Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[CH3:15][O:16][C:17]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=[CH:19][N:18]=1.N1C=C(C)C=C(C)C=1.Cl>C(#N)C.CS(C)=O>[CH3:14][O:13][C:5]1[N:4]2[N:3]=[C:2]([NH:1][S:23]([C:22]3[C:17]([O:16][CH3:15])=[N:18][CH:19]=[CH:20][C:21]=3[C:27]([F:30])([F:28])[F:29])(=[O:24])=[O:25])[N:10]=[C:9]2[C:8]([O:11][CH3:12])=[CH:7][N:6]=1
Reactant: COc1nccc(C(F)(F)F)c1S(=O)(=O)Cl
Reactant: COc1cnc(OC)n2nc(N)nc12
Agent: Cc1cncc(C)c1
Agent: Cl
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1nccc(C(F)(F)F)c1S(=O)(=O)Nc1nc2c(OC)cnc(OC)n2n1
Temperature: 40 °C
Reaction time: 17 h
Yield: 87.5 %

Procedure:
2-Amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (19.5 g, 0.10 mol) and 2-methoxy-4-(trifluoromethyl)pyridine-3-sulfonyl chloride (27.5 g, 0.10 mol) were combined in acetonitrile (35 mL). To this was added 3,5-lutidine (32 g, 0.30 mol), followed by DMSO (0.23 g, 0.0030 mol). A slight exotherm was noted (to about 30° C.) in the initial hours as the reaction slurry was stirred at ambient conditions for 17 hours. The mixture was then warmed to 40° C. and treated with 2 N HCl (140 mL). The new slurry was stirred while being allowed to cool to room temperature over one hour. The solids were isolated by filtration, washed with water, and dried under vacuum to afford 38 g of product as a solid assaying at 97 wt % (85% yield).
Reaction SMILES: O[C@@H]1CC2C(=CC=CC=2)C1=O.C(O[C@H](CC1C=CC=CC=1)C(O)=O)(=O)C.[OH:27][CH:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[N:37]O.Br>[Pd]>[NH2:37][C@H:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:36][C@H:28]1[OH:27]
Reactant: ON=C1c2ccccc2CC1O
Agent: [Pd]
Agent: Br
Agent: CC(=O)O[C@H](Cc1ccccc1)C(=O)O
Product: N[C@H]1c2ccccc2C[C@H]1O

Procedure:
Kajiro et al., Bull. Chem. Soc. Jap. 1999, 72: 1093-1100, discloses the preparation of (R)-2-hydroxy-1-indanone by the intramolecular Friedel-Crafts acylation of (R)-2-acetoxy-3-phenylpropanoic acid. Kajiro et al. further discloses the preparation of the corresponding hydroxyindanone oxime from (R)-2-hydroxy-1-indanone, and then hydrogenating the oxime in the presence of HBr and Pd black to obtain (1S,2R)-1-amino-2-indanol.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[O:1]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][N:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Ic1ccccc1
Reactant: CCOC(=O)C1CCNC(=O)C1
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Ethyl 2-oxopiperidine-4-carboxylate (0.50 g, 2.9 mmol), iodobenzene (0.77 g, 3.8 mmol, 1.3 equiv), copper(I) iodide (56 mg, 0.29 mmol, 0.1 equiv), 4,7-bis(methoxy)-1,10-phenanthroline (70 mg, 0109 mmol, 0.1 equiv) and potassium carbonate (0.40 g, 3.8 mmol, 1 equiv) were combined in dimethylsulfoxide (10 mL) and placed into a preheated oil bath at 100° C. for 120 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL) and washed with water (2×25 mL) and once with brine (25 mL). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[N+:12]([O-])=O.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[NH:12][C:16](=[O:18])[CH3:17]
Reactant: COC(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(Cl)cc1NC(C)=O
Reaction time: 2 h

Procedure:
An argon filled flask was charged with (4-Chloro-2-nitro-phenyl)-acetic acid methyl ester (40 g, 175 mmol), 10% Pd/C (2.5 g), acetic anhydride (64 mL, 677 mmol), water (9 mL) and acetic acid (150 mL). The flask was vacuum flushed with hydrogen gas at 30 PSI and shook vigorously. After 2 hours, more 10% Pd/C (2 g) was added, and the reaction was complete after a total of 4 hours reaction time. The 10% Pd/C was removed by filtration, and the solvent was removed by rotary evaporation.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Cl:24])C(=O)C1.[OH-].[Na+]>O1CCCC1.O.C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[Cl:24]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Temperature: 70 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
To a 500 mL flask was added methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (5 g, 19.48 mmol) [from Example 95] and NCS (3.12 g, 23.37 mmol) in tetrahydrofuran (THF) (100 ml) (50 mL). After stirring for 4 h at 70° C., the yellow reaction solution was treated with 6M NaOH (32 mL, 195 mmole) and stirred an additional 2 hours. The reaction solution was diluted with H2O (50 mL) and DCM (200 mL). The organic layer was separated and the aqueous layer made acidic with 6N HCl. The acidic aqueous solution was extracted with DCM (3×200 mL), dried over Na2SO4, and concentrated to give the crude product [2.6 g, 48%] as a tan solid: LCMS (ES) m/z 277 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[N:14][CH:15]=1)#[CH:9].S([O-])([O-])(=O)=O.[Mg+2].Br[C:24]1[C:32]2[NH:31][C:30]3[CH2:33][CH:34]4[CH2:38][CH:37]([C:29]=3[C:28]=2[CH:27]=[CH:26][CH:25]=1)[NH:36][CH2:35]4>O1CCCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[Cu]I>[CH3:16][C:13]1[N:14]=[CH:15][C:10]([C:8]#[C:9][C:24]2[C:32]3[NH:31][C:30]4[CH2:33][CH:34]5[CH2:38][CH:37]([C:29]=4[C:28]=3[CH:27]=[CH:26][CH:25]=2)[NH:36][CH2:35]5)=[CH:11][CH:12]=1
Reactant: C#Cc1ccc(C)nc1
Reactant: Brc1cccc2c3c([nH]c12)CC1CNC3C1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2cccc3c4c([nH]c23)CC2CNC4C2)cn1
Temperature: 105 °C
Reaction time: 18 h

Procedure:
Triethylamine (1.0 mL) was added to a mixture of bis(tri-t-butylphosphino)palladium (7.4 mg, 0.014 mmol; Strem), 5-ethynyl-2-methylpyridine (51 mg, 0.43 mmol; International Publication No. WO2005090333), CuI (2.8 mg, 0.014 mmol; Aldrich), magnesium sulfate (2 mg, 0.014 mmol) and the product of Example 30A (80 mg, 0.29 mmol) in anhydrous tetrahydrofuran (1.0 mL). The mixture was purged with a nitrogen stream for 2 minutes, and then it was stirred in a sealed tube under nitrogen at 105° C. for 18 hours. The mixture was cooled to ambient temperature and filtered though a microfiber frit, rinsed with a minimal amount of methanol. The resulting solution was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 60-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.91-1.97 (m, 1H), 2.01-2.12 (m, 1H), 2.56 (s, 3H), 2.85 (dd, J=16.9, 2.3 Hz, 1H), 3.01-3.09 (m, 1H), 3.11-3.20 (m, 2H), 3.46 (t, J=3.7 Hz, 1H), 3.81-3.94 (m, 1H), 6.96-7.02 (m, 1H), 7.21 (dd, J=7.3, 0.9 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.50 (dd, J=7.9, 0.9 Hz, 1H), 7.93 (dd, J=7.9, 2.1 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H); MS (ESI+) m/z 314 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](=[O:42])[C@H:18]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:29]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1(C)C=CC=CC=1.CN(C=O)C.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>[CH3:15][O:16][C:17](=[O:42])[C@H:18]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:32][CH:33]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1cccs1
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: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccs2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a mixture of 2-thienylboronic acid (1.135 g) and anhydrous K2CO3 (2.23 g) in toluene/DMF (75 mL/7.5 mL) under N2 was added a solution of N-(tert-butoxycarbonyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester (3.42 g) in 5 mL of toluene. Pd(PPh3)4 (1.4 g) was added and the mixture was heated at 80° C. for 24 h. After usual work-up as shown in Example 1 the crude material was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1:3) to yield N-(tert-butoxycarbonyl)-4-(2-thienyl)-L-phenylalanine methyl ester (1.81 g). ESMS: m/z 362 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(C)(C)C.Cl>CCOC(C)=O>[C:6]([CH2:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([OH:20])=[O:5]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)O)Cc2ccccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CC1(C(=O)O)Cc2ccccc2C1

Procedure:
A solution of 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylic acid from Step B (1.50 g, 5.43 mmol) in EtOAc (100 mL) was saturated with HCl (g) and stood at ambient temperature for 1b, then concentrated to dryness in vacuo, to give the title compound. MS: m/z=284 (M+Na+CH3CN).
Reaction SMILES: [CH:1]#[CH:2].C[Mg]Br.C.[CH:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH:1]#[C:2][CH:7]([OH:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC=O
Reactant: C#C
Agent: C
Agent: C[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(O)CCCCC
Reaction time: 0.5 h

Procedure:
A rapid stream of acetylene was passed through a solution of 2M methyl magnesium bromide (100 ml) in THF until no more methane evolution was observed. 10 g of hexanal was added at 0° C., stirred for 1/2 h and a saturated solution of NH4Cl was added. The organic product was isolated by extraction with ether. The ether solution was washed with water, brine, dried over MgSO4 and evaporated to give a liquid, which was purified by distillation, to give oct-1 yn-3 ol, b.p. 85° C./0.1 mm Hg.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([Cl:24])=[N:16][N:15]=1>C1COCC1.[NH4+].[Cl-]>[Cl:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[C:9]#[N:10])=[N:15][N:16]=1
Reactant: N#CCc1ccncc1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: N#CC(c1ccncc1)c1nnc(Cl)c2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
4-Pyridylacetonitrile hydrochloride (5.00 g, 32.3 mmol) in 40 mL of THF was sonicated for 10 min, and the mixture was added to 10 mL THF solution of NaH (1.55 g, 64.7 mmol) using dripping funnel while the temperature was kept below 15° C. After the addition, the mixture was cooled to 0° C. and 1,4-dichlorophthalazine (3.22 g, 24.3 mmol) was added to the mixture. The mixture turned into red instantly. The reaction was continued for another 4 hrs, and the mixture was poured in cold NH4Cl solution. The resulting red solid was filtered, washed with H2O, and dried to give 4.4 g of 1-chloro-4-(4-pyridylcyanomethyl)phthalazine (65%); mp 265° C. (dec); 1H NMR (CDCl3) δ 6.00 (s, 1H), 7.39-8.60 (m, 8H); LC/MS MH+281.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1SC(C)=NN=1)=[O:17])(=[O:10])=[O:9].[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31](N)=[C:30](C)[CH:29]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:25])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[CH:33]=[CH:34][C:28]([O:27][CH3:26])=[CH:29][C:30]=1[CH3:31])=[O:17])(=[O:9])=[O:10]
Reactant: COc1ccc(N)c(C)c1
Reactant: Cc1nnc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)s1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)-aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sulfonamide (EXAMPLE 150), except that 4-methoxy-2-methylaniline was used instead of 2-amino-5-methyl-1,3,4-thiadiazole and that pyridine was not used. The title compound was obtained via HPLC purification as a dull yellow powder (66% yield, m.p. 58-62° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)#N.C(O)(=[O:20])C>N1C=CC=CC=1.O.[Ni]>[CH:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)=[O:20]
Reactant: COC(=O)C[C@H]1CCc2c1ccc(C#N)c2C
Reactant: CC(=O)O
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C[C@H]1CCc2c1ccc(C=O)c2C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of methyl (R)-(5-cyano-4-methyl-indan-1-yl)acetate (1.00 g, 4.36 mmol, from EXAMPLE 110, Step J) in pyridine (28 mL), acetic acid (15 mL), H2O (15 mL) and NaH2PO2 (3.07 g, 34.9 mmol) Rainey nickel was added (1.0 g) and the mixture was heated to 50° C. After 5 hr, the reaction was concentrated in vacuo and filtered through Celite®. The filtrate was concentrated in vacuo and partitioned between EtOAc (150 mL) and H2O (50 mL). The organic layer was washed with 5.0 N HCl (7×50 mL), sat. NaHCO3 (2×50 mL), brine (1×50 mL) and dried (MgSO4). The mixture was filtered, concentrated in vacuo and purified by flash chromatography (10% EtOAc/hexanes) to give 882 mg of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.76-1.84 (m, 1H), 2.41-2.51 (m, 2H), 2.57 (s, 3H), 2.78 (dd, 1H, J=5.5, 15.6 Hz), 2.81-2.87 (m 1H), 2.93-2.99 (m, 1H), 3.61-3.67 (m, 1H), 3.72 (s, 3H), 7.16 (d, 1H, J=7.8 Hz), 7.63 (d, 1H, 7.8 Hz), 10.2 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH2:31][CH3:32].ClCCl>N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH2:31][CH3:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2-Thiophenesulfonyl chloride (0.3 g in 10 ml dichloromethane, 1.6 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (0.5 g, 1.6 mmol), dichloromethane (40 ml), and pyridine (0.8 ml). The reaction was maintained at room temperature for a few hours and then an additional portion of 2-thiophenesulfonyl chloride (0.1 g, 0.6 mmol) was added. The reaction was maintained overnight and then concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane/methanol) and the fractions containing product were washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, and concentrated to provide 0.2 g of N2-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-thiophenesulfonamide as an off white powder, m.p. 137.5-141.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J=8.0 Hz, 1H), 7.89 (dd, J=5.0, 1.3 Hz, 1H), 7.83 (broad s, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.54 (dd, J=3.7, 1.3 Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.44 (broad s, 2H), 4.47 (t, J=7.4 Hz, 2H), 2.87 (m, 4H), 1.80 (m, 4H), 1.58-1.38 (m, 4H), 6.44 (t, J=7.4 Hz, 3H); IR (KBr) 3467, 3361, 3167, 3091, 2957, 2933, 2870, 1644, 1617, 1585, 1533, 1478, 1405, 1336, 1154, 1095, 1014, 854, 761, 733 cm−1; MS (EI) m/e 457.1606 (457.1606 calcd for C22H27N5O2S2); Anal calcd for C22H27N5O2S2: C, 57.74; H, 5.95; N, 15.30. Found: C, 57.50; H, 5.98; N, 15.15.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[O:16][Si](C(C)(C)C)(C)C)[CH:4]=[CH2:5].CI.C(Cl)Cl.[O:29]1CCC[CH2:30]1>CO.Cl>[CH3:30][O:29][CH2:5][CH2:4][CH2:3][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[OH:16]
Reactant: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: ClCCl
Product: COCCCc1ccc2ccccc2c1O
Temperature: 25 °C
Yield: 66 %

Procedure:
A suspension of sodium hydride (60% in mineral oil; 0.28 g, 0.007 mole) in dry tetrahydrofuran (5 mL) was stirred at 0°. A solution of the product of Example 122 Part B (2.00 g, 0.006 mole) was added slowly, and the mixture warmed to room temperature. Methyl iodide (0.8 mL, 0.013 mole) was added, the mixture was stirred for 3 hours, then was poured into 1.0N hydrochloric acid. The crude material was isolated by extraction with methylene chloride, dissolved in a mixture of methanol (20 mL) and 1.0N hydrochloric acid (20 mL), and heated at reflux for 20 hours. The cooled solution was extracted with methylene chloride, and the residue was chromatographed with 9:1 petroleum ether/ether to provide the title compound (0.90 g, 66%) as a colorless oil. Mass spectrum: m/z 216.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4](OCC)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.CCN(CC)CC>CC(O)=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:4](=[O:5])[CH2:3][C:2]([CH2:9][CH2:10][CH3:11])=[N:21]2)=[CH:16][CH:15]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: COc1ccc(NN)cc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCCC1=NN(c2ccc(OC)cc2)C(=O)C1
Temperature: 120 °C
Reaction time: 30 h
Yield: 58.9 %

Procedure:
To a suspension of ethyl 3-oxohexanoate (0.58 mL, 3.62 mmol) and (4-methoxyphenyl)hydrazine (0.50 g, 3.62 mmol) in AcOH (3.5 mL) was added Et3N (0.58 mL, 4.16 mmol). The mixture was stirred at 120° C. for 30 h. The solvent was removed by evaporation, and the residue was dissolved in DCM/EtOAc which was washed with saturated aqueous NaHCO3, followed by water and dried using phase separator. Concentration in vacuo, and purification using silica chromatography (CH2Cl2:Et2O 3:1) gave 1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5(4H)-one (495 mg, 59%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]2=C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O.[O:39]=[O+][O-].O=[O+][O-].CSC>CO>[C:8]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C@H:21]3[S:20][CH2:19][C:18]2=[O:39])=[O:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CSC
Solvent: CO
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 0.50 g of 3-methylene-7β-phenylacetylamino-cepham-4α-carboxylic acid diphenylmethyl ester in 100 ml of methanol is treated for 6.5 minutes at -70° C. with an oxygen-ozone stream containing 0.175 mmol of ozone/minute. The reaction mixture is mixed with 0.5 ml of dimethyl sulphide and stirred for one hour at -70° C., then for 2 hours at room temperature and evaporated to dryness. The residue, in methylene chloride is chromatographed on 15 g of silica gel. Elution with methylene chloride yields amorphous 7β-phenylacetylaminocepham-3-one-4ξ-carboxylic acid diphenylmethyl ester, thin layer chromatography (silica gel): Rf~0.47 (system: toluene/acetone/methanol/acetic acid, 80:10:5:5); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95μ, 5.61μ, 5.77μ, 5.85μ, 5.95μ, 6.21μ and 6.87μ; the compound shows a positive reaction with iron-III chloride.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:12]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=O)=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1>>[O:12]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=3[CH3:1])=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: Cc1c(NCc2ccc3c(c2)OCCO3)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitroaniline and 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[N:17]=[C:16]2[N:33]([CH:36]([CH3:38])[CH3:37])[N:34]=[CH:35][C:15]=12)=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:35]=[N:34][N:33]([CH:36]([CH3:38])[CH3:37])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Tert-butyl 4-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) carbamoyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)piperidine-1-carboxylate (0.2 g, 0.383 mmol) was taken in DCM (3 mL), to it TFA (0.6 mL) was added at 0° C. and stirred at room temperature for 3 h. On completion of reaction, DCM was removed under reduced pressure, saturated NaHCO3 solution was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (60% yield). LCMS: 423.25 (M+1)+; HPLC: 99.121% (@ 254 nm) (Rt; 4.628); 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (t, J=4.8 Hz, 1H); 8.26 (s, 1H); 7.49 (s, 1H); 5.89 (s, 1H); 5.22-5.16 (m, 1H); 4.36 (d, J=4.8 Hz, 2H); 3.04 (d, J=12.0 Hz, 2H); 2.84-2.92 (m, 1H); 2.60 (t, J=, 8.4 Hz, 2H); 2.20 (s, 3H); 2.10 (s, 3H); 1.65-1.81 (m, 4H); 1.49 (d, J=6.8 Hz, 6H).