Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br.N>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)c2ncccn2)cc1
Agent: Br
Agent: N
Product: O=S(=O)(c1ccc(O)cc1)c1ncccn1
Temperature: 90 °C

Procedure:
A mixture of 4.6×10-3 mol of 2-(4-methoxybenzenesulphonyl)pyrimidine and 10 of 47%-hydrobromic acid was heated for - hour at 90° C. The reaction medium was neutralized to a pH of 7 with an ammonia solution and the pasty residue was extracted with dichloromethane. The organic phase was then dried and evaporated and the residue so provided was purified by chromatography on a silica column using dichloromethane as eluent.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:9]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][C:14]([F:18])=[C:15]([F:17])[CH:16]=2)[NH:19][C:29]1=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)c(F)cc1C(=O)NN(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 198.7 %

Procedure:
2-Amino-4,5-difluorobenzoic acid, 2,2-dibenzylhydrazide (Example 15) (0.81 g, 2.2 mmol) and triphosgene (0.33 g, 1.1 mmol) are combined in 100 mL of methylene chloride and stirred at 25° C. for 20 hours. The solution is poured into 200 mL of saturated NaHCO3, the layers are separated, and the aqueous layer is washed three times with ethyl acetate. The combined organic layers are dried over magnesium sulfate and then concentrated to give 0.86 g of the title compound as a solid. MS CI: m/z 394 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([N:23]1[CH2:24][CH2:25][CH:20]([N:18]2[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]3[C:8]4[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=4[C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[N:19]2)[CH2:21][CH2:22]1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4F)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 2-fluorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[N:9]=[C:10]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[O:11][CH:12]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1.CC(=O)OCC.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[C:16]([SiH2:15][O:14][C:13]([CH3:21])([CH3:20])[C:10]1[O:11][CH:12]=[C:8]([CH2:6][OH:5])[N:9]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1coc(C(C)(C)O[SiH2]C(C)(C)C)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(CO)co1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazole-4-carboxylic acid ethyl ester (410 mg, 1.43 mmol) in THF (10.0 mL) was treated at 0° C. with DiBAL (5.70 mL of a 1M sol in toluene, 5.70 mmol) and the reaction mixture was stirred for 45 min at 0° C. The reaction mixture was then diluted with EA (5.0 mL), sat. aq. Rochelle's salt (20.0 mL) was added and the mixture stirred at rt for 2 h. The layers were separated and the aq. layer extracted with EA (3×20 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow solid. TLC: rf (EA)=0.59. LC-MS-conditions 02: tR=0.94 min; [M+H]+=244.46.
Reaction SMILES: [CH2:1]([C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH:4]1[OH:8])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(Cl)Cl.S(=O)(=O)(O)O>[CH2:1]([C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH:4]1[O:8][C:14](=[O:16])[CH3:15])[CH3:2]
Reactant: CCOC(=O)C1(CC)CCCC1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CC)CCCC1OC(C)=O

Procedure:
5.58 grams of ethyl 1-ethyl-2-hydroxy-cyclopentane carboxylate obtained in Example 15 was diluted with 50 ml of methylene chloride. To the solution were added several drops of concentrated sulfuric acid, then dropwise added 4.32 ml of acetic anhydride. The mixture was allowed to react under reflux condition for 2 hours. The reaction mixture was washed with 50 ml of ethyl acetate and 50 ml of water, and organic layer was separated. Then the organic layer was washed with 10% aqueous solution of sodium carbonate twice, then with saline solution to neutrality, and dried over anhydrous magnesium sulfate. Removing solvent gave 5.91 g of colorless liquid. Yield after chromatography purification: 83.20%. MS: m/e 228(M+′), 183(M+—OCH2CH3), 169 (M+—CH3CO2), 158, 155, 140, 129, 113, 101.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:32][CH3:33])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[NH:26][C:27]([CH:30]=O)=[CH:28][CH:29]=1)=[O:24])[CH3:18]>>[CH2:32]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[NH:26][C:27]([CH:30]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])=[CH:28][CH:29]=1)=[O:24])[CH3:33]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CCN(CC)CCNC(=O)c1ccc(C=O)[nH]1
Product: CCN(CC)CCNC(=O)c1ccc(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)[nH]1
Yield: 42 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (209 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-diethylaminoethyl)amide to give 182 mg (42%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[C:7]#[C:8][C:9]([O-])=[O:10].Cl>O.CO.C(Cl)Cl>[C:9]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:10])[C:8]#[CH:7]
Reactant: CC#CC(=O)[O-]
Reactant: C1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: C#CC(=O)N1CCCC1
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a stirred solution of pyrrolidine (4.2 mL, 50.0 mmol) in water (25 mL) and MeOH (35 mL) at −50° C. was added methylpropiolate (4.5 mL, 50.0 mmol) dropwise. The reaction mixture was stirred at this temperature for 5 h then diluted with DCM (200 mL). 2M aqueous HCl (200 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with aqueous sat. NaHCO3 (200 mL), water (200 mL), then brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (6.0 g, 98%) as a white solid that was used without further purification. δH (CDCl3) 3.68 (2H, t, J 6.8 Hz), 3.50 (2H, t, J 6.3 Hz), 3.04 (1H, s), 2.01-1.90 (4H, m).
Reaction SMILES: [NH2-].[Na+].[CH3:3][CH:4]([CH3:8])[C:5](=[O:7])[CH3:6].[CH3:9][O:10][CH:11]([CH3:16])[C:12](OC)=[O:13].O>C(O)(=O)C>[CH3:9][O:10][CH:11]([C:12](=[O:13])[CH2:6][C:5](=[O:7])[CH:4]([CH3:8])[CH3:3])[CH3:16]
Reactant: CC(=O)C(C)C
Reactant: COC(=O)C(C)OC
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(C)C(=O)CC(=O)C(C)C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
In a 200 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 5.15 g (132 mmol) of sodium amide, and the flask was purged with argon. Then, 80 mL of toluene was placed in the flask. Subsequently, 12.0 g (139.3-mmol) of 3-methyl-2-butanone was slowly dropped into the flask, and the resulting mixture was stirred for 15 minutes. Into the flask was further dropped 5.65 g (47.8 mmol) of methyl 2-methoxy-propionate (prepared by the method of Reference Example 1), and the mixture was stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 50 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, neutralized with acetic acid, and subjected to extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (41° C., 27 Pa) to give 4.25 g (yield: 52%) of 2-methoxy-6-methyl-3,5-heptanedione as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=O)[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[S:32])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=S)N3C)C(=O)O1
Temperature: 75 °C
Yield: 89.2 %

Procedure:
To a stirred suspension of the (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 62, Step 5, 1.26 g, 3.907 mmol) in dry dioxane (25 mL) is added Lawesson's reagent (2.37 g, 5.861 mmol). This reaction mixture is heated at 70-80° C. for 1.5-2 h at which time the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is washed with EtOAc (15 mL×3), sonicated and filtered to give the title compound as a yellow solid (1.18 g, 89%), MS (m/z): 339.5 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:14])=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C:2]1[N:3]=[CH:4][C:5]([NH2:14])=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cnc(Br)c(-c2cccnc2)n1
Reactant: CC1(C)OB(c2ccncc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cnc(-c2ccncc2Cl)c(-c2cccnc2)n1
Reaction time: 16 h
Yield: 48.2 %

Procedure:
An oven dried resealable Schlenk tube was charged with 5-bromo-6-pyridin-3-ylpyrazin-2-amine (Preparation 6, 0.3 g, 1.17 mmol), 3-cloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.56 g, 2.35 mmol), cesium carbonate (1.15 g, 3.525 mmol) in dioxane (10 mL) and water (2.8 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (58 mg, 0.071 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 90° C. oil bath. After 16 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (95:5 dichloromethane/methanol) gave the title compound (0.16 g, 48%) as a solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:17])[CH:12]([NH2:16])[CH2:13][CH2:14]C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>>[NH2:16][CH:12]([CH2:13][CH3:14])[C:11]([NH:10][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[O:9][N:8]=1)=[O:17]
Reactant: CCCC(N)C(=O)Nc1cc(C(C)(C)C)on1
Agent: Cl
Product: CCC(N)C(=O)Nc1cc(C(C)(C)C)on1

Procedure:
Prepared by methods analogous to those used in the preparation of 2-amino-pentanoic acid (5-tert-butyl-isoxazol-3-yl)-amide starting with the corresponding N-t-BOC analogs and HCl(g) in an appropriate solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cn1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cnc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 4-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (15-3, 0.40 g, 1.22 mmol) in THF (6.1 mL) was added triethylamine (0.370 g, 3.65 mmol) followed by isonicotinoyl chloride hydrochloride (0.430 g, 2.42 mmol). The reaction mixture was stirred at 60° C. overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was purified by column chromatography on silica gel (EtOAc:hexanes=5:1 as eluant) to give N-(4-(4-(5-methoxypyrazin-2-yloxy)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (15, 0.12 g) as yellow solids in 23% yield: 1H NMR (500 MHz, CDCl3) δ 8.87 (d, J=5.0 Hz, 2 H), 8.03 (d, J=6.5 Hz, 2 H), 7.96 (s, 1 H), 7.91 (s, 1 H), 6.81 (s, 3 H), 3.97 (s, 3 H), 2.08 (s, 6 H). ESI-MS: m/z 433.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@H:20]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=4)[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:35][O:23][C:22](=[O:24])[CH2:21][C@H:20]([NH:19][C:17]([C:16]1[C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=[N:14][CH:15]=1)=[O:18])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CS(=O)(=O)c1cc([C@H](CC(=O)O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propionic acid in methanol (1 mL) and benzene (4 mL) was added a 2 M solution of (trimethylsilyl)diazomethane in hexanes (126 μL, 0.252 mmol). After 10 minutes, the mixture became homogeneous and the resulting reaction mixture was stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography using a gradient of 0-8% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].Br[CH2:14][C:15]#[CH:16]>C1(C)C=CC=CC=1>[CH3:16][C:15]1[N:3]=[N:2][N:1]([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[CH:14]=1
Reactant: C#CCBr
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: Cc1cn(-c2ccc(N)cc2)nn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A solution of 1-azido-4-nitrobenzene (0.500 g, 3.05 mmol) and 3-bromoprop-1-yne (1.45 g, 12.2 mmol) in toluene (3 mL) was heated to 60° C. for 24 hours in a sealed tube. Additional 3-bromoprop-1-yne (1.45 g, 12.2 mmol) was added and the solution stirred at 60° C. overnight. The reaction mixture was concentrated to an orange solid. The crude residue was dissolved in ethanol (100 mL). 10 wt % Palladium on carbon (150 mg) was added and the mixture was pressurized to 50 psi hydrogen and stirred for 18 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was slurried in ethyl acetate. The mixture was filtered, and the solid dried under vacuum to give 4-(4-methyl-1H-1,2,3-triazol-1-yl)aniline (300 mg). 1HNMR (400 MHz, CD3OD, δ): 8.37 (s, 1H), 8.03 (m, 2H), 7.58 (m, 2H), 2.44 (s, 3H).
Reaction SMILES: [NH2:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1>O>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:1][NH2:2])[N:5]=1
Reactant: NN
Reactant: Brc1cccc(Br)n1
Solvent: O
Product: NNc1cccc(Br)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Hydrazine (27 mL, 83 mmol) was added to 2,6-dibromopyridine (20 g, 84 mmol), and the resulting suspension was heated at 70° C. for 30 min. The solution was cooled to 50° C. and diluted with H2O (150 mL). The resulting solids were stirred for 2 h, collected by filtration, and washed with H2O (350 mL) to provide the title compound (13 g, 83%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.34 (overlapping dd, J=7.8 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 6.65 (d, J=7.8 Hz, 1H), 4.19 (s, 2H).
Reaction SMILES: Cl.[C:2]1([C:8]2[N:9]=[C:10]([CH2:13][NH:14]C(=O)C3C=CC=CC=3)[S:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CO>O1CCOCC1>[C:2]1([C:8]2[N:9]=[C:10]([CH2:13][NH2:14])[S:11][CH:12]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1nc(-c2ccccc2)cs1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NCc1nc(-c2ccccc2)cs1
Temperature: 100 °C
Reaction time: 24 h
Yield: 77.3 %

Procedure:
6N HCl (4.5 mL) was added to a solution of N-((4-phenylthiazol-2-yl)methyl)benzamide (150 mg, 0.51 mmol) in dioxane (10 mL) and the reaction mixture was stirred at 100° C. for 24 h (reaction monitored by TLC, eluant CHCl3/MeOH). Reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The aqueous layer was washed twice with EtOAc. The pH of the aqueous layer was then adjusted to pH ˜9 using 10% NaHCO3 and the organic product was extracted with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure to yield (4-phenylthiazol-2-yl)methanamine (75 mg, yield 77%) as orange colored liquid, which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.91-7.88 (m, 2H), 7.45-7.40 (m, 3H), 7.36-7.31 (m, 1H), 4.25 (br s, 2H), 3.79-3.75 (m, 1H), 3.68-3.63 (m, 1H). MS (ESI) m/z: Calculated for C10H10N2S: 190.06. found: 191.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:16][C:13]1[C:8]2[N:7]=[N:6][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:9]=2[CH:10]=[CH:11][C:12]=1[O:14][CH3:15]
Reactant: [Br-]
Reactant: COc1ccc2c(c1)nnn2CC1CC1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: COc1ccc2c(nnn2CC2CC2)c1Br
Reaction time: 14 h

Procedure:
1-(Cyclopropylmethyl)-5-methoxy-1H-benzotriazole (22.0 g, 108 mmol) was dissolved in acetic acid (250 ml) and treated with pyridinium tribromide (41.5 g, 130 mmol). After stirring for 14 hours, the mixture was concentrated to the minimum amount of solvent with stirring volume. The residue was dissolved in ethyl acetate and washed with 1 N aqueous NaOH and diluted in an equal volume of water. The organic layer was removed, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10 to 50% ethyl acetate in heptane), providing the titled compound as an orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]2[N:9]=[N:10][CH:11]=[C:4]2[CH:3]=1.NC(N)=[S:14]>CO>[CH3:8][C:6]1[N:5]2[N:9]=[N:10][CH:11]=[C:4]2[CH:3]=[C:2]([SH:14])[N:7]=1
Reactant: NC(N)=S
Reactant: Cc1nc(Cl)cc2cnnn12
Solvent: CO
Product: Cc1nc(S)cc2cnnn12
Temperature: 0 °C

Procedure:
A mixture of 14.5 g (85 mmole) of 5-chloro-7-methyltriazolo[1,5-c]pyrimidine and 15 g (200 mmole) of thiourea in 100 ml of methanol was heated at reflux for one hour, and then cooled to 0° C. The product was collected by filtration and recrystallized from a 50:50 mixture of ethanol and hexanes with treatment with decolorizing charcoal to provide 7-methyltriazolo[1,5-c]pyrimidine-5-thiol. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3([CH3:32])OCC[O:28]3)[CH:22]=2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3]>C(O)(=O)C.C(OCC)(=O)C>[C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][C:15]1[N:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH2:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:10][CH2:9]1)=[O:33])(=[O:28])[CH3:32]
Reactant: CC1(c2cccc(Oc3ncccc3C(=O)NCC3CCC(C(C)(C)O)CC3)c2)OCCO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1cccc(Oc2ncccc2C(=O)NCC2CCC(C(C)(C)O)CC2)c1

Procedure:
A solution of N-[4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-2-[3-(2-methyl-[1,3]dioxolan-2-yl)-phenoxy]-nicotinamide (0.400 grams, 0.88 mmole) in acetic acid (10 ml) was stirred for 3 hours at room temperature. The mixture was diluted with 250 ml ethyl acetate, washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to an oil which was purified by chromatography on silica eluting with 40% ethyl acetate/hexane. Recrystalization gave a solid. (0.055 g). M.P. 105-107° C.; Anal. calcd. for C24H30N2O4: C, 70.22; H, 7.37; N, 6.82. Found: C, 68.43; H, 7.32; N, 6.71.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([O-:27])(=O)=[O:25])[CH:18]=[CH:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na+]>CN(C)C=O>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([Cl:3])(=[O:27])=[O:25])[CH:18]=[CH:17]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccc2cc(S(=O)(=O)[O-])ccc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To a solution of thionyl chloride (0.692 ml) and N,N-dimethylformamide (0.022 ml) was added sodium 6-octyloxy-2-naphthalenesulfonate (1 g) under ice-cooling and stirred for 1.5 hours at 95° C. The reaction mixture was evaporated under reduced pressure to give 6-octyloxy-2-naphthylsulfonyl chloride (1 g).