Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCCC1=O>CO>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: Clc1ncnc2cc[nH]c12
Solvent: CN1CCCC1=O
Solvent: CO
Product: Clc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg), 4-(benzyloxy)-3-chloroaniline (365 mg) and 1-methyl-2-pyrrolidone (3 mL) was stirred at 80° C. for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→15:75) and recrystallized from ethanol-ethyl acetate to give the title compound (226 mg) as a pale-brown powder.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](O)([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11][C:10]3([CH3:25])[CH3:24])OCC[O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:24][C:10]1([CH3:25])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2](=[O:3])[CH3:1])[CH:8]=2)[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH2:11]1
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C3(C)OCCO3)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC1=CCC(C)(C)c2cc(C(C)=O)ccc21

Procedure:
A solution of (+/-) 6-(2-methyl-1,3-dioxolan-2-yl)-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxymethyl)-naphthlene ((Compound D16, 321 mg, 0.90 mmol) and catalytic amount of TsOH in 20 ml of benzene was refluxed for 12 h. During the reaction the water generated from the reaction was periodically removed by a Dean-Stark trap. The solvent was removed and the residue was purified by column chromatography (silica, ethyl acetate/hexane (1/3)) to give the title compound as an oil (215 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][C:23](=[O:29])[NH:24]2)([OH:19])=[O:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:20]([C:17]([OH:19])=[O:18])=[CH:28][CH:27]=[CH:26][C:25]=2[NH:24][C:23]1=[O:29])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2c(cccc2C(=O)O)N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cccc(C(=O)O)c32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 4-carboxy-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid as a yellow-orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])=[C:11]([F:26])[CH:10]=1)(=[O:7])=[O:6].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>C(#N)C>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:7])=[O:6])=[CH:10][C:11]=2[F:26])=[C:17]([O:24][CH3:25])[CH:18]=1)[CH3:23]
Reactant: CCc1ccc(Oc2ccc(NS(=O)(=O)CCCCl)cc2F)c(OC)c1
Reactant: C1COCCN1
Solvent: O
Solvent: CC#N
Product: CCc1ccc(Oc2ccc(NS(=O)(=O)CCCN3CCOCC3)cc2F)c(OC)c1
Temperature: 50 °C
Yield: 36.1 %

Procedure:
To a solution of 3-chloro-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]propane-1-sulfonamide (0.38 mmol; 153 mg) in dry acetonitrile (2 mL), under argon, was added morpholine (1.1 mmol; 100 μL). The reaction was heated at 50° C. overnight. After cooling to room temperature, the mixture was hydrolysed with 5 mL of water and extracted with dichloromethane (3*2 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, the title compound (62 mg; 36%) was obtained after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—40/60).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13](=C=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2Cl)=[CH:8][CH:7]=1)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl.C[CH2:30][O:31]CC>[N+](C1C=CC=CC=1)([O-])=O>[O:31]=[C:30]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:3])=[O:23])=[CH:7][C:8]1=2
Reactant: CCOCC
Reactant: CCOC(=O)Cc1ccc(SC(=C=O)c2ccccc2Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CS2

Procedure:
7.0 g of 4-(2-chloro-carbonyl-benzyl-thio)phenylacetic acid ethyl ester are dissolved in 30 cc of nitrobenzene and this solution is added dropwise, at room temperature, to a solution of 3.32 g of aluminium chloride in 50 cc of nitrobenzene. The resulting red solution is then heated in an oil bath of 100° for 3 hours. The reaction solution is subsequently poured on a mixture of ice and 10 N hydrochloric acid, is diluted with ether, and the organic phase is separated, washed with water, dried with sodium sulphate, purified with charcoal and filtered. The solvent is completely removed at reduced pressure and the oily residue is dissolved in ether, the ether phase is washed with a 10% sodium bicarbonate solution and then with water, is dried with sodium sulphate, filtered, and the solvent is removed by distillation at reduced pressure. 6,11-Dihydro-11-oxo-dibenzo[b,e]thiepine-2-acetic acid ethyl ester crystallizes from ether/pentane. M.P. 96°-97°.
Reaction SMILES: [H-].[Na+].C(COC)OC.[C:9]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])([CH3:12])([CH3:11])[CH3:10].C(OCCOCCO[C:29]([F:33])=[C:30]([F:32])[F:31])C>CCCCC.C1OCCOCCOCCOCCOCCOC1>[C:9]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:29]([F:33])=[C:30]([F:32])[F:31])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OCCOCCO
Reactant: CCOCCOCCOC(F)=C(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: COCCOC
Product: CC(C)(C)OCCOCCOC(F)=C(F)F
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 63 %

Procedure:
Bu-TFVE was prepared by mixing 2.66 g of NaH (0.111 mol) and 1 g of 18-crown-6 with 135 mL of glyme under inert atmosphere at 65° C. 15.0 g (0.092 mol) of 2-(2-t-butoxyethoxy)ethanol was slowly added to the flask and stirred at 65° C. 1 h. The alkoxide was transferred to the dry 300 mL Parr reactor, stirred and heated at 65° C. for 1 h after which TFE gas was added. The pressure was maintained at ˜50-60 PSI. A very slight exotherm (˜5° C.) was initially observed. After 45 minutes, stirring was stopped and the reactor was cooled to room temperature. Excess TFE was carefully vented and the reactor contents transferred to a 500 mL Erlenmeyer flask. The mixture was diluted to 300 mL with pentane to effect complete precipitation of sodium salts. The mixture was filtered through a course frit funnel to remove sodium salts. The liquid fraction was rotary evaporated to give a clear yellow crude product. The crude product was vacuum fractionally distilled over potassium carbonate. 14.1 g (63% yield) of the desired product, 1-[2-(2-ethoxyethoxy)ethoxy]-1,2,2-trifluoroethene, was isolated at a boiling point of 26-27° C. (pressure 0.15 mmHg, >99% purity by GC). 19F NMR: δ=−123.5 (dd, 1F J=56, 104 Hz, CF), −130.3 (dd, 1F J=104, 108, CF), −135.1 (dd, 1F J=56, 108 Hz, CF); 1H NMR: δ=4.15 (m, 2H, CFOCF2), 3.75 (t, 2H, OCH2), 3.65-3.45 (m, 4H, OCH2), 1.2(s, 9H, C(CH3)3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][CH:25]([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[N:8]2[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccc(Cl)cc2n1CC(C)C

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and 1-bromo-2-methylpropane.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.[H-].[Na+].I[CH2:25][CH3:26]>CN(C)C=O>[CH2:25]([O:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]2[N:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:3]=[C:2]([CH3:1])[C:14]=12)[CH3:26]
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To an ice-cold solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (2.76 g, 10 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (oiliness, content 60%, 0.48 g, 12 mmol), and the mixture was stirred at room temperature for 1 hour. Subsequently, iodoethane (1.96 mL, 24.5 mmol) was added to the mixture and the mixture was stirred at room temperature further for 16 hours. Ice water was added to the mixture, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate:chloroform=3:1:1) to give the title compound (1.02 g, 34% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]=3[C:15]=2[CH3:24])(=[O:13])=[O:12])=[C:6]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=1)(=[O:3])[CH3:2].[Br-:29].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:29][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:16]=3[C:15]=2[CH3:24])(=[O:12])=[O:13])=[C:6]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(F)cc3c2C)c(S(C)(=O)=O)c1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1c(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 137.5 %

Procedure:
Into 4.0 mL of chloroform was dissolved 200 mg of Compound 19, and 194 mg of benzyltrimethylammonium tribromide was added, followed by 1 hour of stirring at room temperature. The reaction was terminated by adding water to the reaction solution and then the solvent was once removed by evaporation. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was washed with methanol to obtain 201 mg of N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide as a colorless solid. The thus obtained N-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide (150 mg) was dissolved into a mixed solution of 1.5 mL of dioxane and 1.5 mL of ethanol, and 53 mg of sodium hydrogen carbonate and 26 mg of thioacetamide were successively added, followed by 2 hours of stirring under heating and refluxing. The reaction was terminated by adding water to the reaction solution and then the solvent was removed by evaporation under reduced pressure. The residue was adjusted to pH 2 to 3 by adding 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain 61 mg of the title compound as light yellow powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21])[CH:4]=[CH2:5].CC1C=CC(S(O[CH2:33][C@@H:34]2[O:36][CH2:35]2)(=O)=O)=CC=1>CCCCCC.CN(C)C=O>[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:9][C:8]=1[O:21][CH2:33][CH:34]1[CH2:35][O:36]1)[CH:4]=[CH2:5]
Reactant: C=CCOc1cc(OCc2ccccc2)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCOc1cc(OCc2ccccc2)ccc1OCC1CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (4.3 g, 0.11 mole of 60% mineral oil dispersion) was washed with hexane and suspended in 100 mL of N,N-dimethylformamide. To this suspension was added a solution of 25.4 g (0.10 mole) of 2-allyloxy-4-(benzyloxy)phenol in 100 mL of DMF. The mixture was stirred at room temperature for 30 minutes and then 22.8 g (0.10 mole) of (2R)-(−)-glycidyl tosylate was added. The mixture was heated at 60° C. under nitrogen for 2 hours and then at 35° C. for 15 hours. The solvent was removed in vacuum and replaced with 800 mL of methylene chloride. The resulting solution was washed with 200 mL of water and the water back-extracted with 200 mL of methylene chloride. The combined organic phases were washed with 400 mL of saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to a brown solid. Column chromatography on silica gel with methylene chloride as eluant gave 28.5 g of the (S)-enantiomer of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[C:11]([O:12][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1ncccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccnc1C(=O)N(C)OC
Yield: 28.2 %

Procedure:
3-Hydroxy-pyridine-2-carboxylic acid methoxy-methyl-amide (5.21 g, 28.60 mmol), N,N-dimethylformamide (500 ml), potassium carbonate (15.91 g), and methyl iodide (3.6 ml, 57.70 mmol) were stirred for 18 hours at room temperature. The reaction was concentrated. Water and ethyl acetate was added. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (0-70% [10% methanol in ethyl acetate] in hexanes) to give 1.58 g (28%) of 3-methoxy-pyridine-2-carboxylic acid methoxy-methyl-amide. 1H NMR (250 MHz, CDCl3) δ 8.20-8.11 (m, 1H), 7.32-7.18 (m, 2H), 3.83 (s, 3H), 3.51 (s, 3H), 3.35 (s, 3H); MS: m/z 310.6+197.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20]1([NH2:30])[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][CH2:16][CH2:15][N:4]1[C:3](=[O:19])[C:2]([NH:30][C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: Nc1cccc2c1CCCC2
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COCCN1C(=O)C(Nc2cccc3c2CCCC3)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 5,6,7,8-tetrahydronaphthalen-1-amine in a similar manner as described for e.g. Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 7.37 (bs, 1H), 7.20-7.15 (m, 1H), 7.11-7.01 (m, 4H), 6.75 (d, 1H), 6.70 (t, 1H), 6.63-6.60 (m, 1H), 3.90 (t, 2H), 3.72 (t, 2H), 3.38 (s, 3H), 2.60-2.54 (m, 4H), 1.76-1.69 (m, 2H), 1.66-1.59 (m, 2H); Mass Spectrum: M+H+ 413.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[N:13]=1.[ClH:31]>C(#N)C.[Cu]Cl>[Cl:31][C:9]1[S:10][C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[N:13]=1
Reactant: CCOC(=O)c1sc(N)nc1OCc1ccccc1C(F)(F)F
Reactant: Cl
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
Copper(I) chloride (0.342 g, 3.45 mmol) and t-butyl nitrite (0.52 mL, 4.37 mmol) were stirred in 20 mL of acetonitrile. Ethyl 2-amino-4-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate (1.00 g, 2.88 mmol) was added, and the reaction was stirred for 1.5 hours. The reaction was heated to 65° C. with an oil bath for an hour and cooled to room temperature. The reaction mixture was slowly pipeted onto 40 mL of 6N HCl stirring at 0° C. The ice bath was removed, and the mixture was warmed to room temperature, where it stirred for 30 minutes. The mixture was poured into ethyl acetate and water, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide 0.537 g (51%) of ethyl 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 7.88-7.73 (m, 3H), 7.60 (m, 1H), 5.63 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(Cl)c(Cl)c1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)c(Cl)c1)CCCC3
Yield: 80.9 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.190 g; 0.46 mmol), LHMDS 1N in THF (0.5 mL; 0.5 mmol), 1-iodopropane (0.067 mL; 0.69 mmol) in DMF (1.8 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.172 g (82%) of the title compound as a yellow oil.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NC1CCOCC1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 43 %

Procedure:
As described for example 5d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (358 mg, 1.2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (160 mg, 43%) which was obtained as a white solid after purification by chromatography (silica, 0 to 70% ethyl acetate in heptane). MS: m/e=374.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)Cc1ccc(Cl)cc1
Yield: 92 %

Procedure:
A solution of 4-chlorobenzylsulfonyl acetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 92% yield.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[C:13](O)(=O)[CH2:14][CH2:15][C:16]#[CH:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[CH2:16]([C:17]1[O:1][N:2]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH3:11])[N:12]=1)[CH2:15][C:14]#[CH:13]
Reactant: C#CCCC(=O)O
Reactant: COc1ccccc1C(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C#CCCc1nc(-c2ccccc2OC)no1
Temperature: 80 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
In a reactor tube, a mixture of N′-hydroxy-2-methoxybenzamidine (598 mg, 3.6 mmol), 4-pentynoic acid (350 mg, 3.6 mmol), HOBT (0.55 g, 3.6 mmol) and EDCI.HCl (1.03 g, 5.4 mmol) in dioxane (7.4 mL) was stirred at R.T for 3h. After this time the mixture was heated at 80° C. overnight in a reaction block. The mixture was concentrated and the crude product was purified by flash chromatography (Prepacked column 25 g with DCM as eluent) to afford 299 mg of 5-(but-3-ynyl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole (36%) as yellow oil.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=1)[C:17]([OH:19])=O.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>C1COCC1>[Br:13][C:14]1[CH:22]=[C:21]([CH:20]=[C:16]([C:17]([N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])=[O:19])[CH:15]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCCNCCC
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reaction time: 0.5 h

Procedure:
Carbonyl diimidazole (3.0 g, 18 mmol) is added to a solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (XIX, PREPARATION 2, 3.9 g, 15 mmol) in THF (30 mL). The mixture is stirred for 0.5 hours. Dipropylamine (AMINE, 4.2 mL, 30 mmol) is added to the mixture, which is then stirred for 24 hours. The solvent is then removed under reduced pressure and the mixture is partitioned between ethyl acetate and water. The organic phase is then washed with saline, dried over anhydrous magnesium sulfate, filtered, and concentrated. Column chromatography (silica gel; ethyl acetate/hexanes, 15/85) gives the title compound, IR (diffuse reflectance) 2968, 2958, 1714, 1637, 1479, 1440, 1422, 1321, 1310, 1288, 1273, 1252, 889, 772 and 718 cm−1; NMR (300 MHz, CDCl3) δ 8.21, 7.96, 7.70, 3.95, 3.46, 3.15, 1.69, 1.57, 1.00 and 0.78; MS (ESI+) for C15H20BrNO3 m/z (M+H)+=344.1.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:13])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:14][C:15]1[CH:16]=[C:17]([O:21][CH2:22][CH2:23]Br)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:14].[ClH:1].[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:22][CH2:23][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][N:4]([CH3:3])[CH3:13])[CH2:8][CH2:9]1
Reactant: Clc1cccc(OCCBr)c1
Reactant: CN(C)CCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCC1CCN(CCOc2cccc(Cl)c2)CC1

Procedure:
A mixture of 4-(2-dimethylaminoethyl)piperidine dihydrochloride (7.0 g), 2-bromoethyl 3-chlorophenyl ether (7.2 g), triethylamine (12.75 ml) and DMF (50 ml) was heated on a steam bath for 16 hours then worked up as described in Example 16 to give 1-[2-(3-chlorophenoxy)ethyl]-4-(2-dimethylaminoethyl)piperidine dihydrochloride, m.p. 260°-264° C.