Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[S:25][C:26]([CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[N:27][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[C:24]1[S:25][C:26]([CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)=[N:27][N:28]=1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1(C)CC(Cc2nnc(Br)s2)CC(C)(C)N1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-n2cccn2)ccc1-c1nnc(CC2CC(C)(C)NC(C)(C)C2)s1
Temperature: 120 °C

Procedure:
To a stirred suspension of 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole [Intermediate 4] [39 mg, 0.128 mmol) and 2-bromo-5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazole (34 mg, 0.107 mmol) in dioxane (1 mL) was added Pd(PPh3)4 (6 mg, 0.005 mmol), followed by a solution of Na2CO3 (34 mg, 0.32 mmol) in water (0.25 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (10 mL). The organic phase was separated and concentrated in vacuo to afford the crude product as a brown oily residue. The crude material was purified by UV directed preparative HPLC under acidic conditions (formic acid modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a slightly off-white solid 28.6 mg, 65% yield). LC-MS: Rt 0.88 min; MS m/z 412.5 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, J=2.53 Hz, 1H), 8.39 (d, J=8.59 Hz, 1H), 7.83 (d, J=1.01 Hz, 1H), 7.73 (d, J=1.52 Hz, 1H), 7.67 (dd, J=8.59, 2.02 Hz, 1H), 6.64-6.61 (m, 1H), 4.11 (s, 3H), 3.01 (d, J=6.57 Hz, 2H), 2.17-2.28 (m, 1H), 1.53 (dd, J=12.63, 2.53 Hz, 2H), 1.09 (s, 6H), 1.00 (s, 6H), 0.86 (t, J=12.38 Hz, 2H).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(O)C.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
24.g of magnesium turnings are suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride are added, and, when the reaction has started, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous toluene is added dropwise at 50°-60° C. Thereafter, the mixture is heated to 50°-60° C. for a further hour, and cooled to -5° C. to -10° C. with dry ice acetone, and a solution of 212.5 g of 2,3,4,5-tetrafluorobenzoyl chloride (1) in 80 ml of absolute toluene is slowly added dropwise at this temperature. The mixture is stirred for 1 hour at 0° to -5° C., and is allowed to reach room temperature overnight, and a mixture of 400 ml of ice water and 25 ml of concentrated sulphuric acid is allowed to run in whilst cooling with ice. The phases are separated, and extraction with toluene is repeated twice. The combined toluene solutions are washed with saturated NaCl solution and dried with Na2SO4, and the solvent is stripped off in vacuo. 335 g of diethyl 2,3,4,5-tetra-fluorobenzoylmalonate (3) are obtained as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:19]/[C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=1)/[CH2:5]2
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COc1cc2c(cc1Br)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 11 (200 mg, 0.829 mmol) in toluene was added 3-(trifluoromethyl)benzaldehyde 99 (158.86 mg, 0.9128 mmol). PTSA (285.5 mg, 172.20 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 152 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-5-bromo-6-methoxy-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one 152 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[OH-].[Na+].[NH2:12]O.Cl.Cl>O>[C:2]([C:3]1[O:7][N:6]=[C:5]([NH2:12])[CH:4]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
4,4-dimethyl-3-oxopentanenitrile (3 g, 23.97 mmol) was dissolved in distilled water, stirred, and added with NaOH (1.06 g, 26.4 mmol) and NH2OH.HCl (1.83 g, 26.4 mmol). The reaction solution was stirred for about 30 minutes at room temperature. The reaction mixture was calibrated to yield pH in a range of 8 to 9 by adding an aqueous solution of 1 N NaOH, followed by further stirring for 10 hours or more at 50° C. The reaction mixture was washed 2 to 3 times with carbon tetrachloride, and aqueous layer was calibrated to yield pH in a range of 4 to 5 by adding concentrated HCl. The reaction mixture was further stirred for about 3 hours at 50° C. The reaction mixture was cooled to room temperature, and calibrated to yield pH 12 by adding an aqueous solution of 1 N NaOH. The resulting solid was filtered under reduced pressure, and washed with distilled water. The filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (2.6 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: COc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(OC)cc2)n1

Procedure:
Following the procedures in preparation 1, the desired compound was prepared using 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 9 g of p-methoxyphenyl isocyanate and 80 ml of dimethylformamide as yellow powders. The product has the following physical properties.
Reaction SMILES: [N:1]1([C:7]([CH2:9][C:10]2[S:11][C:12]3[CH2:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:13]=3[N:14]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[N:1]1([CH2:7][CH2:9][C:10]2[S:11][C:12]3[CH2:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cc1nc2c(s1)Cc1ccccc1-2)N1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)Cc1sc(CCN3CCCCC3)nc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
A solution of 500 mg of 2-[(piperidinocarbonyl)methyl]-8H-indeno[1,2-d]thiazole in 10 ml of tetrahydrofuran was added to a suspension of 160 mg of lithium aluminum hydride in 10 ml of tetrahydrofuran at 0° C., followed by heating under reflux for 1.5 hours. The reaction mixture was cooled to 0° C. again, and sodium sulfate decahydrate was added. The resulting mixture was stirred at room temperature for 30 minutes. After the insoluble matter was removed by filtration, the solvent was evaporated. The resulting oily substance was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1), whereby 120 mg of 2-(2-piperidinoethyl)-8H-indeno[1,2-d]thiazole was obtained. Fumaric acid was added to the product in ethanol to cause crystallization, and the crystals were recrystallized to give a fumarate.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][OH:14])=[CH:12][C:5]=2[O:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:35]([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:36].CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[CH2:35]([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42]([O:14][CH2:13][C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][C:2]([CH3:15])([CH3:1])[CH2:3][O:4][C:5]=3[CH:12]=2)=[CH:41][CH:40]=1)[CH3:36]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)COc2ccc(CO)cc2OC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCc2ccc3c(c2)OCC(C)(C)CO3)cc1
Reaction time: 1 h

Procedure:
To a mixture of (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-methanol (31) (100 mg), polymer bound PPh3 (412 mg, ˜3 mmol/g on polystyrene) and ethyl-4-hydroxybenzoate in CH2Cl2 (4 ml) is added di-tert-butylazodicarboxylate (111 mg). The mixture is shaken 1 h, then the polymer is filtered off and the solvent is evaporated. Flash chromatography yields 74 mg of 4-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethoxy)-benzoic acid ethyl ester as a colourless oil, MS (ESI) 357.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[NH:17][C:18](=S)[NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>[Ni].C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[CH:18][NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Ni]
Solvent: CCO
Product: Cc1[nH]cnc1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 74.1 %

Procedure:
A mixture of 1.5 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline, 0.5 g of a Raney nickel catalyst, and 50 ml of absolute ethanol was refluxed for one hour and after filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of cyclohexane and n-hexane to provide 1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylimidazole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][CH:25]2[CH2:27][CH2:26]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC1CC1
Yield: 115.8 %

Procedure:
This compound was prepared as described in Example 37: 6.0 g (0.015 mol) of product of Example 28, 2.1 ml (0.030 mol) of cyclopropylamine in 25 ml of DMF were reacted at room temperature affording 7.24 g of oil. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent afforded 4.77 g of solid which was recrystallized in hot hexane to give 3.92 g (62.7%) of product as a beige solid; mp 72°-73.5° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.[Cl:22][C:23]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([Cl:42])[C:24]=1[O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35]O)=[CH:31][CH:30]=1.N1C=CN=C1>ClCCl>[Cl:22][C:23]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([Cl:42])[C:24]=1[O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][I:20])=[CH:31][CH:30]=1
Reactant: II
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CO)cc2)c(Cl)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CI)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (1.2 eq.) in dichloromethane (0.09 M) was added iodine (1.2 eq.) and the resulting reddish-orange mixture was stirred at RT for 15 min. At 0° C., a dichloromethane solution (0.1 M) of {4-[2-(2,6-dichloro-4-methylphenoxy)ethyoxy]phenyl}methanol prepared in the previous step (1 eq.) and imidazole (3 eq.) was then added dropwise over 15 min. The resulting orange-yellow suspension was stirred at 0° C. for 1 h and then at RT for 15 min. The reaction was quenched with 10% (w/w) aq. NaHSO3 and extracted with ether. The organic extracts were combined, washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. The resulting residue was triturated in a 10:1 (v/v) Hex:ether solution and filtered through a pad of SiO2. The filtrate was concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[F:11][C:12]1[CH:20]=[CH:19][C:18]2[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]3[CH2:28][N:29]([C:31](OCC)=O)[CH2:30][C:15]=3[C:14]=2[CH:13]=1>O1CCCC1>[F:11][C:12]1[CH:20]=[CH:19][C:18]2[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]3[CH2:28][N:29]([CH3:31])[CH2:30][C:15]=3[C:14]=2[CH:13]=1
Reactant: CCOC(=O)N1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 244 mg. (6.4 m moles) of lithium aluminum hydride in 20 ml. of dry tetrahydrofuran under a nitrogen atmosphere and cooled to -10° C. is added 284 mg. (2.1 m moles) of aluminum chloride and the resulting reaction mixture allowed to stir for 30 min. 7-Fluoro-4-(p-fluorophenyl)-2-carbethoxy1,2,3,4-tetrahydropyrrolo[3,4-b]indole (2.9 m moles) in 10 ml. of the same solvent is added dropwise to the cold solution with stirring. After one hour, the reaction is quenched with 5 ml. of water added dropwise, and the mixture allowed to warm to room temperature. The mixture is filtered and the solids washed with hot tetrahydrofuran. The combined filtrate and washings are concentrated to a brown solid, which on dissolution in diethyl ether followed by treatment with ether saturated with hydrogen chloride provides 448 mg. of the desired product, m.p. 160°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH2:25]([O:27][C:28](=O)[CH2:29]C1C2C(=CC=C(OC)C=2)N(CC2C=CC=CC=2)C=1C)[CH3:26].NN>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].[CH3:26][CH2:25][O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(OC)cc12
Agent: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1
Agent: NN
Solvent: CO
Product: CCOCC
Yield: 96 %

Procedure:
5-Methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide. A solution of 1.0 g (2.96 mmol) of 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester and 5 mL of hydrazine in 50 mL of MeOH was reacted as described in Example 3, Part C, to give by trituration with ether 920 mg (96% yield) of 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide mp, 161°-162° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[S:21](Cl)(=[O:23])=[O:22]>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[S:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1F
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccccc1F
Yield: 31 %

Procedure:
The title compound was synthesized as described for Example 178 in 31% yield, starting from 2-aminobenzenesulfonamide and (E)-2-(2-fluorophenyl)ethenesulfonyl chloride.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:27]=[CH:26][C:11]([CH:12]=[CH:13][C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[OH:1][CH:2]([C:8]1[CH:27]=[CH:26][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(O)c1ccc(C=CC(=O)OCc2ccc(OC)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)CC(O)c1ccc(C=CC(=O)O)cc1
Yield: 90.8 %

Procedure:
44 mg of p-anisyl 4-[1-hydroxy-2-(methoxycarbonyl)ethyl]cinnamate was dissolved in 0.1 ml anisole, and then treated with 0.1 ml trifluoroacetic acid on ice for 30 minutes to give 4-[1-hydroxy-2-(methoxycarbonyl)ethyl]cinnamic acid (27 mg, 91%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[F:35])=[O:25])[C:21](O)=[O:22]>>[F:35][C:29]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=1[CH2:27][NH:26][C:24](=[O:25])[CH:20]([CH3:19])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)ccc1F
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCc1cc(F)ccc1F)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=464.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(2,5-difluoro-benzyl)-malonamic acid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[S:16][CH:17]=[CH:18][N:19]=1)CCC>>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1nccs1
Yield: 39 %

Procedure:
Prepared in 39% yield from 2-chloro-3-cyanopyridine and 2-(tributylstannyl)thiazole according to the procedure described for Example 164A. MS (ESI+) m/z 187.9 (M+H)+; 1H NMR (CDCl3) δ 7.44 (dd, J=7.8, 4.7 Hz, 1H), 7.57 (d, J=3.0 Hz, 1H), 8.10-8.14 (m, 2H), 8.80 (d, J=3.4 Hz, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].P(Br)(Br)[Br:12].CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10]
Reactant: BrP(Br)Br
Reactant: COc1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1CBr
Reaction time: 1.5 h
Yield: 137.2 %

Procedure:
To a solution of 1-hydroxymethyl-2-methoxy-benzene (28.7 g, 0.207 mol) in CH2Cl2 (574 mL) at 0° C. under nitrogen was added slowly PBr3 (13.66 mL, 0.145 mol). After stirring for an additional 1.5 hours, MeOH (13.66 mL) was added and stirred for 5 minutes. To this mixture was added dropwise 10% Na2CO3 (2 mL) solution and stirred for 5 minutes. The mixture was then washed with 10% Na2CO3 (50 mL, 2×) and brine (100 mL). It was dried over MgSO4, and filtered. The filtrate was removed under vacuum to give an oil (40 g) of 1-bromomethyl-2-methoxy-benzene. This material was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]#[N:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:27][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: NC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)c1nc(C#N)c2cc(Br)ccc2c1O
Product: CCOC(=O)c1nc(C#N)c2cc(NC(=O)c3ccc(F)cc3)ccc2c1O

Procedure:
1-Cyano-7-(4-fluoro-benzoylamino)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-Bromo-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using 4-fluorobenzamide. 1H NMR (200 MHz, DMSO): δ ppm=10.85 (s, 1H), 8.83 (s, 1H), 8.39 (m, 2H), 8.11 (m, 2H), 7.37 (m, 3H) 4.49 (q, 2H), 1.41 (t, 3H.)
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[CH2:14][N:13]([CH2:15][CH2:16][CH3:17])[C:12](=[O:18])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@@H:9]1[CH2:14][N:13]([CH2:15][CH2:16][CH3:17])[C:12](=[O:18])[CH2:11][CH2:10]1
Reactant: CCCN1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CCC1=O
Agent: [Pd]
Solvent: CO
Product: CCCN1C[C@@H](N)CCC1=O
Reaction time: 19 h
Yield: 82.1 %

Procedure:
0.569 g (S)-5-dibenzylamino-1-propylpiperidin-2-one are placed in 25 ml of methanol and hydrogenated with 0.150 g Pd/C 10% at a pressure of 3 bar and a temperature of 60° C. After 19 hours the catalyst is suction filtered and the filtrate is evaporated to dryness. 0.217 g of the product are obtained as an oil.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](NCCCCCC(NN)=O)=[O:11])[C@H:3]2[NH:22][C:23]([NH:25][C@@H:2]12)=[O:24].C(Cl)CCl.C1N(CCS(O)(=O)=O)CC[O:32]C1>CS(C)=O>[OH:32][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:25][C:23]([NH:22]2)=[O:24])[CH2:1][S:5]1)=[O:11]
Reactant: O=S(=O)(O)CCN1CCOCC1
Reactant: NNC(=O)CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CS(C)=O
Solvent: ClCCCl
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 20 h

Procedure:
Natural GAGs (NAH, HS, HA, HEP, Ch, CS-A(S), CS-A(W), CS-B, CS-C, CS-D, CS-E, and KS) were dissolved in 0.1 M MES buffer (pH 5.5) to prepare 10 mg/ml GAG solutions. 25 μl of 20 mM biotin-LC-hydrazide (manufactured by Pierce Biotechnology) dissolved in dimethylsulfoxide (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 1 ml of each GAG solution. Subsequently, 12.5 μl of a 100 mg/ml EDC (manufactured by Pierce Biotechnology) solution prepared with 0.1 M MES buffer (pH 5.5) was added thereto. The mixture was mixed well, and then allowed to react with stirring at normal temperature (15° C. to 25° C.) for 16 to 24 hours. After completion of the reaction, the reaction products were dialyzed by using a dialysis membrane (cutoff molecular weight: 10,000 or less) against phosphate buffered saline (pH 7.2 to 7.5, containing no divalent ions such as calcium ion: hereinafter, referred to as “PBS(−)”) as dialysis solution, to thereby sufficiently remove free biotin. After completion of dialysis, the concentration of Bi-GAG was adjusted to 5 mg/ml, followed by freeze preservation.