Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1>CO.O>[O:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(Oc2ccccc2)n1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-phenoxythiazole-4-carboxylate (0.17 g, 0.68 mmol) and LiOH monohydrate (0.14 g, 3.40 mmol) in 2 mL of MeOH, 2 mL of H2O, and 2 mL of THF was stirred at RT overnight, the solvents were removed in vacuo and the residue was diluted with water. The aqueous mixture was acidified with 1N HCl (aq) to pH=1−2, then extracted with EtOAc, the combined organic portions were washed with brine, dried over MgSO4, filtered, removal of the solvents in vacuo yielded the title compound as a white solid. EI-MS =222.4 (M+H)+. Calc'd for C10H7NO3S: 221.01.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]([C:10]1[N:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:14]([CH3:16])[N:15]=1)[NH2:9]>C(Cl)Cl>[C:5]([NH:9][NH:8][C:10]1[N:11]=[N:12][C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Solvent: ClCCl
Product: CC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
Acetic anhydride (1.6 g) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3 g) in methylene chloride (30 ml) under ice cooling and then the stirring was continued for 15 minutes. The solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized from a mixture of methylene chloride and diisopropyl ether to give 3-(2-acetylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (3.37 g).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=4)[CH:20]=O)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[N:4]1)[CH3:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[N:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(-c2ccnc3c2cc(-c2cccc(C=O)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(CN4CCCC4)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using 3-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde and pyrolidine provided the title compound. ESMS [M+H]+: 633.0.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:8]([C:9]([NH:11][CH:12]([CH2:15]O)CO)=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:19][O:20][C:21]([O:24]C)([CH3:23])[CH3:22].CO>C1(C)C=CC=CC=1>[CH3:22][C:21]1([CH3:23])[O:24][CH:12]([NH:11][C:9](=[O:10])[C:8]2[C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=[N:6][CH:7]=2)[CH2:15][CH2:19][O:20]1
Reactant: COC(C)(C)OC
Reactant: O=C(NC(CO)CO)c1cnccc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)OCCC(NC(=O)c2cnccc2C(F)(F)F)O1

Procedure:
In the presence of 0.50 g of p-toluolsulfonic acid hydrate, 2.64 g (10 mmol) of N-(4-trifluoromethylnicotinoyl)serinol and 4.20 g (40 mmol) of acetone dimethyl acetal in 50 ml of toluene were stirred at 80° C. for 12 hours, with distillative removal of the methanol that was formed. After cooling, the mixture was extracted with dilute sodium hydroxide solution and water and the organic phase was dried and concentrated. This gave 1.5 g of product (49.3% of theory) as a colorless solid of melting point 155-156° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[C:7]=2[N:8]=1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1.CCN(CC)CC>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH:16]1([CH2:15][O:13][C:9]2[C:7]3[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[CH:12]=[CH:11][N:10]=2)[CH2:18][CH2:17]1
Reactant: BrCC1CC1
Reactant: CSc1ncc2cc[nH]c(=O)c2n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSc1ncc2ccnc(OCC3CC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.4 %

Procedure:
A suspension of 2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (Preparation 32, 502 mg, 2.60 mmol) and silver carbonate (988 mg, 3.58 mmol) in CHCl3 (25 mL) was treated with bromomethyl cyclopropane (310 μl, 3.19 mmol) and stirred at room temperature for 18 hours. The mixture was stirred at reflux for 4 hours and additional bromomethyl cyclopropane (310 μl, 3.19 mmol) was added. The reaction was stirred for 18 hours at 6° C. Further bromomethyl cyclopropane (310 μl, 3.19 mmol) was added and heated continued for 2 hours. Et3N was added (6 mL), the mixture filtered through celite washing with DCM and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0 to 80% EtOAc in cyclohexane to give the title compound (112 mg, 17%).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[NH2:8][C:9]1[N:13]=[CH:12][NH:11][N:10]=1>C(O)(=O)C>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=1)[CH3:7]
Reactant: Nc1nc[nH]n1
Reactant: CCC(=O)CC#N
Solvent: CC(=O)O
Product: CCc1cc(N)n2ncnc2n1
Temperature: 150 °C
Yield: 11.3 %

Procedure:
A mixture of 3-oxopentanenitrile (1.0 g, 103 mmol) and 3-amino-1,2,4-triazole (0.91 g, 10.8 mmol) in 10 mL of acetic acid was heated in a pressure tube at 150° C. for 24 h. The reaction mixture was allowed to cool to room temperature, and solvent was removed in vacuo. The solid was removed via filtration. The filtrate partially solidified upon standing at room temperature, and the solid was collected via filtration to give the title compound (200 mg, 12% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:12]([N:15]([CH3:17])[CH3:16])[C:13]#[CH:14]>C(NCC)C.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+].[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:16][N:15]([CH3:17])[CH2:12][C:13]#[C:14][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: Cc1ncc(C#CCN(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
To a mixture of 5-bromo-2-methyl-3-nitropyridine (6.50 g, 30.0 mmol), copper iodide (280 mg, 1.5 mmol) and bis(triphenylphosphine)palladium(II)chloride (520 mg, 0.75 mmol) in diethylamine (17 mL) was added propargyl(dimethylamine) (4.04 mL, 37.5 mmol). The reaction mixture was allowed to stir for 15 h at rt. The resulting mixture was diluted with EtOAc (200 mL) and 1M aqueous Na2CO3 (150 mL). After stirring for 30 min, the organic solution was separated and the aqueous solution was extracted with EtOAc (2×100 mL). The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give N,N-dimethyl-3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-amine (5.98 g, 91%) as a dark oil. LCMS (FA): Rt=0.77 min, m/z=220.1 (M+H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH:18]=[C:19]2[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:28])[C@:7]1([CH3:27])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:26])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[CH3:29][SH:30].C(#N)C.C(=O)=O.B(F)(F)F.CCOCC>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:23][CH2:24][CH3:25])[S:30][CH3:29])[C@H:15]2[C@@:6]1([F:28])[C@:7]1([CH3:27])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:26])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CS
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Agent: FB(F)F
Agent: O=C=O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: CCSC1(SC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Temperature: -40 °C
Reaction time: 3 h

Procedure:
A solution of 1.01 g (2.5 mmole) of 11β-acetyloxy-17-(ethylthio)-9-fluoroandrosta-1,4,16-trien-3-one in 15 ml of dry dichloromethane and 3.4 ml of a solution of methyl mercaptan in dichloromethane (1.82 g in 10 ml of dry dichloromethane) is cooled to about -40° C. (acetonitrile-dry ice bath) under nitrogen; boron trifluoride etherate (0.7 ml) is then added. The solution is stirred at approximately -40° C. under nitrogen for 3 hours, quenched with a saturated sodium bicarbonate solution at -40° C. under vigorous stirring, diluted with chloroform, washed with water, dried over anhydrous Na2SO4 and evaporated in vacuo to give 1.0 g of the title compound, melting point 185°-186° C., with consistent spectral data.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9]([NH2:16])([CH2:10]3)[CH2:8]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]#[N:34])=[O:27]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:10][C:9]([NH:16][CH2:25][C:26]([N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[C:33]#[N:34])=[O:27])([CH2:8]1)[CH:13]([CH2:12]3)[CH2:14]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred mixture of 1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.03,7]nonan-3-amine prepared as in preparation 10 (0.17 g, 0.66 mmol), and K2CO3 (0.28 g, 2.0 mmol) in DMSO (2.6 mL) at ice bath temperature was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.13 g, 0.66 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl) hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.1 g) in 40% yield. m/z (M+1) 393; 1H NMR (CDCl3) 300 MHz δ 4.80-4.75 (m, 1H), 3.70-3.37 (m, 4H), 3.36 (t, J=6.6 Hz, 2H), 3.16 (t, J=7.4 Hz, 2H), 2.43-2.37 (m, 1H), 2.35-2.13 (m, 9H), 2.05-1.99 (m, 1H), 1.95-1.75 (m, 5H), 1.70-1.63 (m, 1H), 1.54-1.47 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH2:8][CH:7]([NH:22][C:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[O:24])[C:6]1=[O:35].[Li+].[OH-]>C1COCC1.O>[C:14]([NH:13][CH2:12][C:10]1[CH2:11][N:5]([CH2:4][C:3]([OH:36])=[O:2])[C:6](=[O:35])[CH:7]([NH:22][C:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[O:24])[CH2:8][CH:9]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution containing {6-(benzoylamino-methyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 30, (84 mg, 0.17 mmol) in THF/H2O (4 mL of 3:1) is treated with excess LiOH and the solution stirred for 2.5 hours at room temperature. The solution is then acidified and extracted with EtOAc. The EtOAc layer was dried (Na2SO4) and concentrated to the crude product which is used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]2[C:21](=[O:24])[N:22]=[N:23][C:3]=12.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[C:25]([O:1][C:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]2[C:21](=[O:24])[N:22]=[N:23][C:3]=12)(=[O:27])[CH3:26]
Reactant: O=c1nnc2c(O)c(=O)n(-c3ccccc3)c3cc(Cl)ccc3n1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c2nnc(=O)n-2c2ccc(Cl)cc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3.4 g of 4-hydroxy-8-chloro-6-phenyl-1H-s-triazolo[4,3-a] [1,5]benzodiazepine-1,5-dione and 1.0 g of acetic anhydride in 10 ml of pyridine are warmed in a steam bath for 0.2 hour and stirred at room temperature for 10 hours. The reaction mixture is cooled, diluted with 100 ml of methylene chloride and washed with 100 ml water containing 0.84 g sodium bicarbonate. The organic phase is washed four times with water, dried and evaporated. The residue is triturated with a minimum amount of ether and the title compound filtered off, dried and recrystallized from methylene chloride and ether.
Reaction SMILES: [Mg].II.[C:4]1([CH3:11])[C:5](Br)=[CH:6][CH:7]=[CH:8][CH:9]=1.[P:12]([O-:19])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:11][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[PH:12](=[O:19])[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:11]
Reactant: Cc1ccccc1Br
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1[PH](=O)c1ccccc1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
Under an argon atmosphere, a solution of magnesium (3.55 g, 1.0 equivalent) and a small amount of iodine in THF (40 mL) was stirred at room temperature for 1 hr. A solution of o-tolyl bromide (25 g, 0.146 moL) in THF (5 mL) was added at 30° C. After stirring at 40° C. for 30 min., the mixture was stirred at 5° C. for 1 hr. Then, a solution of diethyl phosphite (10.08 g, 0.5 equivalent) in THF (10 mL) was added at 5° C., and the mixture was stirred at 5° C. for 1 hr. Water (20 mL) was added at 3° C., and then toluene (50 mL) and 6M-HCl (20 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with water (10 mL), 5% aqueous NaHCO3 solution (10 mL) and 5% aqueous NaCl solution (10 mL). Then the organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from heptane to give the title compound (6.70 g, white crystals). yield 39.9%. melting point: 91.3° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[C:47]([S:48](Cl)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:47]2[C:42]([CH3:41])=[N:43][CH:44]=[CH:45][CH:46]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ncccc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Yield: 86.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 34 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (226 mg), 15-crown-5 (185 mg) and a solution of 2-methylpyridine-3-sulfonyl chloride (174 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=17:3→1:1) to give the title compound as a yellow oil (yield 288 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 71.8 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine (Compound IX-7) (1.33 g, 4.6 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (2.22 g, 4.84 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:6) to obtain the title compound (2.41 g, 68%).
Reaction SMILES: [CH3:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O>CC(O)=O.[Pd]>[CH3:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COC(=O)C1(C)Cc2ccccc2C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1(C)Cc2ccccc2C1
Reaction time: 4 h

Procedure:
A mixture of the methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2.04 g, 9.99 mmol) and 10% Pd/C (0.200 g; wet) in HOAc/conc H2SO4 (22/2 mL respectively) was hydrogenated under 50 psi H2 for 4 h using a Parr hydrogenation apparatus. The mixture was filtered through Celite (2×MeOH wash) and the filtrate was partially concentrated in vacuo. The residue was neutralized with satd Na2CO3 and the whole was extracted with EtOAc (2×25 mL). Combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo affording the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.35 (s, 3H), 2.81 (d, J=15.6 Hz, 2H), 3.47 (d, J=15.6 Hz, 2H), 3.71 (s, 3H), 7.12-7.23 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][OH:15].O>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[N:14][OH:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: NO
Solvent: O
Solvent: CCO
Product: ON=C1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 61.38 %

Procedure:
To a solution of 4-phenylcyclohexanone (1.50 g, 8.609 mmol) in 95% ethanol (20 ml) was added 50% hydroxylamine in water (5.276 ml, 86.09 mmol), and the reaction was heated to reflux for 1 hour. The reaction was allowed to cool to ambient temperature, and the product was precipitated by the slow addition of water. The solids were collected via filtration to yield 1.0 g of the title compound (61.38% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:19][CH2:15][CH:16]([CH3:18])[CH3:17])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CC(C)CN
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCC(C)C)c([N+](=O)[O-])c1
Yield: 81.2 %

Procedure:
4-Isobutylamino-3-nitro-benzoic acid methyl ester (950.0 mg) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (1.0 g) and isobutyl amine (402.0 mg) in DMF (10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: C1C=[C:5]2[N:7]=NN(O)C2=CC=1.O.C(Cl)CCl.[Cl:16][C:17]1[S:21][C:20]([NH:22][C:23](=[O:49])[N:24]([C:40]2[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=2)[C:43]([OH:45])=O)[CH2:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:19][C:18]=1[C:50]1[CH:55]=[CH:54][C:53]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])=[CH:52][CH:51]=1.CN>CCOC(C)=O.CN(C=O)C>[Cl:16][C:17]1[S:21][C:20]([NH:22][C:23]([N:24]([CH2:25][CH2:26][CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=2)[C:43]([NH:7][CH3:5])=[O:45])=[O:49])=[N:19][C:18]=1[C:50]1[CH:51]=[CH:52][C:53]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])=[CH:54][CH:55]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2nc(NC(=O)N(CCC(c3ccccc3)c3ccccc3)c3cccc(C(=O)O)c3)sc2Cl)cc1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)c(Cl)s2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of HOBt hydrate (0.042 g, 0.27 mmol), EDC (0.037 g, 0.19 mmol), and 3-(3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)benzoic acid 78 (0.089 g, 0.13 mmol) was added DMF (1.5 mL). The reaction mixture was stirred at room temperature for 10 min and methylamine (2 mL, 2 M in MeOH, 4 mmol) was added. The reaction mixture was stirred at room temperature for 1 d and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 20% to 80% EtOAc in hexanes) gave 3-(((5-chloro-4-(4-((methylsulfonyl)amino)phenyl)-1,3-thiazol-2-yl)carbamoyl)(3,3-diphenylpropyl)amino)-N-methylbenzamide 79. Mass spectrum, calculated for C34H32ClN5O4S2 673.2; found 674.2 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[C:6]([O:22][C@@H:23]2[O:49][C@H:48]([CH2:50][O:51]C(=O)C(C)(C)C)[C@@H:40]([O:41]C(=O)C(C)(C)C)[C@H:32]([O:33]C(=O)C(C)(C)C)[C@H:24]2[O:25]C(=O)C(C)(C)C)=[N:5]1.O.O.[OH-].[Li+]>CO>[C@@H:23]1([O:22][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[N:4]([CH2:3][CH2:2][OH:1])[N:5]=2)[O:49][C@H:48]([CH2:50][OH:51])[C@@H:40]([OH:41])[C@H:32]([OH:33])[C@H:24]1[OH:25]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2nn(CCO)c3cccc(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccc(O)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-4-[2-(4-hydroxy-phenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (0.31 g) in methanol (6 mL) were added water (0.6 mL) and lithium hydroxide monohydrate (0.16 g), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. To the solution was added acetic acid (0.45 mL), and the resulting mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.14 g)