Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[Br:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])Br.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[O:3][C:2]1[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=1[O:8][CH3:9]
Reactant: COc1ccccc1O
Reactant: FC(F)(Br)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1OC(F)(F)C(F)(F)Br
Temperature: 100 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
30.0 g of guaiacol, 70.0 g of 1,2-dibromotetrafluoroethane, 50.0 g of anhydrous potassium carbonate and 450 ml of dry DMSO were introduced into a stirred autoclave made of stainless steel. After the autoclave had been flushed with argon, it was sealed and subsequently heated to 100° C. After the reaction mixture had been stirred at this temperature for 24 hours, it was cooled to 20° C., poured into water and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate. The dichloromethane was then evaporated in vacuo and the residue was distilled. 62.3 g of a mixture of 70 area % of 1-(2-bromo-1,1,2,2-tetrafluoroethoxy)-2-methoxybenzene (59.2% of theory) and 30 area % of 1-(1,1,2,2-tetrafluoroethoxy)-2-methoxybenzene (GC analysis) were obtained, distilling over at 80-95° C./14 mbar.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:39]([C:36]2([CH3:35])[CH2:38][CH2:37]2)=[O:40])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3(C)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 98 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 1-methylcyclopropanecarboxylic acid (29 mg, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-{cis-4-[(1-methyl-cyclopropanecarbonyl)-amino]-cyclohexyl}-2-(3-methylsulfanyl-phenoxy)-nicotinamide (109 mg) as a white solid.
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14]C)[CH3:12]>ClCCl>[CH3:14][N:13]1[CH2:16][CH2:17][CH:12]([CH2:6][CH:5]=[O:9])[CH2:11]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN1CCC(CC=O)C1
Temperature: 25 °C

Procedure:
Dimethylsulphoxide (0.36 ml) was added dropwise to a solution of oxalyl chloride (0.33 ml) in dry dichloromethane (8 ml) at -72°, with stirring under nitrogen. The solution was stirred at -72° for 5 min then a solution of the compound of stage (i) (325 mg) in dry dichloromethane (5 ml) was added in a stream over 3 min. The solution was stirred at -72° for 15 min then triethylamine (1.75 ml) was added. The mixture was then warmed to room temperature over 1 h. The solvent and excess triethylamine were evaporated to give the crude title compound which was used immediately in the next step.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Br)=[C:10]([O:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH3:17].BrC1C([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=C(OC)C2C(C=1OC)=CC=CC=2.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[C:11]([CH2:12][CH:34]([CH3:33])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:10]([O:14][CH3:15])[C:9]2[C:4]([C:3]=1[O:16][CH3:17])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: COc1c(Br)c(CBr)c(OC)c2ccccc12
Reactant: CCOC(=O)CCc1c(Br)c(OC)c2ccccc2c1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Cc1c(Br)c(OC)c2ccccc2c1OC

Procedure:
Compound 67b was prepared from 36 (0.244 g, 0.678 mmol) as described above for 67a to give 0.258 g (0.678 mmol, 100%) of the product as a EtOAc following flash chromatography (1:1 to 3:1 CH2Cl2:hexanes).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:43]([O:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([C:59](O)=[O:60])[CH2:55][CH2:54]1)=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:59]([CH:56]2[CH2:57][CH2:58][N:53]([C:51]([O:50][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:52])[CH2:54][CH2:55]2)=[O:60])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (2.00 g, 0.0107 mol) and N,N-diisopropylethylamine (2.2 g, 0.017 mol) in DCM (27.0 mL) was treated with and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.2 g, 0.017 mol), 1-hydroxybenzotriazole (1.5 g, 0.011 mol) and 1-[(benzyloxy)carbonyl]-4-piperidine carboxylic acid (3.8 g, 0.014 mol). The mixture was stirred at rt overnight then diluted with DCM (30 mL), washed with sat. NaHCO3 (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude material thus obtained was chromatographed over silica gel eluting with EtOAc:hexane 1:1 yielding 3.38 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.68-1.78 (m, 2H), 1.91-1.94 (m, 2H), 2.44 (m, 1H), 2.89-2.92 (m, 2H), 4.24-4.26 (m, 2H), 4.70 (d, J=4.8 Hz, 2H), 5.14 (s, 2H), 6.85 (br, 1H), 7.30-7.37 (m, 5H), 8.34 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H). MS (ES+): m/z 389.17 [MH+].
Reaction SMILES: C(O[CH:4]=[C:5]([CH2:8][CH3:9])[C:6]#[N:7])C.[NH2:10][C:11]([NH2:13])=[O:12].CC[O-].[Na+].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[CH2:8]([C:5]1[C:6]([NH2:7])=[N:10][C:11](=[O:12])[NH:13][CH:4]=1)[CH3:9]
Reactant: CCOC=C(C#N)CC
Reactant: NC(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCc1c[nH]c(=O)nc1N
Yield: 66.1 %

Procedure:
25 g (0.2 mol) of 3-ethoxy-2-ethyl-acrylonitrile were added over a period of 1 hour to a refluxing mixture of 15.6 g (0.26 mol) of urea and 15.7 g (0.23 mol) of sodium ethylate in 50 g of xylene, and the resulting mixture was heated for 3 additional hours at its boiling point. Thereafter, the ethanol in the reaction mixture was distilled off, and the residue was taken up in 120 g of water. The aqueous phase was separated and admixed with 13.8 g (0.23 mol) of acetic acid. The precipitated product was collected by suction filtration and recrystallized from water in the presence of activated charcoal. 18.4 g (66.3% of theory) of pure 5-ethyl-cytosine were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[C:22]([F:25])([F:24])[F:23])[N:3]=1.O.[NH2:27][NH2:28]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]3[C:11]([C:12]([NH2:13])=[N:27][NH:28]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[C:22]([F:25])([F:24])[F:23])[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCCC3C(F)(F)F)nc(N)n2)cc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCC2C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
4-{2-Amino-6-[2-(trifluoromethyl)-1-pyrrolidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (60 mg, 0.17 mmol) was disolved in ethanol (1.5 mL) with stirring in a 5 mL microwave vessel. Hydrazine monohydrate (0.207 mL, 4.27 mmol) was added, and the mixture was capped and heated at 100° C. in an oil bath overnight. HPLC showed complete conversion. The hot mixture was filtered through a 0.2 um filter disc, rinsing with ethanol (1 mL). Water (˜3 mL) was added to the filtrate with stirring, and the mixture was heated to evaporate most of the ethanol to a volume of ˜4 mL. The mixture was allowed to cool with stirring to room temperature, at which time some product had precipitated as a gum. Stirring was continued for approximately one hour and the precipitate became a free flowing white solid, which was filtered, washed with water and dried to afford the title compound (42 mg) as an off-white solid. LC-MS (ES) m/z=364 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.98-2.08 (m, 2H), 2.08-2.23 (m, 2H), 3.49-3.60 (m, 1H), 3.60-3.72 (m, 1H), 5.06-5.17 (m, 1H), 5.39 (s, 2H), 6.22 (s, 2H), 6.52 (s, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][O:11][CH2:12][CH2:13]Br.O>CN(C)C=O>[CH3:10][O:11][CH2:12][CH2:13][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 4.70 g of phenol and 35 mL of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 1.30 g of sodium hydride (95%, dispersion in mineral oil) in 15 mL of dry N,N-dimethylformamide at 5° C. Stirring was continued for 2 hours at 5° C., followed by dropwise addition of 5.20 mL of 2-bromoethyl methyl ether (technical grade, 90%) at 5° C. The mixture was allowed to come to room temperature and stirring was continued for 72 hours. The mixture was poured into water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (sodium sulfate) and concentrated to give 5.90 g of (2-methoxy-ethoxy)-benzene as an oil. EI-MS: 159 (M+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[N:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:31]=[CH:32][CH:33]=2)O1.CN(C)C(=O)C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:9]1[N:8]=[CH:7][N:6]2[C:2]([C:32]3[CH:31]=[C:30]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:29]=[CH:28][CH:33]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Cc1cc2ncc(Br)n2cn1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cc2ncc(-c3cccc(-c4ccccc4C#N)c3)n2cn1
Temperature: 80 °C
Yield: 49 %

Procedure:
A stirred mixture of 3-bromo-7-methylimidazo[1,2-c]pyrimidine (0.1013 g, 0.478 mmol), dried potassium phosphate (0.2027 g, 0.955 mmol) and a 0.5 M solution of 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile in N,N-dimethylacetamide (1.91 ml, 0.955 mmol) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (28.7 mg, 0.0248 mmol) was then added and the mixture was degassed with two more evacuation-refilling cycles before heating at 80° C. under nitrogen for 45 h, adding more dried potassium phosphate (0.0503 g, 0.237 mmol), a 0.5 M solution of 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile in N,N-dimethylacetamide (0.48 ml, 0.240 mmol) and tetrakis(triphenylphosphine)palladium(0) (8.0 mg, 0.0069 mmol) after 21 h with degassing. The mixture was diluted with ethyl acetate and filtered through glass fibre filter paper, washing solid with more ethyl acetate. The combined filtrates were washed with saturated aqueous NaCl (15 ml), and the aqueous layer was further extracted with ethyl acetate (2×25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc) to give 72.8 mg (49%) of the title compound as a yellow-brown solid: mp 119° C. (softens) (CH2Cl2-EtOAc-isohexane); 1H NMR (400 MHz, CDCl3) δ 2.57 (3H, s), 7.36 (1H, s), 7.51 (1H, td, J 7.6, 1.2 Hz), 7.57-7.72 (6H, m), 7.78 (1H, fine m), 7.82 (1H, dd, J 7.5, 1.4 Hz), 9.34 (1H, s); MS (ES+) m/z 311 [M+H]+; Anal. Found: C, 71.93; H, 4.68; N, 16.35%. Required for C20H14N4.1.4H2O: C, 71.58; H, 5.05; N, 16.70.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1>C(#N)C>[Br:25][C:10]1[N:9]2[CH:13]=[C:14]([CH2:16][OH:17])[N:15]=[C:8]2[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:12][CH:11]=1
Reactant: OCc1cn2ccnc(N3CCOCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Temperature: -20 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of compound 1d (2.40 g, 10.3 mmol) in ACN (200 mL) was added NBS (2.40 g, 13.5 mmol) in portions at −20° C. The resulting solution was stirred at −20° C. for 2 h, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:1 v/v) to obtain compound 1e as a yellow solid (1.48 g, 41% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C11H13BrN4O2: 313.0 (M+H). Found 313.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=2)[N:8]=1.[CH:22]1([NH:25][S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH2:23]1>N1C=CC=CC=1>[CH:22]1([NH:25][S:26]([NH:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15]3)(=[O:28])=[O:27])[CH2:24][CH2:23]1
Reactant: COc1ccccc1CNc1ccc2cc(N)ccc2n1
Reactant: O=S(=O)(Cl)NC1CC1
Solvent: c1ccncc1
Product: COc1ccccc1CNc1ccc2cc(NS(=O)(=O)NC3CC3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (example 10, step B, 40 mg, 0.143 mmol) was dissolved in 1 mL pyridine. Cyclopropylsulfamoyl chloride (29 mg, 0.186 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated off and the residue purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10→34:66 gradient). The title compound was obtained as a yellow solid (22 mg, 39%), MS: m/e=397.5 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].CO>C(OCC)(=O)C>[CH3:18][N:19]([CH3:21])/[CH:20]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OC
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)/C=C/N(C)C)ccc1OC
Temperature: 95 °C
Yield: 90.1 %

Procedure:
Methyl 5-acetyl-2-methoxybenzoate (11.98 g, 48.0 mmol) was added to N,N-dimethylformamide dimethyl acetal (44.6 g, 374.5 mmol) held under a nitrogen atmosphere. The resulting solution was heated at 95° C. for 60 minutes. Methanol (10 ml) was then removed by atmospheric distillation and further N,N-dimethylformamide dimethyl acetal (8.90 g, 74.9 mmol) added. The resulting solution was heated at 95° C. for a further 270 minutes. The reaction was then cooled to 50° C. and ethyl acetate (35 mL) added. Solvent (35 mL) is removed from the reaction by atmospheric distillation and fresh ethyl acetate (35 mL) added. Further solvent (35 mL) is removed from the reaction by atmospheric distillation and fresh ethyl acetate (50 mL) added. The reaction mixture is cooled to RT whereby the desired product crystallises out as a granular, free flowing solid. The solid was isolated by filtration, washed twice with fresh ethyl acetate (2×30 mL) and dried to constant weight to afford 11.39 g of the desired methyl 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-methoxybenzoate (8).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH:13]=[O:14])=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].C[Si](C)(C)[O:17][CH2:18][CH2:19]O[Si](C)(C)C.C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>N1C=CC=CC=1>[O:14]1[CH2:19][CH2:18][O:17][CH:13]1[C:5]1[S:4][C:3]([CH2:1][CH3:2])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=1
Reactant: CCOC(=O)c1cc(C=O)sc1CC
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C2OCCO2)sc1CC
Reaction time: 2 h

Procedure:
To a mixture of ethyl 2-ethyl-5-formylthiophene-3-carboxylate (7.82 g) synthesized above, 1,2-bis(trimethylsiloxy)ethane (9.93 mL) and methylene chloride (80 mL) was added trimethylsilyl trifluoromethanesulfonate (661 μL) at −78° C., and the mixture was stirred for 2 hr under a nitrogen atmosphere. Pyridine (890 μL) was added to quench the reaction, and saturated aqueous sodium hydrogen carbonate solution was added. Methylene chloride was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (9.71 g, quantitative) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cnc(Oc2ccc(Cl)cc2)c(Cl)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
In a falsk, 4.0 g of 2,3-dichloro-5-trifluoromethyl pyridine, 10 ml of dimethyl sulfoxide, 5.1 g of anhydrous potassium carbonate and 2.9 g of p-chlorophenol were charged. The flask was heated in an oil bath at 110° C. to react them with stirring for 2 hours. The completion of the reaction was confirmed by a gas chromatography. The reaction mixture was cooled and poured into suitable amount of water. The reaction product was extracted with methylene chloride and the extracted phase was washed with a diluted sodium hydroxide aqueous solution and then, with water and dried over anhydrous sodium sulfate. Methylene chloride was distilled off under a reduced pressure and the oily residue was distilled to obtain 4.4 g of the object compound having a boiling point of 124°-127° C./2.5 mmHg.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[C:8]1[C:9]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH3:23])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31](=[N:33]O)[NH2:32])[CH:30]=1.CCN(C(C)C)C(C)C>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31]2[N:32]=[C:13]([C:12]3[CH:16]=[CH:8][C:9]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]4[CH3:23])=[N:10][CH:11]=3)[O:15][N:33]=2)[CH:30]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: Cc1cc(C(=O)O)cnc1N1CCCCC1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)nc2)n1

Procedure:
Oxalyl chloride (138 μL; 1.63 mmol; 3 eq.), Intermediate 39 (120 mg; 0.54 mmol; 1 eq.), Intermediate 23 (100 mg; 0.54 mmol, 1 eq.) and DIEA (282 μL; 1.54 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 50/50) afforded the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:11][C:12]#[N:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].Cl>N1C=CC=CC=1>[S:11]([C:4]1[S:3][C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=2)=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9])[C:12]#[N:13]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: N#CSc1sc(N)nc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: N#CSc1sc(NC(=O)c2cccc(C(F)(F)F)c2)nc1C(F)(F)F
Temperature: 0 °C
Yield: 56.7 %

Procedure:
2-Amino-5-thiocyanato-4-trifluoromethylthiazole (0.8 g) was dissolved in pyridine (5 ml) and 3-trifluoromethylbenzoylchloride (0.8 g) was added at room temperature with stirring. The mixture was stirred for one night at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from carbon tetrachloride to give N-(5-thiocyanato-4-trifluoromethylthiazol-2-yl)-3-trifluoromethylbenzamide (0.8 g), m. p. 167-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:21]([C:23]1[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:24]=1[CH3:34])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:21][C:23]4[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:24]=4[CH3:34])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)N(C)c3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)O
Yield: 22.5 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (80 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) at 80° C. for 2 hours to give 36 mg (23%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.15 (br s, 1H, NH), 12.07 (br s, 1H, COOH), 9.18 (s, 1H), 8.33 (s, 1H), 7.71 (m, 1H), 7.40 (s, 1H), 7.30-7.39 (m, 2H), 3.32 (s, 3H, CH3), 2.63 (m, 2H, CH2), 2.35 (m, 2H, CH2), 2.33 (s, 3H, CH3), 2.13 (s, 3H, CH3).