Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[NH2:23][C:24]1[CH:29]=[C:28]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(N)c3)c(F)cn2c1=O
Yield: 24.6 %

Procedure:
Ethyl 8-(3-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (102.5 mg, 0.32 mmol) and (3-amino-phenyl)-boronic acid (54.8 mg, 0.40 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (30 mg, 25%). ESI-MS m/z: 381 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
5-chloro-1H-indole (2.15 g; 13.90 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.08 g; 15.29 mmol) and potassium hydroxide (3.67 g; 55.6 mmol) were added in MeOH (50 mL) and heated to reflux for 24 hours. The reaction mixture was cooled to room temperature and poured into ice water (70 mL). The reaction mixture was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulphate and concentrated to give 4.52 g (98%) of tert-butyl 4-(5-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23][CH2:24][C:25]([OH:27])=O.[NH2:28][C@@H:29]1[C:36](=[O:37])[N:35]2[C@@H:30]1[S:31][CH2:32][C:33](/[CH:41]=[C:42]1/[C:43](=[O:51])[N:44]([CH2:47][CH:48]3[CH2:50][CH2:49]3)[CH2:45][CH2:46]/1)=[C:34]2[C:38]([OH:40])=[O:39]>CN(C)C=O>[CH:48]1([CH2:47][N:44]2[CH2:45][CH2:46]/[C:42](=[CH:41]\[C:33]3[CH2:32][S:31][C@H:30]4[N:35]([C:36](=[O:37])[C@H:29]4[NH:28][C:25](=[O:27])[CH2:24][S:23][C:14]4[CH:15]=[CH:16][C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH:13]=4)[C:34]=3[C:38]([OH:40])=[O:39])/[C:43]2=[O:51])[CH2:50][CH2:49]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1ccc2ccccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CSc1ccc2ccccc2c1)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12

Procedure:
With 167.0 mg (1.03 mmol) 1,1′-carbonyldiimidazole, 225.0 mg (1.03 mmol (naphthalen-2-ylsulfanyl)-acetic acid and 300.0 mg (0.86 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 4 ml N,N-dimethylformamide.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1(S([N:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]4[CH:42]=[CH:41][C:40]([CH2:43][N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[CH:39][CH:38]=4)=[CH:34][CH:35]=3)[C:30]3[CH:50]=[C:51]([Cl:54])[CH:52]=[N:53][C:29]2=3)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:54][C:51]1[CH:52]=[N:53][C:29]2[NH:28][C:36]3[C:31]([C:30]=2[CH:50]=1)=[CH:32][C:33]([C:37]1[CH:38]=[CH:39][C:40]([CH2:43][N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:41][CH:42]=1)=[CH:34][CH:35]=3
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(CN4CCOCC4)cc3)cc2c2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Clc1cnc2[nH]c3ccc(-c4ccc(CN5CCOCC5)cc4)cc3c2c1
Yield: 61 %

Procedure:
At Room Temperature and Under Inert Atmosphere, 1.0 M TBAF in THF (1.75 mL, 5 equiv.) was added a solution of 30 (181 mg, 0.35 mmol) in anhydrous THF (16 mL). The solution was refluxed for 4 h. The resulting mixture was then cautiously quenched at 0° C. with H2O. The mixture was extracted with EtOAc (3×20 mL). The resulting organic layers were dried over MgSO4, filtered, and solvents were removed under reduced pressure. The crude product was purified by flash chromatography (eluent: CH2Cl2/EtOAc 7:3 to EtOAc) to afford R313 in 61% yield as a yellow solid; 1H-NMR (300 MHz, DMSO-d6): δ 12.05 (bs, 1H), 8.75 (d, 1H, J=2.4 Hz), 8.55 (d, 1H, J=1.7 Hz), 8.43 (d, 1H, J=2.4 Hz), 7.81 (dd, 1H, J=1.7, 8.7 Hz), 7.70 (d, 2H, J=8.1 Hz), 7.58 (d, 1H, J=8.7 Hz), 7.41 (d, 2H, J=8.1 Hz), 3.59 (t, 4H, J=4.4 Hz), 3.51 (s, 2H), 2.39 (t, 4H, J=4.4 Hz); 13C-NMR (75 MHz, DMSO-d6): δ 150.6 (C), 144.2 (C), 139.5 (C), 139.2 (C), 136.3 (C), 132.3 (C), 129.6 (2 CH), 128.3 (C), 126.5 (2 CH), 126.4 (CH), 121.8 (C), 120.2 (C), 119.8 (CH), 116.7 (C), 111.9 (CH), 66.2 (2 CH2), 62.1 (CH2), 53.2 (2 CH2); MS (ESI) m/z 378 [M+H+]
Reaction SMILES: [I-:1].[Na+].[CH3:3][C:4](=O)[CH2:5][CH3:6]>>[CH2:3]([C:4]1[CH:3]=[CH:3][C:4]([CH2:5][CH2:6][I:1])=[CH:6][CH:5]=1)[CH2:4][CH2:5][CH2:6][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [I-]
Reactant: CCC(C)=O
Agent: [Na+]
Product: CCCCCCCCc1ccc(CCI)cc1
Yield: 80 %

Procedure:
Sodium iodide (18.13 g) was added to a solution (500 ml) of the above-mentioned compound (31.5 g) in 2-butanone and the mixture was refluxed under heating for 4 hours. The reaction mixture was concentrated and poured into ice water. The resultant mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate: hexane=1:20) to give 27.5 g of the subject compound as an oily substance (yield 80%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:10]1[CH:2]=[CH:3][CH:4]=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1c(F)cccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 41, substituting 6-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid. 1H NMR (400 MHz, CD3OD): 7.96 (s, 2H), 7.87-7.82 (m, 1H), 7.70 (td, J=8.1, 5.1 Hz, 1H), 7.59 (ddd, J=9.7, 8.4, 1.4 Hz, 1H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[Cl:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>CC(C)=O>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)=[CH:20][C:19]=1[Cl:25])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Nc2ccc(OCc3ccccc3)c(Cl)c2)n1
Temperature: 2.5 °C

Procedure:
To cyanuric chloride (1.208 g, 6.4 mmol) dissolved in acetone (10 mL) stirring at 0-5° C., was added a solution of 160a (1.505 g, 6.4 mmol) in acetone (15 mL) followed by the addition of 2.5 N NaOH (2.6 mL, 6.4 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 h under nitrogen. The reaction mixture was poured over crushed ice and neutralized with 5% NaOH. The solid that formed was collected by vacuum filtration and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a light beige solid (160b, 1.46 g, 60%), mp 145° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 111.2 min, 97.1% purity.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:21].C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[C:7]([O:9][CH2:10][C:11](=[O:13])[N:25]([CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)COC(=O)/C=C/C(=O)OC
Yield: 12.5 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetic acid (23) (0.50 g, 2.65 mmol) was activated with oxalyl chloride (0.27 mL, 0.40 g, 3.15 mmol) in dichloromethane (DCM) at ca. 0° C. and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). A DCM solution of the freshly prepared crude acid chloride was reacted ca. 0° C. (ice bath) with N-benzyl glycine ethyl ester (Bn-Gly-OEt) (0.61 g, 3.18 mmol) in DCM and an excess of diisopropylethylamine (DIEA) in the presence of a catalytic amount of 4-(N,N-dimethyl)aminopyridine (DMAP). After aqueous work-up and isolation, and purification by silica gel flash chromatography afforded 0.12 g (13% yield) of the title compound (36) as a white solid. 1H NMR (CDCl3, 400 MHz, all rotamers): δ 7.37-7.20 (m, 5H), 6.97-6.86 (m, 2H), 4.94-4.83 (2s, 2H), 4.63-4.55 (2s, 2H), 4.18-4.14 (m, 2H), 4.04-3.88 (2s, 2H), 3.79 (s, 3H), 1.24-1.20 (m, 3H). MS (ESI): m/z 364.15 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH2:3]1.[Cl:17][C:18]1[N:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:17][C:18]1[N:19]=[C:20]([C:25]([NH:1][CH:2]2[CH2:5][N:4]([C:6]3[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=3)[CH2:3]2)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]
Reactant: CCOC(=O)c1sc(N2CC(N)C2)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 63.3 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-(3-aminoazetidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (218b) (144 mg, 0.60 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (104 mg, 0.60 mmol), WSC hydrochloride (343 mg, 1.79 mmol), 1-hydroxybenzotriazole (81 mg, 0.60 mmol) and N-methylmorpholine (0.13 mL, 1.19 mmol), to obtain 151 mg of the title compound as a white solid (64%).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([Cl:33])[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=O)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[Cl:33][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:10]2([CH3:17])[CH2:9][CH2:8][C:7]3[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([OH:4])[C:6]=3[CH3:34])[O:11]2)=[CH:25][CH:24]=1)[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC(Cl)C(=O)O)cc1)O2

Procedure:
0.48 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate was dissolved in a mixture of 5 ml of 99.5% ethanol and 2 ml of tetrahydrofuran. To this was added dropwise, under a nitrogen stream at 8°-10° C., a solution prepared by dissolving 133 mg of sodium hydroxide in 1 ml of 99.5% ethanol. When the whole of the solution had been added, the mixture was reacted for a further 18 hours at 0°-5° C., after which it was neutralized by adding to it dropwise a solution prepared by dissolving 0.37 g of concentrated hydrochloric acid in 1 ml of 99.5% ethanol. The solvent was then distilled off from the mixture under reduced pressure. The pale reddish oil thus separated was extracted with chloroform, and the chloroform extract was washed with water and then dried over anhydrous sodium sulfate. The crude product obtained by distilling the chloroform off under reduced pressure was subjected to silica gel column chromatography, and the desired 2-chloro-3-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]propionic acid was obtained from the fractions eluted with a 10:1 by volume mixture of benzene and ethyl acetate. Rf value on thin layer chromatography: 0.4 (tailing) [silica gel; developing solvent; benzene:99.5% ethanol=6:1 by volume]. Melting point 148°-149° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([OH:30])([CH2:23][CH2:24][CH2:25][C:26]([CH:28]=[CH2:29])=[CH2:27])[CH3:22].CC(C)=CC(O)/C=C(/C=C)\C>>[CH3:27][C:26]1([CH:28]=[CH2:29])[CH2:25][CH2:24][CH2:23][C:21]([CH3:20])([CH3:22])[O:30]1
Reactant: C=CC(=C)CCCC(C)(C)O
Agent: C=C/C(C)=C/C(O)C=C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CC1(C)CCCC(C)(C)O1
Yield: 11.7 %

Procedure:
Example 12 was repeated except that only 0.105 g triphenylphosphine was used and 22.6 g of N,N-diethyl-7-hydroxygeranylamine was used as the amine. After 9 hours at 120° there was obtained a yield of 11.7% 2,6,6-trimethyl-2-vinyltetrahydropyran, 29.6% myrcenol, 22.2% cis and 17.3% trans-ocimenol.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10]1([CH2:20][CH:21]([C:27]([CH3:29])=O)[C:22](OCC)=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:27]([CH3:29])=[C:21]([CH2:20][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)[C:22](=[O:23])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(C)=O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: Cc1c(Cc2cccc3ccccc23)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (0.47 g) and ethyl 2-(1-naphtylmethyl)acetoacetate (1.00 g) in ethanol (20 ml) was treated with dry HCl at 0° C. for 3 hours and the solution kept at that temperature overnight. Solvent was evaporated and the precipitate triturated with water and recrystallized from isopropanol-water (1:1). Yield 0,96 g (78%). Melting point 275-280° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:6]([C:13]([O:15]CC)=O)=[C:7]([CH:11]=O)[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].O.[NH2:29][NH2:30]>C(O)C.C(O)(=O)C>[C:1]([C:4]1[CH:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:6]2[C:13](=[O:15])[NH:30][N:29]=[CH:11][C:7]=2[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(C)=O)C1c1ccc(C#N)cc1OC
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C#N)ccc1C1C(C(C)=O)=C(C)Nc2cn[nH]c(=O)c21

Procedure:
208 mg (0.565 mmol) of ethyl 5-acetyl-4-(4-cyano-2-methoxyphenyl)-2-formyl-6-methyl-1,4-dihydropyridine-3-carboxylate and 41.5 mg (0.830 mmol) of hydrazine hydrate are taken up in 6.6 ml of ethanol/acetic acid (10:1) and reacted at 100° C. for 5 h. The volatile components are removed in a rotary evaporator, and the residue is taken up in acetonitrile. The precipitated product is filtered off and dried under high vacuum. 66 mg (34.7% of theory) of the title compound are obtained.
Reaction SMILES: C([Al](CC)CC)C.[CH3:8][C:9](=[CH:11][CH2:12][CH2:13][CH:14]([CH2:16][CH:17]=[O:18])[CH3:15])[CH3:10].C(OC(=O)C)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:15][C@H:14]1[CH2:16][C@@H:17]([OH:18])[C@H:11]([C:9]([CH3:10])=[CH2:8])[CH2:12][CH2:13]1
Reactant: CC(C)=CCCC(C)CC=O
Agent: CC[Al](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
8.0 g (13.6 mmol) of the ligand Ia2-3 were dissolved in 140 ml of toluene at room temperature under argon. 4.78 ml (9.09 mmol) of a 25% strength triethylaluminum solution in toluene were added and the mixture was after-stirred for 1 h. The resulting catalyst suspension was cooled to 0° C. and, over the course of 5 h, a mixture of 70.0 g (0.45 mol) of citronellal and 0.7 g (6.86 mmol, 1% by weight with regard to citronellal) of acetic anhydride was added. The mixture was after-stirred for 1 h at 0° C. and for 12 h at room temperature. At the end of the experiment, 100 ml of 8% strength sodium hydroxide solution were added and the phases separated. The organic phase was dried with sodium sulfate and the solvent was removed under reduced pressure. The crude product was distilled at 1 mbar over a short column. At a top temperature of 58° C., 68.4 g of isopulegol with the following composition (in each case GC area %) were obtained: isopulegol: 98.4%, neo-isopulegol: 0.6%, neoiso-isopulegol: 0.4%. This corresponds to a chemical yield of 97%, based on all diastereomers and a diastereoselectivity of 99:1 (isopulegol: other diastereomers).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:14])[NH:12][CH3:13])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:14])[NH:12][CH3:13])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: CNC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 2,6-dichloro-4-(methylcarbamoyl)benzoic acid (400 mg, 1.6 mmol) and thionyl chloride (1.91 g, 16 mmol) in dichloromethane (10 mL) was stirred at 50° C. for 5 hours. The reaction mixture was concentrated under rotary evaporator and used as such for next step.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)=[O:24]
Reactant: N[C@H]1CC[C@H](CO)CC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
(trans-4-Amino-cyclohexyl)-methanol (73 mg, 0.56 mmol) and triethylamine (225□l, 1.61 mmol) were dissolved in dimethylformamide (225 μl) and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol) in dimethylformamide (5 ml) was added. The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between 0.5N HCl (10 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (97.5:2.5:0.25, by volume). The product was triturated with ethyl acetate (3 ml) to give 5-Fluoro-N-(trans-4-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (60 mg) as a white solid.
Reaction SMILES: OO.FC(F)(F)[C:5]([O:7][C:8](=O)[C:9](F)(F)F)=O.[N+:16]([C:19]([N+:25]([O-:27])=[O:26])([C:23]#[N:24])[CH2:20][CH:21]=[CH2:22])([O-:18])=[O:17].P([O-])([O-])(O)=O.[Na+].[Na+]>O.C(Cl)Cl>[N+:16]([C:19]([N+:25]([O-:27])=[O:26])([C:23]#[N:24])[CH2:20][CH:21]=[CH2:22])([O-:18])=[O:17].[N+:16]([C:19]([N+:25]([O-:27])=[O:26])([C:23]#[N:24])[CH2:9][CH:8]1[O:7][CH2:5]1)([O-:18])=[O:17]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: C=CCC(C#N)([N+](=O)[O-])[N+](=O)[O-]
Agent: O=P([O-])([O-])O
Agent: OO
Solvent: O
Solvent: ClCCl
Product: N#CC(CC1CO1)([N+](=O)[O-])[N+](=O)[O-]
Yield: 63 %

Procedure:
A solution of peroxytrifluoracetic acid was prepared from 1.70 ml, 0.062 moles, of 90% hydrogen peroxide, 10.5 ml, 0.074 moles, of trifluoroacetic anhydride, and 12 ml of methylene chloride. This reagent was added over a 35 minute period to a well stirred, boiling mixture of 8.2 g, 0.048 moles, of 1,1-dinitro-1-cyano-3-butene, 50 ml of methylene chloride, and 27.5 g, 0.192 moles, of disodium hydrogen phosphate. After this mild exothermic reaction had subsided, the solution was heated under reflux for 21/2 hours. The resulting mixture was stirred with 75 ml of water until all the inorganic salts had dissolved. The organic layer was separated and the aqueous layer was extracted with 2-10 ml portions of methylene chloride. The combined methylene chloride extracts were washed with 15 ml of 10% sodium bicarbonate solution and dried over magnesium sulfate. The solvent was removed at reduced pressure and the residual liquid was fractionated through a small Vigreux column to yield 3.6 g of unreacted 1,1-dinitro-1-cyano-3-butene and 3.17 g (63% yield) of 1,1-dinitro-1-cyano-3,4-epoxybutane, b.p. 62°-64°/0.005 mm., N25D 1.4672. The infrared spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:18]1([C:17]2[CH:20]=[CH:21][C:14]([OH:13])=[CH:15][CH:16]=2)[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Reaction time: 12 h
Yield: 93.9 %

Procedure:
To a stirred solution of tryptamine (5.0 g, 31.2 mmole) in dry CH2Cl2 (100 mL) at RT was added 4-hydroxybenzaldehyde (3.81 g, 31.2 mmole) followed by dropwise addition of trifluoroacetic acid (7.11 g, 62.4 mmole). After 12 hr, the reaction solution was washed with 10% aqueous NaHCO3 (100 mL), H2O (100 mL) and brine. The organic solution was dried over Na2SO4 and concentrated under reduced pressure to give a yellow oil. The yellow residue was washed with hexanes and dried under high vacuum to afford the title compound (7.74 g, 94%) as a light yellow solid: MS (ES) m/e 265 (M+H)+.