Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([CH3:12])[CH:4]=1)#[N:2].[CH3:13][C:14]1([CH3:21])[C:19](=[O:20])[CH:18]=[CH:17][CH2:16][CH2:15]1.C([O-])(=O)C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[CH3:13][C:14]1([CH3:21])[CH2:15][CH2:16][CH:17]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH3:12])[CH2:18][C:19]1=[O:20]
Reactant: CC1(C)CCC=CC1=O
Reactant: Cc1cc(C#N)ccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C#N)ccc1C1CCC(C)(C)C(=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.7 %

Procedure:
4-Cyano-2-methylphenylboronic acid (0.81 g, 5 mmol), 6,6-dimethylcyclohex-2-enone (Canadian Journal of Chemistry, 1981, 59, 2096-2115) (0.55 g, 5 mmol), SbCl3 (0.11 g, 0.5 mmol), sodium acetate (0.82 g, 10 mmol), and palladium acetate (0.11 g, 0.5 mmol) are added to acetic acid (30 mL) under an atmosphere of argon. The reaction mixture is stirred at room temperature for three days. The mixture is filtered and the filtrate is poured into water (150 mL). The organic phase is separated and the aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with saturated sodium bicarbonate solution (3×100 mL), brine (3×50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with pet ether: EtOAc=10:1 to give the title compound as a light yellow solid (0.6 g, 50%). GC/MS 241 (M+1).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[C:31]([CH3:32])=[C:30]([Br:33])[C:29](=[O:34])[N:28]([CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:10][CH:9]1[CH3:40])=O)(C)(C)C.[Cl:41]CCl>Cl>[ClH:41].[Br:33][C:30]1[C:29](=[O:34])[N:28]([CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)[C:26]2[N:27]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH:13]([CH3:14])[NH:8][CH:9]([CH3:40])[CH2:10]4)=[CH:16][N:17]=3)[N:23]=[CH:24][C:25]=2[C:31]=1[CH3:32]
Reactant: ClCCl
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)C(C)C4)cn3)ncc12
Agent: Cl
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)NC(C)C4)cn3)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.051 g, 0.083 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl (2 mL) was added and the mixture was stirred at room temperature for 2 hours. This mixture was concentrated and allowed to sit for 10 days, it was then dissolved in 2 N HCl (2 mL) and stirred at room temperature for 5 hours. The solvent was removed to give 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.039 g, 71.4%). 1H NMR δ(400 MHz, DMSO-d6) 9.51 (m, 1H), 9.02 (m, 1H),8.98 (s, 1H), 8.07 (s, 1H), 7.83 (s, 2H), 5.90 (m, 1H), 3.85 (d, J=11.2 Hz, 2H),3.35 (m, 2H), 2.76 (dd, J=12.0, 12.0 Hz 2H), 2.58 (s, 3H), 2.14 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H),1.58 (m, 2H), 1.28 (d, J=6.4 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][O:22][C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[O:18][C:17]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH:13]=[N:14]O)[N:10]=[CH:9]1.C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][O:22][C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[O:18][C:17]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]#[N:14])[N:10]=[CH:9]1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(-n2cnc(C=NO)c2)c(F)c1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cn(-c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)cn1
Yield: 39.3 %

Procedure:
3-(3-Fluoro-4-(4-hydroximinomethyl-imidazol-1-yl)phenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one (360 mg, 0.93 mmol) and acetic anhydride (3 ml) were heated under nitrogen at reflux for 2 hours. After cooling and pouring onto ice, the mixture was extracted into dichloromethane (3×15 ml). dried (magnesium sulfate) and evaporated. The residue was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 2.5% MeOH in dichloromethane, to give the desired compound (135 mg).
Reaction SMILES: C([NH:4][C:5]1[N:14]=[C:13]2[C:8]([C:9](=[O:28])[CH:10]=[C:11]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:12]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH3:29])[CH:6]=1)C=C.CS(O)(=O)=O>CCO.CCOC(C)=O.[Pd]>[NH2:4][C:5]1[N:14]=[C:13]2[C:8]([C:9](=[O:28])[CH:10]=[C:11]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:12]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH3:29])[CH:6]=1
Reactant: C=CCNc1cc(C)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 80 °C
Yield: 135.6 %

Procedure:
Pd/C (30 mg, 1.75 mmol, 10%) was added to a 25 mL round bottom flask and was blanketed with argon. 7-(allylamino)-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (150 mg, 0.392 mmol) was dissolved in EtOH (2 mL) and was added to the Pd/C followed by methane sulfonic acid (0.041 mL, 0.63 mmol). The reaction was heated to 80° C. for 3 d at which time it was cooled to room temperature, diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by Biotage silica gel chromatrography eluting with 100% EtOAc to provide 7-amino-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (182 mg, 41%) as a yellow solid: LCMS RT: 2.01 min, MH+: 343.3.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: CCOC(=O)CC(=N)N
Reactant: COc1ccccc1C(=O)CBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2OC)[nH]c1N

Procedure:
Analogously to Step 8.1, 14.5 g (87 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride in 150 ml of abs. ethanol are reacted with 5.9 g (87 mmol) of sodium ethanolate and 10.3 g (44 mmol) of 2-bromo-1-(2-methoxy-phenyl)-ethan-1-one (2-bromo-2'-methoxy-acetophenone; Aldrich; Milwaukee/USA) to form the title compound; m.p.: 128° C.; TLC-Rf =0.25 (hexane/ethyl acetate [2:1]).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:23]4([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
1-(4-Fluorophenyl)-5-iodo-1H-indazole (2.0 g, 5.9 mmol) was dissolved in dry THF (30 mL), cooled to −78° C., and treated with nBuLi (4 mL, 1.6 M in hexanes, 6.5 mmol). After 1 h, cyclohexanone (919 uL, 8.88 mmol) was added all at once and the reaction was allowed to warm to rt. The crude reaction was extracted from water using EtOAc and the combined organic layers were dried with MgSO4, concentrated in vacuo, filtered, and chromatographed on a SiO2 MPLC column using 25% EtOAc in hexanes. Obtained 700 mg (38%) of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)cyclohexanol. MS found: (M+H)+=311.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:17]1[CH2:19][C@@H:18]1[C@@H:20]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(O)C>[CH2:7]([NH:6][C:5]1[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=1)[CH2:2][NH:1][CH2:19][C@@H:18]([OH:17])[C@@H:20]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: NCc1cccc(NCc2ccccc2)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(NCc2ccccc2)c1
Temperature: 90 °C
Yield: 53.1 %

Procedure:
1 ml anhydrous iPrOH was added to a flask charged with 3-(aminomethyl)-N-benzylaniline (0.057 g, 0.269 mmol, 1.3 eq) and tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (0.054 g, 0.207 mmol, 1 eq) under Ar. The mixture was heated to reflux at 90° C. overnight. After cooling to room temperature the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.0526 g (0.11 mmol, 53% yield) of the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([NH:20][O:21]C2CCCCO2)=[O:19])[C:11](=[O:33])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CO>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:32])([S:28]([CH3:31])(=[O:29])=[O:30])[C:18]([NH:20][OH:21])=[O:19])[C:11](=[O:33])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
4-[4-(Benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (536.3 mg, 1.12 mmol) was dissolved in methylene chloride (5 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 8.41 mL, 30 mmol) and the slurry was stirred at RT for 15 minutes. Methanol (1 mL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material purified via silica gel chromatography eluting with methylene chloride/methanol to afford title compound as a solid 117.8 mg. LCMS: (M+1) 395.3 1H NMR (CD3OD) 7.51 (1H, d, J=7.62 Hz), 7.42-7.32 (5H, m), 6.18 (1H, dd, J=7.42, J=2.73), 5.09 (2H, s), 4.21-4.13 (1H, m), 3.85-3.77 (1H, m), 3.08 (3H, s), 2.53-2.45 (1H, m), 2.32-2.25 (1H, m), 1.65 (3H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)(C)=O>CO.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cc(O)cc(Br)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a flask containing 3-bromo-5-hydroxybenzoic acid (2.0 g, 9.2 mmol) in anhydrous MeOH (10 mL) at 0° C. under N2 was added AcCl (912 μL, 12.9 mmol). The reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with EA and washed with NaHCO3. The organic layers were dried and concentrated to provide 2.1 g (97%) of methyl 3-bromo-5-hydroxybenzoate as a white solid. LCMS-ESI (m/z) calculated for C8H7BrO3: 231.04. found 232.9 [M+H]+, tR=3.06 min.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[CH2:29](O)[CH3:30]>S(=O)(=O)(O)O>[C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH:9]=[CH:8][CH:7]=2)([O:3][CH2:29][CH3:30])=[O:2]
Reactant: COc1ccc(OCC(O)COc2cccc3oc(C(=O)O)cc(=O)c23)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3ccc(OC)cc3)cccc2o1

Procedure:
A mixture of 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-methoxy-phenoxypropane (10.0 g), ethyl alcohol (5 ml) benzene (100 ml) and concentrated sulphuric acid (5 drops) was heated under a Dean and Stark phase separator for 20 hours. The cooled solution was washed with saturated sodium bicarbonate solution and then with water. Removal of the benzene under reduced pressure afforded a solid which was recrystallized from aqueous dioxane to give 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-3-p-methoxyphenoxypropane, m.p. 135°-136.5° C as white needles.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[NH:17]1C=CN=[CH:18]1>>[N:2]1([CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)=[O:6])[CH:1]=[CH:18][N:17]=[CH:16]1
Reactant: CN(C)CCC(=O)c1c[nH]c2ccccc12
Reactant: c1c[nH]cn1
Product: O=C(CCn1ccnc1)c1c[nH]c2ccccc12

Procedure:
3-(Dimethylamino)-1-(1H-indol-3-yl)-1-propanone was converted to the methiodide (12.75 g) which was then reacted with imidazole (12.75 g) to give the title compound (4.67 g), m.p. 193°-197°; λmax (EtOH) 242.5 nm (ε11,130), λinf 257.5 nm (ε9,120), λmax 299 nm (ε12,420), identical with the material obtained in Example 2.
Reaction SMILES: [SH2:1].[Na].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([Cl:13])[CH:7]=1)=[O:5]>CN1CCCC1=O>[Cl:13][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH3:3])[CH:11]=[CH:10][C:9]=1[SH:1]
Reactant: S
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na]
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(S)c(Cl)c1
Temperature: 140 °C
Yield: 90.6 %

Procedure:
110 g (1.48 mol) of sodium hydrogen sulphide (NaSH·H2O) are initially introduced together with 1 l of N-methylpyrrolidone and the water is removed at 160° C. with nitrogen. The mixture is cooled to 140° C. and 112 g (0.59 mol) of 3,4-dichloroacetophenone are added, and the mixture is reacted further at 160° C. for 3 hours, and N-methylpyrrolidone is distilled off. The residue is taken up in 1 l of water and filtered, and the filtrate is acidified at 0°-10° C. with half-concentrated hydrochloric acid. The precipitate is filtered off with suction, washed neutral and dried. Distillation under reduced pressure gives 99.8 g (90.7% of theory) of 2-chloro-4-acetylthiophenol of boiling point: 125°-130° C./0.1 mbar.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH3:25])[CH:20]=O>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]3[CH:22]=[CH:23][C:24]([CH3:25])=[C:17]([CH3:16])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: Cc1ccc(C=O)cc1C
Product: Cc1ccc(CN2CCN(C(=O)Nc3ccccc3)CC2)cc1C

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3,4-dimethylbenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.35-7.26 (m, 4H), 7.11-7.00 (m, 4H), 6.31 (s, 1H), 3.51-3.48 (m, 6H), 2.49-2.26 (m, 4H), 2.26 (d, J=3.8 Hz, 6H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:40][N:41]1[CH2:45][CH2:44][CH:43](Br)[C:42]1=[O:47].O>CS(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:43]2[CH2:44][CH2:45][N:41]([CH3:40])[C:42]2=[O:47])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CN1CCC(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C(=N\OC1CCN(C)C1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
2.7 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2hydroxyiminoacetate are dissolved in 12 ml of dimethylsulfoxide, and 1.0 g of anhydrous potassium carbonate is added thereto under nitrogen gas atmosphere. The mixture is stirred at room temperature for 10 minutes. 1.2 g of 1-methyl-3-bromo-2-pyrrolidone are added to the mixture, and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into 100 ml of water, and crystalline precipitates are collected by filtration. The crystals are dissolved in ethyl acetate, and the solution is washed with water and then dried. The solution is concentrated under reduced pressure to remove solvent. Then, the residue is crystallized with isopropyl ether and collected by filtration. 2.1 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:23]=[C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]2)[C:21]([CH3:30])=[CH:20][C:18]=1[NH2:19]>CC(O)C.Cl>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[N:7][C:2]([NH:19][C:18]2[CH:20]=[C:21]([CH3:30])[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]3)=[CH:23][C:17]=2[CH3:16])=[N:3][CH:4]=1
Reactant: Cc1cc(C2CCCCN2)c(C)cc1N
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCCCN4)cc3C)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (120 mg, 0.49 mmol) and 2,5-dimethyl-4-(piperidin-2-yl)aniline (100 mg, 0.49 mmol) in 2-propanol (10 mL) was treated with conc. aqueous HCl (7 drops). The mixture was sealed and heated in a microwave at 130° C. for 45 min. The mixture was concentrated to afford 5-Chloro-N2-(2,5-dimethyl-4-(piperidin-2-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; ESMS m/z 412.1 (M+H+). The crude product was used directly for the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]#[N:22])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].[Sn](Cl)Cl>Cl>[CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][NH2:22])=[CH:19][CH:20]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc([N+]#N)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(NN)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude 4-(2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-benzenediazonium salt (14) (1.8 g, 6.16 mmol) was dissolved in 40 ml of conc. HCl. After addition of tin(II)chloride (1.75 g, 9.24 mmol) the reaction mixture was stirred for 30 min at r.t. The reaction mixture was concentrated and used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nnc(SCc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.2 %

Procedure:
In 35 ml of water and 70 ml of ethanol, 12.8 g of 2-amino-5-mercapto-1,3,4-thiadiazol and 43 g of sodium hydroxide were added. To this mixture, 14.8 g of 4-chlorobenzyl chloride was added and the mixture was stirred at room temperature for 1 hour. Water was added and the reaction mixture was filtered. The residue was washed with water and an ethanol/n-hexane (1:1) mixture, and was dried under reduced pressure, and thus 23:1 g of 2-amino-5-(4-chlorobenzylthio)-1,3,4-thiadiazole was obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Br)c(C)cc1O
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(Br)c(C)cc1OCOCC[Si](C)(C)C
Reaction time: 1 h
Yield: 91 %

Procedure:
4-Bromo-2-methoxy-5-methyl-phenol (see Chien-Hsun et al., Syn. Lett., 12, 1351–1352 (1997)) was stirred in dry CH2Cl2 (100 mL) at 23° C. DIEA (6.05 mL, 34.6 mmol), and then 2-(trimethylsilyl)ethoxymethyl chloride (5.6 mL, 31.7 mmol) were added. After stirring for 1 h, the solution was washed with H2O, 0.1 N HCl, H2O, saturated NaHCO3, and brine (25 mL each). Organics were dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (6% ethyl acetate/hexanes) gave 9.06 g (91%) of [2-(4-bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.06 (s, 1 H), 7.02 (s, 1 H), 5.24 (s, 2 H), 3.84 (s, 3 H), 3.79 (t, 2 H, J=8.4 Hz), 2.31 (s, 3 H), 0.96 (t, 2 H, J=8.4 Hz), 0.01 (s, 9 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[O:9]1[CH2:11][CH:10]1[CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:12][CH:10]2[CH2:11][O:9]2)[CH:3]=1
Reactant: OCC1CO1
Reactant: Oc1cncc(Br)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cncc(OCC2CO2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
To a solution of 5-Bromo-pyridin-3-ol (0.50 g, 2.87 mmol), oxiranyl-methanol (0.38 mL, 5.74 mmol) and triphenylphosphine (1.50 g, 5.74 mmol) in anhydrous THF (20 mL) was added di-tert-butyl azodicarboxylate (DBAD) (1.32 g, 5.74 mmol) and the reaction mixture stirred at room temperature for 18 hrs and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10%-35% ethyl acetate/hexanes to provide the desire product (0.48 g, 73%).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([CH3:18])[N:3]=1.N(OCCC(C)C)=O.[ClH:27]>C(#N)C.[Cu](Cl)Cl>[Cl:27][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]([C:16]#[N:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(N)c(C#N)c(C2CCCCO2)c1C#N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1nc(Cl)c(C#N)c(C2CCCCO2)c1C#N
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
610 mg (2.52 mmol) of the compound from Example 39A are initially charged in 44 ml of acetonitrile, and 590 mg (5.04 mmol) of isopentyl nitrite and 677 mg (5.04 mmol) of copper(II) chloride are added. The reaction mixture is stirred at 60° C. for 30 min. 40 ml of 1 N hydrochloric acid are then added to the mixture and the mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product is used in the next reaction without further purification.