Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCO.[Pd]>[F:11][C:5]1[CH:4]=[C:3]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:2]([F:1])=[CH:7][C:6]=1[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCOCC2)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(N2CCOCC2)cc1F
Reaction time: 5 h
Yield: 91.2 %

Procedure:
A mixture of 4-(2,5-difluoro-4-nitrophenyl)morpholine (11 g, 44 mmol) and 10% Pd—C (50% wet, 1.1 g) in EtOH (150 mL) was hydrogenated for 5 h at room temperature. The reaction mixture was filtered by celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from iPr2O/AcOEt to give the title compound (8.6 g, 91% yield) as a pale red powder: NMR (300 MHz, DMSO-d6): δ ppm 2.66-2.95 (4H, m), 3.56-3.83 (4H, m), 5.00 (2H, s), 6.55 (1H, dd, J=13.8, 8.5 Hz), 6.77 (1H, dd, J=12.8, 8.3 Hz). LC-MS (ESI) m/z 215 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29]>ClCCl>[C:28](=[O:29])([O:19][CH2:18][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:30][CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: OCc1nc2ccccn2c1C#Cc1ccccc1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COC(=O)OCc1nc2ccccn2c1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
0.1 g (0.403 mmol) of (3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl) methanol were solubilised in 3 ml of dichloromethane with magnetic stirring. 0.084 ml (0.604 mmol) of triethylamine and 0.059 ml (0.443 mmol) of isobutyl chloroformate were added. The mixture was stirred at r.t. for 15 min before being concentrated in vacuo. The residue was taken up in 10 ml of diisopropyl ether and a solid was isolated by filtration. The solid was purified by preparative HPLC and 0.084 g (yield=59%) of isobutyl ((3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)methyl) carbonate were obtained as a pale yellow solid. LC-MS: m/z=349 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.70 (d, J=6.8 Hz, 1H), 7.79-7.65 (m, 3H), 7.60-7.45 (m, 4H), 7.23 (td, J=6.8, 1.1 Hz, 1H), 5.42 (s, 2H), 3.91 (d, J=6.6 Hz, 2H), 1.95-1.80 (m, 1H), 0.86 (d, J=6.7 Hz, 6H).
Reaction SMILES: O=[C:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)(=O)C>O1CCCC1>[CH2:9]([O:8][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)CCCC(=O)c1cn(-c2cccnc2)c2ccccc12
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCCCc1cn(-c2cccnc2)c2ccccc12

Procedure:
To a solution of 0.5 g of 3-(1-oxo-4-ethoxycarbonylbutyl)-N-(3-pyridyl)-indole in 25 ml of tetrahydrofuran is added 0.6 g of borane-tert-butylamine complex and 0.6 ml of glacial acetic acid. The reaction mixture is heated at 90° and monitored by high pressure liquid chromatography. When complete, the reaction mixture is evaporated under reduced pressure, water and methylene chloride are added, the pH is adjusted to 7-8 with sodium carbonate solution, the organic layer is separated, washed with water, dried and evaporated to dryness to yield 3-(4-ethoxycarbonylbutyl)-N-(3-pyridyl)-indole.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4]>C1CCCCC1.ClC(Cl)C.[Fe](Cl)Cl>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:2]([CH3:5])([CH3:3])[CH3:1])=[CH:8][CH:7]=1)[CH2:3][OH:4]
Reactant: CC(CO)Cc1ccccc1
Agent: Cl[Fe]Cl
Solvent: C1CCCCC1
Solvent: CC(Cl)Cl
Product: CC(CO)Cc1ccc(C(C)(C)C)cc1
Yield: 84 %

Procedure:
DE 29 52 719 likewise describes the iron chloride-catalyzed Friedel-Crafts alkylation of 2-methyl-3-phenylpropanol. In cyclohexane or dichloroethane as solvent, a yield of 84-86% of 2-methyl-3-(4-tert-butylphenyl)propanol was obtained. The formation of the m-isomeric compound (2-methyl-3-(3-tert-butylphenyl)propanol), was not demonstrated. A disadvantage of the described Friedel-Crafts alkylations is the small amount of the m-isomeric compound formed (m:p ratio is max. 1:5).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6][C:5]=1[O:14][CH3:15].Cl>CO.[OH-].[Na+]>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[C:5]([O:14][CH3:15])[CH:6]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1ccc(C(=O)OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1ccc(C(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A mixture of 4-bromo-2-methoxybenzoic acid methyl ester (3.0 g, 0.0122 mole), lithium chloride (1.56 g), tetra butyl tin (4.51 g) and bis (triphenyl phosphine palladium (II) chloride (214 mg, 0.3 mmol) were heated at 100° C. for 24h. The solvent was then removed in vacuo and the residue taken up in dichloromethane. The black solid was removed by filtration and the filtrate concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography (Biotage) on silica gel using 10% ether in hexane to afford a colourless oil (1.63 g). A portion of the foregoing 4-n-butyl-2-methoxybenzoic acid methyl ester (1.50 g) was dissolved in methanol (35 ml) with sodium hydroxide solution (2N, 30 ml). The mixture was allowed to stir at room temperature overnight. Then added dil. HCl until pH-5. The solvent was then removed in vacuo and the residue taken up in ethyl acethate and washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford an oil (1.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].Cl.Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH:4]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:5]#[N:6]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC(CCCN1CCCCC1)c1ccc(Cl)cc1Cl

Procedure:
This intermediate (10 g.) was prepared using the procedure described in Example 14a except using 10.0 g. (0.054 mole) of 2,4-dichlorobenzyl cyanide, 11.0 g. (0.054 mole) of 1-(3-chloropropyl)piperidine hydrochloride, 11.0 g. (0.135 mole) of 50% aqueous sodium hydroxide, and 50 ml. of DMSO.
Reaction SMILES: ON=[C:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.C.CN(C)C=[O:24]>Cl.CS(C)=O>[CH:16]1[N:14]2[C:15]3[C:3](=[O:24])[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[C:10]=3[NH:11][C:12](=[O:19])[C:13]2=[N:18][CH:17]=1
Reactant: O=c1[nH]c2c(n3ccnc13)C(=NO)c1ccccc1-2
Reactant: CN(C)C=O
Agent: Cl
Solvent: CS(C)=O
Product: O=C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 7 h

Procedure:
A suspension of 1.5 g of 10-(hydroxyimino)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 90 ml of approximately 5N aqueous hydrochloric acid solution is stirred while boiling for 7 hours, cooled and then concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 70° C. The product obtained (2 g) is dissolved in 50 ml of dimethylformamide and, after addition of 0.1 g of decolorizing charcoal, the solution is filtered and the filter is then washed 3 times with 30 ml in total of dimethylformamide. The filtrate and the washings are combined, 600 ml of distilled water are added and they are centrifuged. The solid is suspended in 20 ml of distilled water, filtered, washed with 20 ml in total of acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. The product obtained (1.13 g) is dissolved in 115 ml of dimethyl sulphoxide and, after addition of 0.1 g of decolorizing charcoal, the solution is filtered and the filter is then washed twice with 30 ml in total of dimethyl sulphoxide. The filtrate and the washings are combined, 115 ml of distilled water are added and they are centrifuged. The solid is suspended in 20 ml of distilled water, filtered, washed twice with 20 ml in total of acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4,10-dione is thus obtained, in the form of a red-orange solid melting at 360° C. (decomposition) [N.M.R. spectrum: (200 MHz; DMSO d6 ; d in ppm): 7.42 and 7.55 (2t, J=7 Hz, 2H: --H7 and --H8); 7.52 and 7.72 (2d, J=7 Hz, 1H each: --H6 and --H9); 7.62 and 8.13 (2d, J=1 Hz, 1H each: --H of the imidazole); 13.60 (cplx, 1H: --NH--)].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH:8]([C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CO.Cl>O>[OH:7][CH:8]([C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC/C=C/C(O)c1nc2ccccc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCC/C=C/C(O)C1=Nc2ccccc2C(=O)C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of 502 mg (3.63 mmols) of potassium carbonate in 2 ml of water was added to a solution of 1.23 g (3.63 mmols) of 2 (trans-1-hydroxy-2-nonenyl)-3-methyl-4-acetoxyquinoline, 15 ml of water and 80 ml of methanol and stirred at room temperature for 10 minutes. After neutralization by addition of 1N hydrochloric acid, the solvent was distilled off under reduced pressure and 30 ml of chloroform was added to the resultant residue, followed by washing with water and drying with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (Wako Gel C-200) (solvent: n-hexane : ethyl acetate=1:2) to obtain 746 mg (yield 69%) of 2-(trans-1-hydroxy-2-nonenyl)-3-methyl-4-quinolone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][C:12]([CH3:14])=[N:11][CH:10]=1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:28]3[CH2:29][CH2:30][CH2:31][CH:26]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:20][CH:21]=4)[C:27]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: COc1cc(NC(N)=S)ccc1-c1cnc(C)s1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1cnc(C)s1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of [3-methoxy-4-(2-methyl-thiazol-5-yl)-phenyl]-thiourea (110 mg, 0.39 mmol) and 2-bromo-6-phenyl-cyclohexanone (105 mg, 0.41 mmol) in ethanol (4 ml) was heated to reflux over night. The precipitated solid was filtered off after cooling to room temperature and dried to yield the title compound (160 mg, 94%) as a yellow solid. MS ISP (m/e): 434.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.32 (br s, 1H, NH), 8.10 (s, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.29 (t, 2H), 7.15-7.21 (m, 3H), 6.85 (d, 1H), 4.00 (m, 1H), 3.48 (s, 3H), 2.75 (m, 2H), 2.68 (s, 3H), 2.14 (m, 1H), 1.70-1.94 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:12][CH2:13]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(Cc2ccc(N)cc2)CC1
Reaction time: 0.33 h
Yield: 29.5 %

Procedure:
A suspension of 1-[(4-nitrophenyl)methyl]-4-methylpiperazine (3.5 g, 0.015 M) and 700 mg of 5% Pd/C in 200 ml of absolute ethanol is hydrogenated for 20 minutes. This is then filtered, washed with more ethanol and concentrated to a white oil. This is crystallized from acetate/Skellysolve® B to give 900 mg (30%) of white crystalline 1-methyl-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCCC1.O[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:29])[CH3:28]>CO.CCCCCC>[O:29]=[C:27]1[C:22]2[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:1][C:2]2([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:28]1
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 70.7 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (93.7 g, 470 mmol) in pyrrolidine (56.0 mL, 673 mmol) and anhydrous MeOH (112 mL) was added 1-(2-hydroxyphenyl)ethanone (56 mL, 468 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. Methanol was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 mL), washed with 1 M aqueous HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. This oil was diluted with hexane (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. Crystals were collected via vacuum filtration and rinsed with hexane to obtain tert-butyl 4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (105 g, 70%) as a light yellow solid. ESI-MS m/z calc. 317.2, found 318.2 (M+1)+; Retention time: 1.78 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=7.8, 1.5 Hz, 1H), 7.55-7.45 (m, 1H), 7.10-6.90 (m, 2H), 3.95-3.80 (m, 2H), 3.26-3.17 (m, 2H), 2.72 (s, 2H), 2.03 (d, J=13.0 Hz, 2H), 1.68-1.58 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19]3[O:23][NH:22][C:21](=[O:24])[CH:20]=3)[CH2:16][CH2:15][N:14]2C(OC)=O)[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].Br>>[F:12][C:6]1[CH:5]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19]3[O:23][NH:22][C:21](=[O:24])[CH:20]=3)[CH2:16][CH2:15][NH:14]2)[CH:3]=[C:2]([F:1])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(C(F)(F)F)c(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3cc(F)c(C(F)(F)F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.2 %

Procedure:
(2R,4S)-Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (226 mg, 0.56 mmol) was dissolved in hydrobromic acid (33% in AcOH, 5 mL, 30.38 mmol) and stirred at room temperature for 20 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (133 mg, 68%). 1H NMR (600 MHz, dmso) δ 1.30 (q, 1H), 1.43 (dq, 1H), 1.84-1.89 (m, 1H), 2.02-2.07 (m, 1H), 2.70 (dt, 1H), 2.86 (tt, 1H), 3.07-3.13 (m, 1H), 3.75 (dd, 1H), 5.73 (s, 1H), 7.37 (d, 2H). HRMS Calcd for [C15H13F5N2O2+H]+: 349.0975. Found: 349.0972.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]=[C:17]=[O:18].[CH2:19]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:19]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:17]([NH:16][C:10]2[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:15])=[O:18])=[CH:32][CH:33]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CCCCCCCCc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(NC(=O)Nc2c(Cl)cccc2Cl)cc1
Reaction time: 16 h
Yield: 68 %

Procedure:
To 10.6 ml (5.3 mmol) of a toluene solution of 0.50M 2,6-dichlorophenyl isocyanate was added 1.21 ml (5.32 mmol) of 4-octylaniline at room temperature and the whole was stirred for 16 hours. After removal of the solvent under reduced pressure, the residue was recrystallized from methanol to give 1.42 g (68% yield) of 1-(4-octylphenyl)-3-(2,6-dichlorophenyl)urea, the physical properties of which being shown in the following Table 3. The compounds No. 1, No. 13, No. 14, No. 17, and No. 18 listed in Table 3 were similarly prepared as above.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH:16]=[CH2:17])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH:16]=[CH2:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C=CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
In a solution of THF/H2O (1:1, 35 mL) containing the product (IX) (1 g, 4.1 mmol) LiOH.H2O (432 mg, 10.3 mmol) is added in one portion. The mixture is stirred for 1 h at room temperature. The solvent is then evaporated and then a 5% H3PO4 solution in water is added until a pH=3 is obtained. The product is then extracted with EtOAc, dried (MgSO4), and then evaporated. After purification, the product (X) (840 mg, 89%) is isolated as a colorless lacquer.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][CH2:12][C:13](OCC)=[O:14])[N:10]=1.[Li].[H-]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[N:10]=1
Reactant: CCOC(=O)CCc1coc(-c2cccs2)n1
Agent: [H-]
Agent: [Li]
Product: OCCCc1coc(-c2cccs2)n1
Yield: 97 %

Procedure:
In substantially the same manner as in Reference Example 72, ethyl 3-[2-(2-thienyl)-4-oxazolyl]propionate was subjected to reduction with lithium alminum hydride to obtain 3-[2-(2-thienyl)-4-oxazolyl]propanol as an oil. The yield was 97%.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)[O:3]1.CC[N:22]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:22])=[O:17])=[CH:11][CH:10]=2)[O:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2ccc(CC(N)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (500 mg) and HOBt ammonium salt (435 mg) in DMF (5 mL) was added EDCI hydrochloride (539 mg), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (420 mg).
Reaction SMILES: [C:1]([C:3]([CH3:12])([CH2:9][CH2:10][CH3:11])[C:4]([O:6]CC)=[O:5])#[N:2].C(O)C.[OH-].[Na+]>O>[C:1]([C:3]([CH3:12])([CH2:9][CH2:10][CH3:11])[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCCC(C)(C#N)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC(C)(C#N)C(=O)O
Yield: 94.5 %

Procedure:
In a 200 ml two-necked round-bottom flask with ground fitting, 16.00 g (94.7 mM) of ethyl 2-cyano-2-methylpentanoate and 90 ml of ethanol were placed. To the mixture under stirring with a magnetic stirrer, a solution of 10.8 g (270 mM) of sodium hydroxide in 35 ml of distilled water was added dropwise. The mixture was stirred for 5 hours at room temperature, followed by removal of the solvent and addition of 3N-HCl until the solution reacted pH 1. The reaction mixture was transferred to a separating funnel, followed by three times of extraction with 50 ml of diethyl ether and washing with 50 ml of distilled water. The organic layer was dried on anhydrous sodium sulfate, followed by distilling-off of the solvent and reduced-pressure distillation to obtain 12.61 g (89.4 mM) of 2-cyano-2-methylpentanoic acid. Yield:94.4%, b.p.:120° C./2 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:20]
Reactant: O=C(Br)CBr
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A solution of methyl 4-aminobenzoate (5.0 g, 33 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (6.66 g, 2.9 mL, 33 mmol) was added dropwise, keeping the internal temperature between 0° to 5° C. over a 1/2 h period. After the addition the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 6.83 g (76%) of the title compound as a pale brown solid; mp 153°-155° C.: 1H NMR (DMSO-d6) δ10.72 (s, 1H), 7.93 (d, J=8.8, 3H), 7.72 (d, J=8.8, 2H), 4.07 (s, 2H), 3.82 (s, 3H) 13C NMR (DMSO-d6) δ165.69, 165.36, 124.91, 130.26, 124.49, 118.64, 51.92, 30.25; MS (EI, m/z) 271 (M+ ).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)O.[OH-].[NH4+]>>[N+:1]([C:20]1[CH:19]=[C:10]([CH:9]=[CH:8][C:7]=1[Cl:6])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:12])([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1ccncc1)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=C(c1ccncc1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
15.5 g. (0.153 mol) of potassium nitrate was added portion-wise to a stirred solution of 33 grams (0.152 mol) of 4-(4-chlorobenzoyl)pyridine in 200 ml. of sulfuric acid while maintaining the temperature below 40° C. After one hour the mixture was cautiously poured into 2 liters of ice-water, neutralized with ammonium hydroxide and the product collected to yield 4-(3-nitro-4-chlorobenzoyl)pyridine as yellow prisms, mp. 114° -116° C. (cyclohexane-Norite).