Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][CH3:15])[N:13]=1)(C)(C)C.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH:22][C:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=3)=[O:33])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][CH3:15])[N:13]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC[C@@]1(c2cc(N)ccc2F)CCOC(NC(=O)OC(C)(C)C)=N1
Product: CC[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-ethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F2 (R3=Et) and 5-chloro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7]CN.[CH3:11][N:12](CCCN)[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:32])[CH:27]=3)[NH:22][C:21]=2[C:20]([N+:33]([O-:35])=[O:34])=[CH:19][CH:18]=1.NCCN1CCN(CCN)CC1.NCCN1CCN(CCNC2C3C(=O)C4C(=CC=C(F)C=4)NC=3C([N+]([O-])=O)=CC=2)CC1>>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:11][N:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17]2[C:30]3[C:29](=[O:31])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:32])[CH:27]=4)[NH:22][C:21]=3[C:20]([N+:33]([O-:35])=[O:34])=[CH:19][CH:18]=2)[CH2:7][CH2:6]1
Reactant: CN(CCCN)CCCNc1ccc([N+](=O)[O-])c2[nH]c3ccc(F)cc3c(=O)c12
Reactant: CN(CCCN)CCCN
Agent: NCCN1CCN(CCN)CC1
Agent: NCCN1CCN(CCNc2ccc([N+](=O)[O-])c3[nH]c4ccc(F)cc4c(=O)c23)CC1
Product: NCCCN1CCN(CCCNc2ccc([N+](=O)[O-])c3[nH]c4ccc(F)cc4c(=O)c23)CC1

Procedure:
Beginning with N,N-bis(3 -aminopropyl)methylamine, 1-{3-[methyl(3-aminopropyl)amino]propyl}amino-7-fluoro-4-nitro-10H-acridin-9-one (compound 2c) is prepared by the above method. By the same method, but beginning with 1,4-bis(2-aminoethyl)piperazine, it is possible to prepare 1-{2-[4-(2-aminoethyl)piperazin-1-yl]ethyl}amino-7-fluoro-4-nitro-10H-acridin-9-one.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCCCCCC>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:7][CH:8]=1
Reactant: OCCCc1ccc(C(F)(F)F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=CCCc1ccc(C(F)(F)F)cc1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
In an inert atmosphere, 3-(4-trifluoromethyl-phenyl)-propan-1-ol (1.02 g, 5 mmol) was dissolved in DCM (10 ml) and slowly added to a suspension of PCC (1.61 g, 7.5 mmol) in anhydrous DCM (15 ml). Stirring was continued for 4 h at rt. Anhydrous heptane (10 ml) was added to the reaction mixture followed by filtration over a pad of silicagel (15 g). The filtrate was evaporated to give 850 mg of 3-(4-trifluoromethyl-phenyl)-propionaldehyde. LC-MS: tR=0.94 min; [M+H]+=no ionisation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:11][C:10]([C:33]([C:39]([F:42])([F:41])[F:40])([C:35]([F:38])([F:37])[F:36])[OH:34])=[N:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:33]([C:35]([F:37])([F:36])[F:38])([C:39]([F:41])([F:42])[F:40])[OH:34])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 148 %

Procedure:
1-(2-Chloro-phenyl)-5-[4-(4-BOC-homopiperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (350.0 mg, 0.8 mmol) prepared in Example 321 was added to a saturated solution of hydrochloric acid in ethyl acetate (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 330.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: O1CCCC1.C([Sn](CCCC)(CCCC)[C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[CH:12]=1)CCC.[I:39]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[I:39][C:11]1[O:15][N:14]=[C:13]([CH2:16][C:17]2[CH:30]=[CH:29][C:20]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[CH:12]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Ic1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
To a tetrahydrofuran solution (15 mL) of 2-(4-(5-tributylstannyl-isoxazol-3-ylmethyl)-benzyloxy)-pyridine (5.1 g) described in Manufacturing Example 2-8-1 was added iodine (2.5 g) at 0° C. This mixture was stirred at that temperature for 20 minutes. To the mixture were then added 10% sodium thiosulfate aqueous solution and ethyl acetate. The organic layer was isolated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1 to 4:1) to obtain the title compound (2.4 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](O)=O.[CH3:10][NH:11][C:12](=[S:15])[NH:13][NH2:14].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[CH3:10][N:11]1[C:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[CH3:1])=[N:14][NH:13][C:12]1=[S:15]
Reactant: Cc1ncoc1C(=O)O
Reactant: CNC(=S)NN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ncoc1-c1n[nH]c(=S)n1C
Temperature: 20 °C
Reaction time: 6 h

Procedure:
4-Methyl-1,3-oxazole-5-carboxylic acid (commercially available) (12.9 g, 101.5 mmol) was dissolved in DMF (60 mL) and treated with 4-methyl-3-thiosemicarbazide (11.61 g, 1.10 eq). Then DIPEA (31.0 mL, 1.75 eq) was added at 20° C. Under ice bath cooling, T3P 50% w/w in EtOAc (90 mL) was added dropwise, maintaining the temperature below 15° C. over 20 minutes. The resulting mixture was then stirred at 20° C. for 6 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O1CCCC1>[CH2:23]([NH:31][C:6]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=1)=[O:8])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCCc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
A solution of 10 g of 6-chloro-nicotinic acid in 80 ml of N,N-dimethylformamide and 160 ml of tetrahydrofuran was treated with 10.75 g of 1,1'-carbonyldiimidazole and stirred at room temperature for 4 h. Thereafter, the reaction mixture was treated with 8.76 g of phenethylamine and stirred at 70° C. for a further 2 h. The mixture was cooled to room temperature, evaporated to dryness and the residue was taken up in 200 ml of dichloromethane. The organic phase was washed three times with 50 ml of water each time, dried over sodium sulfate and evaporated to dryness. Recrystallization of the residue from isopropanol yielded 11.9 g of 6-chloro-pyridine-3-carboxylic acid phenethyl-amide as a colorless product, m.p. 115° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]=1[N:10]([C:35]([C@H:32]1[CH2:33][CH2:34][C@H:29]([CH3:28])[CH2:30][CH2:31]1)=[O:36])[CH:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2cncn2)CC1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2cncn2)CC1

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester (0.27 g, 0.70 mmol) is acylated with trans-4-methylcyclohexyl carboxylic acid chloride as previously described to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,4]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([Cl:19])[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:19][C:16]1[C:15]2[O:14][C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([F:20])[C:8]=3[C:7](=[O:21])[C:6]=2[CH:5]=[C:4]2[CH2:1][CH:2]([C:37]([OH:38])=[O:40])[O:18][C:17]=12
Reactant: C=CCc1cc2c(=O)c3c(F)cccc3oc2c(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1Cc2cc3c(=O)c4c(F)cccc4oc3c(Cl)c2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.5 %

Procedure:
A mixture of 2-allyl-4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene (2.8 g), m-chloroperbenzoic acid (4.7 g) and chloroform (100 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (10 g) and water (200 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (500 ml) and, to the stirred solution, a mixture of chromium trioxide (2.8 g), water (16 ml) and concentrated sulfuric acid (4.8 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.0 g of 11-chloro-6-fluoro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 300° C. This compound showed a mass spectrum having a molecular ion peak at m/e 334.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]#[C:16][CH2:17][OH:18])[C:9](=[O:13])[O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CC[O:25]CC>C(#N)C.O.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH2:1]([N:8]([CH2:14][CH2:15][C:16](=[O:25])[CH2:17][OH:18])[C:9](=[O:13])[O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CCOC(=O)N(CC#CCO)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Hg+2]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N(CCC(=O)CO)Cc1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl benzyl(4-hydroxybut-2-ynyl)carbamate (0.05 g, 0.202 mmol), mercury(II) acetate (6.44 mg, 0.020 mmol) and boron trifluoride etherate (5.12 μl, 0.040 mmol) in Acetonitrile (0.5 ml) and Water (0.250 ml) stirred at 90° C. in wheaton vial for 30 min. By HPLC-MS the main peak corresponds to expected product.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N1CCCCC1)=O>CCOC(C)=O>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5]
Reactant: C1CCNCC1
Reactant: Cc1cccc(Cl)c1C#N
Agent: O=CN1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCCCC2)c1C#N
Temperature: 150 °C
Reaction time: 96 h

Procedure:
2-Methyl-6-piperidin-1-ylbenzonitrile (1 b) was prepared according to the method described by Grell, W. J. Med. Chem. 1998, 41, 5219. A mixture of 2-chloro-6-methylbenzonitrile (1a, 8.5 g), piperidine (16.6 mL, 3 eq) and N-formyl piperidine (12.5 mL) was heated in an oil bath at 150° C. under N2. After a period of 4 days, HPLC indicated complete conversion of starting materials to product. The reaction mixture was cooled to RT, dissolved in 100 mL of EtOAc, washed with water, 10% HCl, and NaHCO3 (sat), dried over anhydrous MgSO4 and treated with charcoal. The product was concentrated under vacuum to give the crude product (1 b) as pale yellow oil (12.01 g); C18 reversed phase HPLC indicated 88% homogeneity at 220 nm. This crude product was purified by flash column chromatography (hex-EtOAc, 1:0 to 20:1 to 10:1) to afford 2-methyl-6-piperidin-1-ylbenzonitrile (1 b) as colorless oil which solidifies upon standing (˜80% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH:11]=O)[CH:7]=[CH:8][CH:9]=1.I.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([NH:27][NH2:28])=[NH:26]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:27]=[N:28][CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:15])([F:14])[F:1])[CH:5]=2)[N:26]=1
Reactant: N=C(NN)c1ccc(F)cc1F
Reactant: O=CC(=O)c1cccc(OC(F)(F)F)c1
Agent: I
Product: Fc1ccc(-c2nncc(-c3cccc(OC(F)(F)F)c3)n2)c(F)c1

Procedure:
(3-Trifluoromethoxyphenyl)oxoacetaldehyde was reacted with 2,4-difluorobenzenecarboximidic hydrazide hydriodide salt using the method described in Example 1 to give 3-(2,4-difluorophenyl)-5-(3-trifluoromethoxyphenyl)-[1,2,4]triazine as a yellow solid (655 mg): δH (400 MHz, CDCl3) 7.01-7.12 (2H, m), 7.47-7.51 (1H, m), 7.65 (1H, t, J 8.2 Hz), 8.15-8.18 (2H, m), 8.32-8.38 (1H, m), 9.64 (1H, s); m/z (ES+) 354.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][N:15]=2
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccnc2o1
Product: C(#Cc1ccccn1)CCc1nc2cccnc2o1
Yield: 37.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (92 mg, 0.58 mmol) and 2-(but-3-ynyl)oxazolo[5,4-b]pyridine (100 mg, 0.58 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5 to 98:2) to yield 56 mg (0.22 mmol, 39%) of 2-(4-(pyridin-2-yl)but-3-ynyl)oxazolo[5,4-b]pyridine as a colorless oil.
Reaction SMILES: FC1C=C(OC)C=C(F)C=1[C:11]1=[C:12]([CH:42]=[CH:43][C:44]2[C:52]([CH3:54])([CH3:53])[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([S:55]([O-:58])(=[O:57])=[O:56])[CH:50]=3)[N+:45]=2[CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH2:13][CH2:14][CH2:15]/[C:16]/1=[CH:17]\[CH:18]=[C:19]1\[N:20]([CH2:34][CH2:35][CH2:36][CH2:37][S:38]([O-:41])(=[O:40])=[O:39])[C:21]2[C:26]([C:27]\1([CH3:29])[CH3:28])=[CH:25][C:24]([S:30]([O-:33])(=[O:32])=[O:31])=[CH:23][CH:22]=2.[Na+:67].[Na+].[Na+].B([C:73]1[C:74]([F:88])=[C:75]([CH2:81][CH2:82][CH2:83][CH2:84][C:85]([OH:87])=[O:86])[C:76]([F:80])=[CH:77][C:78]=1[F:79])(O)O>>[C:85]([CH2:84][CH2:83][CH2:82][CH2:81][C:75]1[C:74]([F:88])=[C:73]([C:11]2=[C:16]([CH:17]=[CH:18][C:19]3[C:27]([CH3:29])([CH3:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([S:30]([O-:33])(=[O:31])=[O:32])[CH:25]=4)[N+:20]=3[CH2:34][CH2:35][CH2:36][CH2:37][S:38]([O-:41])(=[O:40])=[O:39])[CH2:15][CH2:14][CH2:13]/[C:12]/2=[CH:42]\[CH:43]=[C:44]2\[N:45]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[C:46]3[C:51]([C:52]\2([CH3:54])[CH3:53])=[CH:50][C:49]([S:55]([O-:58])(=[O:56])=[O:57])=[CH:48][CH:47]=3)[C:78]([F:79])=[CH:77][C:76]=1[F:80])([OH:87])=[O:86].[Na+:67].[Na+:67].[Na+:67]
Reactant: O=C(O)CCCCc1c(F)cc(F)c(B(O)O)c1F
Reactant: COc1cc(F)c(C2=C(C=CC3=[N+](CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC/C2=C\C=C2\N(CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c(F)c1
Agent: CC1(C)C(/C=C/C2=C(c3c(F)cc(F)c(CCCCC(=O)O)c3F)/C(=C/C=C3/N(CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Agent: COc1cc(F)c(C2=C(/C=C/C3=[N+](CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC/C2=C\C=C2\N(CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c(F)c1
Agent: [Na+]
Product: CC1(C)C(C=CC2=C(c3c(F)cc(F)c(CCCCC(=O)O)c3F)/C(=C/C=C3/N(CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 39 is prepared analogously to compound 17 (Example 17), except with 5-(3-borono-2,4,6-trifluorophenyl)pentanoic acid as a starting material.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Br[C:20]1C=C(C=CC=1)C(OCC)=O.C1(C)C=CC=CC=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:20])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: CCOC(=O)c1cccc(-c2ccc(C)cc2)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-c2ccccc2C)c1

Procedure:
2′-Methyl-biphenyl-3-carboxylic acid ethyl ester was synthesized as described for 4′-methyl-biphenyl-3-carboxylic acid ethyl ester. Ethyl 3-bromobenzoate (8.02 g, 35.03 mmol, 1 eq.) and o-tolylboronic acid (5.0 g, 36.78 mmol, 1.05 eq.) in THF were treated with aqueous 2M sodium carbonate (38.5 mL, 77.07 mmol, 2.2 eq.), palladium(II) acetate (0.79 g, 3.50 mmol, 10 mol %), triphenylphosphine (4.04 g, 15.40 mmol, 4.4×Pd), and copper(I) iodide (0.22 g, catalyst). When complete, the reaction was worked up as described leaving a dark brown oil.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[S:8][C:7]([C:9]([F:12])([F:11])[F:10])=[N:6][CH:5]=1.[N:13]#[C:14][NH2:15].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>ClCCl>[CH3:1][S:2]([CH2:3][C:4]1[S:8][C:7]([C:9]([F:12])([F:10])[F:11])=[N:6][CH:5]=1)=[N:15][C:14]#[N:13]
Reactant: N#CN
Reactant: CSCc1cnc(C(F)(F)F)s1
Agent: C/S(Cc1cnc(C(F)(F)F)s1)=N\C#N
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CS(Cc1cnc(C(F)(F)F)s1)=NC#N
Temperature: 25 °C

Procedure:
A solution of 5-[(methylthio)methyl]-2-(trifluoromethyl)-1,3-thiazole (140 mg, 0.62 mmol) and cyanamide (35 mg, 0.83 mmol) in 6 mL of dichloromethane was cooled to 0° C. and treated with iodobenzene diacetate (860 mg, 2.59 mmol). A clear yellow solution was obtained. The mixture was allowed to warm to room temperature over an hour and then the solvent removed under reduced pressure and the residue further purified by flash column chromatography on silica gel using a 50% mixture of acetone and petroleum ether as the eluant. The solvents were removed under reduced pressure to yield 130 mg (83%) of (1E)-methyl{[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}-λ4-sulfanylidenecyanamide as a pale yellow syrup: 1H NMR (CDCl3) δ 8.00 (s, 1H), 4.60 (s, 2H), 2.85 (s, 3H); LCMS (ESI) m/z 254 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18](Cl)=[C:17]([NH2:20])[N:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)[CH3:2].[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([C:32]3[CH:33]=[CH:34][C:29]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][CH:31]=3)=[C:17]([NH2:20])[N:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)Cc1ccc(Nc2ncnc(N)c2Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccc(Nc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 3 h
Yield: 94.8 %

Procedure:
Into a microwave vial was placed [4-(6-amino-5-chloro-pyrimidin-4-ylamino)-phenyl]-acetic acid ethyl ester (1.4 g; 3.423 mmol; 1.0 eq.), (4-phenoxyphenyl)boronic acid (1598.9 mg; 7.470 mmol; 2.18 eq.), palladium acetate (38.4 mg; 0.171 mmol; 0.1 eq.), dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (140.5 mg; 0.342 mmol; 0.1 eq.), potassium carbonate (1419.2 mg; 10.269 mmol; 3.0 eq.) suspended in dioxane (15.0 ml) and water (1.5 ml). The vial was flushed with nitrogen. The reaction vial was run in a microwave for 3 hours at 150° C. The mixture was filtered, quenched in water and extracted with EtOAc (3×). The combined organic layer were dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified using Biotage column chromatography (50/50% Hexanes/EtOAc to 100% EtOAc). Fractions containing the desired product were collected and concentrated to afford (4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid ethyl ester (1.43 g, 90% yield) as a yellow foam. MS: m/z=441 [M+H]+. 1H-NMR (DMSO-d6) δ 8.06 (s, 1H), 7.45 (t, 4H), 7.34 (d, 2H), 7.16 (dd, 8H), 5.77 (bs, 2H), 4.10 (q, 2H), 3.56 (s, 2H), 1.20 (t, 3H).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH2:11][O:10][CH:9]([N:12]2[CH:20]=[N:19][C:18]3[C:17](=[O:21])[NH:16][C:15]([NH:22]C(=O)C)=[N:14][C:13]2=3)[CH2:8][CH2:7]1)(=O)C.C[O-].[Na+].Cl>CO>[OH:4][CH2:5][CH:6]1[CH2:11][O:10][CH:9]([N:12]2[CH:20]=[N:19][C:18]3[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]2=3)[CH2:8][CH2:7]1
Reactant: CC(=O)Nc1nc2c(ncn2C2CCC(COC(C)=O)CO2)c(=O)[nH]1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(ncn2C2CCC(CO)CO2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
9-(5-Acetoxymethyltetrahydropyran-2-yl)-N2 -acetylguanine (80 mg) was dissolved in dried methanol, and catalytic amount of sodium methoxide was added thereto. After stirring at room temperature overnight, the mixture was neutralized with methanolic hydrochloric acid and concentrated under reduced pressure. The residue was purified on a silica gel column (eluent: chloroform/methanol=7/1) to obtain the desired product (45 mg, 73%) as pale gray solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(O)C>[CH3:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C1COCCN1
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of 6-bromo-2-methyl-3-nitropyridine (2.05 g, 9.45 mmol) in ethanol (10 mL) was added morpholine (1.728 mL, 19.84 mmol) and the reaction mixture was stirred at 70° C. for 5 hours. The reaction mixture was allowed to cool to room temperature causing a precipitate. The solid was collected by filtration and washed with ethanol (5 mL), then dried in vacuo. The crude was redissolved in a mixture of saturated sodium carbonate solution and ethyl acetate. The organic phase was separated, washed with further saturated sodium carbonate solution, then dried over magnesium sulphate and evaporated in vacuo to give the title compound (1.47 g) as a yellow solid. LCMS (2 min, formic) Rt 0.92 min, m/z (ES+) 224 (M+H).