Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[S:13].[CH3:14]I.[OH-].[Na+].O>CC(C)=O>[CH3:1][N:2]1[C:3]([S:13][CH3:14])=[N:4][N:5]=[C:6]1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: Cn1c(-c2ccncc2)n[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CSc1nnc(-c2ccncc2)n1C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a mechanically stirred and cooled (9° C.) suspension of 4-methyl-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione (267 g) and methyl iodide (197.7 g) in acetone (2.6 L), was added a solution of sodium hydroxide (54 g in 600 mL of water) at such a rate (ca. 20 mL/min) as to maintain the temperature between 10 and 15° C. Another portion of water (50 mL) was then added and the temperature was allowed to come to 21 to 24° C. After another 2 h, the acetone was distilled off from the reaction mixture in vacuo (water-bath kept at 30° C.). Another portion of water (750 mL) was then added before cooling (17 to 18° C.) and collection of the formed precipitate by filtration. This solid was then washed with water (2×1 L) before drying at 100 mbar under a gentle stream of air for 3 days to yield 235 g of the title compound as a white powder. 1H NMR (DMSO-d6): 2.7 (s, 3H), 3.6 (s, 3H), 7.7 (m, 2H), 8.8 (d, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:94][CH2:93][CH2:92][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:88]([O:90][CH3:91])=[O:89])[CH2:76][CH2:77][CH2:78][CH2:79][NH:80]C(OC(C)(C)C)=O)=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(OC(C)C)(C)C>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:94][CH2:93][CH2:92][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:88]([O:90][CH3:91])=[O:89])[CH2:76][CH2:77][CH2:78][CH2:79][NH2:80])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: COC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N
Reaction time: 0.42 h

Procedure:
77 mg of H-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys(Boc)-OMe (from Example 17) are dissolved in 0.4 ml of 95% strength TFA and left to stand for 25 minutes. By adding 5 ml of diisopropyl ether and filtering off the precipitate, H-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys-OMe is obtained in the form of an amorphous, hygroscopic powder; Rf (D)=0.04; Rf (M)=0.04; Rf (O)=0.05.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]([OH:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH:20]([CH3:23])[C:21]#[CH:22])(=O)=O>O1CCCC1>[CH3:22][CH:21]([O:14][C@H:12]([CH3:13])[CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:20]#[CH:23]
Reactant: C[C@@H](O)COCc1ccccc1
Reactant: C#CC(C)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(C)O[C@H](C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a suspension of sodium hydride (60 wt % dispersion in mineral oil) (1380 mg, 34.6 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was added (2R)-1-benzyloxypropan-2-ol (5.00 g, 30.1 mmol) dropwise. The solution was stirred at 0° C. for 1 h then 1-methylprop-2-ynyl methanesulfonate (4780 mg, 32.3 mmol) was added dropwise and the reaction mixture was allowed to warm to room temp and stirred overnight. The reaction mixture was quenched by the addition of sat. aq. ammonium chloride and extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was adsorbed onto silica and purified by column chromatography (0-20% EtOAc in Heptane) to afford the title compound as a yellow oil (2.36 g, 36%, mixture of diastereomers).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[C@H:12]2[CH2:17][C@@H:9]1[C@H:10]([OH:18])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25]#[N:26].CN(C)CCCN=C=NCC>CN(C)C=O>[C:25]([C@@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:14]([C@@H:13]1[C@H:12]2[CH2:17][C@H:9]([C@H:10]([OH:18])[CH2:11]2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])#[N:26]
Reactant: N#C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.8 %

Procedure:
To a solution of (1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 5-6 (90 mg) in N,N-dimethylformamide (1.6 mL), was added (2S)-2-pyrrolidinecarbonitrile hydrochloride (55.7 mg) 1-hydroxy-7-azabenzotriazole (57.2 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (65 mg). The mixture was then stirred at room temperature for 6 hrs. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (85.4 mg) as a solid.
Reaction SMILES: [Br:1][CH:2]([OH:5])[C:3]#[CH:4].[OH-].[Na+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>O.O1CCCC1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:5][CH:2]([Br:1])[C:3]#[CH:4])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C#CC(O)Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(Br)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
In a 100 mL 3-necked round bottom flask, equipped with a magnetic stirrer, nitrogen inlet, thermometer, addition funnel, and ice bath, were placed bromopropargyl alcohol (5 g, 0.037 mole) and tetrahydrofuran (10 mL). A cold solution of NaOH (2.2 g, 0.55 mole) in water (10 mL) was added. To the above stirred mixture a solution of p-toluenesufonyl chloride (7.06 g, 0.037 mole) in tetrahydrofuran (10 mL) was slowly added. The reaction mixture was stirred at 0°-5° C. for 4 hrs. The reaction mixture was then poured into ice water and the resultant white precipitate was collected by suction-filtration and washed with water. After drying in air, an off-white solid was obtained yielding 9.9 g (92.5% yield) m.p. =43°-46° C. An NMR (CDCl3) spectrum indicated the desired compound (V, R3 =p-tolyl). This compound is used in the next example without further purification.
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]1O)([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1]([C:4]1[CH2:12][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)([CH3:3])[CH3:2]
Reactant: CC(C)C1Cc2ccccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C1=Cc2ccccc2C1

Procedure:
2-i-Propyl-1-indanol, non-purified, was dissolved in 300 ml of benzene to which was added 5 g of p-toluenesulfonic acid monohydrate and the resulting mixture was refluxed to allow dehydration reaction to occur. After the reaction was over, the reaction mixture was washed with saline, dried over magnesium sulfate, and concentrated in an evaporator. The reaction mixture was purified by column chromatography (silica gel, development solvent: n-hexane) to fractionate the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[NH:6].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:6][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)=[N:7][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1cccc(Cl)c1
Product: NCc1c(N)nc(-c2cccc(Cl)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=378.8 (M+H+), was prepared from 3-chlorobenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.[CH2:9]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13]>C(#N)C>[CH2:9]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([N:24]=[C:5]=[O:4])=[CH:22][CH:23]=1)(=[O:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCNS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCCCNS(=O)(=O)c1ccc(N=C=O)cc1
Temperature: 65 °C

Procedure:
Under argon, trichloromethyl chloroformate (135 μL, 1.118 mmol) is added to N-(pentyl)-4-aminobenzenesulfonamide (Example 26, 0.572 mmol) in anhydrous acetonitrile (4 mL). The solution is heated to 65° C. for 5 hours and the solvent removed at reduced pressure. The formation of the isocyanate is confirmed by infrared spectroscopy of the residue, then immediately used without further purification in the next reaction.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[NH2:15][NH2:16]>>[CH3:8][C:7]1[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[N:3][C:2]=1[NH:15][NH2:16]
Reactant: NN
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Product: Cc1cc(-c2ccccc2)nnc1NN
Temperature: 100 °C

Procedure:
3-Chloro-4-methyl-6-phenylpyridazine (0.510 g, 2.49 mmol) was dissolved in hydrazine (1.56 ml, 49.8 mmol) then the reaction mixture was heated at 100° C. for 1.5 hours. The precipitate that had formed in the mixture was collected and washed with iPrOH. The solid was dried under high vacuum to afford 1-(4-methyl-6-phenylpyridazin-3-yl)hydrazine as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([C:11]4=[O:18])[CH2:9]2)[CH2:15]3)[CH:7]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([C:11]3=[O:18])[CH2:9]1)[CH2:15]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C2CC3CC1CC(c1cc(Br)ccc1O)(C3)C2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C2CC3CC1CC(c1cc(Br)ccc1OCc1ccccc1)(C3)C2
Yield: 93.8 %

Procedure:
To a solution of 5-(5′-bromo-2′-hydroxyphenyl)-2-adamantanone (4.57 g, 14.20 mmol) in acetone (42 mL) was added benzyl bromide (2.67 g, 15.6 mmol) followed by K2CO3 (2.65 g, 19.2 mmol). The mixture was stirred at reflux for 25.7 h under argon. Acetone was removed, and 2 N HCl (60 mL) was added. The resultant mixture was extracted with EtOAc (250 mL), and the organic layer was washed with brine and dried. After removal of solvent at reduced pressure, the residue was purified on silica gel (14% to 20% EtOAc/hexane) to give 5.48 g (94%) of 5-(2′-benzyloxy-5′-bromophenyl)-2-adamantanone as a white solid, mp 163-165° C. 1H NMR (DMSO-d6) δ 1.79-2.42 (m, 13H, AdCH and AdCH2), 5.12 (s, 2H, C6H5CH2), 7.03 (d, J=8.5 Hz, 1H, 3′-ArH), 7.21 (d, J=2.4 Hz, 1H, 4′-ArH), 7.29-7.44 ppm (m, 6H, 6′-ArH, C6H5).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH:20]=[O:21])=[CH:7]2.O.[CH2:23]1COCC1>>[OH:21][CH:20]([C:8]1[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:10](=[O:12])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH3:23]
Reactant: Cc1ccccc1-n1c(C=O)cc2cccc(C)c2c1=O
Reactant: C1CCOC1
Solvent: O
Product: Cc1ccccc1-n1c(C(C)O)cc2cccc(C)c2c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
8-Methyl-1-oxo-2-o-tolyl-1,2-dihydroisoquinoline-3-carbaldehyde 4161 (2.4 g, 8.6 mmol) was dissolved in anhydrous THF (280 mL) and cooled to −78° C. under a nitrogen atmosphere. Methyl MgBr (2 M, 5 mL, 10 mmol) was added slowly, and the resulting mixture was stirred at −78° C. for 2 h. H2O (5 mL) was added and then the solution was poured into ice-water (200 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue product was purified by flash column chromatography on silica gel (10-50% EA/PE) to afford the product, 3-(1-hydroxyethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one 4102 (1.8 g, 71% yield) as a white solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[OH:11][CH:12]([CH:23]([CH3:25])[CH3:24])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14].Cl[C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[N:34]=[CH:35][C:28]=12>C1COCC1.CCOC(C)=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[N:33]1[C:29]2=[N:30][CH:31]=[N:32][C:27]([O:11][CH:12]([CH:23]([CH3:25])[CH3:24])[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)=[O:14])=[C:28]2[CH:35]=[N:34]1
Reactant: Cc1ccc(NC(=O)C(O)C(C)C)nc1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)C(Oc2ncnc3c2cnn3-c2ccccc2Cl)C(C)C)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
A solution of LHMDS (0.999 mL, 1.00 mmol) in anhydrous THF (15 mL) was added dropwise to a stirred solution of racemic 2-hydroxy-3-methyl-N-(5-methylpyridin-2-yl)butanamide C1 (208 mg, 1.00 mmol) in anhydrous THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes, then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine B1 (265 mg, 1.00 mmol) in anhydrous THF (3 mL) was added dropwise over 1 minute and the resulting mixture heated to 50° C. for 3 hours. The mixture was allowed to cool to room temperature then diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The material was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-methyl-N-(5-methylpyridin-2-yl)butanamide (320 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:20])=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=2[CH3:20])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc(CCc2ccc(Cl)cc2)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1[nH]c(C(=O)O)cc1CCc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-[2-(4-Chlorophenyl)-ethyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (109) in dioxane, 10 equiv of NaOH aq (1.5 M) was added then the mixture was heated at 80° C. for 3 hours. When the reaction is judged complete, the solvent is removed under vacuum, H2O was added and an equal volume of Et2O was added. The organic layer was removed then the aqueous layer was made acidic with HCl (1M). If the product precipitates out at this point, it was filtered off, washed with H2O, and dried to obtain pure desired product. If the product didn't crash out when the aqueous layer is made acidic, Et2O was added, and the organic layer was removed (2×). The organic layer was dried with Na2SO4, filtered, and concentrated to obtain desired product. Purification: precipitation. Amount: 20.6 mg. 1H (MeOD 400 MHz): δ 7.2 (2H, dd), 7.08 (2H, dd), 6.59 (1H, s), 2.76 (2H, dd), 2.63 (2H, dd), 1.97 (3H, s) ppm. DEPT (CD3OD, 100 MHz): CH3: δ 10.8, CH2: □□ 28.9, 38.0, CH: 116.4, 129.1, 131.3 ppm. HPLC (20 min): 97.8%. LC/MS: 100%.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH:16]=[C:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:6]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:3])[CH3:2].B(F)(F)F.O>ClCCl>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]2[O:15][C:17]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][C:7]=2[C:6]=1[C:22]([CH3:23])([CH3:24])[CH3:25])(=[O:3])[CH3:2]
Reactant: CCC(=Cc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C)CC
Agent: FB(F)F
Solvent: O
Solvent: ClCCl
Product: CCC1(CC)Cc2c(cc(C(C)(C)C)c(OC(C)=O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-2-(2-ethyl-1-butenyl)phenol (0.85 g, 2.5 mmol) was dissolved in dichloromethane (10 ml) and BF3 etherate (0.4 ml) was added dropwise to the solution under a nitrogen atmosphere. After stirring at room temperature for 3 h, water was added to the reaction mixture and extracted with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2,2-diethyl-2,3-dihydrobenzofuran [0.45 g (yield, 53%)] as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[CH:10][N:9]=1.[NH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([OH:25])=[CH:18][C:17]=1[CH3:26]>CN(C=O)C>[Cl:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([O:25][C:19]2[CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]([NH2:15])=[C:17]([CH3:26])[CH:18]=2)[CH:13]=1
Reactant: Cc1cc(O)cc([N+](=O)[O-])c1N
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc([N+](=O)[O-])c1N
Temperature: 50 °C
Reaction time: 6 h

Procedure:
1.66 g (12.0 mmol) potassium carbonate were added to 0.922 g (6.00 mmol) 4,6-dichloropyrimidine and 1.11 g (6.60 mmol) 4-amino-3-methyl-5-nitro-phenol in 1.5 mL DMF and the mixture was stirred for 6 h at 50° C. Then the mixture was added to ice water and extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, evaporated down and purified by flash chromatography. The product-containing fractions were combined and evaporated down. The residue was triturated with EtOAc, suction filtered and dried under HV.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(Cl)CCl.[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>C(Cl)Cl>[CH3:25][C:26]1[CH:34]=[N:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:29]
Reactant: Cc1cnccc1C(=O)O
Reactant: Cc1ccc(-c2cccnc2)cc1-c1ccc(N)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cnccc1C(=O)Nc1ccc(-c2cc(-c3cccnc3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
Amide Coupling Reaction: To a solution of 2′-methyl-5′-(pyridin-3-yl)biphenyl-4-amine n (40 mg, 0.15 mmol) in DCM (3 mL) was added EDC (85 mg, 0.45 mmol) and 3-methylisonicotinic acid (40 mg, 0.3 mmol). The solution was stirred at room temperature for 6 hr before it was concentrated and chromatographied to give Compound 20 (50 mg, 88%).
Reaction SMILES: [CH:1]([N:4]([C:9]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:5](OC)=[O:6])([CH3:3])[CH3:2].[OH:18]O.Cl>C(O)C.[OH-].[Na+]>[CH:1]([N:4]1[C:9]2[C:10](=[CH:13][CH:14]=[C:15]([CH3:17])[CH:16]=2)[C:11](=[O:18])[NH:12][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)N(c1cc(C)ccc1C#N)C(C)C
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(=O)[nH]c(=O)n(C(C)C)c2c1

Procedure:
To a suspension of 300 g 2-(N-isopropyl-N-carbomethoxyamino)-4-methyl-benzonitrile in 750 ml of ethanol and 234 ml 10N sodium hydroxide are added dropwise over 80 minutes 576 g of a 40% solution of hydrogen peroxide. The resulting clear solution is acidified with 195 ml of concentrated hydrochloric acid, whereupon the title compound precipitates, m.p. 250°-251°.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[N:24](C(=O)C)[N:23]=3)[C:18]([C:33]#[C:34][Si](C)(C)C)=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CCO>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:28][CH2:29]4)[NH:24][N:23]=3)[C:18]([C:33]#[CH:34])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNC(=O)c1ccc(-c2ncc(C#C[Si](C)(C)C)c(Nc3cc(C4CC4)n(C(C)=O)n3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cnc(-c2ccc(C(=O)NCCNC(C)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of N-(2-acetamidoethyl)-5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)thiophene-2-carboxamide (96.1 mg, 0.17 mmol, 1.0 eq) and K2CO3 (70.4 mg, 0.51 mmol, 3.0 eq) in EtOH (10 mL) was stirred at room temperature for 1 h. The reaction mixture was filtered. The filtrate was concentrated to 2 mL. The conc. liquid was extracted with EtOAc and washed with water, brine and dried (Na2SO4) and filtered. The filtrate was concentrated to generate N-(2-acetamidoethyl)-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophene-2-carboxamide (Compound 206) (53.2 mg, 72.1%) as pale yellow solid. LC-MS (m/z)=436.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.74-0.78 (m, 2H), 0.97-1.01 (m, 2H), 1.82 (s, 3H), 1.93-1.99 (m, 1H), 3.20-3.23 (m, 2H), 3.27-3.30 (m, 2H), 4.87 (m, 1H), 6.49 (m, 1H), 7.76 (d, J=4.4 Hz, 1H), 7.84 (d, J=4.0 Hz, 1H), 8.01 (t, J=5.2 Hz, 1H), 8.50 (s, 1H), 8.70 (t, J=5.2 Hz, 1H), 8.76 (s, 1H)
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[NH:11][C:12](=[NH:19])[CH:13]=[CH:14][C:15]=2[CH2:16]OC)[N:9]=1)[NH2:3].[S:20]([NH2:24])([NH2:23])(=[O:22])=[O:21].O>COCCO>[NH2:19][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[C:15]([CH:16]=[N:23][S:20]([NH2:24])(=[O:22])=[O:21])=[CH:14][CH:13]=1
Reactant: NS(N)(=O)=O
Reactant: COCc1ccc(=N)[nH]c1-c1csc(N=C(N)N)n1
Solvent: COCCO
Solvent: O
Product: NC(N)=Nc1nc(-c2nc(N)ccc2C=NS(N)(=O)=O)cs1
Reaction time: 3 h
Yield: 49.8 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-(imino)(methoxy)methylpyridin-2-yl]thiazole (2.1 g) and sulfamide (2.9 g) in 2-methoxyethanol (10.5 ml) was stirred for 3 hours at 70°-75° C. The mixture was added to water, isolated precipitate was collected by filtration and dried. The precipitate was recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-[6-(amino)(aminosulfonylimino)methylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (1.28 g).