Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1.[H-].[Na+].CI.[C:18]([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:18][O:1][CH2:2][C:3]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2ncc(CO)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COCc1cnc2ccc(C#N)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(hydroxymethyl)-imidazo[1,2-a]pyridine-6-carbonitrile (7-2) (346 mg, 2 mmol) in 20 mL of THF was added sodium hydride (240 mg, 60% in oil) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then methyl iodide (615 mg, 4.3 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was treated with aqueous Na2CO3, then concentrated. The residue was diluted with water and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated to afford the title compound (300 mg). MS (m/z): 188.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:20]([NH2:22])=[O:21].[O:23]1[CH2:28][CH2:27][N:26]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][C:39](OC)=O)=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:25][CH2:24]1>>[OH:19][CH:17]([CH:7]([N:6]1[C:2]2[N:1]=[C:39]([CH2:38][C:35]3[CH:34]=[CH:33][C:32]([S:29]([N:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)(=[O:31])=[O:30])=[CH:37][CH:36]=3)[NH:22][C:20](=[O:21])[C:3]=2[N:4]=[N:5]1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: CC(O)C(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Product: CC(O)C(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(S(=O)(=O)N4CCOCC4)cc3)nc21

Procedure:
Analogously to the procedure of Example 29, the title compound is prepared from 10 mg (0.024 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-[1,2,3]triazole-4-carboxamide and 30 mg (0.107 mmol) of methyl 4-morpholinosulphonylphenylacetate.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:11][C:12](=[O:24])[CH2:13][CH2:14][CH:15]([OH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH:7]=[CH:8][CH2:9][CH3:10].N1C=CC=CC=1.[CH2:31]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C1(C)C=CC=CC=1.O>[CH2:5]([O:11][C:12](=[O:24])[CH2:13][CH2:14][CH:15]([O:23][C:1](=[O:2])[N:41]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH:7]=[CH:8][CH2:9][CH3:10]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCNCCCCCCCCCC
Reactant: CCC=CCCOC(=O)CCC(O)CCCCCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCC=CCCOC(=O)CCC(CCCCCCC)OC(=O)N(CCCCCCCCCC)CCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 6.20 ml of an ice-cooled 20% solution of phosgene in toluene was slowly added a solution of 3 g 4-hydroxy-undecanoic acid hex-3-enyl ester and 0.93 g pyridine in 3 ml toluene. The reaction mixture was stirred for 16 hours at room temperature. A mixture of 3.48 g didecylamine and 0.93 g pyridine was added and the mixture was stirred for another 16 hours. Water was added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, 2N hydrochloric acid, water, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel to give 2.9 g of a colorless liquid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)#[N:22]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-cyanobenzoic acid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCN(C(=O)OC)C(CC2CCCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 2-(cyclohexylmethyl)piperidine-1,4-dicarboxylate (2.20 g, 7.40 mmol) was dissolved in THF (25 mL) and water (25 mL). LiOH (0.266 g, 11.1 mmol) was added and the resulting mixture was stirred at room temperature overnight and heated under reflux for 30 min. The reaction mixture was partitioned between 1 M KHSO4 and diethyl ether. The organic phase was dried (Na2SO4), filtered through Celite® and the solvent was evaporated. The crude product was dissolved again in THF (25 mL) and water (25 mL). LiOH (0.23 g) was added to the reaction flask. The reaction mixture was stirred overnight. The reaction was worked up as above to give the product. 1H NMR (600 MHz, cdcl3) δ 0.85 (ddd, 2H), 1.19 (dddd, 5H), 1.38-1.48 (m, 1H), 1.61 (d, 4H), 1.72 (tt, 2H), 1.97 (qd, 3H), 2.56-2.65 (m, 1H), 3.02-3.14 (m, 1H), 3.67 (d, 3H), 3.88 (d, 1H), 4.22 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:25]=[C:26]=[O:27].N[C:29]1[C:38]2[NH:37][C:36](=[O:39])[CH2:35][O:34][C:33]=2[CH:32]=[CH:31][CH:30]=1>CCOC(C)=O.CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:26]([NH:25][C:29]2[C:38]3[NH:37][C:36](=[O:39])[CH2:35][O:34][C:33]=3[CH:32]=[CH:31][CH:30]=2)=[O:27])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: [N-]=C=O
Reactant: Nc1cccc2c1NC(=O)CO2
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1COc2cccc(NC(=O)NCc3ccc(C(F)(F)F)cc3)c2N1
Temperature: 80 °C
Yield: 32 %

Procedure:
Commercially available 4-trifluoromethylbenzylamine (1 ml, 7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (2 g, 7 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1e (766 mg, 4.66 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 550 mg of a white solid. Yield=32% 1HNMR (DMSO, 400 MHz) δ 4.40 (2H, d, J=5.6 Hz), 4.52 (2H, s), 6.70 (1H, dd, J=8 Hz, J′=1.2 Hz), 6.86 (2H, t, J=8 Hz), 7.16 (1H, dd, J=8 Hz, J′=1.2 Hz), 7.54 (2H, d, J=8 Hz), 7.70 (2H, d, J=8.4 Hz), 8.18 (1H, s), 10.11 (1H, bs); [M+1] 366.2 (C17H14F3N3O3 requires 365.31).
Reaction SMILES: [OH:1][C@@H:2]([CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([O:1][C@@H:2]([CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:39])[CH3:38]
Reactant: CON(C)C(=O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc2c(OC[C@H](CN3CCC(c4ccc5ccccc5c4)CC3)OC(C)=O)cccc2o1
Reaction time: 24 h

Procedure:
(S)-4-(2-Hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N-methoxy-N-methylbenzo(b)furan-2-carboxamide (0.40 g) obtained in Example 6 was dissolved in pyridine (20 ml) and acetic anhydride (10 ml) was added at room temperature. The mixture was stood for one day. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (S)-4-(2-acetoxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N-methoxy-N-methylbenzo(b)furan-2-carboxamide (0.34 g) as a brown oil. This was dissolved in ethanol and maleic acid (0.10 g) was added. The precipitated crystals were collected by filtration and dried to give the title compound (0.25 g) as pale-yellow crystals, melting point 125–127° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=O)[CH3:17].C([O-])(=O)C.[NH4+].C([BH3-])#[N:25].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]([NH2:25])[CH3:17]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc(F)cc1-c1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc(F)cc1-c1ccc(F)cc1F

Procedure:
The title compound was prepared from 1-(2′,4′,5-trifluoro-1,1′-biphenyl-2-yl)ethanone (720 mg, 2.9 mmol), anhydrous methanol (10 mL), ammonium acetate (4.44 g, 58 mmol), and sodium cyanoborohydride (362 g, 5.8 mmol) according to the procedure and in the same manner as described in Example 105, step b. The crude amine was immediately used without further purification in Example 114, step c;
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([C@@H:13]([C@H:15]([C:17]([O:19]CC)=O)[OH:16])[OH:14])([O:10]CC)=O.O>CO>[CH:1]1([NH:7][C:8](=[O:10])[C@@H:13]([C@H:15]([C:17]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:19])[OH:16])[OH:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Solvent: CO
Solvent: O
Product: O=C(NC1CCCCC1)[C@H](O)[C@@H](O)C(=O)NC1CCCCC1
Reaction time: 0.5 h
Yield: 13 %

Procedure:
N,N′-Di-cyclohexyl L-tartaramide was prepared by the reaction of cyclohexyl amine with diethyl L-tartrate. Diethyl L-tartrate (19.997 g, 1.0 eq) and HPLC grade methanol (40 mL) were weighed into a 250 mL round-bottomed flask equipped with a teflon coated magnetic stir bar. Cyclohexyl amine (20.205 g, 2.0 eq) was slowly poured into the stirring diethyl L-tartrate solution. Some fuming and a color change from water-white to pale yellow were observed. Additional methanol (10 mL) was used to rinse all of the amine into the reaction flask. After stirring the solution for 30 min, the flask was stoppered and refrigerated at approximately 45° F. (70C). The product crystallized after 3 days at 45° F. (7° C.). The white crystals were filtered, washed with methanol (2×15 mL), and dried under vacuum. A first crop of 3.952 g (12.65 mmole, 13% yield) were obtained in this manner, and a second crop of 16.063 g were obtained by removing the solvent under vacuum. Overall yield was 66%.
Reaction SMILES: I[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([CH2:20]I)[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[C-:29]#[N:30].[Na+].O.C[N:34]([CH:36]=O)C>>[CH2:14]([O:13][C:9]1[CH:10]=[CH:11][C:12]2[C:3]([CH2:2][C:29]#[N:30])=[C:4]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:5]=[CH:6][C:7]=2[C:8]=1[CH2:20][C:36]#[N:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CN(C)C=O
Reactant: [C-]#N
Reactant: CCCCCCOc1ccc2c(CI)c(OCCCCCC)ccc2c1CI
Agent: [Na+]
Solvent: O
Product: CCCCCCOc1ccc2c(CC#N)c(OCCCCCC)ccc2c1CC#N
Temperature: -4 °C
Yield: 63 %

Procedure:
A mixture of 1,5-bis(iodomethyl)-2,6-dihexyloxynaphthalene (0.50 g, 0.83 mmol) and sodium cyanide (0.16 1.74 mmol) was stirred in DMF (50 ml) at 55° C. for 1 g, h. Water (50 ml) was added to the cooled mixture and the resulting precipitate was filtered, washed with water and dried. It was redissolved in a minimum of dichloromethane, hexane (40 ml) was added, and the solution was cooled to -4° C. overnight. The product was filtered to yield (14) (0.21 g, 63%), m.p. 135°-6° C.; 1H NMR (250.1 MHz, CDCl3) δ0.9-1.9 (22H, m, alkyl), 4.11 (4H, s, CH2CN), 4.14 (3H, t, J=7 Hz, CH2O), 7.35 and 7.88 (2H, 2d, J- 10 Hz, aromatic); 13C NMR. (62.9 Mhz, CDCl3) δ13.5, 14.2, 22.8, 25.9, 29.6, 31.7, 69.8, 112.2, 115.8, 118.3, 121.5, 127.9, 152.9; IR (KBr) vmax /cm-1 2248 w, 1598 s, 1261 s, 1067 s, 802 m. m/z 406 (M, 28), 238 (100), 91 (95).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[C:18]=1[C:19]([C:3]1[C:4]2[C:9](=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:20]
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12

Procedure:
N-[3-(2,4,6-Trichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (Compound No. 45) was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2,4,6-trichlorobenzoyl chloride.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:15]([CH2:24][CH3:25])[C:16]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])=[O:17].O>CN(C=O)C>[CH2:22]([O:21][CH2:20][CH2:19][O:18][C:16]([CH:15]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7])[CH2:24][CH3:25])=[O:17])[CH3:23]
Reactant: CCOCCOC(=O)C(Br)CC
Reactant: O=Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOC(=O)C(CC)n1cccc1C=O
Yield: 62 %

Procedure:
A mixture consisting of pyrrole-2-carboxaldehyde (9.5 g, 0.1 mole), anhydrous potassium carbonate (27.6 g, 0.2 mole) and 2-ethoxyethyl α-bromobutyrate (23.6 g, 0.105), as previously described, were kept under stirring in 20 ml DMF at room temperature for 12 hours. The reaction mixture was carefully poured into water, extracted with ethylacetate and the extracts were dried on sodium sulfate. After evaporation of the solvent, 15.5 g of 1-[1-(2-ethoxyethoxycarbonyl)-propyl]-2-formyl pyrrole were obtained as a brown oil, which was used in the subsequent step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[Se:6][C:5]([C:7]([C:9]2[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=O)=[CH:4][CH:3]=1.[CH2:18]([NH:25][NH2:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[CH2:18]([N:25]1[C:4]2[CH:3]=[C:2]([CH3:1])[Se:6][C:5]=2[C:7]([C:9]2[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(C)[se]2)o1
Reactant: NNCc1ccccc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc(C)[se]c23)o1

Procedure:
Compound 7 (5.94 g, 0.02 mole), benzylhydrazine 50 (4.88 g, 0.04 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 56. Yield: 1.56 g (19.5%); white crystals;
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1.[C:18](O[K])(C)(C)C.CI>ClCCl>[CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]([CH3:18])([CH:9]=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)O[K]
Reactant: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Solvent: CI
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(C)(C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the title compound from step 1 (11.6 g, 50.0 mmol) in abs. dichloromethane (200 mL) was mixed with tert-BuOK (6.50 g, 58.0 mmol) and methyl iodide (3.42 mL, 55.0 mmol) at 0° C. in argon. After 30 min the batch was heated to RT and then stirred overnight (solid separated out). The reaction mixture was washed with water and saturated NaCl solution (50 mL), dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue purified by flash chromatography with ethyl acetate/MeOH 20:1.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH3:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH3:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 70.4 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methylbenzyl)oxy]-1H-pyrazole-4-carboxylate (0.15 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methylbenzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.10 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 176-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12.[CH3:13][O:14][C:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[CH:17][N:16]=1.CC([O-])=O.[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([O:14][CH3:13])[CH:20]=2)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12
Reactant: Cn1ncc2c(Cl)cc(Cl)nc21
Reactant: COc1cc(B(O)O)ccn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(-c2cc(Cl)c3cnn(C)c3n2)ccn1
Temperature: 120 °C
Yield: 51.5 %

Procedure:
4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5 (0.5 g, 4.9 mmol) was dissolved in acetonitrile (8 mL) and 2-methoxypyridine-4-boronic acid (0.4 g) and 1 M KOAc (8 mL) were added in a microwave tube. Nitrogen was bubbled through the solution for 5 minutes. 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (1.21 g) was added and the resultant mixture was then heated by microwave at 120° C. for 5 minutes. The reaction mixture was concentrated in vacuo and purified by flash chromatography (30% EtOAc in hexane) to provide 4-chloro-6-(2-methoxypyridin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.37 g).
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>COCCOC>[F:9][C:3]1[C:2]([C:14]2[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=2)=[CH:7][N:6]=[C:5]([NH2:8])[CH:4]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1cc(F)c(Br)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cnc(N)cc2F)cn1
Temperature: 120 °C
Yield: 75.4 %

Procedure:
To the reaction mixture of 5-bromo-4-fluoropyridin-2-amine (369 mg, 1.932 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (603 mg, 2.90 mmol), PdCl2(dppf)DCM (141 mg, 0.193 mmol) and DME (9.660 μL), 2M Na2CO3 (3.220 mL) was added. The reaction mixture was heated at microwave synthesizer (120° C., 12 min). To the reaction mixture, anhydrous sodium sulfate was added, filtered, and concentrated. The crude product was purified by flash chromatography eluting with 0-100% EtOAc (containing 10% of MeOH/heptane to provide 280 mg of desired product in 75% yield. LCMS (m/z): 193.1 (MH+), 0.35 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]3[C:16]4=[N:17][O:18][C:19]([C:21]5[O:25][N:24]=[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[C:22]=5[C:32]([F:35])([F:34])[F:33])(O)[CH:15]4[CH2:14][O:13][C:11]=3[CH:12]=2)[CH2:4][O:3]1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:36])[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]3[C:16]4=[N:17][O:18][C:19]([C:21]5[O:25][N:24]=[C:23]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[C:22]=5[C:32]([F:35])([F:33])[F:34])=[C:15]4[CH2:14][O:13][C:11]=3[CH:12]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(c2ccc3c(c2)OCC2C3=NOC2(O)c2onc(-c3ccccc3)c2C(F)(F)F)O1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)OCC(c2ccc3c(c2)OCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 124.3 %

Procedure:
To a stirred suspension of 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3a,4-dihydro-3H-chromeno[4,3-c]isoxazol-3-ol (Preparation 61A, 0.035 g, 0.070 mmol) in anhydrous toluene (1.0 mL) at room temperature was added pyridine (0.012 mL, 0.153 mmol) followed by thionyl chloride (8.64 μl, 0.118 mmol). The reaction mixture was stirred at room temperature for 15 min. and then at 80° C. for 15 min. The reaction mixture was cooled to room temperature and concentrated. The solid residue was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a yellow film. The combined crude products were triturated with methanol with sonication. The solid was collected to provide 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4H-chromeno[4,3-c]isoxazole (0.042 g, 0.087 mmol, 62% yield) as an off-white solid. The product had an HPLC with a ret. time=3.63 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=484.9.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:24].Cl[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]>CCCCCC.C1COCC1>[CH3:33][O:32][C:27]1[CH:26]=[C:31]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][N:17]([CH3:16])[C:18]2=[O:24])[CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccccc1Cl
Reactant: CN1CCCCCC1=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C2CCCCN(C)C2=O)c1
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium (0.05 mole) in hexane (34.4 ml), was treated with 2,2,6,6-tetramethylpiperidine (9.3 ml) followed by dry THF (100 ml) under an inert atmosphere at 0° C. The mixture was treated with N-methylcaprolactam (6.9 ml, 55 mM) and stirred for 30 minutes. A solution of butyl lithium (0.05 mole) in hexane (34.4 ml) was added, the reaction mixture stirred 15 minutes then treated with o-chloroanisole (3.1 ml). After 30 minutes a solution of butyl lithium (0.05 moles) in hexane (31.25 ml) was added, the mixture stirred for 15 minutes and treated with o-chloroanisole (3.1 ml). After a further 30 minutes, the reaction was quenched with water (100 ml) and the solvents removed under reduced pressure. The residue was partitioned between 5 N HCl (100 ml) and toluene (250 ml). The organic phase was washed with brine, dried and the solvents removed under reduced pressure.