Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>O>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[CH:14][CH:13]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(O)cc1
Solvent: O
Product: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reaction time: 2 h
Yield: 94 %

Procedure:
Condensation with Meldrum's acid was carried out according to the method of Bigi et. al. Tet. Lett. 2001, 42, 5203-5205. A 2 L pear-shaped flask was charged with 4-hydroxybenzaldehyde (50 g, 409 mmol) (commercially available from Aldrich) and water (400 mL). The flask was placed in a water bath at 75° C. and Meldrum's acid (62 g, 430 mmol) (commercially available from Aldrich) was added as a slurry in water (400 mL). The reaction mixture was agitated for 2 hours and then cooled in an ice bath for 2 hours. The product was collected by filtration and rinsed with cold water. After drying thoroughly, 95 g (94%) of adduct 21.1 was obtained as a fine yellow powder. 1H NMR (500 MHz) (DMSO-d6) δ 9.75 (br s, 1H); 8.27 (s, 1H); 8.24 (d, 2H, J=10 Hz); 6.98 (d, 2H, J=10 Hz), 1.76 (s, 6H). MS ESI (pos.) m/e: 519.0 (2M+Na).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH:25]([F:27])[F:26])=[CH:21][CH:22]=3)[C:17]([C:28]3[N:29]=[C:30]4[C:36]([C:37]([NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][N:34](COCC[Si](C)(C)C)[C:31]4=[N:32][CH:33]=3)=[N:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:40]([NH:39][C:37]([C:36]1[C:30]2[C:31](=[N:32][CH:33]=[C:28]([C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[C:20]([O:24][CH:25]([F:27])[F:26])[CH:19]=4)[N:15]([CH2:14][CH:10]4[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9]4)[N:16]=3)[N:29]=2)[NH:34][CH:35]=1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(Cc5ccccc5)CCO4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC4CN(Cc5ccccc5)CCO4)c4ccc(OC(F)F)cc34)nc12
Reaction time: 15 h
Yield: 76.3 %

Procedure:
To a stirred solution of 2-(1-((4-benzylmorpholin-2-yl)methyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 55.6 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrate. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-[1-(4-benzyl-morpholin-2-ylmethyl)-5-difluoromethoxy-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (25 mg, 76%). MS (M+H)+=590; 1H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.39 (s, 1H), 8.18 (d, J=2.3 Hz, 1H), 7.88 (d, J=4.0 Hz, 1H), 7.36-7.41 (m, 1H), 7.29-7.33 (m, 5H), 7.22-7.27 (m, 1H), 6.98-7.21 (m, 1H), 4.54-4.68 (m, 2H), 3.96-4.03 (m, 1H), 3.74 (d, J=11.0 Hz, 1H), 3.49 (s, 2H), 3.40-3.48 (m, 1H), 2.86 (d, J=11.3 Hz, 1H), 2.58 (d, J=12.3 Hz, 1H), 1.87-2.11 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([OH:28])[CH:27]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:34]=CC=C[CH:30]=1.C(O)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([O:28][CH:29]([CH3:34])[CH3:30])[CH:27]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3)c2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.5 %

Procedure:
Methyl 6-[(3-benzyloxy-5-hydroxybenzoyl)amino]-3-pyridinecarboxylate(2.20 g, 5.81 mM), triphenylphosphine (1.59 g, 6.10 mM), iso-propanol (0.445 ml, 5.81 mM) and THF (50 ml) were combined and diisopropylazodicarboxylate (1.2 ml, 6.10 mM) was added dropwise. The reaction was stirred for 72 hours at ambient temperature. The mixture was concentrated in vacuo and the resulting brown oil was purified by column chromatography on Kieselgel 60, eluting with a gradient of 50–100% methylene chloride in iso-hexane and then 5% EtOAc in methylene chloride to give methyl 6-[(3-benzyloxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate as a colourless oil (1.92 g); H1 NMR δ (d6-CDCl3) 1.36 (6H d) 3.95 (3H s) 4.60 (1H sept) 5.09 (2H s) 6.72 (1H s) 7.02 (1H s) 7.10 (1H s) 7.30–7.50 (4H m) 8.39 (2H ddd) 8.68 (1H s br) 8.92 (1H s). [M+H] 421; [M-H] 419.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]([F:29])[F:28])[CH:19]=1)([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:7][C:8]([O:10]C)=O)#[N:4]>COCCOC>[C:14]([CH:13]1[CH2:12][C:5]([C:3]#[N:4])([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]([F:29])[F:28])[CH:19]=2)[CH2:6][CH2:7][C:8]1=[O:10])([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OC(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC(F)F)c2)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (95%, 0.33 g, 13.2 mmol) in dry 1,2-dimethoxyethane (70 mL) under an argon atmosphere was added a solution of dimethyl 4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)pimelate (1.7 g. 4.4 mmol) in dry 1,2-dimethoxyethane (70 mL). The resulting mixture was refluxed for 5h, cooled to room temperature, stirred overnight and quenched with water. The mixture was partitioned between ethyl acetate and acidic water, extracted three times with ethyl acetate, the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, provided an oil (0.51 g, 33%, 51% based on recovered starting material).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C[O-].[Na+]>CO.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([C:16]([O:18][CH3:19])=[O:17])([C:12]([O:14][CH3:15])=[O:13])[CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23]
Reactant: C=CC(=O)OC
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCC(C(=O)OC)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reaction time: 40 h
Yield: 84.7 %

Procedure:
To a solution of the nitro diester, Dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (86) (0.44 g, 1.62 mmol) and methyl acrylate (0.22 mL, 2.43 mmol) in absolute methanol (5 mL) was added a catalytic amount of sodium methoxide at 21° C. under argon. The reaction mixture was stirred for 40 h at the same temperature and then diluted with dichloromethane (50 mL). The resulting mixture was washed with water, brine and dried. The residue obtained upon evaporation of the solvents was purified on a silica gel (hexane:ethyl acetate, 8:1) to give Trimethyl 1-(2-fluoro-4-nitrophenyl)propane-1,1,3-tricarboxylate (85) (0.49 g, 85%): 1H NMR δ 8.04 (dd, 1H, J=8.7, 2.3 Hz), 7.95 (dd, 1H, J=10.9, 2.3 Hz), 7.57 (dd, 1H, J=8.7, 7.5 Hz), 3.81 (s, 6H), 3.62 (s, 3H), 2.64-2.69 (m, 2H), 2.35-2.40 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[N:10]=[N:9]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:25](=[N:27]O)[NH2:26]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[O:16][N:26]=[C:25]([C:19]3[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=3[F:17])[N:27]=2)[N:10]=[N:9]1
Reactant: Cc1c(C(=O)O)nnn1-c1ccccc1Br
Reactant: NC(=NO)c1cc(F)ccc1F
Product: Cc1c(-c2nc(-c3cc(F)ccc3F)no2)nnn1-c1ccccc1Br
Temperature: 100 °C

Procedure:
The title compound was prepared following procedure described for Example 1, but starting from 1-(2-bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid, prepared according to Zhang, Z.-Y. et al. Magn. Reson. Chem. 1998, 36, 159-460 (56.42 mg; 0.20 mmol) and 2,5-difluoro-N′-hydroxybenzenecarboximid amide (JRD-Fluoro, 37.87 mg; 0.22 mmol). The reaction mixture was filtered through an NH2 SPE column (1 g) and evaporated. The residue was taken up into pyridine and heated at 100° C. for 7 h, in order to complete oxadiazole formation. Pyridine was evaporated and the crude product was purified by flash chromatography (SiO2: 10 g; cyclohexane/EtOAc gradient from 90/10 till 50/50) and dried to afford Example 3 as a yellow solid. 1H NMR: (DMSO-d6, 300 MHz) δ 8.06 (dd, J=1.70 Hz, J=7.73 Hz, 1H), 8.02-7.97 (m, 1H), 7.86 (dd, J=1.89 Hz, J=7.53 Hz, 1H), 7.80-7.69 (m, 2H), 7.63 (dt, J=1.91 Hz, J=6.58 Hz, 2H), 2.61 (s, 3H). LC/MS: 419.93 (M+H)+. HPLC (Method A) Rt 4.92 min (Purity: 96%).
Reaction SMILES: N([O-])=O.[Na+].NC1C=CC(C)=CC=1.Cl.[Cl-].[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([N+:21]#[N:22])=[CH:17][CH:16]=1.[CH2:24]([O:26][C:27](=[O:30])[CH2:28][Cl:29])[CH3:25].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:24]([O:26][C:27](=[O:30])[C:28]([Cl:29])=[N:22][NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH3:23])=[CH:16][CH:17]=1)[CH3:25]
Reactant: Cc1ccc([N+]#N)cc1
Reactant: CCOC(=O)CCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccc(N)cc1
Product: CCOC(=O)C(Cl)=NNc1ccc(C)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 15.2 g. of sodium nitrite in 40 ml. of water is added dropwise to a solution at 0° C. of 21.4 g. of p-toluidine and 400 ml. of 7.5% hydrochloric acid. The suspension of p-toluene diazonium chloride obtained is added dropwise at 5° C. to a mixture consisting of 36.2 g. of 2-chloroacetic acid ethyl ester, 400 ml. of 50% ethanol and 164 g. of sodium acetate. The mixture then is stirred for three hours at 20° C. and extracted with ethyl acetate. The organic phase is concentrated and the residue is treated with petroleum ether. 41 g. of 2-chloro-2-(4-methyl-phenylhydrazono)-acetic acid ethyl ester with a melting point of 100°-101° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: OCc1cncn1-c1ccc(Br)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cncn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(4-bromophenyl)-3H-imidazol-4-yl]-methanol (5) (500 mg, 2.0 mmol) in dry methylene chloride (30 mL) was added MnO2 (1.74 g, 20.0 mmol) and the resulting mixture stirred overnight at rt. The suspension was then filtered through Celite and the filtrate concentrated under reduced pressure to give 3-(4-bromophenyl)-3H-imidazole-4-carbaldehyde (6). MS (ES+): m/z 251/253 (1/1) [MH+]. 1H NMR (CDCl3, 400 MHz): δ=7.24 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.77 (s, 1H), 7.94 (s, 1H), 9.78 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].Cl[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 86.5 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.00 g, 51.54 mmol) in DMF (100 mL) was cooled to 0° C. in an ice bath and treated with sodium hydride (60% dispersion in oil) (3.092 g, 77.30 mmol) in one portion. The reaction mixture was stirred at 0° C. for 2 minutes, then at ambient temperature for 30 minutes. The reaction mixture was cooled to 0° C. and (2-(chloromethoxy)ethyl)trimethylsilane (11.82 mL, 67.00 mmol) was added. The reaction mixture was warmed to ambient temperature and allowed to stir overnight. The reaction mixture was poured into aqueous saturated ammonium chloride (100 mL) containing ice (approximately 100 mL) and stirred until the ice melted. After the ice melted, the cold mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated under reduced pressure to afford the title compound (14.45 g, 44.56 mmol, 86.46% yield). MS (apci) m/z=325.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:37]([O:40][CH2:41][C:42](O)=[O:43])(=[O:39])[CH3:38].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:42](=[O:43])[CH2:41][O:40][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: CC(=O)OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(=O)COC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Yield: 60.6 %

Procedure:
To (1S,2R,4aS,5R,8R,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethenyl)-1, 2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 139, 210 mg, 0.4 mmol) and 4-dimethylaminopyridine (65 mg, 0.53 mmol) in dichloromethane (10 ml) was added (acetyloxy)acetic acid (60 mg, 0.51 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.58 mmol). The resultant mixture was stirred at room temperature and upon completion was concentrated in vacuo. The crude product was purified by chromatography on a Biotage® 12M column eluting with hexane:ethyl acetate (2:1). The pure fractions were combined and the solvent removed in vacuo to give the title product (150 mg, 61%).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5](=[NH:7])[NH2:6].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35])[C:27](OC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO.O1CCOCC1>[CH2:32]([C:31]1[N:7]=[C:5]([CH2:4][O:3][CH3:2])[NH:6][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: COCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 66.1 %

Procedure:
A solution of 2-methoxyethanimidamide hydrochloride (10 g), 28% sodium methoxide (24 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (15 g) in methanol (150 mL) and 1,4-dioxane (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and acetic acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (11 g, 71%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:6][CH2:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[CH:19]=3)[CH:12]=[CH:11][N:10]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:6][CH2:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[C:18]3[C:23](=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[CH:19]=3)[CH:24]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc2cc(-c3ccnc(NCCc4ccc(OC)c(OC)c4)n3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Product: COc1ccc2cc(-c3ccnc(NCCc4ccc(OC)c(OC)c4)n3)cc(N3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound (109) was dissolved in methanol (2 mL) and charged with HCl (1 mL, 4 M solution in dioxane). The resulting mixture was stirred at room temperature for 16 h. It was then filtered and dried under high vacuum to afford N-(3,4-dimethoxyphenethyl)-4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)pyrimidin-2-amine (110) as a yellow solid (0.125 g). M.p.=138-140° C. 400 MHz 1H NMR (DMSO-d6) δ: 9.36 (br s, 2H), 8.44-8.43 (m, 2H), 8.02 (d, J=9.0 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.31 (d, J=6.3 Hz, 1H), 6.92-6.82 (m, 3H), 3.97 (s, 3H), 3.73-3.68 (m, 8H), 3.41-3.31 (m, 8H), 2.89 (m, 2H); Experimental Elemental Analysis (2.9 equivalents of HCl)=57.53% C, 5.90% H, 11.37% N; Calculated Elemental Analysis 57.54% C, 5.98% H, 11.57% N; LCMS (m/z): 500 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (190 mg) was prepared from (3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (183 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure A. LC-MS (m/z) 736.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32][OH:33])([CH3:29])[C:27]#[CH:28]>>[CH2:34]([N:30]([C:26]([CH3:25])([CH3:29])[C:27]#[C:28][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2)[CH2:31][CH2:32][OH:33])[CH3:35]
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C#CC(C)(C)N(CC)CCO
Product: CCN(CCO)C(C)(C)C#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1

Procedure:
In analogy to example 17.3, Trifluoro-methanesulfonic acid 1-(4-fluoro-phenyl)-1H-indol-5-yl ester and 2-[(1,1-Dimethyl-prop -2-ynyl)-ethyl-amino]-ethanol were converted to Yield 2-(Ethyl-{3-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-1,1-dimethyl-prop-2-ynyl}-amino)-ethanol as orange viscous oil, MS: 365 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.Br[C:63]1[CH:68]=[CH:67][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:65][CH:64]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([C:63]3[CH:68]=[CH:67][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:65][CH:64]=3)[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (75 mg, 0.17 mmol) in toluene (1.0 mL) was added Pd2(dba)3 (1.6 mg, 0.0017 mmol), racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.7 mg, 0.0017 mmol), 1-bromo-4-trifluoromethyl-benzene (38 mg, 0.17 mmol) and sodium tert-butoxide (22 mg, 0.23 mmol). The mixture was heated, in a sealed-tube, to reflux for 3.5 h. The reaction was quenched with H2O at room temperature and extracted with EtOAc (3×10 mL). The organic was washed with brine (2×10 mL), dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-{4′-trifluoromethyl-5-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-biphenyl-3-yl}-pentanoic acid ethyl ester and methyl ester. Calcd for C32H33F6NO2 (M+H) 578.60, Found 578.4 (methyl ester) and Calcd for C33H35F6NO2 (M+H) 592.63, Found 592.31 (ethyl ester).