Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:8].[C:25](Cl)(=[O:27])[CH3:26]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]2)[S:5][C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)c2sc(NC3CCNCC3)nc2N)cc1F
Product: COc1ccc(C(=O)c2sc(NC3CCN(C(C)=O)CC3)nc2N)cc1F
Yield: 77 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluoro4-methoxy-phenyl)methanone (0.125 g, 0.36 mmol) (Example 7) was treated with acetylchloride in a manner similar to Example 9 to give 100 mg (77% yield) of 1-[4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidin-1-yl]ethanone. 1H NMR (DMSO−d6, 300 MHz) δ1.38 (dm, 2H, CH2), 1.92 (m, 2H, CH2), 2.02 (s, 3H, COCH3), 2.76 (t, 1H, NCH), 3.26 (t, 1H, NCH), 3.6-4.0 (broad, 1H, CH), 3.77 (m, 1H, NCH), 3.90 (s, 3H, OCH3), 4.22 (m, 1H, NCH), 7.23 (t, 1H, Aromatic), 7.47 (t, 1H, Aromatic), 7.50 (t, 1H, Aromatic), 7.9-8.5 (brd, 2H, 2NH), 8.69 (brd, 1H, NH). HRMS: (M+H)+: observed: 393.1396; calcd for 393.1391.
Reaction SMILES: ClC1C=C2C(C)(C)/C(=C\C=C(/C3C=CC=C(CCCCC(O[N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=O)C=3)\C=C\C3C(C)(C)C4C5C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=5C=CC=4[N+]=3CCCCS([O-])(=O)=O)/N=C2N(CCCCS([O-])(=O)=O)C=1.[Na+:77].[Na+].[Na+].[C:80]([CH2:83][CH2:84][CH2:85][CH2:86][C:87]1[CH:88]=[C:89](/[C:93](/[CH:118]=[CH:119]/[C:120]2[C:121]([CH3:138])([CH3:137])[C:122]3[C:123]([N:136]=2)=[N+:124]([CH2:129][CH2:130][CH2:131][S:132]([O-:135])(=[O:134])=[O:133])[CH:125]=[C:126]([Cl:128])[CH:127]=3)=[CH:94]\[CH:95]=[C:96]2\[N:97]([CH2:111][CH2:112][CH2:113][S:114]([O-:117])(=[O:116])=[O:115])[C:98]3[C:103]([C:104]\2([CH3:106])[CH3:105])=[CH:102][C:101]([S:107]([O-:110])(=[O:109])=[O:108])=[CH:100][CH:99]=3)[CH:90]=[CH:91][CH:92]=1)([OH:82])=[O:81].[Na+].[Na+]>>[Cl:128][C:126]1[CH:127]=[C:122]2[C:121]([CH3:138])([CH3:137])[C:120](/[CH:119]=[CH:118]/[C:93](/[C:89]3[CH:90]=[CH:91][CH:92]=[C:87]([CH2:86][CH2:85][CH2:84][CH2:83][C:80]([O:82][N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=[O:81])[CH:88]=3)=[CH:94]/[CH:95]=[C:96]3/[N:97]([CH2:111][CH2:112][CH2:113][S:114]([O-:117])(=[O:115])=[O:116])[C:98]4[C:103]([C:104]/3([CH3:105])[CH3:106])=[CH:102][C:101]([S:107]([O-:110])(=[O:108])=[O:109])=[CH:100][CH:99]=4)=[N:136][C:123]2=[N+:124]([CH2:129][CH2:130][CH2:131][S:132]([O-:135])(=[O:134])=[O:133])[CH:125]=1.[Na+:77].[Na+:77]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)ON3C(=O)CCC3=O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 33 is prepared analogously to compound 29 (Example 38), except that compound 32 is used as a starting material.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])=[N:15][C:16]([CH3:19])=[N:17][CH:18]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])=[N:15][C:16]([CH3:19])=[N:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
Isoamyl nitrite is added to a mixture of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine, copper(I) chloride, copper(II) chloride and acetonitrile dropwise at room temperature, and the mixture is stirred for 1 hour. This reaction solution is poured into 2% hydrochloric acid, and extracted with ethylacetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine [present compound4-76].
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[CH3:16][C:17]1O[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[N:19][N:18]=1>O1CCCC1>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[C:17]([CH3:16])=[N:18][N:19]=[C:20]2[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1
Reactant: Cc1nnc(-c2ccc(C#N)cc2)o1
Reactant: Nc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(C#N)cc2)n1-c1ccc(Cl)cc1

Procedure:
Trifluoroacetic acid (600 μl, 8.1 mmol) was added to a suspension of 4-chloroaniline (2.1 g, 16.2 mmol) and 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzonitrile (Journal für Praktische Chemie, 1994; 336(8); 678-85) (3.0 g, 16.2 mmol) in tetrahydrofuran (50 mL) and the reaction was heated at reflux for 22 hours. The cooled mixture was partitioned between ethyl acetate (300 mL) and 20% aqueous 0.88 ammonia (120 mL), and then the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue was triturated with ether and a minimum volume of ethyl acetate to afford the title compound as a white crystalline solid, 2.82 g.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:24]2[C:25]([CH2:31][OH:32])=[C:26]([C:28]([OH:30])=[O:29])[O:27][C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CI.Cl>CN(C=O)C>[CH3:1][O:29][C:28]([C:26]1[O:27][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH2:17][CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]=2[C:25]=1[CH2:31][OH:32])=[O:30]
Reactant: CC(C)(C)OC(=O)N(CCCOc1cccc2oc(C(=O)O)c(CO)c12)C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c2c1CO
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a suspension of potassium carbonate (4.0 mg) and 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-hydroxymethyl-benzofuran-2-carboxylic acid (5.0 mg) in dry DMF (0.8 ml) was added methyl iodide (48 μl) at room temperature and the mixture was stirred overnight. The solvent was evaporated in vacuo to give the crude material as a white heavy syrup, which was then treated with 0.1N HCl (10 ml). The product was extracted with ethyl acetate (10 ml) three times and washed with saturated sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate to give 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-hydroxymethyl-benzofuran-2-carboxylic acid methyl ester (3.7 mg) as a white solid. FAB-MS: m/z 436 (MH+); 1H-NMR (CDCl3): δ 1.42-1.48 (18H, m), 2.11 (2H, quintet, J=7.3 Hz), 3.54 (2H, t, J=7.3 Hz), 4.07 (1H, t, J=6.9 Hz), 4.12 (2H, t, J=7.3 Hz), 4.48 (3H, s), 5.22 (2H, d, J=6.9 Hz), 6.68 (1H, d, J=7.9 Hz), 7.18 (1H, d, J=7.9 Hz), 7.40 (1H, dd, J=7.9 Hz, 7.9 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na].C(O)(=O)C>C(#N)C.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][NH:14]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1(C)CN=C(c2ccc3c(c2)OCO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CNC(c2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.8 %

Procedure:
To a solution of 5-(1,3-benzodioxol-5-yl)-3,3-dimethyl-3,4-dihydro-2H-pyrrole (363 mg, 1.673 mmol) in acetonitrile (35 mL) add sodium triacetoxyborohydride (390 mg, 1.84 mmol) and stir at room temperature for two days. Then add more sodium triaxetoxyborohydride (390 mg, 1.84 mmol) and acetic acid and stir for 3 h. Add more add sodium triaxetoxyborohydride (390 mg, 1.84 mmol). After 0.5 h dissolve the reaction by adding methanol and load onto an ion-exchange SCX-2 (25 g), wash with methanol and then extract with ammonia in methanol. Concentrate under reduced pressure the basic solution, to afford 289 mg (79%) of the title compound. MS: 220 [M+H]+; 1H NMR (300 MHz, CDCl3): δ 6.90 (s, 1H), 6.72-6.75 (m, 1H), 6.72-6.75 (m, 1H), 5.91 (s, 2H), 4.20-4.25 (m, 1H), 2.68-2.72 (m, 1H), 2.75-2.79 (m, 1H), 1.72-1.98 (m, 2H), 1.45-1.1.53 (m, 1H), 1.10-1.18 (m, 6H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][C:8]1([CH3:15])[CH2:13][O:12]S(=O)[O:10][CH2:9]1.[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20](O)=[CH:19][C:18]=1[CH3:25]>CN(C)C=O>[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([O:10][CH2:9][C:8]([CH3:15])([CH3:7])[CH2:13][OH:12])=[CH:19][C:18]=1[CH3:25]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC1(C)COS(=O)OC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(C)(C)CO)cc(C)c1Br
Temperature: 120 °C

Procedure:
In a microwave vial Cs2CO3 (5.4 g) is added to a solution of 5,5-dimethyl-[1,3,2]dioxathiane 2-oxide (500 mg) and 4-bromo-3,5-dimethylphenol (670 mg) in N,N-dimethylformamide (5 mL). The vial is sealed and the mixture is heated to 120° C. for 12 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is washed three times with 2 M aqueous NaOH and with brine. After drying (MgSO4) and concentration the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. Yield: 372 mg; LC (method 7): tR=1.17 min; Mass spectrum (ESI+): m/z=287 [M+H]+.
Reaction SMILES: O.[C:2]1([C:8](B(O)O)=[CH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:14]1[N:19]=[C:18]2[S:20][C:21]([CH3:23])=[N:22][C:17]2=[CH:16][CH:15]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:23][C:21]1[S:20][C:18]2[C:17]([N:22]=1)=[CH:16][CH:15]=[C:14]([C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH2:9])[N:19]=2
Reactant: C=C(B(O)O)c1ccccc1
Reactant: Cc1nc2ccc(Cl)nc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ccccc1)c1ccc2nc(C)sc2n1
Temperature: 90 °C

Procedure:
A 1000 mL rbf was charged with 1-phenylvinylboronic acid hydrate (36.7 g, 221 mmol), (amphos)2PdCl2 (3.26 g, 4.60 mmol), and 5-chloro-2-methylthiazolo[5,4-b]pyridine (34.0 g, 184 mmol) under argon. Dioxane (200 mL) was added followed by a solution of potassium carbonate (61.1 g, 442 mmol) in 60 mL water, and the reaction was fitted with a water cooled reflux condenser and flushed with argon. The resulting slurry was heated to 90° C. for 3 h. The reaction mixture was allowed to cool, and was diluted with 200 mL MTBE and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick brown oil. The oil was purified by silica gel chromatography, 0-30% EA/hexanes to give 2-methyl-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine as a brown oil. MS (ESI) m/z: calculated: 252.1; Observed: 253.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:24])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.FC1C=C(NC(NC(=O)CC2C=CC(F)=CC=2)=S)C=CC=1OC1C2=C(C)C=CN2N=CN=1>>[F:1][C:2]1[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:24])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cc1ccn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Yield: 79.9 %

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.05 mmol) was converted to the title compound (16 mg, 87%) in a manner similar to the preparation of Compound B of Example 28. 1H NMR (CDCl3) δ 7.86–7.83 (m, 1H), 7.50–7.38 (m, 2H), 7.09–7.00 (m, 1H), 6.56–6.45 (m, 1H), 4.14 (t, 2H, J=5.5 Hz), 2.99–2.38 (m, 18H); MS(ESI+) m/z 401.4 (M+H)+.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(C1C=CC(C)=CC=1)(O[IH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[F:56][Sb-:57]([F:62])([F:61])([F:60])([F:59])[F:58].[Na+]>CC(C)=O.C(O)(=O)C>[F:56][Sb-:57]([F:62])([F:61])([F:60])([F:59])[F:58].[CH2:8]([O:7][C:1]1[CH:6]=[CH:5][C:4]([I+:30][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:3][CH:2]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Cc1ccc(S(=O)(=O)O[IH](=O)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOc1ccc([I+]c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
In accordance with the procedure of Example 1, octadecyl phenyl ether was prepared and a quantitative yield was obtained. There was added 50 ml of glacial acetic acid to a mixture of 196 grams (0.5 mol) of phenyliodoso tosylate and 173 grams (0.5 mols) of octadecyl phenyl ether dissolved in 200 ml dicholoromethane. After 1 hour stirring at 40° C., the reaction mixture was filtered then triturated with ether. A product, (4-octadecyloxyphenyl)phenyliodonium tosylate crystallized from solution and was recovered by filtration. There was obtained 340 grams (94.4% yield). The entire amount of the tosylate salt was dissolved in 1000 ml of hot acetone and 125 grams of sodium hexafluoroantimonate was added. The reaction mixture was stirred for 1 hour and the solution filtered to remove the sodium tosylate. The main filtrate was triturated with water and a white crystalline product (4-octadecyloxyphenyl)phenyliodonium hexafluoroantimonate was obtained. Recrystallization from ethanol/water gave the pure iodonium salt having a melting point of 94° C. and an 83 % yield. The acute oral toxicity of this photoinitiator was found to be greater than 5 g/kg. No toxic effects were observed during the 14 day test period and all the test animals (rats) gained weight during the test period.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[CH:19]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:19]#[C:18][C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1)=[O:17]
Reactant: C#CC1(O)CCCCC1
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(NCCCc1cccc(C#CC2(O)CCCCC2)c1)C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of bromide 10 (2.0 g, 6.45 mmol) and 1-ethynylcyclohexanol (1.2 g, 9.67 mmol) in triethylamine (40 mL) was added CuI (0.0246 g, 0.129 mmol). The mixture was degassed with argon for 2-3 min, then PdCl2(PPh3)2 (0.0905 g, 0.129 mmol) was added. The reaction mixture was degassed with argon again then stirred at 70° C. overnight under argon. After cooling to room temperature, the mixture was concentrated under reduced pressure and suspended in EtOAc-hexanes (50%, 50 mL). Solids were removed by filtration and the filtrate was concentrated under reduced pressure. Purification by flash chromatography gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide as a clear oil. Yield (1.74 g, 76%): 1H NMR (400 MHz, DMSO-d6) δ9.40 (brs, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.17-7.24 (, 3H), 5.37 (s, 1H), 3.16 (q, J=6.8 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.15-1.83 (m, 12H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[F:11][C:12]([F:39])([F:38])[C:13]1[CH:14]=[C:15]([NH:19][C:20]2[N:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22](OC2C=CC([N+]([O-])=O)=CC=2)=[O:23])[CH:16]=[CH:17][CH:18]=1>C1(C)C=CC=CC=1>[C:3]([CH:5]([C:22](=[O:23])[C:21]1[C:20]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:39])([F:11])[F:38])[CH:14]=2)=[N:37][CH:36]=[CH:35][CH:34]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(=O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a stirred mixture of NaH (524 mg, 21.8 mmol) in toluene (20 mL) was added dropwise ethyl cyanoacetate (3.7 g, 32.7 mmol, 3.5 mL). The slurry was stirred for 1 h and then 4-nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate (4.4 g, 10.9 mmol) was added. The reaction mixture was stirred for 1 h and then quenched with water (20 mL). CH2Cl2 (30 mL) was added and the layers were partitioned. The organic layer was washed with brine (2×) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (5:1 to 2:1 Hex:EtOAc) to afford 3 Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate.(6 g, 87%): LCMS RT: 2.83 min, MH+: 378.0.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)=CC=1)([O-])=O.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:30][CH2:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[O:29])[N:27]=1>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]([NH:30][CH2:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:35])[CH3:36])=[O:29])[N:27]=2)=[O:21])=[CH:17][CH:16]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)N(CCNC(=O)c1csc(N)n1)C(C)C
Product: CC(=O)c1ccc(C(=O)Nc2nc(C(=O)NCCN(C(C)C)C(C)C)cs2)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To 831 mg of 4-acetylbenzoic acid p-nitrophenyl ester, 788 mg of 2-amino-4-[(2-diisopropylaminoethyl)aminocarbonyl]-1,3-thiazole were added. The resulting mixture was stirred at 130° C. for 8 hours. The reaction mixture was purified by column chromatography on NH silica gel (chloroform), whereby 693 mg of 2-[N-(4-acetylbenzoyl)amino]-4-[(2-diisopropylaminoethyl)aminocarbonyl]-1,3-thiazole were obtained. After 2 ml of a 4N hydrochloric acid--dioxane solution were added to the resulting compound, the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of isopropyl ether and ethanol, whereby 395 mg of the title compound were obtained as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2(O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].S(Cl)([Cl:39])=O>C(Cl)(Cl)Cl>[Cl:39][C:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][C:23]([F:24])([F:26])[F:25])(=[O:13])=[O:12])[C:6]1=[O:27]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2C(=O)C(Cl)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a solution of 3.00 g of compound obtained in Step 7-2-2 in CHCl3 (30 ml) was added sequentially 654 mg of Py and 984 mg of thionyl chloride under ice cooling, and the reaction mixture was stirred for 2 hours at the same temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/4; v/v) to obtain 2.63 g of the title compound (orange color solid).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.OCCOC1N=CN=C([NH:34][S:35]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:37])=[O:36])C=1C1C=CC(C)=CC=1>>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=[C:2]([NH:34][S:35]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:36])=[O:37])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCO)cc1
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCc1ccccc1

Procedure:
2-Phenylethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-amide was prepared in analogy to Referential Example 7 from 4,6-dichloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (prepared as disclosed in [6]) and 2-phenylethane sulfonamide potassium salt (Referential Example 1). LC-MS: tR=4.85 min, [M+1]+=498.38, [M−1]−=496.19.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[O:18][CH2:19][CH:20]([CH3:22])[CH3:21].[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:17][CH2:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:12]=3)[CH:37]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COc1ccc(F)c(-c2ncc(CO)cc2OCC(C)C)c1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1cccc(OCc2cnc(-c3cc(OC)ccc3F)c(OCC(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of (6-(2-fluoro-5-methoxyphenyl)-5-isobutoxypyridin-3-yl)methanol (100 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (72 mg) in toluene (4.7 mL) were added 1,1′-(azodicarbonyl)dipiperidine (132 mg) and tributylphosphine (131 μL), and the mixture was stirred at room temperature for 14 hr. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (132 mg) as a colorless oil.