Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:30])[CH2:13][CH2:12]1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[ClH:43]>CN(C)C=O.C(O)C>[ClH:43].[ClH:43].[CH2:41]([O:40][C:38]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28](=[O:29])[N:19]([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH3:3])[CH2:16][CH2:15]2)[C:20]1=[O:30])=[O:39])[CH3:42]
Reactant: CCOC(=O)CCCCCCBr
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)CCCCCCn1c(=O)n(CCN2CCN(c3ccccc3OC)CC2)c(=O)c2ccccc21
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 60% sodium hydride (0.44 g) in dimethylformamide (50 ml), was added 3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione (3.80 g) in a small portion under a nitrogen stream, and the mixture was stirred at room temperature for 30 minutes and at 50° C. for 10 minutes. After cooling to room temperature, a solution of ethyl 7-bromoheptanoate (2.37 g) in dimethylformamide (20 ml) was added to the mixture and the resulting mixture was stirred at room temperature overnight. The solvent was distilled off under vacuum and the resulting residue was extracted with chloroform. The chloroform layer was washed with water and dried with sodium sulfate. When the solvent was distilled off under vacuum, an oily substance was obtained and upon column chromatography on silica gel (eluted with a chloroformethanol 25:1 mixture), a pale yellow oil of 1-(6-ethoxycarbonylhexyl)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H, 3H)quinazolinedione (3.62 g) was obtained. The oil was dissolved in ethanol (50 ml) and hydrogen chloride gas was introduced into the solution for about 5 minutes. After distilling off the solvent, the crystalline residue was recrystallized from a mixture of ethanol and n-hexane to give colorless needles of 1-(6-ethoxycarbonylhexyl)-3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2,4-(1H,3H)quinazolinedione dihydrochloride (3.45 g) having a m.p. of 109°-111° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([O:12]C)=[O:11])([CH3:4])([CH3:3])[CH3:2].[S:22]([CH2:26][CH2:27]O)[CH2:23][CH2:24]O.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:3])([CH3:4])[CH3:2].[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:3])([CH3:4])[CH3:2].[S:22]([CH:26]=[CH2:27])[CH:23]=[CH2:24]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: OCCSCCO
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: C=CSC=C
Product: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Temperature: 120 °C

Procedure:
Using the general procedure of Example 11, 731 g (2.5 moles) of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate, and 150 g (1.23 moles) of 2,2'-thiodiethanol are heated to 120° C. Then, 0.26 g of dibutyltin diacetate (Fascat® 4200, Elf-Atochem, calculated 98 ppm Sn), is added and a vacuum of <50 mm Hg is imposed . The reaction mixture is heated to 160° C. The vacuum is reduced to <5 mm Hg and the reaction mixture is heated at 160° C. for a total of 7 hours. The vacuum is broken and the temperature is reduced to 100° C. to yield the title compound after crystallization from aqueous isopropanol. The product exhibited excellent transmission >99% at 425 nm.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.S(OC)(O[CH3:16])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:2](=[O:1])[C:3]1[CH:11]=[CH:10][C:8]([O:9][CH3:16])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C=O)cc1OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
100 g of vanillin (0.658 mol), 128 g of dimethyl sulfate (1.00 mol), and 96.0 g of sodium carbonate (0.91 mol) were heated with stirring to 80° C over b 0.5 hr. Stirring was continued at this temperature for 1.0 hr. over which time 60 ml of water were added in 5 ml portions. Work-up as in Example 1 gave a quantitative yield of veratraldehyde which contained not more than 0.1% vanillin, as determined by g.l.c. analysis.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:12]([CH3:14])[CH3:13])OC(C(F)(F)F)=[C:3]1[C:19]([O:21][CH3:22])=[O:20].[C:23]([C:27]#[N:28])([Cl:26])([Cl:25])[F:24].C1CCN2C(=NCCC2)CC1.Cl>COCCOC>[Cl:25][C:23]([Cl:26])([F:24])[C:27]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[C:2]([OH:1])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH:12]([CH3:14])[CH3:13])[N:28]=1
Reactant: N#CC(F)(Cl)Cl
Reactant: COC(=O)c1c(C(C)C)oc(C(F)(F)F)c(C(=O)OC)c1=O
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1c(C(C)C)nc(C(F)(Cl)Cl)c(C(=O)OC)c1O
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of 17.80g (0.073 mol) of dimethyl 2-(isobutyryl)-3-oxo-1,5-pentendioate (Step B of Example 208) in 300 mL of DME at -78° C. was added 18 g (0.14 mol) of CFCl2CN followed by 11.lg (11 ml, 0.073 mol) of DBU. The reaction was warmed up to 25° C., poured into 3.7% HCl, and extracted twice with EtOAc. The EtOAc extract was wasned again with 3.7% HCl, saturated NaCl and dried (MgSO4). The solvent was removed in vacuo to give 25.88g of a dark brown solid. The crude was purified by HPLC using 2% HOAc/16% EtOAc/82% cyclohexane as eluting solvent, affording 21g (81%) of product as a beige solid. For elemental analysis a portion of this solid was washed with hexane affording the product as a white solid: mp 75°-76° C.
Reaction SMILES: [OH-:1].[Na+].[BH4-].[Na+].[CH3:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12](O)=[CH:11][C:10]=1[OH:16])=O.[H][H].Cl>O>[CH2:7]([C:9]1[C:14]([OH:1])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])[CH2:6][CH3:5]
Reactant: [OH-]
Reactant: CCC(=O)c1ccc(O)cc1O
Reactant: [H][H]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCc1c(O)cccc1O
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
A 12 L round bottom flask equipped with a mechanical stirrer, reflux condenser and nitrogen inlet was charged with of sodium hydroxide (440 g, 11 moles) and 4.5 L of distilled water. Sodium borohydride (440 g, 11.6 moles) was added and the batch was held at 50° C. until all the solids dissolved. To the mixture there was added 2,4-dihydroxypropiophenone (440 g, 2.6 moles) resulting in a 10-15° C. exotherm and some hydrogen evolution. The batch was held at 80° C. for 90 minutes then cooled to 10-20° C. in an ice bath. Hydrogen evolution was observed during the 90 minute hold at 80° C. 1.9 kg of hydrochloric acid (37%) was added drop-wise (hydrogen evolution) bringing the batch to pH 6. The product was extracted into methylene chloride (5×500 mL). The methylene chloride was stripped off and replaced with toluene (2 L). The product was crystallized from toluene to give propyl resorcinol (261.5 g, 1.7 mol, 65% yield).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH:21]=O)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1.O>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:7][C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH:21]=[CH2:1])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C=O)ccc12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step 1 A solution of potassium tert-butoxide (3.40 g, 30.3 mmol) in THF (249 mL) at 0° C. was treated with methyltriphenylphosphonium bromide (8.79 g, 24.60 mmol), forming a bright yellow suspension. After 1 h, 4-bromo-7-formyl-9H-carbazole-1-carboxamide (prepared according to the procedure of Step 1 of Example 41-1, 4 g, 9.46 mmol) was added, and the resulting suspension was warmed to rt and stirred for 3 h. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 70:30 hexane-EtOAc to EtOAc). The crude material was suspended in methanol, and the precipitate was collected by filtration and dried. The filtrate was concentrated to provide additional solid which was collected by filtration, dried and combined with the first crop to provide 4-bromo-7-vinyl-9H-carbazole-1-carboxamide as a light brown solid (1.66 g, ca. 90% purity, 50%). 1H NMR (400 MHz, DMSO-d6) δ 11.68 (1 H, s), 8.52 (1 H, d, J=8.3 Hz), 8.06-8.29 (1 H, m), 7.79-7.88 (2 H, m), 7.58 (1 H, br. s.), 7.35-7.45 (2 H, m), 6.78-6.98 (1 H, m), 5.88 (1 H, d, J=17.6 Hz), 5.32 (1 H, d). Mass spectrum m/z 344, 346 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:28](Cl)(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[C:28]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCC=CCCCCCCCC(O)CC(=O)OC(C)(C)C
Reactant: CCCCCCCCC=CCCCCCCCC(=O)Cl
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
Starting from tert-butyl 3-hydroxy-11-eicosenoate (11 g) and 9-octadecenoyl chloride (15 g), tert-butyl 3-(9-octadecenoyloxy)-11-eicosenoate (14 g) was obtained as an oil according to a similar manner to that of Preparation A-2 (4).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(OCC)(=O)C>C(#N)C.[Cu]I.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>[Br:8][C:6]1[N:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
To a 500 ml three necked round bottom flask, 3,5-dibromopyrazine-2-amine (25.0 g, 0.0988 mole) was taken in acetonitrile (250 ml). The reaction mixture was cooled to 0° C. and triethylamine (50.0 g, 0.4941 mole), copper (1) iodide (2.26 g, 0.0119 mole), and Pd(PPh3)4 (5.7 g, 0.0049 mole) were added under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0° C. followed by slow addition of trimethylsilylacetylene (10.7 g, 0.1089 mole) over 15 min at the same temperature. After completion of the addition, the reaction mixture was warmed up to RT and stirred for 90 min. The completion of the reaction was monitored on TLC using hexanes:ethyl acetate (5:5) as a mobile phase. After completion of the reaction, the reaction mixture was diluted by ethyl acetate and filtered through high flow. Filtrate was collected and washed with water. Layers were separated and aq. layer was re-extracted by ethyl acetate. Combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product which was subjected for the column purification. The crude compound was purified using column purification by eluting the compound with 7-10% ethyl acetate in hexanes to yield 20.0 g of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-amine.
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:50](=[O:51])[N:13]3[C:14]([C:34]([O:36][CH:37]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:35])=[C:15]([C:18]4[CH:19]=[CH:20][C:21]5[C:22](=[O:33])[C:23]6[C:28]([C:29]=5[CH:30]=4)=[CH:27][CH:26]=[C:25]([CH2:31]O)[CH:24]=6)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:59].OP([O-])(O)=O.[K+]>C(Cl)Cl.CO>[NH2:10][C@@H:11]1[C:50](=[O:51])[N:13]2[C:14]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[C:22](=[O:33])[C:23]5[C:28]([C:29]=4[CH:30]=3)=[CH:27][CH:26]=[C:25]([CH2:31][Cl:59])[CH:24]=5)[CH2:16][S:17][C@H:12]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3ccc4c(c3)-c3ccc(CO)cc3C4=O)CS[C@H]12
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3ccc4c(c3)-c3ccc(CCl)cc3C4=O)CS[C@H]12
Reaction time: 1.08 h

Procedure:
Benzhydryl 7β-phenylacetamido-3-(7-hydroxymethyl-9-fluorenon-3-yl)-ceph-3-em-4-carboxylate (150 mg) was dissolved in methylene chloride (6 ml), cooled to -15° under nitrogen. Pyridine (0.240 ml was added followed by PCl5 (2.4 ml, 8% solution in CH2Cl2). The reaction mixture was stirred at -15° to -10° for 65 min. The temperature was then lowered to -300 and MeOH (1.5 ml) was added drop wise and the reaction was stirred at -10° to -5° for 1.5 hrs, then at 0° for 1 hr. and then at room temperature for 1 hr. KH2PO4 (6.0 ml, 0.5M solution) was added. The reaction mixture was stirred vigorously for 0.5 hr. The organic solvents were removed under reduced pressure and the residual suspension was filtered, the residue was washed well with water and then with ether and the residue dried to give the desired product as a yellow solid (108.3 mg).
Reaction SMILES: Br[C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=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>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:2]1[C:3]([C:11]#[N:12])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1cc2nccn2cc1Br
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: CCOC(C)=O
Product: N#Cc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A mixture of 6-bromo-imidazo[1,2-a]pyridine-7-carbonitrile (1.5 g, 6.8 mmol), 2,4-dichloro-benzeneboronic acid (1.9 g, 10.1 mmol), Pd(PPh3)4 (390 mg, 0.34 mmol) and Na2CO3 (2.0 M solution in water, 12 mL) in OME (30 mL) was refluxed for 14 h under an inert atmosphere of argon. The reaction mixture was cooled to RT, diluted in AcOEt (200 mL) and washed with water (200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→1:1) to yield the title compound (750 mg, 2.6 mmol, 39%) as an orange foam. MS. 289 [M+1]+; HPLC: AtRet=1.50; TLC: RF 0.16 ([hexane/DCM 1:1]/TBME 3:7).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][C:31](OC(C)(C)C)=[O:32])[CH2:12][C@@H:11]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:46]([Mg]Br)[CH3:47].O1CC[CH2:52][CH2:51]1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:30][C:31]([CH2:46][CH3:47])([OH:32])[CH2:51][CH3:52])[CH2:12][C@@H:11]([O:38][Si:39]([C:42]([CH3:43])([CH3:45])[CH3:44])([CH3:41])[CH3:40])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Product: CCC(O)(CC)COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.3 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(tert-butoxycarbonylmethoxymethyl)androsta-5,7,16-triene (175 mg, 0.266 mmol) in tetrahydrofuran (4 ml) was subjected to reaction with a 0.96M ethylmagnesium bromide/tetrahydrofuran solution (3 ml, 2.88 mmol) using a procedure similar to that of Example 27(2) (external temperature of −30° C. for 1.5 hours), worked up and purified by preparative thin layer chromatography (3 sheets (each 0.5 mm thickness), hexane:ethyl acetate=20:1, developed twice, hexane:ethyl acetate=15:1, developed twice, and hexane:ethyl acetate=10:1, developed once) to give the titled compound (139.5 mg, 81%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:9][CH2:8][CH2:7]2.[F:22][C:23]1([CH:43]=[CH:42][CH:41]=[CH:40][CH2:39]1)[CH2:24][N:25]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)[C:26](=[O:29])[CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:22][C:23]1([CH:39]=[CH:40][CH:41]=[CH:42][CH2:43]1)[CH2:24][N:25]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)[C:26](=[O:29])[CH2:27][C:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:13]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:8][NH:9]1
Reactant: O=C(CBr)N(CC1(F)C=CC=CC1)C1Cc2ccccc2C1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)NCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1OC)C(CC(=O)N(CC1(F)C=CC=CC1)C1Cc3ccccc3C1)(c1ccccc1)NCC2
Temperature: 80 °C
Yield: 77.8 %

Procedure:
A mixture of 6, 7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (160, 153 mg, 0.5 mmol), N-(1-fluorobenzyl)-N-indan-2-yl-2-bromoacetamide (161, 180 mg, 0.5 mmol) and potassium carbonate (500 mg) in acetonitrile is heated at 80° C. overnight. After cooling, the mixture is filtered and concentrated. The resulting residue is purified by column chromatography eluting with 5% methanol in chloroform to provide the title product (162) as a thick oil (215 mg, 78%). 1H NMR (CDCl3) 6.8-7.3 (m, 14H), 6.60(s, 1H), 6.05 (s, 1H),
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][CH2:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.[CH3:23][P:24](Cl)([CH3:26])=[O:25]>ClCCl.O>[CH3:23][P:24]([O:10][CH2:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)([CH3:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CP(C)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(COP(C)(C)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
Diisopropyl ethyl amine (124.28 g, 0.961 mol) was added dropwise to stirred solution of compound tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (150 g, 0.80 mol) in dichloromethane (500 mL) at 0° C. Dimethyl phosphinyl chloride (90 g, 0.80 mol) in dichloromethane (300 mL) was added to above reaction mixture over a period of 90 min at same temperature. Then, the reaction mixture was warmed to room temperature and continued stirring for 2 h. After completion of the reaction, the mixture was diluted with water (300 mL). The layers were separated. The organic layer was washed with brine (300 ml), dried over sodium sulfate and concentrated. The resultant concentrated product was purified via column chromatography on silica gel using chloroform/methanol (95/5) to afford tert-butyl 3-{[(dimethylphosphoryl)oxy]methyl}azetidine-1-carboxylate (146.8 g, 68.3%) as brown liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20].[N:21]#[C:22][Br:23]>C1(C)C(C)=CC=CC=1>[BrH:23].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[C:22]1=[NH:21]
Reactant: N#CBr
Reactant: Cc1cccc(C)c1NCCNc1c(C)cccc1C
Solvent: Cc1ccccc1C
Product: Br
Product: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=N
Yield: 99.4 %

Procedure:
500 ml of xylene are introduced into a 1 liter four-necked flask equipped with a stirrer, reflux condenser, thermometer and dropping funnel of 100 ml capacity. 72.5 g (0.27 moles) of 1,2-bis(2',6'-dimethylphenyl-amino)-ethane are dissolved in the xylene, and a solution of 33.9 g (0.32 moles) of cyanogen bromide in 200 ml of xylene is added dropwise, within about 1.5 hours, to the stirred solution at an internal temperature of 110° to 115° C. After the addition the mixture is stirred for a further hor at 110° to 115° C. and then it is allowed to cool. The separated precipitate is filtered off, washed with xylene and diethyl ether, and dried at room temperature. 100.5 g (99.4%) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine hydrobromide are obtained as colourless crystals melting at 289°-290° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][C:5](Cl)=[O:6].Cl.Cl.[CH3:10][N:11]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=3)=[N:20][CH:21]=2)=[N:12]1>C(Cl)Cl.O>[Cl:3][CH2:4][C:5]([N:25]1[CH2:24][CH2:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:14]=[CH:15][N:11]([CH3:10])[N:12]=3)=[CH:21][N:20]=2)=[CH:27][CH2:26]1)=[O:6]
Reactant: Cn1cnc(-c2ccc(C3=CCNCC3)nc2)n1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1cnc(-c2ccc(C3=CCN(C(=O)CCl)CC3)nc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Added 1N NaOH (50 ml, 50 mmol) and Chloroacetyl chloride (3 ml, 37.7 mmol) in CH2Cl2 (50 ml) dropwise to a solution of 5-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridine dihydrochloride (5BX) (1 g, 3.60 mmol) in CH2Cl2 (50 ml at 0° C., maintaining pH at >12. Mixture was stirred for 2 hours at 0° C., then reaction was diluted with CH2Cl2 (200 ml) and H2O (100 ml). The organic layer was separated, washed with H2O (50 ml), dried (Na2SO4), filtered and solvent evaporated yielding title product as a white solid (1.1 g, 100%) MS (MH, 318)
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:12][C:9]1[CH:10]=[N:11][C:2]([CH3:13])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CB(O)O
Reactant: COC(=O)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)cnc1C
Temperature: 110 °C
Yield: 70 %

Procedure:
A mixture of methyl 2-chloro-5-fluoronicotinate (step 1, 1.5 g, 7.91 mmol), tetrakis(triphenylphoshine)palladium (914 mg, 0.79 mmol), methyboronic acid (521 mg, 8.70 mmol) and potassium carbonate (3.28 g, 23.7 mmol) in 1,4-dioxane (20 ml) was heated at 110° C. for 20 h under nitrogen atmosphere. The reaction mixture was filtered through a pad of celite (Celite(trademark) (diatomaceous earth)) and the filtrate was concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20/1 to 4/1) to afford 936 mg (64%) of the title compound: