Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B-](F)(F)(F)[CH:25]=[CH2:26].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl.[Pd](Cl)Cl.C(OCC)(=O)C.O.O1CCCC1>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:25]=[CH2:26])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(Br)cc2)c(C)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Temperature: 140 °C

Procedure:
To a microwave vial was added 4-bromo-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (4.44 g, 11.20 mmol), potassium trifluoro(vinyl)borate (4.50 g, 33.6 mmol), triphenylphosphine (0.176 g, 0.672 mmol), cesium carbonate (10.95 g, 33.6 mmol) and palladium(II) chloride (0.040 g, 0.224 mmol). Tetrahydrofuran (THF) (12 mL) and water (1.333 mL) were then added, ensuring all particles were below the solvent level. The reaction vessel was sealed and heated in a microwave (Biotage Initiator) to 140° C. for 60 minutes, cooled to room temperature and ethyl acetate (40 mL) added to the mixture. The organic phase was washed with water (50 mL), dried using a hydrophobic frit and evaporated in vacuo to give the crude product as a orange oil. The sample was loaded in dichloromethane and purified by silica (Si) chromatography using a 0-25% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product, 1.8 g, as an off-white solid. LCMS [LCMS1] Rt 1.47 min, m/z (ES+) 344 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][N:3]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.[OH:26]S(O)(=O)=O>CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]=[O:26])=[CH:8][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(Cl)nc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Combine 6-chloro-nicotino-nitrile (1.00 g, 7.21 mmol) and toluene (24 mL). Cool the resulting solution at 0° C. and add DIBAL-H (1.0 M in toluene, 7.58 mL, 7.58 mmol) dropwise. Stir the resulting red solution at 0° C. for 1 h. Then, add methanol (2 mL) followed by H2SO4 (aq. 2.0 M, 6 mL). Stir for 1 h at rt. Add CHCl3:isopropanol (3/1, 15 mL) and wash with Rochelle's salt solution (20 mL), followed by NaHCO3 (20 mL) and brine. Dry the combined organic layers over magnesium sulfate, filter and concentrate. Purify by flash chromatography (EtOAc/hexanes 10%) to give the title compound (530 mg, 62%).
Reaction SMILES: O1CCCC1.[CH3:6][CH:7]([OH:10])[CH2:8][CH3:9].[H-].[Na+].[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40]Br>O>[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40][O:10][CH:7]([CH2:8][CH3:9])[CH3:6]
Reactant: CCC(C)O
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To 4 ml of dehydrated tetrahydrofuran solution containing 0.96 ml of 2-butanol was added 0.30 g of sodium hydride (60% dispersed material in mineral oil), and the mixture was stirred at room temperature for 3 hours. Then, 0.85 g (1.50 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added to the mixture under cooling in ice-bath, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.46 g of the title compound as a colorless oil. (Yield: 55%)
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3](=[NH:5])[NH2:4].C(O[CH:14]=[C:15]([C:21](=O)[CH:22]([F:24])[F:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.CC[O-].[Na+]>C(O)C>[F:23][CH:22]([F:24])[C:21]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:4]=[C:3]([C:2]([F:10])([F:1])[C:6]([F:9])([F:8])[F:7])[N:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Reactant: N=C(N)C(F)(F)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Yield: 39.4 %

Procedure:
A mixture of 1.62 g (10 mmol) of 2,2,3,3,3-pentafluoropropanimidamide and 2.22 g (10 mmol) of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate (for preparation see WO 2005/123690) in 10 ml of ethanol is stirred under reflux for 4 days after adding 0.68 g (10 mmol) of sodium ethylate. Concentration by evaporation in vacuo is then carried out and the residue is taken up in 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic phases are washed successively with 5 ml of water and 5 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. Chromatographic purification with a mixture of cyclohexane and ethyl acetate gives 1.26 g of ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate (40%) as a white solid.
Reaction SMILES: C[C@H](N)[C@H](O)C1C=CC=CC=1.Cl.C(O)(=O)C.[BH4-].[Na+].[CH:19]1(/[CH:25]=[C:26](/[N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)\[C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O.ClCCCl>[CH:19]1(/[CH:25]=[C:26](/[N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)\[CH:27]([OH:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)C(=O)/C(=C\C1CCCCC1)n1cncn1
Agent: C[C@H](N)[C@H](O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Temperature: -30 °C
Reaction time: 24 h

Procedure:
In a nitrogen atmosphere, 0.338 g (1.8 mmoles) of (-)-norephedrine hydrochloride was suspended in a mixture comprising 15.4 μl (0.27 mmole) of acetic acid and 5 ml of 1,2-dichloroethane, and after cooling to -30° C., a solution of 0.0749 g (1.98 mmoles) of sodium borohydride in 1 ml of dimethylformamide was added. The temperature of the resulting suspension was raised from -30° C. to room temperature over 2 hours. Thereafter, to this suspension was added at room temperature a solution of 0.31 g (1.2 mmoles) of (E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-one (E/Z=99.9/0.1) and 10.3 μl (0.18 mmole) of acetic acid in 1,2-dichloroethane, and stirring was carried out for 24 hours. The subsequent treatment was carried out in the same manner as in Example 6 to obtain (-)-(E)-1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol. The conversion was 100%, and the composition of the product obtained was: E-form alcohol, 97.4% and Z-form alcohol, 2.6%. The enantiomer ratio of the E-form alcohol was: (-)-isomer, 77.7% and (+)-isomer, 22.3%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](C1C=CC=CN=1)=[O:17].[C:34]([OH:37])(=O)[CH3:35]>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][N:11]([CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:4]1[CH:9]=[CH:35][C:34]([OH:37])=[N:1][CH:5]=1
Reactant: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccccn1
Reactant: CC(=O)O
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccc(O)nc1
Reaction time: 0.5 h

Procedure:
To a solution of the above amine (63 mg, 0.14 mmol) in acetic acid (2 mL) was added hydrobromide saturated acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated with diethyl ether four times to afford the title compound as a white solid (80 mg), which was dried in vacuo. 1H NMR (D2O) δ 1.81-2.01 (m, 4H), 2.16-2.20(m, 1H), 2.37-2.41 (m, 1H), 2.50-2.59 (m, 1H), 2.87-2.92 (m, 1H), 3.00 (br s, 2H), 3.11-3.16 (m, 1H), 3.37-3.42 (m, 1H), 3.53 (q, 1H, J=6.0 Hz), 4.25 (ABq, 2H, J=43.8, 15.3 Hz), 4.57-4.79 (m, 1H), 6.36 (d, 1H, J=9.6 Hz), 7.46-7.48 (m, 2H), 7.53 (s, 1H), 7.57-7.63 (m, 3H), 7.85 (t, 1H, J=6.3 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.65 (d, 1H, J=5.4 Hz). 13C NMR (D2O) δ 20.33, 20.45, 36.87, 47.77, 48.22, 59.04, 114.10, 119.38, 125.90, 126.99, 130.69, 137.16, 139.46, 139.85, 140.66, 148.01, 150.87, 151.39. ES-MS m/z 457 [M+H]+. Anal. Calcd. for C26H28N6O2.3.0HBr.3.4H2O.0.2C4H10O: C, 41.52; H, 5.17; N, 10.84; Br, 30.92. Found: C, 41.70; H, 4.90; N, 10.71; Br, 30.63.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:29][C:30]1[N:31]=[C:32](Cl)[C:33]2[CH:38]=[CH:37][N:36]([CH3:39])[C:34]=2[N:35]=1.O1CCOCC1>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.O>[Cl:29][C:30]1[N:31]=[C:32]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:19]([F:20])([F:21])[F:22])[CH:6]=2)[C:33]2[CH:38]=[CH:37][N:36]([CH3:39])[C:34]=2[N:35]=1
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Reactant: Cn1ccc2c(Cl)nc(Cl)nc21
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(-c2nc(Cl)nc3c2ccn3C)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
2-[4-ethoxy-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (188 mg), Na2CO3 (217 mg), and tetrakis(triphenylphosphine)palladium (0) (29 mg) were added to a mixture of 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg), dioxane (2 mL), and water (0.3 mL) in an argon atmosphere, and the reaction mixture was stirred at 100° C. for 6 hours. After the reaction mixture was cooled to room temperature, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 7:3), whereby 2-chloro-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (130 mg) was obtained as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](Br)[CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1.Cl.CCN(C(C)C)C(C)C>C(O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[N:7]=[C:6]([N:18]2[CH2:17][CH2:16][N:15]([CH:12]3[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)[CH2:20][CH2:19]2)[CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccnc(Br)n1
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Brc1nccc(N2CCN(C3CCOCC3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of 2,4-dibromopyrimidine (50 mg, 0.210 mmol) and 1-(tetrahydro-2H-pyran-4-yl)piperazine, 2 Hydrochloride (51.1 mg, 0.210 mmol) in Ethanol (1 mL) was treated with DIPEA (0.147 mL, 0.841 mmol) and DMAP (cat.) and stirred at ambient temperature for 1 h. The reaction mixture was concentrated in vacuo and triturated with water, filtered and the solid washed with water then dried in vacuo to provide 2-bromo-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyrimidine (43 mg, 0.130 mmol, 61.9% yield) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (s, 2H) 1.73 (br. s., 2H) 2.48 (br. s., 1H) 2.61 (br. s., 4H) 3.38 (t, J=11.24 Hz, 2H) 3.65 (br. s., 4H) 4.02 (br. s., 2H) 6.40 (d, J=6.25 Hz, 1H) 7.95 (d, J=5.86 Hz, 1H). LC/MS (m/z) ES+=327 (M+1).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[Li][CH3:24]>C1COCC1.C(Cl)Cl>[CH3:24][C@@:14]1([OH:22])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13]1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [Li]C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
A solution of 17β-methoxy-5α-androstan-3-one (101 mg, 0.33 mmol) in dry THF (20 mL) was treated with MeLi (1 mL, 1.5M in THF, 1.5 mmol) at −75° C. After stirring the mixture at −78° C. for 0.5 hr, the mixture was quenched with NH4Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-methyl-3α-hydroxy-17β-methoxy-5α-androstane (35 mg); mp 151-154° C.; TLC Ff (hexane:acetone 7:3)=0.43; and then 3α-methyl-3β-hydroxy-17β-methoxy-5α-androstane (30 mg) as a colorless solid; TLC Rf (hexane:acetone 7:3)=0.27.
Reaction SMILES: [ClH:1].NC1N=C(CCCCC[CH2:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:19]=2)=[O:16])C=C(C)C=1.Cl.[NH2:35][C:36]1[N:41]=[C:40]([CH2:42][CH2:43][CH2:44][CH2:45]NC(=O)C2C=C(O)C=C(C)C=2O)[CH:39]=[C:38]([CH3:58])[CH:37]=1.BrCCCCCCO>>[ClH:1].[NH2:35][C:36]1[N:41]=[C:40]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:14][C:15]([NH:17][C:18]2[CH:19]=[C:20]([C:29]([CH3:31])([CH3:32])[CH3:30])[C:21]([OH:28])=[C:22]([C:24]([CH3:25])([CH3:26])[CH3:27])[CH:23]=2)=[O:16])[CH:39]=[C:38]([CH3:58])[CH:37]=1
Reactant: Cc1cc(N)nc(CCCCNC(=O)c2cc(O)cc(C)c2O)c1
Reactant: Cc1cc(N)nc(CCCCCCC(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Agent: Cl
Agent: OCCCCCCBr
Product: Cc1cc(N)nc(CCCCCC(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1

Procedure:
The experimental protocol used is the same as that described for compound 16, the trimethylsilylated derivative of 5-chloro-1-pentanol (prepared according to J. Org. Chem., (1988), 53 (12), 2732-7) replacing the trimethylsilyl derivative of 6-bromo-1-hexanol. Off-white solid. Melting point: 101-103° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Li]CCCC.[C:17]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[OH:24][C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)[CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH2:26]1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 1-iodo-4-(trifluoromethyl)benzene (0.92 g, 3.4 mmol) in dry THF at −78° C. was added n-BuLi (3 mL, 1.6 M in hexane) dropwise and the mixture was stirred at the same temperature for 30 min. To this was added a solution of tert-butyl 4-benzoylpiperidine-1-carboxylate (1.0 g, 3.4 mmol) in minimum amount of dry THF dropwise and the resulting reaction mixture was allowed to warm up to rt over 2 h. The reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to afford tert-butyl 4-(hydroxy(phenyl)(4-(trifluoromethyl)phenyl)methyl)-piperidine-1-carboxylate (1.0 g, 66% yield) as a pale yellow solid which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH3:12]>>[CH3:5][C:2]([N:11]([CH2:10][CH2:9][O:8][CH3:7])[CH3:12])([CH3:6])[C:3]#[CH:4]
Reactant: C#CC(C)(C)Cl
Reactant: CNCCOC
Product: C#CC(C)(C)N(C)CCOC

Procedure:
In analogy to example 37.1, 3-Chloro-3-methyl-1-butyne and N-(2-Methoxyethyl)methylamine were converted to yield (1,1-Dimethyl-prop-2-ynyl)-(2-methoxy-ethyl)-methyl-amine as colorless oil, MS: 155 (M).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([CH2:20][CH2:21][N:22]([CH2:35][CH:36]=[CH2:37])[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])(=[O:25])=[O:24])[S:16]([CH3:19])(=[O:18])=[O:17])=[C:11](I)[CH:12]=2)[O:7][C:6]=1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:4].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(O[Pd]OC(=O)C)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:36](=[CH2:37])[CH2:35][N:22]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N+:32]([O-:34])=[O:33])(=[O:25])=[O:24])[CH2:21][CH2:20][N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:4]
Reactant: C=CCN(CCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Temperature: 122 °C
Yield: 22.7 %

Procedure:
6-({2-[Allyl-(2-nitro-benzenesulfonyl)-amino]-ethyl}-methanesulfonyl-amino)-2-(4-fluoro-phenyl)-5-iodo-furo[2,3-b]pyridine-3-carboxylic acid methylamide (50 mg, 0.07 mmol) is dissolved in DMF/H2O (10:1, 2 mL: 0.2 mL) and diacetoxypalladium (0.5 mg, 2.64 umol), 1,3-bis(diphenylphosphino)propane (8.17 mg, 0.02 mmol) and potassium carbonate (13.7 mg, 0.10 mmol) are added together then heated in the microwave for 20 min at 122° C. The mixture is then filtered through a bed of celite and the solid is washed with EtOAc (25 mL). The combined organic is then washed with H2O (10 mL), Brine (10 mL) and dried over Na2SO4, followed by evaporation of the solvent. HPLC (CH3CN/H2O/0.1% TFA) provides 2-(4-Fluoro-phenyl)-10-methanesulfonyl-5-methylene-7-(2-nitro-benzenesulfonyl)-5,6,7,8,9,10-hexahydro-1-oxa-7,10,11-triaza-cycloocta[f]indene-3-carboxylic acid methylamide (10 mg, 27%). MS-ES [M+H]+=632.3 and 2-(4-Fluoro-phenyl)-5-iodo-6-{methanesulfonyl-[2-(2-nitro-benzenesulfonylamino)-ethyl]-amino}-furo[2,3-b]pyridine-3-carboxylic acid methylamide (3 mg, 7%). MS-ES [M+H]+=718.0.
Reaction SMILES: Br[C:2]1[NH:11][C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:12]([NH:16][C:17]1[C:26]([CH3:27])=[N:25][C:24]2[C:19](=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=[CH:22][CH:23]=2)[N:18]=1)([CH3:15])([CH3:14])[CH3:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C(Cl)Cl>[C:12]([NH:16][C:17]1[C:26]([CH3:27])=[N:25][C:24]2[C:19]([N:18]=1)=[C:20]([C:2]1[NH:11][C:5]3[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=3[CH:3]=1)[CH:21]=[CH:22][CH:23]=2)([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Reactant: O=c1[nH]ncc2[nH]c(Br)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c(=O)[nH]ncc4[nH]3)c2nc1NC(C)(C)C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 21.8 %

Procedure:
A mixture of 2-bromo-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (47.0 mg, 0.220 mmol), N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b; 94 mg, 0.220 mmol), K3PO4 (140 mg, 0.659 mmol), Pd2dba3 (Aldrich; 10.05 mg, 10.98 μmol), and XPhos (Strem Chemicals, Inc., 10.47 mg, 0.022 mmol) in a mixture of dioxane (1.5 mL) and water (0.38 mL) was stirred under argon at 70° C. for 1.5 h. The reaction mixture was subsequently heated at 90° C. for 17 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (16.8 mg, 0.048 mmol, 22% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.60 (1H, br. s.), 12.24 (1H, s), 8.16 (1H, d, J=0.4 Hz), 7.97 (1H, dd, J=7.4, 1.4 Hz), 7.75 (1H, dd, J=8.0, 1.4 Hz), 7.43 (1H, t, J=7.7 Hz), 7.38 (1H, s), 6.11 (1H, s), 2.58 (3H, s), 1.54 (9H, s). m/z (ESI, +ve) 349.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH:25]=1>>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[O:17])=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCCCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCCCCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
7-(4-Acetyl-3-hydroxy-2-propylphenoxy)heptanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by chromatography on silica gel to give 7(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]heptanamide, the title compound, mp 57°-59° (from acetone-hexane) in 75% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Cn1cccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)Cc1cccn1C
Reaction time: 0.02 h

Procedure:
In a flask is placed 9.72 grams (120 mmol) N-methyl pyrrole and 158 mg (.016 mmole; 1.5 mol%) Cu(acetylacetonate)2, abbreviated herein as "Cu(acac)2 ". The mixture is heated to 50° C. after which a few drops of the 4.56 grams (40 mmol) ethyl diazoacetate are added with stirring. Nitrogen gas is evolved after about 1 minute and the mixture darkens, whereupon the remainder of the ethyl diazoacetate is added drop by drop over a period of 15 minutes. The reaction mixture is then heated and stirred for a further 45 minutes to insure completion of the reaction.
Reaction SMILES: C(O)(=O)C.C([O-])(=O)C.[Na+].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:24]([O-])=O)=[C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=O)[CH:16]=1>C(O)C.O.[Fe].C(O)(=O)C.[Fe]>[Cl:10][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[NH:24][C:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=1
Reactant: O=C1CCCCC1c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Clc1ccc2[nH]c3c(c2c1)CCCC3
Yield: 19.7 %

Procedure:
The reduction can also be carried out using Fe/acetic acid. A mixture of 0.784 g of iron, 1.62 mL of glacial acetic acid, 0.544 g of sodium acetate, and 1 g of 2-(5-chloro-2-nitrophenyl)cyclo-hexanone was refluxed in 80 mL of 4:1 (v/v) ethanol/water for 2 hr. The mixture was cooled, ethanol was evaporated, and the residue was extracted into methylene chloride. Work-up followed by column chromatography on silica yielded 0.160 g (20%) of the named product.