Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@:11]1([NH:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[C@@H:15]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:13]([CH2:27][OH:28])[C:12]1=[O:29])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[OH:37].C(Cl)Cl.OO.[OH-].[Na+]>CCOCC>[Si:1]([O:8][C@H:9]([C@@:11]1([NH:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[C:12](=[O:29])[C@@:13]2([CH2:27][OH:28])[C@H:14]([O:37]2)[C@@H:15]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)C(CO)=C[C@@H]1NC(=O)OCc1ccccc1
Reactant: CO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)[C@]2(CO)O[C@@H]2[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 200-mL round-bottomed flask was charged with enone 10 (1.1 g, 2.2 mmol, 1.0 equiv) and MeOH:CH2Cl2 (7:1, 32 mL). The resulting solution was cooled to 0° C., and a cooled solution of H2O2 (30% aq., 20 mL) and NaOH (20% aq., 5 mL) was added dropwise. The reaction was stirred at 0° C. for 2 h, and diluted with Et2O (30 mL). The layers were separated and the aqueous layer was extracted with Et2O (3×15 mL). The combined organics were washed with H2O (3×30 mL), brine (20 mL), dried with magnesium sulfate, and concentrated in vacuo. The crude product was purified via flash chromatography (70:30 petroleum ether:acetone) affording the title compound as a clear, viscous oil with >20:1 diastereoselection (0.91 g, 81%). Analytical data: [α]D19 −22.4 (c=1.00, CHCl3); 1H NMR (600 MHz, CDCl3): δ 7.32-7.26 (m, 5H), 5.66 (d, J=9.6 Hz, 1H), 5.20 (d, J=12.0 Hz, 1H), 4.93 (d, J=12.6 Hz, 1H), 4.68 (s, 1H), 4.68-4.66 (m, 1H), 4.07-4.04 (m, 2H), 4.02-3.98 (m, 2H), 2.64 (s, 6H), 1.15 (d, J=6.6 Hz, 3H), 0.89 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 204.4, 156.9, 156.0, 136.6, 128.3, 128.1, 128.0, 74.0, 69.3, 66.4, 65.9, 60.7, 56.0, 52.3, 36.1, 25.5, 18.2, 17.7, −3.9, −4.8; LRMS (ESI+) Calcd. for C25H39N3O7Si+, 522.26. Found, 522.23. IR (thin film, cm−1) 3402, 2954, 2857, 2359, 2249, 2125, 1650, 1519, 1227, 830, 732; TLC (70:30 petroleum ether/acetone): Rf=0.30.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH2:5]1[C@@H:15]2[C@H:9]([CH:10]=[CH:11][C:12]3[C:13]4[N:14]2[C:16]2[CH:25]=[CH:24][N:23]=[CH:22][C:17]=2[C:18]=4[CH2:19][CH2:20][CH:21]=3)[CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.O>CN(C=O)C>[CH2:3]([CH:7]1[CH2:8][CH:9]2[CH:10]=[CH:11][C:12]3[C:13]4[N:14]([C:16]5[CH:25]=[CH:24][N:23]=[CH:22][C:17]=5[C:18]=4[CH2:19][CH2:20][CH:21]=3)[CH:15]2[CH2:5][CH2:6]1)[C:2]#[CH:1]
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Reactant: C#CCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Propargyl bromide, 2.38 g, was added to a solution of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine (5.52 g) and triethylamine (3ml) in 90 ml DMF. The reaction mixture was stirred at room temperature for 41/2 hours. Some precipitate had formed. The reaction mixture was poured into 300 ml of cold water. A solid precipitated which was filtered off and washed with cold water. Recrystallization from 300 ml ethanol gave 4.05 g of the title compound as pale yellow needles, m.p. 160°-161.5°. An analytical sample was recrystallized again from ethanol to give almost colorless needles, m.p. 162°-163° C.
Reaction SMILES: [Br-:1].[NH2:2][C:3]1[S:4][C:5]([CH3:17])=[CH:6][N+:7]=1[CH2:8][C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[BrH:1].[CH3:17][C:5]1[S:4][C:3]2=[N:2][C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][N:7]2[CH:6]=1
Reactant: CCOC(=O)CC(=O)C[n+]1cc(C)sc1N
Reactant: [Br-]
Solvent: CCO
Product: Br
Product: CCOC(=O)Cc1cn2cc(C)sc2n1
Yield: 97 %

Procedure:
Ethyl 4-bromo-3-oxobutanoate (92 g, 0.35 mol) was added to a solution of 5-methylthiazol-2-amine (40 g, 0.35 mol) in acetone (400 mL). The mixture was left to stand overnight and then evaporated to give 2-amino-3-(4-ethoxy-2,4-dioxobutyl)-5-methylthiazol-3-ium bromide in 82% yield, 101 g. 2-amino-3-(4-ethoxy-2,4-dioxobutyl)-5-methylthiazol-3-ium bromide (101 g, 0.28 mol) was then refluxed in ethanol (250 mL) for 2 hours. The solvent was then evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate hydrobromide as yellow crystals in 97% yield, 85 g. Solid K2CO3 was added to a solution of ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate hydrobromide (85 g, 0.28 mol) in water (300 mL) to pH ˜8. The product was extracted with chloroform (3×100 mL), and the combined extracts were dried over Na2SO4 and evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate in 84% yield 52 g. Ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate (52 g, 0.23 mol) was refluxed in 10% aqueous HCl (150 mL) for 2 hours. The solution was evaporated to dryness to give the title compound as brown crystals in 59% yield 32.3 g; m/z 197 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]#[N:11])=[C:6]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[F:21])[N:5]=[C:4]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=2[F:31])[N:3]=1.[OH-].[K+]>CO.ClCCl>[Cl:30][C:26]1[C:25]([F:31])=[C:24]([CH2:23][S:22][C:4]2[N:5]=[C:6]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[F:21])[C:7]3[C:2](=[N:1][C:10]([NH2:11])=[CH:9][N:8]=3)[N:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: N#CCNc1c(N)nc(SCc2cccc(Cl)c2F)nc1SCc1cccc(Cl)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Nc1cnc2c(SCc3cccc(Cl)c3F)nc(SCc3cccc(Cl)c3F)nc2n1

Procedure:
A solution of the product from example 13, step (b) (1.4 g) and potassium hydroxide (110 mg) in methanol (80 ml) and dichloromethane (120 ml) was stirred at room temperature for 24 hours. After evaporation in vacuo, the residue rendered the subtitled compound as a pale yellow solid (1.4 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C@@H:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:28][CH2:29][N:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:21]=2)=[CH:12][CH:11]=1)(C)(C)C.Cl>ClCCl.C(OCC)C>[NH3:7].[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C@@H:27]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:28][CH2:29][N:30]([CH:34]([CH3:35])[CH3:36])[CH:31]([CH3:33])[CH3:32])[CH:21]=2)=[CH:14][CH:15]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1O)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCN)cc2)ccc1O)C(C)C
Product: N

Procedure:
tert-Butyl{2-[4-(3-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}propoxy)phenyl]ethyl}carbamate (Preparation 7, 400 mg, 0.68 mmol) was dissolved in dichloromethane (15 ml) and hydrochloric acid (10 ml of a 2M solution in diethyl ether) was added to the stirred solution at 0° C. After 3 hours the solvent was removed in vacuo, and ethyl acetate (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml) were added and the organics separated. The aqueous was washed with dichloromethane:methanol (90:10, by volume, 2×20 ml) and the organics combined, dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (80/20/2.0 by volume) to furnish the title compound as a glass, 135 mg.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:29][C@@H:30]2[C:36](=[O:37])[N:35]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:34]3[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=3[O:32][CH2:31]2)[C:24]([O:26]CC)=[O:25])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)C>[C:24]([C@H:23]([NH:29][C@@H:30]1[C:36](=[O:37])[N:35]([CH2:38][C:39]([OH:41])=[O:40])[C:34]2[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=2[O:32][CH2:31]1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:26])=[O:25]
Reactant: CCOC(=O)[C@@H](CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CN1C(=O)[C@@H](N[C@H](CCCCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
To a solution of tert-butyl 3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in acetic acid (1.5 ml) is added 30% hydrogen bromide-acetic acid solution (1.5 ml). The resulting mixture is allowed to stand for 0.5 hour at room temperature and then diluted with ethyl ether (100 ml). The supernatant layer is removed by decantation and the precipitate is dissolved in 1N sodium hydroxide solution (10 ml). The solution is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (2 ml), the mixture is chromatographed on Amberlite XAD-2 using water-methanol (1:1) as an eluent. The eluate is concentrated in vacuo and lyophilized to give 3(S)-[1(R)-carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.1 g) as colorless powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH3:32])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1>>[ClH:1].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH3:32])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:29][CH2:30]2)[CH:24]=1
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3cc(Cl)ccc3OC)CC2)C(=O)Nc2ccccc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(5-chloro-2-methoxyphenyl)-piperazine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[F:32][CH:33]([F:43])[CH2:34]OS(C(F)(F)F)(=O)=O>O>[F:32][CH:33]([F:43])[CH2:34][O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 26.3 %

Procedure:
To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate (2,2-difluoroethyl) ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60° C. for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 162”).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17]C(C)(O)C)=[CH:12][CH:11]=1.[H-].[Na+].C(OC(C)C)(C)C.Cl>C1(C)C=CC=CC=1.O>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:12]=1)#[CH:17]
Reactant: COCCCCCCOc1ccc(C#CC(C)(C)O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O
Product: C#Cc1ccc(OCCCCCCOC)cc1
Yield: 99.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of 4-[4-(6-methoxyhexyloxy)phenyl]-2-methyl-3-butyn-2-ol (3.0 g) in toluene (18 ml) was added sodium hydride (abt. 60% in oil suspension), and the mixture was refluxed for 2 hours. After cooling, to the reaction mixture was added isopropyl ether (100 ml) and water (100 ml), and neutralized by 1N-hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude red oil. The crude red oil was purified by silica gel chromatography (10:1 hexane-ethyl acetate) to give 1-ethynyl-4-(6-methoxyhexyloxy)benzene (2.39 g) as an orange powder.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4]1.[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:17]([O:20][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4]1)(=[O:19])[CH3:18]
Reactant: CCOC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCOC(=O)C[C@H]1C[C@@H](COC(C)=O)OC(C)(C)O1
Temperature: 27.5 °C

Procedure:
Mixture of ethyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (60 grams), tetra butyl ammonium bromide (79 grams) and anhydrous sodium acetate (61.2 grams) was heated to reflux temperature and stirred. After the completion of the reaction, the reaction mixture was cooled to 25-30° C. and petroleum ether (50 ml) was added to it then stirred for 60 minutes at 25-30° C. The reaction mixture was filtered and washed with petroleum ether. The solvent from the filtrate was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[F:20][C:21]([CH:24]=[CH:25]C(Cl)=O)([F:23])[F:22].[O:29]1CCC[CH2:30]1>>[F:23][C:21]([F:20])([F:22])[C:24](=[CH2:25])[C:30]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)=[O:29]
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: C1CCOC1
Reactant: O=C(Cl)C=CC(F)(F)F
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC1(C)C2CC3CC(C2)CC1C3)C(F)(F)F
Temperature: 0 °C
Reaction time: 10 h
Yield: 70.3 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 83.1 g (0.50 mol) of 2-methyl-2-adamantanol, 101.2 g (1.0 mol) of triethylamine and 200 g of tetrahydrofuran. Then 118.9 g (0.75 mol) of α -trifluoromethylacryloyl chloride was dropwise added to the content in the flask over a period of about 1 hour, while the content was maintained at a reaction temperature of about 0° C. Then the content was stirred for 10 hours at room temperature. After completion of the reaction, the reaction mixture was washed with water and then with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 101.2 g (yield: 70.3%) of the object 2-methyl-2-adamantyl α-trifluoromethylacrylate was obtained.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.[C:26]1([NH:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([N:32]2[C:10]([NH2:11])=[C:9]([N:8]=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([NH2:13])=[N:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNc1ccccc1
Reactant: N#CC(C#N)=NNc1ccccc1
Solvent: N#CCC#N
Solvent: Nc1ccccc1
Product: Nc1nn(-c2ccccc2)c(N)c1N=Nc1ccccc1
Temperature: 25 °C

Procedure:
1-phenyl-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 200 mg (1.2 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and phenylhydrazine (767 mg, 7.1 mmol). Solids had not formed after heating the reaction at 75° C. for 3 hrs, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 77 mg (23%) of the compound as an orange coloured solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([C:14]#[C:15][C:16]23[CH2:22][CH:19]([CH2:20]C2)CC3O)=[CH:12][CH:11]=[C:10]([N:24]2[CH2:28][C@@H:27]([O:29][CH3:30])[C@H:26]([OH:31])[CH2:25]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC1.CCCCCC.C([Li])(CC)C.[N:49]12[CH2:56][CH2:55][CH:52]([CH2:53][CH2:54]1)[C:51](=[O:57])[CH2:50]2>O1CCCC1>[CH2:1]([C:8]1[C:13]([C:14]2[CH:20]=[CH:19][C:22]([C:51]3([OH:57])[CH:52]4[CH2:55][CH2:56][N:49]([CH2:54][CH2:53]4)[CH2:50]3)=[CH:16][CH:15]=2)=[CH:12][CH:11]=[C:10]([N:24]2[CH2:28][C@@H:27]([O:29][CH3:30])[C@H:26]([OH:31])[CH2:25]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(C#CC34CCC(CC3O)C4)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: O=C1CN2CCC1CC2
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CO[C@@H]1CN(c2ccc(-c3ccc(C4(O)CN5CCC4CC5)cc3)c(Cc3ccccc3)n2)C[C@H]1O
Temperature: -90 °C
Reaction time: 0.67 h
Yield: 18.5 %

Procedure:
To a mixture of 280 mg of 2-(4-bromophenyl)-6-methyl-1,3,6,2-dioxyazaborocane (Production Example 14) and 10 ml of tetrahydrofuran was added dropwise 2 ml of a 1 M cyclohexane-hexane solution of sec-butyllithium under nitrogen atmosphere while cooling in a liquid nitrogen-tetrahydrofuran bath at −90° C., followed by stirring as it was for 40 minutes. Then, a solution of 130 mg of 3-quinuclidinone in 1 ml of tetrahydrofuran was added to the mixture, the liquid nitrogen-tetrahydrofuran bath was removed and the mixture was stirred at room temperature for 30 minutes. 1 ml of an aqueous ammonium chloride solution was added to the reaction mixture, followed by evaporating. To the residue were added 5 ml of methanol, 2 ml of a 5 Maqueous solution of potassium carbonate, 220 mg of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine hydrochloride and 5 ml of diethoxymethane, followed by heating under stirring under nitrogen atmosphere in an oil bath at 60° C. for 3 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography using NH-silica gel with 50% ethyl acetate-hexane and 0–5% methanol-ethyl acetate, to give 60 mg of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[CH3:1][CH:2]([CH3:21])[CH:3]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(C(Oc2ccccc2)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(Oc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of methyl 4-(2-methyl-1-phenoxypropyl)benzoate (240 mg, 0.84 mmol), lithium hydroxide monohydrate (178 mg, 4.2 mmol), tetrahydrofuran (12 mL), methanol (4 mL) and water (4 mL) was stirred at 20° C. for 4 hours. The reaction mixture was concentrated, acidified with concentrated hydrochloric acid to pH=1, extracted with ethyl acetate (20 mL×3). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 4-(2-methyl-1-phenoxypropyl)benzoic acid as a white solid (227 mg, 100%). LRMS (M+H)− m/z: calcd 268.15. found 268.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[Mn]([O-])(=O)(=O)=[O:11].[K+].[OH2:16]>>[Br:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(F)c(Br)n1
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc(F)c(Br)n1
Yield: 17 %

Procedure:
To 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in H2O (30 mL) was added potassium permanganate (1.0 equiv.). The solution was heated at 100° C. for 5 hours at which time more potassium permanganate (1.0 equiv.) was added. After heating for an additional 48 hours the material was filtered through celite (4 cm×2 inches) and rinsed with H2O (150 mL). The combined aqueous was acidified with 1N HCl to pH=4, extracted with ethyl acetate (200 mL), washed with NaCl(sat.), dried over MgSO4, filtered and concentrated to yield 6-bromo-5-fluoropicolinic acid (17%) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=2.05 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:35])=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:35])=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2cc3c(cc2C)N(CC(C)C)CCCC(C(=O)OC)=C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2cc3c(cc2C)N(CC(C)C)CCCC(C(=O)O)=C3)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To methyl 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (770 mg) were added tetrahydrofuran (15 ml) and methanol (15 ml), followed by adding aqueous 1N sodium hydroxide solution (4.8 ml), and the mixture was stirred at 90° C. overnight. After cooling to 0° C., water was added and the mixture was neutralized with 1N hydrochloric acid. After extracting with ethyl acetate, the organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from hexane-ethyl acetate to give 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (408 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][O:15][C:16]([C:18]1[CH:22]=[CH:21][O:20][C:19]=1[CH2:23]Br)=[O:17]>>[CH3:14][O:15][C:16]([C:18]1[CH:22]=[CH:21][O:20][C:19]=1[CH2:23][O:10][C:9]1[C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Br:1])=[O:17]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: COC(=O)c1ccoc1CBr
Product: CCOc1cc(C=O)cc(Br)c1OCc1occc1C(=O)OC

Procedure:
Alkylation of 3-bromo-5-ethoxy-4-hydroxy benzaldehyde (123 mg) with 2-bromomethyl-furan-3-carboxylic acid methyl ester (109 mg) was performed according to the method described in example 1a. Yield: 191 mg. MS-ESI: [M+H]+=383/385