Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Br:25]>C1COCC1>[Br:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:10]([CH3:12])([CH3:11])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrCCCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCCCBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Under N2 atmosphere at 0° C., LDA (2 M solution in THF/heptane/ethylbenzene, 13.0 mL, 26.0 mmol) was added dropwise to a mixture of ethyl isobutyrate (3.5 mL, 3.0 g, 25.9 mmol) and 1,7-dibromoheptane (9.84 g, 38.2 mmol) in dry THF (50 mL) over 1.5 h, while keeping the temperature below 5° C. After 3 h, the mixture was poured into ice-cold saturated aqueous NH4Cl solution (150 mL). The layers were separated and the aqueous phase was extracted with Et2O (3×100 mL). The combined organic layers were washed with aqueous HCl (1 M, 100 mL), saturated aqueous NaHCO3 solution (100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (12.4 g) was purified twice by column chromatography (heptane:ethyl acetate=40:1) to give 205j (3.42 g, 45%) as a colorless liquid. 1H NMR (CDCl3): δ (ppm): 4.11 (q, J=7.2, 2 H), 3.40 (t, J=6.9, 2 H), 1.85 (quintet, J=6.9, 2 H), 1.52-1.47 (m, 2H), 1.45-1.36 (m, 2H), 1.35-1.20 (m, 6H), 1.24 (t, J=7.2, 3 H), 1.15 (s, 6H). 13C-NMR (CDCl3): δ (ppm): 177.8, 60.0, 42.0, 40.5, 33.7, 32.7, 29.7, 28.5, 28.0, 25.0 (2×), 24.7, 14.1. HRMS: Calcd for C13H25BrO2 (M+): 292.1038, found: 292.1034.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH:6]([CH3:8])[NH:5][CH:4]1[CH2:9][OH:10].[C:11](#[N:14])[CH:12]=[CH2:13]>C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>[CH3:2][CH:3]1[CH2:7][CH:6]([CH3:8])[N:5]([CH2:13][CH2:12][C:11]#[N:14])[CH:4]1[CH2:9][OH:10]
Reactant: C=CC#N
Reactant: CC1CC(C)C(CO)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1CC(C)N(CCC#N)C1CO

Procedure:
The entire amount of 3,5-dimethyl-2-hydroxymethylpyrrolidine hydrochloride was dissolved in aqueous potassium carbonate solution (50 mL) and chloroform (50 mL), and acrylonitrile (20 mL) was added. The mixture was heated under reflux for 2 hr. After the completion of the reaction, the organic layer was separated and dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography. The fraction eluted with chloroform:methanol=40:1 was concentrated to give 3-(3,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl)propionitrile (2.3 g).
Reaction SMILES: [C:1]([C:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:5]=1)(=[O:3])[CH3:2].C(O)(=[O:22])C>>[CH3:8][C:4]1[C:1](=[O:3])[C:2](=[O:22])[C:7](=[O:9])[N:6]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:14][CH:15]=2)[N:5]=1
Reactant: CC(=O)C1=NN(c2ccc(S(N)(=O)=O)cc2)C(=O)C1
Reactant: CC(=O)O
Product: CC1=NN(c2ccc(S(N)(=O)=O)cc2)C(=O)C(=O)C1=O
Reaction time: 2 h

Procedure:
To a suspension of 1.5 g. (4.09 mmole) of 4-(3-acetyl-5-oxo-2-pyrazolin-1-yl)benzene sulfonamide in 5 ml. of acetic acid was added 1.94 g. (12 mmoles) of FeCl3 and the mixture was heated to 90° C. for 12 hours. After cooling, the solids were collected by filtration and washed with water and dried. The material was then dissolved in 10 ml. of water and triethylamine and 2 g. of sodium sulfide added. After 2 hours, the mixture was acidified with 6 N hydrochloric acid and the solid collected by centrifugation, there was obtained 1.1 g. of material.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C>[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:11][N:10]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in mineral oil, 0.019 g, 0.48 mmol) was added to a stirring solution of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (0.094 g, 0.33 mmol) in 1.5 mL of N,N′-dimethylformamide at 0-5° C. The bubbling yellow mixture was stirred at 0-5° C. for 15 min., then 2-(trimethylsilyl)ethoxymethyl chloride (0.075 mL, 0.42 mmol) was added. The resulting cloudy yellow mixture was stirred at RT for 3 h, then partitioned between 10 mL of water and 10 mL of ethyl acetate. The organic layer was sequentially washed with two 10 mL portions of water and 10 mL of a sat. aq. NaCl solution, dried over MgSO4, filtered, and concentrated to an orange oil. Silica gel chromatography (10% EtOAc/hexanes) afforded 0.129 g (93%) of slightly impure 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow oil that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[CH:5]OCC.C([O-])(=O)C.[Na+].Cl.[NH2:28]O>C(O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[N:28][O:20][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:21]
Reactant: CCOC=C(C(=O)OC)C(=O)c1cccc(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cnoc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of methyl-2-(3'-trifluoromethylbenzoyl)-3-ethoxypropenoate (8.55 g.; 0.028 mol.) in 60 ml. of ethanol and anhydrous sodium acetate (2.5 g.; 0.03 mol.) was treated with hydroxylamine hydrochloride (2.1 g.; 0.03 mol.). The mixture was heated at reflux for 2 hours, cooled to 25° C., and then poured onto 50 g. of ice. The resulting liquid was extracted five times with 40 ml. of methylene chloride. The organic layer was washed with water, sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated to yield methyl-5-(3'-trifluoromethylphenyl)-4-isoxazolecarboxylate as an orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C#N)=[CH:6][C:5]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)([O-:3])=[O:2].C(=O)([O-])[O-:28].[K+].[K+]>CN(C)C(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:28])=[CH:6][C:5]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)([O-:3])=[O:2]
Reactant: N#CC(c1ccccc1)c1ccc([N+](=O)[O-])c(COC2CCCCO2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(COC2CCCCO2)c1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A mixture of 26.2 parts of intermediate 55, namely 4-nitro-α-phenyl-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]benzeneacetonitrile, 10.2 parts of potassium carbonate and 376 parts of N,N-dimethylacetamide was stirred at room temperature while air was bubbled through. The reaction mixture was poured into water and the product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated, yielding 25 parts (98.6%) of [4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl] phenylmethanone (interm. 56).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].C1C=C[NH+]=CC=1.[O-:18][Cr](Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[C:9](=[O:11])[CH3:10]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(=O)Cc1ccccc1Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)C(=O)c1ccccc1Cl
Reaction time: 21.5 h

Procedure:
To a solution of 2-chlorophenylacetone (7.14 g, 42 mmol) in CH2Cl2 (184 mL), PCC (27 g, 127 mmol, 3 eq) and pyidine (10 mL, 127 mmol, 3 eq) in three portions were added over five hours at reflux under vigorous stirring. After the addition was complete, the mixture was further refluxed under vigorous stirring for 21.5 h. The mixture was filtered through a pad of silica gel, washed the pad with CH2Cl2, and concentrated under reduced pressure to provide a dark red syrup. The residue was purified by column chromatography on a 120 g of Redi-Sep™ column using 0-15% gradient of EtOAc in hexane over 40 min as eluent to provide 1-(2-chlorophenyl)propane-1,2-dione as yellow liquid. 1H NMR (choroform-d) δ ppm 7.66 (1 H, dd, J=7.6, 1.8 Hz), 7.48-7.54 (1 H, m), 7.37-7.46 (2 H, m), 2.58 (3 H, s). Mass Spectrum (ESI) m/e=182.9 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][C:20]3=[O:21])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1.CO[CH:34]1[CH2:38][CH2:37][CH:36](OC)O1>C(O)(=O)C>[N:1]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22][C:20]4=[O:21])[CH2:15][CH2:14]3)=[O:12])=[CH:30][CH:31]=2)[CH:34]=[CH:38][CH:37]=[CH:36]1
Reactant: COC1CCC(OC)O1
Reactant: NCCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: CC(=O)O
Product: O=C(c1ccc(OCCCCn2cccc2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1

Procedure:
A mixture of 1-{1-[4-(4-aminobutoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.50 g), acetic acid (10 ml) and 2,5-dimethoxytetrahydrofuran (0.17 ml) is refluxed with stirring under heating for 1 hour. The reaction solution is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (solvent: dichloromethane:methanol=100:1) to give 1-[1-{4-[4-(1-pyrrolyl)butoxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (0.30 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]([CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:6]([OH:8])=O.Cl.[OH:18][C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]([C:6]([C:20]2[CH:21]=[N:22][N:23]([CH3:24])[C:19]=2[OH:18])=[O:8])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: Cn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
To a stirred mixture of 3-methoxy-2-methyl-4-(methylsulfonyl)benzoic acid (340 mg, 1.39 mmol) and 5-hydroxy-1-methylpyrazole hydrochloride (230 mg) in anhydrous methylene chloride (10 mL) were added DCC (dicyclohexylcarbodiimide) (315 mg) and triethylamine (260 mg) at room temperature, followed by stirring for 2 hours. The reaction mixture was subjected to filtration through Celite, the filtrate was concentrated, and the obtained residue was dissolved in 10 mL of anhydrous acetonitrile. Triethylamine (260 mg) and acetone cyanohydrin in a catalytic amount were added thereto, and the reaction solution was stirred overnight at room temperature. 150 mL of ethyl acetate was added, and the solution was washed once with a 1N hydrochloric acid aqueous solution and washed once with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) to obtain 5-hydroxy-1-methylpyrazol-4-yl 3-methoxy-2-methyl-4-(methylsulfonyl)phenyl ketone (115 mg).
Reaction SMILES: OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1([C:33]([CH:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:36](OCC)=[O:37])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CCOC(C)=O.CCCCCC>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:22]=1[C:27]1([CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:33](=[O:34])[C:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:36]2[OH:37]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccccc2F)CCOCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
A flask containing H2SO4 (12 mL, 218 mmol) and P2O5 (12 g, 87 mmol) was cooled in an ice bath for 20 minutes under nitrogen, and then diethyl 2-(4-(2-fluorophenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (8.0 g, 22 mmol) was added dropwise over 10 minutes. The reaction was stirred an additional 10 minutes at 0° C., and then was stirred at room temperature for 1 hour. The reaction was poured over ice and allowed to melt. The aqueous mixture was extracted with EtOAc (3×100 mL) and then the separated organic extracts were dried (Na2SO4), filtered and concentrated to provide an oil. Flash chromatography (20% EtOAc/hexane) afforded an oil (3.6 g). MS m/e=321.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)[CH2:4][CH2:3]1.OO>O1CCCC1.O>[OH:1][C@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCC(=O)[C@H]2C1
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H]2CC[C@@H](O)[C@H]2C1
Temperature: -78 °C
Yield: 81.8 %

Procedure:
Under an inert atmosphere, 1.00 g (4.44 mmol) of tert-butyl (3aR,6aS)-4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate is dissolved in 15 mL of anhydrous tetrahydrofuran; the medium is cooled to −78° C. and 6.66 mL (6.66 mmol) of a solution of lithium tri-sec-borohydride (L-Selectride) at 1N in tetrahydrofuran are then added dropwise. The medium is allowed to warm to room temperature over three hours with stirring, and then cooled to 0° C., followed by dropwise addition of 35% aqueous hydrogen peroxide solution until the evolution of gas has ceased. The medium is diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. 0.826 g (82%) of the expected product is obtained in the form of a colourless oil.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([N:9]([CH2:32][CH2:33][CH3:34])[C:10]1[CH:11]=[C:12]([CH:30]=O)[C:13](=[O:29])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])[CH2:7][CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:32]([N:9]([CH2:6][CH2:7][CH3:8])[C:10]1[CH:11]=[C:12]([CH:30]=[CH2:1])[C:13](=[O:29])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]1[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26])[CH2:33][CH3:34]
Reactant: CCCN(CCC)c1cc(C=O)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(N(CCC)CCC)c2cccc(-c3c(C)cc(C)cc3C)n2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Methyltriphenylphosphonium bromide (0.46 g, 1.28 mmol) was suspended in tetrahydrofuran (10 mL). The solution was cooled to −78° C. n-Butyllithium (1.6M, 0.80 μL, 1.28 mmol) was added. After 0.5 h, the solution was warmed to 0° C. and stirred for an addition 0.5 h. The solution was cooled again to −78° C. and 1-(dipropylamino)-6-mesityl-4-oxo-4H-quinolizine-3-carbaldehyde (A) (0.050 g, 0.128 mmol) was added dropwise as a solution in tetrahydrofuran (0.5 mL). The reaction was warmed to −30° C. for 0.5 h. The reaction was quenched with water, extracted with ethyl acetate, dried, and concentrated. Flash chromatography (15% ethyl acetate/hexanes) gave the desired alkene (0.022 g, 45% yield) as a red oil.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1)([CH3:15])([CH3:14])[CH3:13].CCOCC.OS([O-])(=O)=O.[K+].Br[CH2:39][Cl:40]>>[C:12]([Si:16]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH2:39][Cl:40])[CH:19]=1)([CH3:26])[CH3:25])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Reactant: ClCBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(SCCl)c1
Reaction time: 2 h

Procedure:
DBU (914 mg, 6.0 mmol) was added to a solution of 3-(tert-Butyl-dimethyl-silanyloxy)-benzenethiol (1.00 g, 4.16 mmol) in bromo-chloro methane (5 ml) at room temperature. Stirring was continued for 2 hours and Et2O (50 ml) and 2M KHSO4 (30 ml) were added. The organic layer was separated, washed with 2M KHSO4 (30 ml) and brine (30 ml), dried (Na2SO4) and concentrated under reduced pressure. The resulting oil was analysed by 1H-NMR spectroscopy and was used without further purification. Yield: 1.01 g (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](=[CH:15]\[CH3:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)C.[CH3:20][NH:21][CH3:22]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]([N:21]([CH3:22])[CH3:20])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C/C=C(/C(=O)OCC)c1ccc(Cl)c(Cl)c1
Reactant: CNC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)N(C)C
Temperature: 50 °C
Reaction time: 10 h

Procedure:
In a Parr bomb containing 45 g. of ethyl 2-(3,4-dichlorophenyl)crotonate in 250 ml. of ethanol add 100 ml. of aqueous 33 percent (w/v) dimethylamine and 0.8 ml. of acetic acid. The mixture is maintained with stirring at 50° C for 10 hours, then the solvent is evaporated in vacuo and the residue, after suspension in water, is extracted several times with ether. After evaporation of the dried organic layer, 60 g. of the title compound is obtained which boils at 124° C/0.2 mm Hg. The product is an approximately 50:50 mixture of the two stereoisomers
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH-].[Na+:25]>C(O)C.O>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1.[Na+:25]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)[O-]
Temperature: 90 °C
Yield: 98 %

Procedure:
32.6 g of α-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid was dissolved in 30 ml of ethanol, and an aqueous solution of 4.0 g of sodium hydroxide in 40 ml of water was added. The mixture was maintained at 70° to 75° C. for 1 hour. Then, ethanol and water were removed from the reaction product at reduced pressure. The residue was heated at 90° C. for 4 hours to afford 34.1 g (yield: 98%) of the final product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C.O>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[CH:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: CC(O)c1ccccc1F
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccnc2cc(Cl)ccc12)c1ccccc1F
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A solution of 2.52 g (18 mmol) of 1-(2-fluorophenyl)ethanol in DMF was added dropwise to a mixture of 2.97 g (15mmol) of 4,7-dichloroquinoline and 0.50 g (21 mmol) of sodium hydride in 15 ml of DMF. After addition was complete, the mixture was heated to 160° C. After four hours the mixture was allowed to cool and 0.1 g of sodium hydride was added. Upon completion of the reaction, a few drops of water were carefully added to destroy excess sodium hydride. Then the solution was poured into water. The product was extracted into ethyl acetate, the ethyl acetate solution was washed three times with water, then dried, and evaporated, producing an oil that crystallized from heptane/ethyl acetate. Yield: 0.77 g M.P. 53°-54° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([CH2:14][NH2:15])[OH:13].Cl>>[OH:13][CH2:12][CH2:14][NH:15][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCCO
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Product: O=C(O)c1ccc(Cl)cc1NCCO
Yield: 96.9 %

Procedure:
First, 2,4-dichlorobenzoic acid (VI) (19.1 g) and cupric chloride (200 mg) were added to ethanolamine (XI) (36.6 g) and the solution was reacted at 80 to 90° C. for 4.5 hours. After the reaction, the pH of the reaction solution was adjusted to 1 by addition of concentrated hydrochloric acid, and then the resulting precipitate was collected by filtration to give 20.9 g of 2-(2-hydroxyethylamino)-4-chlorobenzoic acid (IX) (yield, 97%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH2:2][CH3:3].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:8]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: CCCc1noc(N2CCC(=O)CC2)n1
Reactant: NC1CC1
Product: CCCc1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared as its hydrochloride salt from 1-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 7. LC (method 13): tR=0.79 min; Mass spectrum (ESI+): m/z=251 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23](O)=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9])=[O:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: COC(=O)c1c(Br)ccn1N
Product: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 93 %

Procedure:
The title compound was prepared from methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (2.83 g, 12.9 mmol) and (S)-4-(benzyloxy)-2-(tert-butoxycarbonylamino)butanoic acid (4.0 g, 12.9 mmol) following the experimental procedure described in Preparation 73a. 6.12 g (93% yield) of the desired compound were obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>ClCCl>[CH2:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:19][CH2:20][C@H:21]([NH:24][C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH2:22][CH2:23]4)[CH2:14][CH2:15]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.4 g (1 mmol) trans-4-{2-[4-(indan-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine was dissolved in dry dichloromethane (30 ml), ethylisocyanate (0.1 ml, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was recrystallized from acetonitrile giving the title compound (0.22 g, 55%), melting at 198-200° C.