Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:8]([C:16]([O:18][CH3:19])=[O:17])[S:7][C@H:6]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:4].O1[CH2:31][CH2:30][CH2:29][CH2:28]1>CC1C=C(N=C=O)C=CC=1>[CH3:19][O:18][C:16]([C@H:8]1[S:7][C@@H:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:3]([NH:5][C:9]2[CH:10]=[CH:31][CH:30]=[C:29]([CH3:28])[CH:8]=2)=[O:4])[C@H:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:17]
Reactant: COC(=O)[C@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CN)[C@H]1c1ccccc1
Reactant: C1CCOC1
Agent: Cc1cccc(N=C=O)c1
Product: COC(=O)[C@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)[C@H]1c1ccccc1

Procedure:
The process is performed in a similar manner to that described in Example 1, but starting with a solution containing 0.7 g of tert-butyl (2S,4S,5S)-3-(2-aminoacetyl)-5-methoxycarbonyl-4-phenyl-2-thiazolidinecarboxylate in 20 ml of tetrahydrofuran and 250 μl of 3-methylphenyl isocyanate. The crude product is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (20/80 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 0.28 g of tert-butyl (2S,4S,5S)-5-methoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-phenyl-2-thiazolidinecarboxylate is thus obtained in the form of a white foam, Rf=0.39 [ethyl acetate/cyclohexane (50/50 in volume)]; 1H NMR (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 297 K, δ in ppm): 1.48 (s, 9H: CH3 of the tert-butyl); 2.21 (s, 3H: ArCH3); 3.28 and 4.15 (broad d and d respectively, J=17.5 Hz, 1H each: COCH2N); 3.37 (s, 3H: COOCH3); 5.10 (d, J=7 Hz, 1H: H at C5 of the ring); 5.43 (s, 1H: H at C2 of the ring); 5.68 (d, J=7 Hz, 1H: H at C4 of the ring); 6.70 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH3)); 7.06 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH3)); from 7.00 to 7.50 (mt, 5H: aromatic H); 7.72 (mt, 2H: H ortho to the phenyl).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](Cl)(=O)[CH2:11][CH3:12]>>[CH2:11]([CH:12]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][NH:9]1)[CH3:10]
Reactant: CCC(=O)Cl
Reactant: NCCc1ccccc1
Product: CCC1NCCc2ccccc21

Procedure:
In accordance with the same procedures as in Preparation 1-1, except that 11.3 ml of phenethylamine (90 mM) and 7.8 ml of propionyl chloride(90 mM) were used as starting materials, 8.48 g of the title compound was prepared.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:27]1N=C(N2CCC(F)(F)C2)[C:30]2N=[N:34][NH:33][C:31]=2[N:32]=1)(C)(C)C.ClCC1N(C)C(C)=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:32]([CH3:27])[C:31]([CH3:30])=[N:33][N:34]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cc1nnc(CCl)n1C
Product: Cc1nnc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole and isolated as light-yellow solid. MS (m/e): 392.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C.[BH4-].[Na+]>ClCCCl>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: Nc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
A solution of 4-fluoroaniline (32.7 g), N-benzylpiperidinone (106.0 g) and acetic acid (106.0 g) in 1,2-dichlorethane (1200 ml) is brought to a temperature below 15° C. To the stirred solution is added slowly a suspension of acetic acid (495.0 g) and sodium borohydride (31.2 g). After 2 h stirring at 15° C. and another 2 h at r.t., the solvent is removed in vacuo. Ethyl acetate (500 ml) and water (700 ml) are added under stirring and the resulting mixture is neutralised with sodium carbonate (ca. 250 g). The organic phase is separated, washed with a 2 M NaHCO3 solution (100 ml) and water (100 ml) and dried with sodium sulphate. 53.8 g product is obtained as orange crystals after removal of the solvent and recrystallisation from ether/petroleum ether. Mp. 90-92° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>>[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC1CCCN1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Product: CC1CCCN1c1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)ccn1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and 2-methylpyrrolidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.24 (m, 2H), 7.86 (m, 1H), 7.57 (m, 2H), 7.49 (d, 1H), 7.09 (d, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 4.31 (t, 2H), 3.60 (m, 6H), 2.88 (t, 2H), 2.57 (m, 4H), 2.07 (m, 4H), 1.70 (m, 1H), 1.21 (d, 3H). MS: 461.2 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Mg].II.[C:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1>[O:7]([C:8]1[CH:13]=[CH:12][C:11]([C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)([OH:20])[CH3:19])=[CH:10][CH:9]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CC(=O)c1cccnc1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Oc2ccccc2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
25 ml. of a solution of 25.0 g. 4-bromodiphenylether in 75 ml. tetrahydrofuran is added to 2.5 g. magnesium and, admixed with a small crystal of iodine to initiate the Grignard reaction. Thereafter, the remainder of the solution is added dropwise to maintain gentle reflux. The Grignard solution is then refluxed for 0.5 hours, cooled to 5°-10° and to it is added dropwise 12.1 g. of 3-acetylpyridine. The reaction mixture is then stirred at room temperature for 16 hours, decomposed with saturated aqueous ammonium chloride solution and extracted with ether. The ether extracts are combined and after drying over anhydrous sodium sulfate, filtered and evaporated i.v. to dryness. From the residue is crystallized from pentane/ether, 1-(p-phenoxyphenyl)-1-(3-pyridyl)-ethan-1-ol, m.p. 130°-132°.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:22]=1>N1C=CC=CC=1>[CH2:27]([O:26][C:24]([CH2:23][C:21]1[N:22]=[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[S:19][CH:20]=1)=[O:25])[CH3:28]
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: [I-]
Solvent: c1ccncc1
Product: CCOC(=O)Cc1csc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Reaction time: 48 h
Yield: 62.9 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.1 g) is added to a solution of ethyl (2-aminothiazol-4-yl)acetate (10 g) in pyridine (300 cc). After 48 hours at a temperature of the order of 20° C., the solution is concentrated to dryness under reduced pressure (25 mm Hg; 3.3. kPa) at 60° C. The residue is dissolved in a mixture of methylene chloride (200 cc) and N sodium hydroxide solution (100 cc). The organic phase is decanted off, washed with water (3×100 cc), dried over sodium sulphate and then concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. The residue is recrystallised by dissolving it in boiling acetonitrile (100 cc) and then cooling. The crystals formed are filtered off, washed with acetonitrile (20 cc) and then with diethyl ether (20 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(4-ethoxycarbonylmethylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (11.7 g), m.p.=105° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11](=[O:13])[CH3:12])=[N:6][C:7]=1[CH:8]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11](=[O:13])[CH3:12])=[N:6][C:7]=1[CH:8]=[N:20][S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: CC(=O)Nc1ccc(Br)c(C=O)n1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)c(C=N[S@@](=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Copper(II) sulfate (anhydrous 2.8 g, 17.2 mmol) was added to a solution of N-(5-bromo-6-formylpyridin-2-yl)acetamide (crude material, assume 8.6 mmol) and (S)-2-methylpropane-2-sulfinamide (1.2 g, 9.4 mmol) in DCM (30 ml). The suspension was stirred overnight at room temperature. The reaction was filtered and washed with DCM (3×20 ml). The filtrate was concentrated. The crude product was purified by flash column (30% EtOAc/Hexanes). MS (m/z) 346.1 [M+H]+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:20]=[CH:19][C:11](/[CH:12]=C/N2CCCC2)=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1>C1COCC1.O>[Br:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[O:2])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Br)ccc1/C=C/N1CCCC1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 15 h
Yield: 85.3 %

Procedure:
To a solution of sodium periodate (298 g, 1.40 mol) in THF—H2O (4 L, 1:1) at 0° C. was added (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine (138 g, 464 mmol). The mixture was stirred for 15 h and then filtered to remove solid precipitates. The aqueous layer from the filtrate was separated and extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (2×200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that was purified by silica gel flash column chromatography (5% EtOAc in hexanes) to afford 91 g (86%) of 4-bromo-2-nitrobenzaldehyde.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(O)C.C(OCC)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N+:36]2[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:33][CH:32]=1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Reactant: Cc1ccc(CN)cc1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccc(C[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A solution of 2,4,6-triphenylpyrylium tetrafluoroborate (2.97 g, 7.5 mmol) in ethanol (15 mL) was treated with 4-methylbenzylamine (1 g, 8.25 mmol). The reaction was stirred overnight at room temperature and diluted with diethyl ether to precipitate the product. The product was recrystallized from ethanol/diethyl ether to give 3.15 g of N-(4-methylbenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate as a tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:38][C:24]([C:21]3[O:22][C:23]4[C:15]([N:12]5[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH2:14][CH2:13]5)=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=3)=[O:25])=[CH:39][CH:40]=2)[CH2:32][CH2:33]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: [Li+]
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (60 mg, 0.16 mmol) and 4-morpholinoaniline (37 mg, 0.20 mmol). Yield: 38 mg (44%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][NH:10][C:5]2=[C:4]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH:3]=1.Cl.CS(C)=O.[CH2:26](O)[CH3:27]>>[C:16]([C:15]1[CH:19]=[CH:20][C:12]([NH:11][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]3[CH:8]=[N:9][NH:10][C:5]=23)=[CH:13][CH:14]=1)([O:18][CH2:26][CH3:27])=[O:17]
Reactant: Cc1cc(Nc2ccc(C(=O)O)cc2)c2[nH]ncc2n1
Reactant: CCO
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Nc2cc(C)nc3cn[nH]c23)cc1

Procedure:
The carboxylic acid (E2) of Example 2 (0.5 g, 0.0019 mole) was heated at reflux in ethanol (25 ml) to which several drops of a saturated ethanol solution of hydrogen chloride had been added. Dimethyl sulphoxide (5.5 ml) was added after 11/2 h to aid solution and heating continued for a further 71/4 h. The solution was filtered and solvent removed under reduced pressure. Ether and a small amount of ethyl acetate were added and the resulting yellow solid (518 mg, 94%) collected, m.p. 247°-250° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]2)=[CH:3][N:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][N:41]3[C:42](=[O:44])[CH2:43][O:39][C:40]3=[O:45])[CH2:15][CH2:16]2)=[CH:3][N:2]=1
Reactant: O=C1COC(=O)N1
Reactant: OCCC1CCN(c2cncc3ccccc23)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1COC(=O)N1CCC1CCN(c2cncc3ccccc23)CC1
Yield: 94.4 %

Procedure:
The procedure described in Example 5 (step 5.2) is used. Starting with 0.801 g (3.12 mmol) of 2-[1-(4-isoquinolyl)-4-piperidyl]ethanol, prepared in step 7.1, 0.902 g (3.44 mmol) of triphenylphosphine, 0.379 g (3.75 mmol) of 1,3-oxazolidine-2,4-dione and 0.632 g (3.12 mmol) of diisopropyl azodicarboxylate (DIAD), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 1 g of product is obtained in the form of a green paste.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CC1(C)C(C)(C)OB([C:19]2[C:28]3[C:23](=CC=C[CH:27]=3)[CH:22]=[N:21][CH:20]=2)O1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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.O>[F:10][C:3]1[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:28]=2[CH3:27])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
Reactant: N#Cc1cccc(Br)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccncc1-c1cccc(C#N)c1F
Temperature: 90 °C
Yield: 86.9 %

Procedure:
To a solution of 3-bromo-2-fluorobenzonitrile (2.0 g, 10.00 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (2.81 g, 11.00 mmol) in a mixture of DME (30 mL), ethanol (15 mL), and water (15 mL) was added Na2CO3 (4.24 g, 40.0 mmol). This suspension was degassed with a stream of N2 for 10 minutes and then tetrakis(triphenylphosphine)palladium(0) (0.578 g, 0.500 mmol) was added followed by degassing with nitrogen for 10 minutes. The tube was then sealed and heated to 90° C. for 14 hours. The vessel was cooled to room temperature and diluted with EtOAc and water. The mixture was further diluted with brine and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated to give the crude product as a brown oil. The crude material was purified by flash chromatography on silica using an ISCO machine (80 g SiO2 column, 60 mL/min, 0-20% acetone in CH2Cl2 over 20 minutes, tr=8 minutes) to give the title compound (2.18 g, 8.69 mmol, 87% yield) as a pale yellow solid. ESI MS (M+H)+=249.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:13]([CH2:15][CH3:16])([CH3:14])[O:12][C:11]([CH2:18][CH3:19])([CH3:17])[C:10]2=[O:20])=[C:4]([CH2:21][CH3:22])[CH:3]=1.[OH:23]O.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3([C:10](=[O:20])[C:11]([CH2:18][CH3:19])([CH3:17])[O:12][C:13]3([CH2:15][CH3:16])[CH3:14])[O:23]2)=[C:4]([CH2:21][CH3:22])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C=C1C(=O)C(C)(CC)OC1(C)CC
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(Br)ccc1C1OC12C(=O)C(C)(CC)OC2(C)CC
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 71.5 %

Procedure:
To a solution of 4-[1-(4-bromo-2-ethylphenyl)methylidene]-2,5-diethyl-2,5-dimethyldihydrofuran-3-one (20 g, 0.055 mol) in methanol (800 ml) is added a solution of 50% aqueous hydrogen peroxide (9.58 ml, 0.165 mol) and a solution of 2N aqueous sodium hydroxide (10.98 ml, 0.02 mol) at ambient temperature. The reaction mixture is stirred at ambient temperature for 12-15 hours. The reaction mixture is quenched with a solution of saturated aqueous sodium metabisulfite, evaporated under reduced pressure to remove most of the solvent and extracted with dichloromethane (3×100 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure to give 2-(4-bromo-2-ethylphenyl)-4,6-diethyl-4,6-dimethyl-1,5-dioxaspiro[2.4]heptan-7-one (15 g), used without further purification in the next step.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([OH:11])#[C:8][CH2:9][CH3:10].C(NC(C)C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1(C)C=CC=CC=1.O.[Cu]I>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:10]#[C:9][CH2:8][CH2:7][OH:11]
Reactant: CCC#CO
Reactant: Brc1cccs1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: OCCC#Cc1cccs1
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a solution of 1.2 g of 2-bromothiophene and 0.9 g of butynol in 15 ml of degassed dioxane were added 100 mg of PdCl2(PheCN)2, 50 mg of CuI, 1 ml of diisopropyl amine, 750 μl of a 1M solution of tri-tert-butyl phosphine in toluene. The mixture was stirred under N2 atmosphere for 16 hr and then diluted with 50 ml of water and extracted with ethyl acetate. The organic layers were combined and washed with water, dried and concentrated. The residue was chromatographed using a gradient of heptane/ethyl acetate as eluent, to provide 850 mg of 1a; Rf (heptane/ethyl acetate 1/1) 0.50. NMR (CDCl3) δ 1.83 (t, 1, OH), 2.72 (t, 2, CH2), 3.83 (q, 2, CH2), 6.95, 7.16, 7.20 (3×m, 3, thiophene-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: NCc1ccccn1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCc3ccccn3)nc21
Temperature: 130 °C
Reaction time: 0.03 h
Yield: 38.7 %

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37, 1.08 g (10.0 mmol) of 2-(aminomethyl)pyridine and 0.5 mL of dimethylformamide was heated with stirring in a 130° C. oil bath. After 2 minutes, solution was complete. After 2 hours, the excess amine and dimethylformamide were evaporated at reduced pressure. Ether (5 mL) was added to the residue. Crystals immediately developed. Water (5 mL) was added, and the entire mixture was filtered. The cake was washed 5 mL of ether, 5 mL of water, and then dried; wt 0.164 g. Recrystallization from ethyl acetate gave 0.075 g of pure product; mp 198°-201° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([O:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C.Cl>O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:10]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Nc1nccs1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C(F)(F)F
Reaction time: 1.25 h
Yield: 23.1 %

Procedure:
Into a 250 ml three-necked flask equipped with magnetic stirrer, thermometer, dropping funnel and nitrogen inlet, 5.0 g (49.9 mmol) of 2-aminothiazol and 14.3 g (99.85 mmol) of ethyltrifluoroacetate in 100 ml of tetrahydrofuran are introduced. A solution of 14.4 g (124.8 mmol) of potassium-t-butylate in 50 ml of tetrahydrofuran is added dropwise within 15 minutes to the stirred brown solution, whose internal temperature is kept in the range 20-25° C. using an ice bath. Stirring is continued for another 75 minutes, then 300 ml of a buffer solution is added and pH 7 is adjusted by addition of 2N aq. HCl. Extraction with 300 ml of ethyl acetate is carried through 3 times, the combined organic phases are washed with 250 250 ml of water, dried over MgSO4, and filtered. After evaporating the solvent, the crude product is recrystallized from 2-propanol, yielding 2.26 g of the title product.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([C:18]1[N:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:21]=[C:20]([C:27]([NH2:29])=O)[CH:19]=1)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[CH2:14]([C:18]1[N:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:21]=[C:20]([C:27]#[N:29])[CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1cc(C(N)=O)nn1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCc1cc(C#N)nn1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A solution of trifluoroacetic anhydride (13.5 mL, 95.4 mmol) in dichloromethane (84 mL) was added over 15 minutes to a 0° C. solution of 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxamide (18.7 g, 86.7 mmol) and triethylamine (36.3 mL, 260 mmol) in dichloromethane (167 mL). The reaction was allowed to stir for 10 minutes before the ice bath was removed. The reaction was stirred at ambient temperature for 1 hour and then 2 M aqueous sodium carbonate was added. The mixture was transferred to a separatory funnel and was extracted with dichloromethane three times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, eluted with 20% ethyl acetate in hexanes). The appropriate fractions were combined, dried over magnesium sulfate, and concentrated under reduced pressure to yield 11.00 g of 5-butyl-1-tert-butyl-1H-pyrazole-3-carbonitrile as an orange oil.