Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.O.[NH2:7][NH2:8].[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10].[Na]>>[C:12]1([C:9]2[CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][N:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccccc1
Reactant: NN
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
490 parts (3 mol) of 60% strength by weight sulfuric acid were initially introduced into the stirring flask. 46.9 parts (0.75 mol) of 80% strength by weight hydrazine hydrate, 90 parts (0.75 mol) of acetophenone, 79.5 parts (0.75 mol) of benzladehyde and 1.5 parts (0.01 mol) of sodium iodidewere metered in in succession at room temperature. The reaction mixture wasbrought to 120° C. by distilling off water and kept at 120° C. for 2.5 hours. 110 parts of water were distilled off. The mixture was diluted with the distilled-off water and neutralized with 717 parts (4.5 mol) of 25% strength by weight sodium hydroxide solution. The precipitate was filtered off at room temperature, and the filter residue was washed with water and dried. 160.6 parts of 3,5-diphenylpyrazole having a purity of 94.4% (HPLC) were obtained, which corresponds to a yield of 91.9% of theory. M.p.: 194° C.
Reaction SMILES: CC([O-])=O.[K+].[C:6]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])#[N:7].[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]#[N:18].O>C(O)(C)C>[NH2:18][C:17]([C:16]([Cl:20])([Cl:19])[Cl:15])=[C:8]([C:6]#[N:7])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C=CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: C=CCOC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a solution of KOAc (589.4 g, 6.006 mol) in isopropanol (3 L) was added allyl cyanoacetate (429.4 g, 403.2 mL, 3.432 mol) and the reaction mixture was cooled to 5° C. Trichloroacetonitrile (495.5 g, 3.432 mol) was added in 50 mL portions, maintaining temperature below 15° C. The reaction mixture was then allowed to warm to 20° C. and stirred for 3 h. Water (˜4 L) was added to dissolve the inorganic materials and precipitate out the desired product. The mixture was stirred for 20 minutes and the solid was isolated by filtration under vacuum. This solid was filtered, washed with water (2×0.5 L) and dried in a vacuum oven overnight at 40° C. to afford allyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate 2 as an off-white powder (787 g, 85%). 1H NMR (500 MHz, CDCl3) δ 10.17 (br s, 1H), 6.97 (m, 1H), 5.99 (m, 1H), 5.44 (m, 1H), 5.31 (m, 1H), 4.76 (m, 2H).
Reaction SMILES: [OH:1][C@@:2]1([CH3:16])[CH2:6][C:5](=[O:7])[N:4](C(OC(C)(C)C)=O)[C@H:3]1[CH3:15]>C(OCC)(=O)C.Cl>[OH:1][C@:2]1([CH3:16])[C@H:3]([CH3:15])[NH:4][C:5](=[O:7])[CH2:6]1
Reactant: C[C@@H]1N(C(=O)OC(C)(C)C)C(=O)C[C@]1(C)O
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(=O)C[C@]1(C)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.9 %

Procedure:
tert-Butyl (2S,3S)-3-hydroxy-2,3-dimethyl-5-oxo-pyrrolidine-1-carboxylate (1.00 g) was dissolved in hydrogen chloride-ethyl acetate solution (10 mL, 4 mol/L), and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure, and recrystallized from isopropanol/n-hexane to give the title compound (309 mg, 55%) as colorless crystals. Furthermore, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate→methanol/ethyl acetate=1/10), and the obtained solid was crystallized from diisopropyl ether to give the title compound (220 mg, 39%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
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: O
Solvent: CCO
Product: COc1ccc(-c2ccc(C=O)cc2)cc1
Reaction time: 12 h
Yield: 71.4 %

Procedure:
To a solution of (4-methoxyphenyl)boronic acid (1 g, 6.6 mmol) and 4-bromobenzaldehyde (1.2 g, 3.5 mmol) in ethanol water mixture was added potassium carbonate (1.7 g, 12.0 mmol) and degasified well and added tetrakis (0.7 g, 0.6 mmol) and stirred under argon for 12 h, reaction mass diluted with water and extracted with ethyl acetate, organic layer was washed with water and brine solutions, dried over anhydrous Na2SO4 and concentrated to brown solid as product (1 g, yield: 71.4%). 1H NMR (300 MHz, CDCl3): δ 9.96 (s, 1H), 7.84 (d, 2H), 7.63-7.66 (d, 2H), 7.51-7.54 (s, 2H), 6.93-6.95 (d, 2H), 3.80 (s, 3H)
Reaction SMILES: FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.[NH:16]1[CH:23]=[N:22][C:20]([NH2:21])=[N:19][C:17]1=[O:18].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(O[CH:40]1[O:62][C@H:61]([CH2:63][O:64]C(=O)C2C=CC=CC=2)[C@@H:51]([O:52]C(=O)C2C=CC=CC=2)[C@H:41]1[O:42]C(=O)C1C=CC=CC=1)(=O)C.C(=O)(O)[O-].[Na+].C[O-].[Na+]>C(#N)C.CO.C(O)(=O)C.O.ClCCl>[CH:23]1[N:16]([C@@H:40]2[O:62][C@H:61]([CH2:63][OH:64])[C@@H:51]([OH:52])[C@H:41]2[OH:42])[C:17](=[O:18])[N:19]=[C:20]([NH2:21])[N:22]=1
Reactant: Nc1nc[nH]c(=O)n1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.3 %

Procedure:
34.7 mL of BSTFA are added to a suspension of 6.3 g of azacytosine in 126 mL of acetonitrile. The mixture is brought to 50° C. and it is stirred for 90 minutes. 11.35 mL of trimethylsilyltriflate and then a suspension of 29.0 g of 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in 50 mL of acetonitrile are added to the limpid solution, in about ten minutes. Stirring is maintained for 75 minutes, it is cooled to ambient temperature and it is slowly poured onto a mixture constituted by 500 ml of dichloromethane and 330 ml of water into which 9.5 g of sodium bicarbonate had been previously dissolved. Stirring is carried out for 15 minutes and the pH is adjusted to pH=4.5 using acetic acid. The mixture is left to settle and phases are separated. The aqueous phase is washed twice using 125 ml of dichloromethane for each washing. The organic phases which are anhydrified by treating them with anhydrous calcium chloride are combined. Concentration is carried out at low pressure until a viscous residue is obtained. The residue is recovered with 250 mL of methanol, it is concentrated once again at low pressure until a viscous residue is obtained. 250 mL of methanol are added, it is heated to 50° C. and 15 mL of a 10% solution of sodium methylate in methanol are added. It is stirred for 1 hour, it is cooled to ambient temperature, it is stirred to complete precipitation and the solid is filtered by washing it on the filter with methanol. 5.4 g of azacitidine with HPLC purity (UV 254 nm) of 94.1% are obtained after drying at low pressure.
Reaction SMILES: I[Si](C)(C)C.[CH:6]1([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][C:18]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][P:32]([O:37]CC)([O:34]CC)=[O:33])=[CH:27][CH:26]=4)=[O:23])=[CH:19]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)(Cl)(Cl)Cl>[CH:6]1([C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][C:18]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][P:32]([OH:37])([OH:34])=[O:33])=[CH:27][CH:26]=4)=[O:23])=[CH:19]3)=[CH:14][CH:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOP(=O)(Cc1ccc(NC(=O)C2=Cc3cc(C4CCCCC4)ccc3CC2)cc1)OCC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(CP(=O)(O)O)cc1)C1=Cc2cc(C3CCCCC3)ccc2CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
Iodotrimethylsilane [(CH3)3SiI] (0.458 g) was added to a suspension of 7-cyclohexyl-N-(4-diethoxyphosphorylmethylphenyl)-3,4-dihydronaphthalene-2-carboxamide (0.5 g) in carbon tetrachloride (10 ml) at 0° C. After stirring at 0° C. for 1 hour and then at room temperature for 15 hours, this mixture was concentrated under reduced pressure. To the residue, methanol (6 ml) was added; this mixture was acidified with 1N HCl and stirred at room temperature for 30 minutes. The resulting crystals were collected by filtration and recrystallized from methanol-water to yield 7-cyclohexyl-N-(4-phosphonomethylphenyl)-3,4-dihydronaphthalene-2-carboxamide (0.28 g, 63%) as pale yellow prisms having a melting point of 203°-205° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:32](O)=[O:33])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:47]([N:50]1[C:54]([CH2:55][S:56]([C:58]2[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=2)=[O:57])=[CH:53][N:52]=[CH:51]1)[CH2:48][CH3:49]>ClCCl.O1CCCC1.O.N1C=CC=CC=1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:32]([NH:62][C:61]4[CH:63]=[CH:64][C:58]([S:56]([CH2:55][C:54]5[N:50]([CH2:47][CH2:48][CH3:49])[CH:51]=[N:52][CH:53]=5)=[O:57])=[CH:59][CH:60]=4)=[O:33])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1cncc1CS(=O)c1ccc(N)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccnn2C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCN3Cc2ccnn2C)cc1
Reaction time: 0.5 h

Procedure:
(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartarate 1hydrate (174 mg) was dissolved in ethyl acetate (5 ml) and 1N hydrochloric acid (1.77 ml) to separate the layers. To the aqueous layer was added 25% aqueous solution of potassium carbonate (1.77 ml) and the mixture was extracted with 2-propanol-ethyl acetate (1:4). The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue was added tetrahydrofuran, and the solvent was distilled off again under reduced pressure to give (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-[(1-methylpyrazol-5-yl)methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (95 mg) in dichloromethane (10 ml) were added one droplet of DMF and oxalyl chloride (0.023 ml) under nitrogen atmosphere and the mixture was stirred for 30 minutes. This solution was added dropwise to a solution of (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine (0.42 ml) in tetrahydrofuran (10 ml), at 0° C. under nitrogen atmosphere. The mixture was allowed to be at room temperature and stirred for 3 hours, and water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% acetic acid solution twice, an aqueous solution of saturated sodium bicarbonate twice, and saturated brine once, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=11:1), to give (−)-7-[4-(2-butoxyethoxy)phenyl]-1-[(1-methylpyrazol-5-yl)methyl]-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (81 mg) (Compound 455) as yellow amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[I:21]Cl.C([O-])(=O)C.[Na+].COC(=O)NC1SC2C=CC=C(OC)C=2N=1>C(O)(=O)C>[I:21][C:6]1[C:7]2[S:11][C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: ClI
Reactant: COc1cccc2sc(NC(=O)c3ccc(C)s3)nc12
Agent: CC(=O)[O-]
Agent: COC(=O)Nc1nc2c(OC)cccc2s1
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 93 %

Procedure:
Iodination of 5-methyl-thiophene-2-carboxylic acid (4-methoxy-benzothiazol-2-yl)-amide (5.17 g, 17 mmol) with iodine monochloride (2.26 ml, 44 mmol), sodium acetate (3.63 g, 44 mmol) and acetic acid (200 ml) in the same manner as described for (4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester affords the product as off-white solid in 93% yield. MS: m/e=430 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CC#N>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc(C=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C=O)cc1OCCN1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 3-hydroxy-4-methoxybenzaldehyde (8.56 g, 56.26 mmol) in CH3CN (50 ml) was added K2CO3 (17.1 g) with CH3CN (20 ml), followed 20 minutes later by N-(2-chloroethyl)morpholine hydrochloride (11.52 g). The reaction mixture was refluxed overnight, and then was cooled to room temperature, filtered, and the solvent was stripped to give, as an amber oil, 4-methoxy-3-[2-(4-morpholinyl)ethoxy]benzaldehyde.
Reaction SMILES: [CH:1]([C@H:4]1[C@H:9]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:7]2([CH3:8])[C:6](=[O:24])[CH2:5]1)[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Cl-].[NH4+]>O1CCCC1.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH:1]([C:4]1[C@H:9]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:7]2([CH3:8])[C:6](=[O:24])[CH:5]=1)[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)CC[C@H]1[C@@H]3[C@H](C(C)C)CC(=O)[C@@]3(C)CC[C@H]21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)[N-]C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C(C(C)C)[C@@H]12
Temperature: 0 °C
Yield: 81.9 %

Procedure:
A solution of the 15β-isopropyl ketone (9) (210 mg; 0.64 mmol) in dry tetrahydrofuran (10 ml) was added to a solution of lithium diisopropylamide (3.2 mmol) [prepared at 0° C. from diisopropylamine (0.9 ml; 6.35 mmol) in tetrahydrofuran (2 ml) and butyl lithium (1.9 ml; 3.04 mmol)] at -78° C. After 30 min. at this temperature, chlorotrimethylsilane (1 ml; 7.88 mmol) was added. The mixture was allowed to warm to 0° C. over 20 min. Saturated aqueous ammonium chloride was added and the residue upon work-up (ethyl acetate). (242 mg) was dissolved in dry acetonitrile (20 ml). Palladium(II) acetate (140 mg; 0.62 mmol) was added and the mixture was heated to refluxing temperature for 20 min. The solution was cooled to 20° C., filtered and evaporated. The residue (230 mg) was chromatographed on silica gel (23 g), and eluting with ethyl acetate-toluene (1:19) gives 15-isopropyl-3-methoxyestra-1,3,5(10),15-tetraen-17-one (10) (170 mg; 81% from 9), m.p. 113°-116° C. (from chloroform-methanol); [α]D -18° (c 1.0); υmax 1690 cm-1 (CO); δH 1.10 (3H, s, 13β-Me), 1.16 and 1.22 (each 3H, d, J 6.6 Hz, 15-CHMe2), 2.57 (1H, dd, J 11.2 and 2.7 Hz, 14α-H), 2.92 (2H, m, 6-H2), 3.79 (3H, s, 3-OMe), 5.80 (1H, dd, J 2.7 and 1.2 Hz, 16-H), 6.65 (1H, d, J 2.7 Hz, 4-H), 6.74 (1H, dd, J 8.6 and 2.7 Hz, 2-H), and 7.24 (1H, d, J 8.6 Hz, 1-H); δC 21.1 (C-18), 21.6 and 21.7 (15-CHMe2), 25.6 (C-11), 28.1 (C-7), 29.1 (C-6), 29.7 (C-8), 30.8 (15-CHMe2), 37.4 (C-12), 45.4 (C-9), 52.6 (C-13), 55.2 (3-OMe), 56.3 (C-14), 111.6 (C-2), 113.6 (C-3), 123.9 (C-16), 126.3 (C-1), 132.2 (C-10), 137.2 (C-5), 157.7 (C-3), 185.7 (C-15), and 212.4 (C-17) (Found: C, 81.6; H, 8.9%; M+, 324. C22H28O2 requires C, 81.4; H, 8.7%; M, 324).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.NC1O[C:22]([CH:33]([CH3:35])[CH3:34])=[N+:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=12>C(#N)C>[CH:33]([C:22]1[N:23]2[CH:32]=[CH:31][C:30]3[C:25]([C:24]2=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:26][CH:27]=[CH:28][CH:29]=3)([CH3:35])[CH3:34]
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CC(C)c1oc(N)c2c3ccccc3cc[n+]12
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Yield: 16.4 %

Procedure:
Ethyl phenylpropiolate (10.1 g, 0.058 mol) was added with stirring to a solution of 1-amino-3-isopropyloxazolo[4,3-a]isoquinolinium tetrafluoroborate (9.1 g) in acetonitrile (90 ml) at 50° C. The solution was then heated at reflux for 30 minutes and it was then evaporated in vacuo to give a viscous orange-brown oil, which was extracted with hot petroleum ether (b.p. 60°-80° C.)(4×100 ml). The petroleum extract was evaporated in vacuo and the residue was subjected to flash chromatography on silica gel using as eluent a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (19:1 v/v), giving an oil, which crystallised on standing, to give ethyl 3-isopropyl-1-phenylpyrrolo-[ 2,1-a]isoquinoline-2-carboxylate (1.7 g), in the form of a colourless solid, m.p. 82°-84° C. [N.M.R. (in CDCl3): 0.88 (3H, t, J=7 Hz), 1.52 (6H, d, J=7 Hz), 4.01 (2H, q, J=7 Hz), 4.14 (1H, septet, J=7 Hz), 6.75 (1H, d, J=8 Hz), 7.00-7.50 (9H, m), and 7.85 (1H, d, J=8 Hz)].
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)(O)[CH2:16][CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN(C=O)C.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6](/[CH:14]=[C:15](/[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)\[CH2:16][CH3:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCC(O)(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)butan-2-ol (0.5 g, 1.43 mmol) was dissolved in dry DCM (15 mL) and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.5 g, 4.29 mmol) diluted with dry DCM (2 mL) was added dropwise. Stirring was continued for 1 h at 0° C. and then at RT for 2 h. The solution was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. 1H NMR (CDCl3, freebase) δ (ppm): 8.65 (d, 2H), 7.40 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 6.80 (s, 1H), 3.70 (s, 2H), 2.90 (m, 2H), 2.80 (m, 2H), 2.60 (s, 3H), 2.45 (m, 5H), 0.9 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27](/B(O)O)=[CH:28]/[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.[Cl-].[Na+].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>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](/[CH:27]=[CH:28]\[CH3:29])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C/C=C\B(O)O
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
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: [Cl-]
Solvent: O
Solvent: COCCOC
Product: C/C=C\c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (54 mg, 0.12 mmol) in DME (1.2 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.7 mg, 0.0015 mmol). After 15 min., cis-1-propenylboronic acid (31 mg, 0.37 mmol), potassium carbonate (17 mg, 0.12 mmol), and water (0.3 mL) were added. The reaction was heated to reflux for 3 h and then cooled to room temp. The reaction was diluted with brine and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a yellow oil. The oil was purified by flash chromatography (silica gel, 0-50% EtOAc in hexanes) to give 42 mg of the desired product as a colorless oil. MS (ESI) 397 (M+H).
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH2:10][CH2:11][OH:12]>CO>[OH:12][CH2:11][CH2:10][S:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: OCCBr
Reactant: COC(=O)CCS
Agent: [Na]
Solvent: CO
Product: COC(=O)CCSCCO

Procedure:
A solution of 2.3 g. sodium in 80 ml. methanol, which contains 12 g. methyl 3-mercaptopropionate and 12.5 g. 2-bromoethanol, is stirred under reflux for 4 hours. After evaporating, the residue is taken up in chloroform, filtered and evaporated. 16 g. Methyl 3-(2-hydroxyethylthio)-propionate are obtained in the form of an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([O-])=[O:12].[O-]CC.[Na+].[Na]>C(O)C>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11](=[O:12])[C:10]([O:15][CH2:16][CH3:17])=[O:14])#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C(C#N)c1ccccc1

Procedure:
A mixture of 117.1 g. (1.0 mol.) of phenylacetonitrile and 326 ml. (2.4 mol.) of ethyl oxalate was added to an ethanol solution of sodium ethoxide [prepared by dissolving 23.8 g. (1.08 g. -atom) of sodium in 500 ml. of absolute ethanol] and refluxed for two hours. After cooling, diluting with 2500 ml. of water and extracting with ether, the solution was acidified with acetic acid. The solid was removed by filtration and washed with water to give ethyl 3-cyano-3-phenylpyruvate, m.p. 127°-129°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:32].C(OCC)C>O1CCOCC1>[ClH:32].[ClH:32].[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A solution of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (5.47 g, 12.25 mmol) in 1,4-dioxane (70 mL) was treated with 4.0M HCl in 1,4-dioxane (30 mL, 122 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Diethyl ether was added to the reaction mixture and the resulting solid was collected by filtration. The crude product was then dissolved in methanol and filtered. The filtrate was concentrated to give 4.36 g (85%) of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine dihydrochloride as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.62 (d, 1H, J=2.7 Hz), 8.31 (d, 1H, J=2.7 Hz), 8.23-8.12 (m, 5H), 4.22 (d, 2H, J=6.1 Hz), 3.51-3.46 (m, 2H), 3.20 (s, 3H), 3.13-3.05 (m, 2H), 2.34-2.23 (m, 1H), 2.16-2.10 (m, 2H), 1.75-1.64 (m, 2H); LRMS (APCI), m/z 347 (M+H).