Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:49]1([CH2:55][C@H:56]([NH2:65])/[CH:57]=[CH:58]\[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:65][C@H:56](/[CH:57]=[CH:58]\[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@H](/C=C\c1ccccc1)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C\c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3Z)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]-pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 7.1 mg (32 μmol) (2S,3Z)-1,4-diphenylbut-3-en-2-amine (intermediate 12).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:14](I)=[CH:13]1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29](N(OC)C)=[O:30])[CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([C:14]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:12]([CH:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:13]=2)=[O:30])[CH:24]=1
Reactant: CON(C)C(=O)c1cc(Br)ccn1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(Br)ccn2)c2cnccc21

Procedure:
Prepared according to the method described for Preparation 37 using 1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 55) and 4-bromo-N-methoxy-N-methylpyridine-2-carboxamide. Purified using silica gel column chromatography eluting with 35-40% EtOAc in hexane.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6].[CH3:12][S-:13].[Na+]>CS(C)=O.O>[CH:10]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[S:13][CH3:12])=[O:11]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(C#N)ccc1C=O
Reaction time: 0.75 h

Procedure:
3-Fluoro-4-formylbenzonitrile (2.00 g, 13.4 mmol) was dissolved in DMSO (27 ml), and sodium methanethiolate (1.50 g, 21.5 mmol) was added with ice-bath cooling. The mixture was stirred for 45 min and then diluted with water (100 ml). The resulting precipitated product was filtered off with suction, washed with water and dried under reduced pressure. This gave 1.36 g (51% of theory) of the target compound as a yellow crystalline solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1F
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccncc4)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 2,4-difluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 65 to give 2-[3-(2,4-difluoro-3-(pyridin-4-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as an off-white solid. Bis-hydrochloride (from ethanol/ethyl acetate): δH (360 MHz, DMSO) 1.56 (6H, s), 7.62-7.67 (1H, m), 7.85 (1H, d, J 7), 7.88-7.94 (1H, m), 7.99 (2H, d, J 6), 8.50 (1H, s), 8.94 (2H, d, J 6), 9.26 (1H, dd, J 7 and 3); m/z (ES+) 367 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br)#[N:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([C:32]#[N:33])[CH:35]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:27]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Oc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Reactant: N#Cc1cccc(CBr)c1
Product: COC(=O)c1ccc(Oc2ccc(N(Cc3cccc(C#N)c3)C3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 89.7 %

Procedure:
Using general procedure H, 4-[4-(4-methoxycarbonyl-phenoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 96) (440 mg, 1.07 mmol) and 3-cyanobenzyl bromide (314 mg, 1.6 mmol) afforded 4-{(3-cyano-benzyl)-[4-(4-methoxycarbonyl-phenoxy)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid (520 mg, 90%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@@H:30]3[O:35][C:34]4=[N:36][C:37]([N+:39]([O-:41])=[O:40])=[CH:38][N:33]4[CH2:32][CH2:31]3)=[CH:24][CH:23]=2)[CH2:17][C@H:16]1[CH3:42])=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:21][C@H:19]1[CH2:20][NH:15][C@H:16]([CH3:42])[CH2:17][N:18]1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C@@H:30]2[O:35][C:34]3=[N:36][C:37]([N+:39]([O-:41])=[O:40])=[CH:38][N:33]3[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: C[C@@H]1CN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)[C@@H](C)CN1
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (4 ml) was added to a dichloromethane solution (4 ml) of (2R,5S)-2,5-dimethyl-4-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (1.31 g), and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown amorphous compound (1.35 g).
Reaction SMILES: [F:1][C:2]([F:29])([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C1COCC1.CO.[Pt](=O)=O>[F:29][C:2]([F:1])([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3=[N:15][S:16](=[O:19])(=[O:20])[CH2:17][CH2:18][N:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Cc1cc(C(F)(F)c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(F)(F)c2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[difluoro(4-fluoro-3-methylphenyl)methyl]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (148 mg) in THF (dry) (50 mL) and MeOH (50 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (46.5 mg) as colorless crystals.
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][C:46]4[CH:51]=[CH:50][C:49]([CH2:52][CH3:53])=[CH:48][CH:47]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:52]([C:49]1[CH:50]=[CH:51][C:46]([CH2:45][CH2:44][NH:43][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:54]=[CH:55][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:56])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])=[CH:47][CH:48]=1)[CH3:53]
Reactant: CCc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1ccc(CCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 35.2 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(4-ethylphenethyl)-1-piperidinecarboxamide (0.295 g, 0.369 mmol) -was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.078 g, 0.13 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[NH:6][CH:7]([CH2:10][CH3:11])[CH2:8][CH3:9])([O-])=O.[H][H]>[Pd]>[CH2:8]([CH:7]([NH:6][C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=1[NH2:1])[CH2:10][CH3:11])[CH3:9]
Reactant: [H][H]
Reactant: CCC(CC)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Product: CCC(CC)Nc1ccccc1N

Procedure:
In a 2 liter hydrogenator is placed 2.5 g. of 10% palladium on carbon catalyst, 800 ml. of absolute alcohol and 250 g. of o-nitro-N-(1-ethylpropyl) aniline. Hydrogen is introduced and the reduction is complete in about 21/2 hours. The reaction is exothermic and the temperature subsides as the reaction goes to completion. The catalyst is removed by filtration and the ethanol is evaporated to yield a nearly quantitative yield (214 g.) of product as a dark oil. A pure sample is obtained by vacuum distillation, b.p. 2.0 mm Hg=125°-126° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH:12]=O.[CH2:14]1COCC1>>[CH:12]([C:4]1[NH:3][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH2:14]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: C=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
NaH (2.6 g, 66.2 mmol) at 0° C. was added to a mixture of 1H-indole-2-carbaldehyde (4.00 g, 27.6 mmol) and PPh3CH3Br (19.7 g, 55.2 mmol) in dry THF (100 mL) After being stirred at room temperature for 16 hours, the reaction was quenched with water. After partition, the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give 2-vinyl-1H-indole (4.0 g, 83% yield) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C[O-].[Na+].[CH3:15][O:16][C:17](=[O:25])/[CH:18]=[C:19](/[O:22][CH2:23]C)\[CH2:20]Cl>CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])/[CH:18]=[C:19](/[O:22][CH3:23])\[CH2:20][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCO/C(=C/C(=O)OC)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C/C(=C\C(=O)OC)OC)C(=O)OCC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
83.9 g (0.5 mol) of malonic acid diethyl ester was placed in 250 ml of N,N'-dimethylformamide. 27.8 g (0.5 mol) of sodium methylate was added at 20° C., 10 minutes later 48 g (0.25 mol) of 4-chloro-3-ethoxy-2E-butenoic acid methyl ester was added within 5 minutes. It was stirred for 2 hours at 20° C. Then 10.8 g (0.2 mol) of sodium methylate was added once more. After stirring for 15 hours at 20° C., the solvent was distilled off. After working up according to Example (a), 63.75 g (79 percent) of the title compound, with a purity of 98 percent (GC), was obtained. Data for the compound was:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:31]=[CH:30][C:15]([O:16][S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:29])[CH:21]=2)(=[O:19])=[O:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:36](OC(=O)C)(=[O:38])[CH3:37].O>CCOC(C)=O.CN(C)C1C=CN=CC=1>[C:36]([O:29][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:9]3[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[O:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:31][CH:30]=2)(=[O:18])=[O:19])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])(=[O:38])[CH3:37]
Reactant: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(OC(C)=O)c2)cc1
Reaction time: 24 h
Yield: 76 %

Procedure:
At ambient temperature, to a stirred solution containing 4-{4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.298 g, 0.602 mmol) and acetic anhydride (1 mL) In EtOAc (2 mL) was added 4-(dimethylamino)pyridine (3.7 mg, 0.0301 mmol). The reaction was refluxed for 72 h. The reaction was cooled to ambient temperature, hydrolyzed with H2O (5 mL) and stirred for 24 h. The reaction was diluted with EtOAc and the organic phase washed sequentially with H2O (2×), brine (2×), dried (MgSO4) and concentrated. Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 10 & 20% EtOAc/pet ether step gradient gave 0.122 g (76%) of the title compound as a yellow solid, mp 54-57° C. 1H NMR consistent. IR (KBr) 3400, 2900, 1700, 1380 and 1190 cm−1. mass spectrum (−ESI) m/z 535 (M−H).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:16]1([NH:22][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate (5.73 g, 0.0269 mol) was dissolved in 25 mL of DMF. While stirring under an atmosphere of nitrogen, cyclohexanamine in 5 mL of DMF (3.4 mL, 0.030 mol) and N,N-diisopropylethylamine (14 mL, 0.080 mol) were added simultaneously via two seperate syringes. The reaction mixture turned immediately into a deep yellow/orange gel and was diluted with another 5 mL of DMF. The reaction mixture was slightly exothermic and stirring was maintained until the reaction was complete as determined by LC/MS. The reaction mixture was then diluted with ethyl acetate and washed with 5% citric acid then brine. The organic phase was collected, dried over sodium sulfate and concentrated to a yellow oil which solidified under high vacuum to yield 8.47 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([S:11][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([Cl:8])[C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(SCc2ccccc2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A solution of 6.23 g of 2,3-dichloro-4-methoxythiophenol in 60 ml of sieved-dried dimethylformamide is added to 0.75 g of sodium hydride over a period of 2-3 minutes. After stirring at room temperature for 20 minutes, the yellowish solution is treated with 5.10 g of benzyl bromide at a rate so that the temperature does not rise above 40°. Stirring is continued for an additional 30 minutes. The cloudy mixture is poured onto 200 g of crushed ice with caution and the white precipitate is collected on a filter after 1 hour at 10° C. The air-dried product is recrystallized from acetone-hexane to give 7.8 g of 4-benzylthio-2,3-dichloroanisole as white needles, mp 116°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCCC(=O)O)cc1
Product: COc1ccc(CCCC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(4-Methoxyphenyl)butyric acid (2.0 g, 10.3 mmol) was treated with thionyl chloride (20 mL). The reaction was stirred at rt for 3 h, heated at 65° C. overnight and then concentrated under reduced pressure to give 4-(4-methoxyphenyl)butyryl chloride (2.3 g) as a yellow oil which was used without farther purification. IR (NaCl): 1795, 1510, 1244 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:14]([O:16]CC)=O)[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:20]([NH:33][NH2:34])(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:14]([NH:34][NH:33][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:16])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(C)c1=O
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(C)c1=O

Procedure:
Reagents: Comp 39 (0.36 mmols, 0.10 g); dodecanoyl hydrazine (0.39 mmols, 0.08 g). Yield: 0.105 g (65%), white solid, m.p.=165° C.-166° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[C:17]=2[CH3:29])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[C:17]=2[CH3:29])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)Cc1cccc(-c2ccc(O)cc2)c1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Cc1cccc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
tert-Butyl(dimethyl)silyl chloride (370 mg, 2.48 mmol) was added to a solution of allyl (4′-hydroxy-2-methyl-1,1′-biphenyl-3-yl)acetate (830 mg, 2.48 mmol) obtained in Example (98-1) and imidazole (170 mg, 2.48 mmol) in N,N-dimethylformamide (12 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was diluted with ethyl acetate and successively washed with water and a saturated aqueous NaCl solution, it was dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=95/5-90/10) to give allyl (4′-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-1,1′-biphenyl-3-yl)acetate (675 mg, yield: 69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([F:18])[CH:10]=1)[CH2:5][CH2:6]Br.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH2:6][CH2:5]1)=[O:19]
Reactant: COC(=O)C(CCBr)Oc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
The solution of 7.5 g (22.3 mmol) 4-bromo-2-(3-fluoro-4-nitro-phenoxy)-butyric acid methyl ester in 100 mL tetrahydrofuran was cooled to −15° C. and 2.63 g (23.4 mmol) potassium tert-butoxide were added. The cooling bath was removed and the reaction was stirred for 5 h at room temperature. The dark solution was poured 200 mL ethyl acetate and 200 mL aqueous hydrochloric acid, extracted and the phases were separated. The organic layer was washed with brine and the aqueous layers extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:30 to 70:30 v/v) to afford the title compound as a light yellow oil (79%). MS (TS) m/e (M): 255.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:15][CH3:16])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[K+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:15][CH3:16])[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(CC)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(CC(=O)O)c1ccc(F)cc1
Yield: 83.1 %

Procedure:
This compound was prepared in an analogous manner to Example 18c with the replacement of 3-(4-fluorophenyl)butyrate with ethyl 3-(4-fluorophenyl)valerate (38.95 g 0.144 mol, containing 29% triethyl phosphoneacetate) and using an excess of 85% potassium hydroxide (18.05 g, 0.273 mol, Mallinckrodt). The dichloromethane layers were combined, washed with deionized water (50 ml) and concentrated by spin evaporation in vacuo. The residue was crystallized from hexanes to give 23.47 g (83%) of 3-(4-flurophenyl)valeric acid as a white crystalline solid: NMR (DMSO-d6): d 12 (s, 1H), 7.28-7.24 (m, 2H), 7.14-7.08 (m, 2H), 2.91-2.89 (m, 1H), 2.64-2.41 (m, 2H), 1.66-162 (m, 1H), 1.56-1.51 (m, 1H), 0.71 (t, 3H, J=7.3 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[O:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)[CH3:2].Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+].O>C(O)C>[CH:28]1([NH:27][C:25]([C:10]2[N:11]=[N:12][N:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:9]=2[CH2:8][O:7][C:6]2[CH:31]=[CH:32][CH:33]=[C:4]([C:1](=[N:35][OH:36])[CH3:2])[CH:5]=2)=[O:26])[CH2:29][CH2:30]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COc2cccc(C(C)=O)c2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COc2cccc(C(C)=NO)c2)cc1
Yield: 85.1 %

Procedure:
To a solution of 5-[(3-acetylphenoxy)methyl]-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (100 mg) obtained in Example 489 in ethanol (4 ml) were added hydroxylamine hydrochloride (78 mg) and sodium acetate (92 mg), and the mixture was heated under reflux for 4 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (88 mg).