Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N)CN.C(O)(=[O:13])CC.[C:15]([O-:19])(=[O:18])[CH2:16][OH:17]>C(O)=O>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:16]([OH:13])(=[O:17])[C:15]([OH:19])=[O:18]
Reactant: O=C([O-])CO
Reactant: CCC(=O)O
Reactant: O=C(O)CO
Solvent: NCCN
Solvent: O=CO
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Reaction time: 20 h

Procedure:
The reaction in Example 4 was repeated using 10 mL of a solution containing glycolic acid (0.75M), ethylenediamine (0.86M), propionic acid (0.075M, HPLC internal standard), flavin mononucleotide (0.2 mM), 2.5 IU of spinach glycolate oxidase immobilized on Eupergit C, and 14,000 IU of Aspergillus niger catalase immobilized on Eupergit C (the two enzymes were not co-immobilized on the same support). After 20 hours, the yields of glyoxylic acid, oxalic acid, and formic acid were 99%, 0.2%, and 0.5%, respectively, with a 100% conversion of glycolic acid. The final activities of glycolate oxidase and catalase were 72% and 66% of their initial values, respectively.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C@@H:19]([OH:22])[CH:20]=[CH:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1.[C:23]([OH:36])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(O)C.C(O)C.CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.C(OCC)(=O)C>[CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C@@H:19]([OH:22])[CH:20]=[CH:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1.[C:23]([O-:36])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCC(=O)O
Agent: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCCCCCC(=O)[O-]
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Codeine base (4.0002 g; 12.60 mmol) was dissolved in ethanol (100 mL; 99.7-100%) with stirring. Lauric acid (2.7822 g; 13.86 mmol; 10% excess relative to codeine base) was dissolved in the ethanol/codeine solution. The resulting solution was stirred for 5 minutes. The ethanol was removed by rotary-evaporation to give a pale yellow residue. The residue was redispersed in ethyl acetate (10 mL) by heating on a water bath (60° C.). Once all the material had redissolved the solution was placed at 4° C. for 16 hours. A white precipitate formed which was isolated by vacuum filtration. The precipitate was dried further in a vacuum oven for 16 hours at 40° C. to give codeine laurate (2.4757 g; 36.50%). The material was analysed by Differential Scanning Calorimetry in order to determine the melting point. However, thermal analysis from 50 to 200° C. showed no thermal event.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[C:20]([O:24][C:25]([CH2:27][C@@H:28]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:29](N1[C@H](C(C)C)COC1=O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1C=CC=C1.O1CCCC1>[CH2:1]([O:8][C:29](=[O:30])[C@H:28]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccoc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred solution of dry benzyl alcohol (0.55 ml, 5.33 mmol) in anhydrous tetrahydron furan (18 ml) under a nitrogen atmosphere at 0° C. was added a hexane solution of n-butyllithium (2.58 ml; 4.00 mmol). To this solution was added the product from Example 141 in anhydrous tetrahydrofuran (10 ml). After stirring 1 h at 0° C. the reaction was quenched by adding excess saturated aqueous ammonium chloride. The volatiles were removed by rotary evaporation and the resulting aqueous residue extracted two times with ether. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo provided an oil which was purified by chromatography on SiO2 (15% ether acetate/hexanes) to provide the desired product (0.89 g, 94%) as a colorless oil. Mass spectrum: (M)+ =354.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Li+].[OH-].Cl[C:15]([O:17][CH3:18])=[O:16].Cl>O>[CH3:18][O:17][C:15]([NH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:16]
Reactant: COC(=O)Cl
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a solution of (R)-2-amino-2-phenylacetic acid (14 g, 92.6 mmol) in water (250 mL) was added LiOH (14.8 g, 618.7 mmol) at 0° C. and the mixture was stirred for 15 minutes. To this solution, methyl chloroformate (17.9 mL, 231.5 mmol) was added drop wise and the mixture was stirred for 2 hours at 0° C. The mixture was then acidified until pH 1 with concentrated HCl. The mixture was extracted with EtOAc and the organic phase was concentrated in vacuum. The residue was dried overnight in vacuum, resulting in (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (11.8 g; 60.9 mmol).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[CH3:21][C:22]1[C:27]([CH:28]=O)=[CH:26][N:25]=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[N:23]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:28]([C:27]3[C:22]([CH3:21])=[N:23][C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[N:25][CH:26]=3)=[N:9][C:4]=2[C:3]=1[CH3:10]
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1c(F)ccc(N)c1N
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1-c1nc2c(C)c(F)ccc2[nH]1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a 2 L Erlenmeyer flask were added 4-fluoro-3-methyl-benzene-1,2-diamine.HCl (46.32 g, 262.3 mmol), Na2S2O5 (64.82 g, 341.0 mmol), and 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde (72.5 g, 262.3 mmol) in DMF (725 mL). To the resultant mixture was then added triethylamine (36.6 mL, 262.3 mmol), and the reaction was warmed on a hot plate with stirring to 90° C. and held at this temperature for 2 hours. The resultant mixture was then concentrated to near dryness and partitioned between dichloromethane (1 L) and 1 N NaOH (1 L). After separation of the layers, the aqueous layer was extracted a second time with dichloromethane (1 L). The combined organic layers were then washed with saturated aqueous NaHCO3 (1.6 L). The organics were then extracted with a 1 M mono/dibasic phosphate buffer (pH 5.62, 1.23 L). The aqueous layer was then basified with 50% NaOH (80 mL) to pH 10.8. The resultant heterogeneous layer was then extracted with dichloromethane (1.5 L and 500 mL), and the combined organics were concentrated to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.O.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 78.6 %

Procedure:
Beginning with 5.0 gm (34.0 mMol) 5-methoxy-1H-indole and 10.0 gm (65.0 mMol) 4-piperidone hydrochloride monohydrate, 6.1 gm (79%) of the title compound were recovered as a yellow solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.O>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 65 °C

Procedure:
KOH (8.44 g, 150 mmole), 5-methoxyindole (5.0 g, 34 mmole) and piperidine-4-one hydrochloride (10.53 g, 88.3 mmole) were suspended in methanol (50 ml) and heated for 8 hours at 65° C. under argon. Water (50 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The solid thereby formed was filtered off, washed with water (3×20 ml) and recrystallised from methanol (20 ml). 5-methoxy-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole was obtained in a yield of 4.66 g (75%) as a yellow solid with an m.p. of 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[I:12]I>C(O)C.O.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[I:12]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 6-chloro-3-nitropyridin-2-amine (630 mg, 3.63 mmol) in ethanol (11 mL) was add I2 (920 mg, 3.62 mmol) and Ag2SO4 (1132 mg, 3.63 mmol).). The resulting solution was stirred overnight at room temperature and dissolved in water (100 mL), then extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to produce 6-chloro-5-iodo-3-nitropyridin-2-amine as a yellow solid (640 mg, 59%). Next, to a solution of 6-chloro-5-iodo-3-nitropyridin-2-amine (640 mg, 2.14 mmol) in ethanol (40 ml) and water (10 ml) was added Fe powder (1.93 g, 34.46 mmol) and NH4Cl (887 mg, 16.58 mmol). The resulting solution was heated to reflux for 4 h and then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (3×80 ml). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 33% ethyl acetate in petroleum ether to produce 6-chloro-5-iodopyridine-2,3-diamine as a brown solid (560 mg, 97%). The mixture of 6-chloro-5-iodopyridine-2,3-diamine (100 mg, 0.37 mmol), (2,3-dichlorophenyl)boronic acid (147.3 mg, 0.77 mmol), Pd(Ph3P)4 (42.9 mg, 0.04 mmol) and sodium carbonate (118.2 mg, 1.12 mmol) in water (5 mL) and dioxane (15 mL) was heated to reflux overnight. Then the resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine as a brown solid (80 mg, 75%). Finally, the solution of 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine (80 mg, 0.28 mmol) in trifluoroacetic acid (10 mL) and hydrochloric acid (conc., 2 mL) was heated to reflux overnight. Then the resulting mixture was quenched with water (100 mL), adjusted pH to 8 with sodium carbonate and extracted with ethyl acetate (3×80 mL). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,3-dichlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. Trifluoroacetic acid as a off-white solid (2 mg, 2%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.C(Cl)Cl.O>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Agent: O=C1CCC(=O)N1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A four-necked glass flask equipped with a stirrer and reflux condenser was charged with 180 g of methylene chloride, 63.2 g of 4'-methylbiphenyl-2-carbonitrile, 58.8 g of N-bromosuccinimide and 90 mg of 2,2'-azobis (2,4-dimethylvaleronitrile) and the reaction was conducted under reflux with stirring at an internal temperature of 45°-47° C. for 3 hours. Refluxing was further continued for 1 hour and after cooling to an internal temperature of 35°-38° C., the reaction mixture was treated with 200 g of water twice to transfer the byproduct succinimide into the water layer. The methylene chloride layer was allowed to cool gradually to 0° C., whereupon white crystals separated. The crystals were recovered by filtration, washed with cold methylene chloride and dried to give 71.6 g of 4'-bromomethylbiphenyl-2-carbonitrile. Yield 80.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.CN(C)C=O.[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49]>CC(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:45]([O-:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([O-:50])=[O:49]
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Nilotinib base form A (4.00 g, 7.55 mmol) was stirred with IPA (40 mL, 10V) and the suspension was heated to 80° C. Stirring was continued at the same temperature for 30 min. To the stirred suspension was added a solution of maleic acid (0.96 g, 8.31 mol. 1.1 eq) in IPA (10 mL, 2.5V) in one portion. The resulting mixture was stirred at 80° C. for 1 h and then cooled to room temperature and stirred over night. The solids were isolated by filtration to give Nilotinib maleate form V. The obtained Nilotinib maleate form V was dried in a vacuum oven (35 mmHg) at 60° C. for 32 hours. The dried product was analyzed by PXRD and was found to be Nilotinib maleate form V. Mono maleate was obtained as confirmed by assay determination.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].C(OCCC)CC>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][CH2:29]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Solvent: CCCOCCC
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Maleic acid (1.161 g, dissolved in 10 ml of 2-propanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (20 ml) with stirring at room temperature followed by adding 10 ml of dipropyl ether. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 126.8° C.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(CC)CC)C>CN(C=O)C.O>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH3:14]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CN
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.8 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (6.00 g, 17.3 mmol) and glycine ethyl ester hydrochloride (2.41 g, 17.3 mmol) in DMF (200 mL) was treated with triethylamine (7.8 mL, 56 mmol). After stirring at room temperature for 3.5 h, the cloudy mixture was diluted with H2O (300 mL) and then extracted with EtOAc (2×300 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2) gave the title compound (2.83 g, 57%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.3 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 5.56 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.71 (s, 2H), 3.38 (s, 2H), 1.73 (s, 1H), 1.30 (t, J=7.2 Hz, 3H); MS (ESI) m/e 288 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14](Cl)[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CO.CN(C)[CH:31]=[O:32]>O>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14]([O:32][CH3:31])[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=c1c2ccc(Cl)cc2oc2c(OCc3ccccc3)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(=O)c3cccc(OCc4ccccc4)c3oc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-benzyloxy-3-chloroxanthone (8.5 g.), sodium hydride (3 g.), methanol (20 ml.) and dimethylformamide (100 ml.) is stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is filtered. The residue is recrystallised from isopropanol to give 5-benzyloxy-3-methoxyxanthone, m.p. 158° C.
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26].[OH2:31].ClCCl>N1C=CC=CC=1>[C:21]([OH:28])(=[O:31])[CH3:22].[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Reactant: CCCS(=O)(=O)Cl
Reactant: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O
Product: CCCS(=O)(=O)Nc1cccc(C2(C)C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 200 mg, 0.65 mmol) in pyridine (2 ml) under nitrogen at 0° C. was added n-propanesulfonyl chloride (140 mg, 0.98 mmol), then the mixture was stirred at room temperature for 16 hours. Water (5 ml) and dichloromethane (5 ml) were added, and the mixture was stirred for 30 minutes. The organic phase was washed further with water (5 ml) for 30 minutes, separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (10 g) column chromatography eluting with ethyl acetate:hexane:ammonia solution (0.880) (20:80:1 then 50:50:1). Product-containing fractions were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (condition 4). Combination and evaporation of appropriate fractions gave the title compound as a pale brown solid (11 mg, 4%).
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:19][CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: c1ccccc1
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O

Procedure:
2,500 ml of benzene was added to 1,423 g of N-(1'-hydroxy-2',2',2'-trichloroethyl)-2-hydroxy benzamide and then 833 g of thionyl chloride was added thereto and heated under reflux at 70°-80° C. for 4 hours to obtain N-(1',2',2',2'-tetrachloroethyl)-2-hydroxy benzamide (white crystal, melting point of 113°-113.5° C., Anal. Found: C,35.74; H,2.12; N,4.70 Calcd. for C9H7Cl4NO2 : C,35.68; H,2.33; N,4.62 and the resultant reaction mixture, without separation of the crystals, was cooled to below 30° C. and mixed with 1,250 g of methanol and heated under reflux for 2 hours at 55°-60° C. followed by removing the solvent and the residue was poured into water, filtered and dried to obtain 1,380 g (yield 92.4%) white crystals of N-(1'-methoxy-2',2',2'-trichloroethyl)-2-hydroxy benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Cc2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: COC(=O)CC1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C

Procedure:
A solution of the product from Step A of Example 21 above (1320 mg, 4.56 mmol), pyrrolidine (972 mg, 13 mmol) and p-toluenesulfonic acid (33 mg) in benzene (30 ml) was refluxed through 3A molecular sieves for about 17 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in benzene (10 ml) and cooled to about 0° C. Methyl bromoacetate (1530 mg, 10 mmol) was added dropwise. The reaction mixture was slowly allowed to warm to room temperature and then was heated under reflux for about 17 h at which point H2O (5 mL) was added. After refluxing for about another 2 h, the reaction mixture was cooled to room temperature and extracted with EtOAc (3×100 ml). The combined organic extracts were dried and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 15% ethyl acetate/hexanes to give 280 mg of product. 1H NMR (250 MHz, CDCl3): d 7.35 (m, 5H), 4.5 (m, 1H), 3.8 (s, 3H), 3.4 (dd, 1H), 3.1 (m, 1H), 2.85 (m, 4H), 2.6 (m, 1H), 2.4 (m, 1H), 1.5 (s, 9H); MS (APCl): 362 (M+1).