Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[C:13]([F:27])[CH:12]=2)=[O:9])[C:4](=[O:28])[N:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:52].O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:52][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:28])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:12][C:13]=2[F:27])[CH:21]=[CH:20][N:19]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)picolinamide (0.4 g, 0.86 mmol) and PhI(OAc)2 (419 mg, 1.5 mmol) in a mixture of EtOAc (8 mL), MeCN (8 mL) and H2O (4 mL) was cooled to 0° C. and stirred for 30 minutes. The reaction was then allowed to warm to rt, and stirred for another 8 h. The mixture was diluted with NaHCO3 (aq., 60 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the title compound as a white solid (0.21 g, 56%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:7]=1[Cl:8].O.[NH2:17][NH2:18]>CCOCC>[Cl:8][C:7]1[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:5][N:4]=[N:3][C:2]=1[NH:17][NH2:18]
Reactant: CN1CCN(c2cnnc(Cl)c2Cl)CC1
Reactant: NN
Solvent: CCOCC
Solvent: O
Product: CN1CCN(c2cnnc(NN)c2Cl)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
3,4-Dichloro-5-(4-methylpiperazin-1-yl)pyridazine (500 mg, 2.023 mmol) was placed in a microwave tube and hydrazine monohydrate (1.772 g, 1.717 mL, 35.40 mmol) was added. The resulting suspension was stirred at 100° C. for ˜10 mins. The brown reaction mixture was allowed to cool to RT, whereupon solid started to precipitate. The suspension was sonicated and the suspended solid was collected by filtration. This material was dissolved in water, basified with saturated NaHCO3 and partitioned with 10% MeOH in DCM. The aqueous layer was extracted with further 10% MeOH in DCM (6×10 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow solid. This material was sonicated in ether and the suspended solid was collected by filtration to give [4-chloro-5-(4-methylpiperazin-1-yl)pyridazin-3-yl]hydrazine as an ochre powder (155.9 mg, 32% Yield).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[H-].[Na+].[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26]Br>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:26][CH:25]([O:28][CH3:29])[O:24][CH3:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(CBr)OC
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(OC)OC)c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a stirred solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in published International patent application WO2004/087714) (0.2 M, 1 eq.) in DMF at RT was added NaH (60% dispersion in mineral oil, 1.75 eq). After 1 h, KI (8 mol %) and bromoacetaldehyde dimethyl acetal (2.5 eq) were added and the reaction heated at 80° C. for 17 h. After cooling to RT, the reaction was quenched by addition of aqueous HCl (1N) and extracted into EtOAc (×3). The combined organics were washed with HCl (1N), H2O and brine before being dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash column chromatography (Biotage, 5-10% EtOAc/PE gradient) gave the title compound as a white solid (79%); MS (ES+) m/z 446 (M+H)+, 448 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3]1.[C:13](=O)([O-])[O-].[K+].[K+].CI.CO>CN(C=O)C>[CH3:13][O:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3]1
Reactant: COC(=O)c1ccc(=O)n(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CI
Product: COC(=O)c1ccc(=O)n(OC)c1
Reaction time: 8 h

Procedure:
To a solution of methyl 1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (0.75 g, 4.43 mmol) in 5 mL DMF at 23° C., were added potassium carbonate (1.8 g, 13.3 mmol) and MeI (1.5 g, 11 mmol). The resulting mixture was stirred overnight and then MeOH (6 mL) was added and the resulting mixture was stirred for 2 h. The volatiles were removed under vacuum, and the resulting residue was dissolved in EtOAc (75 mL), washed with water (2×50 mL), brine (50 mL), dried (MgSO4), and concentrated to give methyl 1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylate as a brown oil.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[O:13][C:11](=O)[C:10]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC1[NH:23][CH2:24][CH2:25][N:26]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11](=[O:13])[N:23]2[CH2:24][CH2:25][N:26]=[C:14]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC1=NCCN1
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2N(Cc2ccccc2)C2=NCCN12

Procedure:
A mixture of 12.7 g. of N-benzylisatoic anhydride, 5.8 g. of 2-methylmercapto-imidazoline and 2 pellets of sodium hydroxide in 200 ml. of dioxane was refluxed for 2 hours. While still hot, the mixture was then filtered through Celite and the filtrate concentrated to about 50 ml. volume. 50 ml. of diethyl ether was added and the crystalline precipitate removed by filtration. The residue was dissolved in methylene chloride, treated with charcoal, filtered through alumina, and the filtrate evaporated. The residue was crystallized from methylene chloride/diethyl ether to obtain the heading compound, m.p. 203°-205°C.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH2:19].C(N(CC)CC)C>CCO>[Br:1][C:2]1[C:6]2[C:7]([NH:19][CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: NCc1ccccn1
Reactant: Clc1nccc2scc(Br)c12
Solvent: CCN(CC)CC
Solvent: CCO
Product: Brc1csc2ccnc(NCc3ccccn3)c12
Temperature: 25 °C
Yield: 4.5 %

Procedure:
3-Bromo-4-chloro-thieno[3,2-c]pyridine (409 mg, 16.5 mmol) was dissolved in anhydrous EtOH (20 ml), and 2-picolylamine (184 μl, 17.9 mmol) and triethylamine (241 μl, 17.3 mmol) were added. The reaction was heated to reflux and this was maintained for 24 h. The reaction was then allowed to cool to room temperature. The solvent was removed in vacuo and the residue partitioned between DCM (20 ml) and a saturated sodium, chloride solution (20 ml). The organic layer was dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was subjected to flash column chromatography (eluent petroleum spirit 40-60° C.:EtOAc, 3:1, Rf 0.3). This afforded the title compound as a yellow solid (236 mg, 44%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([Si:10]([CH3:12])([CH3:11])[O:4][CH2:3][CH:2]([NH2:1])[CH3:5])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N)CO[Si](C)(C)C(C)(C)C
Yield: 67.1 %

Procedure:
A mixture of (S)-(+) 2-amino-1-propanol (1.04 g, 13.85 mmol), tert butyldimethylsilyl chloride (2.09 g, 13.85 mmol) and triethylamine (2 ml, 1.05 eq) was stirred in DCM overnight ca 16 h. The reaction was diluted with DCM, washed with water, satd. NH4Cl, brine, dried and evaporated to an oil. Silica gel purification of the crude using 3% MeOH/CH2Cl2 as eluent provided 2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethylamine (1.76 g, 80%); 1H NMR (300 MHz, CDCl3) 0.0 (s, 6H), 0.82 (s, 9H), 0.99 (d, J=6.5 Hz, 3H), 2.22 (bs, 2H), 2.98 (bs, 1H), 3.30 (dd, J=10 Hz, J=17.0 Hz, 1H), 3.48 (dd, J=10.0 Hz, J=4.3 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: c1cc(OCC2CO2)ccn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCC(O)COc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 36.6 %

Procedure:
To a sealed tube was added 4-oxiranylmethoxy-pyridine (80 mg, 0.529 mmol) in 4 mL of DMF, followed by the addition of 4-amino-1-N-boc-piperidine (148 mg, 0.739 mmol). The reaction mixture was stirred at 80° C. for 48 h. The reaction mixture was concentrated in vacuo. The residue was loaded to a flash chromatography column. The column was eluted with 0–5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 68 mg (36.6%) of 4-[2-hydroxy-3-(pyridin-4-yloxy)-propylamino]-piperidine-1-carboxylic acid tert-butyl ester as a light brown oil. (TLC: Rf=0.15, 5% 2M NH3 in MeOH/CH2Cl2, UV). ES+ 352.43 m/z (MH+)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]1[C:15]([NH:16][C:17]3[CH:18]=[C:19]([N:25]([CH3:32])[C:26](=[O:31])[CH2:27][N:28]([CH3:30])[CH3:29])[CH:20]=[CH:21][C:22]=3OC)=[N:14][C:13]3[N:33](S(C4C=CC(C)=CC=4)(=O)=O)[CH:34]=[CH:35][C:12]=3[C:6]1=[N:7]2.[CH3:47][NH2:48].[OH-].[Na+].[C:51](=[O:54])(O)[O-].[Na+]>O1CCCC1.O1CCOCC1.C(OCC)(=O)C>[CH3:29][N:28]([CH3:30])[CH2:27][C:26]([N:25]([CH3:32])[C:19]1[CH:20]=[CH:21][C:22]([O:54][CH3:51])=[C:17]([NH:16][C:15]2[NH:14][C:13]3=[N:33][CH:34]=[CH:35][C:12]3=[C:6]([NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[C:3]=3[C:4]([NH:48][CH3:47])=[O:46])[N:5]=2)[CH:18]=1)=[O:31]
Reactant: O=C([O-])O
Reactant: CN
Reactant: COc1ccc(N(C)C(=O)CN(C)C)cc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc(N(C)C(=O)CN(C)C)ccc2OC)[nH]c2nccc1-2
Temperature: 25 °C
Yield: 21.64 %

Procedure:
A solution of N1-[3-({8-fluoro-3-[(4-methylphenyl)sulfonyl]-7-oxo-3,7-dihydropyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-5-yl}amino)-4-(methyloxy)phenyl]-N1,N2,N2-trimethylglycinamide (0.800 g, 1.243 mmol) in tetrahydrofuran (75 ml) was treated with 2.0M methyl amine (3.11 ml, 6.21 mmol) and maintained at room temperature overnight. The reaction was taken to a residue under reduced pressure, dissolved in 1,4-dioxane (8 ml), and added to a microwave vial along with 2.0N NaOH (aq) (8 ml). The mixture was maintained under microwave heating at 120° C. for 12 minutes, cooled, and poured into saturated sodium bicarbonate and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-[(2-{[5-[(N,N-dimethylglycyl)(methyl)amino]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.140 g, 0.269 mmol, 21.64% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 11.47 (br. s., 1 H), 10.05 (s, 1 H), 8.54 (d, J=3.8 Hz, 1 H), 8.44 (br. s., 1 H), 8.14 (d, J=8.2 Hz, 7.59 (s, 1 H), 7.36-7.50 (m, 1 H), 6.93-7.06 (m, 3 H), 6.84 (br. s., 1 H), 6.35 (br.s., 1 H), 3.91 (s, 3 H), 3.11 (s, 3 H), 2.86 (s, 2 H), 2.77 (d, J=4.4 Hz, 3 H), 2.11 (s, 6 H). ESIMS (M+H)+=521.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=1[CH3:24].ClC1C=CC=C(C(OO)=[O:35])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].CCCCCC>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:26][C:2]([F:1])([F:25])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17]([CH2:18][C:19]([F:20])([F:21])[F:22])=[O:35])[C:14]([CH3:23])=[CH:13][C:12]=1[CH3:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c(SCC(F)(F)F)cc1OCCCCCCSC(F)(F)F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)CC(F)(F)F)cc1OCCCCCCSC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
In 40 ml of chloroform was dissolved 1.36 g (3.23 mmol) of 6-trifluoromethylthiohexyl-[2,4-dimethyl-5-(2,2,2-trifluoroethylthio)phenyl]ether. Thereto was added 0.67 g (2.72 mmol) of 3-chloroperbenzoic acid (purity: about 70%) under ice cooling, and the mixture was stirred for 30 minutes at room temperature. Then, saturated aqueous solution of sodium thiosulfate was added to the reaction mixture to decompose excess peroxide. Thereafter, the solvent was distilled off under reduced pressure, and extraction was conducted by adding ethyl acetate and water. The organic phase obtained was washed by aqueous potassium carbonate solution and saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=5:1), to obtain 0.87 g (yield: 62%) of an intended product.
Reaction SMILES: O=[C:2]([CH2:13][CH3:14])[CH:3]([CH2:9][C:10](=O)[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([F:23])[CH:22]=1)[NH2:19]>C(O)(=O)C>[F:15][C:16]1[CH:17]=[C:18]([N:19]2[C:10]([CH3:11])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]2[CH2:13][CH3:14])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)CC
Reactant: Nc1cc(F)cc(F)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2cc(F)cc(F)c2)c1CC
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
Ethyl 3-oxo-2-(2-oxopropyl)pentanoate (200 mg) and 3,5-difluoroaniline (380 mg) were dissolved in acetic acid (10 mL), and stirred at 80° C. for 2.5 hours. The reaction liquid was cooled to room temperature, then the solvent was evaporated off, the residue was diluted with chloroform, and washed with aqueous saturated sodium hydrogencarbonate solution. The extract was washed with saturated saline water, then dried with anhydrous sodium sulfate, then the solvent was evaporated off, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain the entitled compound (287 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[CH2:10]([O:14][CH:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:16]=[O:17])[CH2:11][CH2:12][CH3:13]>C(O)CCC>[CH2:6]([O:5][C:1]([C:2]([CH:16]([OH:17])[CH:15]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])[O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH2:3])=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: C=CC(=O)OCCCC
Reactant: CCCCOC(C=O)OCCCC
Solvent: CCCCO
Product: C=C(C(=O)OCCCC)C(O)C(OCCCC)OCCCC

Procedure:
0.4 moles butyl acrylate and 70 g (0.355 mole) of 95.5% by weight dibutoxyethanal in butanol were reacted using the method of example 1 to form 2-butoxycarbonyl-4,4-dibutoxy-3-hydroxy-1-butene as a colourless liquid which distilled at 130° C. under 0.2 mbar.
Reaction SMILES: Br[C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7](=[O:15])[N:8]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH2:9][C:4]=2[CH:3]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23]([O:22][C:18](=[O:21])/[CH:19]=[CH:20]/[C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7](=[O:15])[N:8]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH2:9][C:4]=2[CH:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C)CCN1Cc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Yield: 54 %

Procedure:
To a solution of 6-bromo-3-(2-dimethylamino-ethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one (240 mg, 0.802 mmol) in propionitrile (16 mL) and DMF (4 mL) was added tert-butyl acrylate (0.46 mL, 3.2 mmol) and (i-Pr)2EtN (0.28 mL, 1.6 mmol), Pd(OAc)2 (18 mg, 0.080 mmol) and P(o-tol)3 (49 mg, 0.16 mmol). The mixture was degassed with Ar for 15 min. The mixture was heated to reflux overnight, and then allowed to cool. The dark solution was filtered through a pad of Celite. The filtrate was concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH/Et3N, 94/5.5/0.5) gave the title compound (150 mg, 54%) as a pale-yellow solid: MS (ESI) m/e 347 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O1CCOCC1.[NH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].CN(C1C=CC=CN=1)C>C(N(CC)CC)C.C(Cl)Cl>[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](=[O:22])[NH:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 18.0 g. of 4-(8-cyclohexyloctylamino)-benzoyl chloride hydrochloride in 100 ml. of dioxane is added to freshly prepared ethyl glycinate in 300 ml. of CH2Cl2 containing 1 g. of dimethylaminopyridine and 10 ml. of triethylamine. After 16 hours at room temperature the reaction mixture was refluxed for 2 hours, cooled and filtered. The mother liquor is extracted with water and 10% hydrochloric acid. The solution is dried over magnesium sulfate and concentrated in vacuo to an amber liquid. A 6 g. sample is pre-absorbed on 30 g. of silica III and placed on 250 ml. of alumina and eluted with ether giving 4.2 g. of solid. Thin-layer chromatography (hexane:ethylacetate, 3:1) indicates three components so this material (3 g.) is chromatographed on silica giving a solid which is recrystallized from acetonitrile to yield the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>C1COCC1.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]([F:20])([F:33])[F:32])=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccccc2OC(F)(F)F)c2cc(Br)cnc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
A mixture of 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (3.5 g, 7.7 mmol), 2-trifluoromethoxyphenylboronic acid (2.2 g, 7.7 mmol), dichloro[1,1′bis(diphenyl-phosphino)ferrocene]palladium(II) dichloromethane adduct (284 mg, 0.4 mmol) in THF/Acetonitrile/saturated NaHCO3 (25 ml/25 ml/30 ml) was stirred at 60° C. for 4 hours. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-3-(2-trifluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (2.2 g, 59% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.02 (s, 9H), 0.94 (m, 2H), 3.77 (m, 2H), 6.00 (s, 2H), 7.75 (m, 2H), 7.80 (d, 1H), 8.01 (d, 1H), 8.66 (s, 1H), 8.91 (s, 1H). MS: m/z 489.1 (M+H+).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[O:8][CH3:9])[C:1]([OH:11])=[O:10])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of chlorosulfonic acid (90 mL) at room temperature is treated with p-anisic acid (40 g), portionwise, during 30 minutes. When the addition is complete, the mixture is stirred at 90° C. for 75 minutes, then it is cooled and poured onto ice. The white precipitate is collected and dissolved in ethyl acetate (300 mL). The organic extract is washed with brine (2×250 mL), dried over magnesium sulfate, and concentrated, to give 3-chlorosulfonyl-4-methoxybenzoic acid (34 g), in the form of a white solid m.p. 168°-170° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)(=[S:3])[NH2:2].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])=O.C(N(C(C)C)CC)(C)C.C1COCC1>O>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:2]=[C:1]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9]2)[S:3][CH:21]=1
Reactant: O=C(CBr)c1ccccc1F
Reactant: NC(=S)N1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 120 °C
Yield: 27.2 %

Procedure:
A solution of benzyl 4-thiocarbamoylpiperazine-1-carboxylate (2.7 g, 9.7 mmol), 2-bromo-1-(2-fluorophenyl)ethanone (2.1 g, 9.7 mmol), diisopropyl ethylamine (1.9 mL, 11 mmol), and THF (32 mL) was sealed in a microwave vessel and heated by microwave irradiation at 120° C. for 20 seconds. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0%-30% EtOAc/hexanes) to give benzyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate (1.05 g, 27% yield). LC/MS: m/z 398.3 (M+H)+ at 3.84 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[C:4]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([O-:35])=[O:34].[Na+]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:9][C:8]=2[C:4]2[C:3]([F:26])=[C:2]([NH:1][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S([O-])c1ccccn1
Reactant: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(N)c2F)n1
Agent: [Na+]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccccn3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 278 using 4-[4-(3-amino-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.269 mmol) and sodium 2-pyridinesulfinate (224 mg, 1.346 mmol), the title compound was obtained as a yellow solid (58 mg, 42% yield). MS (ESI): 513 [M−H]+.