Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:35][CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Reactant: CCCCN
Agent: Cl
Product: CCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 17.1 mg (0.23 mmol) of n-butylamine are reacted together by general method E. 49.4 mg (87.5% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:47]#[CH:48])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:47]#[CH:48])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(Oc2ccc(C(=O)OC)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 72.7 %

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-methoxycarbonyl-phenoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.45 g, 0.63 mmol) was reacted with trimethylsilyl acetylene (0.45 g, 6.3 mmol), CuI (3 mg), triethylamine (2.63 mL, 18.9 mmol), and dichlorobis(triphenylphosphine) palladium (0) (35.3 mg, 0.05 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(4-methoxycarbonyl-phenoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.28 g, 73%)
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][C:18]([Br:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:24][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][C:19]=1[O:22][CH3:23])[CH:12]([CH2:11][N:9]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:10]1)[O:13][CH2:14][CH2:15]2
Reactant: COc1cc2c(cc1Br)CCOC2CN1CCN(C(=O)[O-])C(C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl-4-{[6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromen-1-yl]methyl}piperazine-1-carboxylate (150 mg, 0.34 mmol) in 5 mL of DCM was added 5 mL of TFA and the mixture was stirred at room temperature for 1 h. The reaction was concentrated and the 1-{[6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromen-1-yl]methyl}piperazine was directly used in next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:32])[O:17][C@H:16]([CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([CH2:30]O)[CH:24]=[CH:23]3)[CH2:15][O:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:30][C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([O:19][CH2:18][C@@H:16]4[CH2:15][O:14][C:13]([CH3:32])([CH3:12])[O:17]4)[CH:21]=3)[CH:26]=2)=[CH:11][CH:10]=1
Reactant: CC1(C)OC[C@@H](COc2ccc3cc(CO)ccc3c2)O1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCc2ccc3cc(OC[C@@H]4COC(C)(C)O4)ccc3c2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-hydroxybenzoate (0.5 g, 3.28 mmol), [6-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-yl]-methanol (0.9 g, 3.12 mmol) and triphenylphosphine (0.83 g, 3.16 mmol) in DCM (20 ml) is cooled to 0° C. Diethyl azodicarboxylate (0.5 ml, 3.17 mmol) is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and purified by column chromatography (SiO2, EtOAc/iso-hexane) to obtain white solid. The product obtained is once again purified by column chromatography (neutral alumina, EtOAc/petroleum ether) to obtain 4-[6-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalen-2-ylmethoxy]-benzoic acid methyl ester as white solid; 1H NMR (d6-DMSO): 1.32 (3H, s), 1.38 (3H, s), 3.77-3.82 (4H, m), 4.08-4.16 (3H, m), 4.46-4.49 (1H, m), 5.30 (2H, s), 7.15-7.21 (3H, m), 7.37 (1H, d, J=2.0 Hz), 7.53 (1H, dd, J=8.50, 1.5 Hz), 7.83 (2H, dd, J=9.0, 6.0 Hz), 7.92 (3H, m).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[C:9]([CH:37]=1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:21]3[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:20]=3[N:19]=2)=[CH:14][CH:13]=1)(O)=[O:3].C(Cl)(=O)C(Cl)=O.[CH3:51][N:52](C)C=O>ClCCl>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:8]2[CH:7]=[CH:6][C:5]([C:2](=[O:3])[NH:52][CH3:51])=[CH:37][C:9]=2[CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)=[CH:39][CH:40]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(C(=O)O)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3nc4cc(C(=O)OC)ccc4n3C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Methyl 2-{4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylate hydrochloride (400 mg) obtained in Example 246 was suspended in dichloromethane (5 ml), and oxalyl chloride (0.08 ml) and dimethylformamide (catalytic amount) were added. The mixture was stirred for 2 hr at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (5 ml). The resulting solution was added dropwise to a mixed solution of 40% aqueous methylamine solution (5 ml) and tetrahydrofuran (5 ml) under ice-cooling. The reaction mixture was stirred for 1 hr and concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from ethyl acetate and diisopropyl ether. The crystals were collected by filtration and dried under reduced pressure to give the title compound (335 mg, yield 86%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:32][C@:31]2([C:33](=[O:36])CO)[C@@H:10]([CH2:11][C@H:12]3[C@H:25]4[C@@:16]([F:29])([C@:17]5([CH3:28])[C:22]([C@@H:23]([F:26])[CH2:24]4)=[CH:21][C:20](=[O:27])[CH:19]=[CH:18]5)[C@@H:15]([OH:30])[CH2:14][C@@:13]32[CH3:37])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:38].[Na+]>C1COCC1.O>[CH2:1]([N:8]1[CH2:32][C@:31]2([C:33]([OH:36])=[O:38])[C@@H:10]([CH2:11][C@H:12]3[CH:25]4[C@@:16]([F:29])([C@:17]5([CH3:28])[C:22]([C@@H:23]([F:26])[CH2:24]4)=[CH:21][C:20](=[O:27])[CH:19]=[CH:18]5)[C@@H:15]([OH:30])[CH2:14][C@@:13]32[CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)CC1[C@@H]3C[C@H]4CN(Cc5ccccc5)C[C@@]4(C(=O)O)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
A mixture of compound 8 (460 mg, 0.899 mmol) and NaOH 6N (1350 μl, 11.10 mmol) in THF (20 ml) and water (10 ml) is stirred at RT for 3 days. Water is added and the organic solvent is evaporated. The basic aqueous solution (pH 12) is washed with AcOEt. The aqueous phase is then treated with HCl 6N until pH 6 when a solid precipitated. The solid is recovered by filtration and the aqueous phase is extracted with AcOEt, washed with brine, dried over Na2SO4 and then evaporated. The two fractions of obtained solid are combined and triturated with AcOEt (containing 2% MeOH) to give the title compound (150 mg, 0.301 mmol, 33.5% yield).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(#N)C>[F:25][C:24]([F:26])([F:27])[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]2)=[CH:18][CH:19]=1)([OH:32])[C:28]([F:29])([F:31])[F:30]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 24 h
Yield: 63.4 %

Procedure:
A mixture of tert-butyl 1,4-diazepane-1-carboxylate (24.52 mmol, 4.91 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (24.52 mmol, 8.26 g) and sodium hydrogencarbonate (36.8 mmol, 3.09 g) in acetonitrile (100 mL) was stirred for 24 hours then was concentrated under reduced pressure. Dichloromethane was added and the suspension was filtered. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica eluting with dichloromethane to dichloromethane/methanol (5%) to give the title compound (7.1 g). MS (ESI) m/z 457.2 [M+H]+
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35](C2C=CC=CC=2CSCCO)=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[C:39]([C:14]2[CH:13]=[CH:12][CH:17]=[CH:16][C:15]=2[CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ccccc1-c1ccccc1CSCCO
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester (5.0 g, 15.80 mmol, 1 eq.) in anhydrous THF was treated with phenol (2.08 g, 22.12 mmol, 1.4 eq.), triphenylphosphine (5.80 g, 22.12 mmol, 1.4 eq.), and diisopropyl azidocarboxylate (4.47 g, 22.12 mmol, 1.4 eq.). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:4](=[O:7])[O:5][CH3:6])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][Br:15])[C:4](=[O:7])[O:5][CH3:6])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN(C(=O)OC)c1ccccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(C(=O)OC)c1ccccc1CBr
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 30 g (0.155 mol) of methyl N-ethyl-N-(o-methylphenyl)-carbamate (Example 1b), 33 g (0.185 mol) of N-bromosuccinimide and 0.1 g of azoisobutyronitrile in 300 ml of carbon tetrachloride is exposed to a 300 W UV lamp for 6 hours. During this procedure, the contents of the flask heat up to about 70° C. Thereafter, the reaction mixture is washed four times with water, dried and evaporated down. The residue obtained comprises 41 g of a brown oil which contains the title compound in about 50% purity and is used without further purification in the next reaction.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]([CH3:13])[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([N:5]([CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])[CH3:13])=[CH:11][N:10]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN(C)CCN(C)c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)CCN(C)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
A 100-mL two-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 270b (1.00 g, 5.20 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.53 g, 5.72 mmol), cesium carbonate (5.09 g, 15.6 mmol), and 1,4-dioxane (52 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (257 mg, 0.442 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (239 mg, 0.260 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with methanol (20 mL) to afford a 63% yield (700 mg) of 270c as an off-white solid: mp 161-163° C.; 1H NMR (300 MHz, DMSO-d6) d 8.50 (d, 1H, J=2.3 Hz), 8.39 (s, 1H), 7.75 (d, 1H, J=2.4 Hz), 7.40 (d, 1H, J=2.4 Hz), 7.17 (m, 2H), 3.50 (s, 3H), 3.56 (t, 2H, J=6.9 Hz), 2.86 (s, 3H), 2.35 (t, 2H, J=7.1 Hz), 2.16 (s, 6H); MS (ESI+) m/z 380.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:6]([CH:22]=1)[CH2:7][NH:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:6]([CH:22]=1)[CH2:7][N:8]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([O:32][CH3:31])=[O:42])=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl 4-[5-bromo-2-benzyloxybenzylamino]benzoate (16.9 g) and methyl-4-bromomethylbenzoate were dissolved in dimethylformamide (30 ml) and potassium carbonate (18 g) added. The mixture was stirred at ambient temperature for 24 hours and then poured into water (300 ml). The reaction mixture was extracted with ether (4×100 ml). The combined ether extracts were washed with water (3×100 ml) and brine (1×100 ml), dried over magnesium sulphate and evaporated. The residue was purified by MPLC eluting with 1:1 dichloromethane/hexane to give tert-butyl 4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate (3.6 g) m.p. 154-155° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].B(F)(F)F.[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.[OH-].[Na+]>CCOCC.O>[CH2:1]([O:5][CH2:10][CH:12]1[O:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: ClCC1CO1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCOCC1CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
370 g (5 mol) of n-butanol and 3 ml of BF3.(C2H5)2O catalyst were heated to 45° C. and stirred for 4 h. An amount of 466 g (5 mol) of epichlorohydrin was added dropwise at 40°-50° C. The mixture was cooled down to room temperature and 6.25 mol of a 50% aqueous solution of sodium hydroxide (250 g of sodium hydroxide dissolved in 250 ml of water) was added dropwise. The mixture was stirred for 1 h. Water was added until complete dissolution of the inorganic salt. The organic phase was separated and 0.5 l of ethyl acetate was added thereto. The organic phase was rinsed twice with water, dried over sodium sulphate, filtered, and concentrated by evaporation. Fractionation was carried out then at normal pressure. Yield: 290 g of 1-butoxy-2,3-epoxypropane boiling at 170°-174° C.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:5]#[N:6])[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [O-][n+]1ccccc1Cc1ccccc1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 16.1 %

Procedure:
Trimethylsilyl cyanide (14.56 g, 19.6 ml, 0.147 moles) was added dropwise to a solution of 2-benzylpyridine-N-oxide (10.86 g, 0.059 moles) and triethylamine (8.91 g, 12.3 ml, 0.088 moles) in acetonitrile (40 ml) at 20° C. After complete addition the mixture was heated under reflux for 20 hours, cooled to room temperature and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous magnesium sulphate. Removal of the solvent gave an orange oil which was purified by column chromatography (silica gel eluted with hexane:ethyl acetate 9:1) to give 2-benzyl-6-cyanopyridine (1.84 g, 16%) as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=3)[C@@H:10]([CH3:35])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl.O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:15]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[CH3:35])=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:24]([OH:26])=[O:25])[CH:21]=3)[N:16]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CNCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of methyl 3-[(2S)-4-[(tert-butoxy)carbonyl]-2-methylpiperazin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (260 mg, 0.54 mmol) in dichloromethane (30 mL) was added CF3COOH (2 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in methanol (15 mL), and sodium hydroxide (20 mg, 0.50 mmol) in water (1 mL) was added. The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (3 mL), the pH adjusted to 6, and the resulting solution concentrated in vacuo. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC(MS-Directed)): Column, 1#-PrepC-001(XBridge Shield RP18 19*150 186002987 111130103113 03), N; mobile phase, WATER WITH 0.03% NH3H2O and CH3CN (10% CH3CN up to 22% in 7 min, hold 100% in 2 min, hold 10% in 2 min); Detector, UV 220 nm) to afford 2-(4-fluorophenyl)-3-[(2S)-2-methylpiperazin-1-yl]quinoxaline-6-carboxylic acid as a yellow solid (31 mg, 59%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([F:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[C:13]([F:21])[CH:12]=2)[C:3]([OH:22])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.1 %

Procedure:
A solution of 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid methyl ester (1.80 g, 5.69 mmol) in tetrahydrofuran (15 mL) was treated with a 0.8M aqueous lithium hydroxide solution (7.1 mL, 5.69 mmol). The reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was concentrated in vacuo. The resulting residue was diluted with ethyl acetate (100 mL) and then washed with a 5% aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (1.11 g, 64%) as a white solid: mp 93-95° C.; FAB-HRMS m/e calcd for C15H16F4O2 (M+H)+ 305.1165, found 305.1175.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:11]2([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:16][CH2:17]1
Reactant: CN1CCN(C2(C)CCN(Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C2(C)CCNCC2)CC1
Reaction time: 22 h

Procedure:
A suspension of 0.99 g (3.27 mmol) 1-(1-benzyl-4-methyl-piperidin-4-yl)-4-methyl-piperazine and 200 mg 10% Pd/C in 25 mL MeOH was hydrogenated at 50° C. and 50 psi hydrogen pressure for 2 h. To complete the reaction a further 200 mg catalyst were added and the reaction mixture was hydrogenated for a further 22 h at 60° C. and 50 psi hydrogen pressure. The catalyst was filtered off and the filtrate evaporated to dryness. The product was reacted further without purification.