Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(NC=CP(=O)(OCC)OCC)CCCCC1.[H-].[Na+].[CH2:20]([N:24]1[C:29]2[N:30]=[C:31]([CH:43]([CH3:45])[CH3:44])[C:32]([CH:41]=O)=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:28]=2[C:27](=[O:46])[NH:26][C:25]1=[O:47])[CH2:21][CH2:22][CH3:23].O.O.[C:50]([OH:55])(=O)[C:51](O)=O>O1CCCC1.O.C1(C)C=CC=CC=1>[CH2:20]([N:24]1[C:29]2[N:30]=[C:31]([CH:43]([CH3:44])[CH3:45])[C:32](/[CH:41]=[CH:51]/[CH:50]=[O:55])=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:28]=2[C:27](=[O:46])[NH:26][C:25]1=[O:47])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)C(=O)O
Reactant: CCCCn1c(=O)[nH]c(=O)c2c(-c3ccc(F)cc3)c(C=O)c(C(C)C)nc21
Agent: CCOP(=O)(C=CNC1CCCCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCn1c(=O)[nH]c(=O)c2c(-c3ccc(F)cc3)c(/C=C/C=O)c(C(C)C)nc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.15 g (4.4 mol) of diethyl 2-(cyclohexylamino)-vinyl-phosphonate in 15 ml of tetrahydrofuran is added dropwise in the course of 10 min at 0°-5° C. under argon to a suspension of 0.25 g (8.4 mmol) of 80% strength sodium hydride in 15 ml of anhydrous tetrahydrofuran. The mixture is stirred at 0° C. for 15 min, a solution of 1.5 g (4 mmol) of the compound from Example 5 in 15 ml of tetrahydrofuran is added dropwise at 0° C. in the course of 20 min, and the mixture is stirred at room temperature for 1 h and under reflux for 20 min. The mixture is cooled, 50 ml of water are added cautiously, the mixture is extracted twice with ethyl acetate, and the combined organic phases are washed with sodium chloride solution and concentrated in vacuo. The residue is heated under reflux with a mixture of 25 ml of toluene, 35 ml of water and 2.6 g (36 mmol) of oxalic acid dihydrate for 1 h. The phases are separated, the aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is crystallized from ether/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][Br:8])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:35])[C:14]1[CH:34]=[CH:33][C:17]([CH:18]=[N:19][N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>C(#N)C>[Br-:8].[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][N+:22]2[CH:23]=[CH:24][N:20]([N:19]=[CH:18][C:17]3[CH:16]=[CH:15][C:14]([N:13]([CH3:12])[CH3:35])=[CH:34][CH:33]=3)[C:21]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COc1ccc(-c2nccn2N=Cc2ccc(N(C)C)cc2)cc1
Solvent: CC#N
Product: COc1ccc(-c2n(N=Cc3ccc(N(C)C)cc3)cc[n+]2CC(=O)c2ccc(Cl)cc2)cc1
Product: [Br-]
Reaction time: 6 h

Procedure:
0.93 g of p-chlorophenacyl bromide is added to a solution of 0.64 g of 1-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)imidazole in 20 ml of acetonitrile. After stirring at 60° for 6 hours, the mixture is left to stand for 16 hours and the product is removed by filtration and washed with ether. There is obtained 1-(p-chlorophenacyl)-3-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)imidazolium bromide of melting point 242°.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: Fc1ccc2c(C3CCN(CCN4CCOCC4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2CO (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~7.1 g). Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded, 2.1 g (48%), m.p.=131°-132° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][CH2:7][C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:4].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.[NH2:25]/[C:26](/[CH3:32])=[CH:27]\[C:28]([O:30][CH3:31])=[O:29]>CO>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([CH3:32])[NH:25][C:8]([CH2:7][O:6][CH2:5][C:3]([OH:2])=[O:4])=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)COCC(=O)OC
Solvent: CO
Product: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Yield: 16.2 %

Procedure:
A solution of ethyl 4-(methoxycarbonylmethoxy)acetoacetate (200 g), 2-chlorobenzaldehyde (128.8 g) and methyl 3-aminocrotonate (105.4 g) in methanol (600 ml) was heated under reflux for 16 hours and then evaporated. The residue was treated with 10% aqueous sodium hydroxide solution and the mixture heated under reflux for 1.5 hours, allowed to cool to room temperature, washed three times with dichloromethane, acidified with concentrated hydrochloric acid and extracted into dichloromethane. The dichloromethane extracts were washed with water, dried over magnesium sulphate and evaporated. The residue was recrystallised from ethyl acetate to give the title compound (63 g), m.p. 150°-154° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:4]([CH:5]=[C:6]2[CH2:10][CH2:9]O[C:7]2=O)[CH:3]1[C:12](Cl)=[O:13].[OH:16][C@H:17]1[CH2:21][C:20](=[CH2:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26].O.[CH:28]1C=CC=CC=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C@@H:4]([CH:5]=[C:6]2[CH2:10][CH2:9][CH2:28][CH2:7]2)[C@H:3]1[C:12]([O:16][CH:17]1[CH2:21][C:20](=[CH2:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26])=[O:13]
Reactant: CC1(C)C(C=C2CCOC2=O)C1C(=O)Cl
Reactant: c1ccccc1
Reactant: C=CCC1=C(C)[C@@H](O)CC1=C
Solvent: O
Solvent: c1ccncc1
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@H](C=C3CCCC3)C2(C)C)CC1=C
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of 5.4 g of (1R, trans) 2,2-dimethyl-3-(2-oxo-3-tetrahydrofuranylidenemethyl)-cyclopropane-1-carboxylic acid chloride in 50 ml of benzene was added at less than 25° C. over 15 minutes to a suspension of 3 g of (1S)-hydroxy-2-methyl-3-allyl-4-methylene-cyclopent-2-ene in 10 ml of benzene and 3 ml of pyridine at 20° C. and the mixture was stirred at 20° C. for 20 hours. 30 ml of water were added and the mixture was stirred for 15 minutes. The decanted aqueous phase was extracted with benzene and the combined organic phases were washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl acetate mixture containing 1‰ triethylamine yielded 2.61 g of (1S) 2-methyl-3-allyl-4-methylene-cyclopent-2-ene-1-yl (1R, trans) 2,2-dimethyl-3-(2-oxo-3-tetrahydrofuranylidenemethyl)-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-28.5°±2.5° (c=0.5% in ethanol).
Reaction SMILES: C(OC(N[C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.[C:15]([O:19][C:20]([NH:22][C@H]1CCNC1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH:14]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: CC(C)(C)OC(=O)NC1CCNCC1

Procedure:
3-(S)-tert-butoxycarbonylaminopiperidine (B=formula (2)) and 3-(S)-tert-butoxycarbonylaminopyrrolidine (B=formula (3)) (Synth. Comm. 1998, 28, 3919) in the last two cases Y═COOC(CH3)3; tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-exo-carbamate (B=formula (4), tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-endo-carbamate (B=formula (5)) (J. Med. Chem 1991, 34, 656), tert-butyl-9-azabicyclo[3.3.1]-non-3-yl-exo-carbamate (B=formula (6)) and tert-butyl-9-azabicyclo-[3.3.1]-non-3-yl-endo-carbamate (B=formula (7)), (J. Med. Chem 1993, 36, 3720)) (Y═COOC(CH3)3).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].O.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:2][CH2:3][CH2:4][CH2:5][N:6]=[CH:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: NCCCCl
Reactant: O=Cc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: ClCCCN=Cc1ccncc1

Procedure:
To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol)) and H2O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol), then K2CO3 (8.28 g, 0.060 mol) then CH2Cl2 (100 mL) and the mixture was stirred for 40 min. The phases were separated and the aq phase was extracted with additional CH2Cl2 (2×50 mL), dried (Na2SO4) and concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (d, J=4.5 Hz, 2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.71 (m, 2H), 3.63 (t, J=6 Hz, 2H), 2.24 (t, J=6Hz, 2H). The presence of 9% of the aldehyde was evident by 1H NMR.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1O)[C:11]#[N:12]>CN(C=O)C>[Cl:4][C:15]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[F:7]
Reactant: N#Cc1cc(F)c(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(Cl)c([N+](=O)[O-])c1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (5.44 g; 42.8 mmol) was added dropwise to a solution of 3-fluoro-4-hydroxy-5-nitrobenzonitrile (3.9 g; 21 mmol) in DMF (40 mL) at −25° C. The mixture was stirred at −25° C. for 15 min and thereafter at 80° C. for 2.5 h. The mixture was slowly poured into ice, the precipitate was filtered off and the filtrate was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was combined with the precipitate and filtered through a plug of silica gel to give the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCCCC2)c2ccc(C#CCO)cc2c1=O
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and K2CO3 (0.55 g, 4.0 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.375 g, 2.0 mmol) are added. The reaction mixture is heated to 90° C. for 3 h, and then allowed to stir at room temperature for 48 h. Water is added and a precipitate formed. The precipitate is filtered and allowed to dry at room temperature and then under reduced pressure to give 0.171 g of a solid. The solid is dissolved in CHCl3 and filtered. The filtrate is concentrated in vacuo and crystallized from ethyl acetate to give 0.066 g of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.C([O-])([O-])=O.[K+].[K+].[CH3:20][O:21][C:22](=[O:47])[C@H:23]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](OS(C(F)(F)F)(=O)=O)=[CH:35][CH:34]=1)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCOC(C)=O>[CH3:20][O:21][C:22](=[O:47])[C@H:23]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])=[CH:37][CH:38]=1)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26]
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: COc1cccc(OC)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 97.7 %

Procedure:
2,6-Dimethoxybenzeneboronic acid (0.5 g) was dissolved in DME (10 mL). To the solution was added K2CO3 (0.7 g), N-(tert-butoxycarbonyl)-O-(trifluoromethane-sulfonyl)-L-tyrosine methyl ester (0.4 g), Pd(Ph3P)4 (0.6 g) and water (0.2 mL). The resulting mixture was heated to 80° C. overnight. Subsequently EtOAc and water were added to the mixture. The EtOAc layer was dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1:2) to give N-(tert-butoxycarbonyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (380 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8]O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:11][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: OCCN1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a mixture of 0.656 g (5 mmole) of 2-morpholin-4-yl-ethanol and 20 mL of dichloromethane at 0 degrees was added 2.49 g (7.5 mmole) of carbon tetrabromide and then 1.57 g (6 mmole) of triphenylphosphine. The mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure and 50 mL of hexanes was added. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 0:100-30:70) gave 0.580 g of 4-(2-bromo-ethyl)-morpholine as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[C:18]([N:20]=[C:21]=[O:22])[CH:17]=[CH:16][C:15]=1[CH2:23][N:24]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[CH2:26][O:25]1.C(OCC)C>O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([NH:20][C:21]([N:4]([O:3][CH3:2])[CH3:5])=[O:22])[CH:17]=[CH:16][C:15]=1[CH2:23][N:24]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[CH2:26][O:25]1
Reactant: CC1(C)CON(Cc2ccc(N=C=O)cc2Cl)C1=O
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CON(C)C(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
A stirred solution of 2.0 grams (0.02 mole) of O,N-dimethylhydroxylamine hydrochloride in 25 ml of dry tetrahydrofuran was cooled to -30° C. and 2.0 grams (0.02 mole) of triethylamine in 25 ml of dry tetrahydrofuran was added. The reaction mixture was stirred for 20 minutes and 5.6 grams (0.02 mole) of 2-(2-chloro-4-isocyanatophenyl)methyl-4,4-dimethyl-3-isoxazolidinone in 75 ml of dry tetrahydrofuran was added dropwise. The reaction mixture temperature was maintained at -30° C. throughout the addition. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature as it stirred for 16 hours. The reaction mixture was heated under reflux for one hour then cooled to ambient temperature. The reaction mixture was placed in a separatory funnel and 20 ml of diethyl ether was added. The mixture was washed with three portions of 50 ml each of water, then dried with sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual oil. The oil was crystallized from heptane/ethyl acetate to give 4.2 grams of 2-(2-chloro-4-[(N-methoxy-N-methylamino)carbonylamino]phenyl)methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 93°-95° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)=[N:2]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][C:32](Cl)=[O:33]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:32](=[O:33])[CH2:31][C:27]4[S:26][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: O=C(Cl)Cc1cccs1
Product: O=C(Cc1cccs1)Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1

Procedure:
N-{4-[3-(4-1,2-Benzoisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-thiophen-2-yl-acetamide was prepared according to the procedure outlined in Example 1, starting with 4-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (200 mg) and 2-thiopheneacetyl chloride (0.069 mL). The resultant white solid was purified using an ISCO autocolumn eluting with 80% ethyl acetate in hexanes. N-{2-[3-(4,1,2-Benzoisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-(4-chloro-phenyl)-acetamide was isolated in 100% purity @ 254 nm; LCMS (APCI): 477 [M+H]+.
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][CH2:6]N=C=NCC.[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=2)[C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:25]=2[C:38](O)=[O:39])=[CH:19][CH:18]=1.C(N)CC.O>C(Cl)Cl>[CH2:4]([NH:3][C:38]([C:25]1[N:26]([CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[C:27]2[C:32]([C:24]=1[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][O:14][CH3:13])=[CH:18][CH:19]=1)[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:39])[CH2:5][CH3:6]
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)O)n(CCN(C)C)c3ccccc23)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCCN
Solvent: O
Solvent: ClCCl
Product: CCCNC(=O)c1c(C(c2ccc(OCOC)cc2)c2ccc(OCOC)cc2)c2ccccc2n1CCN(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (728 mg, 3.80 mmol) was added to a solution of 3-{bis[4-(methoxymethoxy)phenyl]methyl}-1-(2-dimethylaminoethyl)indole-2-carboxylic acid (1.0 g, 1.90 mmol) obtained in Example 48 and propylamine (0.23 ml, 2.85 mmol) in 10 ml of methylene chloride, followed by stirring at room temperature for 3.5 hours. Water was added to the reaction solution followed by extraction with chloroform. The resulting organic layer was washed successively with 2N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.2 g (quantitative) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([C:6]1[C:7]([OH:20])=[CH:8][C:9]2[C:10]([CH3:19])([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1)[CH3:5].[F-].[Cs+].I[CH2:24][CH2:25][CH3:26]>CN(C=O)C.CCOC(C)=O>[OH:1][CH2:2]/[CH:3]=[C:4](\[C:6]1[C:7]([O:20][CH2:24][CH2:25][CH3:26])=[CH:8][C:9]2[C:10]([CH3:19])([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1)/[CH3:5]
Reactant: CC(=CCO)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: CCCI
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1cc2c(cc1/C(C)=C\CO)C(C)(C)CCC2(C)C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
(2Z)-3-(4-Hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy)naphthalene (Structure 8 of Schemes 1 and 2, where R1, R4, R6=H, R2 and R3 together form a tetramethyl saturated six-membered carbocyclic ring, R5=methyl, R7=n-propyl). To a flame-dried 25-mL r.b. flask containing 3-(4-hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-ol (133 mg, 0.48 mmol) in 2 mL anhydrous DMF at room temperature was added cesium fluoride (365 mg, 2.40 mmol, 5.00 equiv) and 1-iodopropane (52.0 μL, 0.53 mmol, 1.10 equiv), and the mixture was stirred for 12 h. The reaction mixture was then diluted with EtOAc (20 mL) and the resultant organic layer was washed with water (2×10 mL), brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure to afford 150 mg (99%) of (2Z)-3-(4-hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy) naphthalene as a colorless viscous oil. 1H NMR (400 MHz, CDCl3) 6.91 (s, 1H), 6.77 (s, 1H), 5.78 (dt, 1H, J=6.6, 1.4 Hz), 3.88 (m, 4H), 2.04 (s, 3H), 1.75 (m, 2H), 1.28 and 1.23 (2s, 2×3H), 1.01 (t, 3H, J=7.5 Hz). 13C NMR (100 MHz, CDCl3) 153.3, 144.9, 138.4, 137.0, 127.7, 126.5, 110.1, 70.3, 60.7 35.2, 35.1, 34.4, 33.6, 31.9, 31.8, 25.1, 22.8, 10.7. IR (thin film) 3336 (br, s), 2919 (s), 1498 (m), 1455 (m). Anal. Calcd for C21 H32O2: C, 79.70; H, 10.19. Found: C, 79.60; H, 10.44.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15]1>>[CH2:23]([O:22][C:20]([CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:15]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2cccc(C(=O)O)c2)C1

Procedure:
The intended compound (7.12 g, 92%) was produced as a colorless solid according to the method of Reference Example 1 but using 3-(chlorosulfonyl)benzoic acid (5.00 g) and ethyl piperidine-3-carboxylate (7.04 mL) as the starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21]Cl)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[O:1][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 109.3 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzoic acid (4.5 g, 26.8 mmol), 3-morpholinopropyl chloride (9.5 g, 58.0 mmol), (prepared according to J. Am. Chem. Soc. 1945, 67, 736), potassium carbonate (8.0 g, 58 mmol), potassium iodide (1.0 g, 0.22 mmol) and DMF (80 ml) was stirred and heated at 100° C. for 3 hours. The solid was removed by filtration and the filtrate evaporated. The residue was dissolved in ethanol (50 ml), 2 M sodium hydroxide (50 ml) was added and the mixture heated at 90° C. for 2 hours. After partial evaporation, the mixture was acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with a gradient of methanol (0 to 25%) in hydrochloric acid (pH2). Partial evaporation of the solvents and lyophilisation gave 3-methoxy-4-(3-morpholinopropoxy)benzoic acid (8.65 g, 97%).