Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH2:29](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[CH:29]=[N:16][C:15]4[C:10]3=[N:11][C:12]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH3:21])=[N:13][CH:14]=4)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Reactant: CCO
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1ncc2ncn(-c3cc(C4CC4)[nH]n3)c2n1)c1ccc(F)cn1
Temperature: 25 °C

Procedure:
N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-5-nitropyrimidine-2,4-diamine (Intermediate 19, 0.25 g) was dissolved into ethanol (20 mL) with Pd—C (40 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 95° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.03 g of the title compound. MS (electrospray): 365 (M+1) for C18H17FN8. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.55 (s, 1H) 8.50 (s, 1H) 7.50 (d, 2H) 6.30 (br, 1H) 5.20 (dd, 1H) 2.00 (m, 1H) 1.65 (d, 3H) 1.10 (m, 2H) 0.90 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]2[C:12](=[O:30])[NH:13][C:14]3[C:19]([C:10]=2[CH:9]=1)=[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27](O)=[O:28])[N:22]=1)[CH:17]=[CH:16][N:15]=3)=[O:7].CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[F:58][C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][CH:65]=1)[NH2:62]>C(Cl)Cl>[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]2[C:12](=[O:30])[NH:13][C:14]3[C:19]([C:10]=2[CH:9]=1)=[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([NH:62][C:61]2[CH:63]=[CH:64][CH:65]=[C:59]([F:58])[CH:60]=2)=[O:28])[N:22]=1)[CH:17]=[CH:16][N:15]=3)=[O:7]
Reactant: Nc1cccc(F)c1
Reactant: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4ccn(CC(=O)O)n4)c3c2c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4ccn(CC(=O)Nc5cccc(F)c5)n4)c3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
299 (18 mg, 0.04 mmol), DIEA (16 mg, 0.12 mmol), BOP-Cl (13 mg, 0.05 mmol), and 3-fluoroaniline (13 mg, 0.12 mmol) were suspended in CH2Cl2 (1 mL), and stirred overnight at room temperature. The crude reaction mixture was purified directly via HP-LC to provide 300 (10 mg, 37% yield) as a solid. LC-MS (M+H=543, obsd.=543).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([Cl:18])[CH:9]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1>O.C1(C)C=CC=CC=1.C(O)C.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>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([Cl:18])[CH:9]=2)=[CH:28][N:29]=1
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cnc(N)nc2)cc1Cl
Temperature: 120 °C
Yield: 59.6 %

Procedure:
A solution of potassium carbonate (0.39 g, 2.8 mmol) in water (3 mL) was added to a mixture of methyl 4-bromo-2-chlorobenzoate (0.49 g, 2.0 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.31 g, 1.4 mmol), and tetrakis(triphenylphosphine)palladium (0.08 g, 0.07 mmol) in toluene (5.3 mL) and ethanol (3 mL). The resulting mixture was heated at 120° C. for 15 min. The reaction mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was recrystallized from methanol and ether. The precipitate was collected by filtration, and washed with ether to afford the desired product (0.22 g, 59%). LCMS: (M+H)=264.0/266.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:33][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[OH:9])[CH:17]=2)[N:22]=[C:21]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2nc(-c3cccnc3)c(-c3ccccc3)c(Cl)c2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of (4-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol (75 mg, 0.15 mmol, Example 17), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (37 mg, 0.18 mmol), PdCl2(dppf) (11 mg, 0.015 mmol) and K2CO3 (42 mg, 0.30 mmol) in 10 mL of dioxane was combined with 2 mL of water and heated to 70° C. After 3 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified on an ISCO using 0-10% methanol in ethyl acetate and lyophilized to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ=8.60 (s, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.45 (d, J=3.5 Hz, 1H), 8.27-8.34 (m, 2H), 8.15 (d, J=8.6 Hz, 1H), 7.73 (dd, J=8.6, 2.0 Hz, 2H), 7.58 (d, J=7.6 Hz, 1H), 7.28-7.36 (m, 8H), 7.08-7.16 (m, 3H); MS m/e 534.8 [M+H]+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH:11]3[CH:17]([OH:18])[C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]([CH3:22])=[CH:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(O)C>[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH:17]([OH:18])[C:16]([CH3:19])([CH3:20])[CH2:15][C:14](=[O:21])[C:13]([CH3:22])=[CH:12]2)[CH2:7][CH2:6]1
Reactant: CC1=CC(N2CCC3(CC2)OCCO3)C(O)C(C)(C)CC1=O
Agent: Cl
Solvent: CCO
Product: CC1=CC(N2CCC(=O)CC2)C(O)C(C)(C)CC1=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
To an ethanol solution (5 ml) containing the 4-(1,4-dioxa-8-aza-spiro[4.5]decan-8-yl)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 26 (1 g, 3.24 millimoles) there was added 6N hydrochloric acid (2 ml), and the mixture was stirred at 75° C. for 4 hours. The reaction solution was concentrated, water was added, and a 1N aqueous sodium hydroxide solution was used for neutralization. The aqueous solution was subjected to extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The crude product obtained by concentration of the ethyl acetate solution was recrystallized from a benzene-hexane mixed solvent to obtain 0.53 g (60.9%) of 4-(4-oxopiperidino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([I:26])[S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([I:26])[S:25][C:16]=12
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (380 mg, 2.0 mmol) and 60% sodium hydride (80 mg, 2.0 mmol) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (320 mg, 1.0 mmol) is added and the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2% methanol in chloroform to provide 240 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 233–234° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.38 (s, 1H), 7.77 (s, 1H), 7.79 (s, 1H), 8.56 (s, 1H), 9.74 (s, 1H); MS 475.9 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][N:4]=1.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:2][C:3]1[CH:7]=[CH:6][S:5][N:4]=1)[CH3:9]
Reactant: CCN
Reactant: BrCc1ccsn1
Solvent: C1CCOC1
Product: CCNCc1ccsn1

Procedure:
prepared by reaction of 3-bromomethyl-isothiazole (Buttimore D. et al J. Chem. Soc. 1965, 7274-7276) with 2M ethylamine in THF.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:28])[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c1ccccc1n2C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2C
Yield: 117.1 %

Procedure:
A mixture of 4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester (511 mg), NBS (354 mg), and BzOOBz (12.7 mg) in carbon tetrachloride (20 mL) was refluxed for 25 min; then cooled, solvents were removed, the residue was purified with column to give the title compound (773 mg). ESI MS (m/z): 349 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C@@H:5]([CH3:9])[C:6](O)=[O:7].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([NH:32]O)=[NH:31]>C1COCC1.C(OCC)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C@H:5]([C:6]1[O:7][N:32]=[C:30]([C:29]2[CH:34]=[CH:35][CH:36]=[C:27]([Cl:26])[CH:28]=2)[N:31]=1)[CH3:9]
Reactant: N=C(NO)c1cccc(Cl)c1
Reactant: COC(=O)C[C@@H](C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](C)c1nc(-c2cccc(Cl)c2)no1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of (R)-2-methylsuccinic acid 4-methyl ester (2.2 g, 15 mmol) and triethylamine (4.54 g, 45 mmol) in THF (30 ml), isobutylchloroformate (2.16 g, 15.8 mmol) was added dropwise at 0° C. After being stirred for 30 min, the 3-chloro-N-hydroxy-benzamidine (2.56 g, 15 mmol) was added. The reaction mixture was stirred at room temperature for another 30 min and then heated to 135° C. with DMF for 45 min. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried and concentrated to give 4.0 g (95%) of (R)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid methyl ester as pale-yellow oil. Step 2: (R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid hydrazide: (R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid hydrazide (430 mg, 77%) was obtained from (R)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid methyl ester (461.4 mg, 2.0 mmol) reacted with hydrazine hydrate (2 mL) in methanol (2 mL) at 65° C. for 1 h. 1H-NMR(CDCl3) d (ppm): 8.07 (s, 1H), 7.96 (d, 1H), 7.46 (m, 2H), 6.98 (w, 1H), 3.93 (w, 2H), 3.78 (m, 1H), 2.86 (dd, 1H), 2.55 (dd, 1H) and 1.59 (d, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].C(CCC(Cl)=S)(=O)C.SCC(SC)C([N:25]1[CH2:32][C:31](=[O:33])[CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=O>>[C:1]([S:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([N:25]1[CH2:32][C:31](=[O:33])[CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(C)(C)C(=O)Cl
Reactant: CSC(CS)C(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: CC(=O)CCC(=S)Cl
Product: CC(=O)SCC(C)(C)C(=O)N1CC(=O)C[C@H]1C(=O)O

Procedure:
Following the procedure of Example 1 but substituting 3-acetylthio-2,2-dimethylpropionyl chloride for the 3-acetylthiopropionyl chloride in part (d), one obtains 1-[3-(acetylthio)-2,2-dimethyl-1-oxopropyl]-4-oxo-L-proline.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CCCCCC.[I:27]I.[Cl-].[NH4+]>C1COCC1>[CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]1[I:27])[CH2:2][CH2:3][CH3:4]
Reactant: II
Reactant: CCCCn1cnc(-c2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCn1cc(-c2ccccc2)nc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 1-butyl-4-phenylimidazole (4.0 g, 20 mmol) in 60 ml of anhydrous THF at −78° C. under nitrogen is added a solution of n-butyllithium in hexane (1.6M, 13.13 ml, 21 mmol, 1.05 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 h followed by dropwise addition of a solution of iodine (5.33 g, 21 mmol, 1.05 eq.) in 40 ml of THF. The resulting solution is stirred at −78° C. for 30 min. and then warmed to room temperature. Saturated ammonium chloride (30 mL) is added to quench the reaction. The resulting mixture is evaporated a reduced pressure to remove THF, extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and evaporated. Purification by silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 5:1) affords 5.73 g of 1-butyl-2-iodo-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.73 (2H, dd, J=1.2, 8.4 Hz), 7.36 (2H, m), 7.30 (1H, s), 7.24 (1H, m), 3.92 (2H, t, J=7.2 Hz), 1.79 (2H, m), 1.41 (2H, m), 0.98 (3H, t, J=7.2 Hz); MS (+VE) m/z 327 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[CH:5]=[CH:6][CH:7]=1>[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C=Cc2ccc3ccccc3c2)c1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Fc1cccc(CCc2ccc3ccccc3c2)c1
Reaction time: 20 h
Yield: 89.6 %

Procedure:
A 60 ml Solumix/toluene (1:1) solution of 11.54 g (46.48 mmol) of the above 2-[2-(3-fluorophenyl)vinyl]naphthalene was added with 0.58 g of 5%-Pd/C and then stirred for 20 hours in an H2-atmosphere. The 5%-Pd/C was filtrated away from the reaction solution, and then the filtrate was condensed under a reduced pressure. The obtained gray solid of 11.18 g was purified with silica gel chromatography using toluene as the eluent to obtain a white solid of 11.05 g, which was recrystallized with a mixed solvent of Solumix/heptane in a ratio of 2:1 to obtain 10.43 g of 2-[2-(3-fluorophenyl)ethyl]naphthalene as white crystals.
Reaction SMILES: NC1C=CC=CC=1.[OH:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=1Cl)(=[O:13])=[O:12].[CH2:24]([CH2:26][NH2:27])[OH:25]>CO>[OH:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[NH:27][CH2:26][CH2:24][OH:25])[NH2:20])(=[O:13])=[O:12]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Solvent: Nc1ccccc1
Solvent: CO
Product: Nc1ccc(NCCO)c(S(=O)(=O)CCO)c1
Reaction time: 6 h

Procedure:
The aniline compound employed under (a) with the β-sulfatoethylsulfonyl group can be prepared, for example, as follows: 132.8 parts of 2-(β-hydroxyethylsulfonyl)-4-nitrochlorobenzene are added slowly to a solution of 76.5 parts of ethanolamine in 500 parts by volume of methanol at a temperature of 65° C., and the reaction batch is stirred for a further 6 hours at this temperature. 400 parts by volume of methanol are subsequently distilled off from the reaction batch while simultaneously and continuously adding water. 2-(β-hydroxyethylsulfonyl)-4-nitro-1-(β-hydroxyethyl)aminobenzene crystallizes on cooling from the now aqueous medium in high purity. This compound can be employed for the conversion of the nitro group to the amino group during catalytic hydrogenation. For this, 58 parts of this nitro compound are dissolved in 400 parts by volume of methanol and hydrogenated in an autoclave in the presence of a nickel catalyst at a temperature of 100° C. and pressure of 50 bar of hydrogen. The catalyst is subsequently filtered off and the filtrate allowed to crystallize out by cooling of the methanolic solution. 3-(β-hydroxyethylsulfonyl)-4-(β-hydroxyethylamino)aniline is obtained in good yield and high purity.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[S:14][C:15]2[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:16]=2[N:17]=1.[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[CH3:27][O:26][C:19]1[C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:15]2[S:14][C:13]([CH:12]=[O:11])=[N:17][C:16]=2[CH:18]=1
Reactant: COc1cc2nc(CO)sc2c(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2nc(C=O)sc2c(OC)c1OC
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.78 mL) was dissolved in dichloromethane (10 mL), DMSO (1.49 mL) was added dropwise at −78° C., and the mixture was stirred for 30 minutes. After a solution of 2-hydroxymethyl-5,6,7-trimethoxybenzo-thiazole (1.53 g) in dichloromethane (10 mL) was added dropwise at −78° C. to the mixture, stirring was conducted for 1 hour, triethylamine (6.46 mL) was added, and the resultant mixture was warmed to room temperature. After an aqueous solution of ammonium chloride was added to the mixture, extraction was conducted with dichloromethane. The resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9) to obtain the title compound.
Reaction SMILES: [CH:1]1[N:5]([CH:6]2[O:10][CH:9]([CH2:11][OH:12])[CH:8]([OH:13])[CH:7]2[OH:14])[C:4]2[N:15]=[C:16]([Cl:20])[N:17]=[C:18]([NH2:19])[C:3]=2[C:2]=1[C:21]#[N:22].[NH2:23][OH:24]>C(O)C>[NH2:19][C:18]1[C:3]2[C:2]([C:21](=[N:23][OH:24])[NH2:22])=[CH:1][N:5]([C@@H:6]3[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]3[OH:14])[C:4]=2[N:15]=[C:16]([Cl:20])[N:17]=1
Reactant: N#Cc1cn(C2OC(CO)C(O)C2O)c2nc(Cl)nc(N)c12
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(Cl)nc(N)c12
Reaction time: 24 h
Yield: 72.6 %

Procedure:
2-Chlorotoyocamycin (6, 250 mg) and solid hydroxylamine (250 mg) were added to 20 ml of absolute ethanol and the mixture was heated at reflux temperature for 30 min. The solution was allowed to stand at -10° for 24 hr and the solid was collected by filtration, washed with 10 ml of ice cold ethanol and recrystallized from water to yield 200 mg (76%) of 10, mp 170° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22]Br.O>CN(C)C=O>[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22][N:10]1[C:11]([CH3:13])=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1
Reactant: Cc1cc(-c2ccc(Cl)cc2)n[nH]1
Reactant: COC(=O)CCC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)Cn1nc(-c2ccc(Cl)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
3-(4-Chloro-phenyl)-5-methyl-1H-pyrazole (1.84 g, 9.6 mmol) was dissolved in dimethylformamide (20 ml) followed by the addition of sodium hydride (60% dispersion in oil, 384 mg, 9.6 mmol). The reaction was stirred at room temperature for 15 min, followed by the addition of 5-bromo-4-oxo-pentanoic acid methyl ester (2 g, 9.6 mmol). The reaction was stirred at room temperature for a further 30 min, before the addition of water (200 ml). The solution was then extracted with ethyl acetate (2×150 ml). The organics were dried over magnesium sulfate and concentrated in vacuo. The crude product was then purified by column chromatography (120g column, DCM to 90% DCM/EtOAc over 50 mins) to give 5-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-oxo-pentanoic acid methyl ester (1.84 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[C:4](=[O:12])[N:3]1[C:13]1[CH2:14][O:15][C:16](=[O:18])[CH:17]=1.C(N(C(C)C)CC)(C)C.[CH3:28][C:29]1[C:37]([C@@H:38]2[CH2:40][O:39]2)=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][O:32][C:33]2=[O:41]>C(O)C>[OH:39][C@H:38]([C:37]1[C:29]([CH3:28])=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:41])[O:32][CH2:31]2)[CH2:40][N:9]1[CH2:8][CH2:7][C:5]2([C:4](=[O:12])[N:3]([C:13]3[CH2:14][O:15][C:16](=[O:18])[CH:17]=3)[CH:2]([CH3:1])[CH2:6]2)[CH2:11][CH2:10]1
Reactant: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCC3(CC2)CC(C)N(C2=CC(=O)OC2)C3=O)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
3-Methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-22, 0.257 mmol) was dissolved in ethanol (3 mL), and treated with diisopropylethylamine (135 μl, 0.771 mmol) followed by (R)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one (I-4B, 73.3 mg, 0.385 mmol). The mixture was heated at 80° C. in a sealed tube for 12 hours. The reaction mixture was then cooled to room temperature and concentrated. The resulting crude product was purified by column chromatography eluting with a 0-20% MeOH/EtOAc gradient to give the title product as a mixture of diastereomers. LC-MS (IE, m/z): 441.3 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(OC(C)=O)c2cc3ccccc3n2CC1C(=O)OCC

Procedure:
From a mixture of 29.3 g of diethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-7,8-dicarboxylate, 100 ml of pyridine and 30 ml of acetic anhydride, the solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The organic extract was washed with saturated sodium bicarbonate solution and water, dried and evaporated to give 33 g of diethyl 9-acetoxy-6,7-dihydropyrido[1,2-a]indole-7,8-dicarboxylate.