Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23]Cl)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]1>CC(=O)CC.O>[CH3:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCCCl)cc2)CC1
Reactant: CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC1CCCCN1CCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 88.2 %

Procedure:
1,1-Dimethylethyl 4-{4-[(3-chloropropyl)oxy]phenyl}-1-piperazinecarboxylate (D9) (1.6 g), was dissolved in 2-butanone (10 ml). Potassium carbonate (1.38 g) and a catalytic amount of potassium iodide were added, followed by 2-methylpiperidine (0.99 g). The mixture was heated at reflux for 72 h under nitrogen. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phases were separated using a hydrophobic frit, combined and evaporated in vacuo. The residue was purified on a 100 g silica SPE bond elut cartridge, eluting with a gradient of 0% to 20% [0.880 ammonia-methanol (1:9)]-dichloromethane mixtures, to give the title compound (1.66 g). LCMS RT=2.48 min.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:5](=O)[C:3]1=[O:4].NN.[Na].O>C(O)C>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:5][C:3]1=[O:4]
Reactant: CN1C(=O)C(=O)c2c(Cl)cc(Cl)cc21
Agent: NN
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CN1C(=O)Cc2c(Cl)cc(Cl)cc21
Temperature: 25 °C
Yield: 87 %

Procedure:
1-Methyl-4,6-dichloroisatin (4.0 g) was suspended in dry ethanol (40 ml), hydrazine (9 ml) was added and the mixture was refluxed in 6 h. The mixture was then added slowly at 70° C. to a solution of sodium (1.74 g)in dry ethanol (80 ml) and refluxed overnight. The reaction mixture was cooled to room temperature, water (50 ml) was added and the volume was reduced to about one third by evaporation. The mixture was then poured onto icewater (1000 ml) and acidified with 6M HCl (pH=1). The precipitate was filtered off washed with water and dried to afford 3.27 g (87%) of (43). M.p. 144°-145° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:12](=[O:14])[CH3:13])[C:5]([O:7]C(C)(C)C)=[O:6].[Br:15]Br.[Cl-].[Na+].ClCCCl>O1CCOCC1>[Br:15][CH2:13][C:12](=[O:14])[C:4](=[N:3][O:2][CH3:1])[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)OC(C)(C)C
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CON=C(C(=O)O)C(=O)CBr
Temperature: 20 °C
Reaction time: 20 h
Yield: 41.1 %

Procedure:
In 50 ml of 1,4-dioxane was dissolved 20.1 g (0.1 mole) of tert-butyl 2-methoxyimino-3-oxobutyrate, and 32.0 g (0.2 mole) of bromine was added dropwise at 0° to 5° C. over a period of 1 hour and 30 minutes and stirred at 20° C. for 20 hours. After completion of the reaction, 25 ml of a saturated aqueous sodium chloride solution and 50 ml of 1,2-dichloroethane were added and then stirred, and the resulting mixture was allowed to stand and then separated and the aqueous layer was removed. The organic layer was further washed with 25 ml of water and dried over anhydrous magnesium sulfate, after which the 1,2-dichloroethane was distilled off under reduced pressure, and the residue was crystallized from 50 ml of xylene to obtain 9.2 g (yield 41.1%) of 4-bromo-2-methoxyimino-3-oxobutyric acid as white crystals.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[CH3:34][O:35][C:36]1[CH:55]=[CH:54][C:39]([CH2:40][O:41][C:42]([C:44]2[CH:49]=[CH:48][C:47](=[O:50])[N:46]([CH2:51][CH2:52]O)[CH:45]=2)=[O:43])=[CH:38][CH:37]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:40][O:41][C:42]([C:44]2[CH:49]=[CH:48][C:47](=[O:50])[N:46]([CH2:51][CH2:52][O:32][C:31](=[O:33])[C@H:27]([CH:28]([CH3:29])[CH3:30])[NH:26][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH:45]=2)=[O:43])=[CH:54][CH:55]=1
Reactant: COc1ccc(COC(=O)c2ccc(=O)n(CCO)c2)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)c2ccc(=O)n(CCOC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a mixture of DCC (5.06 g, 24.5 mmol), DMAP (318 mg, 2.6 mmol) and N-CBz-L-valine (6.48 g, 25.8 mmol) in CH2Cl2 (200 mL) at 0° C., was added dropwise a solution of 1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester (6.40 g, 24 mmol) in CH2Cl2 (200 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 2→5% MeOH in CH2Cl2), to give 6.81 g 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:26][CH:27]1[CH2:30][NH:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([N:29]4[CH2:30][CH:27]([OH:26])[CH2:28]4)=[O:23])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: OC1CNC1
Agent: Cl
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)N2CC(O)C2)n(C)n1
Yield: 17 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 3-hydroxyazetidine hydrochloride instead of 2-amino-2-methyl-1-propanol, to the title compound (20 mg, 17%) which was obtained as a colorless gum. MS: m/e=387.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][CH3:12].[Mg].CN(C)[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:12][O:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:16]=[O:17]
Reactant: COCCc1cccc(C)c1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCc1cccc(C)c1C=O
Temperature: 25 °C
Yield: 15 %

Procedure:
To a stirred solution of 2-(2-bromo-3-methylphenyl)ethyl methylether (1.5 g, 6.5 mmol) in anhydrous tetrahydrofuran (10 ml) was added magnesium (turnings) (0.16 g, 6.6 mmol). The mixture was refluxed in a nitrogen atmosphere until the reaction started and then stirred without heating for 15 min. The mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature and N,N-dimethylformamide (0.7 g) was added and the mixture was stirred for 30 min. A saturated ammonium chloride solution (10 ml) was added and the mixture was stirred for 1 h. at room temperature. Toluene (20 ml) was added and the organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride as eluent to separate the lipophilic biproducts and methylene chloride/diethyl ether(7:3) as eluent to isolate (0.17 g, (15%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH:8]=O.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].Cl>C(O)C.O.[OH-].[K+]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH:8]=[CH:16][C:15](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
3-(3-fluoro-4-formyl-phenyl)-acrylic acid (500 mg, 2.57 mmol) was dissolved in ethanol/water (1:1, 10 ml) and 1.7M KOH (3 ml). To the resulting solution was added acetophenone (0.3 ml, 2.57 mmol). The mixture was stirred at room temperature overnight then acidified with 10% HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuo. The crude product was triturated in EtOAc and filtered to give 560 mg of 3-[3-fluoro-4-(3-oxo-3-phenyl-propenyl)-phenyl]-acrylic acid.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[C:14]([NH:21][OH:22])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>C1COCC1>[C:17]([O:16][C:14]([NH:21][O:22][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-mesitylene sulphonyl chloride (2.0 g, 9.14 mmol) in dry THF (50 mL), is added N-Boc-hydroxylamine (1.21 g, 9.14 mmol) and cooled to 0° C. under N2 atmosphere. The reaction mixture is stirred for 5 minutes. To this mixture triethylamine (1.1 g, 11 mmol) is added slowly over 10 minutes. The reaction mixture is stirred for 1 hour at 0° C. and upon completion, the solvent removed in vacuo. The residue is redissolved in dichloromethane (50 mL) and washed with water (2×50 mL), 10% aqueous NaHCO3 (50 mL) and dried over MgSO4. It is then concentrated under reduced pressure at room temperature to get the product as an off white solid; (2.1 g, 73%). TLC: pet ether/ethyl acetate (8/2) Rf—0.4. 1H NMR (DMSO-d6; 400 MHz): δ 11.16 (s, 1H), 7.12 (s, 2H), 2.49 (s, 6H), 2.28 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][C:3]=1[O:19][CH3:20].[CH:21]1([Mg]Br)[CH2:23][CH2:22]1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH:21]1([CH:6]([C:5]2[CH:17]=[CH:18][C:2]([F:1])=[C:3]([O:19][CH3:20])[CH:4]=2)[CH:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[CH2:23][CH2:22]1
Reactant: COc1cc(C=C2C(=O)OC(C)(C)OC2=O)ccc1F
Reactant: Br[Mg]C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(C2CC2)C2C(=O)OC(C)(C)OC2=O)ccc1F
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of (5-(4-fluoro-3-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.00 g) in THF (20 mL) was added dropwise a 1.0 M solution of cyclopropylmagnesium bromide in THF (53.5 mL) at 0° C., and the mixture was stirred for 1 hr. 3N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was stirred for 15 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.40 g) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[O:13])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Na+].Cl>C(O)C>[S:1]1[C:7]2[CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)=[O:13])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)SCCCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)SCCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
1.20 g of ethyl p-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoate were dissolved in 40 ml of ethanol and treated with 14 ml of water containing 1.40 g of NaOH. The mixture was stirred at room temperature overnight, poured on to ice and acidified with conc. HCl. The mixture was then extracted twice with ethyl acetate, washed with water, dried and evaporated. Recrystallization from ethyl acetate gave 925 mg of p-(2,3,4,5-tetrahydro-1-benzothiepine-8-carboxamido)benzoic acid as colorless crystals of m.p. 261°-262° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[C:3]=1[O:20][CH2:21][CH:22](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]2[N:9]([CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[CH:22]([CH3:23])[CH2:21][O:20][C:3]=2[C:2]=1[F:1]
Reactant: COC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(=CN1c2ccc(F)c(F)c2OCC1C)C(=O)OC
Temperature: 80 °C
Yield: 92.7 %

Procedure:
A mixture of 749 mg of the compound obtained in Example 7, 207 mg of potassium carbonate and 5 ml of anhydrous DMF was heated at 80° C. for 8 hours. The mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 455 mg of the titled compound.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(Cl)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 using 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole and using 3-chlorobenzyl bromide instead of benzyl bromide.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[N+:15]([C:18]1[CH:19]=[CH:20][C:21]2[S:25][C:24]([SH:26])=[N:23][C:22]=2[CH:27]=1)([O-:17])=[O:16]>>[N:5]1([C:3](=[O:4])[CH2:2][S:26][C:24]2[S:25][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:27][C:22]=3[N:23]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: O=[N+]([O-])c1ccc2sc(S)nc2c1
Product: O=C(CSc1nc2cc([N+](=O)[O-])ccc2s1)N1CCCc2ccccc21
Yield: 56 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 5-nitrobenzo[d]thiazole-2-thiol (12) as the nucleophile to yield 31 as a pale yellow solid (56%): MS m/z: 386 (M+H)+. Anal. Calcd. For, C18H15N3O3S2: C, 56.09; H, 3.92; N, 10.90; S, 16.64. Found: C, 56.22; H, 3.95; N, 10.81; S, 16.67.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5.00 g, 26.8 mmol) in DCM (200 ml) was added DIPEA (9.85 ml, 56.4 mmol) and then 4-(trifluoromethyl)benzenesulfonyl chloride (7.22 g, 29.5 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then reduced to dryness in vacuo, to yield the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][C:15]=2[O:28]CC2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[OH:28])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)N1CCC(c2ccc(O)cc2O)CC1
Reaction time: 4 h
Yield: 90.5 %

Procedure:
In a 25 ml round-bottomed flask, 0.25 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid butylamide is dissolved in 9 ml of methanol in the presence of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 4 hours under a hydrogen atmosphere. The reaction mixture is filtered. 0.14 g of 4-(2,4-dihydroxyphenyl)piperidine-1-carboxylic acid butylamide is obtained. Yield=90%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]O.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Reactant: CN(C)CCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCCN(C)C)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (for a preparation see Intermediate 18) (250 mg, 0.575 mmol) in DMF (10 mL) were successively added 3-(dimethylamino)-1-propanol (71.2 mg, 0.690 mmol), EDC (220 mg, 1.150 mmol) and DMAP (7.0 mg, 0.057 mmol). The resulting mixture was stirred at room temperature overnight, then concentrated in vacuo, dissolved in a 1:1 MeOH/DMSO mixture and purified by MDAP (HpH). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(dimethylamino)propyl 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (41 mg, 17%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.94 min, MH+=520.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH2:23])[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>CC1C=CC=CC=1C>[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH:23][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CN
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNc1ncc(Br)cn1
Temperature: 138 °C

Procedure:
5-Bromo-2-chloro-pyrimidine (8.62 mmol) is added to a solution of (1R,3S,4S)-3-aminomethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (6.63 mmol) in o-xylene (25 mL). K2CO3 (20.0 mmol) and DIPEA (19.9 mmol) are added successively and the mixture is heated to 138° C. for 16 h. The mixture is cooled to rt and filtered. The residue is washed with DCM and the combined filtrates are concentrated in vacuo to give the desired product which is used without further purification. LC-MS: tR=1.09 min; [M+H]+=383.3.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=1)#[N:4].S(OCC)(O[CH2:26][CH3:27])(=O)=O.O>CN(C=O)C>[C:3]([C:5]1[CH:21]=[CH:20][C:8]([N:9]([CH2:26][CH3:27])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=1)#[N:4]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a suspension of sodium hydride (65%, 3.39 g (91.8 mmol)) in DMF (60.0 ml), 4′-cyano-p-toluenesulfonanilide (10.0 g (36.7 mmol)) was added with stirring at room temperature. To the resulting mixture, after stirring for an hour at room temperature, diethyl sulfate (12.0 ml (91.8 mmol)) was added dropwise, and the resulting mixture was heated with stirring at 75° C. for 4 hours. Then, the reaction mixture was allowed to cool to room temperature, poured into water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with chloroform as eluent, to give 9.8 g (89%) of the title compound as white crystals.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[P:7]12(SP3(SP(SP(S3)(S1)=S)(=S)[S:9]2)=S)=[S:8]>>[C:1]1([P:7](=[S:9])=[S:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1=CCCCC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: S=P(=S)C1=CCCCC1

Procedure:
Fay and Lankhelma, in J. Am. Chem. Soc., 74, 4933-5 (1952), disclose the reaction of cyclohexene and phosphorus pentasulfide to produce Δ2 -cyclohexenylthionophosphine sulfide, which they propose exists as the dimer having the formula ##STR2##
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCCC.[Cu]>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Reactant: C1COCCN1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: CSc1ccc(N2CCOCC2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
A mixture of 2-Chloro-5-(methylthio)-benzoic acid (1 g, 4.7 mmol), morpholine (620 ul, 7.1 mmol), potassium carbonate (1.05 g, 7.6 mmol) and Copper (24 mg, 0.38 mmol) in pentanol (6 ml) was stirred for 1 h at room temperature. The mixture was heated to 100° C and stirred for 40 minutes. The solvent was evaporated. The residue was taken up in water and acidified to pH 2. The aqueous layer was extracted twice with ethylacetate. The organic layers were combined, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over silicagel: eluent: heptane/ethylacetate 0-20% over 15 minutes to provide the title compound as a brown solid (120 mg, 10%), MS (m/e): 252.1 (M−H, 100%)