Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)[C:9]1=[O:20])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)[C:9]1=[O:20]
Reactant: CC=CCC1Cc2ccc(OCC)cc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 1.5 h
Yield: 64 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 90 minutes while stirring through a solution, cooled to -70°, of 5.6 g of (RS)-2-(2-buten-1-yl)-6-ethoxy-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.72 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 170 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 3.4 g (64%) of (RS)-2-(2-oxoethyl)-6-ethoxy-1-indanone were obtained as a red-brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: BrCCCCBr
Reactant: Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1cccc(N2CCCC2)c1
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A solution of m-aminophenol (12.6 gm, 0.115 moles) and 1,4-dibromobutane (50 gm, 0.23 moles) was heated to 130° C. for 12 hr. The mixture was cooled to room temperature and triturated with diethylether and then ethyl acetate. The residue was dissolved in ethyl acetate and extracted with 1 M NaOH, water, and sat. NaCl. After drying the organic layer with MgSO4, filtering, and evaporating solvent under vacuum, the crude product was purified by silica gel chromatography to give a pale yellow solid. The solid was refluxed with 500 ml toluene and 17 ml triethylamine (0.12 moles) for one hr, cooled to room temperature and washed with water and sat. NaCl. The solution was dried again over MgSO4, filtered, and evaporated under vacuum to give 3-pyrrolidinylphenol as a white solid (6.0 gm, 0.037 moles, 32%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[CH:18][CH:19]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cccnc1Oc1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1107.4 %

Procedure:
Take up 2-[4-(2-aminoethyl)phenoxy]nicotinamide (0.0555 g, 0.216 mmol) in methanol (2.1 mL). Add benzaldehyde (0.022 mL, 0.216 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.0082 g, 0.216 mmol) and stir for 6 hours before loading directly onto an SCX column. Wash the column with methanol then elute with 2.0 M NH3 in methanol. Purify by flash chromatography, eluting with 4% (2.0 M NH3 in methanol) in dichloromethane to give the title compound (0.831 g, 79%): TOF MS ES+ 348.2 (M+H)+, HRMS calcd for C21H22N3O2 348.1712 (M+H)+, found 348.1721, time 0.35 min; TLC [silica gel 60 F254, 5% (2.0 M NH3 in methanol) in dichloromethane] Rf=0.20.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1[O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]=[CH:26][C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]>C1(C)C(C)=CC=CC=1>[C:17]([O:20][C:21]1([C:37](=[O:39])[CH3:38])[CH2:30][C:29]2[C:28](=[O:31])[CH:27]3[CH:26]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:8]4[C:7]([CH:6]3[O:13][C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:25](=[O:32])[C:24]=2[C:23]2([S:36][CH2:35][CH2:34][S:33]2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: CC(=O)OC1(C(C)=O)CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Solvent: Cc1ccccc1C
Product: CC(=O)OC1c2ccccc2C(OC(C)=O)C2C(=O)C3=C(CC(OC(C)=O)(C(C)=O)CC34SCCS4)C(=O)C12
Yield: 78.8 %

Procedure:
A solution of 220 mg (1.0 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 234 mg (0.66 mmol) of rac-3'-acetoxy-3'-acetyl-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,1'-naphthalene] [prepared as described in Example 5(A)] in 15 ml of dry xylene was stirred and heated under reflux under an atmosphere of nitrogen for 30 minutes. The pale orange solution was evaporated and the resulting yellow oil was triturated with 15 ml of diethyl ether to yield 298 mg (79%) of rac-3',6',11'-triacetoxy-3'-acetyl-1',2',3',4',5',5a',6',11',11a',12'-decahydro-5',12'-dioxospiro[1,3-dithiolane-2,1'-naphthacene] in the form of a pale yellow solid of melting point 135°-145° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:3]=1[CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:3]=1[CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sccc2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sccc2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a solution of methyl 2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.051 g; 0.144 mmol) in methanol (3 mL) and ethanol (1.5 mL) was added a 5% sodium hydroxide solution (3.9 mL; 4.875 mmol). The reaction mixture was heated under reflux for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.027 g (55%) of the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[NH2:16][CH2:15][CH2:14][NH:17][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: NCCN
Reactant: CCOC(=O)CN1CCC(O)C1=O
Product: NCCNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3.5 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate and 11.2 g of 1,2-ethylene-diamine is left to stand at room temperature for 20 hours. The excess 1,2-ethylenediamine is evaporated in vacuo. The residue is dissolved in 40 ml of hot acetonitrile and stirred at room temperature for 2 hours and then in an ice-bath for 1 hour. By filtration there is isolated N-[2-(amino)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide of melting point 110°-112°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)C(O)=C[CH:4]=1.[C:14]([O:17][C:18](=[O:20])[CH3:19])(=O)[CH3:15]>>[C:18]([O:17][C:14]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:15]=1)(=[O:20])[CH3:19]
Reactant: COc1ccc(O)c2ccccc12
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(OC(C)=O)c2ccccc12

Procedure:
1.75 g. (10 mmole) 4-Methoxy-1-naphthol is boiled under reflux for 2.5 hours in 18 ml. acetic anhydride. Thereafter, the solution is evaporated in a vacuum and the oily residue purified by column chromatography (silica gel; toluene/ethyl acetate 40:1 v/v). After evaporation of the appropriate fractions, the crude product is recrystallised from petroleum ether (b.p. 90°-110° C.). Yield 1.27 g. (58% of theory) of colourless crystals; m.p. 51°-53° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])=[O:33].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:38]3[CH:39]=[CH:40][C:35]([S:32]([CH3:31])(=[O:34])=[O:33])=[CH:36][CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(S(C)(=O)=O)cc2)CC1
Yield: 25 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-methylsulfonylphenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless solid (25%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=O.[NH2:20][CH:21]([CH:24]([OH:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22][OH:23]>C(OCC)(=O)C.CCCCCCC>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([NH:20][CH:21]([CH:24]([OH:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22][OH:23])=[O:5]
Reactant: CCCCCCCCCCCCCCCC(O)C(N)CO
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCC(O)C(CO)NC(=O)C(O)CCCCCCCCCCCCCC
Yield: 70 %

Procedure:
4.9 g (0.018 mol) of 2-hydroxyhexadecanoic acid and 5.4 g (0.018 mol) of 2-aminooctadecane-1,3-diol were mixed in a glass tube; the mixture was irradiated with microwaves with the aid of a Synthewave 402™ apparatus from Prolabo--frequency 2450±50 MHz--modulable power rating 300 W. After an irradiation of 15 minutes at 155° C.±5° C., the reaction mixture was solubilized at high temperature in a mixture of 80 ml of ethyl acetate and 20 ml of heptane. The precipitate obtained was recrystallized from ethanol and 7 g of expected pure product were obtained with a yield of 70%.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH2:27][C:28](O)=[O:29])[C:16]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH2:39])[CH3:35].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([S:7]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH2:27][C:28]([NH:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:40])=[O:29])[C:16]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CN
Reactant: N#Cc1ccc(Cc2nc3cc(NS(=O)(=O)c4ccccc4)ccc3n2CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Cn1c(Cc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.7 g (6.1 mmol) of 4-[(5-benzenesulphonylamino-1-carboxymethyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile, 0.85 g (6.1 mmol) of glycine-ethyl ester-hydrochloride and 1.5 g (15 mmol) of triethylamine are dissolved in 80 ml dimethylformamide and after the addition of 2.4 g (7.5 mmol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate the mixture is stirred for 16 hours at ambient temperature. The solvent is evaporated off, the residue chromatographed on silica gel and eluted with methylene chloride/ethanol 99:1 and 98:2. The desired fractions are concentrated by evaporation, the residue is triturated with ether, suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([Cl:13])=[O:10]
Reactant: O=C(O)c1ccncc1Br
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccncc1Br

Procedure:
3-Bromopyridine-4-carboxylic acid (5.0 g) was dissolved in thionyl chloride (50 ml) and the solution heated under reflux for 4 hours, cooled and evaporated in vacuo. Re-evaporation of added toluene gave 3-bromopyridine4-carbonyl chloride, m.p.151°-154° C. (dec.) (5.45 g) as a green solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([OH:36])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)C.CCCCCCC>[CH3:1][C:2]1([CH3:37])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]([OH:36])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc(C(O)CNCCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)ccc2O1
Solvent: CCCCCCC
Solvent: CCO
Product: CC1(C)OCc2cc([C@H](O)CNCCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)ccc2O1
Yield: 23.8 %

Procedure:
Resolution of 3-{4-[(6-{[2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide (0.403 g) on an HPLC Chiralcel OJ column using 40% ethanol/heptane afforded the title compound (0.096 g).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][C:23](=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].Cl>C(O)C.O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][CH:23]([OH:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Yield: 99.4 %

Procedure:
Sodium tetrahydridoborate (1.55 g, 41.1 mmole) was added with stirring to a cooled solution (5° C.) of methyl (E)-7-(2,4-dichloro-6-phenylmethoxyphenyl)-5-hydroxy-3-oxo-6-heptenoate (34.8 g, 82.3 mmole) in ethanol (200 ml) at a rate sufficient to maintain the internal temperature at 15°-20° C. The resulting solution was stirred with ice-bath cooling for 15 min. and then acidified with 6N hydrochloric acid. The resulting mixture was diluted with water (500 ml) and extracted with ether (3×250 ml). The organic extracts were combined, washed with brine (4×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo, leaving the title compound as a yellow oil (34.8 g, 99.5%): pmr CDCl3) δ2.45 (2H, d), 3.65 (3H, s), 4.18 (H, m), 4.45 (H, m), 4.98 (2H, s), 7.28 (5H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13]I)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][N:18]3[CH2:19][CH2:20][N:15]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:16][CH2:17]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(CCI)coc12
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cccc2c(CCN3CCN(c4cccc5cccnc45)CC3)coc12

Procedure:
A mixture of 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored low melting solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetae:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a dark brown low melting solid. Yield: (HCl salt) 90 mg (21%); (M+H): 388; 1H NMR: δ□11.9 (bs, 1H), 9.2 (d, 1H), 9.0 (bs 1H), 8.2 (m, 2H), 7.9 (s1H), 7.84 (m, 2H), 7.45 (d, 1H), 7.21 (t, 1H), 6.98 (d, 1H), 4.01 9s, 3H), 3.77 (m, 4H), 3.67 9m, 2H), 3.59 (m, 4H), 3.3 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[C:6](Br)=[CH:5][CH:4]=1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C([O-])(=O)C.[K+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[C:6]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: CNc1ccc(Nc2ccc(OC(F)(F)F)cc2)c2c1C(=O)c1ccccc1C2=O
Temperature: 132 °C

Procedure:
12.64 parts of 1-methylamino-4bromo-anthraquinone, 9.9 parts of para-trifluoromethoxyaniline, 6 parts of potassium acetate and 2 parts of copper acetate are introduced into 43 parts of 4-methyl-2-pertanol and the mixture is heated at 132° C. for 8 hours. The mixture is then cooled to 60° C., filtered, washed with water, then the precipitate is taken up in dilute caustic soda, filtered, washed and dried. 9.6 parts of 1-methylamino-4-(p-trifluoromethoxy-anilino)-anthraquinone are obtained.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[CH:16]1([NH2:19])[CH2:18][CH2:17]1.S(=O)(=O)(O)O>>[CH:16]1([NH:19][C:2]2[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=2[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6])[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1NC1CC1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
5.0 g (22 mmol) of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid were dissolved in 25.0 ml (356 mmol) of cyclopropylamine. The mixture was heated at 120° C. with stirring in an autoclave for 1 day, cooled to room temperature (RT), added to ice and conc. sulfuric acid and extracted with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC. This gave 1.8 g of a beige solid in a purity of 95%.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].CN([CH:19]=[O:20])C.O>C1COCC1>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[CH:19]([OH:20])[O:11][C:10]2=[O:12]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a stirred solution of n-butyllithium 1.6 M in hexanes (17.5 mL, 28.1 mmol) was added at −20° C. under argon 2,2,6,6-tetramethylpiperidine (4.7 mL, 28.1 mmol) in anhydrous THF (40 mL). After cooling (−50° C.), 3-bromobenzoic acid (2.54 g, 12.8 mmol) in anhydrous THF (10 mL) was added dropwise and the mixture was stirred for 1 h. The mixture was then treated with an excess of DMF (3.7 g, 50.4 mmol). The resulting solution was allowed to warm up to ambient temperature, after which water was added. The aqueous layer was washed with diethyl ether, and then acidified with 4M HCl. The mixture was diluted with diethyl ether and the organic layer was separated and dried with MgSO4. The residue was purified by crystallization using with EtOAc/PE to give the crude title product (1.18 g, yield: 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17](O)=[O:18])=[CH:7]1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C>[CH3:27][O:26][N:25]([CH3:24])[C:17]([C:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[CH:3]=2)[CH:7]=1)=[O:18]
Reactant: O=C(O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 5 of Example 60, from crude 1-(3-Chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 2.21 g (22.6 mmol) of N,O-dimethylhydroxylamine hydrochloride, 14.3 mL (10.4 g, 103 mmol) of triethylamine and 14.6 mL (15.6 g, 24.5 mmol) of 50% 1-propanephosphonic acid cyclic anhydride in 100 mL acetonitrile to give 3.10 g of the product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[H-].[Na+].CN(C=O)C>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:17]([F:18])([F:20])[F:19]
Reactant: COCCCO
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
3-Methoxypropan-1-ol (217 mg, 2.40 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (500 mg, 2.40 mmol), and NaH (240 mg, 6.0 mmol) were combined in THF (10 mL) and DMF (1 mL) at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was partitioned between ethyl acetate and a 1M aqueous solution of hydrochloric acid. The layers were separated and then the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude material was purified by column chromatography utilizing a gradient of 0-5% methanol in dichloromethane to yield 4-(3-methoxypropoxy)-3-(trifluoromethyl)benzoic acid (213 mg, 32%) as a white solid. ESI-MS m/z calc. 278.1. found 279.3 (M+1)+; Retention time: 1.38 minutes (3 min run). 4-Propoxy-3-(trifluoromethyl)benzoic acid was prepared from 4-fluoro-3-(trifluoromethyl)benzoic acid and 3-fluoro-4-(2-methoxyethoxy)benzoic acid was prepared from 3,4-difluorobenzoic acid using the procedure described above.