) solution of 6-(thiazolo[4,5-b]pyridin-2-yloxy)-1H-indole-2-carboxylic acid methyl ester (1.0 g, 3.1 mmol) in DCM (30 mL) was added DIBALH (1 M in THF, 15.4 mL, 13.2 g, 15.4 mmol) and the reaction mixture was stirred (0° C., 2 h). The reaction mixture was treated with saturated aqueous NH4Cl (1 mL), partitioned with EtOAc (50 mL) and saturated aqueous Rochelle's salt (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH (0.2 M NH3):DCM (0-15%) to provide the title compound as yellow solid (287 mg, 31%). MS (ESI): mass calcd. for C16H11N3O2S, 297.1; m/z found, 298.0 [M+H]+. 1H NMR (400 MHz, CDCl3/CD3OD 10:1): 8.49 (dd, J=4.9, 1.6, 1H), 7.99 (dd, J=7.9, 1.6, 1H), 7.53 (d, J=8.5, 1H), 7.43 (d, J=2.0, 1H), 7.20 (dd, J=7.9, 4.9, 1H), 6.99 (dd, J=8.5, 2.2, 1H), 6.36 (s, 1H), 4.77 (s, 2H).
Reaction SMILES: [S:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1.[CH:8]1([CH2:14][CH2:15][Mg]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1.C(OCC)C>[S:1]1[C:5]([CH:6]([OH:7])[CH2:15][CH2:14][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][N:3]=[CH:2]1
Reactant: Br[Mg]CCC1CCCCC1
Reactant: O=Cc1cncs1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(CCC1CCCCC1)c1cncs1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A solution of thiazole-5-carboxaldehyde (2.31 g, 20.4 mmol) in 20 mL of in THF was added to a cold (0° C.) solution of 2-cyclohexylethylmagnesium bromide (prepared from 2-bromoethylcyclohexane (7.88 g) and magnesium turnings (1.22 g)) in 30 mL of ethyl ether and the mixture stirred 30 minutes. The cold bath was removed and the mixture stirred for 2 hours more and then quenched by the addition of 3N aqueous HCl. The solution was stirred until 2 clear phases resulted and then the layers were separated. The pH of the aqueous phase was adjusted to 4 with 2M aqueous sodium carbonate and then extracted with 3 portions of ethyl acetate. All the organic phases were combined and washed with brine, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (125 g, 50% ethyl acetate/hexanes) to provide 2.69 g (58%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1)#[CH:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1.CCN(CC)CC>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.[Cu]I>[Cl:15][C:16]1[N:21]=[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]2)[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2C#Cc2nc(Cl)ncc2Cl)CC1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
PdCl2(PPh3)2 (16 mg, 0.023 mmol) was added to a stirred solution of 1-(2-ethynylphenyl)cyclopropanecarboxamide (K6) (0.420 g, 2.26 mmol), 2,4,5-trichloropyrimidine (0.338 mL, 2.94 mmol), Et3N (1.26 mL, 9.07 mmol) and copper(I) iodide (8.6 mg, 0.045 mmol) in 1,4-dioxane (4.5 mL). The resulting mixture was stirred at 60° C. for 2.5 hours under a nitrogen atmosphere before being diluted with petroleum benzine 40-60° C. (25 mL). The resultant precipitate was filtered, dried, washed with water (50 mL) and dried to give the title compound A13 as light coloured tan solid (0.570 g, 75%); 1H NMR (300 MHz, d6-DMSO) δ 9.01 (s, 1H), 7.72 (d, J=7.1 Hz, 1H), 7.41-7.57 (m, 3H), 6.97 (brs, 1H), 6.20 (brs, 1H), 1.53 (dq, J=4.0 Hz, 2H) 1.06 (dq, J=3.7 Hz, 2H). LCMS-B: rt 6.593 min; m/z 332 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=O>C(O)C.C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[NH:17][C:16]2[CH:15]=[CH:14][CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=2[N:6]=1
Reactant: COCC(=O)Nc1c(C(=O)OC)cccc1[N+](=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: COCc1nc2c(C(=O)OC)cccc2[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
[step 2] methyl 2-(2-methoxyacetamido)-3-nitrobenzoate (1.9 g, 6.9 mmol) obtained in step 1 was dissolved in a mixed solvent of ethanol (14 mL) and acetic acid (14 mL), reduced iron (2.3 g, 41.4 mmol) was added, and the mixture was stirred at 120° C. for 3 hr. After completion of the reaction, the mixture was filtered through celite. Saturated aqueous sodium hydrogen carbonate was added to the solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-20/80 v/v) to give methyl 2-(methoxymethyl)-1H-benzo[d]imidazole-4-carboxylate (1.1 g, 71%).