Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[OH:5].[C:13]([NH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH:26]=[CH:25][O:24]2)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>O=P(Cl)(Cl)Cl>[C:13]([NH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C@@H:23]2[O:24][C@@H:25]([O:5][CH:4]([C:6]3[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=3)[CH2:3][CH2:2][Cl:1])[CH2:26][CH2:27][CH2:28]2)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(OCC2CCC=CO2)cc1
Reactant: OC(CCCl)c1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(OC[C@H]2CCC[C@H](OC(CCCl)c3ccc(F)cc3)O2)cc1

Procedure:
A catalytic amount (2 drops) of phosphorus oxytrichloride was added to 10 ml of an ethereal solution containing 277 mg of 3-chloro-1-(4-fluorophenyl)propanol and 330 mg of 2-(4-acetamidophenoxymethyl)-3,4-dihydro-2H-pyran and the mixture was allowed to react at room temperature for 8 days. The precipitated crystals were separated by filtration, giving 240 mg of the isomer of lesser polarity of the title compound, melting at 133°-135° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](OC)=[O:24])[CH:12]=[C:13]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][OH:24])[CH:12]=[C:13]([C:15]2[C:16]([CH3:22])=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:21])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2c(C)cccc2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cc(CO)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of methyl 5-(benzyloxy)-2′,6′-dimethylbiphenyl-3-carboxylate (1.04 g, 3.00 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.114 g, 3.00 mmol) by small portions, and the mixture was stirred under a nitrogen atmosphere at room temperature for 2 hr. Sodium sulfate decahydrate (0.967 g, 3.00 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitated insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.934 g, yield 98%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.N.[CH3:24][N:25](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:24]#[N:25])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C=O
Agent: N
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Under a nitrogen stream, 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.13 g) was dissolved in N,N-dimethylformamide (30 mL), zinc cyanide (1.03 g) and tetrakistriphenylphosphine palladium(0) (0.51 g) were added, and the mixture was stirred at 120° C. for 4 hr. After completion of the reaction, to the reaction mixture was added water/saturated aqueous ammonium chloride solution/28% aqueous ammonia (4:4:1), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (2.46 g).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][CH:11]([SH:13])[CH3:12].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:13][CH:11]([CH3:12])[CH3:10])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC(C)C
Yield: 61.7 %

Procedure:
Ethyl 2-bromoisobutyrate (100 g, 0.513 mole), 2-propanethiol (42.95 g, 0.564 mole), potassium hydroxide (36.0 g, 0.564 mole), ethyl alcohol (200 g) were combined and reaction mixture was refluxed for three hours prior to quenching. Crude yield: 74.7%, distilled yield: 61.7%.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]([C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:34]5[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=5)[CH:25]=[CH:24][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)[O:20][N:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a degassed solution of 5-(4-(6-bromobenzo[d]thiazol-2-yloxy)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (697 mg, 1.646 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (764 mg, 2.470 mmol), and potassium carbonate (683 mg, 4.94 mmol) in dioxane (12 mL) and water (4 mL) was added Pd(Ph3P)4 (114 mg, 0.099 mmol). The mixture was stirred at 100° C. under argon overnight. The mixture was cooled to rt, diluted with water (40 mL), and extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford tert-butyl 4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (238 mg, 0.453 mmol, 28% yield) as a yellow foam. LCMS (m/z)=526 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([C:17]#[C:18][Si](C)(C)C)=[CH:12]2)=[O:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([C:17]#[CH:18])=[CH:12]2)=[O:5]
Reactant: C[Si](C)(C)C#Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-(trimethylsilylethynyl)quinoline (150 mg) in tetrahydrofuran (3 ml) was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.04 ml) under ice-cooling, and the mixture was stirred for 2 hours at the same temperature. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane, 1:4, v/v) to give 8-(2,6-dichlorobenzoylamino)-3-ethynylquinoline (111 mg).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:4]/[C:3]2[CH:6]=[CH:7][C:8]([F:11])=[C:9]([F:10])[C:2]=2[F:1])/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(F)c(F)c1F
Product: COc1ccc(/C(C#N)=C/c2ccc(F)c(F)c2F)cc1OC
Yield: 28.2 %

Procedure:
2,3,4-Trifluorobenzaldehyde (160 mg) and 3,4-dimethoxybenzyl cyanide (177 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (90 mg, yield: 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[NH:15][CH2:14][CH:13]2[C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:27]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH3:28].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:27]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:15]2[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH2:18][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:14]2)=[O:35])=[CH:32][CH:31]=1)[CH3:28]
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C1CNc2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(C(=O)N2CC(C(=O)OC)N(S(=O)(=O)c3ccc(OC)cc3)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A mixture of 0.270 g of methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 500 μl of triethylamine in 5 ml of CH2Cl2 was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O and the CH2Cl2 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0.276 g of methyl 1-(4-ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as white crystals, mp 187-190° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Se](=O)=[O:18]>O1CCOCC1>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH:16]=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[Se]=O
Reactant: Cc1nc2ccccc2n1-c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1nc2ccccc2n1-c1ccccc1
Yield: 50.2 %

Procedure:
To a solution of 5.0 g (0.024 mole) of 1-phenyl-2methylbenzimidazole in 200 ml of dioxane was added 2.66 g (0.024 mole) of selenium dioxide and the reaction heated to reflux for 7 hours. The solids were filtered and the filtrate concentrated to a brown oil. The residue was chromatographed on 200 g of silica gel using 7% ethyl acetate in chloroform as the eluent to give 2.68 g of purified product.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S(Cl)([Cl:17])=O>CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]([Cl:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2nc1Cl
Temperature: 60 °C

Procedure:
To 2-chloroquinoline-3-carboxylic acid (5 g, 24.08 mmol) was added thionyl chloride (22.83 mL, 313.0 mmol) and DMF (12 drops) and the reaction was heated at 60° C. for 16 hours. The excess thionyl chloride and N,N-dimethyl formamide were removed in vacuo to yield 2-chloroquinoline-3-carbonyl chloride as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[BrH:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][Br:12])=[CH:6][N:7]=1
Reactant: Br
Reactant: OCCCc1ccc(Br)nc1
Product: BrCCCc1ccc(Br)nc1

Procedure:
300 mg (1.38 mmol) of 3-(6-bromopyridin-3-yl)propan-1-ol were stirred in 5 ml of hydrobromic acid (33% in acetic acid) at 80° C. for 6 h. After concentrating, a potassium carbonate solution was added, the resulting mixture was extracted with ethyl acetate, and the organic phase was separated and concentrated. Yield: 368 mg (95%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:13](=[O:21])[N:14]([CH2:16]C(F)(F)F)[CH2:15][C:9]=2[CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:13](=[O:21])[N:14]([CH3:16])[CH2:15][C:9]=2[CH:8]=1
Reactant: COC(=O)CC1Cc2ccc(OC)cc2CN(CC(F)(F)F)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccc(O)cc2CN(C)C1=O
Temperature: -5 °C
Reaction time: 1 h
Yield: 120.5 %

Procedure:
A solution of BBr3 in CH2Cl2 (1.0 M, 60 mL, 60 mmole) was added dropwise over 30 min to a solution of methyl (±)-8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (5.16 g, 14.94 mmole) in anhydrous CH2Cl2 (60 mL) at −5 to −10° C. under argon. After an additional 1 hr at −5 to −10° C., the reaction was recooled thoroughly to −10° C. and quenched by careful dropwise addition of MeOH (60 mL). The reaction was stirred at −10 to 0° C. for 1 hr, then was concentrated on the rotavap. The residue was reconcentrated from MeOH (2×) then from EtOAc, then was filtered through a pad of silica gel (EtOAc eluent). Concentration of the filtrate left a yellow solid which was triturated with hot hexanes. The title compound (4.74 g, 96%) was obtained as an off-white solid: TLC (1:1 EtOAc/hexanes) Rf 0.40; 1H NMR (400, DMSO-d6) δ 9.28 (s, 1 H), 6.90 (d, J=8.3 Hz, 1 H), 6.62 (dd, J=8.3, 2.5 Hz, 1 H), 6.57 (d, J=2.5 Hz, 1 H), 5.27 (d, J=16.7 Hz, 1 H), 4.22-4.38 (m, 1 H), 4.07-4.22 (m, 1 H), 4.07 (d, J=16.7 Hz, 1 H), 3.72-3.83 (m, 1 H), 3.58 (s, 3 H), 2.94 (dd, J=17.0, 3.8 Hz, 1 H), 2.72 (dd, J=16.7, 9.1 Hz, 1 H), 2.65 (dd, J=17.0, 14 Hz, 1 H), 2.49 (dd, J=16.7, 5.0 Hz, 1 H, partially obscured by residual solvent signal); MS (ES) m/e 354 (M+Na)+.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][C:9]1[C:10](=O)[CH2:11][CH2:12][CH:13]=1)([O:3][CH2:4][CH3:5])=[O:2].Cl.[CH3:16][O:17][NH2:18]>>[C:1]([CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[N:18][O:17][CH3:16])[CH2:11][CH2:12][CH:13]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCC1=CCCC1=O
Reactant: CON
Agent: Cl
Product: CCOC(=O)CCCC1=CCCC1=NOC

Procedure:
In the manner described for the preparation of the compound of Example 20, 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 18) and methoxyamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([O:36]CC)=[O:35].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:33])[NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([OH:36])=[O:35]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCCC(c5ccccc5)C4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NC1CCCC(c2ccccc2)C1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(3-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate (58 mg, 0.11 mmol) in 3:1 THF/ethanol (1 ml) was added 1M sodium hydroxide (228 μl, 0.23 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated and then acidified with 1M HCl and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 55 mg of the title compound (100% yield). MS (apci) m/z=506.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1)=[O:14].[BH4-].[Na+].Cl.C(Cl)Cl.CO.[CH3:36][C:37]([CH3:39])=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:23][CH2:24][N:25]([CH:37]([CH3:39])[CH3:36])[CH2:26][CH2:27]2)[CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: O=C(Nc1cccc(C2CCNCC2)n1)Nc1ccnc2c(F)cccc12
Reactant: CC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCC(c2cccc(NC(=O)Nc3ccnc4c(F)cccc34)n2)CC1

Procedure:
To a solution of 50 mg of 1-(8-fluoro-quinolin-4-yl)-3-(1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-urea (example 62) (0.137 mmol) in 50 ml of acetone were added 26 mg of sodium borohydride (0.684 mmol) in small portions. The reaction was slightly exotherm. After stirring the reaction mixture over night a small amount of 2M HCl was added to the reaction mixture up to a pH of 3 to destroy the excess of sodium borohydride. After neutralization with sodium bicarbonate, acetone was evaporated under reduced pressure, water added to the residue, the reaction mixture extracted three times with DCM, the organic phases combined and dried over sodium sulfate and the solvent evaporated under reduced pressure. 45 mg of the desired product were obtained as off white powder (yield: 81%) after column chromatography (silica gel, DCM/MeOH 98/2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=O)=[CH:13][C:12]([CH:17]([OH:19])[CH3:18])=[C:11]([CH3:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=CC=CC=1C=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:8]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:10]=[C:9]1[CH:14]=[CH:15][C:14]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][C:11]([CH3:20])=[C:12]([CH:17]([OH:19])[CH3:18])[CH:13]=1
Reactant: O=Cc1cccnc1OCc1ccccc1
Reactant: Cc1nc(OCc2ccccc2)c(C=O)cc1C(C)O
Product: Cc1nc(OCc2ccccc2)c(C=Cc2nc3ccccc3o2)cc1C(C)O

Procedure:
Following substantially the same procedure described in Example 3, Step E, but substituting 2-benzyloxy-5-(1-hydroxyethyl)-6-methylpyridin-3-carboxaldehyde for the benzyloxynicotinaldehyde compound used therein, the title compound is obtained.
Reaction SMILES: [CH2:1]([C@@H:7]([C@@H:18]([O:39][Si](C(C)(C)C)(C)C)[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([C@@H:7]([C@@H:18]([OH:39])[CH2:19][C@H:20]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCC[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCC[C@H](C[C@H](O)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Reaction time: 12 h
Yield: 60.4 %

Procedure:
M)g) 480 mg benzyl (2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate and 350 mg of tetrabutylammonium fluoride trihydrate were dissolved in 8 ml of THF and stirred for 12 hours. After evaporation the residue was dissolved in 50 ml of ether and washed with water. The ethereal phase was dried and evaporated. The product was chromatographed on silica gel. There was obtained 240 mg of benzyl (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate, MS: 463 [(M+H)+ -dihydro-2H-pyran-2-yl].
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]([CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12])#[CH:10].C(NCC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:10]#[C:9][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])[CH:4]=1
Reactant: C#CC(O)c1ccccc1
Reactant: Brc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: OC(C#Cc1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place 3-bromopyridine hydrochloride (0.78 g, 4 mmol), α-(ethynyl)-benzenemethanol (661 mg, 5 mmol) and diethylamine (25 mL) under nitrogen atmosphere. Add bis(triphenylphosphine)palladium(II) chloride (140 mg) then copper(I) iodide (20 mg). Stir overnight at room temperature and filter. Evaporate the solvent in vacuo and filter through silica gel (2:1 ethyl acetate/hexane). Evaporate the solvent in vacuo and recrystallize (25% ethyl acetate/hexane) to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21](Cl)=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21]([C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][C:32]=4[Cl:34])=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cnc(Cl)cn3)cc2s1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cnc(-c4ccc(Cl)cc4Cl)cn3)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using 5-chloro-pyrazine-2-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (0.077 g, 0.20 mmol) and 2,4-dichloro-phenyl boronic acid. (0.045 g, 0.24 mmol) to afford the product. LC/MS, Retention time=5.12 min; (m/z): calcd for C23H22Cl2N6O2S: 501.4; found: 501.0.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C(OCOCC)C.P(Cl)(Cl)(Cl)=O.[CH3:18][C:19]1[C:36](=[O:37])[CH2:35][CH2:34][C@@:33]2([CH3:38])[C:20]=1[CH2:21][CH2:22][C@@H:23]1[C@@H:32]2[CH2:31][CH2:30][C@@:28]2([CH3:29])[C@H:24]1[CH2:25][CH2:26][C:27]2=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:18][C:19]1[C:36](=[O:37])[CH2:35][CH2:34][C@@:33]2([CH3:38])[C:20]=1[C:21](=[CH2:1])[CH2:22][C@@H:23]1[C@@H:32]2[CH2:31][CH2:30][C@@:28]2([CH3:29])[C@H:24]1[CH2:25][CH2:26][C:27]2=[O:39]
Reactant: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O
Reactant: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCOCC
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C(C)=C12
Yield: 60 %

Procedure:
Alternatively, a mixture of androst-4-ene-3,17-dione, thiophenol, 40% aqueous formaldehyde, triethylamine and ethanol was heated under reflux for a period of about 48 hours. The cooled solution was poured onto an aqueous sodium hydroxide solution and the product isolated by ether extraction. The ether extracts were washed with water and dried over magnesium sulfate. The resulting residue was triturated with hexane to remove any condensation by-product derived from the thiophenol and formaldehyde. The 4-phenylthiomethylandrost-4-ene-3,17-dione so obtained was desulfurized by dissolving in acetone and adding to a suspension of Raney Nickel in refluxing acetone. The mixture was refluxed for about 5 hours under stirring. The hot solution was filtered and the catalyst washed with boiling ethanol and water. The combined filtrates were concentrated under vacuum whereupon the product separated as a solid mass. Recrystallization from acetone/hexane yielded 4-methylandrost-4-ene-3,17-dione. A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 4-methylandrost-4-ene-3,17-dione (0.81 g, 2.7 mmol) was refluxed for about 7 hours, i.e. until the starting material has disappeared. The suspension was allowed to cool and under vigorous stirring a saturated sodium carbonate solution was added dropwise until the pH of the aqueous layer became alcaline (~1 hour). The organic layer was separated, neutralized with water, and dried over sodium sulfate. After concentration under reduced pressure the oily residue was purified by chromatography on silica gel using hexane/ethylacetate as eluent. Thus the pure 4-methyl-6-methylenandrost-4-ene-3,17-dione was obtained in 60% yield; I.R. (KBr): 3080 (6=CH2), 1735 (17-oxo), 1665 (3-oxo), 1635, 1595 cm-1 (Δ4 and 6=CH2).