Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH:6]([CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].[N:17]#[C:18]Br>>[CH3:14][CH:6]1[C:7]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:13][C:18]2=[N:17][CH:3]=[CH:4][N:5]12
Reactant: N#CBr
Reactant: COC(CNC(C)c1ccccc1N)OC
Product: CC1c2ccccc2Nc2nccn21

Procedure:
4 g of crude N-(2,2-dimethoxyethyl)-α-methyl-o-amino-benzylamine and 1.9 g cyanogen bromide are reacted and the product is worked up in the same manner as in Example 1e to afford the heading compound. M.p. 171°-172° (crystallisation from ethanol).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:12][N:10]1[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6][CH:5]([CH2:4][CH2:3][N:19]([CH3:18])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11]1
Reactant: CNc1ccccc1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: Cl
Product: CN1CC(CCN(C)c2ccccc2)Oc2ncccc2C1=O
Temperature: 95 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride, 4.00 g (0.015 mole) was dissolved in N-methylaniline (30 ml) and heated to 95° C. with stirring for 2 days. Excess N-methylaniline was removed by rotary evaporation (95° C., vacuum pump). The residue was taken up in chloroform (80 ml) and washed with dilute aqueous sodium hydroxide (30 ml) The chloroform layer was decolorized with activated carbon and dried over sodium sulfate, filtered and concentrated by rotary evaporation. The remaining residue was dissolved in ethyl acetate (50 ml) and purified by high pressure liquid chromatography using a silica gel column and ethyl acetate as the eluent. After purification, crystals formed from ethyl acetate. These crystals were recrystallized from ethyl acetate, giving 1.40 g (31%) of pale brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1I.C([Mg]Br)(C)C.CN(C)[CH:23]=[O:24]>C(OCC)C.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1ccc(-c2ccc(Br)c(I)c2)cc1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: -75 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 4-bromo-4′-chloro-3-iodobiphenyl (4.80 g, 0.012 mol) (described in WO 2008/071405) in anhydrous diethyl ether/tetrahydrofuran (120 ml, 1:1 ratio) at −75° C. is added isopropyl magnesium bromide (18.96 ml, 15% solution in tetrahydrofuran) dropwise such as to maintain an internal temperature below −70° C. Once addition is complete the reaction mixture is stirred at −75° C. for 2 hours, then warmed to −45° C. Anhydrous N,N-dimethylformamide (1.71 g, 0.0184 mol) is next added dropwise, maintaining temperature below −40° C., followed by warming to room temperature and quenching with 2M hydrochloric acid (60 ml). The reaction mixture is further diluted with diethyl ether, the two phases separated, and the aqueous phase extracted with additional diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography (2% ethyl acetate in hexane eluant) to afford 4-bromo-4′-chloro-biphenyl-3-carbaldehyde (2.7 g, 75%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([OH:21])[CH2:17][N:18]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([OH:21])[CH2:17][NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC(O)COCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COCCCCCCCc1ccccc1
Yield: 81.8 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 1.1 g of 3-(7-phenylheptyloxy)-2-hydroxypropylazide (prepared as described in Preparation 68), 0.287 g of lithium aluminum hydride and 50 ml of anhydrous tetrahydrofuran were used, to give 0.82 g of the title compound having an Rf value of 0.12 (on silica gel thin layer chromatography, using a 5:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the developing solvent).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[CH:5][C:4]=1[C:12]#[N:13])#[N:2].[C:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[OH:24])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]2[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:4]=1[C:12]#[N:13])#[N:2]
Reactant: CC(C)(C)C1CCCCC1O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Product: CC(C)(C)C1CCCCC1Oc1ccc(C#N)c(C#N)c1
Yield: 50 %

Procedure:
As in Synthesis Example 1 but using 1.73 grams of 1,2-dicyano-4-nitrobenzene and 4.7 grams of 2-t-butylcyclohexanol, there was obtained 1.41 grams of 1,2-dicyano-4-(2-t-butylcyclohexyloxy)benzene (yield of 50%). Next, as in Synthesis Example 1 but using 1.41 grams of this compound and 0.42 gram of BBr3, there was obtained 0.77 gram of the end product (yield 50%, mp 162°-165° C.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][N:19]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([O:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:21]=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCCC(Oc2ccnc(Cl)c2)C1
Yield: 84.5 %

Procedure:
Using the method of Example 3, Step A, tert-butyl 3-hydroxypiperidine-1-carboxylate (1.90 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9-46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide tert-butyl 3-(2-chloropyridin-4-yloxy)piperidine-1-carboxylate (2.50 g, 84% yield) as an oil. 1H NMR (CDCl3) δ 8.20 (d, 1H), 6.84 (s, 1H), 6.76 (d, 1H), 4.34 (m, 1H), 3.10-4.05 (bm, 4H), 1.50-2.05 (bm; 4H), 1.40 (bs, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O.O.NN>[Pd].[OH-].[Na+]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: NN
Agent: [Na+]
Solvent: O
Product: Nc1cc(CC(=O)O)ccc1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Compound III was synthesized according to the method of Zupancic and Trpin J. Prac. Chem. 33, 307-308 (1966); CA 66, 37580c. To a stirred solution of sodium hydroxide solution (1 g in 40 ml) in a round bottom flask was added 3-nitro-4-hydroxyphenylacetic acid (4.93 g, 0.025 mol). The solid dissolved at once giving an orange color solution. 10% Pd—C (50 mg) was added followed by dropwise addition of hydrazine monohydrate (3.25 ml). After the completion of the addition (5 minutes), the mixture was heated at 60° C. for 1.5 hr. The temperature was raise to reflux and heating continued for additional 0.5 hr. The solution appeared clear with Pd—C suspended in it. The solution was filtered hot, concentrated to half of the volume and then cooled. The solution was acidified carefully to pH 4-5 with acetic acid. The white precipitate separated after cooling was filtered off and washed with ethanol. m.p. 225-227° C. lit2. 229-230° C. (3.4 g, yield 30%). 1H NMR(D2O, δ) 7.9 (1H, d, j=7 Hz, 6-H); 7.8 (s, 1H, 2-H); 7.65 (1H, d, J=7 Hz, 5-H); 3.4 (2H, s, CH2COOH).
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35]Br)[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13]>CC(C)=O>[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35][O:7][C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8])[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: O=C(O)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C1CCCC1
Yield: 106.6 %

Procedure:
In 40 ml of acetone is dissolved 0.6 g of cyclopentanecarboxylic acid, and 6.0 ml of 1N-NaOH and 16 ml of water are added, followed by addition of 1.2 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 6 hours. The solvent is distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. After serial passage of diisopropyl ether-n-hexane mixtures (1:9, 200 ml; 2:8, 200 ml; and 3:7, 200 ml), elution is carried out with 800 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.38 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[S:15][C:16]([C:20]([O:22]CC)=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].CC(C)=O.[OH-].[Na+].Cl>C(OCC)(=O)C.O>[CH3:19][C:17]1[N:18]=[C:14]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:3]([C:1]#[N:2])[CH:4]=2)[S:15][C:16]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(OCC(C)C)c(C#N)c2)sc1C(=O)O
Temperature: 25 °C
Yield: 2.2 %

Procedure:
Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (50.0 g), acetone (500 mL), water (200 mL), and sodium hydroxide (6.96 g) were placed into a round bottom flask and heated to reflux. The mixture was maintained under reflux until reaction completion. After the reaction was completed, the mass was cooled to about 25° C., water (500 mL) and ethyl acetate (500 mL) were added, and the pH was adjusted to about 1 to 2 with hydrochloric acid (10.3 mL). The organic layer was separated and the aqueous layer was extracted into ethyl acetate (250 mL). The ethyl acetate layer was washed with water (300 mL). The ethyl acetate layer was distilled completely under vacuum below 60° C. The residue was dried at about 60° C. under vacuum to a constant weight to yield 1.0 g of the title compound. Purity by HPLC: 98.9%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])N1CC(=O)CC(S)C1.CC(OC(CP(OC)(OC)=O)=O)(C)C.[H-].[Na+].ClCCl>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19]
Reactant: COC(=O)C(c1ccccc1Cl)N1CC(=O)CC(S)C1
Agent: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1Cl
Reaction time: 0.33 h
Yield: 133 %

Procedure:
The crude (2-chlorophenyl)-(3-mercapto-5-oxopiperidin-1-yl)-acetic acid methyl ester (0.36 g, 1.14 mmol) was dissolved in THF (5 mL, argon sparged) and added to a mixture of tert-butyl P,P-dimethylphosphonoacetate (0.50 g, 2.23 mmol) and 60% sodium hydride (0.075 g, 1.87 mmol) in THF (4 mL, argon sparged), at room temperature under an argon atmosphere. After 20 minutes, dichloromethane (25 mL, argon sparged) was added and the mixture was washed with water (25 mL, argon sparged). The dichloromethane solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining yellow oil was purified by column chromatography on silica gel (15 g), eluting with heptane-ethyl acetate (4:1, argon sparged) to provide 3-tert-butoxycarbonylmethylene-5-mercaptopiperidin-1-yl)-(2-chlorophenyl)-acetic acid methyl ester (0.28 g, 59% yield) as a clear gel that was kept under an argon atmosphere at low temperature to prevent oxidation to the disulfide. 1H NMR (300 MHz, CDCl3/TMS): δ=7.60-7.15 (m, 4H), 5.55 (m, 1H), 4.77 (m, 1H), 3.67 (s, 3H), 3.20-2.00 (m, 7H), 1.41 (m, 9H). 13C NMR (75 MHz, CDCl3/TMS): δ=170.63 (2×), 165.26 (2×), 151.09 (3×), 134.64, 133.11 (4×), 129.83 (5×), 127.21, 118.35 (2×), 80.32 (2×), 67.57 (5×), 57.28 (6×), 52.28, 42.49-40.14 (8×), 34.54, 28.38 (2×). HRMS (DIP-CI): Calculated for (M+H+): 412.1349, found 412.1312.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH2:16])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>O1CCCC1>[Cl:24][CH2:25][C:26]([NH:16][CH2:15][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(CNC(=O)CCl)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
A mixture of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine(15 g, described in Example 3), triethylamine(7 g), chloroacetyl chloride (7.9 g) and tetrahydrofuran (300 ml) is stirred at 0° C. for 5 minutes and at 25° C. for 18 hours, filtered and evaporated. The residue is crystallized from chloroform-diethyl ether to obtain the title compound (13.7 g); mp 186°-187° C.; nmr (CDCl3) δ 3,41 (d), 3.61 (d), 3.89 (m), 4.09 (s), 6.75-7.50 (m) and 8.0 (t).
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([N:36]=[C:37](SC)SC)=[N:33][C:32]=2[CH:42]=1>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([NH:36][C:37]3[O:11][C@:3]4([CH2:2][N:1]=3)[CH:8]3[CH2:7][CH2:6][N:5]([CH2:10][CH2:9]3)[CH2:4]4)=[N:33][C:32]=2[CH:42]=1
Reactant: CSC(=Nc1nc2cc(Cl)ccc2o1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2oc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A 10 ml vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HCl salt (106 mg, 0.550 mmol), DMF (2 ml), DIEA (0.096 mL, 0.550 mmol), and Cs2CO3(358 mg, 1.100 mmol) at room temperature, followed by dimethyl 5-chlorobenzo[d]oxazol-2-ylcarbonimidodithioate (150 mg, 0.550 mmol). The resulting suspension was stirred at room temperature for 1 hr. LC/MS then indicated consumption of starting material. The reaction mixture was diluted with MeOH and purified by preparative HPLC to afford the expected product, (R)—N-(5-chlorobenzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (106.5 mg, 0.3 mmol, 53.0% yield), as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 2.08-2.30 (m, 3H) 2.35-2.48 (m, 1H) 2.60-2.73 (m, 1H) 3.48 (qd, J=7.53, 7.28 Hz, 3H) 3.54-3.68 (m, 1H) 3.79-4.00 (m, 2H) 4.18 (d, J=10.54 Hz, 1H) 4.35 (d, J=10.54 Hz, 1H) 7.19 (dd, J=8.53, 2.01 Hz, 1H) 7.30-7.47 (m, 2H) 9.10 (br. s., 1H). MS(LC/MS) R.T.=1.56; [M+H]+=333.13.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=[C:16]2[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1.[I:32][C:33]1[CH:44]=[CH:43][C:36]([C:37](N(OC)C)=[O:38])=[CH:35][CH:34]=1>C1COCC1>[Cl:31][C:27]1[CH:26]=[C:25]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:37]([C:36]4[CH:43]=[CH:44][C:33]([I:32])=[CH:34][CH:35]=4)=[O:38])[CH:14]=3)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(I)cc3)ccc2n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 127.9 %

Procedure:
BuLi 1.6M in hexane (0.0316 mol) was added dropwise at −70° C. to a mixture of 6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline (0.0287 mol) in TBIF (100 ml). The mixture was stirred at −70° C. for 30 minutes and a solution of 4-iodo-N-methoxy-N-methyl-benzamide (0.0244 mol) in THF (30 ml) was added. The mixture was stirred at −70° C. for 30 minutes, poured out into ice water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 15.6 g (>100%) of [4-(3-chlorophenyl)-2-methoxy-6-quinolinyl](4-iodophenyl)methanone, (intermediate 18).This product was used without further purification.
Reaction SMILES: [OH-].[K+].[OH:3][C@@H:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[CH2:10])[C:6]([O:8]C)=[O:7]>O.CO>[OH:3][C@@H:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[CH2:10])[C:6]([OH:8])=[O:7]
Reactant: C=C(C(=O)OC)[C@@H](O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C(=O)O)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of potassium hydroxide (2.27 g, 0.040 mol, 1.3 eq) in water (45 mL) was added drop wise to a solution of 1a (6 g, 0.031 mol, 1 eq) in methanol (15 mL) (see FIG. 4). The mixture was stirred at room temperature for 15 h. The solution was then concentrated under vacuum. The aqueous phase was washed with ether (2×100 mL), acidified with 6N aqueous HCl solution and extracted with ether (3×100 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. Evaporation of the solvent afforded a colorless oil which crystallized upon standing. The desired product 9a was obtained as a solid (5.34 g, 96%). Rf 0.26 (hexane/EtOAc=6:4).). 1H NMR δ (DMSO-d6) 5.41 (s, 1H), 5.61 (s, 1H), 5.93 (s, 1H), 6.15 (s, 1H), 7.22 (m, 5H), 12.45 (s, 1H). [MH]− 177.2: tR=1.28 min; purity: 88%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=2)[CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=3)[CH:17]=2)=[C:4]([CH3:15])[CH:5]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OC4CCCCO4)cc3C)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A mixture of methyl 3-[4-[[2′,6′-dimethyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy]phenyl]propanoate (2.92 g, 6.15 mmol), p-toluenesulfonic acid monohydrate (0.12 g, 0.62 mmol) and methanol (60 mL) was stirred at room temperature for 2 hrs., and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (2.12 g, yield 88%) as a red oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1)(=[O:19])[CH3:18]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:29]2[CH:28]=[CH:27][C:24]3[CH2:25][CH2:26][N:20]([C:17](=[O:19])[CH3:18])[CH2:21][CH2:22][C:23]=3[CH:30]=2)=[O:16])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc2CC1
Reactant: CC(=O)N1CCC(CCCCC(=O)O)CC1
Product: CC(=O)N1CCc2ccc(C(=O)CCCCC3CCN(C(C)=O)CC3)cc2CC1

Procedure:
Using 5-(1-acetyl-4-piperidinyl)valeric acid and 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine, the procedure of Example 23-1 was otherewise repeated to provide the title compound as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:19])[C:25]=4[Cl:26])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(Cl)c4Cl)cc3CC[C@@H]12
Yield: 79.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2,3-dichlorophenylboronic acid (187 mg, 0.98 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 193 mg (79%) of the title compound as an off-white solid. mp 131°-134°. FDMS: m/e=373 α[D]589 =+81.02 (c=1.05, chloroform).