Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:28][NH:29][C:30]([CH3:43])([CH3:42])[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)[CH2:3][N:4]([CH3:27])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]([O:24]CC)=[O:23])[CH:15]=1)(=[O:7])=[O:6].O.[OH-].[K+].Cl>O1CCCC1>[OH:1][C@H:2]([CH2:28][NH:29][C:30]([CH3:43])([CH3:42])[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)[CH2:3][N:4]([CH3:27])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])[CH:15]=1)(=[O:7])=[O:6]
Reactant: CCOC(=O)C=Cc1cccc(-c2ccccc2S(=O)(=O)N(C)C[C@H](O)CNC(C)(C)Cc2ccc3ccccc3c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccccc1-c1cccc(C=CC(=O)O)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Ethyl (R)-3-(2′-(N-(2-hydroxy-3-(2-methyl-1-(naphthalen-2-yl)propan-2-ylamino)propyl)-N-methylsulfamoyl)biphenyl-3-yl)acrylate synthesized from Example 3-1 Step A was dissolved in tetrahydrofuran (4 mL), water (1 mL) and potassium hydroxide (five granules) were added thereto followed by stirring at 50° C. for 1 day. The residue was neutralized with 2N hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Thus obtained residue was purified by HPLC to obtain the target compound (3.7 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:28])[NH:19][C:20]3[S:21][C:22]([C:25]([OH:27])=O)=[CH:23][N:24]=3)=[CH:12][C:11]=12.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([NH:19][C:20]3[S:21][C:22]([C:25]([NH:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])=[O:27])=[CH:23][N:24]=3)=[O:28])=[CH:12][C:11]=12
Reactant: O=C(NCc1ccn2ccnc2c1)Nc1ncc(C(=O)O)s1
Reactant: CC(C)CCN
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CCNC(=O)c1cnc(NC(=O)NCc2ccn3ccnc3c2)s1

Procedure:
The title compound was prepared as described in Example 1A, substituting 3-methylbutan-1-amine for 3-methylbutan-1-amine and 2-(3-(imidazo[1,2-a]pyridin-7-ylmethyl)ureido)thiazole-5-carboxylic acid for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.49 (d, J=7.8 Hz, 1H), 8.21 (t, J=5.9 Hz, 1H), 7.88-7.89 (m, J=1.4 Hz, 1H), 7.87 (s, 1H), 7.52 (d, J=1.4 Hz, 1H), 7.39 (s, 1H), 7.18 (t, J=5.8 Hz, 1H), 6.83 (dd, J=6.8, 1.7 Hz, 1H), 4.38 (d, J=6.1 Hz, 2H), 3.16-3.25 (m, 2H), 1.52-1.67 (m, 1H), 1.38 (q, J=6.9 Hz, 2H), 0.83-0.91 (m, 7H); MS (ESI(+)) m/e 387 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH3:19])[CH2:9][CH2:10][C:5]2=[C:4]([N:20]2[CH:24]=[CH:23][C:22]([N:25]3[S:29](=[O:31])(=[O:30])[N:28](C(OC)=O)[CH2:27][CH2:26]3)=[N:21]2)[CH:3]=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[O:31]=[S:29]1(=[O:30])[NH:28][CH2:27][CH2:26][N:25]1[C:22]1[CH:23]=[CH:24][N:20]([C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]3[N:8]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[CH3:19])[CH2:9][CH2:10][C:5]=23)[N:21]=1
Reactant: COC(=O)N1CCN(c2ccn(-c3cc(C)nc4c3CCN4c3ccc(OC)cc3C)n2)S1(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N2CCc3c(-n4ccc(N5CCNS5(=O)=O)n4)cc(C)nc32)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of example 5-1 (7.2 mg, 0.0144 mmol) in anh. MeOH (1 mL) and anh. CH2Cl2 (2 mL), at r.t., under N2, was added 25% NaOH (40 μL). The reaction mixture was stirred at r.t. for 30 min. It was then poured into sat.aq. NaHCO3 and CH2Cl2 was added. The phases were separated and the aqueous layer was further extracted with CH2Cl2 (2×10 mL). The combined organic extracts were dried over anh. Na2SO4, the solids were filtered and the solvent evaporated to give the title compound (6.4 mg, quantitative yield) as a white solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH3:31][N:32]([CH3:47])[C:33]1[CH:34]=[C:35]([C:39]2([OH:46])[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1>>[CH3:31][N:32]([CH3:47])[C:33]1[CH:34]=[C:35]([C:39]2([OH:46])[CH2:44][CH2:43][CH:42]([N:8]3[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=5)[N:18]([CH3:29])[N:17]=4)[CH2:11]3)[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CN(C)c1cccc(C2(O)CCC(=O)CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-(3-dimethylamino-phenyl)-4-hydroxy-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]1[CH:29]=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]1([O:34][C:35]2[CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:39][C:40]=2[O:41][CH:42]([F:44])[F:43])[CH2:33][CH2:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.O>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:37]2[CH:38]=[CH:39][C:40]([O:41][CH:42]([F:44])[F:43])=[C:35]([O:34][CH:31]3[CH2:32][CH2:33]3)[CH:36]=2)=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]1[CH:29]=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Reactant: CCOC(=O)c1c(Cc2ccccc2F)c(Br)n(COCc2ccccc2)c1C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Cc2ccccc2F)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To 4.04 g (8.52 mmol) of ethyl 1-benzyloxymethyl-5-bromo-4-(2-fluorobenzyl)-2-formyl-1H-pyrrol-3-carboxylate obtained in Reference example 36-(e) were added 3.62 g (11.1 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in Reference example 1-(a), 7.23 g (34.0 mmol) of potassium phosphate, 60 ml of toluene and 3.6 ml of water, the mixture was degassed under reduced pressure and replaced with argon. Further, 40 mg (0.178 mmol) of palladium acetate and 128 mg (0.356 mmol) of butyl-di-1-adamantylphosphine were added to the mixture, and the mixture was stirred at 100° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=19:1→9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 5.01 g of the title compound as a yellowish oil substantially quantitatively.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+].FC(F)(F)C(O)=O>CO>[CH2:25]([NH:24][C:22]([NH:21][C:17]1[CH:16]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])[C:3]([OH:43])=[O:2])=[O:8])[CH2:14][CH2:13]2)[CH:20]=[CH:19][CH:18]=1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H](CNC(=O)C1CCN(c2cccc(NC(=O)NCc3ccccc3)c2)CC1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NCc1ccccc1)Nc1cccc(N2CCC(C(=O)NC[C@H](NC(=O)OCc3ccccc3)C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 29 in methanol (10 ml) is added 2M aqueous sodium hydroxide solution (10 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is neutralized with trifluoroacetic acid, purified by CHP-20 (eluent: gradient, 35% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([NH:28][C@@H:29]([C:31](O)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:18]([NH:28][C@@H:29]([C:31]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@@H](C)NC(=O)OCc1ccccc1)C2
Yield: 98.1 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.3 g, 10 mmol) was dissolved in dimethylformamide (100 ml) while cooled on ice. To the obtained mixture, carbobenzyloxy-D-alanine (2.3 g, 10.5 mmol), WSC.HCl (2.3 g, 11.0 mmol), and HOBT (1.4 g, 11.0 mmol) were added, and the resultant mixture was stirred at room temperature for two days. The reaction mixture was condensed under reduced pressure. The obtained residue was extracted with chloroform, washed with 1N-HCl, saturated aqueous NaCl solution, and dried over magnesium sulfate anhydride. The solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol=15:1) to obtain 4.27 g of the title compound as colorless powdery crystals (98.0%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:60]=[CH:59][C:51]([CH2:52][NH:53][CH2:54][CH2:55][CH2:56][CH:57]=[CH2:58])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][N:53]([CH2:54][CH2:55][CH2:56][CH:57]=[CH2:58])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:59][CH:60]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: C=CCCCNCc1ccc(C(C)(C)C)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 69 mg (0.3 mmol) of (4-tert-butyl-benzyl)-pent-4-enyl-amine in 1 ml DMF was added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (8 g silica gel; heptane/EtOAc 6:1) to give 62 mg (53%) of a light yellow viscous oil. MS (ISP) 375.5 (M+H)+.
Reaction SMILES: [Zn](CC)[CH2:2][CH3:3].[CH3:6][C:7](=[CH:10][CH2:11][CH3:12])[CH:8]=[O:9]>>[CH3:6][C:7](=[CH:10][CH2:11][CH3:12])[C@@H:8]([OH:9])[CH2:2][CH3:3]
Reactant: CCC=C(C)C=O
Reactant: CC[Zn]CC
Product: CCC=C(C)[C@@H](O)CC
Yield: 73 %

Procedure:
The product was prepared by General procedure L using 1.0 mL (2.0 mmol, 2.0 M in hexanes) Et2Zn, 9.6 mg (0.04 mmol) (−)-MIB, and 114 μL (1.0 mmol) 2-methyl-2-pentenal. The crude product was purified by column chromatography on silica (10% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 73% yield (93 mg, 0.73 mmol). [α]D20=−5.8 (c=0.73, CHCl3, 95% ee); 1H NMR (CDCl3, 500 MHz) δ 0.77 (t, 3H, J=7.4 Hz), 0.89 (t, 3H, J=7.5 Hz), 1.45-1.49 (m, 2H), 1.51 (s, 3H), 1.61 (br s, 1H), 1.96 (q, 2H, J=7.4 Hz), 3.81 (t, 1H, J=6.7 Hz), and 5.29 (t, 1H, J=6.9 Hz) ppm; 13C {1H} NMR (CDCl3, 125 MHz) δ.10.0, 10.8, 14.0, 20.7, 27.6, 79.4, 128.6, and 136.1 ppm; IR (neat) 3360, 2962, 2932, 2875, 2348, 1722, 1670, 1461, 1376, 1335, 1308, 1261, 1097, 1054, and 1008 cm−1; HRMS-CI m/z 128.1206 [M+; calcd for C8H16O: 128.1201].
Reaction SMILES: Br[C:2]1[C:3]([NH2:22])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.[CH3:23][CH2:24][C:25]#[C:26][CH2:27][CH3:28].[Cl-].[Li+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:24]([C:25]1[NH:22][C:3]2=[N:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[N:7]=[C:2]2[C:26]=1[CH2:27][CH3:28])[CH3:23]
Reactant: CCC#CCC
Reactant: Cc1ccc(-c2nc(N)c(Br)nc2-c2ccc(C)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1[nH]c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1CC
Temperature: 120 °C

Procedure:
A solution of 3-bromo-5,6-di-p-tolylpyrazin-2-amine (Ex 1, step 3) (20 mg, 0.056 mmol) in DMF (1 ml) bubbled with nitrogen was treated with hex-3-yne (0.013 ml, 0.113 mmol), palladium acetate (0.634 mg, 2.82 μmol), lithium chloride (2.393 mg, 0.056 mmol) and K2CO3 (39.0 mg, 0.282 mmol). The resulting mixture was heated at 120° C. for 30 min using microwave radiation. In parallel, a separate identical reaction mixture was prepared and heated thermally at 120° C. for 1 hour. After cooling to RT, the two reaction mixtures were combined in water (50 ml). The aqueous was extracted with EtOAc (×3). The combined organic extracts were washed sequentially with water (×1) and brine (×1), dried (MgSO4), filtered and concentrated under reduced pressure. Purification of the crude product by chromatography on silica eluting with 0-10% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[N:10]1[CH:20]=[C:13]2[C:14](Br)=[N:15][CH:16]=[C:17]([Br:18])[C:12]2=[N:11]1)[C:5]#[N:6].[CH3:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[Br:18][C:17]1[C:12]2[C:13](=[CH:20][N:10]([C:9]3[C:2]([Cl:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=3[Cl:21])[N:11]=2)[C:14]([NH:29][C:25]2[CH:24]=[C:23]([CH3:22])[N:28]=[CH:27][N:26]=2)=[N:15][CH:16]=1
Reactant: Cc1cc(N)ncn1
Reactant: N#Cc1cc(Cl)c(-n2cc3c(Br)ncc(Br)c3n2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncc(Br)c3nn(-c4c(Cl)cc(C#N)cc4Cl)cc23)ncn1
Temperature: 90 °C
Yield: 55.2 %

Procedure:
A suspension of 3,5-dichloro-4-(4,7-dibromo-pyrazolo[4,3-c]pyridin-2-yl)-benzonitrile (70 mg, 0.16 mmol), 6-methylpyrimidin-4-ylamine (18 mg, 0.17 mmol), Pd2(dba)3 (7 mg, 0.008 mmol), Xantphos (9 mg, 0.016 mmol) and cesium carbonate (104 mg, 0.31 mmol) in dioxane (3 mL) was sealed in a microwave vial, purged with nitrogen, and heated at 90° C. for 3.5 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane), then futher triturated with diethyl ether then ethyl acetate to afford the title compound as a white solid (42 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 9.35 (s, 1H), 8.71 (d, J=1.2 Hz, 1H), 8.50 (s, 2H), 8.37 (s, 1H), 8.17 (s, 1H), 2.45 (s, 3H). LCMS (Method B): RT=3.75 min, m/z: 476 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:15]([NH2:19])(=[O:18])[CH:16]=[CH2:17]>C(O)C>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:17][CH2:16][C:15]([NH2:19])=[O:18])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(N)=O
Solvent: CCO
Product: CC1=C2CCN(CCC(N)=O)CC2c2ccccc21

Procedure:
A mixture of 18.5 g of 1,3,4,9b-tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and 7.1 g of acrylamide in 250 cc of ethanol is boiled at reflux for 6 hours. The reaction mixture is evaporated to dryness, and the resulting title compound is recrystallized from ethanol. M.P. 169°-170°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]([CH3:21])([CH2:19][CH3:20])[C:9]([O:11]CC1C=CC=CC=1)=[O:10]>[Pd].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]([CH3:21])([CH2:19][CH3:20])[C:9]([OH:11])=[O:10]
Reactant: CCC(C)(Oc1ccccn1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(C)(Oc1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl 2-(2-pyridyloxy)-2-methylbutanoate (1.6 g, 5.5 mmol) and 10% palladium on carbon (50 mg) in 50 mL MeOH was degassed and filled with hydrogen using a balloon. After stirring at room temperature overnight, the reaction mixture was filtered through CELITE diatomaceous earth and washed with MeOH (20 mL), and the filtrate was concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.03 (dd, 1H), 7.64 (ddd, 1H), 6.89 (dd, 1H), 6.76 (dd, 1H), 2.14 (m, 1H), 1.94 (m, 1H), 1.64 (s, 3H), 0.99 (t, 3H). LC-MS: m/e 196 (M+H)+ (1.8 min).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].Br[C:9]1[C:10]([CH:27]([CH3:29])[CH3:28])=[N:11][N:12]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>CN(C=O)C.CCN(CC)CC.CCOCC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:11]=[C:10]([CH:27]([CH3:29])[CH3:28])[CH:9]=2)=[CH:15][CH:16]=1.[C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(C)c1nn(-c2ncccn2)c(-c2ccc(F)cc2)c1Br
Agent: Cl[Pd]Cl
Agent: C=CC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ncccn2)n1
Temperature: 25 °C

Procedure:
Ethyl acrylate (16.2 ml, 0.15 mol) and bis-(triphenylphosphine) palladium (II) chloride (0.84 g, 0.0012 mol) in DMF (75 ml) and Et3N (75 ml) was heated together at reflux under N2 with stirring until a homogeneous solution resulted. 2-[4-Bromo-5-(4-fluorophenyl))-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine (3) (10.8 g, 0.03 mol) was added and the resulting solution was heated at reflux for 24 hours, during which, an additional 1 mol % of catalyst was added. The mixture was then cooled to room temperature and diluted with ether and water. The organic layer was separated and washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting solid (10.4 g) was recrystallized from hexane/ethyl acetate, mp 155°-162° C.
Reaction SMILES: [CH3:1][C:2]([N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)([C:4]#[CH:5])[CH3:3].N1C2C(=CC=CC=2)C=CC=1>[Pd].C1C=CC=CC=1>[CH3:3][C:2]([N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH:4]=[CH2:5])[CH3:1]
Reactant: C#CC(C)(C)n1c2ccccc2c2ccccc21
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: c1ccccc1
Product: C=CC(C)(C)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A mixture of 9-(2-methylbut-3-yn-2-yl)-9H-carbazole (1.600 g, 6.9 mmol), quinoline (0.810 mL, 6.9 mmol), benzene (70.0 mL) and 5% palladium on barium sulfate (0.190 g) was stirred under an atmosphere of hydrogen at room temperature. Once the desired amount of hydrogen was consumed (−45 mins), the reaction was stopped and filtered through Celite and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% methylene chloride/hexanes) to afford the desired product as a colorless oil (1.55 g, 96%). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 2H, J=7.5 Hz), 7.81 (d, 2H, J=8.4 Hz), 7.35 (t, 2H, J=8.1 Hz), 7.21 (t, 2H, J=7.5 Hz), 6.41 (dd, 1H, J=17.7, 10.5 Hz), 5.32-5.20 (m, 2H), 2.06 (s, 6H).
Reaction SMILES: Cl[Sn]Cl.[Cl:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[C:8]([N+:13]([O-])=O)=[CH:7][CH:6]=1.CC[OH:18]>>[NH2:13][C:8]1[C:9]([C:11]([NH2:12])=[O:18])=[N:10][C:5]([Cl:4])=[CH:6][CH:7]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl[Sn]Cl
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 90 °C
Yield: 96 %

Procedure:
SnCl2 (27.5 g, 122 mmol) was added to a suspension of 6-chloro-3-nitropicolinonitrile (5.60 g, 30.5 mmol) in EtOH (40 mL) at room temperature. The reaction mixture was heated at 90° C. for 2 h. After cooled to room temperature, the solvent was removed under reduced pressure, EtOAc was poured into the residue. The mixture was neutralized with aq. Na2HCO3 and aq. NaOH until pH ˜9, filtered through a Celite pad. The filtrate was extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo to give 3-amino-6-chloropicolinamide (5.00 g, 96%) as a yellow solid which was used for the next step without further purification. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 7.01 (2H, brs), 7.22 (1H, d, J=8.8 Hz), 7.30 (1H, d, J=8.8 Hz), 7.42 (1H, brs), 7.71 (1H, brs). m/z=171.98 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[S:26])[CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][C:17]#[C:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[K+].O1CCCCC1OC1CCCCO1.C(O)(=O)C(O)=O>C(OCC)(=O)C>[C:20]1([CH2:19][C:18]#[C:17][CH2:16][C:15]#[C:14][CH2:13][C:12]#[C:11][CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[S:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=S)CCCC#CCC#CCC#CCC#CCc1ccccc1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: O=C(O)C(=O)O
Agent: O=P([O-])(O)O
Solvent: CCOC(C)=O
Product: OC(=S)CCCC#CCC#CCC#CCC#CCc1ccccc1

Procedure:
A mixture of 1.7 g of 16-phenylthiohexadeca-5,8,11,14-tetraynoic acid ethyl ester, 184 ml of the pH 6.7 buffer solution of disodium hydrogen phosphate/potassium dihydrogen phosphate, prepared as in Example 1 and 17.5 g of Sigma Lipase, Type VII, from Candida cylindracea was sonicated for 5 hours at room temperature. The reaction mixture was then transferredto a separatory funnel with ethyl acetate (200 ml) and acidified with saturated solution of oxalic acid. The organic phase was separated and combined with ethyl acetate extracts of the aqueous phase. The ethyl acetate was dried over sodium sulfate and removed under vacuo. The residuewas purified by TLC on silica gel using a Chromatotron using hexane:ethyl acetate:acetic acid (60:40:1) as the eluant. The crude product was crystallized from methylene chloride-hexane, to yield 16-phenylthiohexadeca-5,8,11,14-tetraynoic acid. M.P. 69°-71° C. (dec), which was stored in dry ice.