Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](=[N:39]O)[NH2:38])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:39]=2)=[CH:34][CH:35]=1
Reactant: NC(Cc1ccc(F)cc1)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(Cc3ccc(F)cc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 37 mg (0.22 mmol, 1.1 eq.) of 2-(4-fluorophenyl)-N′hydroxyethanimidamide were reacted according to the General Method 1. Yield: 61 mg (57% of theory)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 23 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-n-butyl-3-L-rhamnopyranosylurea are dissolved in 10 ml of formic acid, and 1.5 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 0.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-L-rhamnopyranosylurea is thereby obtained as yellow caramel.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.5 %

Procedure:
A suspension of 3-bromo-2-fluorobenzoic acid (1.009 g, 4.61 mmol) in DCM (25 mL) was stirred at rt and treated with oxalyl chloride (2.016 mL, 23.04 mmol), followed by a drop of DMF, causing gas evolution to commence. After 2.5 h, the solution was heated to boiling for 1-2 min and allowed to cool to rt. After 3 h total, the solution was concentrated to provide 3-bromo-2-fluorobenzoyl chloride as a dark yellow liquid (1.078 g, 99%). A portion of this (200 mg, 0.842 mmol) was dissolved in THF (1.5 mL) and added to a solution of dimethylamine (2 M in methanol, 2.0 mL, 4.00 mmol) in THF (2 mL). The mixture was stirred at rt for 18 h, then was concentrated. The residue was dissolved in EtOAc, washed sequentially with 1 M hydrochloric acid, NaHCO3 (aq) and brine, and dried and concentrated to provide 3-bromo-2-fluoro-N,N-dimethylbenzamide as a light yellow oil (192 mg, 93%). 1H NMR (400 MHz, chloroform-d) δ 7.60 (ddd, J=8.1, 6.5, 1.6 Hz, 1H) 7.32 (ddd, J=7.6, 5.9, 1.6 Hz, 1H) 7.09 (td, J=7.8, 0.7 Hz, 1H) 3.14 (s, 3H) 2.93 (d, J=1.5 Hz, 3H). Mass spectrum m/z 246, 248 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>CO.C(OCC)C>[O:21]([C:18]1[CH:19]=[CH:20][C:15]([S:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CSc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1ccc(Oc2ccc(SC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
To the product from step 1 (272 mg, 0.705 mmol) in methanol (3 mL) was added 2M HCl in diethyl ether (12 mL) and the resulting mixture was stirred at rt for 6 h. The solvent was removed in vacuo to obtain the title product as a solid (135 mg, 94%); MS; m/z 286 (M+H); LCMS (UV) 99%. 1H NMR (400 MHz, CD3OD) δ 1.73-1.81 (m, 1H), 2.0-2.11 (m, 2H), 2.21-2.27 (m, 1H), 3.08-3.13 (m, 2H), 3.26-3.36 (m, 2H), 3.61-3.64 (m, 1H), 7.50 (d, 2H, J=11.6 Hz), 7.35-7.39 (m, 2H), 7.15 (t, 1H, J=16 Hz); 6.96-7.01 (m, 4H)
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:17]([NH:20][CH2:21][C:22]([CH3:25])([NH2:24])[CH3:23])([CH3:19])[CH3:18].C(O)C>>[CH3:23][C:22]1([CH3:25])[CH2:21][N:20]([CH:17]([CH3:19])[CH3:18])[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:24]1
Reactant: CC(C)NCC(C)(C)N
Reactant: CCCCCCCCCCCC(=O)OCC
Solvent: CCO
Product: CCCCCCCCCCCC1=NC(C)(C)CN1C(C)C
Yield: 56.8 %

Procedure:
22.84 g. (100 mmoles) of ethyl dodecanoate and 15.34 g. (118 mmoles) of N1 -isopropyl-2-methyl-1,2-propanediamine was heated at 130°-230° C. until approximately 100 mmoles of ethanol was collected. Toluene was then cautiously added and the heating was continued until no more water separated. The solution was acidified, the aqueous layer was separated and basified with NaOH. This was extracted with ethyl acetate, the organic extract was dried and concentrated. The oil was distilled at 150°-152° C./1.2 mm to give 16.74 g (58%) of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19](COC(=O)C(C)(C)C)[C:18](=[O:36])[N:17](COC(=O)C(C)(C)C)[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:36])[NH:17][C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
4-[7-(2-Butynyl)-1,3-bis-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo 2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (1.9 g) was dissolved in a solvent mixture of tetrahydrofuran (20 ml) and methanol (10 ml), and sodium hydride (0.31 g) was added to the solution. The mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated by distillation to give 1.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([CH2:50]O)[CH2:46][CH2:45]1>>[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([CH2:50][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:46][CH2:45]1
Reactant: CN1CCC(CO)CC1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCC2CCN(C)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with (1-methylpiperidin-4-yl)methanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-methyl-piperidin-4-ylmethyl ester. MS (ES+) m/z calcd. for C38H43Cl2F2N4O4: [(M+H)+]: 727. found: 727.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[N+](=[CH2:12])=[N-]>C(OCC)C>[CH3:12][O:8][C:7]([CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)=[O:9]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C1CCC(=O)C1

Procedure:
To a solution of 2.8 g of 3-oxocyclopentanecarboxylic acid in 20 ml of diethyl ether was added ethereal solution of diazomethane under cooled with ice until the mixture turned pale yellow, and then the reaction mixture was concentrated under reduced pressure to give about 3.1 g of 3-oxocyclopentanecarboxylic acid methyl ester as crude product. Obtained methyl ester compound was dissolved in 20 ml of methanol and after the mixture was cooled to -50° C., 820 mg of sodium borohydride was added thereto at a time and the mixture was stirred for 20 minutes at the same temperature. After 1.3 ml of acetic acid was dropped slowly to the reaction mixture, methanol was removed under reduced pressure. To the residue was added 10 ml of water and the mixture was extracted with ethyl acetate and the extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3 g of the title compound as crude product having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[CH3:14].[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:15]([C:13]1[C:2]([CH3:1])=[C:3]([CH3:14])[C:4]2[O:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]=2[CH:12]=1)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: Cc1ccc2c(c1C)OC(C(=O)O)C2
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(C(=O)CC(C)C)cc2c(c1C)OC(C(=O)O)C2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,3-dihydro-6,7-dimethylbenzofuran-2-carboxylic acid (9 g.) and isovaleryl chloride (7.5 g.) in dichloromethane (100 ml.) at 5°C. is added aluminum chloride (20 g.) in portions over a 1 hour period. The reaction mixture is stirred at 25° for 18 hours then poured into a mixture of ice (300 g.) and hydrochloric acid (50 ml.) affording 9 lg. of 2,3-dihydro-5-isovaleryl-6,7-dimethyl-benzofuran-2-carboxylic acid which melts at 117° after recrystallization from methylcyclohexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=4)[N:17]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[N:16]=3)[N:13]=[CH:14][C:9]=2[NH:8][S:7]1(=[O:34])=[O:33].[C:41](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=4)[N:17]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[N:16]=3)[N:13]=[CH:14][C:9]=2[N:8]([CH3:41])[S:7]1(=[O:34])=[O:33]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3NS2(=O)=O)c(OC)c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3N(C)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg (approx. 0.115 mmol, 50% purity) of the compound from example 99A were initially charged in 5 ml of DMF, 44 mg (0.138 mmol) of cesium carbonate and 8.5 μl (0.138 mmol) of iodomethane were added and the mixture was stirred at RT overnight. Subsequently, another 14.3 μl (0.230 mmol) of iodomethane were added and the mixture was heated to 50° C. overnight. After cooling, the mixture was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 30.9 mg (46% of theory) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].S(OC)(O[CH3:15])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:15])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1C(C)C

Procedure:
2-Isopropylphenol (300 g), 262 ml of dimethyl sulfate, and 1500 g of potassium carbonate in 1 liter of acetone are stirred mechanically and refluxed for 61/2hours. The mixture is filtered and the filter cake washed with acetone. The combined filtrate is stripped, the residue is redissolved in ether, then extracted with 2N sodira hydroxide (twice) and brine (once). The ether is dried, filtered, and stripped to leave an oil which is distilled under high vacuum to afford 2-isopropylanisole, b.p. 39°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 3,3,3-trifluoropropan-1-ol (61.8 ml) and pyridine (224 ml). Cool to between 0° C. and 10° C. and add portion-wise p-toluenesulfonylchloride (147 g). Allow to warm to ambient temperature and stir overnight. Add HCl 0.5N (1.6 L), extract with ethyl acetate, combine the organic layers, dry over MgSO4, filter, and evaporate to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:13])(P(O)(O)=O)[C:6]([OH:8])=[O:7].[C-]#N.[K+].[C:17](O)(=O)[CH3:18]>C(O)C.O>[C:2]([CH2:3][CH2:4][C:5](=[O:13])[C:6]([O:8][CH2:17][CH3:18])=[O:7])#[N:1]
Reactant: NCCCC(O)(C(=O)O)P(=O)(O)O
Reactant: CC(=O)O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)CCC#N
Temperature: 25 °C

Procedure:
To a solution of 12.8 g (0.10 mole) of ethyl 2-oxo-3-butenoic acid (prepared as in Example 1) in 100 ml of ethanol and 50 ml of water is added 6.5 g (0.10 mole) of potassium cyanide. The mixture is stirred at 30°-50° for about one hour, during which time a solution of 6.0 g (0.10 mole) of acetic acid in 20 ml of ethanol is slowly dripped in. After addition is complete, the mixture is cooled to room temperature and the solvent is removed under vacuum. The residue is partitioned between water and CH2Cl2, the layers separated, and the water extracted further with CH2Cl2. The combined organic layers are dried (Na2SO4) and the solvent is removed to give the crude product. This is purified by flash chromatography on silica gel to give ethyl 4-cyano-2-oxo-butanoate as an oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[OH:20])([CH3:13])([CH3:12])[CH3:11].[CH3:27][O:28][CH2:29]Cl>O1CCCC1>[C:10]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[O:20][CH2:27][O:28][CH3:29])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1c([N+](=O)[O-])cc(C(C)=O)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (65 ml, 373 mmol) was added to a solution of 1-[3-(tert-butyl)-4-hydroxy-5-nitrophenyl]-1-ethanone (58.6 g, 247 mmol) in tetrahydrofuran (350 ml) under a nitrogen atmosphere while cooling on ice, and then chloromethyl methyl ether (24.5 ml, 322 mmol) was added dropwise. After stirring at the same temperature for 30 minutes, ice water (250 ml) was added and extraction was performed twice with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid water, water, saturated aqueous sodium hydrogencarbonate and brine in that order. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to yield the title compound (69.4 g, 99.9% yield) as a light brown oil. This was used without purification for the following reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C2C=NN(C)C=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][C:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[C:21]([CH3:32])[O:20][N:19]=1>>[CH3:17][C:18]1[C:22]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])=[C:21]([CH3:32])[O:20][N:19]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(-c2c(C)noc2C)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole. ESI-MS (m/z): 232 [M+1]+.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1>[CH2:1]([N:4]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Dipropylamine (22.3 g, 0.22 mol) was added to a stirred solution of diethyl bromomalonate (47.8 g, 0.20 mol) in THF (400 mL) and the solution was stirred for 18 hours at room temperature. The precipitate of dipropylamine hydrobromide was filtered off and washed with THF. The THF phase was evaporated and the residual oil was partitioned between ethyl acetate (200 mL) and sodium hydroxide solution (10 mL of 4 N). The ethyl acetate phase was separated, washed with water (2×10 mL), and the solvent was removed under reduced pressure. The residual oil was dissolved in an equal volume of hexane and was applied to a silica gel column (420 g) which was eluted initially with ethyl acetate:hexane (1:20). The concentration of ethyl acetate in the eluant was increased slowly until all the diethyl (dipropylamino)malonate was eluted from the column. Fractions containing the compound as determined by TLC and GC were pooled and the solvent was removed to give diethyl (dipropylamino)malonate as an oil in 80-90% yield.
Reaction SMILES: [I-].[OH:2][C:3]([CH3:30])([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:36]([O:39][C@H:40]1[CH2:44][CH2:43][C@H:42]([CH:45]=O)[C@H:41]1[CH2:47][CH2:48][S:49][C:50]1[S:51][CH:52]=[C:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[N:54]=1)(=[O:38])[CH3:37]>O1CCCC1>[C:36]([O:39][C@H:40]1[CH2:44][CH2:43][C@H:42](/[CH:45]=[CH:5]/[CH2:4][C:3]([OH:2])([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:41]1[CH2:47][CH2:48][S:49][C:50]1[S:51][CH:52]=[C:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[N:54]=1)(=[O:38])[CH3:37]
Reactant: CCOC(=O)c1csc(SCC[C@H]2[C@@H](OC(C)=O)CC[C@@H]2C=O)n1
Reactant: CCCCCC(C)(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(C)(O)C/C=C/[C@H]1CC[C@H](OC(C)=O)[C@@H]1CCSc1nc(C(=O)OCC)cs1
Temperature: 0 °C
Yield: 38.1 %

Procedure:
To a solution of (3-hydroxy-3-methyloctyl)(triphenyl)phosphonium iodide (800 mg) in anhydrous tetrahydrofuran (9.00 mL) was added n-butyllithium (1.60M in hexane, 1.90 mL) at room temperature and the solution was stirred for 1 Hour. To the solution was added a solution of the compound 49 (349 mg) in anhydrous tetrahydrofuran (6.00 mL) was slowly added at −78° C. and the solution was stirred for 2 Hours. The solution temperature was risen to room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (178 mg) having the following physical data.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10]O)=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][Cl:14])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ncccc1CO
Solvent: ClCCl
Product: CC(C)c1ncccc1CCl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The 2-isopropyl-3-hydroxymethylpyridine (240 mg, 1.59 mmol) was dissolved in CH2Cl2 (15 mL) and cooled under nitrogen to 0° C. and thionyl chloride (1.0 mL) was slowly added and the reaction was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 and saturated sodium bicarbonate. The organic layer was dried with MgSO4, filtered and the solvent removed under reduced pressure to give the desired 2-isopropyl-3-chloromethylpyridine. The 2-isopropyl-3-chloromethylpyridine (65 mg, 0.383 mmol) was dissolved in CHCl3 (10 mL) and cooled under nitrogen to 0° C. and m-chloroperbenzoic acid (55%, 150 mg) was added in small portions. The reaction was stirred for 2 hours. The solution was extracted with saturated aqueous sodium bicarbonate (2×5 mL). The organic phase was dried with MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel packed in 99:1 CH2Cl2 :MeOH and eluted with same. The appropriate fractions were combined and the solvent removed under reduced pressure to give the desired 2-isopropyl-3-chloromethylpyridine-N-oxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:18][C:19](=[O:21])[CH3:20])([CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=[O:26])C>O.Cl[Cu].Cl[Pd]Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:18][C:19](=[O:21])[CH3:20])([CH2:14][CH2:15][C:16](=[O:26])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: O
Product: CC(=O)CCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl-4-acetoxy-4-(but-3-en-1-yl)piperidine-1-carboxylate (1 g, 3.36 mmol) in DMF (6 mL) and H2O (2 mL) was added CuCl (0.77 g, 7.73 mmol) and PdCl2 (0.16 g, 0.91 mmol) and the resulting suspension was stirred under an oxygen atmosphere at room temperature for 24 h. The insoluble materials were removed by filtration, and washed with ethyl acetate. The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give 16D (540 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 3.84 (br. s., 2H), 2.97 (t, J=12.1 Hz, 2H), 2.38-2.47 (m, 2H), 2.17-2.24 (m, 2H), 2.15 (s, 3H), 2.04 (s, 3H), 1.39-1.51 (m, 9H).