Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Yield: 74.9 %

Procedure:
Stir a mixture of 4-chlorobenzo[b]thiophene-2-carboxylic acid (0.94 g, 4.44 mmol), N,O-dimethylhydroxylamine hydrochloride (0.86 g, 8.87 mmol), DCC (1.1 g, 5.32 mmol) and DIEA (1.43 g, 1.9 mL, 11.08 mmol) in DCM (8 mL) at ambient temperature for 2 hours. Filter the reaction mixture and the filtrate is washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by column chromatography on silica gel eluting with PE:EtOAc (5:1 to 3:1) to afford 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide as white solid (0.85 g, 75.2%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.02 (m, 2H), 7.61-7.51 (m, 2H), 3.84-3.79 (s, 3H), 3.37-3.35 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[CH2:10][C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=[C:13]([O:24]C)[CH:12]=3)=[O:8])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[CH2:10][C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=[C:13]([OH:24])[CH:12]=3)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccc(OC)cc3C2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(C1=C(c2ccccc2)c2ccc(O)cc2C1)c1ccc(O)cc1
Reaction time: 24 h

Procedure:
To a solution of 4 gms. of the product from Example 1 in dichloromethane were added two equivalents of boron tribromide. The resulting mixture was stirred for 24 hours. Analysis of the reaction mixture by TLC indicated the presence of starting material, product, and some of the monohydroxy compound. Another equivalent of boron tribromide was added, and the mixture was stirred for a total of 72 hrs. TLC indicated no starting material and only traces of the monohydroxy derivative. The product was chromatographed on silica using a mixture of 10 percent ethyl acetate and 90 percent benzene to obtain 3 gms. of the title compound, m.p. 191°-192° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[C:8](Cl)[C:7]([CH3:12])=[CH:6][N:5]=1)([OH:3])=[O:2].C[O-:14].[Na+].Cl>>[C:1]([C:4]1[C:9]([CH3:10])=[C:8]([OH:14])[C:7]([CH3:12])=[CH:6][N:5]=1)([OH:3])=[O:2]
Reactant: Cc1cnc(C(=O)O)c(C)c1Cl
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cnc(C(=O)O)c(C)c1O
Yield: 89 %

Procedure:
Starting with 2-carboxy-4-chloro-3,5-lutidine, a sodium methoxide nucleophilic substitution reaction was conducted as described above for 24 hours. The aqueous layer was acidified to pH 2.5 with concentrated Hydrochloric acid. The precipitate was filtered and washed with water and dried under vacuum at 50ℑ C. The 2-carboxy-4-hydroxy-3,5-lutidine product was obtained as a light brown solid in 89% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].CCN(CC)CC.[NH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:52]=[CH:53][CH:54]=1)[CH2:25][N:26]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)[S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:31]=1[OH:38])(=[O:29])=[O:28]>C(Cl)Cl>[C:43]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:45][C:40]([CH2:39][N:26]([CH2:25][C:24]2[CH:52]=[CH:53][CH:54]=[C:22]([CH2:21][NH:20][S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH:23]=2)[S:27]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:31]=2[OH:38])(=[O:29])=[O:28])=[CH:41][CH:42]=1
Reactant: NCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)NCc2cccc(CN(Cc3ccc(-c4ccccc4)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of 4-cyanobenzene-1-sulfonyl chloride (26 mg, 0.13 mmol) in CH2Cl2 (3 ml) was added Et3N (0.07 ml, 0.49 mmol) followed by N-(3-(aminomethyl)benzyl)-N-(biphenyl-4-ylmethyl)-3,5-dichloro-2-hydroxybenzenesulfonamide (65 mg, 0.12 mmol) at rt under nitrogen. The reaction mixture was stirred at 25° C. for 2 h. It was concentrated and the residue was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give the product as a white solid (50 mg, 56%).
Reaction SMILES: Br[C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][NH:6]1.[CH2:26](B(CC)CC)[CH3:27].[OH-].[K+].Cl.N>C1(C)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:21]([N:20]([CH2:23][CH3:24])[C:19]([NH:18][C@H:8]1[CH2:9][C@H:10]2[C@@H:5]([CH2:4][C:3]3[C:17]4[C:15](=[CH:14][CH:13]=[CH:12][C:11]2=4)[NH:16][C:2]=3[CH2:26][CH3:27])[NH:6][CH2:7]1)=[O:25])[CH3:22]
Reactant: CCN(CC)C(=O)N[C@@H]1CN[C@@H]2Cc3c(Br)[nH]c4cccc(c34)[C@H]2C1
Reactant: CCB(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1[nH]c2cccc3c2c1C[C@H]1NC[C@@H](NC(=O)N(CC)CC)C[C@H]31
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.00 g (2.47 mmol) of 3-(2-bromo-8α-ergolinyl)-1,1-diethylurea is dissolved in 10 ml of toluene, mixed with 90 mg (0.12 mmol) of 1,1'-bis(diphenylphosphino)-ferrocene palladium(II) chloride and stirred for 15 minutes at room temperature. Then 5.5 ml of triethylborane (1M solution in tetrahydrofuran) and 2.5 ml of 4N potassium hydroxide solution are added and the mixture is refluxed for 4 hours. The reaction mixture is acidified with 2N hydrochloric acid, made alkaline with concentrated ammonia and extracted with dichloromethane. The raw product, obtained after drying of the organic phases (sodium sulfate) and removal of the solvent in a vacuum, is chromatographed on silica gel. (dichloromethane/methanol 98:2). Yield after crystallization (ethyl acetate): 307 mg (35%) [α]D +47.6° (c=0.5 in chloroform).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH:12]1[C:27]([OH:29])=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13][CH:12]1[C:27]([O:29][CH3:32])=[O:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a flask containing N,N'-dibenzyloxycarbonylpiperazine-2-carboxylic acid (Step 1, 12.83 g, 32.20 mmol) dissolved in dry DMF (50 mL) is added methyl iodide (5.6 mL, 90.00 mmol) and potassium carbonate (4.60 g, 32.20 mmol). The mixture is stirred for 4 hours at ambient temperature under an inert atmosphere. The reaction is concentrated in vacuo, diluted with ethyl acetate (150 mL), washed with water (3×50 mL) and saline, dried over MgSO4, concentrated in vacuo, and chromatographed on silica gel (70-230 mesh), eluting with hexane/ethyl acetate (50/50). The appropriate fractions are combined (Rf =0.55, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.31, 5.15, 5.12, 4.70, 4.1-2.9.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[N+:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:6][CH:7]=1.[BH3:14].[OH-].[Na+].[H][H]>O1CCCC1>[Br:2][C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:6][CH:7]=1.[BH3:14]
Reactant: Brc1c[nH]c(C=[N+]2CCCC2)c1
Reactant: [H][H]
Agent: B
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1c[nH]c(CN2CCCC2)c1

Procedure:
A suspension of 3.1 g of finely ground 1-(4-bromopyrrol-2-ylmethylene)pyrrolidinium bromide (0.01 mole) in 30 ml of dry tetrahydrofuran (THF) is stirred at room temperature under N2 while 30 ml of 1M borane.- THF complex is added dropwise over 10 minutes with stirring, and the whole is stirred for a further 21/2 hours while being chilled in an ice bath. Then 10 ml of 1N NaOH is added dropwise and hydrogen is evolved. The reaction mixture is acidified and extracted with ether; the combined extracts are washed with brine and dried over potassium carbonate. Evaporation in vacuo gives as a light red viscous oil 4-bromo-2-(1-pyrrolidinemethyl)-pyrrole-borane complex. IR (neat): 3500, 3050, 2400, 2310 cm-1.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30](Cl)=[O:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>C1C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30]([N:1]2[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]2[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[O:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)N2C(=O)CC[C@H]2C(=O)OCc2ccccc2)cc1OC
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A solution of 17.5 g (80 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), in 150 ml of benzene is added over 1 hour to a suspension of 3.85 g (80 mmol) of sodium hydride in 15 ml of dry benzene. After stirring for 1 hour at ordinary temperature, a solution of 17.2 g (80 mmol) of 3,4-dimethoxyphenylacetyl chloride in 150 ml of benzene is run in. The mixture is heated at 55° C. for 6 hours and stirred at ordinary temperature for 15 hours, washed with 2×120 ml of water, dried and evaporated. The residue was purified by chromatography on a silica column using a chloroform/acetone mixture as the eluent. Thus gives 60% of a pure waxy product of Rf=0.46 (A).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH2:11][C:12](O)=[O:13])[C:9](=[S:15])[NH:8][N:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:13][CH2:12][CH2:11][N:10]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][NH:8][C:9]1=[S:15]
Reactant: O=C(O)Cn1c(-c2cccs2)n[nH]c1=S
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCn1c(-c2cccs2)n[nH]c1=S
Reaction time: 2 h

Procedure:
All of the crude [3-(2-thienyl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]acetic acid from the previous step was dissolved in THF (20 ml). This solution was added dropwise at 0° C. to a slurry of LAH (2 g) in THF (80 ml) while stirring before allowed to come to r.t. for 2 h. The r.m. was then quenched with sat. Na2SO4 (aq.) at 0° C. and the pH adjusted to 3-4 before filtration through celite. The THF was removed from the filtrate by concentration and the product extracted with EA from the remaining aq. mixture. The EA-phase was then washed with brine and dried over MgSO4 before concentration to dryness to yield a crude material that was recrystallized from MeOH to provide 485 mg of the title compound. 1H NMR (DMSO-d6): 13.94 (br.s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.24 (dd, 1H), 5.09 (t, 1H), 4.16 (t, 2H), 3.76 (q, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,4,6-trifluorobenzoyl chloride (30 μL, 0.229 mmol) and mixing for 24 h, 45.1 mg (>100%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-bromo-5-nitrobenzoate (5 g, 19.23 mmol), morpholine (1.76 mL, 20.19 mmol), tris(dibenzylideneacetone)dipalladium (0) (1.32 g, 1.442 mmol), XPhos (1.38 g, 2.88 mmol), tripotassium phosphate (5.71 g, 26.9 mmol), and toluene (38.5 mL) was stirred overnight at 95° C. under nitrogen. Upon completion, the reaction was cooled to 23° C. and filtered over Celite. The filtrate was concd, and the crude material was purified by column chromatography (silica; 0-30% EtOAc in hexanes) to afford methyl 3-morpholino-5-nitrobenzoate as an orange amorphous solid. Mass Spectrum (ESI) m/e=267.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22](C)[CH:23]=[O:24])=[C:18]([CH3:26])[CH:17]=2)=[C:12]([CH:27]([CH3:29])[CH3:28])[CH:11]=[N:10]1.ClC1C=CC=C(Cl)C=1N1C(COC2C=CC(C=COC)=C(C)C=2)=C(C(C)C)C=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=[O:24])=[C:18]([CH3:26])[CH:17]=2)=[C:12]([CH:27]([CH3:29])[CH3:28])[CH:11]=[N:10]1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)C=O
Agent: COC=Cc1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1CC=O

Procedure:
The title compound (292 mg, quantitative yield) is prepared essentially according to the preparation of 2-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-propionaldehyde using 1-(2,6-dichloro-phenyl)-4-isopropyl-5-[4-(2-methoxy-vinyl)-3-methyl-phenoxymethyl]-1H-pyrazole. 1H NMR (400 MHz, CDCl3) δ 9.65 (t, 1H, J=2.2 Hz), 7.70 (s, 1H), 7.41 (d, 2H, J=8.4 Hz), 7.31 (dd, 1H, J=8.8, 7.4 Hz), 6.98 (d, 1H, J=7.9 Hz), 6.65-6.58 (m, 2H), 4.80 (s, 2H), 3.60 (d, 2H, J=2.2 Hz), 3.00 (sept, 1H, J=7.0 Hz), 2.18 (s, 3H), 1.31 (d, 6H, J=7.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.C1(C)C=CC=CC=1.[OH-].[Na+].[H][H]>[Ni].O.C(O)(C)C>[OH:28][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: [H][H]
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
38.39 g (0.1 mol) of 2-nitro-2'-hydroxy-3',5'-di-t-amylazobenzene, 5 g of Raney nickel, 100 ml of toluene, 100 ml of isopropyl alcohol (referred to as "IPA" hereinafter) 100 ml of water and 8 g (0.2 mol) of caustic soda were charged into a 500-ml stainless autoclave with an agitator. After the air in the flask had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature was increased at a rate of 20° to 40° C./hour and then 40° to 50° C./hour while the resultant mixture being agitated. Reaction was then effected at 50° to 90° C. for 2 hours and then 90° C. for 7 hours and was stopped when no more hydrogen was absorbed by the reaction solution. The autoclave was cooled, and the catalyst was filtered off. After the filtrate had been allowed to stand, the toluene layer was separated, and most part of the toluene was distilled off. The residual solid obtained was crystallized by IPA and the dried to obtain 28.8 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 82%; melting point, 79° to 80° C.).
Reaction SMILES: C(O)C.NC1C(=O)C2C(C)=CC(C)=CC=2OC=1.[CH3:18][C:19]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]2[C:20]=1[C:21]([OH:31])=[CH:22][C:23](=[O:30])[O:24]2.[N+:32]([O-])([OH:34])=[O:33]>C(O)(=O)C>[CH3:18][C:19]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]2[C:20]=1[C:21]([OH:31])=[C:22]([N+:32]([O-:34])=[O:33])[C:23](=[O:30])[O:24]2
Reactant: Cc1cc(C)c2c(O)cc(=O)oc2c1
Reactant: O=[N+]([O-])O
Agent: Cc1cc(C)c2c(=O)c(N)coc2c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c2c(O)c([N+](=O)[O-])c(=O)oc2c1

Procedure:
5,7-Dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyrane with a melting point of 186°-187° (from ethanol) can be prepared in a manner analogous to that described in Example 1, using 3-amino-5,7-dimethyl-4-oxo-4H-1-benzopyrane as the starting material. The starting material can be obtained, for example, using 5,7-dimethyl-4-hydroxy-coumarin as the starting material, by reacting the latter with nitric acid in acetic acid at 80° to give 5,7-dimethyl-4-hydroxy-3-nitro-coumarin, treating this compound for 24 hours with sodium hydroxide solution and subsequently acidifying, with decarboxylation, to give 4,6-dimethyl-2-hydroxy-β-nitro-acetophenone, analogously to the process described in J. Am. Chem. Soc. 67, 99 (1945), and also reacting the latter compound with the mixed anhydride of formic acid and acetic acid to give 5,7-dimethyl-3-nitro-4-oxo-4H-1-benzopyrane with a melting point of 120°-125° and reducing this compound with sodium dithionite to give 3-amino-5,7-dimethyl-4-oxo-4H-1-benzopyrane (melting point 120°-121°), analogously to the process described in Tetrahedron Letters 1976, 719, and purifying this product via the hydrochloride.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[N:7]=[C:6]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(F)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
6-Fluoro-2-pyridinecarboxylic acid (available from Asymchem Laboratories, 570 mg, 4.0 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1531 mg, 4.0 mmol) were dissolved in DMF (15 ml) and treated with DIPEA (2.11 ml). The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (500 mg, 2.0 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to approx. 5 ml which was added to 2×50 g aminopropyl cartridges that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The mixture was concentrated in vacuo to give an orange oil. DCM (5 ml) was added and the resultant precipitate was collected by filtration to give the title compound (235 mg) as a yellow solid.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[OH:7][C:8]1[C:9]([CH3:28])=[CH:10][C:11]([CH3:27])=[C:12]2[C:20]=1[CH:19]([N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O)[CH:18]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]1.[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[OH:7][C:8]1[C:9]([CH3:28])=[CH:10][C:11]([CH3:27])=[C:12]2[C:20]=1[CH:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:18]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cc1cc(C)c2c(c1O)C(N1CCCC1=O)C1CCCCC21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(c1O)C(N1CCCC1)C1CCCCC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
0.34 Gram of aluminum lithium hydride was suspended in 30 ml of THF and to the suspension was gradually added dropwise 1.6 g of 8-hydroxy-5,7-dimethyl 9-(2-oxo-1-pyrrolidinyl)-1,2,3,4,4a,9a-hexahydrofluorene. This suspension was refluxed with heating for 5 hours and then ice-cooled and excess hydride was decomposed with ethyl acetate. To the reaction mixture was added 1.5 ml of saturated aqueous sodium sulfate solution, followed by stirring at room temperature for 1 hour and then filtration to remove the precipitate. The filtrate was concentrated and to the residue was added ethyl acetate and insoluble matter was removed by filtration. The filtrate was again concentrated and the residue was recrystallized from hydrous ethanol to obtain 1.06 g of 8-hydroxy-5,7-dimethyl-9-(1-pyrrolidinyl)-1,2,3,4,4a,9a-hexahydrofluorene having a melting point of 96°-97° C. and of colorless prism-like crystal.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][CH:6]([F:8])[F:7].[Li+].[OH-]>C1COCC1.O>[CH2:13]([O:12][C:10]([NH:9][C@@H:4]([CH2:5][CH:6]([F:7])[F:8])[C:3]([OH:20])=[O:2])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](CC(F)F)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](CC(F)F)C(=O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 250 mg (S)-2-Benzyloxycarbonylamino-4,4-difluoro-butyric acid methyl ester in 2 ml THF was added a solution of 21 mg LiOH in 0.5 ml water at 0° C. After 2 h the mixture was brought to pH 4 by using Amberlite IR-120 ion exchange resin. The reaction mixture was filtered and concentrated and the crude product obtained used in the next step without further purification. Yield: 229 mg
Reaction SMILES: [CH:1]([OH:9])(O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[ClH:10].C1(C)C=CC=CC=1>O>[Cl:10][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:9]
Reactant: Cl
Reactant: CCCCCCC(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCCCCCCl

Procedure:
A mixture of 44 g of heptane diol, 400 ml of concentrated hydrochloric acid, 150 ml of toluene and 50 ml of water was stirred for two and half hours at reflux. The toluene fraction was removed and 200 ml of toluene were added to the aqueous fraction and the mixture was heated for five hours at 85° C. to 90° C. The toluene was removed and 200 ml of toluene and 100 ml of concentrated hydrochloric acid were added to the aqueous phase. The mixture was heated for five hours, then cooled and the organic fraction was combined with the two preceding toluene fractions. The toluene fraction was washed with water, dried and evaporated to dryness under reduced pressure, then distilled at 70° C. under 0.5 mm of mercury to obtain 37 g of the desired product.