Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.CC(C)([O-])C.[K+].C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Fc1ccccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Brc1ccc(COc2ccccn2)cc1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, to a solution of 4-bromobenzyl alcohol (600 g, 3.21 mol) and 2-fluoropyridine (343 g, 3.53 mol) in tetrahydrofuran (1069 mL) was added a solution of potassium tert-butoxide (396 g, 3.53 mol) in tetrahydrofuran (3208 mL) (63 min, 9.2 to 20.5° C.) dropwise under a 7° C. cooling. After stirring at 22° C. for three hours, an aqueous solution of 5% sodium bicarbonate (prepared from sodium bicarbonate: 160 g and water: 3208 mL) was added thereto dropwise (20 min, 21.0 to 23.9° C.). Then, heptane (3220 mL) was added thereto and extracted, the organic layer was washed with water (800 mL). The organic layer was concentrated under a reduced pressure (to approximately 3200 mL), ethanol (1604 mL) was added thereto and concentrated under a reduced pressure (to approximately 3200 mL). Then, to the layer was added heptane (3200 mL), concentrated under a reduced pressure, heptane (3200 mL) was further added thereto and concentrated under a reduced pressure, so as to obtain a solution of the title compound in heptane (2603 g, containing 789 g of the target product) as a brown oily product (yield: 93.2%).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25]([C:27]([CH3:29])=[O:28])=[CH2:26].N#N>CO>[O:28]=[C:27]([CH3:29])[CH2:25][CH2:26][N:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:26][CH2:25][C:27](=[O:28])[CH3:29])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(C)=O
Reactant: c1ccc(CNCCCCCCCCNCc2ccccc2)cc1
Agent: N#N
Solvent: CO
Product: CC(=O)CCN(CCCCCCCCN(CCC(C)=O)Cc1ccccc1)Cc1ccccc1
Reaction time: 16 h

Procedure:
Dissolve the product obtained in Step A in 1400 ml of methanol and introduce 21.6 of methyl vinyl ketone on a stream of N2 gas. Stir for 16 hours to yield the title compound.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C(C(O)=O)=[CH:9]1>C(Cl)Cl>[CH3:9][N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:7]1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cn1cc(C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (11.86 mL, 136 mmol) was added dropwise to a solution of 1-methyl-1H-indole-3-carboxylic acid (4.76 g, 27 mmol) in 100 mL of methylene chloride. A rapid evolution of gas was observed. The reaction stirred at room temperature for 17 h (overnight). The solvent was removed under reduced pressure to give a pink solid To remove any excess oxalyl chloride the solid was dissolved in benzene and the solvent removed under reduced pressure to give 1-methyl-1H-indole-3-carbonyl chloride which was immediately used in step 2 without additional purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:18](Br)([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(O)c2)cn1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cccc(OC(C)C)c2)cn1
Yield: 95.1 %

Procedure:
A mixture of 696 mg of the compound prepared in Example 11, 405 mg of isopropyl bromide and 248 mg of potassium carbonate in 15 ml of anhydrous dimethylformamide is heated under nitrogen for one hour to 100° C. With incomplete reaction, equivalent amounts of isopropyl bromide and potassium carbonate are furthermore added two to three times. For working up purposes, the solvent is distilled off and the remaining residue is stirred with water. The thus-obtained crude product is filtered off, dried, and purified by chromatography on silica gel with toluene/ethyl acetate (8:2), thus producing 782 mg (95%) of the title compound as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].I[CH3:18]>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:18])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CI
Reactant: COC(=O)Cc1ccc(C#N)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)c1ccc(C#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a stirred solution of methyl 2-(3-chloro-4-cyanophenyl)acetate (931 mg, 4.441 mmol) in dimethylformamide were added 60% sodium hydride (178 mg, 4.441 mmol) and iodomethane (0.3 mL, 4.441 mmol) at 0° C. The reaction mixture was stirred for 1 h at 0° C., then diluted with water. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to give methyl 2-(3-chloro-4-cyanophenyl)propanoate (642 mg, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](I)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: CCCCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1cc(I)ccc1C(=O)OC

Procedure:
A mixture of methyl 2-hydroxy-4-iodobenzoate (25 g, 90 mmol), caesium carbonate (35.2 g, 108 mmol) and n-heptyl iodide (19.2 ml, 117 mmol), in 500 ml of dimethylformamide (DMF) is stirred for 10 hours at room temperature. The solution is neutralized by addition of 2N hydrochloric acid solution. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator. After evaporation of the solvent, 33.84 g (100%) of the expected compound are recovered in the form of a brown oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Br>C1COCC1>[OH:2][CH:1]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:17])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: Cc1ccccc1[Mg]Br
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 2.0 M. 2-methylphenylmagnesium bromide in THF (0.15 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2-methyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][C:11]=1[Cl:21])=[O:9])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].O.[CH3:34][C:35]#[N:36]>>[C:1]([O:5][C:6]([C:7]1[C:35]([C:34]2[CH:11]=[CH:10][CH:8]=[CH:7][CH:6]=2)=[N:36][O:9][C:8]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][C:11]=1[Cl:21])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C(=O)CC(=O)OC(C)(C)C)c(Cl)c1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C

Procedure:
Intermediate 56 (115 mg, 0.35 mmol) is dissolved in MeCN (3 mL). Potassium bis(trimethylsilyl)amide (106 mg, 0.53 mmol) is added slowly while stirring at room temperature. Then the mixture is cooled to 0° C., and a solution of intermediate 58 (55 mg, 0.35 mmol) in CH3CN (1 mL) is added. The mixture is stirred at room temperature overnight, then H2O (5 mL) is added and the mixture is extracted with DCM (3×10 mL). After concentration the crude product is purified on reverse phase HPLC (H2O/MeCN gradient) to afford 5-(2-chloro-4-methoxycarbonylmethyl-phenyl)-3-phenyl-isoxazole-4-carboxylic acid tert-butyl ester 59 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.73 (m, 2H), 7.47 (m, 5H), 7.33 (m, 1H), 3.72 (s, 3H), 3.68 (s, 2H), 1.23 (s, 9H). MS calculated for C23H23ClNO5 (M+H+) 428.1, found 428.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]([CH3:39])[C:37]#[N:38])[CH:35]=2)O1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:32]=[N:33][N:34]([CH:36]([CH3:39])[C:37]#[N:38])[CH:35]=3)[C:16]2=[CH:15][N:14]=1
Reactant: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4cnn(C(C)C#N)c4)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (Example 34, Step 1). LCMS (M+H)+=444.0/446.0. 1H NMR (300 MHz, DMSO-d6) δ: 9.72 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.04 (s, 1H), 5.92 (q, J=7.1 Hz, 1H), 3.97 (s, 6H), 1.88 (d, J=7.1 Hz, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=2)=[CH:10][CH:9]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C@H:38]3[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]3)=[CH:32][CH:31]=2)[C:25]([C:45]#[N:46])=[C:24](SC2C=CC=CC=2)[N:23]=1.O>COCCOC>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][C@H:38]3[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]3)=[CH:34][CH:35]=2)[C:25]([C:45]#[N:46])=[C:24]([O:20][CH2:19][C:17]2[N:18]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=3)[O:15][CH:16]=2)[N:23]=1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(Sc4ccccc4)c3C#N)cc2)O1
Reactant: OCc1coc(-c2ccc(Cl)cc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)OC[C@H](COc2ccc(-c3c(C#N)c(N)nc(OCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
122 mg (1.09 mmol) of potassium tert-butoxide are suspended in 2 ml of dry 1,2-dimethoxyethane. 229 mg (1.09 mmol) of the compound from Example 100A and 100 mg (0.22 mmol) of the compound from Example 98A are then added successively. The reaction mixture is stirred at 60° C. for 2 h and, after cooling, at RT for a further 10 h. 5 ml of water are then added to the mixture. The precipitate formed is filtered off with suction and washed once with about 2 ml of cold water. This is followed by purification by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][CH:2]=[CH:10][CH:9]=3)=[O:13])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Yield: 97.8 %

Procedure:
Treat 1H-indole-2-carboxylic acid 3 (X═H, 1.0 mg, 6.21 mmol) with N-(tert-butoxycarbonyl)piperazine (1.10 equiv., 1.3 g, 6.83 mmol) as described in General Synthetic Procedure VIa to afford 4-(1H-indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester 8 (X═H, R4=piperazin-4-yl-1-carboxylic acid tert-butyl ester; 2.0 g, 99%) as a white solid, mp 205-206° C. 1H NMR (DMSO-d6) δ 11.6 (brs, 1H), 7.6 (d, 1H), 7.4 (d, 1H), 7.2 (t, 1H), 7.1 (t, 1H0, 6.8 (s, 1H), 3.8-3.7 (m, 4H), 3.5-3.4 (m, 4H), 1.4 (s, 9H); m/z=330 (M+1). Treat 4-(1H-indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (329 g, 1.0 mmol) with phenyldisulfide (283 mg, 1.3 equiv., 1.3 mmol) as described in General Synthetic Procedure VIIa and then treat with trifluoroacetic acid (4 mL) in HOAc, to remove the Boc protecting group, to afford (3-phenylsulfanyl-1H-indol-2-yl)-piperazin-1-yl-methanone. Dissolve (3-phenylsulfanyl-1H-indol-2-yl)-piperazin-1-yl-methanone in EtOAc and treat with 1N HCl/Et2O to provide the title compound Iae (103 mg, 29%) as a tan solid, mp 240° C. (dec); m/z=338 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=O)=[C:4]([OH:17])[CH:3]=1.C[O:19][C:20](=O)[CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:21][C:20](=[O:19])[O:17]2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(Cl)cc2o1
Yield: 49.3 %

Procedure:
Under argon atmosphere, a mixture of (4-chloro-2-hydroxyphenyl)(4-fluorophenyl)methanone (1.00 g) and methyl(triphenylphosphoranylidene)acetate (3.00 g) in toluene (15 mL) was heated under reflux for 15 hours. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=95/5 to 85/15) and the product was triturated in n-hexane-diisopropyl ether to give the titled compound (0.54 g) as a pale yellow powder.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[Si]([O:15][CH2:16][C:17]([CH3:59])([CH3:58])[CH2:18][N:19]1[CH:28]=[C:27]([S:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:43]3[CH:48]=[C:47]([C:49](=[O:54])[NH:50][CH:51]4[CH2:53][CH2:52]4)[CH:46]=[C:45]([F:55])[C:44]=3[CH3:56])[CH:25]=2)[C:20]1=[O:57])(C(C)(C)C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:51]1([NH:50][C:49](=[O:54])[C:47]2[CH:48]=[C:43]([C:24]3[CH:25]=[C:26]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:57])[N:19]([CH2:18][C:17]([CH3:58])([CH3:59])[CH2:16][OH:15])[CH:28]=[C:27]4[S:29]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:4])[C:44]([CH3:56])=[C:45]([F:55])[CH:46]=2)[CH2:53][CH2:52]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(SC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic Acid (1 mL) was added to a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)piperidine-1-carboxylate (Example 59a, 0.06 g) in DCM (2 mL), and the reaction was stirred at room temperature for 30 min. Toluene (10 mL) was added and the volatiles were removed under reduced pressure (repeated 3×). The residue was purified by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of 0.1% aqueous NH3 in acetonitrile), and after solvent removal and trituration with diethyl ether gave the title compound (0.01 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13]3[O:21][C:20]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[CH:14]=3)[O:10][N:9]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[C:25]([N+]([O-])=O)=[N:26][CH:27]=[CH:28][CH:29]=1.CC(O)=O>CS(C)=O>[CH3:22][O:23][C:24]1[C:25]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[N:12]=[C:11]([C:13]4[O:21][C:20]5[CH:19]=[CH:18][N:17]=[CH:16][C:15]=5[CH:14]=4)[O:10][N:9]=3)[CH2:3][CH2:2]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1cc2oc(-c3nc(CC4CCNCC4)no3)cc2cn1
Reactant: COc1cccnc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COc1cccnc1N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1
Temperature: 25 °C

Procedure:
2-(3-Piperidin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)furo[3,2-c]pyridine (Preparation 12, 50 mg, 0.176 mmol) and 3-methoxy-2-nitropyridine (41 mg, 0.264 mmol) were shaken in DMSO (1 mL) at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature, before being acidified with AcOH. Purification by RP-HPLC yielded the title compound: RT=4.99 min; m/z (ES+)=392.4 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([O:10][CH:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)C.ClCCl.B.[Na]>O1CCCC1>[OH:3][CH:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([O:10][CH:11]([CH3:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OC(C)c2ccccc2)cc1
Agent: B
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(O)c1ccc(C(=O)OC(C)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
32.17 g (0.12 mol) of methylbenzyl 4-acetylbenzoate, 50 ml of ethanol, 100 ml of dichloromethane and 50 ml of tetrahydrofuran were supplied into the same flask as used in Example 9, and then 2.3 g (0.06 mol) of sodium boron hydride was added at 15°-25° C. over a period of 10 minutes. After standing at the same temperature for 2 hours, the reaction mixture was poured into ice-water and treated similarly to Example 9 to obtain 31.43 g (97% yield) of methylbenzyl 4-(1-hydroxyethyl)benzoate (III-13).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:23])([CH3:22])[CH2:8][CH2:9][N:10]2[C:13]([NH:15]C2C=CC=CC=2)=[O:14])=[CH:5][CH:4]=1)#[N:2].[CH2:24](N=C=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.C(#N)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:22])([CH3:23])[CH2:8][CH2:9][N:10]2[C:13]([NH:15][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)CCN(C(=O)Nc2ccccc2)c2cc(C#N)ccc21
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC1(C)CCN(C(=O)NCc2ccccc2)c2cc(C#N)ccc21
Yield: 87.8 %

Procedure:
A solution of the title J compound from Example 1 (0.20 g, 1.07 mmole), benzyl isocyanate (0.14 g, 1.07 mmole) and 4-dimethylaminopyridine (50 mg) in acetonitrile (4.5 mL) was heated under argon at reflux for one hour. The solvent was recovered under vacuum and the crude product was chromatographed on silica eluting with hexane/ethyl acetate (7:3) to afford 0.30 g of the title compound as a white solid; m.p. 114°-115° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])[CH2:4][CH2:3]1.[C:20](O)(=[O:22])[CH3:21].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:20]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])[CH2:4][CH2:3]1)(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@H](Nc2ccc(C#N)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(trans-4-hydroxycyclohexylamino)-3-nitrobenzonitrile (1.0 g), acetic acid (345 mg) and diethyl azodicarboxylate (2.17 g, 40% solution in toluene) in anhydrous tetrahydrofuran (25 mL) was added portionwise triphenylphosphine (1.31 g) at 0° C., and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated in vacuo and the residue was subjected to a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (5:1 to 3:1) and then chloroform. The obtained substance was triturated with methanol to give 4-(cis-4-acetoxycyclohexylamino)-3-nitrobenzonitrile (530 mg) as yellow powders.
Reaction SMILES: C[O:2][C:3](OC)([C:5]([C:13]#[N:14])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:4].CCCCCC.C(OCC)(=O)C>Cl>[C:13]([C:5](=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:3](=[O:2])[CH3:4])#[N:14]
Reactant: COC(C)(OC)C(C#N)=Cc1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)C(C#N)=Cc1ccccc1
Temperature: 25 °C
Yield: 38 %

Procedure:
A sample of 3-cyano-4-phenyl-3-buten-2-one dimethylketal, prepared in accordance with the procedure of Example 5 (5.0 g, 23 mmol) was suspended in 6N HCl (100 mL) and stirred at room temperature for 72 h1. Thin layer chromatographic analysis (SiO2, hexane—ethyl acetate 7:3) indicated nearly complete conversion of the ketal to the lower Rf ketone which had deposited along the bottom of the reaction flask as a yellow solid. The solid was purified by column chromatography (SiO2, hexane—ethyl acetate 9:1) and the desired fractions evaporated to give 1.5 g (38%) of 3-cyano-4-phenyl-3-buten-2-one, as colorless needles, mp 83-84° C. (lit. 80-81° C.2).
Reaction SMILES: [ClH:1].[N:2]1([C@@H:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:12]([OH:16])[CH2:13][NH:14][CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:23]C1C2C(=CC=CC=2)N([C@@H](C2C=CC=CC=2)[C@H](O)COS(C2C=CC(C)=CC=2)(=O)=O)C=1.CN>CO>[ClH:1].[CH3:15][NH:14][CH2:13][C@@H:12]([OH:16])[C@@H:11]([N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:23])=[CH:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNC[C@@H](O)[C@H](c1ccccc1)n1ccc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2cc(C)c3ccccc32)cc1
Agent: CN
Agent: Cl
Solvent: CO
Product: CNC[C@@H](O)[C@H](c1ccccc1)n1cc(C)c2ccccc21

Procedure:
In an analogous manner to EXAMPLE 5, (1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid 3-(3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and methylamine (2N solution in methanol) as a white solid. [□]D25/MeOH=+116; CD/MeOH=(−); MS (ESI) m/z 295 ([M+H]+); HRMS: calcd for C19H22N20+H+, 295.18049; found (ESI, [M+H]+), 295.1816.
Reaction SMILES: [C:1]([C:3](=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][NH2:23])[O:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH2:7][CH2:6]1)[CH3:4])#[N:2].[Cl:26][CH:27]([Cl:31])[C:28](O)=[O:29]>>[C:1]([C:3](=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:28](=[O:29])[CH:27]([Cl:31])[Cl:26])[O:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH2:7][CH2:6]1)[CH3:4])#[N:2]
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Product: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CNC(=O)C(Cl)Cl)OC3=O)cc2F)CC1
Yield: 63 %

Procedure:
The title compound was prepared by following the procedure of Example 29 and by using (S)-N-{3-[4-(4-(1-cyanoethylidene)-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and dichloroacetic acid in 63% yield.