Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[CH:13][C:8]=2[O:7][C:6]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:4].[CH2:26](N(CC)CC)C.COS(OC)(=O)=O.O>C(OCC)C>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:14][CH3:26])=[CH:13][C:8]=2[O:7][C:6]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OC(C)C)cc12
Reactant: CCN(CC)CC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC)c(OC(C)C)cc12
Yield: 56 %

Procedure:
6-Amino-2-(4-fluoro-phenyl)-5-isopropoxy-benzofuran-3-carboxylic acid methylamide, prepared according to Example 16 (55 mg, 161 μmol) was dissolved in anhydrous diethyl ether (2 mL). Triethylamine (25 μL, 193 μmol) was added to the reaction mixture, followed by the slow addition of dimethylsulfate (17 μL, 177 μmol). Water (1 mL) was added after 2 hours. The reaction was concentrated to dryness, and the crude product was purified on HPLC (reverse phase) to provide 32 mg (56%) of pure product.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:2][CH3:3].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1.C(Cl)Cl>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.O>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: O
Product: CCCNC(=O)c1cccc(C#Cc2ccccc2)c1
Temperature: 70 °C

Procedure:
A mixture of N-n-propyl-4-bromobenzamide from Example 9A, phenylacetylene (1.5 eq.) and Pd(PPh3)2Cl2 (5 mol %) in piperidine (3 eq.) was heated at 70° C. for 30 minutes in a sealed tube. The solidified residue was dissolved with CH2Cl2 and water and poured onto HCl 2N. The acidic phase was extracted three times with CH2Cl2. The combined organic layers were washed once with HCl 2N, twice with saturated NaHCO3, once with water and once with brine. The organic layer was then dried over MgSO4 and concentrated. The resulting residue was purified using SiO2 with CH2Cl2/petroleum ether 80:20 to CH2Cl2 100% to give N-n-propyl-3-phenylethynyl-benzamide as a yellow solid (Quantitative yield). NMR 1H (ppm, CDCl3): 7.73 (d. J3=8.4 Hz, 2H), 7.63-7.51 (m, 5H), 7.36-7.32 (m, 2H), 6.10 (br. s., 1H), 3.45-3.37 (m, 2H), 1.64 (sext., J=7.2 Hz, 2H), 0.99 (t, J3=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Br)=[N:6][CH:7]=1.[CH3:10][NH:11][CH3:12]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:11]([CH3:12])[CH3:10])=[N:6][CH:7]=1
Reactant: CNC
Reactant: BrCc1ccc(Br)cn1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Place 5-bromo-2-bromomethyl-pyridine (1.7 g, 6.7 mmol, 1 eq) (Bioorg. Med. Chem. Lett. 1994, 4(1), 99) in a 250 mL round bottom short neck flask, dissolve in 100 mL of THF, cool to 0° C. and treat with a 2 M N,N-dimethylamine solution in THF (9 mL, 18 mmol, 2.7 eq). After 2 hours, concentrate the reaction, dilute with 50 mL of CH2Cl2, and wash with 20 mL of water. Dry the organics and concentrate to give 0.90 g (64%) of the title compound as a brown oil. MS (ES), m/z 217 (M+1).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccc(OCC(=O)N2CCOCC2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCC(=O)N2CCOCC2)cc1
Reaction time: 1 h

Procedure:
A solution of bromine (8.0g.) in chloroform (30ml.) was added dropwise to a stirred solution of 4-(4-acetylphenoxyacetyl)morpholine (13.15g.) in chloroform (120ml.) at 35° C. After 1 hour, the reaction mixture was filtered and the filtrate was washed with water (2 × 30ml.), dried and evaporated. The residue was recrystallised from methanol/ether to give 4-[4-(bromoacetyl)phenoxyacetyl]morpholine, m.p. 105°-107° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([F:35])[CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([F:35])[CH:34]=4)=[N:25][CH:26]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3cncc(F)c3)nc2)c2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cncc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (601, 0.060 g, 0.12 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.11 g, 0.35 mmol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0324, 13.5mg, 31%). MS (ESI) [M+H+]+=368.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)Cl.C(OCC)(=O)C>[CH3:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 23 °C
Reaction time: 10 h

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (25.0 g, 150 mmol) was dissolved in N,N-dimethylformamide (200 mL, 2000 mmol), followed by potassium carbonate (20.7 g, 150 mmol) and methyl iodide (10.2 mL, 164 mmol). The reaction mixture was stirred for 10 hours at 23° C. Ethyl acetate (1000 mL) was added, and the mixture was washed with water and brine. Organic layer was dried over sodium sulfate. Removal of solvent gave a crude solid product, which was treated with DCM and hexanes. The solid was collected and washed with hexanes (27.0 g, 100%). 1H NMR (CHLOROFORM-d) δ: 10.50 (s, 1H), 8.18 (d, J=9.0 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.16 (dd, J=9.2, 2.9 Hz, 1H), 3.97 (s, 3H). MS (M+1): 182.10.
Reaction SMILES: [OH:1][C:2]1C=CC(C=O)=C(OC)C=1.C([C:14]1[CH:15]=[C:16]([CH:21]=[C:22](C)[C:23]=1[OH:24])[C:17]([NH:19][OH:20])=[NH:18])C>>[OH:24][C:23]1[CH:22]=[CH:21][C:16]([C:17]([NH:19][OH:20])=[NH:18])=[C:15]([O:1][CH3:2])[CH:14]=1
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: COc1cc(O)ccc1C=O
Product: COc1cc(O)ccc1C(=N)NO

Procedure:
The title compound is prepared from commercially available 4-hydroxy-2-methoxybenzaldehyde in analogy to literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine). LC-MS: tR=0.41 min; [M+1]+=183.06; 1H NMR (D6-DMSO): δ 3.74 (s, 3H), 5.47 (s, 2H), 6.35 (dd, J=8.3, 1.5 Hz, 1H), 6.45 (s, 1H), 7.21 (d, J=8.5 Hz, 1H), 9.42 (s, 2H).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](N(OC)C)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([Mg]Br)[CH2:23][CH2:22]1.C(=O)=O.CC(C)=O>C1COCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([CH:21]3[CH2:23][CH2:22]3)=[O:16])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)Cc1ccc(OC2CCCCC2)cc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred solution of 2-(4-cyclohexyloxy-phenyl)-N-methoxy-N-methyl-acetamide (Example 14, 1.31 mmol, 0.36 g) in anhydrous THF (1 mL) at −78° C. was added cyclopropylmagnesium bromide (2 M in diethyl ether, 2.62 mmol, 5.25 mL) dropwise over 5 minutes. The reaction was stirred for 30 minutes at −78° C. The dry ice/acetone bath was replaced with an ice bath and the reaction was stirred for an additional 30 min. The reaction mixture was quenched by addition of saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2×10 mL). The combined ethyl acetate layers were washed with brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 column with 6-8% ethyl acetate in hexanes to give 2-(4-cyclohexyloxy-phenyl)-1-cyclopropyl-ethanone (0.24 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=2[CH:13]=1)=[O:11].C(N(CC)CC)C.O>O1CCCC1>[C:1]([N:18]1[CH2:17][CH2:16][C:15]2[CH:21]=[CH:22][C:12]([C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][Cl:5])=[CH:13][C:14]=2[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(CCCCCl)c1ccc2c(c1)CCNCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCc2ccc(C(=O)CCCCCl)cc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (679 μl) was added to a solution of 5-chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (2.2 g) obtained in Reference Example 121 and triethylamine (1.67 ml) in tetrahydrofuran (30 ml). After stirring at room temperature for 60 minutes, water (50 g) was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give an oil (2.54 g).
Reaction SMILES: C([O-])(=O)C.[Na+].[C:6]([O:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].[CH3:13][N:14]([CH3:21])[N:15]=[CH:16][C:17]([CH2:19][CH3:20])=[CH2:18].BrC1C(OC(=O)C=1)=O>C(Cl)Cl>[CH3:13][N:14]([CH3:21])[N:15]1[CH:16]=[C:17]([CH2:19][CH3:20])[CH2:18][C:7]2[C:6]([O:9][C:10](=[O:12])[C:11]1=2)=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C=NN(C)C)CC
Agent: CC(=O)[O-]
Agent: O=C1C=C(Br)C(=O)O1
Agent: [Na+]
Solvent: ClCCl
Product: CCC1=CN(N(C)C)C2=C(C1)C(=O)OC2=O
Reaction time: 1 h

Procedure:
A mixture of sodium acetate (14.76 g, 180.0 mmol) and acetic anhydride (150 ml) is heated, under N2, to 120° for 10 min., and is then chilled to 10°. 2-Ethyl-2-propenal dimethylhydrazone (11.36 g, 90.0 mmol) is added, followed by addition of bromomaleic anhydride (16.41 g, 92.7 mmol) and the reaction mixture is stirred at 10° for ca. 1 hour. The mixture is then diluted with methylene chloride and filtered, and the solid is rinsed with methylene chloride until colorless. The filtrate is concentrated to remove the solvent and to give 1,4-dihydro-1-dimethylamino-5-ethyl-2,3-pyridinedicarboxylic anhydride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].CN1C(=O)N(C)[CH2:21][CH2:20]C1.[C-]#[C-].[CH3:28][Si:29]([Li])([CH3:31])[CH3:30]>C1COCC1>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][CH2:3][CH2:2][C:20]#[C:21][Si:29]([CH3:31])([CH3:30])[CH3:28]
Reactant: [Li][Si](C)(C)C
Reactant: CN1CCCN(C)C1=O
Reactant: Cc1oc(-c2ccccc2)nc1CCCBr
Agent: [C-]#[C-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCCC#C[Si](C)(C)C
Reaction time: 16 h
Yield: 50 %

Procedure:
Bromide 1-5 (3.2 g, 12.2 mmol) was dissolved in a 1:1 mixture of THF:DMPU (200 mL) and cooled to 0° C. under N2 atmosphere. Trimethylsilyl lithium acetylide (50mL, 25 mmol) was added to the solution via syringe and allowed to equilibrate to 23° C. for 16 hours. The solution was partitioned between water and EtOAc in a separatory funnel. Organic layer was washed with water, brine, and dried over MgSO4. Solvent removed in vacuo and residue chromatographed with 5% EtOAc/hexanes to give 1.9 g of the product as a clear oil (50% yield). NMR CDCl3 (δ): 7.82 (2H, m); 7.27 (3H, m);2.46 (2H, m); 2.20 (3H, s); 2.10 (2H, m); 1.76 (2H, m); 0.01 (9H, s). M+1=298.1
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](Cl)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH2:16][CH2:15]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[O:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Reactant: ClC(c1cccs1)c1cccs1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2cccs2)c2cccs2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using di(2-thienyl)methyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(2-thienyl)methoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[C:12]=S>>[C:5]1([CH:2]2[CH2:3][O:4][C:12]([NH:11][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[N:24]=[CH:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=5)[N:21]=4)=[CH:18][CH:19]=3)=[N:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(CO)c1ccccc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(NC4=NC(c5ccccc5)CO4)cc3)n2)cc1

Procedure:
The title compound was prepared with 2-amino-2-phenylethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as a white solid (0.14 g, 30%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:16]=1.CCO.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:16]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Methyl 2-hydroxy-5-nitrobenzoate (11.82 g, 60 mmol), triphenylphosphine (17.29 g, 66 mmol) and EtOH (3.03 g, 3.85 ml, 66 mmol) were taken up in THF (150 ml) and cooled in ice. Di-isopropyl-azodicarboxylate (8.31 g, 10 ml, 66 mmol) was added carefully, and the reaction was stirred at RT for 1 hr. The reaction was concentrated in vacuo, and the residue was triturated with EtOAc (50 ml). The solid thus formed was collected by filtration, washed with MTBE and dried in vacuo to give 12.2 g of crude methyl 2-ethoxy-5-nitrobenzoate. The filtrate was evaporated in vacuo, and the resulting residue was triturated with EtOAc (25 ml). The resulting solid was collected by filtration, washed with MTBE and dried in vacuo to give 6.31 g of a second crop of crude methyl 2-ethoxy-5-nitrobenzoate. The combined portions of methyl 2-ethoxy-5-nitrobenzoate were taken up in hot IPA (50 ml) and cooled to RT. The resulting solid was collected by filtration, washed with MTBE and dried in vacuo to give pure methyl 2-ethoxy-5-nitrobenzoate (5.49 g, 40.5%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1
Reactant: CN(C)CCO
Reactant: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCCN(C)C)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a solution of N-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (0.85 g, 3.7 mmol) in THF (40 mL), triphenyl phosphine (2.91 g, 11.1 mmol) and 2-dimethylamino ethanol (1.11 mL, 11.1 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (2.15 mL, 11.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was subjected to a purification on preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times to afford N-[4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide as a colorless waxy solid in 51.2% yield. LCMS m/z (%)=303 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 7.63 (d, J=8.93 Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.14 (d, J=8.98 Hz, 1H), 6.25 (s, 1H), 4.07 (t, J=5.82 Hz, 2H), 3.69 (s, 3H), 2.56 (t, J=5.80 Hz, 2H), 2.15 (s, 6H), 2.05 (s, 3H).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:32]12([C:45](O)=[O:46])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][C:34]([C:42]([OH:44])=[O:43])([CH2:35]3)[CH2:33]1)[CH2:39]2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[C:26]1([C:19]2[O:20][C:21]([C:22]([F:23])([F:25])[F:24])=[C:17]([C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([N:2]4[CH2:7][CH2:6][N:5]([C:45]([C:32]56[CH2:41][CH:36]7[CH2:37][CH:38]([CH2:40][C:34]([C:42]([OH:44])=[O:43])([CH2:35]7)[CH2:33]5)[CH2:39]6)=[O:46])[CH2:4][CH2:3]4)=[CH:9][CH:10]=3)=[O:16])[N:18]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCN(C(=O)C34CC5CC(CC(C(=O)O)(C5)C3)C4)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide, hydrochloride (51.5 mg, 0.113 mmol), adamantane-1,3-dicarboxylic acid (51 mg, 0.227 mmol), and triethylamine (48 uL, 0.341 mmol) were dissolved in 1 mL of DMF. To this solution was added BOP (52 mg, 0.122 mmol) in one portion. The mixture was stirred at room temperature overnight. 4-N,N-dimethylamino-pyridine (5 mg) was added and the reaction was stirred for an additional 72 hours and then diluted with 30 ml ethyl acetate. The organic phase was washed with saturated ammonium chloride (1×5 mL), 2.5% KHSO4 (3×5 mL), water (2×5 mL) and saturated sodium chloride. The organic layer was dried over MgSO4, filtered, passed through a plug of silica gel and evaporated to dryness under vacuum to a light brown solid. The residue was purified by flash chromatography to yield 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-adamantane-1-carboxylic acid as light yellow crystals (9.4 mg, 13%). ES-MS calcd for C33H33F3N4O5 (m/e) 622.65, obsd 623 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]2[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=2)[CH2:19]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([NH:24][CH:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:3]=3)[CH2:19]2)=[N:30][CH:29]=1)#[N:32]
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(F)cc4)ccc3C#N)C2)nc1
Temperature: 120 °C

Procedure:
60 mg (0.26 mmol) of 2-chloro-6-(4-fluorophenyl)pyridine-3-carbonitrile, 77 mg (0.31 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) and 0.225 ml (1.29 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 99 mg (50% of theory) of the product were obtained in solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21].O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:5]2=[O:21]
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2cc(Cl)ccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(Cl)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 42.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2d (200 mg, 0.587 mmol), 6-mercaptopurine monohydrate (110 mg, 0.646 mmol), K2CO3 (90 mg, 0.651 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 113 mg of a yellow crystalline solid (42%), mp 237.1-238.2° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.55 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 8.11 (s, 1H); 7.94 (d, J=8.3 Hz, 1H); 7.78 (d, J=8.1 Hz, 2H); 7.66 (d, J=6.7 Hz, 1H); 7.48-7.56 (m, 2H); 4.48 (s, 2H). 13C NMR (DMSO-d6) ppm: 159.8, 156.8, 153.5, 151.5, 149.6, 145.8, 143.6, 135.7, 134.0, 132.2, 132.1, 131.7, 131.5, 130.5, 130.2, 129.8, 128.8, 125.8, 121.9, 32.0. MS (ES): m/z 455.0 (M+). Anal. calcd. for C20H12Cl2N6OS.0.1C2H6O.0.6H2O (0.15KCl: C, 50.34; H, 2.89; Cl, 15.82; N, 17.44; S, 6.65. Found: C, 50.02; H, 2.63; Cl, 15.51; N, 17.39; S, 6.81.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][C:9]=2[C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+].C1COCC1.Cl>O1CCOCC1.O>[CH:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[C:18]([F:19])([F:20])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: OCc1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a stirred solution of methyl 4-(cyclohexylmethyl)-3-(trifluoromethyl)benzoate (280 mg, 0.93 mmol) in dioxane (8 mL) was added 2 M lithium borohydride in THF solution (0.93 mL, 1.86 mmol). The reaction mixture was heated at 80° C. for 2 h, cooled down, poured into water, acidified with 1 M HCl aqueous solution to pH 4, extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3 solution and water, dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (190 mg) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.62-1.72 (m, 6H), 2.67 (d, J=6.7 Hz, 2H), 4.71 (d, J=5.7 Hz, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.45 (dd, J=8.0 and 1.6 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H).