Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:9]([NH2:12])(=[O:11])=[O:10])[S:7][CH:8]=1)([O-:3])=[O:2].[CH2:13]([N:17]=[C:18]=[O:19])[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH2:13]([NH:17][C:18]([NH:12][S:9]([C:6]1[S:7][CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:10])=[O:11])=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])cs1
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cc([N+](=O)[O-])cs1
Temperature: 0 °C

Procedure:
A stirred suspension of 10 g of 4-nitrothiophene-2-sulfonamide, 6 g of n-butyl isocyanate and 7 g of anhydrous potassium carbonate in 100 ml of acetone was heated to reflux for 3 hours. The resultant viscous mixture was poured into ice-water and the pH adjusted to 2 by the addition of concentrated hydrochloric acid. The resulting tarry precipitate thus obtained was extracted into methylene chloride, separated from the aqueous phase, dried over magnesium sulfate, filtered and concentrated in-vacuo. The residue which showed absorption peaks by NMR at 0.7 to 1.7 (multiplet), consistent for butyl and at 8.3 and 8.5, consistent for the thiophene ring was used without further purification in the following example.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.S(Cl)(Cl)=O.[Al+3].[Cl-:19].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:19][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[N:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: [Cl-]
Reactant: Cn1nnc2ccc(C(=O)O)cc21
Agent: [Al+3]
Solvent: Clc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cn1nnc2ccc(C(=O)c3ccc(Cl)cc3)cc21

Procedure:
The carboxylic acid (b) is converted into the corresponding acid chloride with thionyl chloride and then reacted with chlorobenzene and AlCl3, yielding the title compound.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)[CH2:45][C:46]([F:49])([F:48])[F:47])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(c1cccc(CN(CC(F)(F)F)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (92 mg) in DMF (0.89 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (77 μL) and potassium carbonate (74 mg) at 0° C., and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was cooled to 0° C., potassium carbonate (246 mg) was added, and the mixture was stirred at 80° C. for 2 days. The reaction mixture was cooled to 0° C., 2,2,2-trifluoroethyl trifluoromethanesulfonate (256 μL) was added, and the mixture was further stirred at 80° C. for 3 days. The mixture was cooled to room temperature, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was directly used for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C(O)C.[OH-].[K+]>O>[CH3:1][C:2]1[C:3](/[C:16](/[Si:29]([CH3:30])([CH3:32])[CH3:31])=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(/C=C(/c2cc3c(cc2C)C(C)(C)CCC3(C)C)[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1/C(=C/c1ccc(C(=O)O)cc1)[Si](C)(C)C)C(C)(C)CCC2(C)C
Temperature: 50 °C

Procedure:
To a solution of ethyl(Z)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trimethylsilyl)vinyl]benzoate (Compound 4, 0.034 g, 0.076 mmol) and 2 mL of ethyl alcohol was added aqueous 1 N KOH (0.5 mL). The resulting solution was heated in an 50° C. bath until the hydrolysis reaction was completed, as judged by thin layer chromatography. The solution was cooled to room temperature, diluted with water and washed once with 1:1 ether:hexane solution, and the layers were separated. The aqueous layer was acidified with 1 N aqueous HCl and the product extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, and dried over MgSO4, and filtered, and the solvents were removed in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:26]=[CH:25][C:12]([CH2:13]OC3C=CC=CC=3C(OC)=O)=[CH:11][CH:10]=2)[O:3]1.[OH:28][C:29]1[C:34](=[O:35])[CH:33]=[CH:32][N:31]([CH3:36])[C:30]=1[CH3:37].BrCC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:36][N:31]1[CH:32]=[CH:33][C:34](=[O:35])[C:29]([O:28][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:3][C:2]([CH3:27])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]3)=[CH:26][CH:25]=2)=[C:30]1[CH3:37]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: COC(=O)c1ccccc1OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(OCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(=O)ccn1C
Yield: 50 %

Procedure:
The synthesis of B12 was accomplished following the procedure outlined for B1 using 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (80 mg, 0.54 mmol), 4-bromomethylphenyl boronic acid pinacol ester (180 mg, 0.59 mmol), and K2CO3(223 mg, 1.6 mmol) in 8 mL of acetonitrile affording B12 in 50% yield (0.09 g, 0.26 mmol). 1HNMR (400 MHz, CDCl3) δ=7.70 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.27 (d, J=7.6 Hz, 1H), 5.18 (s, 2H), 3.44 (s, 3H), 2.02 (s, 3H), 1.29 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=173.55, 146.13, 141.63, 140.83, 139.19, 134.91, 128.46, 117.21, 84.05, 73.00, 41.80, 24.97, 13.15. ESI-MS(+): m/z 356.20 [M+H]+, 378.10 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:19][C:20]1[C:25]2=[N:26][S:27][N:28]=[C:24]2[C:23]([S:29](Cl)(=[O:31])=[O:30])=[CH:22][CH:21]=1>C(Cl)Cl>[F:19][C:20]1[C:25]2=[N:26][S:27][N:28]=[C:24]2[C:23]([S:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)(=[O:30])=[O:31])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c2nsnc12
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2ccc(F)c3nsnc23)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-aminobenzoate (412 mg, 2.5 mmol) in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) and 7-fluorobenzo[c][1,2,5]thiadiazole-4-sulfonyl chloride (39C) (633 mg, 2.5 mmol). The resulting mixture was stirred at 50° C. overnight. After removal of DCM, the residue was partitioned between water and EtOAc. The organic layer was washed with 2 N HCl, water and brine, dried over Na2SO4 and concentrated to give crude product 39D, which was confirmed by LCMS, and used in the next reaction without further purification. 1H NMR (CHLOROFORM-d) δ: 8.33 (dd, J=8.0, 4.6 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H), 7.66 (s, 1H), 7.35-7.30 (m, 1H), 7.12 (d, J=8.7 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H). LC-MS: m/z 382.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O)[CH3:16].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1OC
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (10.0 g, 50.0 mmol, 1.0 equiv), 3-ethoxy-4-methoxy-benzaldehyde (10.8 g, 60.0 mmol, 1.2 equiv; commercially available) and acetic acid (11.4 mL, 12.01 g, 200.0 mmol, 4.0 equiv) in ethanol (40 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (6.27 g, 100.0 mmol, 2.0 equiv), dissolved in ethanol (20 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 5 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate to yield 9.71 g (53%) of the title compound as a white solid. MS (ISP): 365.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].CC1C=CC(S(O[CH2:31][C@@H:32]2[CH2:34][O:33]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH2:31][C@@H:32]2[CH2:34][O:33]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:16])[CH3:17])[C@H:10]1[CH3:18]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1Cl)C2(C)C
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C[C@@H]3CO3)c(=O)c1Cl)C2(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Chloro-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (120 mg, 0.425 mmol) in N,N-dimethylformamide (2 mL) was mixed with (2S)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (117 mg, 0.513 mmol) and potassium carbonate (71 mg, 0.0514 mmol) at room temperature and stirred at 80° C. for 3 hours. After cooling, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was evaporated under reduced pressure. The resulting crude product was used for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[C:21]#[CH:22].C(NCC)C>C(#N)C.C(#N)C.C(#N)C.[Pd](Cl)Cl.[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:22]#[C:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(I)c(N)c1
Reactant: C#Cc1c(Cl)cccc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CC#N
Solvent: CCNCC
Product: COC(=O)c1ccc(C#Cc2c(Cl)cccc2Cl)c(N)c1
Temperature: 120 °C

Procedure:
A mixture of methyl 3-amino-4-iodobenzoate (604 mg, 2.18 mmol) (from Example 3-4), 2,6-dichlorophenylacetylene (447 mg, 2.61 mmol), palladium (II) chloride bis(acetonitrile) (23 mg, 89 μmol), diethylamine (449 μL, 318 mg, 4.35 mmol), and copper (I) iodide (21 mg, 110 μmol) in acetonitrile (10 mL) was heated for 35 min at 120° C. in a microwave apparatus. The mixture was filtered, and the filtrate concentrated, then chromatographed using a gradient of 0-30% heptane/ethyl acetate to give methyl 3-amino-4-(2,6-dichlorophenylethynyl)-benzoate.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]3[C:18](=[O:21])[NH:19][S:20][C:5]2=3)[CH2:3][CH2:2]1.Cl.Cl.[CH3:24][C:25]1([NH2:29])[CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][C:25]([NH2:29])([CH3:24])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]3[C:18](=[O:21])[NH:19][S:20][C:5]2=3)[CH2:2][CH2:3]1
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(F)c(F)c1n2C1CC1
Reactant: CC1(N)CNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(N)CN(c2c(F)cc3c(=O)c4c(=O)[nH]sc4n(C4CC4)c3c2F)C1
Yield: 74.3 %

Procedure:
A mixture of 250 mg (0.8 mmol) of 9-cyclopropyl-6,7,8-trifluoro-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, 255 mg (1.6 mmol) of 3-methyl-3-aminoazetidine dihydrochloride and 0.6 ml of triethylamine in 10 ml of pyridine is kept refluxing for 2 hours, the mixture is evaporated under vacuum, a mixture of ethanol with water is added, the resulting mixture is filtered and the product is washed. 0.225 g of 9-cyclopropyl-6,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, melting point 294°-300° C., is thereby obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([OH:44])[CH2:21][CH:20]([CH2:22]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:19][CH:18]2[CH:14]1[CH2:15][N:16]([C:33](=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42])[CH2:17]2>CN(C)C=O.O>[N:1]([CH2:22][CH:20]1[CH2:19][CH:18]2[CH:14]([CH2:15][N:16]([C:33](=[O:43])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH2:17]2)[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH3:5])([OH:44])[CH2:21]1)=[N+:2]=[N-:3]
Reactant: COc1ccccc1CC(=O)N1CC2CC(CS(=O)(=O)c3ccc(C)cc3)CC(O)(c3ccccc3OC)C2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CC(=O)N1CC2CC(CN=[N+]=[N-])CC(O)(c3ccccc3OC)C2C1
Temperature: 50 °C
Reaction time: 48 h
Yield: 98.6 %

Procedure:
0.35 g of sodium azide is added to a solution of 2.03 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-6-tosylmethylperhydroisoindol-4-ol in 10 cm3 of dimethylformamide. The reaction mixture is heated at 50° C. for 8 hours and stirred at 20° C. for 48 hours and then diluted with 150 cm3 of water and subjected to extraction twice with 40 cm3 of ethyl acetate. The organic phase is washed with 50 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). 1.6 g of (3aRS,4RS,6SR,7aSR)-6-azidomethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[CH3:27][N:28]1[C:32](=[O:33])[CH2:31][C:30]([CH3:34])=[N:29]1.CC(C)(O)C#N>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[OH:33][C:32]1[N:28]([CH3:27])[N:29]=[C:30]([CH3:34])[C:31]=1[C:9]([C:8]1[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:12]=1)=[O:11]
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: CC1=NN(C)C(=O)C1
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)c1c(C)nn(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
1.0 g (0.004 mol) of 2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinic acid is dissolved in 10 ml of oxalyl chloride. Three drops of dimethylformamide are added, and the mixture is stirred at room temperature for 1 hour. The mixture is then concentrated using a rotary evaporator, and the residue (2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinoyl chloride) is taken up in 10 ml of methylene chloride. At a temperature of 0° C., 0.84 ml (0.006 mol) of triethylamine and 0.45 g (0.004 mol) of 2,5-dimethyl-2,4-dihydropyrazol-3-one are added. After 2 hours at a temperature of 22° C. the solvent is removed using a vacuum rotary evaporator, and the residue that remains is dissolved in 10 ml of acetonitrile and, to rearrange the intermediate (2,5-dimethyl-2H-pyrazol-3-yl 2-(2-methoxyethoxymethyl)-6-trifluoromethytnicotinate), admixed with 0.1 ml of acetone cyanohydrin and 1.13 ml (0.008 mol) of triethyamine. The reaction solution is stirred at room temperature for four hours and then concentrated. The syrup that remains is chromatographed on silica gel. The viscous oil obtained by eluting with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 parts by volume) is dissolved in ethyl acetate and washed successively with 10% hydrochloric acid and water. The organic solution is dried over Na2SO4 and concentrated, giving 0.93 g of (5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-[2-(2-methoxyethoxymethyl)-6-trifluoromethylpyridin-3-yl]methanone in the form of a viscous oil.
Reaction SMILES: N[C:2]([NH2:4])=[O:3].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15]([CH2:22]C(O)=O)([CH2:18][C:19](O)=[O:20])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([N:12]1[CH2:13][CH2:14][C:15]2([CH2:22][C:2](=[O:3])[NH:4][C:19](=[O:20])[CH2:18]2)[CH2:16][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(N)=O
Reactant: O=C(O)CC1(CC(=O)O)CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)CC(=O)N1
Temperature: 160 °C
Reaction time: 3 h
Yield: 104.1 %

Procedure:
Urea (242 mg, 4.03 mmol) was added to 2,2′-(1-benzylpiperidine-4,4-diyl)diacetic acid (390 mg, 1.34 mmol). The mixture was heated to 160° C. After 3 h, additional urea (242 mg, 4.03 mmol) was added and the mixture was heated to 185° C. After 18 h, additional urea (242 mg, 4.03 mmol) was added. After 48 h, the reaction mixture was allowed to cool to ambient temperature and ethanol was added. After 1 h, the mixture was filtered and solid was washed with ethanol. Saturated aqueous sodium bicarbonate was added to the solid and the suspended solution was stirred until gas release was complete. The mixture was filtered and the solid was washed with water, and concentrated to give the title compound (380 mg). MS 273.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](O)=[O:25])[CH:19]=1>>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])[CH:19]=1
Reactant: O=C(O)c1cccnc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccnc4)cc23)CC1
Yield: 73.8 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.1 mg (0.09 mMol pyridine-3-carboxylic acid, 7.4 mg of the title compound were recovered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(CNc2ccc(C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCOc1ccc(CNc2ccc(C(=O)O)cc2)cc1

Procedure:
A mixture of 5 g. of ethyl p-[p-(heptyloxy)benzyl]amino benzoate (prepared as described in Example 54), 1.51 g. of potassium hydroxide and 50 ml. of 95% ethanol is refluxed for 5 hours. Concentrated hydrochloric acid is added and the mixture diluted with 150 ml. of water. Chilling and filtering gives crystals which are recrystallized from ethanol to give white crystals, m.p. 148°-152.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)[NH:9][N:8]=2)=[N:3][CH:2]=1.[H-].[Na+].[CH3:20]I>O1CCCC1>[CH3:20][N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[N:9]1
Reactant: CI
Reactant: c1cc(-c2n[nH]c(-c3ccncn3)n2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(-c2ccncn2)nc1-c1ccncn1

Procedure:
To 3,5-bis(4-pyrimidinyl)-1,2,4-triazole (2.3 g.) in dry tetrahydrofuran (125 ml.) is added 57% sodium hydride in mineral oil (0.46 g.). After refluxing 0.5 hour, methyl iodide (1.4 g.) is added and the mixture is heated at reflux an additional three hours. The reaction mixture is cooled, filtered and concentrated to a solid which after recrystallization yields substantially pure 1-methyl-3,5-bis(4-pyrimidinyl)-1,2,4-triazole.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1>>[NH2:1][C:2]1[C:3]([C:4]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Reactant: Fc1ccc(I)cc1
Product: Nc1nc(Cl)ccc1C(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 1-fluoro-4-iodobenzene (Aldrich 99%) using the procedure described in Example 7. HRMS, observed: 250.0314, Calcd for M+: 250.0309.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH:4]([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]([CH:2]=[P:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: CCCCC(C)C(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCC(C)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 29.9 %

Procedure:
A solution of 1-chloro-3-methylheptan-2-one (49.4 g.) and triphenylphosphine (79.5 g.) in chloroform (250 ml.) was saturated with nitrogen and refluxed under nitrogen overnight. The chloroform was removed in vacuo and the residue (crude 3-methyl-2-oxoheptyltriphenylphosphonium chloride) was added portionwise to a solution of sodium carbonate (109 g.) in water (1500 ml.) and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petroleum ether (b.p. 60°-80° C.) to give 2-methylhexanoylmethylenetriphenylphosphorane (35.2 g.), m.p. 107°-109° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: Cc1onc(-c2ccncn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
To a solution of (5-methyl-3-pyrimidin-4-yl-isoxazol-4-yl)-methanol (313 mg, 1.63 mmol) in THF (20 mL) was added methyl 6-hydroxynicotinate (276 mg, 1.8 mmol) and triphenylphosphine (644 mg, 2.5 mmol) at room temperature under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.1 mL, 2.5 mmol) was added and the reaction mixture was stirred for 30 min at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (95 mg, 18%) as a white solid. MS: m/e=327.3 [M+H]+.