Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19]O.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:12])=[O:19])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 50 °C

Procedure:
The title compound was prepared by adding the 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (15.20 g, 49.65 mmol), ethanol (130 mL), 30% hydrogen peroxide (aqueous) (130 mL), and 6 N sodium hydroxide (aqueous) (9 mL) to a 2 liter round bottom flask. This mixture was heated at 50° C. for 1 hour, and removed from the heat to allow to cool to room temperature. The pH was adjusted to ˜3 by adding 6 N hydrochloride solution (aqueous) resulting in a precipitate. This precipitate was filtered and washed with water (15.13 g, 94%): ES-MS (m/z) 324 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:28][OH:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([O:29][CH2:28][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=1)=[CH:14][CH:15]=2)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1
Product: CC(=O)OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from {1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol -2-yl}methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 440. 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.77 (d, 2H, J=8.87 Hz), 7.48-7.40 (m, 4H), 7.29-7.22 (m, 3H), 7.00 (d, 2H, J=7.01 Hz), 6.72 (s, 1H), 5.50 (s, 2H), 5.24 (s, 2H), and 1.80 ppm (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[N+](=[C:21](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[C:12]1([CH:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][C:10]#[CH:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC(CC=O)c1ccccc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCC(NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To the solution of 1.2 g of tert-butyl 3-oxo-1-phenylpropylcarbamate (Formula 12) and 1.38 g of dimethyl 1-diazo-2-oxopropylphosphonate (Formula 15) in 60 mL of methanol at 0° C. was added 1.32 g of potassium carbonate. The mixture was stirred at room temperature for 16 hours then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Column chromatography (5% ethyl acetate/hexane) gave 1.03 g (87%) of tert-butyl 1-phenylbut-3-ynylcarbamate (Formula 16) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 1.98-2.00 (m, 1H), 2.6-2.8 (m, 2H), 4.88 (br, 1H), 5.16 (br, 1H), 7.23-7.37 (m, 5H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][O:22][N:23]=[C:24]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)\[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:38][CH:39]=1
Reactant: CCOC(=O)CCC(=NOCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-pyridyl)butyrate (670 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-pyridyl)butyric acid (475 mg, yield 75%) as colorless crystals. m.p. 161-162° C.
Reaction SMILES: [C:1]([C:4]([OH:26])([CH2:9][CH:10]([OH:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH2:5][C:6]([OH:8])=[O:7])(O)=[O:2].[Na][Na].Cl>O1CCCC1>[C:6]([CH2:5][C:4]1([OH:26])[CH2:9][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[O:25][C:1]1=[O:2])([OH:8])=[O:7]
Reactant: O=C(O)CC(O)(CC(O)CCCCCCc1ccc(Cl)cc1Cl)C(=O)O
Agent: Cl
Agent: [Na][Na]
Solvent: C1CCOC1
Product: O=C(O)CC1(O)CC(CCCCCCc2ccc(Cl)cc2Cl)OC1=O
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of ±(3R*, 5S*) 3-carboxy-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoic acid, disodium salt (11.8 g, 25.1 mmol), aqueous HCl (3M, 200 ml), and tetrahydrofuran (200 ml) was heated at 60° C. for 6 h, then cooled. Most of the tetrahydrofuran was removed under vacuum. The residual mixture was diluted with water, and extracted with ether. The extracts were washed with water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under vacuum, and the residue recrystallised (ether/petroleum ether 40°-60° C.) to give the title compound (8.80 g, 90%) as a white solid, m.p. 77°-79° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncccn1
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Ic1ccc(Nc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 54.7 %

Procedure:
Under an argon atmosphere, 2-chloropyrimidine (16.5 g) and acetic acid (11.7 ml) were added to a solution of 4-iodoaniline (30 g) in dioxane (500 ml), and the resulting mixture was stirred for 13 hours while heating the mixture to reflux. The reaction solution was cooled to room temperature and saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extracting the resulting mixture 4 times with ethyl acetate. Organic layers were washed 3 times with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane/ethyl acetate=4/1). The product was recrystallized from dichloromethane/hexane mixed solvent to obtain N-(4-iodophenyl)pyrimidin-2-amine (22.27 g). NMR (H1, CDCl3): δ 6.73 (1H, t, J=4.6 Hz), 7.18 (1H, brs), 7.40-7.42 (2H, m), 7.59-7.61 (2H, m), 8.41 (2H, d, J=4.6 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.B.C1COCC1.CO.C(Cl)(Cl)Cl>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
4-Benzyloxy-2-nitrophenylacetic acid (6.38 g, 22.2 mmol) was dissolved in freshly distilled and dry THF (60 mL) and stirred in an ice bath under N2. After 5 min, borane (55.6 mL, 55.5 mmol, 1M solution in THF) was transferred using a canula to a dropping funnel placed over the stirring solution. The BH3-THF solution was then slowly added to the solution, producing much effervescence. The red solution was left stirring in the ice bath for 10 min, and then allowed to stir at room temperature for 4 h. The reaction was checked by TLC (10% MeOH/CHCl3). Water (150 mL) was slowly added to the flask until effervescence no longer occurred. The organic layer was dried with anhydrous sodium sulfate and gravity filtered. The solution was then concentrated down producing a brown oil. Column chromatography (SiO2, 10-60% EtOAc/5% CHCl3 for solubility/hexane gradient elution) afforded 2-(4-benzyloxy-2-nitrophenyl)ethanol (5.72 g, 21.0 mmol, 95%) as a brownish solid. Mp 48-52° C.; TLC (10% MeOH/CHCl3) Rf=0.61; 1H-NMR (CDCl3, 500 MHz) 7.54 (d, 2.5, 1H), 7.42 (m, 5H), 7.31 (d, 8.5, 1H), 7.17 (dd, 2.5, 8.5, 1H), 5.10 (s, 2H), 3.91 (br q, 6.5, 2H), 3.65 (br t, 6.5, OH), 3.10 (t, 6.5, 2H); IR (neat) 3400, 3050, 2965, 2921, 2858, 1622, 1523, 1453, 1344, 1240, 1039, 804. EI-MS m/z (relative intensity) 273 (M+, 14). Accurate mass (EI-MS) for C15H15NO4: calcd. 273.1001, obsd. 273.0992.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:27]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br)#[N:28].C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[C:27]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:9][CH2:10]1)#[N:28]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cccc(CN2CCN(Cc3nnc4nc(N)nc(N)c4n3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added m-cyanobenzyl bromide (23 mg; 0.18 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 12 mg of yellow colored 3-[4-(3-Cyano-benzyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].I[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCOCC1.[Cu]Br.CN(P(N(C)C)(N(C)C)=O)C>[C:14]([O:13][C:3](=[O:12])[CH:4]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [Cu]Br
Agent: [Cl-]
Agent: [H-]
Solvent: C1COCCO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To the suspension of sodium hydride (60%, 1.2 g, 30 mmol) in 50 ml of anhydrous dioxane containing 3.5 ml of HMPA were added di-tert-butyl malonate (6.488 g, 30 mmol) and p-iodotoluene (1), the mixture was stirred at room temperature for 1 hour. To the resulting solution was added copper (I) bromide (5.163 g, 36 mmol, 1.2 equivalents), the mixture was heated at refluxing temperature. Then the reaction mixture was cooled to room temperature, 30 ml of saturated aqueous ammonium chloride solution was added to quench the reaction, and the product was extracted with ethyl acetate (50 ml×3), washed with brine, dried over sodium sulfate. The solvent was evaporated, and the oily residue obtained was purified by chromatography to give p-tolyl-malonic acid di-tert-butyl ester 5.072 g (yield 55.2%) as a white solid. 1H NMR (CDCl3) δ: 7.275 (2H, d, J=8.06 Hz), 7.161 (2H, d, J=8.05 Hz), 4.397 (1H, s), 2.344 (3H, s), 1.471 (18H, s) ppm. FABMS (+Ve), m/z 307 [MH+], 251 [MH+−C4H8], 195 [MH+−2C4H8]. Anal. calcd. for C18H26O4: C, 70.6; H, 8.6. Found: C, 70.34; H, 8.62.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=2[CH:13]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+].Cl.CC(O)C>CN(C=O)C.CO.C(O)(C)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[O:7][C:6]=2[CH:13]=1
Reactant: NCC1COc2ccc(O)cc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1ccc2ccc(OCCCNCC3COc4ccc(O)cc4O3)cc2o1
Yield: 16 %

Procedure:
2,3-Dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine (3.00 g, 16.6 mmole), 7-(3-chloropropoxy)coumarin (2.95 g, 12.4 mmole), diisopropylethylamine (8.0 ml, 46.0 mmole) and sodium iodide (2.58 g, 17.2 mmole) were combined in 150 ml of DMF and heated at 80°-100° C. for 2 days under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on silica gel using first dichloromethane and then 0.25% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the pure free base (1.0 g, an additional 2.0 g were obtained of lower purity) redissolved in methanol and boiled on a hot plate, the methanol gradually being replaced with isopropanol. 4N HCl/IPA was added and the title compound was collected by filtration and dried in vacuum at 80° C. The procedure yielded 0.76 g of beige solid, monohydrochloride, m.p. 252° C. (d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]2[S:14][C:13]([NH2:16])=[N:12][C:11]=2[NH:10][N:9]=1.Cl.[N:18]1([CH2:24][C:25]2[O:29][C:28]([C:30](Cl)=[O:31])=[CH:27][CH:26]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]2[S:14][C:13]([NH:16][C:30]([C:28]3[O:29][C:25]([CH2:24][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:26][CH:27]=3)=[O:31])=[N:12][C:11]=2[NH:10][N:9]=1
Reactant: Nc1nc2[nH]nc(-c3ccccc3Br)c2s1
Reactant: O=C(Cl)c1ccc(CN2CCOCC2)o1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2[nH]nc(-c3ccccc3Br)c2s1)c1ccc(CN2CCOCC2)o1
Temperature: 70 °C
Reaction time: 17 h
Yield: 27.3 %

Procedure:
To a vial charged with 3-(2-bromo-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.135 mmol), PS-DMAP (Argonaut resin, 0.54 g, 6 equiv.), and a stirring bar was added THF (1.5 mL) and 5-morpholin-4-ylmethyl-furan-2-carbonyl chloride hydrochloride (180 mg, 0.675 mmol). The reaction mixture was stirred at 70° C. for 17 hours, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 0.76 g, 20 equiv.) at 50° C. for 8 hours. The resin was filtered, washed with DMF and the solvent was evaporated. Purification on silica gel with 0-8% MeOH in CH2Cl2 as eluent provided 18 mg (27% yield) of 5-morpholin-4-ylmethyl-furan-2-carboxylic acid [3-(2-bromo-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-yl]-amide as a white solid. 1H-NMR (d6-DMSO) δ: 13.7 and 13.5 (2 broad s, 1H, NH+tautomer), 12.8 (broad s, 1H, NH), 7.65-7.82 (m, 3H), 7.49 and 7.55 (2 t, 1H, tautomers), 7.36 and 7.41 ( 2 t, 1H, tautomers), 6.58 (d, 1H), 3.59 (s, 2H), 3.56 (t, 4H), 2.41 (broad s, 4H); HPLC/MS m/z: 488.0, 490.0 [MH]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][C:16]([C:20]([O-:22])=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][C:16]([C:20]([OH:22])=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC12CCCC(C(=O)[O-])(CC1)C2)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC12CCCC(C(=O)O)(CC1)C2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of 5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate (10 g, 31.5 mmol) in MeOH (150 mL) was added NaOH (2N, 50 mL) and the reaction solution was stirred at room temperature overnight. The organic solvent was removed under reduced pressure and the remaining aqueous solution was extracted with ethyl acetate (20 mL) to remove the organic impurities, and then adjusted to pH 3 with 2N aq. HCl. The acidic aqueous solution was extracted with ethyl acetate (3×20 mL) and the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give 9 g (95%) 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid as a colorless oil, which was solidified after standing at room temperature overnight. ESI-MS m/z: 304 (M+H)+.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[CH3:9][C:10]([O:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[CH3:30])([CH3:20])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:20])[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:27]2[C:26]([CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]([CH3:30])[C:22]=2[O:21]1
Reactant: Cc1ccc(C(O)C(C)(C)Oc2cc(C)cc(C)c2C)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C2c3c(C)cc(C)c(C)c3OC2(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Trifluoromethanesulfonic acid (7.5 mL) was added to a solution of 2-methyl-1-(4-methylphenyl)-2-(2,3,5-trimethylphenoxy)-1-propanol (253.7 g) obtained in Example 2 in toluene (1260 mL), and the mixture was stirred at 50° C. for 30 minutes and then for 1 hour under reflux. To the mixture was added 1N NaOH (756 mL) at 25° C. The toluene layer was separated and washed with water, and the solvent was distilled off. The residue was dissolved in isopropanol (1511 mL) and water (756 mL) was added thereto. Precipitated crystals were filtered to obtain the title compound (176.33 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH2:22][C:23]([O:25]C)=[O:24])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[OH-].[Na+].Cl>O1CCOCC1>[C:23]([CH2:22][N:17]([C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2)[S:18]([CH3:21])(=[O:20])=[O:19])([OH:25])=[O:24]
Reactant: COC(=O)CN(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1nc2cc(Cl)c(Cl)c(N(CC(=O)O)S(C)(=O)=O)c2nc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
A mixture of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methoxycarbonylmethyl)-methanesulphonamide (Example 71, WO 96/09295, 1.0 g, 2.357 mmol), 1M sodium hydroxide (12 ml) and 1,4-dioxan (25 ml) was stirred at room temperature for 15 minutes. The resulting solution was acidified to ca. pH5 with 2M hydrochloric acid and concentrated under reduced pressure. The residue was suspended in water (10 ml), collected by filtration and dried under reduced pressure at 80° C. to give N-(carboxymethyl)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (876 mg, 91 %) as a white solid, mp 203°-206° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5]([CH:11]=O)=[CH:4][CH:3]=1.C1(P(=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](/[CH:11]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)c2ccsc12
Product: CCOC(=O)/C=C/c1ccc(O)c2ccsc12
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-hydroxy-1-benzothiophene-7-carbaldehyde (168 mg, 0.85 mmol, 1.00 equiv, 90%), Ethyl (triphenylphosphoranylidene)acetate (493 mg, 1.42 mmol, 1.50 equiv), Tolune (6 mL). The resulting solution was stirred for 4 h at 120° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 5 mL of H2O. The resulting solution was extracted with 3×5 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×10 mL of sodium chloride(aq). The mixture was dried over anhydrous sodium sulfate. The residue was purified by thin layer chromatography developed with ethyl acetate/petroleum ether (1:8). This resulted in 200 mg (81%) of ethyl (2E)-3-(4-hydroxy-1-benzothiophen-7-yl)prop-2-enoate as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:31](=[O:32])[CH2:30][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)CN1CCOCC1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CN1CCOCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and morpholin-4-yl-acetic acid to yield (3aR,4S,7aR)-4-(2-morpholin-4-yl-acetoxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=6.574 min; LC-MS Method III
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:14][C:6]=1[C:7]([O:9]CC(C)C)=[O:8])(=O)C.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36].S(=O)(=O)(O)O.[OH-].[K+].Cl>ClCCl.C(O)C>[OH:4][C:5]1[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:14][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Oc1ccc(C=Cc2ccc(S(=O)(=O)Cl)cc2)cc1C(=O)OCC(C)C
Reactant: Nc1ccccn1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O

Procedure:
Isobutyl 2-acetyloxy-5-[2-(4-(chlorosulfonyl)phenyl)ethenyl]benzoate (1.99 g, 0.0046 mol) and 2-pyridinamine (1.3 g, 0.0138 mol) was stirred in dichloromethane (10 ml) at 45° C. for 1 h. After cooling to room temperature dichloromethane (20 ml) and 2M sulfuric acid (20 ml) were added. The precipitated solid (1.3 g) was collected and washed with water. The organic phase was taken to dryness and the residue treated with boiling methanol containing ammonia (2 ml) for 20 min. After cooling, 0.6 g was collected which was combined with the first crop. The combined material (1.9 g) was refluxed with potassium hydroxide (1 g) in water (50 ml). After acidification and filtration, the solid residue was dissolved in 70% ethanol with about 3 equivalents of potassium hydroxide at the boiling point and acidified while boiling with hydrochloric acid. After filtration and drying, the yield was 1.25 g (70%).