Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([CH:29]=1)[C:26]([OH:28])=O.CCN=C=NCCCN(C)C.Cl.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][N:56]([C:26](=[O:28])[C:25]2[CH:29]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=2[C:30]([F:33])([F:32])[F:31])[CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1cc(F)ccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
HOBt (163 mg, 1.2 mmol) and DIEA (373 mg, 2.9 mmol) were added to a stirred solution of 5-fluoro-2-trifluoromethyl-benzoic acid (200 mg, 0.9 mmol) in DMF (1.0 mL) and the resulting mixture was cooled to 10° C. EDCI.HCl (231 mg, 1.2 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (197 mg, 1.0 mmol) were then added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford the crude residue, which was purified by column chromatography using silica gel 60-120 mesh (30% ethyl acetate in hexane) to afford 301 mg (83%) of 4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester, LCMS purity: 99.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=4)[C@H:16]([CH2:26][OH:27])[O:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[C@H:16]([CH2:26][OH:27])[O:15][C:14]3=[O:28])=[CH:11][CH:12]=2)=[CH:29][CH:30]=1
Reactant: COc1cccc([C@H]2[C@H](CO)OC(=O)N2c2ccc(Oc3ccc(Cl)cc3)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1O[C@@H](CO)[C@H](c2cccc(O)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-(3-methoxyphenyl)oxazolidin-2-one (Example 91) was dissolved in dichlormethane, cooled to −78° C., and treated with boron tribromide (1M solution, 2.1 eq). After 10 min, the cooling bath was removed, and the reaction mixture is stirred for 1 h. The reaction was then quenched with water, extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel (2-5% methanol/dichlormethane) to give the title compound. 1H NMR (acetone-d6) δ (ppm) 8.36 (s, 1H), 7.42 (d, J=9.1 Hz, 2H), 7.23 (d, J=9.0 Hz, 2H), 7.09 (t, J=7.9 Hz, 1H), 6.85-6.81 (m, 4H), 6.77 (d, J=7.6 Hz, 1H), 6.74 (m, 1H), 6.67 (dd, J=8.1, 2.4 Hz, 1H), 5.39 (d, J=5.2 Hz, 1H), 4.49 (t, J=5.9 Hz, 1H), 4.36 (ddd, J=5.6, 3.7, 3.4), 3.96 (ddd, J=12.4, 5.7, 3.6 Hz, 1H), 3.85 (ddd, J=12.3, 5.6, 3.8 Hz, 1H); HPLC-MS calculated C22H18ClNO5 (M+H+): 411.1, found: 410.0.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.I[C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1.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>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([C:20]2[CH:30]=[CH:29][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Magnesium (1.6 g) and p-bromotoluene (10.26 g) in 60 ml of tetrahydrofuran were stirred and warmed until the reaction commenced. When the exothermic reaction had finished, the mixture was refluxed overnight. In a separate flask, 4 ml of DIBAL (1M in toluene) was added to a suspension of bis(triphenylphosphine)palladium(II) chloride (1.4 g) in 100 ml of tetrahydrofuran, followed by ethyl 3-iodobenzoate (11.04 g). To this mixture, the magnesium reagent prepared above was added dropwise, causing an exothermic reaction. The reaction mixture was stirred overnight at room temperature, and then quenched by addition of dilute hydrochloric acid. The mixture was extracted with ether, and the organic layer washed with water, and then saturated brine. The organic layer was separated, dried over sodium sulfate, the solvent evaporated under reduced pressure, and the residue chromatographed on silica gel, eluting with 5% ethyl acetate in heptane, to yield 5.69 g of ethyl 4'-methylbiphenyl-3-carboxylate, a compound of Formula (17), as a pale yellow oil.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH2:7][CH3:8])[CH:3]=[O:4].[CH2:9]([O:11][C:12](=[O:16])[CH2:13][N+:14]#[C-:15])[CH3:10]>>[CH2:9]([O:11][C:12]([CH:13]1[CH:3]([C:2]([CH2:5][CH2:6][CH2:7][CH3:8])=[CH2:1])[O:4][CH:15]=[N:14]1)=[O:16])[CH3:10]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=C(C=O)CCCC
Product: C=C(CCCC)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-hexanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(hexen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed in a manner analogous to that described in Example 15 to 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester. Reaction of the 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[N:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[OH-].[Na+].Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>CCOC(C)=O>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18](=[O:19])[NH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[N:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(CCCO)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCCO)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
A solution of Intermediate 35a (0.94 g, 4.76 mmol) in EtOAc (15 mL) was treated with aqueous NaOH (1M, 8.58 mmol), followed by 2,2,2-trichloroethyl chloroformate (0.79 mL, 5.72 mmol) and stirred at RT for 1.5 h. The two layers were separated, and the organic layer was washed with water (2×10 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a white solid (1.12 g, 63%). LCMS (Method 3): Rt 3.72 min, m/z 372/374 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][C:38]2([CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCCl>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][C:38]2([CH2:45][CH2:44][CH:43]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:42][CH2:41]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 25 °C
Yield: 29.7 %

Procedure:
3,4-Dichloroaniline (364 mg, 2.2 mmol), sodium triacetoxyborohydride (889 mg, 4.20 mmol) and acetic acid (0.24 mL, 4.20 mmol) were added to a solution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (561 mg, 2.10 mmol) in 1,2-dichloroethane (30 mL) with crunched 4A mol sieves (10 g). The mixture was stirred a room temperature over night. Additional 4A mol sieves (12 g) and sodium triacetoxyborohydride (445 mg) was added and the mixture was stirred over night. The reaction was quenched with water and 5% citric acid was added. The mixture was filtered through kieselguhr and the filtrated was evaporated until only the aqueous layer remained. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with brine, dried with sodium sulphate, filtered and evaporated to give the crude product. Flash chromatography (ethyl acetale/heptane) gave 9-(3,4-dichloro-phenylamino)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (258 mg, 0.624 mmol, 30%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH3:14][N:15]1[C:19]2=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=[C:18]2[CH:17]=[CH:16]1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:24][C:21]1[N:20]=[C:19]2[N:15]([CH3:14])[CH:16]=[CH:17][C:18]2=[CH:23][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Cn1ccc2ccc(N)nc21
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc2ccn(C)c2n1
Temperature: 140 °C
Yield: 17.8 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (195 mg, 0.882 mmol) and 1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamine (156 mg, 1.06 mmol) were dissolved in acetonitrile (2.7 mL), then heated at 140° C. for 2 d. The reaction mixture was cooled and concentrated in vacuo. The residue was diluted with water and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 5 to 70% ethyl acetate in hexanes) gave 6-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazine-3-carboxylic acid ethyl ester (52 mg, 18%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.78 (s, 1H) 9.34 (s, 1H) 7.90 (d, J=8.3 Hz, 1H) 7.14 (d, J=3.3 Hz, 1H) 6.74 (d, J=8.3 Hz, 1H) 6.45 (d, J=3.5 Hz, 1H) 4.58 (d, J=7.1 Hz, 2H) 3.90 (s, 3H) 1.52 (t, J=7.2 Hz, 3H); LCMS (EI/CI) m/z: 332 [M+H].
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:2])=[NH:13])=[CH:10][N:9]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
Suspend ammonium chloride (1.16 g, 21.6 mmol) in toluene (10 mL). Cool to 0° C. and slowly add 2.0 M Al(CH3)3 in toluene (10.8 mL, 21.6 mmol) (see Tetrahedron Lett. 1990, 31(14), 1969-1972). After the gas stops evolving, add a solution of 6-chloronicotinonitrile (1.00 g, 7.22 mmol) in toluene (52 mL). Heat to 80° C. overnight. Cool the reaction mixture, then slowly pour into slurry of silica gel (40 g) in CHCl3 (200 mL). Stir for 10 minutes before filtering. Filter and wash the silica plug with methanol (2× 100 mL). Concentrate the filtrate and purify by 10 g SCX column washing with methanol and then eluting with 2.0 M NH3 in methanol to give the title compound (0.458 g, 40.8%): MS ES+ 155.9 (M+H)+: HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.2 min, 97.2% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[CH2:24]([C@H:31]1[CH2:33][O:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:32][C@@H:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][N:15]1[CH2:16][CH2:17][C:12]2([O:11][C:10]3[C:20]4[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=3[S:19][CH2:18]2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=4)[CH2:13][CH2:14]1
Reactant: c1ccc(C[C@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@@H](O)Cc4ccccc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 209 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane following conditions outlined in procedure Y. M.p.=110° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.92 (d, J=8.8 Hz, 1H), 7.21-7.31 (m, 6H), 7.11 (m, 1H), 4.10 (m, 1H), 3.92 (s, 3H), 3.15 (s, 2H), 3.10 (s, 2H), 2.76 (m, 4H), 2.60 (m, 2H), 2.22 (m, 2H), 1.95 (m, 2H); LCMS: 466 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:12]4[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:33])[N:28]([C:34]2[CH:39]=[N:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1N
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cn1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2SC)cn1
Yield: 53 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)pyrido[3,2-b]pyrazin-3(4H)-one and 5-(3-tert-butyl-5-isocyanato-1H-pyrazol-1-yl)-2-methoxypyridine to afford the title compound (97 mg, 53%) as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:15][CH3:16])[C:5]2[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C.[Cl-].[Na+].O>[CH2:15]([N:4]1[C:5]2[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH3:16]
Reactant: CCn1c(CCl)nc2ccc(C(C)=O)cc21
Reactant: c1c[nH]c(-c2nccs2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2ccc(C(C)=O)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(2-Chloromethyl-3-ethyl-3H-benzoimidazol-5-yl)-ethanone (150 mg, 0.63 mmol), 2-(1H-Imidazol-2-yl)-thiazole (95 mg, 0.63 mmol) and K2CO3 (262 mg, 1.9 mmol) in DMF (10 mL) is stirred at room temperature for 48 hours. Brine (6 mL) and DCM (20 mL) are added. The organic layer is separated and the aqueous layer is extracted with DCM (3×29 mL). The combined organic layers are dried and solvent removed. The residue is purified by PTLC (10% methanol in DCM) to give 1-[3-Ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-3H-benzoimidazol-5-yl]-ethanone as a solid. 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.92 (dd, 1H), 7.87 (dd, 1H), 7.81 (dd, 1H), 7.40 (d, 1H), 7.20 (d, 1H), 7.14 (d, 1H), 6.17 (s, 2H), 4.33 (q, 2H), 2.67 (s, 3H), 1.13 (t, 3H).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH2:2][CH:3]=[CH2:4].[K+].[CH:8](Br)=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[C:10]1([CH:9]=[CH:8][CH:4]=[CH:3][CH2:2][C:1]([OH:6])=[O:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrC=Cc1ccccc1
Reactant: C=CCC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)CC=CC=Cc1ccccc1
Temperature: 105 °C

Procedure:
Proceeding as in Example 1, into a 100 cc flask were placed to react: 4.1 g of potassium 3-butenoate (3.3 10-2 mols), 6 g of styryl bromide, a cis-trans mixture, (3.3 10-2 mols), 2.9 g of Ni(PPh3)3 (3.3 10-2 mols) and 40 cc of ethyl alcohol. The mass was heated up to 105° C. under nitrogen atmosphere, for about 2 hours. Operating as in Example 1, there were obtained 2.2 g of 6-phenyl-3,5-hexadienoic acid, a mixture of isomers containing double cis and trans bonds.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]=1.Cl>C(Cl)Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(F)ccc2Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1ccc(Cl)c(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 117 %

Procedure:
To a solution of tert-butyl 4-(2-chloro-5-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (15, 0.573 g, 1.84 mmol) in CH2Cl2 (11 mL) was added HCl (2.0 N solution in Et2O, 11.0 mL) and the mixture stirred at ambient temperature for 18 h. The reaction mixture was diluted with Et2O (30 mL), and the resulting precipitate was collected by filtration to provide 4-(2-chloro-5-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (16) as a white solid (0.267 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ 9.15 (br s, 2H), 7.54 (dd, J=9.0, 5.4 Hz, 1H), 7.29-7.17 (m, 1H), 7.14 (dd, J=9.3, 3.0 Hz, 1H), 5.84-5.79 (m, 1H), 3.76-3.68 (m, 2H), 3.28 (t, J=5.7 Hz, 2H), 2.62-2.53 (m, 2H); ESI MS m/z 212 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.[C:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])#[CH:33].O>ClCCCl.[Cu]I.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>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[C:33]#[C:32][Si:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(-c2nc(C#C[Si](C)(C)C)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 18 h

Procedure:
In the presence of copper(I) iodide (25 mg) and dichlorobis(triphenylphosphine)palladium(II) (91 mg), triethylamine (0.397 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (1.00 g) and ethynyl(trimethyl)silane (0.716 ml) in 1,2-dichloroethane (20 ml) under ice-cooling. The mixture was stirred at same temperature for one hour and at 25-30° C. for 18 hours. After addition of water, an organic layer was collected, washed with sat. aq. sodium chloride, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (80:20 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6-{5-amino-3-phenyl-6-[(trimethylsilyl)ethynyl]-2-pyrazinyl}-2-isopropyl-3(2H)-pyridazinone (431 mg).
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.[OH-].[Na+].Cl[CH2:16][CH:17]([OH:23])[CH2:18][S:19]([OH:22])(=[O:21])=[O:20].[Na]>O1CCOCC1.O>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][CH2:16][CH:17]([OH:23])[CH2:18][S:19]([OH:22])(=[O:21])=[O:20])[CH2:9]2
Reactant: O=S(=O)(O)CC(O)CCl
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(O)CC(O)CNC1C2CC3CC(C2)CC1C3
Temperature: 80 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To an 80° C. solution of 2-adamantanamine hydrochloride (2.50 g, 13.3 mmol) and sodium hydroxide (586 mg, 14.6 mmol) in 1,4-dioxane (7 mL) and water (7 mL) was added via syringe pump (1 hour addition) a solution of 3-chloro-2-hydroxy-propane sulfonic acid, sodium salt (1.76 g, 8.9 mmol) in 1,4-dioxane (1 mL) and water (9 mL). The solution was stirred at 80° C. for an additional 4 hours. The reaction was cooled to room temperature. The solvent was evaporated under reduced pressure. The solid was suspended in EtOH (25 mL). The mixture was heated to reflux for 1 minute. The solid was removed by filtration. The pure product crystallized in the filtrate. The product was filtered, washed with EtOH (1×10 mL) and dried in vacuo. Yield: 30%. 1H NMR (D2O, 500 MHz) δ ppm 4.30 (m, 1H), 3.35 (m, 2H), 3.03 (m, 3H), 2.07 (m, 2H), 1.84 (m, 2H), 1.75 (m, 4H), 1.65 (d, 6H). 13C (D2O, 125 MHz) δ ppm 63.31, 55.03, 49.51, 36.51, 36.33, 36.26, 29.78, 29.23, 28.81, 26.63, 26.38. ES-MS 289 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34](=[O:56])[N:35]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([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)[N:36]=2)[N:33]=1>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34](=[O:56])[N:35]([C:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1n(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
0.326 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 3 ml of N,N-dimethylformamide; 0.044 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 1 hour. 0.326 g of 6-chloro-2-triphenylmethyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was added, followed by stirring at room temperature for 14 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (95:5). The desired fraction was collected and concentrated to yield 0.58 g of 6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-2-triphenylmethyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as an oily substance. 0.58 g of the oily substance obtained was dissolved in 10 ml of acetone; 467 mg of p-toluenesulfonic acid hydrate was added, followed by refluxing under heating in an oil bath for 5 hours. After cooling, the acetone was mostly distilled off under reduced pressure; to the residue, an aqueous solution of sodium hydrogen carbonate was added; the reaction mixture was extracted with ethyl acetate-tetrahydrofuran (2:1); the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (85:15:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with ethyl acetate, and dried, to yield 0.137 g of the title compound.