Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[NH:14][C:15]=1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])([CH3:10])[CH3:9].[C:27]([N:46]1[C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]2[CH:64]=[CH:63][C:60]([CH2:61]Br)=[CH:59][CH:58]=2)=[N:49][N:48]=[N:47]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C(=O)C.C(OCC)(=O)C>[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[N:14]([CH2:61][C:60]2[CH:59]=[CH:58][C:57]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[C:50]3[N:46]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:47]=[N:48][N:49]=3)=[CH:64][CH:63]=2)[C:15]=1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])([CH3:9])[CH3:10]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OCc1nc(C(C)(C)O)c(C(=O)OC(C)C)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)OCc1nc(C(C)(C)O)c(C(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
239 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 550 mg of isopropyl 4-(1-hydroxy-1-methylethyl)-2-isopropoxymethylimidazole-5-carboxylate [prepared as described in Preparation 46(iii)] in 6 ml of N,N-dimethylacetamide, and the resulting mixture was stirred for 30 minutes. A solution of 1.62 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 10 ml of N,N-dimethylacetamide was then added dropwise, and the mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was mixed with water and ethyl acetate and shaken. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.47 g of the title compound as an amorphous powder.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C:21]2([CH:28]3[CH2:30][CH2:29]3)[NH:26][C:25](=[S:27])[CH2:24][O:23][CH2:22]2)[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCOCC1.Cl>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C:21]2([CH:28]3[CH2:29][CH2:30]3)[NH:26][C:25](=[S:27])[CH2:24][O:23][CH2:22]2)[CH:20]=1
Reactant: Fc1ccc(N=C(c2ccccc2)c2ccccc2)cc1C1(C2CC2)COCC(=S)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ccc(F)c(C2(C3CC3)COCC(=S)N2)c1

Procedure:
A solution of (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholine-3-thione (1.42 g, 3.3 mmol) in dioxane (15 ml) and 1 M HCl (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was poured on a saturated solution of sodium hydrogen-carbonate and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated at reduced pressure. The residue was purified by chromatography on silica gel using a 3:1-mixture of dichloromethane and ethyl acetate as the eluent. CH2Cl2/EtOAc 3:1. The (RS)-5-(5-amino-2-fluoro-phenyl)-5-cyclopropyl-morpholine-3-thione was obtained as a white solid (0.810 g, 92% of theory). Mass (calculated) C13H15FN2OS [266.338]; (found) [M+H]+=267.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26](OC)=[O:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][OH:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution of 4.18 g of methyl 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylate in 40 ml of THF is added dropwise, with stirring and under N2, to a suspension of 0.57 g of lithium aluminum hydride in 20 ml of THF. The mixture is stirred for 1 hour at 20° and is decomposed with dilute sodium hydroxide solution and then with water and is filtered, and the filtrate is worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-hydroxymethylindole, m.p. 178°.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[O:13]1[C:17]2([CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-fluorobenzoate (36.16 g, 215 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (35.40 g, 247 mmol), and potassium carbonate (29.72 g, 215 mmol) were added to N,N-dimethylacetamide (500 mL) and heated to 100° C. for 16 hours. The solution was cooled, filtered, added to 2M HCl and extracted with 50% ethyl acetate (in hexanes). The organics were washed with water, brine, and dried on anhydrous sodium sulfate. The solution was concentrated and purified by flash column chromatography on silica gel with 20% ethyl acetate (in hexanes) increasing to 30% ethyl acetate (in hexanes).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+]>CO.O>[CH3:26][C:23]1[C:22]([NH:27][C:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)CC(C)C)cc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)CC(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1-{4′-[3-Methyl-4-(3-methyl-butyrylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.060 g, 0.13 mmol) in MeOH and H2O was treated with lithium hydroxide (0.100 g, 2.4 mmol) and stirred at 60° C. for 1 hour. The mixture was submitted to standard workup to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)=[CH:20][N:21]=3)[N:18]=2)[CH2:8][CH2:7]1)=[O:4].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:28][C:24]1[CH:23]=[C:22]([C:19]2[N:17]3[N:18]=[C:13]([NH:12][C@H:9]4[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:7][CH2:8]4)[CH:14]=[CH:15][C:16]3=[N:21][CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCOCC1)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-N-(trans-4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)acetamide (50 mg, 0.12 mmol), morpholine (0.3 mL) and DIPEA (0.2 mL) in CH2Cl2 (0.6 mL) was stirred at 50° C. for 3 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-84 (9.6 mg, 17%) as a white solid.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccccc1C(O)CCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC/C=C/c1ccccc1CCCCCCCCC

Procedure:
A mixture of 14.4 g of 1-(2-nonylphenyl)-1-hexanol, 2 g of toluene-4-sulphonic acid monohydrate and 250 ml of toluene is heated under reflux for 3 hours using a water separator. After cooling, the reaction mixture is washed twice with 10% strength (w/v) sodium bicarbonate solution and twice with water. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo, and the residue is purified by chromatography on silica gel using hexane as eluant. The desired 1-(2-nonylphenyl)-transhexene is obtained in the form of a pale yellow oil. IR (CH2Cl2): 2960, 2930, 2855, 1465, 970 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:8]2[N:9]([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:3]=[C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[C:35]=4[Cl:36])[CH:28]=[CH:27][CH:26]=3)[N:7]=2)=[CH:20][CH:21]=1
Reactant: O=c1n(Cc2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: O=c1n(Cc2cccc(-c3cccc(Cl)c3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 122, 94 mg (0.20 mmol) of the compound from Example 102A were reacted with 56 mg (0.23 mmol) of 2,3-dichlorophenylboronic acid. This gave 48 mg (45% of theory) of the target compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:5][CH2:4][O:3]1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O.N1CCCCC1>C(O)C>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][N:6]3[CH2:5][CH2:4][O:3][C:2]3=[O:1])[CH:9]=2)[NH:13][C:12]1=[O:17]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2cc(CN3CCOC3=O)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3ccc(CN4CCOC4=O)cc32)[nH]1

Procedure:
A solution of 5-(2-oxo-oxazolidin-3-ylmethyl)-1,3-dihydro-indol-2-one (4.3 mmoles), 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (5.17 mmoles) and piperidine (3 mmoles) in ethanol (30 ml) is heated at reflux for 24 hours. The solid formed is filtered off, washed with ethanol, with water and then with ethanol and dried in vacuo to yield the title product.
Reaction SMILES: O.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:10][C:11]([C:13]2[N+:18]([O-])=[N:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1>C1COCC1.[Mo](Cl)(Cl)(Cl)(Cl)Cl.[Zn]>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:10][C:11]([C:13]2[N:18]=[N:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)[n+]([O-])n1
Agent: Cl[Mo](Cl)(Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)nn1
Yield: 38.1 %

Procedure:
Water (0.2 mL) was added to a suspension of molybdenum(V) chloride (160 mg, 0.56 mmol) in THF (1 mL), then after 5 min zinc dust (60 mg, 0.92 mmol) was added portionwise, followed by (S)-6-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-3-methoxypyridazine 1-oxide (100 mg, 0.23 mmol). The mixture was heated at reflux for 90 min, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. Chromatography (SiO2; heptane-ethyl acetate gradient) afforded the title compound (36 mg, 38%). Colorless gum, MS: 411.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH:7]=1.[CH3:17][NH:18][NH2:19]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:18]([CH3:17])[N:19]=[C:8]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNN
Reactant: O=C(c1ccccn1)c1cc(Br)ccc1F
Solvent: C1COCCO1
Product: Cn1nc(-c2ccccn2)c2cc(Br)ccc21
Temperature: 100 °C

Procedure:
A heavy wall pressure flask was charged with (5-bromo-2-fluorophenyl)(pyridin-2-yl)methanone (0.98 g, 3.5 mmol) and dioxane (10 mL). Methylhydrazine (0.4 mL, 7.7 mmol) was then added, and the mixture was heated to 100° C. for 15 hours. The crude mixture was concentrated, and purified by column chromatography (gradient 0 to 20% EtOAc in hexanes) to give the product. NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.73 (d, J=4.8 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.24 (d, J=7.3 Hz, 1H), 4.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:5][CH:4]=1.C1(C(C2C=NC3C(C=2C2C=CC=CC=2)=CC=CC=3C(F)(F)F)=O)C=CC=CC=1.Cl>CCOCC>[CH2:23]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)cc1
Agent: Cl
Agent: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Solvent: CCOCC
Product: COc1ccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)cc1

Procedure:
This compound was prepared using the procedure of Example 31 substituting [4-(4-methoxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone of Example 2 for 2 phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone. The HCl salt was further prepared using HCl in ether. MS (ESI) m/z 394 ([M+H]+); 1H NMR (acetone-d6) δ 8.97 (s, 1H), 8.12 (d, J=7.2 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.63 (m, 1H), 7.25 (m, 4H), 7.15 (m, 3H), 7.07 (d, J=7.5 Hz, 2H), 4.08 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CC[O:9]CC.[CH2:12]([N:19]1[CH2:24][CH:23]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].OO>C1COCC1.O.C(O)C>[CH2:12]([N:19]1[CH2:20][CH2:21][C@@H:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C@H:23]([OH:9])[CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOCC
Reactant: COc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2O)cc1
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
To a suspension of NaBH4 (2.7 g, 72 mmol) in THF (150 mL) at −10° C. was added boron trifluoride etherate (9.1 mL, 72 mmol) and the solution was stirred for 15 minutes. Then a solution of 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36 mmol) in 100 mL tetrahydrofuran was added and the mixture was stirred for an additional hour. Next were sequentially added 25 mL of water, 25 mL of 10% aqueous sodium hydroxide, 50 mL of ethanol, and 12.8 mL of 30% aqueous hydrogen peroxide (125 mmol) and the final mixture was heated to reflux overnight. The mixture was allowed to cool and was then diluted with 200 mL of water and extracted with 300 mL of ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was triturated with diethyl ether to yield 7.5 g (57%) (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol. LCMS (method A) RT 2.03 min, 81.5% AP, m/z 298.4 (M+H+), 1H NMR (300 MHz, DMSO-d6) δ ppm 7.28-7.35 (m, 5H) 7.14 (d, J=8.69 Hz, 2H) 6.83 (d, J=8.69 Hz, 2H) 4.43 (d, J=6.04 Hz, 1H) 3.51 (d, J=19.26 Hz, 4H) 3.33 (s, 3H) 2.97 (dd, J=10.01, 3.59 Hz, 1H) 2.81 (d, J=10.95 Hz, 1H) 2.19-2.29 (m, 1H) 1.96-1.98 (m, 1H) 1.78 (t, J=10.20 Hz, 1H) 1.58-1.68 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=[O:20])[CH:15]=3)[CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.Br>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=[O:20])[CH:15]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2cc(-c3ccc(O)cc3)ccc2c1
Reaction time: 10 h
Yield: 82.3 %

Procedure:
Into a four-necked flask equipped with a stirring rod, dropping funnel, reflux condenser and thermometer was charged 0.63 g (0.0023 mol) of 2-(4'-methoxyphenyl)naphthalene-6-carboxylic acid of Example 9. To the compound were added 50 ml of acetic acid, 30 ml of acetic anhydride and 15 ml of 48% hydrobromic acid. The reaction was continued for 10 hours while the mixture was being heated with stirring, thereby obtaining clear solution. When 50 ml of water was added to the reaction solution, white precipitate was obtained. The precipitate was separated from the mixture by filtration, and then dried to obtain 0.5 g of 2-(4'-hydroxyphenyl)naphthalene-6-carboxylic acid. The yield of the product was 82 mol % on the basis of 2-(4'-methoxyphenyl)naphthalene-6-carboxylic acid used. The purity of the produce was 98%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]3[CH:20]=[N:21][N:22]=[C:18]3[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[C:16]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C@H:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH3:41])[CH:34]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]3[CH:20]=[N:21][N:22]=[C:18]3[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)=[C:16]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C@H:40]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH3:41])[CH:34]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](Nc1cc(-c2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)n3cnnc3c2-c2cccc(C(F)(F)F)c2)ccn1)c1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: C[C@H](Nc1cc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n3cnnc3c2-c2cccc(C(F)(F)F)c2)ccn1)c1ccccc1
Temperature: 25 °C

Procedure:
5-(1-(t-Butoxycarbonyl)-1,2,3,6-tetrahydropyrid-4-yl)-7-(2-(1(S)-phenylethyl)amino-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine (0.12 g, 0.2 mmol) and platinum oxide (0.03 g, 0.13 mmol) were combined in ethanol (5 ml) and maintained at room temperature under an atmosphere of hydrogen for 18 hours. The catalyst was removed by filtration and the filtrate was concentrated to a syrup. The residue was purified by column chromatography on silica gel (30% ethyl acetate in hexane) to give the product as a syrup; MS m/z (M+H)+ 644.5; C35H36F3N7O2 require 643.3.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>>[Cl:14][C:13]1[C:8]2[CH2:7][O:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc2c1COc1ccccc1C2=CBr
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=[N+]([O-])c1cccc(C=C2c3ccccc3OCc3c(Cl)cccc32)c1

Procedure:
Following procedures essentially as described in Example 230, 11-bromomethylene-7-chloro-6,11-dihydro-dibenzo[b,e]oxepine is combined with m-nitrophenyl boronic acid to provide the title compound. The pure Z isomer is isolated by crystallization (diethyl ether) to give 1.4 g (31.7% yield) product. 1H NMR (400 MHz, CDCl3) δ 8.038-8.017 (d, 1H), 7.976 (s, 1H), 7.511-7.491 (d, 1H), 7.431-7.410 (d, 1H), 7.369-7.253 (m, 3H), 7.160-7.121 (t, 1H), 7.041-7.005 (m, 2H), 6.928-6.919 (d, 1H), 6.908-6.898 (d, 1H), 5.60 (s, 2H).
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]1[NH:19][C:18]2[C:20]3[C:6]=1[CH2:7][C@@H:8]1[C:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:12][C@H:11]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:10][N:9]1C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:4]([C:5]1[NH:19][C:18]2[C:20]3[C:6]=1[CH2:7][C@@H:8]1[C:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)=[CH:12][C@H:11]([NH:21][C:22](=[O:28])[N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[CH2:10][NH:9]1)#[CH:3]
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(C#CC(C)(C)O)c(c34)C[C@H]2N(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1[nH]c2cccc3c2c1C[C@H]1NC[C@@H](NC(=O)N(CC)CC)C=C31
Yield: 25 %

Procedure:
Under nitrogen, 122 mg (0.29 mmol) of 3-[9,10-didehydro-2-(3-hydroxy-3-methyl-1-butynyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea is heated for 2 hours under reflux in 15 ml of absolute toluene after adding 64 mg (1.6 mmol) of pulverized sodium hydroxide. The solvent is then removed by distillation and the residue extracted in ethyl acetate with water and saturated sodium chloride solution. The crude product obtained from the ethyl acetate solution after drying with magnesium sulfate and concentration is purified by column chromatography on 80 g of silica gel with ethyl acetate/ethanol 2:1 as the eluent. Reprecipitation from ethyl acetate/ether/hexane produces 3-(9,10-didehydro-2-ethynyl-8α-ergolinyl)-1,1-diethylurea in a 25% yield.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][CH:4]=[C:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[C:11]=3[C:2](=[O:1])[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c[nH]c2c(c1=O)C(=O)CCC2
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(Br)cc2)c2c(c1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (1.56 g, 6.63 mmol) was dissolved in 20 mL of degassed N,N-dimethylformamide and treated with 4-bromobenzylbromide (1.99 g, 7.96 mmol) and potassium carbonate (1.10 g, 7.96 mmol). The mixture was stirred at ambient temperature for 18 hrs, and then partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined ethyl acetate extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide ethyl 1-(4-bromobenzyl)-4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate.