Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O>O1CCCC1>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)c2c(c1)CCN2
Reactant: CCC(COC)n1cc(Cl)nc(Cl)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O
Reaction time: 18 h
Yield: 20.7 %

Procedure:
To 3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone (1.0 g), prepared as described in Scheme 4, and 7-chloro-5-methoxyindoline hydrochloride (0.92 g), prepared as described in U.S. Pat. No. 6,245,769, stirring in anhydrous tetrahydrofuran (25 mL, 0° C.) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 11.9 mL, dropwise). The reaction mixture was allowed to come to ambient temperature and stirred 18 hours. Water was added, and the mixture was extracted with three portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford the title compound (329 mg). mp 131-133° C. 1H-NMR (CDCl3) δ: 0.93 (3H, t, J=7.3 Hz), 1.83 (2H, m), 3.09 (2H, t, J=7.6 Hz), 3.35 (3H, s), 3.56 (1H, dd), 3.67 (1H, dd), 3.78 (3H, s), 4.34 (2H, t, J=7.7 Hz), 4.94 (1H, m), 6.74 (2H, s), 6.99 (1H, s). MS (APCI+) m/z 398 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[O:1]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccccc1O
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1O

Procedure:
2-Hydroxyethylphenol (XLVa) (15.2 g, 0.11 mol) and t-butyldimethylsilyl chloride (18.2 g, 0.121 mol) were placed together in DMF (120 mL; Aldrich Sure Seal). While the solution was being stirred, imidazole (16.5 g, 0.242 mol) was added portionwise (slightly exothermic). After stirring for 3 h at room temperature, EtOAc (200 mL) was added and the resultant solution was washed with water (3×200 mL) and brine (200 mL). The EtOAc layer was dried over anhydrous sodium sulfate, filtered and concentrated to leave a yellow oil which was purified by silica gel column chromatography (being eluted with 19:1 hexanes/EtOAc) to obtain 27.7 g (0.11 mol, Y: 100%) of the title compound as an oil; Rf: 0.40 (19:1 hexanes/EtOAc); 1H-NMR (CDCl3) δ ppm: 0.067 (6H, s, SiMe2), 0.893(9H, s, SitBu), 2.87 (2H, t, J=5 Hz, ArCH2), 3.91 (2H, t, J=5 Hz, CH2OSi), 6.80 (1H, dt, J=1.3, 7.4 Hz, 5'-H), 6.90 (1H, dd, J=1.2, 8 Hz, 2'-H), 7.00 (1H, dd, J=1,5, 7.3 Hz, 6'-H), 7.12 (1H, dt, J=1.6, 7.5 Hz, 4'-H), 8.29 (1H, s, OH, D2O exchanged); IR (film) 3300 (OH), 1616 cm-1 ; MS (FAB/NOBA) m/e: 253 (MH+), 237, 209.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:6][CH2:5]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: N#Cc1ccc(N2CCN(CCO)CC2)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(C#N)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a solution of 6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-nicotinonitrile (350 mg, 1.51 mmol) and imidazole (236 mg, 3.47 mmol) in anhydrous DMF (3 mL) was added TBDMS chloride (295 mg, 1.96 mmol) in anhydrous DMF (2 mL) and the reaction mixture stirred for 16 h at RT. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was separated, passed through a phase separation cartridge and concentrated in vacuo. The crude residue was purified on silica gel column chromatography eluting with 30% EtOAc/isohexane, and increasing the polarity to 50% EtOAc/isohexane to afford 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-yl}-nicotinonitrile as a pale yellow solid (394 mg, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[CH3:23][N+:24](=[CH2:26])[CH3:25].O>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH2:26][C:7]1[CH:6]=[C:5]([CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:3][C:2]=1[OH:1])[CH3:25]
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Reactant: C=[N+](C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Cc1ccc(O)c(CN(C)C)c1
Reaction time: 72 h

Procedure:
To a solution of ethyl 3-(4-hydroxyphenyl)-2-methylpropanoate (672) (150 mg, 0.72 mmol), potassium carbonate (149.3 mg, 1.08 mmol) in toluene (7 mL) was added N,N-dimethylmethylideneammonium iodide (173.2 mg, 0.94 mmol) and stirred for 72 hours. Water was added and the reaction was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%) to give ethyl 3-(3-((dimethylamino)methyl)-4-hydroxyphenyl)-2-methylpropanoate (673).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([NH:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:21]([CH3:37])([CH3:36])[CH2:20]2)[CH2:12][C:11]1([CH3:39])[CH3:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:40]([N:49]=[C:50]=[O:51])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]=[C:47]=[O:48]>>[CH2:1]([O:9][N:10]1[C:11]([CH3:38])([CH3:39])[CH2:12][CH:13]([N:18]([CH:19]2[CH2:20][C:21]([CH3:37])([CH3:36])[N:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:23]([CH3:25])([CH3:26])[CH2:24]2)[C:47]([NH:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:49][C:50]([N:18]([CH:19]2[CH2:24][C:23]([CH3:25])([CH3:26])[N:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:21]([CH3:36])([CH3:37])[CH2:20]2)[CH:13]2[CH2:12][C:11]([CH3:39])([CH3:38])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:15]([CH3:16])([CH3:17])[CH2:14]2)=[O:51])=[O:48])[CH2:14][C:15]1([CH3:16])[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCON1C(C)(C)CC(NC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Reactant: O=C=NCCCCCCN=C=O
Product: CCCCCCCCON1C(C)(C)CC(N(C(=O)NCCCCCCNC(=O)N(C2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)C2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)C2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of bis(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)amine with hexamethylene diisocyanate.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3(O)[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
To a solution of ethyl (1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacui, and the residue was placed on a small pad of silica gel, eluting with CH2Cl2 to provide the title compound (257 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].C([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])C.Cl>CO>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:3][C:2]=2[N:1]=[C:17]1[C:16]1[NH:15][C:18]2[CH:19]=[CH:5][C:4]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:3][C:2]=2[N:1]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(S(=O)(=O)O)cc1N
Agent: Cl
Solvent: CO
Product: O=S(=O)(O)c1ccc2[nH]c(-c3nc4cc(S(=O)(=O)O)ccc4[nH]3)nc2c1
Temperature: 50 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
A round-bottom 3 neck flask was charged with 3,4-diaminobenzenesulfonic acid (8.0 g, 42.5 mmol) and anhydrous MeOH (0.85 L). O-Methyl-1,1,1-trichloroacetimidate was added (2.8 mL, 3.74 g, 21.2 mmol). The resultant suspension was stirred for 24 h at ambient conditions. Additional amount of O-methyl-1,1,1-trichloroacetimidate was added (1.4 mL, 1.87 g, 10.5 mmol) after this time, then reaction mixture was stirred for 72 h at ambient conditions, heated for 3 h at 50° C. and triethylamine (14 mL, 9.4 g, 93.5 mmol) was added. Stirring was continued at this temperature for 18 hours. Then reaction mixture was cooled to 30° C., and an intensive flow of dry HCl was passed through the solution until a precipitate was formed. The suspension was filtered off at 40° C., precipitate was washed with MeOH (4×150 mL, stirring of suspension for 10-15 min each turn) and with MeOH—HCl 3.5% solution (100 mL, 1 h of stirring). Product 1H,1′H-2,2′-bibenzimidazole-5,5′-disulfonic acid was pale yellow or colorless, weight 3.5 g, yield 42%. It may contain own hydrochloride as a salt. NMR 1H spectrum (Brucker Avance 300 instrument; solvent d6-dimethyl sulfoxide; δ, ppm; J, Hz): 5.27 br.s (—SO3H in exchange with H2O and NH) 7.73 m (2Ha, 2Hb), 8.01 br.s (2Hx). NMR 13C {1H} spectrum (Brucker Avance 300 instrument; solvent d6-dimethyl sulfoxide; δ, ppm): 113.00, 115.41, 123.27, 136.44, 137.60, 142.24, 145.34.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[N:7]([CH2:19][O:20][CH3:21])[S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([Cl:18])=[O:17])(=[O:10])=[O:9].Cl[C:24]1C(C)=NOC=1N(COC)S(C1C=C(C)SC=1C(O)=O)(=O)=O>>[Cl:1][C:2]1[C:3]([CH3:22])=[N:4][O:5][C:6]=1[N:7]([CH2:19][O:20][CH3:21])[S:8]([C:11]1[CH:15]=[C:14]([CH3:24])[S:13][C:12]=1[C:16]([Cl:18])=[O:17])(=[O:9])=[O:10]
Reactant: COCN(c1onc(C)c1Cl)S(=O)(=O)c1ccsc1C(=O)Cl
Reactant: COCN(c1onc(C)c1Cl)S(=O)(=O)c1cc(C)sc1C(=O)O
Product: COCN(c1onc(C)c1Cl)S(=O)(=O)c1cc(C)sc1C(=O)Cl

Procedure:
N-(4-Chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid chloride was synthesized in the same fashion as for N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonyl chloride (Example 51) except that N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid was used instead of N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxylic acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([CH2:20][C:21](Cl)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:20][C:21]([CH:7]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CC2CCCC2)C1
Yield: 59 %

Procedure:
tert-Butyl 3-(2-cyclopentylacetyl)-4-oxopiperidine-1-carboxylate (311 mg, 59%) was synthesised from tert-butyl 4-oxopiperidine-1-carboxylate and 2-cyclopentylacetyl chloride according to the general procedure for the preparation of diketones. MS (ES−) m/z 308.1 (M−H)−
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].Cl[CH2:12]CCl>C(Cl)Cl>[CH3:12][O:1][CH2:2][C@H:3]1[O:4][CH:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: ClCCCl
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Solvent: ClCCl
Product: COC[C@H]1OC(O)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
Vorbr□ggen coupling To the appropriate silylated base (12.9 mmol) was added the appropriate ribose (10.3 mmol) in 15 ml dry 1,2-dichloroethane. The residue was co-evaporated twice with dry 1,2-dichloroethane and subsequently dissolved in 75 ml dry 1,2-dichloroethane. The solution was gently refluxed and after 5 minutes trimethylsilyl-trifluoromethane sulfonate (TMS triflate) (997 □l, 5.16 mmol) was added. The mixture was refluxed for 2 hr, cooled to room temperature and diluted with CH2Cl2. It was extracted with 5% NaHCO3 and water. The organic layer was dried (MgSO4), concentrated and purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([OH:23])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:23])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)O)=C(C)C1=O
Reactant: CC(C)N
Product: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)NC(C)C)=C(C)C1=O
Yield: 27.3 %

Procedure:
3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (15 mg, 0.044 mmol) obtained in Example 69 and isopropylamine (0.005 ml, 0.066 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (4.7 mg, 0.012 mmol, yield 27%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O>O1CCCC1>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: NCc1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccncc1)c1cccc2c1OCCO2
Temperature: 60 °C
Yield: 72.1 %

Procedure:
N,N′-Carbonyidiimidazole (1.62 g, 10 mmol) was added to a stirred solution of 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid(1.64 g, 10 mmol) in tetrahydrofuran (25 mL) and the resulting solution was heated at 60° C. for 15 minutes. The solution was cooled to room temperature and -4-(aminomethyl)pyridine (1.08 g, 10 mmol) was added. The reaction mixture was heated at 60° C. for 2 hours, cooled, poured into water, and extracted 3 times with ethyl acetate. The combined ethyl acetate extract was dried (Na2SO4) and evaporated in vacuo to a crystalline residue which was triturated with water, filtered, and dried in vacuo to give 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid (pyridin-4-ylmethyl)amide as a white solid (1.95 g, 72%); m.p. 120-121° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][C:5](=O)[CH2:6][C:7]#[N:8].O.[NH2:12][NH2:13]>C(O)C>[CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH2:8])[NH:13][N:12]=1
Reactant: NN
Reactant: CN(C)CCC(=O)CC#N
Solvent: CCO
Solvent: O
Product: CN(C)CCc1cc(N)[nH]n1
Temperature: 70 °C
Yield: 70.7 %

Procedure:
To a solution of 5-(dimethylamino)-3-oxopentanenitrile (4.9 g) in ethanol (20 mL) at ambient temperature was added hydrazine monohydrate (1.72 mL, 35.5 mmol) and the reaction mixture was heated to 70° C. for 2 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to give 3.81 g of 3-(2-(dimethylamino)ethyl)-1H-pyrazol-5-amine (65% over 2 steps) which was carried on without further purification. 1H-NMR (400 MHz, DMSO-d6): δ 12.60 (bs, 1H), 6.52 (bs, 2H), 6.1 (s, 1H), 2.69 (m, 2H), 2.65 (m, 2H), 2.27 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[CH:19]2[CH3:25])[CH:3]=1.C(=O)(O)[O-].[Na+].[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:38](=[O:39])[CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:20]([CH3:24])[C@@H:19]2[CH3:25])[CH:3]=1
Reactant: CC1NCCN(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)C1C
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1[C@H](C)N(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1C(=O)Cc1ccccc1
Reaction time: 2 h

Procedure:
To a vigorously stirred solution/suspension of the product from example 71 part a) (0.189 g) and solid sodium bicarbonate (0.215 g) in DCM (2 ml) and water (2 ml) was added phenylacetyl chloride (0.14 ml) dropwise. The mixture was stirred for 2 h. The organic layer and 1 further DCM extract were combined, dried (Na2SO4) and purified by passage through SCX resin eluting with MeCN, MeOH followed by 7M NH3 in MeOH. The basic fractions were concentrated in vacuo to give the sub-titled product as a white foam (0.205 g).
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH2:4][CH:5]=[CH2:6].ClCCl>CO>[CH2:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:1][N:2]=[CH:11][C:10]2[CH:13]=[CH:14][C:7]([CH2:3][CH2:4][CH:5]=[CH2:6])=[CH:8][CH:9]=2)=[CH:9][CH:8]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: NN
Reactant: C=CCCc1ccc(C=O)cc1
Solvent: ClCCl
Solvent: CO
Product: C=CCCc1ccc(C=NN=Cc2ccc(CCC=C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.4 g of a monohydrate of hydrazine and 45 g of 4-(3-butenyl)benzaldehyde were dissolved in 80 ml of methanol. The mixture was stirred at room temperature for 2 hours. To the mixture was then added 150 ml of dichloromethane. The mixture was then washed with saturated aqueous solution of sodium bicarbonate twice. The mixture was then dehydrated and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting crude reaction product was purified through basic alumina column chromatography, and then recrystallized from methanol to obtain 42 g of 1,2-bis[4-(3-butenyl)benzylidene]hydrazine. The compound thus obtained had a melting point of 57° C. and exhibited nematic phase up to 116° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O.C(O[Na])(C)=O.Cl>O>[CH2:19]([O:18][C:12]([C:13]1[C:4]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:3][NH:2][C:14]=1[CH3:16])=[O:17])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: NCC(=O)CCCC(=O)O
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: O
Product: CCOC(=O)c1c(CCCC(=O)O)c[nH]c1C
Temperature: 25 °C
Yield: 70.6 %

Procedure:
6-amino-5-oxohexanoic acid hydrochloride (9.73 g, 49.8 mmol) was dissolved in H2O (35 mL), and ethyl acetoacetate (5.51 g, 42.34 mmol) and AcONa (20.3 g, 14.95 mmol) were added to the above-mentioned solution. The reaction solution was refluxed for 1 h, cooled to room temperature and 0.5N HCl was added until a pH of about 5 was reached. The combined organic layers were anidrified on Na2SO4, filtered and concentrated to give 7.15 g (yield: 60%) of the title compound as brown solid.
Reaction SMILES: C[C:2]1=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:17])[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1.[CH3:18]O>[Pd]>[CH3:18][CH:15]1[CH2:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:17])[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CO
Reactant: CC1=CCCCCC(=O)OCCCCCCC1
Agent: [Pd]
Agent: C/C1=C/CCCCC(=O)OCCCCCCC1
Product: CC1CCCCCCCC(=O)OCCCCC1
Yield: 83 %

Procedure:
25 g (0.10 mol) of Z-8-methyloxacyclopentadec-7-en-2-one were dissolved in 150 ml of methanol and hydrogenated (1.5 hours) with 2 g of 5% palladium-on-carbon with 100 mbar over-pressure. Then, the mixture was filtered over Celite, and the solution was concentrated, distilled in a bulb-tube and chromatographed. There were obtained 20 g (83%) of 8-methyloxacyclopentadecan-1-one were obtained having the following characteristics:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[N:8].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].Cl>C(OCC)(=O)C.CN(C)C=O>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([CH:9]([C:7]#[N:8])[C:10]([O:12][CH3:13])=[O:11])[CH:20]=1
Reactant: COC(=O)CC#N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C#N)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 3.03 g (21.9 mmol) of potassium carbonate, 5.0 ml of N,N-dimethylformamide, 2.17 g (21.7 mmol) of methyl cyanoacetate with a purity of 99% and 1.45 g (8.94 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 60° C. for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, 50 ml of ethyl acetate was added to the mixture, and 2.9 ml (34.8 mmol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 20 ml of water and 30 ml a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: toluene) to obtain 1.81 g (isolation yield: 84%) of methyl 2-(5-fluoro-2-nitrophenyl)-2-cyanoacetate as a yellowish oily product with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][C:11]([CH3:14])([SH:13])[CH3:12]>>[CH3:10][C:11]([CH3:14])([S:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:12]
Reactant: CC(C)(C)S
Reactant: O=Cc1ccccc1Cl
Product: CC(C)(C)Sc1ccccc1C=O

Procedure:
reacting 2-chlorobenzaldehyde with 1,1-dimethylethanethiol in the presence of a base to form 2-(1,1-dimethylethylthio)benzaldehyde;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C=O.[C:14]1(B(O)O)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[CH2:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: OB(O)c1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=C1Cc2ccc(Br)cc2C1=O
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A solution of 6-bromo-2,3-dihydro-1H-inden-1-one (0.3 g, 1.36 mmol), paraformaldehyde (0.4 g, 13.6 mmol), phenylboronic acid (0.2 g, 1.64 mmol) and trifluoroacetic acid (0.1 mL, 0.15 g, 1.36 mmol) in dry toluene (10 mL) was refluxed for 5 hours. When starting material was totally consumed, the crude mixture was cooled to room temperature, neutralized with saturated aqueous Na2CO3, extracted with ethyl acetate, dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, petroleum ether-ethyl acetate, 95:5) to give compound 6-bromo-2-methylene-2,3-dihydro-1H-inden-1-one (89 mg, 30%) as a white solid. 1H NMR (CDCl3, 400 MHz): 3.71 (s, 2H), 5.68 (s, 1H), 6.39 (s, 1H), 7.38-7.40 (d, 1H), 7.70-7.72 (d, 1H), 7.99 (s, 1H).