Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O.[OH:11][C@:12]1([C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C:29](=[CH:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:34])[CH2:25][CH2:26]2)[CH2:21][CH2:20]3)[CH2:17][C@@H:16]1[CH3:35])[C:13](=[O:15])[CH3:14]>C(Cl)(Cl)Cl.COCOC>[OH:11][C@:12]1([C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C:29](=[CH:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:34])[CH2:25][CH2:26]2)[C:21](=[CH2:1])[CH2:20]3)[CH2:17][C@@H:16]1[CH3:35])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: COCOC
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C[C@@H]2C(=CC[C@@]3(C)[C@H]2C[C@H](C)[C@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 65 °C
Reaction time: 6.5 h
Yield: 57 %

Procedure:
A suspension of 10.0 g of sodium acetate in 300 ml of chloroform and 300 ml of formaldehyde dimethylacetal is stirred with 19 ml of phosphorus oxychloride for one hour at a bath temperature of 65° C. After adding 10.0 g of 17α-hydroxy-16β-methyl-4,9(11)-pregnadiene-3,20-dione, another 19 ml of phosphorus oxychloride is added dropwise and the reaction solution is stirred for another 6.5 hours at 65° C. The cooled-off solution is treated with such an amount of a saturated soda solution that the aqueous phase is made permanently alkaline. The organic phase is separated, washed neutral and concentrated after drying. The crude product is purified on 700 g of silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 5.9 g of 17α-hydroxy-16β-methyl-6-methylene-4,9(11)-pregnadiene-3,20-dione, mp 157°-158° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClS([N:13]=[C:14]=[O:15])(=O)=O.S([O-])([O-])=O.[Na+].[Na+].[OH-].[K+]>C(OCC)C.O>[C:3]1([CH:2]2[NH:13][C:14](=[O:15])[CH2:1]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C1CC(c2ccccc2)N1
Yield: 37.4 %

Procedure:
40 g of styrene are slowly dripped into a solution of 54 g of chlorosulphonylisocyanate in 80 cm3 of ethyl ether, maintaining the solvent at reflux temperature. After three hours the reaction mixture is cooled and is added in small quantities to a solution of 48 g of sodium sulphite in 195 cm3 of water, maintaining the temperature at less than 22° C. with an external ice bath and the pH within a range of between 7 and 8 by adding an aqueous solution of potassium hydroxide at 10%. At the end of the addition the mixture is filtered and the organic phase of the filtrate is dried on sodium sulphate and evaporated. 21 g of the desired compound are obtained (yield 38%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:15](O)[CH3:16]>O>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)CNc1cccc([N+](=O)[O-])c1
Solvent: O
Product: CCOC(=O)CNc1cccc([N+](=O)[O-])c1

Procedure:
2 g of 3-nitrophenylglycine are heated for 20 hours with stirring at a temperature in the region of 100° C. in 100 cm3 of absolute ethanol containing 20 cm3 of 6.5N hydrochloric ethanol. The suspension is filtered at a temperature in the region of 50° C.; the filtrate is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in water and then extracted with about 100 cm3 of ethyl acetate. The aqueous phase is made alkaline by addition of sodium carbonate until a pH in the region of 10 is obtained. The medium is extracted with ethyl acetate; the combined extracts are washed with aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure (5 kPa) at 40° C. 1 g of ethyl 3-nitrophenylglycinate is obtained in the form of a yellow oil. (Rf=0.38 in a 95/5 by volume mixture of dichloromethane/methanol, on a Merck 60F254R silica plate).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33](O)=[O:34])=[CH:23][N:22]=1>>[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:23][N:22]=1
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Product: Cc1ncc(C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c(-c2ccccc2)n1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-4-phenyl-pyrimidine-5-carboxylic acid. LC-MS (basic): tR=1.31 min; [M+H]+=453.2.
Reaction SMILES: [BrH:1].[CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)=[CH2:3]>C1C=CC=CC=1>[Br:1][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3]
Reactant: C=Cc1ccc2ccccc2c1
Reactant: Br
Solvent: c1ccccc1
Product: CC(Br)c1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
HBr gas (39.4 g, 486 mmol) was bubbled into a solution of 2-vinylnaphthalene (75 g, 486 mmol) in benzene (100 mL) over a period of 7-8 hours at 55-60° C. The solution was cooled to room temperature, and the benzene with the small excess of HBr was removed under vacuum yielding 105 g (91%) crude of 2-(1-Bromoethyl)-naphthalene. It was used without further purification. C12H11Br; MS: 235.12.
Reaction SMILES: [CH:1]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCC.[CH:14](OCC)=[O:15]>O1CCCC1>[CH:1]1([CH:6]([C:7]#[N:8])[CH:14]=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC=O
Reactant: N#CCC1CCCC1
Solvent: C1CCOC1
Solvent: CCCCC
Product: N#CC(C=O)C1CCCC1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-cyclopentylacetonitrile (0.50 g, 4.59 mmol) in tetrahydrofuran (10 mL) was cooled to −60° C. then treated with 1.7 M tert-buytllithium in pentane (3.25 mL, 5.50 mmol) while maintaining the reaction temperature at less than −55° C. The solution was stirred for 10 minutes then ethyl formate (0.41 g, 5.50 mmol) was added dropwise. The mixture was warmed to ambient temperature and stirred an additional 16 hours. The mixture was concentrated under reduced pressure and the resulting residue applied to a silica gel column and eluted with dichloromethane/ethyl acetate (95:5). The fractions containing material with an Rf of 0.1–0.3 [TLC, dichloromethane/ethyl acetate (95:5), potassium permanganate stain) were combined and concentrated to give an oil which was used without further purification: 1H NMR (Chloroform-d, 400 MHz) δ 9.57 (s, 1H), 3.54 (d, 1H), 2.45 (m, 1H), 1.4–1.9 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][O:15][C:14]2=[O:19])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:21][CH:22]=O>>[N:1]1[CH:21]=[CH:22][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][O:15][C:14]3=[O:19])[C:2]=12
Reactant: O=CCCl
Reactant: Nc1ncccc1OCCCCN1C(=O)COC1=O
Product: O=C1COC(=O)N1CCCCOc1cccn2ccnc12

Procedure:
Using 6.63 g (25 mnmol) of 3-[4-(2-aminopyridin-3-yloxy)butyl]oxazolidine-2,4-dione and 25 ml of a 40% chloroacetaldehyde solution, the same procedure as in Reference Example 18 was followed, to yield 6.48 g (89.5%, yellow oily substance) of the desired product.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A solution 3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 115, 1.03 g, 3.12 mmol) in methylene chloride (31.26 mL) at 25° C. was treated with a 1.0M solution of boron tribromide in methylene chloride (31.26 mL, 31.26 mmol). This solution was stirred at 25° C. for 4 h. At this time, the reaction was cooled to 0° C. and was then quenched by the dropwise addition of a dilute aqueous ammonium hydroxide solution. The resulting solution was stirred at 0° C. for 15 min. This mixture was then poured into water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide (626.8 mg, 63.4%) as a off-white solid: mp 198–200° C.; EI-HRMS m/e calcd for C17H20N2O2S (M+) 316.1245 found 316.1256.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][C:16]3=[O:19])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH:16]3[OH:19])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C1CCCc2ccc(OCc3ccncc3)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC1CCCc2ccc(OCc3ccncc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of Compound 1 (16.41 g, 64.9 mmol) in tetrahydrofuran (75 mL) at 0° C. was added dropwise a 1M solution of diisobutylaluminum hydride in toluene (97.3 mL). After 1 hr, the reaction was quenched with aqueous potassium sodium tartrate and diluted with ethyl acetate followed by warming to room temperature. After stirring for an additional hour, the layers were separated and the aqueous phase was re-extracted with ethyl acetate (2×). The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with ethyl acetate) provided 12.96 g of Compound 2 as an oil which crystallized upon standing.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1>[F:24][C:20]1[CH:19]=[C:18]([N:13]2[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(F)c3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Solvent: C1COCCO1
Product: Fc1cccc(-n2nc3c(c2-c2ccccc2)CCNCC3)c1
Yield: 34.6 %

Procedure:
The title compound (37.6 mg) was prepared from 339.2 mg of 2-(3-fluoro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (made as in Example 176, Steps A and B from (3-fluoro-phenyl)-hydrazine) as described in Example 196, using 1,4-dioxane as the solvent. MS (ESI): exact mass calculated for C19H18FN3, 307.15. found, m/z 308.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.39-7.35 (m, 3H), 7.20-7.14 (m, 3H), 7.00-6.96 (m, 1H), 6.94-6.86 (m, 2H), 3.13-3.09 (m, 2H), 3.06-3.02 (m, 2H), 3.01-2.96 (m, 2H), 2.69-2.66 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[N:7][CH:8]=1)[CH3:2].[Br:11]P(Br)Br>C(Cl)(Cl)Cl>[Br:11][CH2:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCc1cncc(CO)c1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCc1cncc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of (5-ethylpyridin-3-yl)methanol (3.31 g, 24.12 mmol) in anhydrous chloroform (50 mL) at 0° C. was added tribromophosphane (7.18 g, 2.49 mL, 26.54 mmol) dropwise. The reaction mixture was allowed to stir overnight at room temperature. The solvent was evaporated to provide crude 3-(bromomethyl)-5-ethylpyridine (4.82 g, 100% yield), which was used in the next step without any further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[Cl:52]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:41])([CH3:39])[CH3:40])=[C:31]([CH3:50])[CH:30]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[Cl:52]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(Cl)c2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(Cl)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
Trifluoroacetic acid (0.03 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-3-chloro-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 61-(1); 3.0 mg, 0.045 mmol) in dichloromethane (0.15 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (2.3 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6]
Reactant: Nc1ccccc1C(=O)O
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)N1CCCC1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 2-aminobenzoic acid (5.0 g, 36.5 mol) in tetrahydrofuran (50 mL) was added N,N′-carbonyldiimidazole (6.5 g, 40.1 mol) at 25° C., the resulting mixture was stirred for 1 hour at this temperature. Then pyrrolidine (3.5 g, 40.1 mmol) was added and the mixture was stirred overnight. The solvent was removed under the reduced pressure and the residue was washed with water and extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated to afford the product (2-aminophenyl)(pyrrolidin-1-yl)methanone (5.4 g, yield 66%), which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.12-7.21 (m, 2H), 6.66-6.71 (m, 2H), 4.62 (br s, 2H), 3.63 (br s, 2H), 3.47 (br s, 2H), 1.87-1.94 (m, 4H).
Reaction SMILES: Cl.Cl[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5](OC1CNC1)[C:6]1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43]C(C)(C)C)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:28]([O:36][CH:37]1[CH2:38][N:39]([C:41]([NH:43][CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:3]=2)=[O:42])[CH2:40]1)[C:27]1[CH:48]=[CH:49][CH:50]=[CH:51][C:26]=1[Cl:25]
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Agent: Cl
Agent: [N-]=C=O
Product: O=C(NCCc1ccccc1)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:14])=[O:3].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH:20]=O.N1CCCCC1.N1C=CC=CC=1>C(O)C>[CH3:28][O:27][C:23]1[CH:22]=[C:19]([CH:20]2[CH2:1][C:2](=[O:3])[C:4]3[C:5](=[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]4=[CH:12][CH:13]=3)[O:14]2)[CH:18]=[C:17]([O:16][CH3:15])[C:24]=1[O:25][CH3:26]
Reactant: CC(=O)c1ccc2ccccc2c1O
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C2CC(=O)c3ccc4ccccc4c3O2)cc(OC)c1OC
Yield: 38.6 %

Procedure:
A mixture of 1-hydroxy-2-acetonaphthone 1 (15 g, 81 mmol) and 3,4,5-trimethoxy-benzaldehyde 2 (17.66 g, 88 mmol) in 600 mL ethanol was treated with piperidine (40 mL) and pyridine (45 mL) and the dark solution was refluxed for 18 h. The reaction mixture was evaporated to dryness and the dark residue was dissolved in methylene chloride (600 mL). The solution was washed with 2×300 mL of water and 2×300 mL brine and dried with anhydrous MgSO4 after which it was filtered and evaporated to afford 60 g of crude material. This was purified via flash chromatography, eluting with methylene chloride (1 L), followed by the solvent mixture CH2Cl2: EtOAc (95:5) to obtain fractions containing pure product. These were evaporated to afford 11.4 g (39% yield) of pure SR 13177 as a yellow solid. TLC: Hexanes/EtOAc (7:3): Rf=0.26; 1H NMR (300 MHz, CDCl3): δ 3.00 (dd, J=16.69, 3.15, 1H, 3-H), 3.22 (dd, J=16.94, 13.28, 1H, 3-H), 3.92 and 3.94 (2s, 9H, OCH3), 5.66 (dd, J=13.31, 3.17, 1H, 2-H), 6.81 (s, 2H, 2′,6′-Ar—H), 7.46-7.95 (m, 5H, Ar—H), 8.36 (d, 1H, Ar—H); 13C (75 MHz, CDCl3): δ 44.27 (C-3), 56.35 (OCH3), 60.89 (OCH3), 80.62 (C-2), 103.49, 115.61, 121.47, 123.61, 124.91, 126.34, 127.94, 129.71, 134.4, 137.67, 153.68, 159.71, 191.42. Anal. calcd. for C22H20O5; C, 72.51; H, 5.53; Found: C, 72.35; H, 5.64.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N:15]4[CH2:22][CH:21]5[CH:17]([CH2:18][N:19]([CH3:23])[CH2:20]5)[CH2:16]4)=[CH:9][CH:10]=3)[C:5](=[O:24])[C:4]=2[CH:3]=1.[C:25](=[NH:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25](=[N:38][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N:15]4[CH2:22][CH:21]5[CH:17]([CH2:18][N:19]([CH3:23])[CH2:20]5)[CH2:16]4)=[CH:9][CH:10]=3)[C:5](=[O:24])[C:4]=2[CH:3]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN1CC2CN(c3ccc4c(c3)C(=O)c3cc(Br)ccc3-4)CC2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN1CC2CN(c3ccc4c(c3)C(=O)c3cc(N=C(c5ccccc5)c5ccccc5)ccc3-4)CC2C1
Temperature: 90 °C
Yield: 100 %

Procedure:
A mixture of the product of Example 61A (332 mg, 0.867 mmol), benzophenone imine (180 μL, 1.07 mmol; Aldrich), tris(dibenzylideneacetone)dipalladium (0) (Pd2 dba3; 32 mg, 0.035 mmol; Alfa), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 54 mg, 0.087 mmol; Strem) and sodium tert-butoxide (125 mg, 1.30 mmol; Aldrich) in 5 mL toluene was flushed with nitrogen and heated at 90° C. for 18 h. The reaction mixture was cooled to ambient temperature and filtered through diatomaceous earth, rinsing with EtOAc. After concentrating the solution under reduced pressure, the residue was purified by column chromatography (90 g silica gel, 1-12% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to afford the title compound, which was slightly impure (489 mg, >100% yield): MS (DCI/NH3): m/z 484 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C:14]([Zn]C#N)#[N:15]>CC(N(C)C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=1
Reactant: N#C[Zn]C#N
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(CO)cc1C(F)(F)F
Temperature: 150 °C
Yield: 36.6 %

Procedure:
To a solution of (4-chloro-3-(trifluoromethyl)phenyl)methanol (0.300 g, 1.425 mmol) in DMA was added dicyanozinc (0.335 g, 2.85 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.165 g, 0.142 mmol). The reaction flask was degassed and charged with nitrogen, then heated at 150° C. for 6 h under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The EtOAc extract was washed with brine, dried over MgSO4 and purified by silica gel column chromatography to give the title compound as a white solid (0.105 g). LCMS m/z=202.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.98 (bs, 1H), 4.87 (s, 2H), 7.69 (d, J=0.88 Hz, 1H), 7.77-7.88 (m, 2H)
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([CH:29]5[CH2:30][CH2:31][O:27][CH2:28]5)=[O:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C1CCOC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCOC1

Procedure:
The title compound, off-white solid (80 mg, 75%), MS (ISP) m/z=427.3 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-tetrahydro-furan-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH2:12])=[C:6]([O:13][CH3:14])[CH:5]=1.[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>N1C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[NH:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:15])=[CH:5][C:6]=1[O:13][CH3:14])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(OC)c(N)c(OC)c1
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC)c(NC(=O)OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 50.6 g. of 4-amino-3,5-dimethoxy-benzoic acid methyl ester in 1 liter of absolute pyridine was treated during 30 minutes with 82 g. of carbobenzoxy chloride with stirring and ice-cooling. Thereafter, the mixture was stirred at room temperature for 20 hours. The pyridine was evaporated under vacuum and the residue treated with 1 liter of water and 3N hydrochloric acid to obtain a strongly acidic reaction. The resulting emulsion was extracted with two 1.5 liter portions of ethyl acetate. The ethyl acetate extract was washed with two 800 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from ethyl acetate, there was obtained 2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester having a melting point of 132°-133° C.