Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][OH:19])[CH2:4][CH2:3][CH2:2]1.O[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[CH:31]=[CH:30]3)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][O:19][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]=[C:32]([C:37]([O:39][CH3:40])=[O:38])[CH:31]=[CH:30]4)=[CH:25][CH:26]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of [5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (0.12 g, 0.36 mmol), methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (0.10 g, 0.36 mmol) and triphenylphosphine (0.10 mg, 0.39 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.071 mL, 0.39 mmol) dropwise. The solution was heated in a microwave reactor to 90° C. for 10 minutes and the allowed to sit overnight. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-45% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (71 mg, 35%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.16-8.10 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.62-7.51 (m, 3H), 6.92 (d, J=9 Hz, 2H), 4.84 (s, 2H), 4.05-3.97 (m, 1H), 3.93 (s, 3H), 2.43-2.31 (m, 4H), 2.14-2.02 (m, 1H), 1.97-1.89 (m, 1H). LRMS (APCI) m/z 559 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[CH:3]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(F)ccc2c1
Solvent: ClCCl
Product: Oc1ccc2cc(F)ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
A flask was charged with 2-fluoro-6-methoxynapthalene (3.80 g, 21.6 mmol) and dichloromethane (86 mL) and cooled to 0° C. in an icebath under a flow of nitrogen. A solution of borontribromide (26 mL of a 1M solution in dichloromethane, 25.9 mmol) was added via cannula. The reaction solution was stirred 15 minutes at 0° C., the cooling bath was removed and the reaction was stirred for 1.5 h at ambient temperature. The reaction was quenched by slowly adding excess 10% aqueous hydrochloric acid. The two-phased reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed (2×, brine), dried (Na2SO4), filtered and concentrated in vacuo to afford a brown gummy solid. Purification by flash chromatography (silica gel; 20% ethyl acetate/hexane) afforded the desired product (3.63 g, 91% yield). Recrystallization from cold ether/hexanes provided the title compound as a colorless powdery solid. mp 118°-120° C.; 1HNMR (300 MHz, DMSO-d6) δ7.11-7.18 (m; 2H), 7.30 (td; J=9,9,3 Hz; 1H), 7.55 (dd; J=10.5,3 Hz; 1H), 7.73-7.79 (m; 2H), 9.73 (s; 1H).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].CC1C=CC(S(O[CH2:16][C:17]2[N:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[C:28]3[O:32][N:31]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH:29]=3)[N:20]=[C:19]([NH:39][C:40]3[CH:44]=[C:43]([CH3:45])[N:42](S(C4C=CC(C)=CC=4)(=O)=O)[N:41]=3)[CH:18]=2)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C>[NH2:1][CH2:16][C:17]1[N:22]=[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH:29]=2)[N:20]=[C:19]([NH:39][C:40]2[CH:44]=[C:43]([CH3:45])[NH:42][N:41]=2)[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2cc(Nc3cc(C)n(S(=O)(=O)c4ccc(C)cc4)n3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(CN)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 110 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Sodium azide (44 mg, 0.68 mmol) was added to a solution of 6-[(4-methylphenylsulphonyloxy)methyl]-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1-N-[4-methylphenylsulphonyl]-1H-pyrazol-3-ylamino)pyrimidine (Method 52) (159 mg, 0.22 mmol) in anhydrous DMF (2.0 ml) and the mixture heated at 110° C. for 1.5 hours. Triphenylphosphine (282.0 mg, 1.08 mmol) and water (0.10 ml) were then added and the reaction mixture heated at 100° C. for 1 hour. The mixture allowed to cool and was then passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The volatiles were removed by evaporation and the residue dissolved in methanol (5 ml) and 10M aqueous sodium hydroxide solution (0.5 ml) and stirred for 1 hour. The volatiles were removed by evaporation and the residue dissolved in water, and extracted with DCM. The extracts were combined, the solvent removed by evaporation and the residue purified by chromatography on silica gel, eluting with DCM/methanol/aqueous ammonia (100:0:0 increasing in polarity to 80:20:1) to give the title compound (48.5 mg, 53%) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=1.[F:11][C:12]([F:19])([F:18])[C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[CH3:10][C:5]1[C:6]([S:8][CH3:9])=[N:7][C:2]([N:15]2[CH:16]=[CH:17][C:13]([C:12]([F:19])([F:18])[F:11])=[N:14]2)=[N:3][CH:4]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: CSc1nc(Cl)ncc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CSc1nc(-n2ccc(C(F)(F)F)n2)ncc1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 350 %

Procedure:
A mixture of 2-chloro-5-methyl-4-methylthiopyrimidine (2.5 g, 14 mmol), 3-(trifluoromethyl)-1H-pyrazole (2.3 g, 2.5 mmol) and potassium carbonate (4.8 g, 35 mmol) in 25 mL of N,N-dimethylformamide was heated at 70° C. with stirring for 5 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed twice with water and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to provide a white solid which was suspended in hexane and filtered to provide 2.4 g of the title compound of Step B as a solid melting at 126-127° C. 1H NMR (CDCl3): δ 8.63 (d, 1H), 8.24 (s, 1H), 6.73 (d, 1H), 2.68 (s, 3H) 2.25 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].Br[CH:17]([CH3:21])[C:18]([O-:20])=[O:19].[Na+].S(=O)(=O)(O)O>O1CCCC1.O>[F:14][C:4]1[CH:3]=[C:2]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CC(Br)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
A solution of 4-bromo-2-fluorobiphenyl (2.51g;0.01 mole) in dry tetrahydrofuran (15ml) was aded dropwise, with stirring, to magnesium turnings (0.25g;0.0103g. atom) under a nitrogen atomosphere. When the addition was complete, the mixture was stirred and boiled under reflux for 30 minutes. The mixture was then cooled and a suspension of sodium 2-bromopropionate (1.75g;0.01 mole) in dry tetrahydrofuran (20ml) was added. Frothing occurred and when this had subsided the mixture was boiled under reflux with stirring, for one hour. The mixture was then cooled in an ice-bath and water (15ml) was added, followed by sulphuric acid (20%;5ml). The mixture was stirred for 10-15 minutes, and extracted with ether. The extract was washed with water and then extracted with aqueous potassium carbonate (1N). This extract was washed with ether and then added to a mixture of concentrated hydrochloric acid (10ml) and water (20ml). The mixture was cooled overnight and the precipitate filtered, washed with water and dried in vacuo to give 2 -(2-fluoro-4-biphenylyl)propionic acid.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][N:4]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[C:32]([F:35])([F:34])[F:33])[CH2:3]1.C1COCC1.[BH4-].[Na+]>CO>[NH2:29][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([N:4]2[CH2:5][CH2:6][N:7]([S:8]([C:11]3[CH:12]=[C:13]([C:17]([OH:23])([CH3:22])[C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:15][CH:16]=3)(=[O:10])=[O:9])[C@H:2]([CH3:1])[CH2:3]2)=[C:25]([C:32]([F:33])([F:34])[F:35])[CH:26]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C(C)(O)C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(CN)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C(C)(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a flask containing 4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]sulfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile (50 mg, 0.10 mmol) and 2 mL of THF was added CoCl2 (32.5 mg, 0.25 mmol) at 0° C., then NaBH4 (28.4 mg, 0.75 mmol) was added, followed by adding 1 mL of MeOH. The reaction mixture was stirred at 0° C. for 0.5 hr. Reaction was complete as determined by TLC. The reaction mixture was filtered, washed with EtoAc. The filtrate washed with H2O, then washed with sat. brine and dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography to yield 2-[3-({(2R)-4-[4-(aminomethyl)-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol as a white solid. Yield 29%. HRMS: calcd for C22H25F6N3O3S+H+, 526.15936. found (ESI-FTMS, [M+H]1+), 526.15985.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]([F:52])([F:51])[CH2:31][NH:32][C:33]([C:35]1([CH2:48][CH2:49]O)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:34]>>[F:29][C:30]([F:51])([F:52])[CH2:31][NH:32][C:33]([C:35]1([CH2:48][CH2:49][O:25][C:24]([C@H:21]2[CH2:20][CH2:19][C@H:18]([NH:17][C:15]([C:10]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:28])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH2:23][CH2:22]2)=[O:26])[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:34]
Reactant: O=C(NC1CCC(C(=O)O)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCO)c2ccccc2-c2ccccc21
Product: O=C(N[C@H]1CC[C@H](C(=O)OCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
The 4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]cyclohexanecarboxylic acid (0.570 g) obtained in Example 7a) and 9-(2-hydroxyethyl)-9H-fluoren-9-carboxylic acid (2,2,2-trifluoroethyl)amide (0.500 g) obtained in Example 6d) were treated in a similar manner to Example 1g) to give the title compound (0.534 g) as a colorless solid (see Table 57).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]=2)=[CH:2]1.[ClH:23]>ClCCl.O1CCOCC1>[ClH:23].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2coc3ccccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C1=C(c2coc3ccccc23)CCNC1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a stirred solution of tert-butyl 4-(benzofuran-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.06 g, 6.88 mmol) in dichloromethane (50 ml) was added at room temperature hydrochloric acid solution (4M in dioxane, 25.8 ml, 103 mmol) and the reaction mixture was allowed to stir for 2 h. The reaction mixture was diluted with dioxane (25 ml), the precipitate was collected by filtration, washed with dioxane and dried to yield 4-(benzofuran-3-yl)-1,2,3,6-tetrahydropyridine hydrochloride as off-white solid (1.37 g, 85%), MS (ISP) m/z=200.2 [(M+H)−], mp 276° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:25][N:26](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19]([NH:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CNC(=O)c1cnc(-n2ncc(-c3ccc(C#N)cc3)c2O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)-4-methylnicotinic acid (200 mg, 0.625 mmol), HATU (356.25 mg, 0.938 mmol) and triethylamine (315.63 mg, 3.125 mmol) and stirred at room temperature for 0.5 h. Then methanamine (108.75 mg, 1.25 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to afford the title compound as a light yellow solid (88.38 mg, 42.46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (brs, 1H), 8.49-8.48 (m, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.11 (m, 2H), 7.77 (d, J=8.0 Hz, 2H), 2.79 (d, J=4.4 Hz, 3H), 2.48 (s, 3H). MS m/Z [M+H]+ 334.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:23][CH3:24])=[C:8]([C:12]([CH2:15][S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:2]1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:23][CH3:24])=[C:8]([C:12]([CH2:15][S:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)[C:9]([O:11][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:10])=[CH:2]1
Reactant: BrCc1ccccc1
Reactant: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)OCc1ccccc1
Yield: 91.5 %

Procedure:
A solution of 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)benzoic acid (Intermediate 223, 0.83 g), benzyl bromide (0.46 g) and potassium carbonate (0.55 g) in THF (15 ml) was heated to 60° C. for 8 hours. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-10% to give benzyl 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)-benzoate (0.96 g) as a white solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>C(O)C>[O:23]=[C:16]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][C:9]2[C:8](=[N:15][CH:14]=[CH:13][CH:12]=2)[N:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccnc1Nc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2n(-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
6.28 g (31.7 mmol) of 2-(phenylamino)nicotinaldehyde was dissolved in ethanol (150 mL), and 7.62 g (47.6 mmol) of diethyl malonate and 1.35 g (15.9 mmol) of piperidine were added thereto. The resulting mixture was stirred overnight at 100° C. The reaction mixture was cooled, and a solid precipitated thereby was separated by filtration. The solid was washed sequentially with ethanol and diisopropyl ether. Thus, 7.42 g of the title compound was obtained as a pale yellow solid (yield: 800).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:17][C@@:16]2([O:18][CH3:19])[C@@H:6]([CH2:7][C:8]3[C:20]4[C:11](=[CH:12][CH:13]=[CH:14][C:15]2=4)[NH:10][CH:9]=3)[NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][OH:30]>CN(C)C=O>[OH:30][CH2:29][CH2:28][N:5]1[C@H:6]2[C@@:16]([O:18][CH3:19])([C:15]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:20]=3[C:8]([CH2:7]2)=[CH:9][NH:10]4)[CH2:17][C@@H:3]([CH2:2][OH:1])[CH2:4]1
Reactant: CO[C@]12C[C@@H](CO)CN[C@@H]1Cc1c[nH]c3cccc2c13
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CO[C@]12C[C@@H](CO)CN(CCO)[C@@H]1Cc1c[nH]c3cccc2c13

Procedure:
To a stirred solution of 3 g of 8β-hydroxymethyl-10α-methoxy-ergoline, 3 g of potassium carbonate in 25 ml of dimethylformamide was added 1.3 g of 2-bromoethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH2:11]1[C:13]23[CH2:15][C:12]12[CH2:14]3>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]12[CH2:15][CH:13]([CH2:14]1)[CH2:11]2
Reactant: COc1ccccc1[Mg]Br
Reactant: C1C23CC12C3
Product: COc1ccccc1C12CC(C1)C2

Procedure:
Reaction of 2-methoxyphenylmagnesium bromide with [1.1.1]propellane (see A. B. Shtarev et al., J. Am. Chem. Soc. 2001, 123, 3484-3492) afforded 1-(2-methoxyphenyl)bicyclo[1.1.1]pentane, which was treated with boron tribromide to provide the requisite phenol.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[CH2:6][CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][S:13][CH2:12]2)[CH2:8][C:9]=1[OH:10])(=O)[CH3:2].[Cl:18][C:19]1[S:23][C:22]([CH2:24][O:25][NH2:26])=[CH:21][CH:20]=1>C(O)C>[Cl:18][C:19]1[S:23][C:22]([CH2:24][O:25][N:26]=[C:1]([C:4]2[C:5](=[O:17])[CH2:6][CH:7]([CH:11]3[CH2:16][CH2:15][CH2:14][S:13][CH2:12]3)[CH2:8][C:9]=2[OH:10])[CH3:2])=[CH:21][CH:20]=1
Reactant: NOCc1ccc(Cl)s1
Reactant: CC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Solvent: CCO
Product: CC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C2CCCSC2)CC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
A solution containing 5.1 g (0.020 mol) of 2-acetyl-3-hydroxy-5-(tetrahydro-2H-thiopyran-3-yl)cyclohex-2-en-1-one and 3.4 g (0.021 mol) of (5-chlorothien-2-yl)methoxyamine in 200 ml of ethanol was stirred overnight (about 14 hours) at room temperature and then evaporated to remove ethanol. The concentrate was diluted with 150 ml of methylene chloride and then washed with 100 ml of water and then with 100 ml of saturated aqueous sodium chloride solution. The washed methylene chloride solution was dried over anhydrous magnesium sulfate and then evaporated to dryness under reduced pressure to afford a white solid. Recrystallation of this solid with absolute ethanol afforded 7.6 g of the title compound, m.p. 154°-155° C. cl EXAMPLE 2
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH:25]([CH3:27])[CH3:26])[C:17]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)=O>ClCCCl.C(O)(=O)C>[CH:20]1([NH:19][C:17](=[O:18])[C@H:16]([NH:15][CH2:28][C:30]2[CH:35]=[CH:34][N:33]=[C:32]3[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=23)[CH:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC(C)[C@@H](N)C(=O)NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and (R)-2-amino-N-cyclopentyl-3-methylbutanamide (68.1 mg, 0.370 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (105 mg, 90%). [M+H] calc'd for C25H36N4O5, 473; found, 473.7.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:17])=[O:7])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[CH3:23]O>S(=O)(=O)(O)O>[CH3:23][O:17][CH:9]1[CH:8]([C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][C:4]=2[N+:20]([O-:22])=[O:21])[C:14](=[O:15])[CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2
Reactant: O=C(c1ccc(Cl)cc1[N+](=O)[O-])C1C(=O)C2CCC(C2)C1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC1C2CCC(C2)C(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
A solution of 3-(4-chloro-2-nitrobenzoyl)-bicyclo[3,2,1]-octane2,4-dione (2.54 mmol) and 2 drops of conc. sulfuric acid in 20 ml of methanol is heated under reflux for 48 hours. The reaction mixture is concentrated and the residue is taken up in ether. The ethereal solution is washed with aqueous sodium bicarbonate and with brine, dried and evaporated to dryness to give 2-methoxy-3-(4-chloro-2-nitrobenzoyl)bicyclo[3,2,1]-octane-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([NH:23][NH2:24])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2ccc(C(=O)NN)cc2)cc1

Procedure:
A 250 mL round bottomed flask was charged with ethyl 4-(4-methoxybenzyloxy)benzoate (11.45 g, 60.18 mmol) and ethanol (110 mL). Hydrazine monohydrate was then added and the mixture was placed under reflux for 48 h. The reaction mixture was concentrated to dryness and chloroform (150 mL) was added. The mixture was decanted and the insoluble white residue was washed once more with chloroform to remove traces of starting material. The white solid (5.3 g, 32%) was dried in vacuo and 1H NMR analysis was consistent with the title compound. 1H NMR (DMSO d6, 400 MHz) δ 9.6 (br s, 1 H), 7.77 (d, J=9 Hz, 2 H), 7.36 (d, J=9 Hz, 2 H), 7.03 (d, J=9 Hz, 1 H), 6.94 (d, J=9 Hz, 1 H), 5.05 (s, 2 H), 3.74.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH2:7][C:8](O)=[O:9].S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[C:3]2[C:4](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[CH2:7][C:8]([Cl:17])=[O:9]
Reactant: Cc1c(CC(=O)O)sc2ccccc12
Reactant: O=S(Cl)Cl
Product: Cc1c(CC(=O)Cl)sc2ccccc12

Procedure:
A mixture of 2.0 g of 3-methylbenzo[b]thiophene-2-acetic acid and 19.4 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.25 g of the desired product as a residue.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[NH2:19][NH2:20]>C(O)C>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]3[CH2:13][CH2:14][C:15](=[O:17])[NH:19][N:20]=3)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1
Reactant: O=C(O)CCC(=O)c1ccc2c(c1)NC(=O)CS2
Reactant: NN
Solvent: CCO
Product: O=C1CCC(c2ccc3c(c2)NC(=O)CS3)=NN1

Procedure:
4-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-6-yl)-4-oxobutyric acid (2.0 g) was suspended in 60 ml of ethanol and 1 ml of hydrazine added. The mixture was heated at reflux for three hours, then cooled slowly. Filtration gave 1.85 g of the title compound, mp 299°-302° C.