Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>[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.C1COCC1>[CH3:25][O:24][C:19]1[C:18]([NH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([C:37]#[C:36][C:34]([CH3:35])([OH:38])[CH3:33])[CH:10]=4)[CH:6]=[N:7]3)[CH:12]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COc1ncccc1Nc1cc(-n2ncc3ccc(I)cc32)ncn1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ncccc1Nc1cc(-n2ncc3ccc(C#CC(C)(C)O)cc32)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pressure tube was added 6-(6-iodoindazol-1-yl)-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine (120 mg, 0.27 mmol) followed by triethylamine (2 mL) and THF (2 mL). Next, copper(I) iodide (5.15 mg, 0.027 mmol), bis(triphenylphosphine)palladium(II) chloride (18.96 mg, 0.027 mmol) and 2-methylbut-3-yn-2-ol (0.05 ml, 0.54 mmol) were added and the reaction vessel was sealed and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and DCM (5 ml) was added. The organics were washed with 0.5M HCl (2×3 ml), water (3 ml) and brine (3 ml), and dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute column, 4:6 to 1:1 EtOAc:heptanes) to surrender the title compound as a white solid: 1H NMR (500 MHz, CDCl3) delta 1.69 (6H, s), 2.08 (1H, br. s.), 4.07 (3H, s), 6.99 (1H, dd, J=7.80, 4.97 Hz), 7.32-7.41 (2H, m), 7.69 (1H, d, J=8.20 Hz), 7.88 (1H, dd, J=4.97, 1.66 Hz), 8.19 (1H, s), 8.54-8.61 (1H, m), 8.77 (1H, s), 8.99 (1H, s); LC-MS: m/z=+401.10 (M+H)+.
Reaction SMILES: CCCCC[C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/C=C\CCCC(O)=O)[C@@H](O)C[C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C.C([N:36](CC)CC)C>>[OH:25][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH2:36])=[O:24])=[CH:13][CH:14]=1
Reactant: CCN(CC)CC
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Product: NC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2 α , 0.347 ml. of triethylamine, 0.326 ml. of isobutylchloroformate, and 0.433 g. of p-hydroxybenzamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-acetone (3:7). The residue obtained by concentration of selected fractions, 0.455 g., is crystallized from acetone diluted with an equal volume of acetonitrile as the title compound, white, free-flowing crystals, m.p. 129.5°-130.8° C., having Rf 0.32 (TLC on silica gel in ethyl acetate-acetone (3:7).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23](=[O:38])[CH2:24][NH:25][CH2:26][C:27]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:12]>C(OCC)(=O)C>[CH3:12][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:20])[CH3:21])[C:14]=1[NH:22][C:23](=[O:38])[CH2:24][N:25]([C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9])[CH2:26][C:27]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:10]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Reactant: S=C=Nc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(CC1(c2ccccc2)CCCC1)C(=S)Nc1ccccc1
Reaction time: 96 h

Procedure:
Phenylisothiocyanate (0.103 g) was added to the product of Example 6 in a few mL ethyl acetate at room temperature. This mixture was allowed to sit 4 days at room temperature, concentrated, and the resulting solid collected by filtration from a slurry in hexane. 0.31 g (84%). NMR (CDCl3) δ 1.21 (12H, d), δ 1.74-2.14 (8H, m), δ 3.08 (2H, m), δ 3.89 (2H, s), δ 4.92 (2H, bs), δ 618 (1H, s), δ 6.67 (2H, d), δ 7.06-7.51 (11H, m), δ 8.88 (1H, s). IR (KBr) 2963, 2871, 1668, 1600, 1518, 1499, 1350, 1204, 703 cm-1.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[O:16]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][OH:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7]([O:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:24]=2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: OCc1cccc(Oc2ccccc2)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1.8 g (0.007 mole) of trans-3-[2-chloro-3,3,3-trifluoropropenyl]-2,2-dimethylcyclopropanecarbonyl chloride in 10 ml of methylene chloride at ambient temperature was added a solution of 1.6 g (0.008 mole) of 3-phenoxybenzyl alcohol and 0.73 g (0.009 mole) of pyridine in 5 ml of methylene chloride. Upon complete addition the reaction mixture was stirred at ambient temperature for 3 hours, then poured into 50 ml of water. The organic layer was separated, and the aqueous layer was extracted with three portions of 50 ml each of methylene chloride. The combined extracts were dried with sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to a residual oil. Volatile components were removed from the oil at 125° C./0.05 mm using a Kugelrohr distillation system. The pot residue was 99% 3-phenoxybenzyl trans-3-[2-chloro-3,3,3-trifluoropropenyl]-2,2-dimethylcyclopropanecarboxylate, as determined by gas chromatographic analysis. The weight of product was 2.0 g. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[CH3:15]>N1CCCCC1.C(O)C>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:11][C:8]4[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=4[CH3:13])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[CH3:15]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(CCC(=O)O)c2C)c1
Yield: 96.1 %

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 127 mg 6-(3-ethoxyphenyl)-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 200 mg (96%) of the title compound as a brown solid.
Reaction SMILES: B.[Na].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[S:13][C:14]([CH:17]=[O:18])=[CH:15][N:16]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[S:13][C:14]([CH2:17][OH:18])=[CH:15][N:16]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCc1ncc(C=O)s1
Agent: B
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ncc(CO)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A 330 mg potion of sodium boron hydride was added to 25 ml of a methanol solution containing 4.12 g of 2-(N-t-butoxycarbonylamino)methyl-5-formylthiazole under ice-cooling, and the mixture was then stirred at room temperature for 1 hour. Under reduced pressure, the solvent was distilled off, and water was added to the resulting residue, followed by extraction with ethyl acetate (80 ml×3). The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to obtain 2.17 g of 2-(N-t-butoxycarbonylamino)methyl-5-hydroxymethylthiazole.
Reaction SMILES: C(C(=COCC)C(NC(OCC)=O)=O)#N.ClC1C=C(C=CC=1Cl)N.C(O)C.[C:28]([C:30](=[CH:39][NH:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=1)[C:31]([NH:33][C:34](OCC)=[O:35])=[O:32])#[N:29]>C1C2C(=CC=CC=2)CCC1>[C:28]([C:30]1[C:31](=[O:32])[NH:33][C:34](=[O:35])[N:40]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=2)[CH:39]=1)#[N:29]
Reactant: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(Cl)c(Cl)c1
Agent: CCOC=C(C#N)C(=O)NC(=O)OCC
Agent: Nc1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: c1ccc2c(c1)CCCC2
Product: N#Cc1cn(-c2ccc(Cl)c(Cl)c2)c(=O)[nH]c1=O

Procedure:
A mixture of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.047 mol), 3,4-dichloroaniline (8.15 g) and ethanol (70 ml) is heated to prepare α-cyano-β-(3,4-dichloroanilino)-N-ethoxycarbonylacrylamide, which is cyclized by heating overnight in tetralin to yield 5-cyano-1-(3,4-dichlorophenyl)uracil, m.p. 206.5°-207.5°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1)[CH3:2].[H-].[Na+].[CH3:23][NH:24][C:25](=O)[O:26]C1C=CC=CC=1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:20][C:16]1[CH:15]=[C:14]([O:13][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:4]=2[O:3][CH2:1][CH3:2])[N:10]([C:25]([NH:24][CH3:23])=[O:26])[CH:9]=[CH:8]3)[CH:19]=[CH:18][N:17]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: CCOc1cc2[nH]ccc2cc1Oc1ccnc(N)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc2c(ccn2C(=O)NC)cc1Oc1ccnc(N)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 54 %

Procedure:
4-((6-Ethoxy-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 15-6 (6.44 g, 23.9 mmol) was dissolved in N,N-dimethylformamide (80 mL), 50-72% oily sodium hydride (1.41 g) was added under nitrogen atmosphere at 0° C., and the mixture was stirred at mom temperature for 40 minutes. The mixture was cooled to 0° C. again, phenyl methylcarbamate described in Production Example 1-7 (5.78 g, 38.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture for partition. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water twice and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, then the filtrate was concentrated under vacuum. A liquid mixture of diethyl ether and ethyl acetate was added to the residue, then the precipitate was collected by filteration and the resultant was washed with ethyl acetate again to obtain the title compound (4.24 g, 54%). The filtrate was purified with NH silica gel column chromatography (ethyl acetate:methanol=1:0-9:1), the target fraction was concentrated under vacuum, and then the residue was collected by filteration and washed with a liquid mixture of diethyl ether and ethyl acetate to obtain the title compound (1.58 g, 20%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[NH:50])[NH2:49])=[CH:44][C:43]=1[O:51][CH3:52])(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:42]2[CH:47]=[CH:46][C:45]([C:48](=[NH:49])[NH2:50])=[CH:44][C:43]=2[O:51][CH3:52])=[O:18])=[CH:20][CH:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: COc1cc(C(=N)N)ccc1OS(C)(=O)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 3.7 g of 4-benzyloxycarbonylaminomethylbenzoic acid in 40 ml of dried pyridine, was added 3.1 g of DCC with cooling in ice. The mixture was stirred for 30 minutes. After addition of 3.1 g of 4-amidino-2-methoxyphenol methanesulfonate, the mixture was further stirred overnight at room temperature. The reaction mixture was removed of the insolubles and mixed with ethyl ether to precipitate a colorless solid substance which on recrystallization from a methanol-ethyl ether mixture gave 3.2 g of colorless crystals of 4-amidino-2-methoxyphenyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:58](O)=[O:59])[CH2:56][OH:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl>[C:44]([NH:54][C@H:55]([C:56]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:57])[CH2:58][OH:59])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Yield: 76 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-serine. Yield 76%. [α]D =+20.3° (c=0.89, dichloromethane). m.p. 87-89°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.NC1N=CC(S(N2CCN(C3C=CC([C@](O)(C)C(F)(F)F)=CC=3)CC2)(=O)=O)=CC=1.CCCN(C(NC(C1C=C(OC)C(OC)=C(OC)C=1)=O)=S)CCC>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(N)nc3)CC2)cc1)C(F)(F)F
Agent: CCCN(CCC)C(=S)NC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(N)nc3)CC2)cc1)C(F)(F)F
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(N)nc3)CC2)cc1)C(F)(F)F

Procedure:
(2S)-2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol and (2R)-2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1H NMR (400 MHz, CD3OD) δ=8.30 (d, J=2.2 Hz, 1H), 7.74 (dd, J=2.4, 8.9 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 6.64 (d, J=9.0 Hz, 1H), 3.30-3.24 (m, 4H), 3.18-3.08 (m, 4H), 1.68 (s, 3H). m/z (ESI, +ve ion) 431.1 (M+H)+. GK-GKRP IC50 (Binding)=0.359 μM; GK-GKRP EC50 (LC MS/MS-2)=0.605 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:20]([OH:21])=[C:19]([C:22]([OH:24])=[O:23])[C:18]3[C:9](=[C:10]4[C:15](=[CH:16][CH:17]=3)[CH2:14][CH2:13][NH:12][CH2:11]4)[N:8]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(N(CC)CC)C.[O:38]([C:40]#[N:41])[K].N1C=CC=CC=1>>[C:40]([N:12]1[CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[C:18]3[C:9]=2[N:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=2)[C:20]([OH:21])=[C:19]3[C:22]([OH:24])=[O:23])[CH2:14][CH2:13]1)(=[O:38])[NH2:41]
Reactant: N#CO[K]
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c3c(ccc12)CCNC3
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: NC(=O)N1CCc2ccc3c(C(=O)O)c(O)c(Cc4ccc(Cl)cc4)nc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of 2-(4-Chloro-benzyl)-3-hydroxy-7,8,9,10-tetrahydro-(1,9]phenanthroline-4-carboxylic acid (0.213 g, 0.53 mmol), acetic acid (0.6 mL, 5.3 mmol), triethylamine (0.146 mL, 1.06 mmol), KOCN (43 mg, 0.53 mmol), and pyridine (0.84 mL, 5.3 mmol) was stirred at 25° C. overnight. The solid was removed by filtration. HPLC of the mother liquor gave pure product (49.1 mg, 22%) as a beige solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.25 (m, 2H), 3.68 (m, 2H), 4.34 (s, 2H), 4.63 (s, 2H), 7.22-7.45 (m, 5H), 8.47 (d, J=9.09 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=O.CCN(C(C)C)C(C)C.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][N:35]([C:12]([C:3]3[S:4][C:5]4[N:6]=[CH:7][NH:8][C:9](=[O:11])[C:10]=4[C:2]=3[CH3:1])=[O:14])[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(C(=O)O)sc2nc[nH]c(=O)c12
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCN(c3cccc(Cl)c3)CC2)sc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (2 g, 9.5 mmol) in DMF (20 mL) was added DIEA (5 mL, 28.5 mmol), 1-(3-chlorophenyl)piperazine hydrochloride (2.2 g, 9.5 mmol), and HATU (4.7 g, 12.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (60 mL) and the organic layer was washed successively with sat. NaHCO3 aq. (50 mL) and brine (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated to give crude product as a gummy solid. Purification by flash column chromatography using EtOAc as the eluent afforded the 3 g of pure 6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one, (yield: 81%).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:34][C:35](OC(C)=O)=[O:36]>CCO.Cl[Ni]Cl>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:25]=[CH:26][C:27]([CH2:28][NH:29][C:35](=[O:36])[CH3:34])=[CH:30][CH:31]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reaction time: 2 h
Yield: 52 %

Procedure:
In a 100 ml, round-bottom flask equipped with a stir bar, 6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-nicotinonitrile (150 mg, 0.362 mmol) is dissolved in anhydrous EtOH (7 mL) followed by the addition of NiCl2 (0.398 mmol). NaBH4 (0.723 mmol) is added in portions and the reaction is stirred for 2 h under a N2 atmosphere. The septum is removed and Ac2O (1.08 mmol) is added. The reaction is capped again and stirred for one additional hour. LC/MS shows full conversion to the acylated product. The reaction is filtered through a Celite pad and rinsed with 50 ml of MeOH. The final compound is purified by preparative HPLC using a C-18 column and propanol as the modifier (85 mg, 52% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=S)=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31].C(Cl)CCl>CC#N>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[NH:18][C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=4)=[N:19][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(N)c2)ccn1
Solvent: CC#N
Solvent: ClCCCl
Product: CNC(=O)c1cc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(3,4-diamino-phenoxy)-pyridine-2-carboxylic acid methylamide (Step B) (0.07 g, 0.27 mmol) in 20 mL CH3CN was added dropwise, over 5 min, a solution 1-chloro-4-isothiocyanato-2-trifluoromethyl-benzene (0.055 g, 0.27 mmol) in 10 mL CH3CN. The reaction was stirred 18 h at RT. The reaction was diluted with 10 mL CH3CN, then EDC (0.078 g, 0.41 mmol) was added. The reaction was heated at 80° C. for 3 h. The reaction was cooled to RT and concentrated in vacuo. The crude mix was dissolved in EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a hexane-EtOAc gradient to yield the title compound. MS (MH+)=461.9; MW Calc'd 461.09 for C21H15ClF3N5O2.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])C.CO[C:29](=O)[CH2:30][C:31]1C=CC(I)=[CH:33][CH:32]=1>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>[CH2:1]([O:4][C:5]1([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:7][CH2:6]1)[C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-7% EtOAc-hexanes) afforded 64.0 mg (81%) of the title compound as a yellow oil.