Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(S)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: OB(O)c1ccc(SC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-mercaptophenylboronic acid (20.7 mg, 0.135 mmol) in DCM (2.00 mL) was added dihydropyran (0.06140 mL, 0.6730 mmol) and pyridinium p-toluenesulfonate (3.38 mg, 0.0135 mmol) at 0° C. The resulting mixture was then stirred at rt overnight. Solvent was then removed under reduced pressure to give crude product which was used for next step without further purification.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][C:14]2[C:13]([CH3:22])([CH3:21])[CH2:12][CH2:11][C:10]([CH3:24])([CH3:23])[C:9]=2[CH:8]=1)\[CH3:6])/[CH:3]=O.[OH-].[Na+].[CH3:27][C:28]([CH3:30])=[O:29]>>[F:1]/[C:2](=[C:5](/[C:7]1[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][C:14]2[C:13]([CH3:22])([CH3:21])[CH2:12][CH2:11][C:10]([CH3:23])([CH3:24])[C:9]=2[CH:8]=1)\[CH3:6])/[CH:3]=[CH:27]/[C:28](=[O:29])[CH3:30]
Reactant: CC(C)=O
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=O)C(C)(C)CCC2(C)C
Reaction time: 0.67 h

Procedure:
To a solution of (E)-2-fluoro-3-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enal (Intermediate 8, 208 mg, 0.63 mmol) in acetone (2 mL) was added 1M NaOH (2 mL) at 0° C. The mixture was stirred for 40 min, quenched with 2M H2SO4 (2 mL), and was stirred for 10 min. The mixture was then extracted with Et2O (×3). The combined organic layer was washed successively with brine, NaHCO3, brine, was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5%→10%→20% EtOAc-hexane) to give the title compound (35 mg) and the intermediate β-hydroxy ketone (173 mg), which was converted to the title compound using catalytic para-tolunesulfonic acid (PTSA) in refluxing benzene.
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].C(N(C(C)C)CC)(C)C.[OH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1>ClCCl>[CH3:4][O:3][CH2:2][O:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2cccc(CO)c2)cc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1cccc(-c2ccc(C(=O)OC)cc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chloromethylmethyl ether (0.24 ml) and diisopropylethylamine (0.74 ml) was added to a solution of methyl 3′-hydroxymethylbiphenyl-4-carboxylate (504 mg), which is the product of Reference example 15(a), in anhydrous dichloromethane (10 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to stand at ambient temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=2/1 as the eluant to afford the desired compound (467 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:17]([F:29])=[C:18]([CH:24]=[C:25]([F:28])[C:26]=1F)[C:19]([O:21][CH2:22][CH3:23])=[O:20].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:26]2[C:25]([F:28])=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([F:29])[C:16]=2[CH3:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(F)c(F)c(C)c1F
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc(F)c(N2C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C2)c(C)c1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of (3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidine (1.80 g, 8.97 mmol), ethyl 3-methyl-2,4,5-trifluorobenzoate (2.18 g, 10.0 mmol), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (2.24 mL, 15 mmol) in dimethyl sulfoxide (20 mL) was stirred under a nitrogen atmosphere at an external temperature of 60° C. for 70 hours. The temperature of the mixture was cooled to room temperature. The resultant mixture was poured to a 10% aqueous citric acid solution, followed by extraction with ethyl acetate (200 mL×3), washing by water (200 mL), saturated aqueous sodium hydrogencarbonate (150 mL), and saturated brine (150 mL), and dried over anhydrous sodium magnesium. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=6:1), to thereby yield the title compound as colorless crystals (2.51 g, 70.2%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[C:8](Br)[N:7]=1)=[O:5])C.C([Sn](CCCC)CCCC)CCC.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[SnH3].NC1C(C(OC)=O)=NC(C2OC=CN=2)=C(C(F)(F)F)C=1>>[NH2:12][C:11]1[C:6]([C:4]([OH:3])=[O:5])=[N:7][C:8]([C:32]2[O:31][CH:35]=[CH:34][CH:33]=2)=[C:9]([C:13]([F:14])([F:15])[F:16])[N:10]=1
Reactant: [SnH3]c1ccco1
Reactant: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Agent: CCCC[Sn](CCCC)CCCC
Agent: COC(=O)c1nc(-c2ncco2)c(C(F)(F)F)cc1N
Product: Nc1nc(C(F)(F)F)c(-c2ccco2)nc1C(=O)O

Procedure:
The title compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate C1) and tributyltin-2-furylstannane analogously to methyl 3-amino-6-(oxazol-2-yl)-5-(trifluoromethyl)picolinate (Intermediate P)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[NH2:23].[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:23][C:22]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Cc1cnccc1N
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnccc1NC(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a (0° C.) cooled and stirred solution of 5-bromothiophene-2-carboxylic acid (1.91 g, 9.25 mmol) in DCM (20 mL) was added oxalyl chloride (4.05 mL, 46.2 mmol) followed by the addition of catalytic amount of DMF. Reaction was allowed to stir at 0° C. for 2 h. The resulting reaction mixture was then concentrated under vacuum, obtained residue was dissolved in DMF (2 mL) and added to a separately prepared (0° C.) cooled mixture containing 3-methylpyridin-4-amine (1.23 g, 11.37 mmol) and sodium hydride (0.444 g, 18.49 mmol) in DMF (10 mL). After stirring the reaction at RT overnight, quenched with ice cold water (20 mL), followed by the addition of ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×50 mL), brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, DCM-methanol system as eluent) to afford 1.10 g (40%) of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.44 (d, J=5.5 Hz, 1H), 8.40 (s, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.70 (s, 1H), 7.40 (d, J=4.0 Hz, 1H), 7.13 (d, J=4.0 Hz, 1H), ESI-MS (m/z) 297, 298 [(MH)+ Br79,81].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[CH2:16][O:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C[N:29](C=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([NH2:29])=[O:26])=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[CH2:16][O:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Reactant: CN(C)C=O
Product: NC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluoro-phenyl)-5,7-dihydro-furo[3,4-d]pyrimidin-4-ylamino]-nicotinic acid (50 mg, 0.13 mmol, 1 eq) in DMF (2 ml) was added 1-1′-carbonyldiimidazole (50 mg, 0.31 mmol, 2.4 eq) and the reaction mixture was warmed to 70° C. for 2 h. The mixture was cooled to r.t. and NH3(g) was bubbled through for 10 min. The reaction mixture was stirred at r.t. for an additional 1 h. The reaction was concentrated in vacuo and the residue was triturated with water (2×5 ml). To the crude residue was added 1 N NaOH (5 ml) and the suspension was heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature and neutralized with 1 N HCl and the solid was filtered to give 4-[2-(5-Chloro-2-fluoro-phenyl)-5,7-dihydro-furo[3,4-d]pyrimidin-4-ylamino]-nicotinic amide, compound of formula (34) (25 mg, 50%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].O1CCOCC1.Cl>CO>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(NCC3CCN(C(=O)OC(C)(C)C)CC3)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cccc2[nH]c(NCC3CCNCC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid methyl ester (2.28 g, 5.87 mmol) in methanol (3 ml), a 4N hydrogen chloride-1,4-dioxane solution (10 ml, 40 mmol) was added and the mixture was stirred at room temperature overnight. The precipitated crystals were filtered out, washed with ethyl acetate and then dried to obtain 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]#[C:23][CH3:24]>>[C:1]([O:5][C:6](=[O:19])[C:7]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)(=[O:9])=[O:10])([CH2:16][C:11]#[C:12][CH3:13])[CH2:21][C:22]#[C:23][CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCBr
Reactant: COc1ccc(S(=O)(=O)CC(=O)OC(C)(C)C)cc1
Product: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Yield: 90 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-butyne (2.68 g, 20 mmol), 3.50 g of the product was isolated. Yield 90%; white solid; mp 85-87° C.; MS: 391.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-:17])=[O:16])[CH2:13][C:12]([CH2:18][NH2:19])=[CH:11][CH2:10]1.[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-:17])=[O:16])[CH2:13][C:12]([CH2:18][NH:19][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([O:21][CH3:20])=[O:32])=[CH:24][CH:25]=2)=[O:30])=[CH:11][CH2:10]1
Reactant: NCC1=CC[C@@H](c2ccc(Cl)cc2Cl)[C@H]([N+](=O)[O-])C1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of Example 12C (33 mg, 0.11 mmol) in CH2Cl2 (1 mL), 4-chlorocarbonyl-benzoic acid methyl ester (33 mg, 0.16 mmol) and diisopropylethyl amine (0.05 mL, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight. It was concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (41 mg, 81%). 1H NMR (500 MHz, CDCL3) δ ppm 8.06-8.10 (m, 2H), 7.86-7.92 (m, 2H), 7.37-7.41 (m, 1H), 7.15-7.26 (m, 2H), 5.73-5.82 (m, 1H), 5.02-5.13 (m, 1H), 4.01-4.13 (m, 3H), 2.50-2.95 (m, 3H). MS (ESI) m/z 463 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5].[N-:16]=[N+:17]=[N-:18].[Na+].[I-].[Na+]>O>[N:16]([CH2:2][CH2:3][C:4]([C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])=[O:5])=[N+:17]=[N-:18]
Reactant: O=C(CCBr)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 5 L round bottom three-necked flask, equipped with a heating mantle, an overhead stirrer, and a thermometer, is charged with 150 gm bromoethylmannose (525 mmol). The oil is dissolved in 2 L water and treated with 68.3 gm sodium azide (1.05 mol, 2 equiv.; 65 gm/mol; Alfa-Aesar) followed by 7.9 gm sodium iodide (52.5 mmol, 0.08 equiv.; 149.89 gm/mol; Alfa-Aesar) and the solution warmed to 50 C and stirred overnight. The solution is cooled to room temperature and concentrated to dryness on the rotovap. The solid residue is digested with 3×500 mL of 5:1 vol. CHCl3:MeOH at 40 C. The combined organic portions are filtered and evaporated to dryness to afford azidoethylmannose as an off-white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:28][CH3:29])[C:26](=[O:27])[N:12]2[CH:13]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[C:14]([CH3:17])=[CH:15][S:16][C@H:11]12)=[O:8].[Se](=O)=[O:31]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:28][CH3:29])[C:26](=[O:27])[N:12]2[CH:13]([C:18]([O:20][CH2:21][C:22]([Cl:24])([Cl:25])[Cl:23])=[O:19])[C:14]([CH2:17][OH:31])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)=CS[C@@H]21
Reactant: O=[Se]=O
Solvent: CCO
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(CO)=CS[C@@H]21
Reaction time: 2 h

Procedure:
To a solution of β,β,β-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-methyl-2-cephem-4-carboxylate (0.94 mg., 2 mmole) in ethanol (10 ml.) is added selenium dioxide (0.111 g., 1 mmole) keeping the reaction temperature at about 25°C. The reaction mixture is stirred for two hours, filtered, diluted with water (30 ml.) and extracted with chloroform. The chloroform extracts are washed successively with water, sodium bicarbonate and water. The solvent is removed under vacuum to afford a residue which is chromatographed on silica gel using chloroform and ethyl acetate to afford substantially pure β,β ,β-trichloroethyl 7-(2-thienylacetamido)-7-methoxy-3-hydroxymethyl-2-cephem-4-carboxylate.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7](Br)[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]=1[CH3:19])(=[O:3])[CH3:2].C(B(CC)[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)C.[OH-].[K+]>C1(C)C=CC=CC=1.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:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c(Br)n(COCC[Si](C)(C)C)c1C
Reactant: CCB(CC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)c(-c2ccncc2)n(COCC[Si](C)(C)C)c1C
Yield: 36 %

Procedure:
To a stirred solution of 3-acetyl-5-bromo-2,4-dimethyl-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrole (309 mg, 0.85 mmol) in toluene (5 mL) was added diethyl(4-pyridyl)borane [prepared according to the method of M. Terashima et al., Heterocycles, 1984, 22, 2471] (250 mg, 1.70 mmol), potassium hydroxide (85% purity, 168 mg, 2.55 mmol), and tetrakis(triphenylphosphine)palladium (0) (100 mg, 0.085 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3 hours. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:1) to give the title product (105 mg, 36% yield).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[S:28]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])(=[O:29])[CH3:27]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Linoleyl alcohol (10.0 g, 37.5 mmol) was weighed into a 500 mL round bottomed flask with a stir bar. The flask was sealed, flushed with argon, charged with DCM (100 mL) and triethylamine (7.84 mL, 1.5 equiv.) and cooled to 0° C. Methanesulfonyl chloride (4.35 mL), 1.5 equiv.) was measured in a PP syringe and added slowly to the stirring reaction mixture. TLC analysis (7.5% EtOAc/Hexanes) showed the reaction was complete within 1 hr. The reaction was diluted with DCM (100 mL) and washed with saturated bicarbonate solution (2×200 mL). The organic phase was dried over MgSO4, filtered and concentrated to give 12.53 g (97%) of colorless oil that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1.[C:18]([O-])([O-])=O.[K+].[K+].ClCI>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH2:18][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[C:8]3[C:6]=2[N:7]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2c(n1)-c1cc3ccccc3n1CO2
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
To a solution of 6-chloro-2-(1H-indol-2-yl)pyridin-3-ol (480 mg, 2.0 mmol) and K2CO3 (1.38 g, 10.0 mmol) in DMF (50 mL) stirring at 100° C., chloroiodomethane (386 mg, 2.2 mmol) in DMF (10 mL) was added dropwise. After addition, the mixture was allowed to stir for another 0.5 hours. The mixture was then diluted with water (100 mL) and extracted with EtOAc (100 mL*3). The organic layer was washed with brine (100 mL*3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=3:1) to provide the product 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (260 mg, yield: 50.7%). 1H-NMR (CDCl3, 400 MHz) δ 7.63 (d, J=8.0 Hz, 1H), 7.22˜7.27 (m, 3H), 7.19 (d, J=2.4 Hz, 1H), 7.08˜7.12 (m, 2H), 5.86 (s, 2H). MS (M+H)+: 257/259.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:28][C:4]1[C:3]([NH:2][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][N:6]2[C:5]=1[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=1)=[C:9]([C:25]#[N:26])[CH:8]=[N:7]2
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: Cc1c(Nc2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (10.3 mg, 0.026 mmol), benzeneboronic acid (4.7 mg, 0.039 mmol), Cu(OAc)2 (0.039 mmol, 7 mg) and TEA (0.13 mmol, 13 mg) in dichloromethane (1 ml) were stirred at RT for 16 hrs. The reaction mixture was purified by silica gel flash chromatography to isolate 370 as a yellow film (1.4 mg, 15%). [M+H]+=432.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([C:17]([OH:19])=O)[CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(C(C)C)CC)(C)C.[CH3:41][NH:42][O:43][CH3:44].Cl>CC1OCCC1>[CH3:44][O:43][N:42]([CH3:41])[C:17]([C@@H:13]1[CH2:14][C:15](=[O:16])[N:11]([C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH3:10])[CH2:12]1)=[O:19]
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)O)CC2=O)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC1CCCO1
Product: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Reaction time: 1.25 h

Procedure:
To a suspension of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid 1.01 (1.0 g, 3.80 mmol) in 2-MeTHF (5 mL) was added CDI (925 mg, 5.70 mmol) and the mixture was stirred for 75 minutes over which time the reaction became homogenous. Diisopropylethyl amine (800 μL, 4.56 mmol) and N,O-dimethylhydroxylamine (445 mg, 4.56 mmol) were added and the reaction was stirred for 3 hours. 3M HCl (4 mL, 12 mmol) was added and the mixture was stirred for 5 minutes. The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were dried (MgSO4), filtered and concentrated to afford (R)-N-methoxy-1-((R)-1-(4-methoxyphenyl)ethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]([O-])=O.[Na+]>CC(O)=O.O>[NH:1]1[C:2]2[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH:12]=[N:13]1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3-amino-4-methylbenzoate D-1 (5.0 g, 30 mmol) in AcOH (140 mL) at 0° C. was added a solution of sodium nitrite (2.1 g, 30 mmol) in H2O (3.5 mL). After addition, the mixture was stirred at rt for 24 h. Then half of the solvent was removed under reduced pressure and the resulting mixture was diluted with H2O, and extracted with EtOAc. The combined organics were washed H2O and brine, and concentrated to give the title compound. LCMS (ESI) calc'd for C9H9N2O2 [M+H]+: 177. found 177.