Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1F.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:26][C:9]1[C:10]([F:17])=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=1[F:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)c(F)c1
Yield: 70.9 %

Procedure:
Potassium carbonate (7.8 g, 56.4 mmol) was added to a solution of 1,2,3-trifluoro-5-nitrobenzene (5 g, 28.2 mmol) and benzyl alcohol (3.2 g, 29.6 mmol) in N,N-dimethylformamide (70 mL). The resultant mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried (Na2SO4), concentrated under reduced pressure and purified by column chromatography to give 2-(benzyloxy)-1,3-difluoro-5-nitrobenzene (5.3 g, 71% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, J=8.4 Hz, 2H), 7.46-7.37 (m, 5H), 5.39 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>C(OCC)(=O)C.O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 70.1 %

Procedure:
Fluvastatin methyl ester (3.0 g) was dissolved in ethyl acetate (90 ml), a solution of NaOH (0.2 g) in water (1 ml) was added and the mixture was stirred at room temperature over night. The product was isolated by filtration under nitrogen, washed with ethyl acetate (50 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.52 g (49.7%) of fluvastatin sodium crystal Form LXXVII.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14].[C:44](O)(=[O:51])[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1.ON1C2C=CC=CC=2N=N1>C(#N)C>[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[C:44](=[O:51])[C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14]
Reactant: O=C(O)c1ccncc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCCc3cccnc3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)C(=O)c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.8 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC) (0.16 g, 0.85 mmol) was added to an acetonitrile solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.3 g, 0.71 mmol), isonicotinic acid (96 mg, 0.78 mmol), and 1-hydroxybenzotriazole (HOBT) (0.138 g, 0.85 mmol), and then stirred at room temperature for 2 days. The solvent was concentrated under reduced pressure. Ethyl acetate and a sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and stirred for 1 hour. Water was added to the reaction mixture, and extraction with ethyl acetate was conducted. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by medium pressure liquid chromatography (silica gel, dichloromethane:methanol=92:8). The purified product was concentrated under reduced pressure and crystallized from ethyl acetate, diethylether and n-hexane. The precipitated crystals were collected by filtration and dried to thereby obtain 0.21 g (yield:56%) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-N-(2-pyridin-3-ylethyl)isonicotinamide as a white powder.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:15]([O-])([O-])=O.[Cs+].[Cs+].IC>>[CH3:15][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(c1)NCCC2
Agent: [Cs+]
Solvent: CI
Product: COC(=O)c1ccc2c(c1)N(C)CCC2
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 1,2,3,4-tetrahydroquinoline-7-carboxylate (380 mg, 1.987 mmol), Cs2CO3 (1295 mg, 3.97 mmol) and iodomethane (0.118 ml, 1.888 mmol) was stirred for 16 hours at 20° C. After that time, more iodomethane (0.118 ml, 1.888 mmol) was added and stirring was continued for 8 hours at 60° C. The reaction mixture was allowed to cool to room temperature, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, Flow 40 mL/min, ACN: 2 min at 5%, then to 100% within 17.5 min, RT 15.52 min) to yield the title compound. HPLC (Method H) Rt=3.005 min; MS (Method A) [M+H]+=206.1
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([CH3:18])[C:12]([CH:19]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([O:22]C)=[O:21])=[C:11]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([CH3:18])[C:12]([CH:19]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([OH:22])=[O:21])=[C:11]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(Cc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2c3c(nc(C)c2C(OC(C)(C)C)C(=O)O)CCN(Cc2ccccc2)C3)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of methyl 2-(6-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate (intermediate 16) (47.3 mg, 100 mmol) in dioxane (3 ml) was added 1N NaOH (1.0 mL) and the mixture was stirred at 70° C. for 1 h. The mixture was quenched with 1 ml 1N HCl and concentrated. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 20-mM ammonium acetate; Gradient: 60-100% B over 30 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to provide 2-(6-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetic acid (29.9 mg, 65% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.20-7.35 (m, 7H), 7.17 (d, J=7.63 Hz, 1H), 7.09 (dd, J=1.53, 7.63 Hz, 1H), 4.77 (s, 1H), 3.44-3.58 (m, 2H), 3.30 (br. s., 1H), 2.99 (d, J=15.56 Hz, 1H), 2.81-2.89 (m, 2H), 2.75 (td, J=5.49, 10.99 Hz, 1H), 2.56-2.65 (m, 1H), 2.48 (s, 3H), 2.37 (s, 3H), 0.87 (s, 9H). LCMS (M+H) calcd for C29H35N2O3: 459.26. found: 459.3.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20](I)[CH:19]=1>>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:19]=1
Reactant: COC(=O)c1ccnc(I)c1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: COC(=O)c1ccnc(C#Cc2c(-c3ccccc3)noc2C)c1
Yield: 70 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (58 mg, 0.32 mmol) was converted (using 2-iodo-isonicotinic acid methyl ester instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 70 mg, 70%) which was obtained as a light brown solid. MS: m/e=319.1 [M+H]+.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:8][N:7]=1.[Cl:17][C:18]1[C:19]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:33][C@@H:34]([CH2:39][O:40][CH:41]([CH3:43])[CH3:42])[C:35](OC)=[O:36])=[C:27]3[CH:26]=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1.CCCCCC>C1(C)C=CC=CC=1>[Cl:17][C:18]1[C:19]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:33][C@@H:34]([CH2:39][O:40][CH:41]([CH3:43])[CH3:42])[C:35]([NH:5][C:6]4[CH:16]=[CH:15][C:9]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:8][N:7]=4)=[O:36])=[C:27]3[CH:26]=[N:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: CN(C)C(=O)c1ccc(N)nc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C(=O)N(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Trimethylaluminium (2M in hexane, 0.376 mL, 0.75 mmol) was added to 6-amino-N,N-dimethylnicotinamide (CAS no. 827588-33-0) (108 mg, 0.65 mmol) in toluene (20 mL) at 0° C. under Nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (Intermediate L1) (256 mg, 0.65 mmol) in toluene (6 mL) was added dropwise at this temperature. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL) and washed with saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. 2M Trimethylaluminium in hexane (0.376 mL, 0.75 mmol) was added to 6-amino-N,N-dimethylnicotinamide (108 mg, 0.65 mmol) in toluene (20 mL) at 0° C. under Nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. The residue from the above evaporation was dissolved in toluene (6 mL) and added dropwise. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. Allowed to cool to ambient temperature. The reaction mixture was concentrated and diluted with EtOAc (100 mL) and washed with saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH:45]2[CH2:47][CH2:46]2)=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:45]2[CH2:47][CH2:46]2)=[C:32]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:31]=1
Reactant: CC1(C)OB(c2cc(Cl)ccc2C2CC2)OC1(C)C
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(Br)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C2CC2)cc1=O

Procedure:
127 mg (purity 70%, 0.2 mmol) of tert-butyl 4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate) and 67 mg (0.24 mmol) of 2-(5-chloro-2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 66 mg (62% of theory)
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:30])([OH:29])[OH:28])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:40]>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:28])([O-:29])[O-:30])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:40].[Na+:40]
Reactant: O=P(O)(O)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a suspension of ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidic acid (2) (0.070 g, 0.13 mmol) in ethanol (5 mL) was added NaOH (9.95 mg, 0.249 mmol) in 1 mL of water. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue washed with ethyl acetate (2×10 mL), acetone (2×10 mL) and acetonitrile (2×15 mL) to afford disodium (5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonylphosphoramidate (4) (0.040 g, 0.068 mmol, 52% yield) as a yellow solid. 1H NMR (400 MHz, deuterium oxide) δ (ppm) 4.46 (s, 2H), 7.04 (d, J=7.78 Hz, 1H), 7.16 (d, J=6.27 Hz, 1H), 7.18-7.23 (m, 1H), 7.26 (d, J=6.27 Hz, 2H), 7.33 (d, J=6.78 Hz, 3H), 7.57-7.72 (m, 3H), 8.27 (d, J=4.27 Hz, 1H), 8.88 (br. s., 1H), 9.03 (s, 1H), 9.19 (s, 1H); 31P (162.0 MHz, DMSO-d6) δ (ppm) −5.19; LCMS Method I: retention time 1.61 min, [M+1]=549. HPLC Method K: Purity 94%, retention time 8.59 min. Elemental analysis: MF C25H19N6SPO5.2.3 Na.3.8 H2O, Calculated C, 45.03; H, 4.02; N, 12.60; Na, 7.79; H2O, 10.27; Found C, 44.90; H, 3.58; N, 12.40; Na, 7.79; H2O, 10.61.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(Cl)c2cccnc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(Cl)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of 5-chloro-8-hydroxyquinoline-7-carboxylic acid (0.335 g) of Preparation 3 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried to yield 0.167 g of the title product as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH:17]2[CH2:26][C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44]Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>CC#N>[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[CH:10][CH:11]=1)[CH:17]1[CH2:26][C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNC2CCc3cccnc3C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCc3cccnc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
{4-[(5,6,7,8-Tetrahydro-quinolin-7-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (88 mg, 0.24 mmol), 2-Chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (80 mg, 0.30 mmol), DIPEA (0.10 mL, 0.54 mmol), and KI (19 mg, 0.11 mmol) were heated to 80° C. in CH3CN (1.5 mL) for 2 h under N2, then it was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with NH4Cl (aq), NaCl (aq), and dried (MgSO4). Evaporation of the solvent and purification of the residue by flash chromatography on silica gel (1:1:98 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (80 mg, 56%) as a white foam.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[N:19]([CH:24]([CH3:26])[CH3:25])[C:20]([CH3:23])=[N:21][CH:22]=3)[CH:15]=[CH:14][N:13]=2)=[C:8]([CH3:10])[CH:9]=1)=[O:4].[OH-].[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:53]([O:57][C:58](=[O:74])[NH:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)=[CH:62][C:61]=1[NH2:73])([CH3:56])([CH3:55])[CH3:54].CN1CCOCC1>CO.C1COCC1.CN(C=O)C.O.C(#N)C>[C:53]([O:57][C:58](=[O:74])[NH:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:67]=[CH:68][C:69]([F:72])=[CH:70][CH:71]=2)=[CH:62][C:61]=1[NH:73][C:3]([C:5]1[S:6][C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[N:19]([CH:24]([CH3:26])[CH3:25])[C:20]([CH3:23])=[N:21][CH:22]=3)[CH:15]=[CH:14][N:13]=2)=[C:8]([CH3:10])[CH:9]=1)=[O:4])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: COC(=O)c1cc(C)c(Nc2nccc(-c3cnc(C)n3C(C)C)n2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2NC(=O)OC(C)(C)C)sc1Nc1nccc(-c2cnc(C)n2C(C)C)n1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To the above ester in MeOH/THF (10:5) (15 mL) was added 3N NaOH (5.0 mL) and stirred at 60° C. After 14 hours. The reaction mixture was concentrated, diluted with water and washed with ether (30 mL). The aqueous phase was then neutralized with 6 N HCl (1.5 mL), extracted with ethyl acetate, and then dried (MgSO4). Filtration and concentration gave the acid which was used further without purification. MS found for C17H19N5O2S as (M+H)+ 358.24. To the above acid (70 mg, 0.2 mmol) in DMF (2 mL), was added HATU (114 mg, 0.3 mmol), (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester (118 mg, 0.4 mmol) and NMM (0.1 mL, 0.78 mmol) and stirred at 50° C. for 16 hours. The reaction mixture was diluted with water and acetonitrile. The resulting solid was filtered, washed with water, and dried to give [4′-fluoro-3-({5-[4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-pyrimidin-2-ylamino]-4-methyl-thiophene-2-carbonyl}-amino)-biphenyl-4-yl]-carbamic acid tert-butyl ester. MS found for C34H36FN7O3S as (M+H)+ 642.02.
Reaction SMILES: C(O[CH:4]=[C:5]([C:21](=[O:23])[CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])=[O:7])C.Cl.[NH2:25]O>C(O)C>[N+:18]([C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[C:6]([C:5]1[CH:4]=[N:25][O:23][C:21]=1[CH3:22])=[O:7])([O-:20])=[O:19]
Reactant: NO
Reactant: CCOC=C(C(C)=O)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Cc1oncc1C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 37.5 %

Procedure:
A mixture of crude 2-ethoxymethylene- 1-(2-nitro-4-trifluoromethylphenyl)butan-1,3-dione (13.25g) and hydroxylamine hydrochloride (3.7 g) in ethanol (80 ml) was stirred for 5 hours. The solution was evaporated almost to dryness and the resultant solution was diluted with ethyl acetate (100 ml). The solution was washed with water (3×40 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with a mixture of ether and petroleum spirit (bp 60°-80° C.) (1:1) and the resultant buff solid was filtered off. The solid was dissolved in dichloromethane (100 ml) and filtered through silica. The silica was washed with dichloromethane (100 ml) and the combined filtrates were evaporated to dryness to give 4-(2-nitro-4-trifluoromethylbenzoyl)-5-methylisoxazole (Compound 1,4.5 g) as an off-white solid mp 85°-86° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[S:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=1>C1COCC1>[N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:17]3[S:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)[CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCOCC2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(N3CCOCC3)ncn2)s1
Temperature: 45 °C

Procedure:
6-Morpholin-4-yl-pyrimidin-4-ylamine (185 mg, 1.03 mmol) was stirred in 5 mL anhydrous THF under N2. Sodium hydride (82 mg, 60% dispersion, 2.05 mmol) was added and the reaction was warmed to 45° C. for 5 minutes. 2-chloro-thiazole-5-carbonitrile (208 mg, 1.44 mmol) was added and the reaction was heated to reflux. After 30 minutes added additional 2-chloro-thiazole-5-carbonitrile (85 mg, 0.59 mmol). After an additional 1 hour the reaction was cooled to room temperature, quenched with water and the THF was removed in vacuo. The mixture was neutralized with 1 M HCL and the resulting precipitate was filtered and washed with water. The solid was suspended in DMSO, filtered and washed with EtOAc to provide the title compound. 1H-NMR (400 MHz, CD3OD) 8.44 (1H, s), 7.95 (1H, s), 6.13 (1H, s), 3.81 (t, 4H, J=5.0 Hz), 3.63 (t, 4H, J=4.9 Hz). M+1=289.1.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:9][O:10][C:11]1[C:12](OC)=[CH:13][C:14]2[Te:18][C:17]([CH3:19])=[N+:16]([CH2:20][C:21]#[CH:22])[C:15]=2[CH:23]=1.COC1C=CC2[Te]C(C)=NC=2C=1>>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[Te:18][C:17]([CH3:19])=[N+:16]([CH2:20][C:21]#[CH:22])[C:15]=2[CH:23]=1
Reactant: C#CC[n+]1c(C)[te]c2cc(OC)c(OC)cc21
Agent: COc1ccc2[te]c(C)nc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Product: C#CC[n+]1c(C)[te]c2ccc(OC)cc21

Procedure:
This compound was prepared in the same way and on the same scale as the compound of Example 46, except that 5-methoxy-2-methylbenzotellurazole (Example 20) was used in place of the 5,6-dimethoxy-2-methylbenzotellurazole. Yield 1.23 g, 80% of theory, pale tan powder, m.p. 172°-174° C. (dec). The infrared, nuclear magnetic resonance, and mass spectra were in agreement with that expected for the structural formula.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[Cl:15]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:15][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1ccc2ccccc2c1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c2ccccc2c1O
Temperature: 100 °C
Yield: 67.3 %

Procedure:
To a stirred solution of 1-(1-hydroxy-2-naphthyl)ethanone (5.00 g, 26.8 mmol, from Aldrich) in acetic acid (100 mL) was added N-chlorosuccinimide (3.94 g, 29.5 mmol) and the resulting mixture heated at 100° C. for 18 hours. After allowing to be cooled to ambient temperature, the reaction mixture was concentrated in vacuo and then diluted with ethyl acetate. The precipitated solid was collected by filtration to afford the desired product (3.98 g, 67%). LCMS calculated for C12H10ClO2 (M+H)+: m/z=221.0; Found: 221.1.