Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:8]([O:15][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Succinic anhydride (30 g, 300 mmole) was dissolved in methylene chloride (300 ml). To the solution were added benzyl alcohol (10.2 ml, 100 mmole), 4-dimethylaminopyridine (1.22 g, 10 mmole) and pyridine (48 ml). After 3 hours the reaction mixture was poured in to citric acid aqueous solution. The organic phase was concentrated to small volume and sodium hydrogen carbonate and water were added. Then mixture was stirred for 30 min. The aqueous phase was collected, and to it was added citric acid aqueous solution. The product precipitated out, was collected and mixed 15.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]2[C:14]([F:17])([F:16])[F:15].N1C=CC=CC=1.[CH3:24][C:25]1[CH:35]=[CH:34][C:28]([CH2:29][CH2:30][N:31]=[C:32]=[S:33])=[CH:27][CH:26]=1>CN1C(=O)CCC1>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:32]([NH:31][CH2:30][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([CH3:24])=[CH:35][CH:34]=3)=[S:33])=[CH:11][CH:10]=2)[C:5]([C:14]([F:17])([F:15])[F:16])=[CH:6][C:7]1=[O:13]
Reactant: Cc1ccc(CCN=C=S)cc1
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(N)ccc21
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Cc1ccc(CCNC(=S)Nc2ccc3c(c2)c(C(F)(F)F)cc(=O)n3C)cc1
Reaction time: 168 h
Yield: 20 %

Procedure:
6-Amino-1-methyl-4-trifluoromethyl-1H-quinolin-2-one (Preparation 1, 200 μL of a 0.2 M solution in NMP, 40 μmol) was treated with pyridine (20 μL of a 0.2 M solution in NMP, 4 μmol) & 4-methylphenethyl isothiocyanate (240 μL of a 0.2 M solution in NMP, 48 μmol). After 7 d, the mixture was concentrated, then the residue was washed with MeCN (2×150 μL) to give the title compound (3.3 mg, 20%): RT=1.87 min; m/z (ES+)=420.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)s1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C(=O)O)s1
Reaction time: 7 h

Procedure:
2.37 g (11.18 mmol) of 5-(2-methoxycarbonyl-vinyl)-thiophene-2-carboxylic acid were dissolved in 170 ml of methanol. After addition of 500 mg of 10% palladium on charcoal (Degussa E 101 R/D 10%) the mixture was hydrogenated for 7 hours at atmospheric pressure (approx. 1 bar) and room temperature. After filtration and evaporation the yield of the title compound was 2.4 g (purity >99% (HPLC)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14]>>[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:18][CH:17]=1)[CH3:14]
Reactant: CCOc1ccc(N)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: CCOc1ccc(Nc2nc(C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloro-2-methylquinazoline and 4-ethoxyaniline by a procedure similar to example 28 (93%). 1H NMR (CDCl3): 7.83 (m, 1H), 7.81 (m, 1H), 7.42 (m, 1H), 7.65-7.71 (m, 2H), 7.46 (ddd, J=8.4, 6.9, 1.5, 1H), 7.37 (s, broad, 1H), 6.92-6.97 (m, 2H), 4.06 (q, J=6.9, 2H), 2.68 (s, 3H), 1.43 (t, J=6.9, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCCCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCSc1nnc(N)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
In 32 ml of water and 32 ml of ethanol, 27.2 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 9.0 g of sodium hydroxide were added. To this solution, 45.2 g of 1-iodoheptane was added, and the mixture was stirred at 60° C. for 2 hours. After cooling, water was added to the mixture and the mixture was filtered. The residue was washed with water, dried under reduced pressure, and recrystallized from an ethanol/n-hexane (1:1) mixture. Thus 36.1 g of 2-amino-5-heptylthio-1,3,4-thiadiazole was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C@H:11]2[CH2:13][C@H:12]2[C:14](O)=[O:15])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]2[CH:11]3[CH:12]([C:14](=[O:15])[NH:20][N:21]=2)[CH2:13]3)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 84.6 %

Procedure:
6.0 g (24.3 millimoles) of cis-2-(p-acetylaminobenzoyl)-cyclopropanecarboxylic acid, 1.33 g (26.6 millimoles) of hydrazine hydrate and 150 ml of ethanol are refluxed for 6 hours. After filtering off the product at 0° C. and drying it under reduced pressure at 50° C., 5.0 g (85% of theory) of 2-(p-acetylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as colorless crystals, melting point 269°-270° C. after recrystallization from a methanol/water mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:38]=[CH:37][C:32]([O:33][CH2:34][CH2:35]O)=[CH:31][CH:30]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:35][CH2:34][O:33][C:32]2[CH:37]=[CH:38][C:29]([C:28]([F:27])([F:39])[F:40])=[CH:30][CH:31]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the tosylate of 2-(4-trifluoromethylphenoxy)ethanol (1.8 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 4:1 ) and crystallized from diethyl ether-hexane to provide 1 g of alpha-oxo-4-[[2-(4-trifluoromethylphenoxy)ethyl]oxy] benzeneacetic acid methyl ester, mp 96°-98° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)([O-])C.[K+]>>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10]1
Reactant: CN1CCNCC1
Reactant: Brc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
A 1 L flask was charged with 141.3 g of bromobenzene, 30.1 g of 1-methylpiperazine and 43.8 g of potassium tert-butoxide. The flask was then placed on an ice bath for 10 minutes and the contents rapidly stirred. 2.04 g of “PEPPSI” catalyst[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)-palladium (II) dichloride was then added and the flask fitted with a reflux condenser. The reaction was refluxed under a nitrogen atmosphere for 2 hours and then cooled to room temperature. The reaction mixture was then filtered through a pad of 800 mL of silica gel in a 2 L D-filter flask and the pad subsequently rinsed with 600 mL of ether. Then the product was extracted from the pad with ethanol. Evaporation of the ethanol gave 39.4 g of 1-methyl-4-phenylpiperazine.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([Cl:13])=[C:2]3[Cl:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. After 3 hours of stirring at room temperature, a solution of 4-(4-chlorobenzoyl)benzyl bromide (681 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 18 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was then purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=2:1→1:1) to provide the title compound as white powder (351 mg, yield 39%). 1H-NMR (DMSO-d6) δ: 3.68(3H,s), 5.73(2H,s), 7.30(2H,d,J=8.6Hz), 7.61(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 8.71(1H,s).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:37])[F:38])=[CH:35][CH:34]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-tert-butylphenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.75 g of α,α,α-trifluoro-p-cresol in 75 ml of tetrahydrofuran at 80° C. for 24 hrs to give the product as a gum.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[O:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ncco3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1coc(-c2ccc(N3CCNCC3)cc2)n1

Procedure:
Prepared in analogy to example 4.4 (b) from 4-(4-Oxazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 230.1 (MH+, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11](=[O:27])[C:10]=2[C:28](O)=[O:29])=[CH:5][CH:4]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:11](=[O:27])[C:10]=2[C:28](=[O:29])[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Reactant: Nc1ccccc1
Product: COc1ccc(-c2nn(CC(C)C)c(=O)c(C(=O)Nc3ccccc3)c2-c2ccc(OC)cc2)cc1
Yield: 89 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one and aniline as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained in a yield of 89.0%.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@H:6]([CH2:7][C:8]3[C:15]([O:16]C)=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)[CH2:5][CH2:4][CH2:3]1.Cl>>[CH3:1][N:2]1[C@H:11]2[C@@H:6]([CH2:7][C:8]3[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)[CH2:5][CH2:4][CH2:3]1
Reactant: COc1cccc2c1C[C@H]1CCCN(C)[C@@H]1C2
Agent: Cl
Product: CN1CCC[C@@H]2Cc3c(O)cccc3C[C@H]21

Procedure:
This compound is obtained from the title compound of Example 6, analogously to Example 3 and 5. M.p. 323°-325° (Hydrochloride).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][O:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[NH:16][N:15]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:57]([O:61][C:62]([N:64]([CH:77]([CH3:79])[CH3:78])[CH2:65][C@H:66]([C:70]1[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=1)[C:67](O)=[O:68])=[O:63])([CH3:60])([CH3:59])[CH3:58]>C(Cl)Cl>[Cl:76][C:73]1[CH:74]=[CH:75][C:70]([C@H:66]([C:67]([N:26]2[CH2:25][CH2:24][N:23]([C:21]3[C:20]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:19][N:18]=[C:17]4[NH:16][N:15]=[C:14]([O:13][CH3:12])[C:22]=34)[CH2:28][CH2:27]2)=[O:68])[CH2:65][N:64]([CH:77]([CH3:78])[CH3:79])[C:62](=[O:63])[O:61][C:57]([CH3:59])([CH3:58])[CH3:60])=[CH:71][CH:72]=1
Reactant: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0558 mL, 0.320 mmol) was added to 3-methoxy-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.034 g, 0.080 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0308 g, 0.0961 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0274 g, 0.080 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. It was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.029 g, 60%). MS APCI (+) m/z 533.3 detected.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH2:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1.[H-].[Na+].O>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH:18][C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(N)n1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(Nc2ncc(C#N)s2)n1
Temperature: 75 °C
Reaction time: 8.5 h

Procedure:
4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-ethylpyridin-2-amine 12-1 (0.159 g, 0.60 mmol) was dissolved in 2 mL THF. 2-Chloro-1,3-thiazole-5-carbonitrile (0.103 g, 0.72 mmol) and sodium hydride (60% dispersion in mineral oil) (0.057 g, 2.38 mmol) were added and the solution was heated to 75° C. After 4 hours more 2-chloro-1,3-thiazole-5-carbonitrile (0.043 g, 0.30 mmol) and sodium hydride (0.014 g, 0.60 mmol) were added. After 5.5 hours more 2-chloro-1,3-thiazole-5-carbonitrile (0.086 g, 0.60 mmol) and sodium hydride (0.029 g, 1.19 mmol) were added. After 8.5 hours the solution was allowed to cool to room temperature. H2O was added and the reaction was concentrated in vacuo (to remove THF). 1N HCl was added to adjust to neutral pH. The resulting precipitate was filtered and washed with water to afford the desired compound 12-2 as a yellow solid. 1H NMR (DMSO-d6) δ 12.23 (s, 1H), 8.25 (s, 1H), 6.70 (s, 1H), 6.83 (s, 1H), 4.73 (bs, 2H), 2.79 (q, 2H, J=7.63 Hz), 1.32 (t, 3H, J=7.63 Hz), 0.94 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([NH2:30])[CH2:28][OH:29])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:28][OH:29])=[CH:25][CH:26]=1
Reactant: NC(CO)c1ccc(Cl)cc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CO)c2ccc(Cl)cc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(4-chloro-phenyl)-2-hydroxy-ethylamine and DIEA to give 2-[1-(4-chloro-phenyl)-2-hydroxy-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 455 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:15])[NH:9][C@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:15])[NH:9][C@H:10]1[CH2:13][C@H:12]([O:14][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)[CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(O[C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride, 60% in oil (0.141 mL, 6.70 mmol) was added portionwise to a solution of tert-butyl(trans-3-hydroxycyclobutyl)carbamate (0.57 g, 3.04 mmol) and 2-chloro-1-methyl-1H-benzoimidazole (0.558 g, 3.35 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 3 h, diluted with water and extracted with EtOAc. EtOAc extract was concentrated and residue purified with ISCO eluting with 0-40% EtOAc/hexanes to give the desired product tert-butyl(trans-3-((1-methyl-1H-benzo[d]imidazol-2-yl)oxy)cyclobutyl)carbamate (0.388 g, 1.222 mmol, 40.2% yield). m/z: 318.2 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15](COCC[Si](C)(C)C)[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(C#Cc2cn(COCC[Si](C)(C)C)c3ncnc(N)c23)cc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C#Cc2c[nH]c3ncnc(N)c23)cc(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
A solution of 5-((3,5-dimethoxyphenyl)ethynyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4.27 g) obtained in Step 3 in methylene chloride (20 ml) was cooled to 0° C., and TFA 10 ml was added thereto. The reaction mixture was stirred at room temperature for 5 hours, and the solvent was distilled off under reduced pressure. THF (50 ml) was added to the residue, and the mixture was cooled to 0° C. 4N aqueous sodium hydroxide (12.5 ml) was added thereto, and the mixture was stirred at room temperature overnight. The result was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure, and chloroform was added to the resulting residue. The mixture was subjected to filtration to obtain the title compound as a white solid (2.60 g). Physical properties: m/z [M+H]+ 295.3
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.[SH:12][CH2:13][CH2:14][OH:15].[OH-].[K+]>>[CH3:11][C:4]1[N:3]=[C:2]([S:12][CH2:13][CH2:14][OH:15])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1nc(F)ccc1[N+](=O)[O-]
Reactant: OCCS
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(SCCO)ccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 105.6 %

Procedure:
To a solution of 2-fluoro-5-nitro-6-picoline (5.0 g, 32 mmol) and 2-mercaptoethanol (4.5 ml, 64 mmol), KOH (2 g, 36 mmol) was added at 0° C. The mixture was stirred at the same temperature for 15 minutes. The crude mixture was extracted with AcOEt and brine. Organic phase was dried over MgSO4, filtered, and concentrated to provide the crude 2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol as an oil (7.238 g). 1HNMR (DMSO-d4, 400 MHz) δ 2.75 (s, 3H), 3.30-3.33 (m, 2H), 3.63-3.67 (m, 2H), 4.65-4.68 (m, 1H), 7.40-7.43 (m, 1H), 8.24-8.26 (m, 1H). Exact mass calculated for C8H10N2O3S 214.04 found 215.1 (MH+).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.C[N:30]1[S:34](=[O:36])(=[O:35])[N:33]([CH2:37]OCC[Si](C)(C)C)[C:32]2[CH:45]=[CH:46][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:48][C:31]1=2.[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>>[F:61][C:60]([F:63])([F:62])[C:58]([OH:64])=[O:59].[CH3:37][N:33]1[C:32]2[CH:45]=[C:46]([C:2]3[N:7]4[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)[CH:47]=[CH:48][C:31]=2[NH:30][S:34]1(=[O:35])=[O:36]
Reactant: CN1c2cc(B3OC(C)(C)C(C)(C)O3)ccc2N(COCC[Si](C)(C)C)S1(=O)=O
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Solvent: O=C(O)C(F)(F)F
Product: CN1c2cc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)ccc2NS1(=O)=O

Procedure:
Compound 2b was subjected to Suzuki coupling conditions with (3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydrobenzo[c][1,2,5]thiadiazole 2,2-dioxide and the resulting product was deprotected with TFA using the methods described in Example 37, Steps B and C) to obtain the title compound 43. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.79 (d, J=9.0 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.07-8.18 (m, 4H), 8.02 (td, J=7.8, 1.2 Hz, 1H), 7.78-7.87 (m, 2H), 7.72 (s, 1H), 7.32 (s, 1H), 7.27 (dd, J=8.1, 2.0 Hz, 1H), 7.10 (d, J=1.7 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.33-4.39 (m, 4H), 3.91-3.99 (m, 4H), 3.34 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H25N7O3S: 540.2 (M+H). Found 540.4.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[N:5][C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1.[CH3:15][OH:16]>>[CH3:15][O:16][C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[N:5][C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1
Reactant: COC(=O)c1nc(C)c(C)nc1Cl
Reactant: CO
Agent: [Na]
Product: COC(=O)c1nc(C)c(C)nc1OC

Procedure:
To 20 ml. of a solution of 0.1 g. metallic sodium in methanol was added 0.3 g. of methyl 3-chloro-5,6-dimethylpyrazine-2-carboxylate and the mixture was refluxed for one hour. The methanol was distilled off from the reaction mixture and the residue obtained was added to 20 ml. of water and the mixture was extracted three times each time with 20 ml. of dichloromethane. The extracts were combined, dried over anhydrous magnesium sulfate, and then the dichloromethane was distilled off to provide 0.2 g of methyl 3-methoxy-5,6-dimethylpyrazine-2-carboxylate. The yellow prism crystals obtained by recrystallizing from n-hexane melted at 80°-81° C.