Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.C([Li])CCC.[C:26](=[O:28])=[O:27].Cl>C(OCC)C.C(OCC)(=O)C.O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:26]([OH:28])=[O:27])[CH:7]=1
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2-bromo-4-methoxy-6-[3-(trifluoromethyl)phenoxy] pyridine (3.00 g, 0.0086 mol) was suspended in about 30 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained suspension was mixed with n-butyl lithium [5.9 ml (ca. 1.6 M in hexane solution), 0.0086×1.1 mol], and the obtained mixture was stirred for about 10 minutes. After replacing an interior of the reactor with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The obtained reaction solution was mixed with about 10 ml of a 1 N aqueous hydrochloric acid solution, distributed in ethyl acetate-water, and then washed with saturated brine. The organic phase separated from the solution was dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:43]1([O:52]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:43][OH:52])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(1-pyrrolidinylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 13) (288 mg, 0.79 mmol) and N,N-diisopropylethylamine (138 μl, 0.79 mmol) in N,N-dimethylformamide (6ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (452 mg, 1.19 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Further N,N-diisopropylethylamine (552 μl, 3.16 mmol) was then added, followed by the hydroxylamine hydrochloride (165 mg, 2.38 mmol) and the mixture stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue wasa partitioned between ethyl acetate and pH 7 aqueous buffer. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2) to afford the title compound as a foam (126 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(CC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:32][CH2:33][CH2:34][OH:35])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([NH:32][CH2:33][CH2:34][O:35][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCc1ccccc1O
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccccc1OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 20 h

Procedure:
Diethyl azodicarboxylate (4.2 ml, 26.4 mmol) was added to a mixture of 2-(tritylamino)ethanol (6.08 g, 20.0 mmol), methyl 3-(2-hydroxyphenyl)propionate (5.00 g, 26.4 mmol), triphenylphosphine (6.91 g, 30.5 mmol) and THF (90 ml) at room temperature under nitrogen, and the mixture was standing for 20 hours at room temperature. The solvent was removed in vacuum. The residue was purified on SiO2, eluting with ethyl acetate-hexane (1:15), to afford the titled product as a colorless oil. (5.88 g, 49%)
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1COCC1.O>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([C:31]2[CH2:32][CH2:33][N:28]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:29][CH:30]=2)=[CH:35]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Yield: 72.1 %

Procedure:
A solution of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-methylbenzenesulfonate (0.192 g, 0.499 mmol), 3-(1,2,3,6-tetrahydropyridin4-yl)-1H-indole (0.119 g, 0.601 mmol) and K2CO3 (0.104 g, 0.753 mmol) in (1:1) THF:DMF (1.4 mL) was heated to 80–83° C. for 10 h. After this time, H2O (3 mL) was added and the suspension was filtered. The filtered solid was washed with CH3OH (2×3 mL), Et2O (2×5 mL) and air-dried to give 0.148 g (72%) of the title compound as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=1)[CH:7]=[C:6]2[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[C:42](Cl)(=[O:58])[O:43][CH2:44][CH:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[C:8]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)[CH:7]=[C:6]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:42]([O:43][CH2:44][CH:45]3[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:51]=4[C:52]4[C:57]3=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:58])[CH2:24][CH2:23]2)=[CH:11][CH:12]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CNc1nccc(-c2cc(NC3CCNCC3)c3cc(OC)ccc3c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNc1nccc(-c2cc(NC3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 4-(6-methoxy-4-(piperidin-4-ylamino)naphthalen-2-yl)-N-methylpyrimidin-2-amine 150 (0.46 g, 1.32 mmol), N,N-diisopropylethylamine (0.92 mL, 5.2 mmol), N,N-dimethylformamide (2 mL), and tetrahydrofuran (10 mL), (9H-fluoren-9-yl)methyl carbonochloridate (0.41 g, 1.6 mmol) was added. The reaction was stirred at room temperature for 30 min and then partitioned between water (100 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated (rotary). The residue was purified by column chromatography (silica gel) using 60% ethyl acetate/hexanes as the eluent to afford (9H-fluoren-9-yl)methyl 4-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)amino)piperidine-1-carboxylate 205 as a yellow solid (0.53 g). LC/MS (m/z): 586 [M+H].
Reaction SMILES: O[C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2ccccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(Nc2ccc(Cl)c(Cl)c2)c2ccccc2n1
Yield: 68 %

Procedure:
Prepared using general procedure 3; 2-Hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (1.5 g, 4.9 mmol) and 9.2 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 1.075 g of material (3.32 mmol, 68%). 1H NMR (300 MHz, DMSO): 9.61(s, 1H), 8.40(d, 1H, J=8.07 Hz), 7.82(m, 2H), 7.65(m, 3H), 7.45(dd, 1H, J=8.68, 2.63 Hz), 6.87(s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.Cl[C:29]1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CN(C)C=O.O1CCOCC1.C1C=CC=CC=1>[F:20][C:21]1[CH:27]=[CH:26][C:24]([N:25]2[C:11]([C:4]3[CH:5]=[CH:6][C:7]([N:8]([CH3:9])[CH3:10])=[C:2]([CH3:1])[CH:3]=3)=[CH:12][C:13](=[O:19])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:29]2)=[CH:23][CH:22]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C=Cc1ccc(N(C)C)c(C)c1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1cn(-c2ccc(F)cc2)c(-c2ccc(N(C)C)c(C)c2)cc1=O
Temperature: 25 °C
Yield: 61.8 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 2.0 g of methyl 5-(3-methyl-4-dimethylaminophenyl)-3-oxo-4-pentenoate, and 1.1 g of N,N-dimethylformamidodimethylacetal was added to the resulting solution, after which they were reacted at 70° C. for 1.5 hours. To the reaction mixture was then added 1.0 g of p-fluoroaniline at 70° C., and they were reacted at 80° C. for 2 hours and further at 140° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain an oily substance. This oily substance was dissolved in 30 ml of dioxane, and to this solution was added dropwise a solution of 2.1 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone in 10 ml of benzene at 80° C. Thereafter, the mixture was subjected to reaction at the same temperature for 30 minutes and the solvent was removed by distillation under reduced pressure. The residue was suspended in 50 ml of chloroform and 50 ml of water, and after adjusting this suspension to a pH 7.5 with sodium hydrogencarbonate, the organic layer was separated, washed successively with 10 ml of water and 20 ml of a saturated aqueous solution of sodium chloride and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.8 g of methyl 1-(4-fluorophenyl)-6-(3-methyl-4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinate having a melting point of 217°-220° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[NH:7]1[C:15]2[C:10](=C[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.[CH2:16](I)[CH3:17]>>[CH2:16]([N:7]1[C:15]2[C:10](=[C:1]([OH:4])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)[CH3:17]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C([O-])[O-]
Reactant: CCI
Agent: [K+]
Product: CCN1CCc2c(O)cccc21
Yield: 23 %

Procedure:
4-Hydroxyindole was reduced with sodium cyanoborohydride and acetic acid to give 4-hydroxy, dihydroindole. A mixture of ethyl iodide (40 ml), potassium carbonate (1.09 gm, 7.8 mmole) and 4-hydroxy, dihydroindole (1.06 gm, 7.8 mmole) was refluxed for 2 hr. Excess ethyl iodide was evaporated under vacuum, water was added (10 ml) and the product was extracted with dichloromethane. Silica gel chromatography gave N-ethyl4-hydroxy-dihydroindole (0.30 gm, 23% yield) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:33]=[CH:32][C:8]2[N:9]=[C:10]([C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:19]([CH3:31])[CH:18]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH3:29][C:26]([CH3:27])([CH3:28])[C:25](=[O:30])[CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]([C:10]2[O:11][C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:33]=[CH:32][C:8]=3[N:9]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:31]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)OC)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2ccc(C(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-6-carboxylic acid methyl ester (1.50 g, 3.32 mmol) in MeOH (10 mL) and THF (10 mL) is treated with NaOH (2.0 M, 20.0 mL). The resulting mixture is stirred at RT for 16 h. The mixture is concentrated, acidified with HCl (5 N) until pH˜3, and extracted with EtOAc (100 mL, then 50 mL). The organic layer is dried over Na2SO4, filtered, and concentrated to afford the title compound (1.40 g, 97%). H-NMR (ppm, CDCl3) δ: 8.16 (1H, d, J=1.3 Hz), 8.11 (1H, dd, J=1.3, 8.4 Hz), 7.78 (1H, d, J=8.4 Hz), 7.02 (1H, d, J=1.8 Hz), 6.97 (1H, dd, J=2.2, 8.4 Hz), 6.54 (1H, d, J=8.4 Hz), 4.85 (2H, s), 2.40 (2H, q, J=7.5 Hz), 2.30 (2H, q, J=7.5 Hz), 2.26 (3H, s), 1.25 (9H, s), 0.77 (6H, t, J=7.5 Hz). MS (ES) m/e: 438.2 (M+1), 436.2 (M−1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:33]([Si:35]([C:40]#[CH:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34].O>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13]=3[C:12]([C:34]#[C:33][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(N3CCCCC3)ncnc21
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC[Si](C#Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCCCC3)c12)(CC)CC
Yield: 80.7 %

Procedure:
To a flamed-dried flask under nitrogen was charged 211 mg (0.5 mmol) of the product from Method R, 19 mg (0.1 mmol) of copper (I) iodide and 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium. To this mixture was then added 0.14 mL (1.0 mmol) of triethylamine and 0.27 mL (1.5 mmol) of triethylsilylacetylene as a solution in 1.5 mL of dry DMF. The resulting mixture stirred at room temperature for 3 hours, at which time, 5.0 mL of water were added and the mixture extracted with ethylacetate. The ethyl acetate extract was dried over MgSO4 and concentrated in vacuo. The resulting crude product was then purified by silica-gel chromatography (7:1 hexanes/ethyl acetate) affording 194 mg (89%) of the title compound. LRMS: 481 (M+1), 341.
Reaction SMILES: [OH-].[K+].C([S:6][CH2:7][CH2:8][C:9]([N:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:13][CH:12]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:10])(=O)C.C(O)(=O)C>CO.O>[SH:6][CH2:7][CH2:8][C:9]([N:11]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[S:13][CH:12]1[C:26]([OH:28])=[O:27])=[O:10]
Reactant: CC(=O)SCCC(=O)N1N=C(c2ccc(C(F)(F)F)cc2)SC1C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C1SC(c2ccc(C(F)(F)F)cc2)=NN1C(=O)CCS
Reaction time: 2 h

Procedure:
Potassium hydroxide in methanol (1M, 4.9 ml) was added to a solution of the product from step c) (0.81 g) in methanol (10 ml) and water (5 ml). The mixture was stirred under an atmosphere of nitrogen for 2 hours. Glacial acetic acid was added and the solvent was removed under reduced pressure The product was purified by flash chromatography using 1% acetic acid/99% ethyl acetate as eluent to yield the title compound (0.23 g) as a fawn solid. mp softens 93°-75°.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:33][CH:34]([O:40][CH:41]([CH3:43])[CH3:42])[C:35]([O:37]CC)=[O:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])=O)(C)(C)C>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:23][CH2:24][C:25]3[CH:26]=[C:27]([CH2:33][CH:34]([O:40][CH:41]([CH3:43])[CH3:42])[C:35]([OH:37])=[O:36])[CH:28]=[CH:29][C:30]=3[O:31][CH3:32])=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(C2CCCCC2)cc1

Procedure:
Using 4-cyclohexylbenzoic acid and ethyl 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl)-2-isopropoxypropanoate, 3-(3-[(4-cyclohexylbenzoyl)amino)methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](OC)=O.[NH3:24]>>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:8][CH2:9][CH2:4][CH:5]([CH3:6])[O:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:16]2[C:15]=1[N:24]=[C:1]([NH2:3])[CH:2]=[CH:17]2)[CH3:12]
Reactant: N
Reactant: COC(=O)c1cccc(O)c1
Reactant: CCN(CC)c1cccc(O)c1
Product: CCN(CC)c1cccc(OCCCC(C)Oc2cccc3ccc(N)nc23)c1

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting 3-(diethylamino)phenol for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, CDCl3) δ ppm 7.97 (d, 1H), 7.32 (t, 1H), 7.28 (m, 1H), 7.21 (dd, 1H), 7.15 (d, 1H), 7.06 (d, 1H), 6.90 (m, 2H), 6.74 (m, 1H), 4.69 (m, 1H), 4.11 (m, 1H), 4.05 (m, 1H), 3.49 (m, 4H), 2.21 (m, 1H), 2.08 (m, 1H), 1.93 (m, 2H), 1.46 (d, 3H), 1.11 (t, 6H); MS (DCI/NH3) m/z 394 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].BrCC1CCCCO1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:14]1=[O:33].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[O:33]=[C:14]1[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]1[CH2:2][C:3]#[N:4]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: N#CCCl
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: N#CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using chloroacetonitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile was obtained (61%) as a colorless solid: mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ7.38 (dt, J=7.7, 1.2 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.11 (dt, J=7.7, 1.1 Hz, 1H), 6.66 (s, 1H), 6.21 (s, 1H), 5.89 (d, J=1.5 Hz, 2H), 4.94 (ABq, J=17.9 Hz, 2H), 4.73 (ABq, J=9.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 155.8, 148.9, 142.232, 141.0, 131.9, 129.4, 124.3, 124.3, 119.8, 116.0, 109.7, 103.5, 101.9, 93.8, 80.1, 57.8, 28.8; MS (ES+) m/z 321.3 (M+1).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23].[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44]>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([NH:27][C:26]1[C:25]([CH:22]([CH3:24])[CH3:23])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:32]([CH3:34])[CH3:33])=[O:44]
Reactant: O=C(O)CCCCCCCBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.7 %

Procedure:
WSC (1.05 g 5.5 mmols) and HOBt (743 mg, 5.5 mmols) were added to a DMF (15 ml) solution of 2,6-diisopropylaniline (886 mg, 5 mmols) and 8-bromooctanoic acid (1.67 g, 7.5 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from other-hexane to obtain 720 mg (yield: 38%) of 8-bromo-N-(2,6-diisopropylphenyl) octanamide as colorless needle-like crystals.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:23]([O:24][CH3:25])[CH3:22])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Ten grams (10 g 65 mmol) of 2-fluoro-3-(trifluoromethyl)benzoic acid and oxalyl chloride in 10 mL of anhydrous CH2Cl2 were treated with a few drops of DMF, and stirred at ambient temperature for 1 hour (gas evolution ceased). N,O-Dimethyhydroxylamine hydrochloride (16.8 g, 174 mmol) was added followed by 16 ml of pyridine. The reaction mixture was stirred overnight, then washed successively with H2O, 2 N HCl, and brine. The resulting solution was dried over sodium sulfate. Evaporation of solvents in vacuo gave 13.3 g of product as an oil, which was pure enough to be used in the next step without further purification.