Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:13]=[C:14]=S)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:18]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])#[N:19].S([O-])([O-])(=O)=O.[Mg+2].[CH2:34]([NH2:39])[CH2:35][CH:36](C)[CH3:37]>[Hg]=O.C(Cl)Cl>[C:24]([O:23][C:21](=[O:22])[C:20]([C:18]#[N:19])=[C:14]([NH:13][C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[NH:19][CH2:18][CH2:20][CH2:21][N:39]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:25][C:24]1=[O:23])([CH3:27])([CH3:26])[CH3:25]
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: CC(C)CCN
Agent: O=S(=O)([O-])[O-]
Agent: O=[Hg]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C#N)=C(NCCCN1CCCCCC1=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a mixture of 3,5-bis(trifluoromethyl)phenylisothiocyanate (2.83 g, 10.4 mmol), DCM (20 mL) and tert-butyl cyanoacetate (1.65 mL, 11.6 mmol) DBU (4.0 mL, 26.8 mmol) was added, whereby an exothermic reaction occurred. The resulting mixture was stirred at room temperature for 2 h, and then magnesium sulfate (2.0 g), isoamylamine (2.35 mL) and mercury(II) oxide (6.80 g, 31.4 mmol) were added. After stirring for 25 h, the mixture was mixed with celite, filtered, and the filtrate was mixed with 0.5 M hydrochloric acid. After an additional filtration the filtrate was extracted (3×100 mL DCM), the combined extracts were washed with brine (2×300 mL, emulgates strongly), dried (magnesium sulfate) and concentrated. Column chromatography (80 g silica gel, gradient elution with heptane/ethyl acetate 10:0 to 2:3) gave 2.23 g (39%) of the title compound as a colourless solid, along with 0.72 g (15%) of 3-[3,5-bis(trifluoromethyl)phenylamino]-2-cyano-3-(3-methylbutylamino)acrylic acid tert-butyl ester. A sample of the title compound was further purified by recrystallization. Colourless solid, mp. 167-168° C. (ethyl acetate). LCMS: elution at 15.4 min, MH+ : 549; 1H NMR (400 MHz, DMSO-d6): δ=1.40 (s, 9H), 1.43 (m, 4H), 1.57 (m, 2H), 1.71 (q, J=7 Hz, 2H), 2.35 (m, 2H), 3.20 (q, J=7 Hz, 2H), 3.31 (m, 2H), 7.66 (s, 2H), 7.68 (s, 1H), 8.95 (s, br, 1H), 9.52 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ=22.93, 27.93, 28.11, 28.32, 29.23, 36.44, 41.55, 44.47, 48.38, 61.93, 79.66, 115.36, 118.75, 119.89, 123.18 (q, J=275 Hz), 131.02 (q, J=33 Hz), 142.33, 160.59, 167.95, 174.74. Anal. Calcd. for C25H30F6N4O3 (548.53): C, 54.74; H, 5.51; N, 10.21. Found: C, 54.62; H, 5.66; N, 9.97.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH2:16]([O:23][C:24]([N:26]1[CH2:30][C@H:29]([O:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:28][C@H:27]1[CH2:42][OH:43])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:16]([O:23][C:24]([N:26]1[CH2:30][C@H:29]([O:31][S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH2:28][C@H:27]1[CH2:42][O:43][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO)N(C(=O)OCc3ccccc3)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
37.4 ml (269 mmol) of triethylamine, 38.76 g (257 mmol) of t-butyldimethylsilyl chloride and 2.99 g (24.5 mmol) of 4-dimethylaminopyridine were added, in turn, to a solution of 104.98 g (245 mmol) of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-(p-toluenesulfonyloxy)pyrrolidine [obtained as described in Preparative Example 12(i)′ above] in 610 ml of methylene chloride, and the resulting mixture was then stirred at room temperature overnight. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 119.34 g (yield: 94%) of (2S,4R)-1-benzyloxycarbonyl-2-(t-butyldimethylsilyloxy)methyl-4-(p-toluenesulfonyloxy)pyrrolidine as a yellow oil.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[CH:3]1.CN(C)[C:15]1[O:16][C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=1.C(O)(=O)C>O>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[N:1]2[C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[NH:20][C:15]2=[O:16])=[CH:6][CH:7]=1
Reactant: COc1ccc2ccn(N)c2c1
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ccn(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2c1
Yield: 57.3 %

Procedure:
A mixture of 0.2 g 1A, 0.268 g 2-dimethylamino-4-trifluoromethyl-1,3-oxazin-6-one (obtained according to M.-A. Decock-Plancquaert et al., Bull. Soc. Chim. Belg. 101 (4) 313-321 (1992)) and 10 ml acetic acid is refluxed for 4 hours. The mixture is poured into water, extracted and chromatographed to yield 0.23 g of 1B as an oil.
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[OH:21][C:18]1([C:1]2([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]2)[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: N#CC1CCC1
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC1(C2(O)CCOCC2)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44.1 %

Procedure:
To a solution of cyclobutanecarbonitrile (405 mg, 5 mmol) in THF (7 mL) was added 2.0M lithium diisopropylamide (2.5 ml, 5 mmol) dropwise at −78° C. and the reaction solution was stirred at −78° C. for 40 minutes. A solution of dihydro-2H-pyran-4(3H)-one (550 mg, 5.5 mmol) in hexamethylphosphoramide (268 mg, 1.5 mmol) was added and the mixture was warmed up to room temperature, and stirred for 3 hours. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (eluted with petroleum ether: EtOAc=20:1) to obtain the title compound as a corloless oil (0.40 g, yield 44%). 1H NMR (400 MHz, CDCl3): δ 3.97 (dd, J=11.4, 4.2 Hz, 1H), 3.60-3.50 (m, 2H), 3.40-3.33 (m, 1H), 2.66-2.57 (m, 2H), 2.30-2.16 (m, 3H), 1.99-1.87 (m, 2H), 1.72 (dd, J=8.8, 3.6 Hz, 2H), 1.63-1.58 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1.[OH-:15].[K+]>O>[OH:15][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1OC
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1cc(CO)ccc1C(=O)O
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A mixture of methyl 4-bromomethyl-2-methoxybenzoate (25.0 g, 96.5 mmol), potassium hydroxide (10.83 g, 193 mmol) and water (400 mL) was refluxed with stirring for 2 hr. The reaction mixture was cooled, further basified to pH 14, and extracted three times with ethyl ether. The reaction solution was then acidified to pH 1 and extracted several times with ethyl acetate. The ethyl acetate layers were combined, dried (Na2SO4) and evaporated to yield 16.3 g (93%) of the title compound as an off white solid, m. pt 106-111°, whose purity was suitable for use without further purification. Additional purification is effected by recrystallization from ethyl acetate and hexane, m. pt, 112-115°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:28])[C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:15]=[C:14](/[CH:25]=[N:26]/[OH:27])[CH:13]=2)[CH3:9])=[N:6][CH:7]=1.[Cl:29]N1C(=O)CCC1=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11]([C:12]2[CH:13]=[C:14]([C:25]([Cl:29])=[N:26][OH:27])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)=[O:28])[CH3:9])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(/C=N/O)cc(C(=O)N[C@H](C)c3ccc(F)cn3)c2)nc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(F)cn3)cc(C(Cl)=NO)c2)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of N-[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]-3-[(E)-(hydroxyimino)methyl]-5-(5-methyl-2-pyridinyl)benzamide (0.703 g, 1.86 mmol) N,N-dimethylformamide (1.9 mL) was added N-chlorosuccinimide (0.260 g, 1.95 mmol). The reaction mixture was stirred at 50° C. for 1 h. The temperature was raised to 70° C. for 1 h. The mixture was cooled to ambient temperature. Water was added. The mixture was extracted with diethyl ether (3×). The combined organic extracts were washed with water (3×), dried over magnesium sulfate, filtered and concentrated to give the title compound (0.795 g) MS 413.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([C:10]([OH:12])=O)[CH:3]=1.C(OC([N:20]1[CH2:25][CH2:24][O:23][C@@H:22]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=2[F:33])[CH2:21]1)=O)(C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([C:10]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([C@@H:22]3[O:23][CH2:24][CH2:25][NH:20][CH2:21]3)=[C:27]([F:33])[CH:28]=2)=[O:12])[CH:3]=1
Reactant: N#Cc1cc(Cl)cc(C(=O)O)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2F)C1
Product: Cl
Product: N#Cc1cc(Cl)cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(F)c2)n1

Procedure:
In analogy to example 83, step a) using 4-chloro-6-cyano-2-pyridine carboxylic acid (CAS 1060812-13-6) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 83) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:17]2[CH:16]=[C:15]3[C:7]([C:8]4[CH:9]=[C:10]5[C:20]([CH3:21])=[CH:19][C:18]([CH3:23])([CH3:22])[C:11]5=[CH:12][C:13]=4[CH2:14]3)=[CH:6][C:5]=2[C:4]([CH3:24])=[CH:3]1.C([Li])CCC.CCCCCC.[C:37]1([CH3:56])[CH:42]=[CH:41][C:40]([C:43]([C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=2)=[C:44]2[CH:48]=[CH:47][CH:46]=[CH:45]2)=[CH:39][CH:38]=1.Cl>O1CCCC1.C(OCC)C>[CH3:1][C:2]1([CH3:25])[C:17]2[CH:16]=[C:15]3[C:7]([C:8]4[CH:9]=[C:10]5[C:20]([CH3:21])=[CH:19][C:18]([CH3:23])([CH3:22])[C:11]5=[CH:12][C:13]=4[CH2:14]3)=[CH:6][C:5]=2[C:4]([CH3:24])=[C:3]1[C:43]([CH:44]1[CH:45]=[CH:46][CH:47]=[CH:48]1)([C:40]1[CH:39]=[CH:38][C:37]([CH3:56])=[CH:42][CH:41]=1)[C:49]1[CH:50]=[CH:51][C:52]([CH3:55])=[CH:53][CH:54]=1
Reactant: Cc1ccc(C(=C2C=CC=C2)c2ccc(C)cc2)cc1
Reactant: CC1=CC(C)(C)c2cc3c(cc21)-c1cc2c(cc1C3)C(C)(C)C=C2C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=CC(C)(C)c2cc3c(cc21)-c1cc2c(cc1C3)C(C)(C)C(C(c1ccc(C)cc1)(c1ccc(C)cc1)C1C=CC=C1)=C2C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 29.6 %

Procedure:
To a 200-ml two-neck flask equipped with a magnetic stirrer, a three-way cock and a 50 ml dropping funnel, 749 mg (2.29 mmol) of 1,1,3,6,8,8-hexamethyl-1H,8H-dicyclopenta[b,h]fluorene and 30 ml of tetrahydrofuran were charged under nitrogen atmosphere. 1.56 ml (2.43 mmol) of 1.56 mol/l n-butyllithium/hexane solution was gradually added thereto, while cooling it in an ice water bath, and the mixture was stirred at room temperature for 6.5 hours. 718 mg (2.78 mmol) of 6,6-di-p-tolylfulvene dissolved in 30 ml of tetrahydrofuran in advance was gradually added thereto over 20 minutes using the dropping funnel, while cooling it in a methanol/dry ice bath. The temperature of the reaction solution was gradually elevated back to room temperature, and the solution was stirred at room temperature for 20 hours. 50 ml of 1 N hydrochloric acid was gradually added thereto, and 50 ml of diethyl ether was further added to the mixture. The organic layer was separated, washed twice with 50 ml of water, once with 50 ml of saturated solution of salt. After the solution was dried over magnesium sulfate, the solvent was distilled off, and the obtained product was purified by column chromatography. The production quantity was 397 mg (0.679 mmol), and the yield was 29.6%. Identification was performed by 1H-NMR spectrum and FD-MS spectrum. The measurement results are shown as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13]SC3C([N+]([O-])=O)=CC=CN=3)[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Br[CH2:66][C:67]([C:69]1[CH:78]=[CH:77][C:72]2[O:73][CH2:74][CH2:75][O:76][C:71]=2[CH:70]=1)=[O:68]>CC(C)=O.O>[O:73]1[C:72]2[CH:77]=[CH:78][C:69]([C:67](=[O:68])[CH2:66][S:13][C@H:10]3[C:11](=[O:12])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C@@H:9]3[C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:70][C:71]=2[O:76][CH2:75][CH2:74]1
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(F)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCCO4)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-{(2R,3R)-1-(4-fluorophenyl)-3-[(3-nitropyridin-2-yl)dithio]-4-oxoazetidin-2-yl}phenoxy)acetate (0.100 g, 0.179 mmol) in acetone (2 ml) and water (0.5 ml) was added triphenylphosphine (0.047 g, 0.179 mmol). After 30 minutes, the mixture was concentrated. To the residue was added dichloromethane (3 ml) followed by the addition of triethylamine (0.073 g, 0.717 mmol) and 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone (0.115 g, 0.448 mmol). After 30 minutes, full conversion of the thiol had been achieved. The mixture was concentrated and to the residue was added formic acid (2 g) and trifluoroacetic acid (0.2 g). The mixture was allowed to stir at room temperature for 3 h. The crude product obtained was purified through preparative HPLC using an eluent of 10-50% CH3CN in 0.1M NH4OAc buffer. Freeze drying of pure fractions afforded the desired compound. 1H NMR [(CD3)2SO), 400 MHz] δ 4.21-4.32 (m, 9H), 5.09 (d, 1H), 6.78-7.44 (m, 11H).
Reaction SMILES: [ClH:1].[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1.Cl.[CH2:28](O)[CH3:29]>>[ClH:1].[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[NH:8][C:2]3[C:7]([C:18]=2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:28][CH3:29])=[O:25])=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:12]=1
Reactant: CCO
Reactant: O=C(O)CCCCCCC(=O)c1cccnc1
Reactant: NNc1ccccc1
Agent: Cl
Product: CCOC(=O)CCCCCc1c(-c2cccnc2)[nH]c2ccccc12

Procedure:
A mixture of 10.32 g of phenylhydrazine hydrochloride and 16.8 g of 7-nicotinoylheptanoic acid in 750 ml of ethanol is heated at refux temperature for 6 hours. After cooling with an ice-water bath, 250 ml of ca 2N ethanolic hydrogen chloride is added and the mixture heated at reflux for 16 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure. The crude product is triturated with petroleum ether and recrystallized from ethanol-ether to yield 2-(3-pyridyl)-3-[5-(ethoxycarbonyl)-pentyl]-indole hydrochloride, m.p. 145°-150°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:25]([CH3:34])=[N:26][C:27]([N+:31]([O-:33])=[O:32])=[CH:28][C:29]=2[CH3:30])[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:34][C:25]1[C:24]([O:23][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:20]=2)=[C:29]([CH3:30])[CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[N:26]=1
Reactant: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (237 mg, 1.139 mmol), 3-((2-chloropyridin-4-yl)oxy)-2,4-dimethyl-6-nitropyridine (245 mg, 0.876 mmol), K2CO3 (363 mg, 2.63 mmol) and Pd(PPh3)4 (51 mg, 0.044 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, heated at 80° C. for 24 h, then cooled to RT. The mixture was diluted with EtOAc. Washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford 2,4-dimethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (100% yield assumed) which was used without further purification. MS (ESI) m/z: 326.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.C([Cl:19])(=O)C>>[Cl-:19].[CH3:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[N+:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Cc1ccccc1C=O
Reactant: CC(=O)Cl
Product: Cc1ccccc1C=[N+]1CCCCC1
Product: [Cl-]

Procedure:
The reaction of 9.5 ml (0.096 mol) piperidine and 4.7 ml (0.040 mol) 2-methylbenzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 2.4 ml (0.040 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 5.8 g (corresponding to 65% of the yield calculated by theory) 1-(2-methyl-benzylidene)-piperidinium chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][OH:14])[C:9]([O:11][CH3:12])=[O:10].[C:15](=O)(O)[O-].S(OC)(OC)(=O)=O.O>C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=NO)c1ccccc1O
Reactant: O=C([O-])O
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1O

Procedure:
2.4 g (0.0106 mol) of methyl 2-(2-hydroxyphenyl)-2-hydroxyimino-acetate (Example VII-1a from process step 3; HPLC: 17.1% E, log p=0.95; 68.9% Z, log p=1.68) in 60 ml of acetonitrile are heated under reflux with 1.08 g (0.011 mol) of potassiun bicarbonate and 1.55 g (0.0123 mol) of dimethyl sulphate for 10 hours. The reaction mixture is poured into water and extracted with diethyl ether, and the solvent is distilled off under reduced pressure. This gives 2.1 g of crude product which is chromatographed over silica gel using a mixture of 7 parts of n-hexane and 3 parts of acetone. This gives 1.6 g of product which, according to HPLC, contains 36.9% of methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.39.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9](=[CH:11][CH2:12][CH2:13]/[C:14](=[CH:16]/[CH2:17]O)/[CH3:15])[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH3:6][C:5]([CH2:7][CH2:17][CH:16]=[C:14]([CH3:15])[CH2:13][CH2:12][CH:11]=[C:9]([CH3:10])[CH3:8])=[CH:4][C:2](=[O:1])[CH3:3]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(=O)C=C(C)CCC=C(C)CCC=C(C)C
Temperature: 200 °C
Yield: 78 %

Procedure:
A mixture of 200 parts of mesityl oxide, 200 parts of geraniol and 400 parts of tetrahydrofuran has 0.01 part of p-toluenesulfonic acid added to it and the whole is heated for 3 hours at 200°C at 50 atmospheres pressure. The reaction mixture is distilled and 133 parts of 4,8,12-trimethyl-3,7,11-tridecatrien-2-one is obtained. At a conversion of 52% the yield is 78% of theory based on geraniol.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([Si:14]([CH3:29])([CH3:28])[O:15][CH2:16][CH2:17]OC1C=CC(I)=CC=1C=O)(C)(C)C.C[Si]([NH:34][Si](C)(C)C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.C(N(CC)CC)C.C(Cl)(=O)C>>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[N:34][C:16]([O:15][Si:14]([CH3:29])([CH3:28])[CH3:10])=[CH2:17])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Reactant: O=Cc1cccc(I)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(N=Cc1cccc(I)c1)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 190b, 3-iodo-benzaldehyde (0.9 g, 3.88 mmol) (Aldrich) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (0.62 g, 3.88 mmol), n-butyllithium (2.5 M, 1.6 mL, 3.88 mmol), trimethylsilyl chloride (0.42 g, 3.88 mmol), triethylamine (0.53 g, 5.28 mmol) and acetyl chloride (0.41 g, 5.28 mmol) to give 1-(3-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])=[CH:20][CH:19]=2)=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[C:32]([O-])([O-])([O-])[O:33][CH2:34][CH3:35]>>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]2[C:7]3[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=[C:32]2[O:33][CH2:34][CH3:35])=[CH:19][CH:20]=1)#[N:31]
Reactant: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC([O-])([O-])[O-]
Solvent: CC(=O)O
Product: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.37 g) was added to a solution of methyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate (2.03 g) in ethyl orthocarbonate (5 ml), and the mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated to dryness and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water. The solvent was evaporated in vacuo to give crystals. Recrystallization from ethyl acetate-hexane afforded colorless crystals (2.01 g, 86%), m.p. 168.5–169.5° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH:6](NC(C)C)(C)[CH3:7].[C:13]([O:17][C:18]([N:20]1[CH2:28][CH2:27][CH:23]([C:24]([O-:26])=[O:25])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(Br)C=C.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH2:3]([CH:21]1[CH2:22][CH:23]([C:24]([O:26][CH2:6][CH3:7])=[O:25])[CH2:27][CH2:28][N:20]1[C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])[CH:2]=[CH2:1]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C=CCBr
Product: C=CCC1CC(C(=O)OCC)CCN1C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
70 cm3 of a solution of butyllithium in hexane (2.5M concentration) were added, with stirring and under an inert atmosphere, to 150 cm3 of tetrahydrofuran cooled to a temperature in the region of −70° C., followed by addition of 50 cm3 of tetrahydrofuran and 23 cm3 of diisopropylamine predissolved in 300 cm3 of tetrahydrofuran. After a further addition of 50 cm3 of tetrahydrofuran, the mixture was stirred for 15 minutes at about −70° C., followed by addition of 45.15 g of ethyl de 1-(tert-butyloxycarbonyl)isonipecotate predissolved in 400 cm3 of tetrahydrofuran, and finally 50 cm3 of this same solvent. After stirring the mixture for 1 hour at a temperature in the region of −70° C., 16.7 cm3 of allyl bromide predissolved in 150 cm3 of tetrahydrofuran were added and the mixture was then warmed to about 20° C. and stirred for 17 hours. The mixture was poured into 200 cm3 of saturated aqueous ammonium chloride solution and then extracted with about 2 liters of ethyl acetate.