Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:26].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:26])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C)ccc2c1O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2cc(C)ccc2c1O

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(1-hydroxy-3,6-dimethylnaphthalen-2-yl)acetate (0.62 g, 1.9 mmol) in MeCN (14 mL) cooled to 0° C. was treated with SelectFluor® fluorinating reagent (0.66 g, 1.9 mmol). The cold bath was removed and after 90 minutes the reaction was quenched with pH 7 buffer solution. The aqueous layer was extracted with EtOAc and the combined organics washed with brine and dried over anhydrous MgSO4 and filtered. Following concentration in vacuo, the desired product was obtained via silica gel chromatography followed by preparatory HPLC to afford (S)-ethyl 2-tert-butoxy-2-(4-fluoro-1-hydroxy-3,6-dimethylnaphthalen-2-yl)acetate. LCMS-ESI− (m/z): [M−H]− calcd for C20H24O4F: 347.4. found: 347.2.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16]Br)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:19].[K+].[K+]>CS(C)=O.O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(CBr)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
To a suspension of 2.0 g of impure 2-butyl-6-(bromomethyl)-4(1H)-quinazolinone (Example 3) in 35 ml of dimethylsulfoxide and 20 ml of water is added 1.0 g of potassium carbonate. The reaction mixture is heated at reflux for 6 hours, resulting in a complete solution. Upon cooling slowly to room temperature a white precipitate forms and is collected by filtration. The filter cake is purified by flash chromatography on silica gel, eluting with 9:1 chloroform-methanol to give 0.67 g of the desired product as a white solid. CI MASS SPEC 233(M+H).
Reaction SMILES: CCCP(=O)=O.[NH2:7][C:8]1[C:16]([Br:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[CH:18]1([NH2:22])[CH2:21][CH2:20][CH2:19]1>CCOC(C)=O>[NH2:7][C:8]1[C:16]([Br:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:22][CH:18]1[CH2:21][CH2:20][CH2:19]1)=[O:12]
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: NC1CCC1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Product: Nc1c(Br)cccc1C(=O)NC1CCC1
Temperature: 23 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Propylphosphonic anhydride solution (T3P; Alfa Aesar, Ward Hill, Mass.; ≧50 wt % in EtOAc; 6.06 mL, 10.18 mmol) was added (dropwise, over 1 min) to a suspension of 2-amino-3-bromobenzoic acid (Aldrich; 2.00 g, 9.26 mmol) and cyclobutylamine (Aldrich; 2.37 mL, 27.8 mmol) in EtOAc (20 mL) at 0° C. The resulting solution was warmed to 23° C. and stirred for 1.5 h Additional propylphosphonic anhydride solution (≧50 wt % in EtOAc; 1.21 mL, 2.04 mmol) and cyclobutylamine (0.790 mL, 9.27 mmol) were sequentially added, and the resulting mixture was stirred at 23° C. for 3 h. The reaction mixture was then partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated, sequentially washed with saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 2-amino-3-bromo-N-cyclobutylbenzamide (2.127 g, 7.90 mmol, 85% yield) as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (1H, dd, J=7.8, 1.2 Hz), 7.27 (1H, d, J=7.8 Hz), 6.52 (1H, t, J=7.8 Hz), 6.12 (2H, br. s.), 5.81-6.06 (1H, m), 4.53 (1H, sxt, J=8.0 Hz), 2.35-2.53 (2H, m), 1.90-1.98 (2H, m), 1.74-1.82 (2H, m). m/z (ESI, +ve) 268.9/271.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:7])/[CH:4]=[CH:5]/[CH3:6].C(N(C(C)C)CC)(C)C.[CH3:17][O:18][C:19](Cl)=[O:20].O>ClCCl>[CH3:17][O:18][C:19](=[O:20])[NH:1][CH2:2][CH:3]([OH:7])/[CH:4]=[CH:5]/[CH3:6]
Reactant: COC(=O)Cl
Reactant: C/C=C/C(O)CN
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C/C=C/C(O)CNC(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
(E)-1-Amino-3-penten-2-ol (1.3 g, 12.9 mmol) (Overman, L. E. in J. Am. Chem. Soc. 55, 22, 1983, 6622-6629) and diisopropylethylamine (2.7 mL, 15.4 mmol) were dissolved in dichloromethane (20 mL). Methylchloroformate (1 mL, 12.9 mmol) was added slowly and the mixture was stirred a 0° C. for 2 h. Water (25 mL) was added and the phases separated. Extraction with dichloromethane (3×25 mL), drying, filtration and evaporation gave the crude product ((E)-2-hydroxy-pent-3-enyl)carbamic acid methyl ester (2.1 g, 100%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br:14]Br>C(OCC)C>[Br:14][CH2:12][C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:10][CH:9]=1)=[O:13]
Reactant: BrBr
Reactant: CCCOc1ccc(C(C)=O)cc1
Solvent: CCOCC
Product: CCCOc1ccc(C(=O)CBr)cc1

Procedure:
To 133 g (750 mmole) of 4'-propoxyacetophenone dissolved in 500 ml of diethyl ether and heated to reflux was dropwise added 120 g (750 mmole) of bromine at a rate to maintain reflux and yet allow decolorization of the red color. The resulting organic solution was twice washed with 500 ml of water, washed once with 200 ml of brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. This mixture, upon analysis via gas chromatography was approximately 10% unbrominated starting material, 80% the desired monobrominated product, and 10% dibrominated compound. It was used as is in the next reaction. It could be crystallized from diethyl ether and hexane to yield pure monobrominated compound, a solid, mp 36°-38° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][CH2:26][CH2:27][CH2:28][OH:29]>CN(C=O)C.CCOC(C)=O>[CH3:24][O:25][CH2:26][CH2:27][CH2:28][O:29][C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1OC1CCOCC1
Reactant: COCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCOc1ccc([N+](=O)[O-])c(OC2CCOCC2)n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A mixture of 6-chloro-3-nitro-2-(tetrahydro-2H-pyran-4-yloxy)pyridine (0.259 g, 1.00 mmol), K2CO3 (0.276 g, 2.00 mmol) and 3-methoxy-1-propanol (0.191 mL, 2.00 mmol) in DMF (3.0 mL) was heated at 60° C. for 6 hours and then at 100° C. for 24 hours. The reaction mixture was diluted with EtOAc, washed with water and brine (×2). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography (100% iso-hexane 75% iso-hexane/EtOAc) to afford an oil (0.17 g, 54%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=[O:8].S1C=C[CH:13]=[CH:12]1.[Cl-].[Cl-].[Cl-].[Al+3].[N+](C)([O-])=O>>[CH2:12]([O:8][C:7](=[O:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13]
Reactant: c1ccsc1
Reactant: O=C(O)C(=O)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)C(=O)c1cccs1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Reaction Scheme III shows the preparation of thiophenyl oxo-acetic acid derivatives IV, IVa and IVb from the corresponding appropriate thiophene derivatives VIII, VIIIa and VIIIb (equations 1-3, respectively). A mixture of an appropriate thiophene derivative such as VIII, VIIIa or VIIIb (1.0 equivalent) and ethyl oxalyl chloride (1.5 equivalents) may be treated with a solution of aluminum trichloride in nitromethane (1.5 equivalents, concentration approximately 3.6 M) at a temperature of approximately 0-10° C. The reaction mixture is stirred at approximately 0° C. for one hour, room temperature for three hours and then poured into ice water. The resulting mixture is then extracted with an appropriate solvent such as diethyl ether. The organic layer is washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is typically purified by either distillation or flash chromatography on silica gel to provide the thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb, respectively.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[CH3:13][Mg]I>>[F:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH2:6][CH2:7][CH:8]=[C:9]2[CH3:13]
Reactant: C[Mg]I
Reactant: O=C1CCCc2ccc(F)cc21
Product: CC1=CCCc2ccc(F)cc21

Procedure:
Using general procedure A (Exp. 1.1), 7-fluoro-3,4-dihydro-2H-naphthalen-1-one (Lit. 16) was reacted with MeMgI to give 6-fluoro-4-methyl-1,2-dihydro-naphthalene as a colorless oil.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[C:20]([CH3:21])=[CH:19][S:18][C:17]=1[C:22]([O:24][CH3:25])=[O:23]>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[CH3:21][C:20]1[C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[C:17]([C:22]([O:24][CH3:25])=[O:23])[S:18][CH:19]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1scc(C)c1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.1 %

Procedure:
A solution of 1-adamantaneacetyl chloride (0.2 g) prepared as described in Example 1a) was added to a solution of methyl 3-amino-4-methylthiophene-2-carboxlate (0.16 g) in pyridine (2 ml) and dichloromethane (4 ml). The reaction mixture was stirred at ambient temperature for 2 days before being diluted with ethyl acetate. The organic phase was then washed with dilute hydrochloric acid and water, dried over magnesium sulphate (MgSO4) and finally concentrated under reduced pressure to give an oil. Purification of the residue by silica gel chromatography, eluitng with 10% ethyl acetate in isohexanes, gave the title compound as a white solid (0.049 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.ClCC(N([CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)C)=O>>[CH:46]1([CH2:8][NH:7][CH2:5][CH2:4][O:39][C:38]2[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=3[CH:16]3[CH2:25][CH2:24][C:23]4[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=4[CH2:17]3)=[CH:3][C:2]=2[F:1])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: CN(C(=O)CCl)C1CCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCNCC3CCCCC3)c(F)c2)C(C)C)c1
Yield: 55 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-cyclohexyl-N-methylacetamide (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.4 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C.C(O)C>[OH-].[OH-].[Pd+2].O>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[N:9][CH:8]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)cn1
Temperature: 25 °C

Procedure:
Into a round bottom flask, 4-(6-Nitro-pyridin-3-yl)-morpholine (1.67 g, 0.00798 mol), 20% Pd(OH)2/C, 50% wet (10:40:50, Palladium hydroxide:carbon black:Water, 0.350 g, 0.000249 mol), and Ethanol (50 mL, 0.9 mol) were added into a parr bottle. The mixture was evacuated under house vacuum and charged with hydrogen at 35 pSi. The reaction was shaken at room temperature at 35 pSi. The solid was filtered. The solvent was removed under vacuum to afford an off white solid. The solid was triturated with Et2O, Filtered and washed with Et2O to give 5-Morpholin-4-yl-pyridin-2-ylamine as an off white solid (1.01, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][NH2:12])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C>C(O)C>[NH2:21][C:20]1[N:11]([C:3]2[C:2]([Cl:1])=[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][N:5]3[N:4]=2)[N:12]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: NNc1nn2c(c1Cl)CCCC2
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: N#Cc1cnn(-c2nn3c(c2Cl)CCCC3)c1N

Procedure:
1.1 g (5.92 mmole) 3-Chloro-2-hydrazino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine and 0.72 g (5.92 mmole) ethoxymethylenemalononitrile in 10 ml ethanol was heated at reflux for 2 hours. The resulting precipitate was suction filtered, washed with ethanol, dried and purified by silica gel column chromatography (hexane/ethyl acetate).
Reaction SMILES: Br.Br[CH2:3][CH:4]1[O:23][C:7]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]3[C:14]([C:15](=[O:16])[C:6]=2[CH2:5]1)=[CH:13][CH:12]=[CH:11][N:10]=3.[OH2:24]>CO.[OH-].[Na+]>[OH:24][CH2:3][CH:4]1[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7](=[O:23])[C:6]=2[CH2:5]1
Reactant: O=c1c2c(n(-c3ccccc3)c3ncccc13)OC(CBr)C2
Reactant: O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1c2c(c3cccnc3n1-c1ccccc1)OC(CO)C2

Procedure:
A solution of 15.0 g. of 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one hydrobromide in 200 ml of methanol, 160 ml of 1.0N sodium hydroxide solution and 150 ml. of water is stirred and refluxed on a steam bath for 21 hours. The reaction is concentrated to a volume of 200 ml in vacuo and the solid filtered and washed with water. Recrystallization of the crude solid from methanol yields the title compound, m.p. 267°-268°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([O:20]C)=O)[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.[NH3:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([NH2:22])=[O:20])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: N
Product: CC1(C)OB(c2ccc(CC(N)=O)cc2F)OC1(C)C
Yield: 84.1 %

Procedure:
A solution of methyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (0.1 g, 0.340 mmol) in ammonia (MeOH, 10 mL, 160 mmol) was stirred at 20° C. for 16 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo to yield 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (100 mg, 0.286 mmol, 84.0% yield): 1H NMR (400 MHz, DMSO-d6) δ 7.56 (t, J=7.2 Hz, 1H), 7.14-6.98 (m, 2H), 3.59 (s, 2H), 1.26 (s, 12H); ES-LCMS m/z 280.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.O>C(O)CO>[CH2:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:2]2[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=2)[CH2:16][CH2:15]1)=[O:18])[CH3:21]
Reactant: CCc1cnc(Cl)nc1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: OCCO
Solvent: O
Product: CCOC(=O)N1CCC(Nc2ncc(CC)cn2)CC1
Yield: 46 %

Procedure:
A mixture of 2-chloro-5-ethylpyrimidine (5.0 g, 35.1 mmol, 1.0 equiv; commercially available), ethyl 4-amino-1-piperidine carboxylate (7.2 g, 42.1 mmol, 1.2 equiv) and triethylamine (5.3 g, 52.7 mmol, 1.5 equiv) in ethylene glycol (60 mL) was heated by microwave irradiation to 200° C. for 15 min. To the crude reaction mixture was added water (120 mL) and the solution extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (20 mL) and a sat. solution of sodium chloride (20 mL), dried over MgSO4 and evaporated under reduced pressure to give an amber oil. The residue was purified by column chromatography on silica eluting with heptane/ethyl acetate (1:1) followed by recrystallization from heptane (200 mL) to afford 4.53 g (46%) of the title compound as a white solid. MS (ISP): 279.3 [M+H]+.
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6](=O)[C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH3:8])C.CO>C1COCC1.C(OCC)C>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][C@@H:7]([CH3:8])[CH2:6][OH:5])([CH3:15])([CH3:16])[CH3:14]
Reactant: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A 2M solution of LiBH4 (2.77 g, 0.13 mol) in THF (60 mL) was added dropwise to a solution of (S)-2-(tert-butyl-dimethyl-silanyloxy)-propionic acid ethyl ester (22.75 g, 0.10 mol) and methanol (5.15 mL, 0.13 mol) in diethyl ether (500 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 1.5 hours before cooling to 0° C. and carefully quenching with water. The reaction mixture was filtered and the filtrate extracted with diethyl ether (2×50 mL), the combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the title product as a colourless oil (18.2 g, 97%). 1H NMR (CDCl3, 400 MHz) 3.86-3.77 (1H, m), 3.45-3.37 (1H, m), 3.31-3.22 (1H, m), 1.96-1.85 (1H, m), 1.03 (3H, d, J=6.23 Hz), 0.81 (9H, s), 0.00 (6H, s).
Reaction SMILES: O=[C:2]1C2C=NN(C3CCCCO3)C=2C2C=CC(C3C(NC(=O)C)=NC=CC=3)=CC=2[N:3]1CC(F)(F)F.[O:36]=[C:37]1[C:46]2[CH2:47][N:48](C3CCCCO3)[NH:49][C:45]=2[C:44]2[CH:43]=[CH:42][C:41]([C:56]3[C:57]([NH:62][C:63](=[O:65])[CH3:64])=NC=[CH:60][CH:61]=3)=[CH:40][C:39]=2[N:38]1[CH2:66][C:67]([F:70])([F:69])[F:68].[ClH:71]>O>[ClH:71].[O:36]=[C:37]1[C:46]2[CH:47]=[N:48][NH:49][C:45]=2[C:44]2[CH:43]=[CH:42][C:41]([C:56]3[CH:61]=[CH:60][N:3]=[CH:2][C:57]=3[NH:62][C:63](=[O:65])[CH3:64])=[CH:40][C:39]=2[N:38]1[CH2:66][C:67]([F:68])([F:69])[F:70]
Reactant: CC(=O)Nc1ncccc1-c1ccc2c3c(c(=O)n(CC(F)(F)F)c2c1)CN(C1CCCCO1)N3
Reactant: CC(=O)Nc1ncccc1-c1ccc2c3c(cnn3C3CCCCO3)c(=O)n(CC(F)(F)F)c2c1
Agent: Cl
Solvent: O
Product: CC(=O)Nc1cnccc1-c1ccc2c3[nH]ncc3c(=O)n(CC(F)(F)F)c2c1
Yield: 66 %

Procedure:
The product is obtained according to the procedure described in Step 3.4. starting with N-{3-[4-oxo-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl]pyrid-2-yl}acetamide and N-{3-[4-oxo-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl]pyrid-2-yl}acetamide, in the form of a white powder (hydrochloride, 1.5 H2O; yield 66%).
Reaction SMILES: [C:1]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][CH2:30][NH2:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][CH2:30][NH:31][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCCCC#Cc1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-dodec-1-ynylbenzaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 444.4. HPLC (Condition A), Rt: 5.27 min (HPLC purity: 83.9 %).
Reaction SMILES: [CH3:1][C@:2]1([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[O:19][C:18](=[O:20])[C:17]2[N:21]=[C:14]([S:15][CH:16]=2)[S:13][CH2:12][CH2:11][N:10]2[C@H:6]([CH2:7][O:8][C:9]2=[O:22])[CH:5]=[CH:4][CH2:3]1.[OH:30][C@@H](C(C)(C)CCCC)/C=C/[C@H]1COC(=O)N1CCSC1SC=C(C(OCC)=O)N=1.O1CCCC1>CO>[O:22]=[C:9]1[N:10]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:19])=[O:20])[N:21]=2)[C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@@:2]([OH:30])([CH3:1])[CH2:23][CH2:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH2:7][O:8]1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Reactant: C[C@@]1(CCCC(F)(F)F)CC=C[C@H]2COC(=O)N2CCSc2nc(cs2)C(=O)O1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@](O)(C/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1)CCCC(F)(F)F

Procedure:
By the same procedure as the reaction of Example 8 using the compound 64-1 (Less polar) instead of the compound 7 and using a mixture of tetrahydrofuran and methanol instead of methanol, the title compound having the following physical data was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH2:11][CH2:10]1.[N:20](CC(O)CCN1CCN(C2C=CC=C(Cl)C=2Cl)CC1)=[N+:21]=[N-:22]>>[N:20]([CH2:19][CH:17]([OH:18])[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=NCC(O)CCN1CCN(c2cccc(Cl)c2Cl)CC1
Reactant: COc1ccccc1N1CCN(CCC2CO2)CC1
Product: COc1ccccc1N1CCN(CCC(O)CN=[N+]=[N-])CC1
Yield: 15 %

Procedure:
Prepared from 28b in a similar fashion as described above for 29a. Yield: 15%, 1H NMR (CDCl3): δ 1.55 (ddd, J 14.6, 6.7, 3.6, 1H), 1.80 (m, 1H), 2.62 (s, 2H), 2.74 (m, 2H), 2.89 (s, 2H), 3.09 (s, 4H), 3.24 (dd, J 11.6, 4.1, 1H), 3.29 (dd, J 11.6, 4.9, 1H), 3.86 (s, 3H), 4.03 (dtd, J 9.8, 5.5, 2.5, 1H), 6.86 (d, J 8.0, 1H), 6.89-6.95 (m, 2H), 7.01 (ddd, J 8.0, 5.1, 4.1, 1H), 13C NMR (CDCl3): δ 28.4, 50.7, 53.5, 53.5, 55.4, 56.6, 57.4, 73.0, 111.2, 118.3, 121.1, 123.2, 140.9, 152.3.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:20]=2)=[O:18])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:20]=2)=[O:18])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC(CCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CCCCC(CCCCCC(=O)c1cn(CCCC(=O)O)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-[3-[7-(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate obtained in Ex. 19 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate to give 4-[3-[7-(4isobutylphenyl)undecanoyl]-1-indolyl]butyric acid.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:8])=[O:5].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([NH:6][C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[CH3:8])=[CH:10][CH:11]=1
Reactant: c1c[nH]cn1
Reactant: CC(NC(=O)C(C)(C)CCl)c1ccc(Cl)cc1
Product: CC(NC(=O)C(C)(C)Cn1ccnc1)c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 6 h

Procedure:
A mixture of 3-chloro-N-[1-(4-chlorophenyl)ethyl]-2,2-dimethylpropionamide (5.0 g) and imidazole (6.2 g) was heated at 125° C. with stirring for 6 hours. Excess imidazole was removed by azeotropic distillation with toluene under reduced pressure. The residue was dissolved in 5M hydrochloric acid and washed with dichloromethane. The acid layer was basified with 5M sodium hydroxide solution and extracted with dichloromethane. The combined extracts were washed with water, dried and evaporated to give N-[1-(4-chlorophenyl)ethyl]-3-(imidazol-1-yl)-2,2-dimethylpropionamide which was used directly in (c) below.