Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>O1CCOCC1>[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: COCc1ccccc1B(O)O
Solvent: C1COCCO1
Product: COCc1ccccc1-c1ccc(OCc2cccc(C(=O)O)c2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of intermediate 1; 37 mg, 0.1 mmol) in dioxane (2 mL) was degassed with nitrogen and then added to a reaction vial containing 2-methoxymethylphenylboronic acid (available from Apollo Scientific Ltd., Stockport, UK). The solution was sonicated and degassed and a solution of sodium hydroxide (4 M, 0.2 mL) was added, followed by bis(tri-cyclo-hexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 0.005 mmol) was added. The mixture was degassed and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica and the silica washed with dioxane (1 mL), and dimethylacetamide (1 mL). 1 M HCl was added until a solid formed. The vial was centrifuged and the solvent was removed. The crude product was washed with water and centrifuged again for 5 min. The water was decanted and the solid was dried in a vacuum oven at 50 degrees to give 3-(2′-methoxymethyl-biphenyl-4-yloxymethyl)-benzoic acid. Mass spectrum MH+=349.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=1>C1(C)C=CC=CC=1.O>[CH2:3]([O:10][CH2:11][CH2:12][O:13][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCOCc1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(OCCOCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (900 mg, 60% dispersion in mineral oil, 22.5 mmol) was added portionwise to an ice-cold solution of 2-(benzyloxy)ethanol (3.0 g, 20.0 mmol) in toluene (100 ml), and the solution stirred for 30 minutes. 2,6-Dibromopyridine (4.75 g, 20.0 mmol) was added, and the reaction heated under reflux for 2 hours. The cooled mixture was diluted with water (100 ml), and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a yellow oil, (quantitative).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[S:17]([Cl:20])(=[O:19])=[O:18]
Reactant: COCCNCCOC
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CCOC)S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A premixed solution of bis-methoxyethylamine (15.0 ml, 102 mmol, 1.00 equiv.) and triethylamine (21.3 ml, 153 mmol, 1.50 equiv.) was added dropwise to a solution of sulfuryl chloride (20.7 ml, 153 mmol, 1.50 equiv.) in CH2Cl2 at 0° C. The reaction mixture was continued stirred at 0° C. for 2 h, poured into ice and extracted with CH2Cl2 (3×100 ml). The combined organic extracts were washed with a saturated NaCl soln (1×100 ml), the organic layer dried (Na2SO4), filtered and concentrated under vacuum to afford the title compound (18.5 g, 80%) which was used without further purification. 1HNMR (CDCl3): 3.37 (s, 6H), 3.64-3.64 (m, 8H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)=[CH:9][N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.[NH2:33][C@H:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:36][CH2:35][C@H:34]([NH:33][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:9]=2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1)[CH:37]([CH3:39])[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C)cnc32)cc1
Reactant: CC(C)[C@@H](N)CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@@H](CO)C(C)C)ncc3C#N)c3cc(C)cnc32)cc1
Yield: 76.9 %

Procedure:
A mixture of 4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (120 mg, 0.257 mmol), (R)-(−)-2-amino-3-methyl-1-butanol (57 □l, 0.515 mmol) and diisopropylethylamine (90 □l, 0.515 mmol) in THF (4 mL) was heated at reflux for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel by flash column chromatography to give the title compound as a colourless glassy solid (97 mg, 77% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH3:30])[CH:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=3[O:29][CH3:30])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(F)cc3OC)cccc2c1N
Yield: 83.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 4-fluoro-2-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (143 mg, 83% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.87 (m, 1H), 7.74-7.67 (m, 2H), 7.34-7.27 (m, 1H), 6.83-6.72 (m, 2H), 3.69 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, 3H, J=7.0 Hz). MS APCI, m/z=355 (M+H). HPLC 1.66 min.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)[Si](OCc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.7 %

Procedure:
Stir a solution of 4-bromobenzyl alcohol (50 g, 267.3 mmol), DBU (48 ml, 320.8 mmol) and dichloromethane (600 mL) in an ice/water bath. Add triisopropylsilylchloride (63 mL, 294 mmol) over 10 min via an addition funnel and stir the reaction mixture for 20 hours at room temperature. Wash the mixture with water (2×600 mL), dry over anhydrous magnesium sulfate, filter and concentrate. Purify the residue via silica chromatography eluting with 9:1 hexanes:ethyl acetate to give the title compound (91.5 g, 99%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.47-7.50 (m, 2H), 7.28-7.30 (m, 2H), 4.81 (s, 1.11-1.24 (m, 21H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][CH:14]=1.[Cl:21]C1C=C2C(C=CC(COC3C=CC(CO)=CC=3)=N2)=CC=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Cl:21])=[CH:15][CH:14]=1
Reactant: OCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: OCc1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Product: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 47 %

Procedure:
The procedure from Example 6, part B was used except 4-(quinolin-2-ylmethoxy)benzyl alcohol was substituted for 4-(7-chloroquinolin-2-ylmethoxy)benzyl alcohol. The intermediate was obtained in 47% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]([NH:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)c1cc2ncnc(Cl)c2s1
Solvent: ClCCl
Product: O=C(NCCN1CCOCC1)c1cc2ncnc(Cl)c2s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.2 %

Procedure:
To a stirred solution of 22 (500 mg, 2.15 mmol) in anhydrous DCM (20 mL) at 0° C. under nitrogen was added 4-(2-aminoethyl)-morpholine (307 mg, 2.36 mmol). The reaction mixture was allowed to warm to the room temperature over 3 hours and was stirred for additional 14 hours, treated with saturated aqueous solution of NHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The residues was purified by flash chromatography on silica gel (eluents MeOH-DCM, 5:95, then 1:9) to afford the title compound 23 (458 mg, 65% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ(ppm): 9.13 (t, J=5.6 Hz, 1H), 9.08 (s, 1H), 8.32 (s, 1H), 3.60-3.54 (m, 4H), 3.44 (q, J=6.8 Hz, 2H), 2.54-2.48 (m, 2H), 2.46-2.40 (m, 4H).
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B-](F)(F)(F)F.CN(C(O[N:45]1[C:50](=[O:51])[CH2:49][CH2:48][C:46]1=[O:47])=[N+](C)C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2]([C:12]([O:14][N:45]1[C:50](=[O:51])[CH2:49][CH2:48][C:46]1=[O:47])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
FmocSer(Bzl) (1 mmol), TSTU (1 mmol), and DIEA (2 mmol) were dissolved in DMF (6 mL). The mixture was shaken at room temperature for half an hour. The solvent was evaporated to form FmocSer(Bzl)-OSu, which was used directly in the following steps.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[OH-].[CH2:16]([N+](C)(C)C)[C:17]1[CH:22]=CC=[CH:19][CH:18]=1.ClC(C)(C)C#C>O.ClCCl>[CH3:16][C:17]1([CH3:22])[CH:18]=[CH:19][C:10]2[CH:11]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=[CH:8][C:9]=2[O:12]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Oc1ccc(C2CCCC2)cc1
Agent: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)C=Cc2cc(C3CCCC3)ccc2O1

Procedure:
4-Cyclopentylphenol (10.0 g), and sodium hydroxide pellets (3.7 g) were stirred in water (60 ml) and dichloromethane (60 ml). Benzyltrimethylammonium hydroxide (75 ml, 40% solution in methanol) was added to the solution, followed by 3-chloro-3-methylbutyne (12.63 g) and the reaction mixture stirred under retlux condenser, with sonication. The layers were separated, and the aqueous phase extracted with chloroform. The combined organic layers were evaporated, and the residue taken up in ether. The ether solution was washed with 10% sodium hydroxide solution, and brine and dried over anhydrous magnesium sulphate. Filtration and evaporation gave a pale brown oil (10.89 g) which was refluxed in o-dichlorobenzene (22 ml) under nitrogen for 2 h. Evaporation and chromatography of the resulting brown oil (9.3 g) gave the title benzopyran (4.18 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: Fc1ccc(N[C@H]2CCN(Cc3ccccc3)C2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)C(=O)N(c1ccc(F)cc1F)[C@H]1CCN(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
To a solution of (3S)-1-benzyl-3-[(2,4-difluorophenyl)amino]pyrrolidine (150 mg, 0.52 mmol) and DMAP (6 mg, 0.05 mmol) in pyridine (7 mL) was added isobutyryl chloride (0.16 mL, 1.5 mmol) at 0° C. After being stirred at 60° C. for 18 h, the reaction mixture was quenched with an aqueous NaH(CO)3 solution and extracted with EtOAc. The extracts were concentrated in vacuo, the reside was purified by column chomatography (MeOH/CHCl3=1/25) to give the title compound (160 mg, 86.0%).
Reaction SMILES: C([O:5][C:6]1[C:7](=[O:24])[C:8](=O)[C:9]=1[CH:10]=[C:11]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH3:22])CCC.Cl.[NH2:26][OH:27].C(N(CC)CC)C>C(O)C>[OH:5][C:6]1[C:7](=[O:24])[C:8](=[N:26][OH:27])[C:9]=1[CH:10]=[C:11]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH3:22]
Reactant: NO
Reactant: CCCCOc1c(C=C2N(C)c3ccccc3C2(C)C)c(=O)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1C(=Cc2c(O)c(=O)c2=NO)C(C)(C)c2ccccc21

Procedure:
A mixture of 200 mg (0.61 mmol)of 3-butoxy-4-(1,3,3-trimethyl-2,3-dihydro-1H-2-indolylidenmethyl)-3-cyclobutene-1,2-dione (18), 50 mg (0.72 mmol) of hydroxylamine hydrochloride and 90 μl (0.64 mmol) of triethylamine is stirring in 8 ml of absolute ethanol at room temperature for 1 h and 30 min at 40° C. The solvent is removed under reduced pressure by a rotary evaporator. The obtained residue is column purified (Silica gel 60, 0–10% methanol-chloroform) to give 2-hydroxy-4-hydroxyimino-3-(1,3,3-trimethyl-2,3-dihydro-1H-2-indolylidenmethyl)-2-cyclobuten-1-one (19a) as an yellow solid. Yield: 80 mg (46%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].C(N(CC)CC)C.[CH2:15]([S:27][C:28]([S:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33])=[S:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][CH2:6][O:7][C:32](=[O:33])[C:31]([S:30][C:28]([S:27][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[S:29])([CH3:36])[CH3:35])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCSC(=S)SC(C)(C)C(=O)Cl
Reactant: [N-]=[N+]=NCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCSC(=S)SC(C)(C)C(=O)OCCCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
3-Azidopropanol (265 mg, 2.62 mmol, 1.0 equiv) is dissolved in methylene chloride (5 mL) in a 50 mL round-bottom flask, and the solution is cooled to approximately 0° C. A solution of triethylamine (0.73 mL) in methylene chloride (5 mL) is added dropwise over 10 min. A solution of DMP-Cl (1.0 g, 2.6 mmol) in methylene chloride (5 mL) is added dropwise, and the solution is allowed to reach room temperature while stirring for 3 h. The solution is concentrated under reduced pressure, diluted with ethyl ether (100 mL), and washed with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and saturated NaCl solution (50 mL), successively. The organic layer is separated, dried over MgSO4 (1.0 g), and filtered. The supernatant is concentrated under reduced pressure to yield the product (1.05 g, 90% yield) as a residual oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C(NC(C)C)(C)C.[C:20](=[O:22])=[O:21].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:20]([OH:22])=[O:21]
Reactant: O=C=O
Reactant: Fc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
3-Fluoropyridine (25 g, 257 mmol) was added to a solution of butyllithium (270 mmol) and diisopropylamine (27.4 g, 271 mmol) in tetrahydrofuran (600 mL) at −78° C. After stirring for one hour, crushed dry ice was added to the solution and the solution was warmed to room temperature during one hour. Aqueous hydrogen chloride was added to the solution to acidify the solution to pH 5. The resulting precipitate was filtered and dried. The title compound (25.2 g, 179 mmol, 70%) was obtained as colorless crystal.
Reaction SMILES: [CH:1](S(C)(=O)=O)=[CH2:2].BrBr.N12CCCN=C1CCCCC2.[OH:20][C:21]1[C:22](=[O:32])[C:23]2[C:28]([C:29](=[O:31])[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2>ClCCl>[O:20]1[CH:2]=[CH:1][C:30]2[C:29](=[O:31])[C:28]3[C:23]([C:22](=[O:32])[C:21]1=2)=[CH:24][CH:25]=[CH:26][CH:27]=3
Reactant: C=CS(C)(=O)=O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: BrBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)c2occc21
Yield: 24.6 %

Procedure:
To the solution of 5 grams (47.2 mmoles) of methyl vinyl sulfone in 100 mL of dichloromethane, 7.9 grams (49.5 mmoles) of bromine was added. The mixture was refluxed for 6 hours, and then evaporated to sticky residue. To the residue solution in 150 mL of tetrahydrofitran cooled in ice bath, 7.5 grams (49.5 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was dropped slowly over 20 minutes while stirring vigorously. The reaction mixture was further stirred for 30 minutes in ice bath, then 8.2 grams (47.2 mmoles) of 2-hydroxy-1,4-naphthoquinone and 7.5 grams (49.5 mmoles) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) were added. The mixture was reflux for 6 hours, and then evaporated to sticky residue. The residue was dissolved in 300 mL of dichloromethane, and washed with 300 mL of water, 300 mL of 2% aqueous citric acid solution, successively, and dried with 30 grams of anhydrous sodium sulfate. The naphtho[2,3-b]furan-4,9-dione product was purified with silica gel column using dichloromethane/hexane (3:1) as elution solvent. 2.3 grams of product (overall yield 25%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 7.17 (d, J=2, 1H), 7.86-7.91 (m, 2H), 8.09-8.13 (m, 2H), 8.32 (d, J=2.1 H). Mass (M+H) is 199.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:10])[C@H:5]([NH3+:9])[CH2:6][C:7]#[CH:8].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1>CS(C)=O>[N+:18]([C:17]1[C:12]([NH:9][C@H:5]([CH2:6][C:7]#[CH:8])[C:4]([O:3][CH3:2])=[O:10])=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C#CC[C@@H]([NH3+])C(=O)OC
Agent: [Cl-]
Solvent: CS(C)=O
Product: C#CC[C@@H](Nc1ncccc1[N+](=O)[O-])C(=O)OC
Reaction time: 120 h

Procedure:
(R)-1-methoxy-1-oxopent-4-yn-2-aminium chloride (6.16 g, 38 mmol) in DMSO (100 mL) added 2-chloro-3-nitropyridine (9.0 g, 56 mmol) and then 2-chloro-3-nitropyridine (9.0 g, 56 mmol). The reaction mixture was stirred for 5 d. EtOAC (500 mL) was added and the diluted reaction mixture was washed with 4×brine (200 mL), dried, evaporated to give 10 g of crude material which was purified by column chromatograph (silica gel, 20-100% hex/tolune, EtOAc) to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O-:18])=O)[C:3]1=[O:19].[Li+].[NH2:21][C:22]1[CH:23]=[C:24]2[C:38](=[CH:39][CH:40]=1)[CH2:37][C:26]1([O:31][C:30](=[O:32])[NH:29][C:28]3[N:33]=[CH:34][CH:35]=[CH:36][C:27]1=3)[CH2:25]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]([CH2:15][C:16]([NH:21][C:22]2[CH:23]=[C:24]3[C:38](=[CH:39][CH:40]=2)[CH2:37][C:26]2([O:31][C:30](=[O:32])[NH:29][C:28]4[N:33]=[CH:34][CH:35]=[CH:36][C:27]2=4)[CH2:25]3)=[O:18])[C:3]1=[O:19]
Reactant: CC1C(=O)N(CC(=O)[O-])C(c2ccccc2)CN1C
Reactant: Nc1ccc2c(c1)CC1(C2)OC(=O)Nc2ncccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1C(=O)N(CC(=O)Nc2ccc3c(c2)CC2(C3)OC(=O)Nc3ncccc32)C(c2ccccc2)CN1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of lithium(3,4-dimethyl-2-oxo-6-phenylpiperazin-1-yl)acetate (30 mg, 0.11 mmol) [Wood et al. US 2007/0265225], 5-amino-1,3-dihydrospiro[indene-2,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one (Intermediate 2, 27 mg, 0.10 mmol) and HATU (42 mg, 0.11 mmol) in DMF (1 mL) is treated with N-methylmorpholine (0.036 mL, 0.33 mmol). The mixture is stirred at rt for 18 h and is then purified directly 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 pure, product-containing fractions are combined and lyophilized to afford the title compound.
Reaction SMILES: C(OC(=O)C)(C)(C)C.[C:9]([O:13][C:14](=[O:25])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1)([CH3:12])([CH3:11])[CH3:10].NO.Cl.[N:29]1C=CC=CC=1>CO>[C:9]([O:13][C:14](=[O:25])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:29])[CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reaction time: 2 h

Procedure:
(3-Hydroxyimino-methyl)-phenoxy)-acetic acid tert-butyl ester. To a solution of (3-formyl-phenoxy)-acetic acid tert-butyl ester prepared of Preparation 20, Step A (2.05 g, 8.68 mmol) in MeOH (30 mL) was added NH2OH.HCl (0.66 g, 9.54 mmol) and pyridine (3.5 mL, 43.4 mmol) and the reaction was stirred for 2 hours. The MeOH was removed in vacuo and the residue was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous solution was washed with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step B (1.99 g). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.23-7.28 (m, 2H), 7.12 (m, 1H), 6.93 (d, 1H), 4.51 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].[CH2:16](Br)[C:17]#[CH:18]>C1COCC1>[CH2:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:15][CH2:18][C:17]#[CH:16]
Reactant: OCCOCCOCCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 740 mg, 18.5 mmol) in THF (50 mL) at 0° C. was added tetraethylene glycol (4.0 g, 20.6 mmol). After stirring for 15 minutes, propargyl bromide (80% in toluene, 2.00 mL, 18.0 mmol) was added slowly. The reaction was allowed to warm to RT and stirred 16 hours. Solids were removed by filtration and rinsed with MTBE (3×20 mL). The combined filtrates were concentrated and purified by flash chromatography on silica gel (EtOAc) to give 3,6,9,12-tetraoxapentadec-14-yn-1-ol (2.14 g).
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C=O.[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH3:1])[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: [BH3-]C#N
Reactant: COC(=O)C(CNCc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)C(CN(C)Cc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Sodium cyanoborohydride (121 mg) was added to a solution of formaldehyde (570 mg), methyl 2-(tert-butoxycarbonylamino)-3-(3,4-dichlorobenzylamino)propionate (720 mg) and acetic acid (0.1 ml) in acetonitrile and the mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydrogen carbonate (10 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless oil (722 mg). NMR δH (360 MHz, CDCl3) 1.45 (9H, s), 2.21 (3H, s), 2.73 (2H, d, J=7.0 Hz), 3.46 (2H, m), 3.75 (3H, s) 4.37 (1H, m), 5.19 (1H, br s), 7.10 (1H, dd, J=11.0 and 1.0 Hz), 7.36 (2H, m).