Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C[O-].[Na+].O.O.C([O-])(=O)C.[Zn+2:18].C([O-])(=O)C>CO>[Zn:18].[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CC(C)[C@H](N)C(=O)O
Agent: C[O-]
Solvent: CO
Solvent: O
Product: [Zn]

Procedure:
L-valine (2.00 g, 17.1 mmol) was added to an MeOH solution of NaOMe (prepared with Na: 0.39 g, MeOH: 50 ml) at 0° C. and stirred. An MeOH solution (30 ml) of zinc acetate dihydrate (1.90 g) was then slowly dropwise added thereto at room temperature. After stirring for 6 hours at that same temperature, the precipitated crystal (in suspension) recovered by filtration, washed with water, air dried, and then dried under a reduced pressure (5 mmHg, 80° C.).
Reaction SMILES: [Li]CCCC.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH:37]([C:39]1[CH:40]=[N:41][N:42]([CH:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:43]=1)=O>C1COCC1>[CH:37]([C:39]1[CH:40]=[N:41][N:42]([CH:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:43]=1)=[CH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCOC(=O)C(c1ccccc1)n1cc(C=O)cn1
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC=Cc1cnn(C(C(=O)OCC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of n-BuLi (127 mL, 254 mmol, 2.0M in hexanes) was added dropwise to a suspension of n-undecyl-triphenylphosphoniumbromide (121.6 g, 244 mmol, obtained from triphenylphosphine and undecylbromide) in 500 mL THF at -78° C. under an atmosphere of N2. The resulting orange solution was stirred for 1 hour before a solution of ethyl (±)-4-formyl-α-phenyl-1H-pyrazole-l-acetate in 250 mL THF was added dropwise. Warmed to room temperature and stirred for 16 hours. Quenched by adding 150 mL water and concentrating in vacuo. The residue was partitioned between water and dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give an oily tan solid. Triturated with boiling hexanes and filtered to remove triphenylphosphine oxide. The filtrate was concentrated and chromatographed (10% EtOAc/hexanes on silica) to give the title compound as a yellow oil, a 1:2 E/Z mixture (44.4 g, 50%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[C:20](#[N:23])[CH:21]=[CH2:22]>>[C:20]([CH2:21][CH2:22][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)#[N:23]
Reactant: C=CC#N
Reactant: c1ccc(N2CCOCC2)c(N=C2CCCCN2)c1
Product: N#CCCN1CCCCC1=Nc1ccccc1N1CCOCC1

Procedure:
The product of Example 1 (2.6 g) was reacted at room temperature with excess acrylonitrile (5 ml). The product was recrystallised from ethylacetate to give 4-{2-[1-(2-cyanoethyl)-2-piperidinylideneamino]phenyl}morpholine. (m.p. 148° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23](Br)=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.[Cu][C:37]#[N:38].[Cu](C#N)C#N.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23]([C:37]#[N:38])=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: N#C[Cu]
Reactant: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2Br)c1=O
Agent: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2C#N)c1=O
Temperature: 100 °C
Yield: 43 %

Procedure:
1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (54.3 mg, 0.10 mmol) was added to a tared reaction vial with magnetic stir bar and weighed. This was dissolved in 2 mL dimethylformamide and copper(I) cyanide (18.0 mg, 0.20 mmol) was weighed out and added. The reaction was heated at 100° C. for three hours, recharged with additional copper cyanide (37.7 mg, 0.42 mmol) and heated overnight at 115° C. The reaction was diluted into ethyl acetate and washed in succession with brine and water to remove DMF. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated onto silica. Product was purified by column chromatography. After drying, 21.1 mg was obtained of the title compound (43% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[NH2:10][C:11]1[CH2:16][N:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1>>[CH3:17][N:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11]([NH:10][C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])[CH2:16]1
Reactant: CC1=CN(C)CC(N)=N1
Reactant: Cc1oncc1C(=O)Cl
Product: CC1=CN(C)CC(NC(=O)c2cnoc2C)=N1

Procedure:
from 5-methylisoxazole-4-carbonyl chloride and 2-amino-4,6-dimethylpyrazine.
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.Cl[C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([F:32])[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][N:6]([C:22]2[CH:23]=[C:24]([CH:29]=[C:30]([F:32])[CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])[CH2:5][C@H:4]1[O:3][CH3:2])=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(F)cc(Cl)c1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: COC(=O)c1cc(F)cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Yield: 34.5 %

Procedure:
The same operation as in Example (42a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (165 mg, 0.55 mmol), methyl 3-chloro-5-fluorobenzoate (103 mg, 0.55 mmol), palladium acetate (12.3 mg, 0.05 mmol), BINAP (68.3 mg, 0.11 mmol) and cesium carbonate (536 mg, 1.65 mmol), to obtain 79 mg of the title compound as a yellow oily substance (35%).
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C[N:61]1CC[O:64][CH2:63][CH2:62]1.NCCO>CN(C=O)C>[OH:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19]=3[C:29]([F:30])([F:32])[F:31])[O:15][N:14]=2)=[CH:11][CH:12]=1)([CH3:6])[C:3]([NH:61][CH2:62][CH2:63][OH:64])=[O:5]
Reactant: CN1CCOCC1
Reactant: CC(O)(C(=O)O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: NCCO
Solvent: CN(C)C=O
Product: CC(O)(C(=O)NCCO)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 14.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (Int-XV, 30 mg, 0.067 mmol), BOP (29.8 mg, 0.067 mmol), 4-methylmorpholine (27.3 mg, 0.269 mmol), and 2-aminoethanol (6.17 mg, 0.101 mmol) were added to DMF (1 mL). The reaction mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.0 min) to provide (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide (6 mg, 9.83 μmol, 14.59% yield): LCMS=489.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.21 (2 H, m), 7.53-7.92 (7 H, m), 3.60 (2 H, td, J=5.61, 3.74 Hz), 3.33-3.43 (2 H, m), 1.80 (3 H, s); HPLC peak RT=9.0 min (Method A).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9][NH:10][NH2:11])[CH2:2][CH2:3][CH3:4].C([O:17][C:18](=O)[CH:19]=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:11][N:10]([CH2:9][C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)[C:18](=[O:17])[CH:19]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: CCCCOc1cccc(CNN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCCCOc1cccc(Cn2[nH]c(N)cc2=O)c1
Reaction time: 2 h

Procedure:
18 g of 3-n-butoxybenzylhydrazine were added dropwise, under nitrogen, to a solution of 14.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 180 ml of ethanol. After stirring for 2 hours, the mixture was left to stand overnight. The compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 110°, 8 g (33%).
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[OH:1][CH:2]([CH2:24][O:25][C:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
A solution of 9 (28 mmol) in 80 ml of dichloromethane/pyridine (1:1) is added dropwise with triphenylmethyl chloride (36 mmol) and stirred at room temperature for 48 hours. The solvent is removed, and the residue is added twice with 50 ml of toluene and concentrated. The residue is diluted with 100 ml of H2O and extracted three times with 50 ml of dichloromethane. The combined organic phases are washed with 50 ml of cold 5% HCl and 50 ml of saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by chromatography on silica gel using heptane/ethyl acetate (2:1). Yield: 81% of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].[CH3:20]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH3:11][N:6]1[CH:5]=[C:4]2[C:8]([CH:9]=[CH:10][C:2]([CH3:20])=[C:3]2[CH:12]2[CH2:14][CH:13]2[CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[N:7]1
Reactant: CB(O)O
Reactant: CC(=O)NCC1CC1c1c(Br)ccc2nn(C)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NCC1CC1c1c(C)ccc2nn(C)cc12
Temperature: 100 °C
Reaction time: 48 h
Yield: 33.4 %

Procedure:
N-{[2-(5-Bromo-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (200 mg, 0.621 mmol) obtained in Example 29, methylboronic acid (74.5 mg, 1.241 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (17.8 mg, 0.0372 mmol), potassium carbonate (206 mg, 1.49 mmol) and tris(dibenzylideneacetone)dipalladium(0) (22.7 mg, 0.0248 mmol) were added to N,N-dimethylformamide (3.1 mL), and the mixture was stirred under nitrogen atmosphere at 100° C. for 2 days, then stirred under heating at 120° C. for 2 days. The reaction solution was diluted with ethyl acetate, and filtered through celite. The obtained filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) and HPLC to give the title compound (53.4 mg, yield 33%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[N:26][N:27]([CH3:34])[C:28]3=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc2c(N)cccc2c1=O
Reactant: CCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Agent: [Ti+4]
Agent: CC[O-]
Product: CCC(CC(O)(C=Nc1cccc2c(=O)n(C)ncc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 29, 265 mg (0.86 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 150 mg (0.86 mmol) of 5-amino-2-methylphthalazin-1-one and 0.42 ml of titanium tetraethoxide are reacted to give 5-{[4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}-2-methylphthalazin-1-one. 410 mg of crude imine are cyclized in the same way as in Example 29 at −20° C. with 3.5 ml (3.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) and subsequent preparative thin-layer chromatography on silica gel with dichloromethane/methanol 9:1 yield 10 mg of product and 8.6 mg of the 8α compound (Example 45).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:23])([CH3:22])[CH2:7][N:8]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:21])(=O)C.[CH:24]1([NH:27][C:28](=[O:46])[C:29]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:32]([CH3:44])=[C:31]([F:45])[CH:30]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.O>[CH:24]1([NH:27][C:28](=[O:46])[C:29]2[CH:34]=[C:33]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[C:9](=[O:21])[N:8]([CH2:7][C:6]([CH3:22])([CH3:23])[CH2:5][OH:4])[CH:17]=[C:16]4[CH:18]=[O:19])[C:32]([CH3:44])=[C:31]([F:45])[CH:30]=2)[CH2:25][CH2:26]1
Reactant: CC(=O)OCC(C)(C)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 101.3 %

Procedure:
A solution of 3-(6-bromo-4-formyl-1-oxoisoquinolin-2(1H)-yl)-2,2-dimethylpropyl acetate (Example 1e, 0.25 g) in DMF (10 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.28 g), Pd-118 (0.024 g) and potassium carbonate (0.31 g) under nitrogen. The resulting mixture was stirred at 70° C. for 6 h. Methanol (10 mL) was added and stirred at room temperature for 1 h. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution with 100% ethyl acetate) to afford the subtitle compound (0.30 g) as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].OCC([C@H]([C@@H]([C@H](CO)O)O)O)=O.C([O-])([O-])=O.[Ca+2]>>[OH:8][C:7]1[C@@H:5]([C@@H:3]([OH:4])[CH2:2][OH:1])[O:6][C:11](=[O:12])[C:9]=1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 20 h

Procedure:
A series of resting cell reactions (0.5 ml reaction mixture in 5 ml reaction tube) was carried out with 2% D-sorbitol or with 2% L-sorbose, and all reaction mixtures further contained 0.3% NaC1, 1% CaCO3 and cells at a final concentration of 5 absorbance units at 600 nanometers (OD600). After 20 h incubation time, G. oxydans DSM 17078 produced 270 mg/l or 670 mg/l of Vitamin C, respectively from 2% D-sorbitol or 2% L-sorbose, respectively. In comparison, strain G. oxydans DSM 17078-dSMS 05 produced 1540 mg/l or 1990 mg/l of Vitamin C, respectively.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[CH:17]=[N:16][C:15]4[C:10]3=[N:11][C:12]([NH:23][C@H:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH3:25])=[N:13][C:14]=4[C:18](OCC)=[O:19])[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[CH:17]=[N:16][C:15]4[C:10]3=[N:11][C:12]([NH:23][C@H:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH3:25])=[N:13][C:14]=4[CH2:18][OH:19])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(N[C@@H](C)c2ccc(F)cc2)nc2c1ncn2-c1cc(C2CC2)[nH]n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Nc1nc(CO)c2ncn(-c3cc(C4CC4)[nH]n3)c2n1)c1ccc(F)cc1
Yield: 331.5 %

Procedure:
A solution of ethyl 9-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(S)-1-(4-fluorophenyl)ethylamino]-9H-purine-6-carboxylate (Example 11; 0.03 g, 0.069 mmol) in THF (3 ml) was cooled to 0° C. To which was slowly added lithium aluminium hydride (1.0 M in THF, 0.076 ml, 1.1 eq.). The reaction mixture was stirred at 0° C. for 30 minutes, at which point sodium sulfate decahydrate was added until bubbling stopped. The reaction was then filtered through a plug of celite, washed with THF (3×30 ml), and concentrated. The resulting residue was purified by column chromatography (DCM:MeOH=15:1) to give the title compound (0.09 g, 33%). NMR (400 MHz, CDCl3) 8.27 (s, 1H), 7.39-7.36 (m, 2H), 7.03-6.98 (m, 2H), 6.32 (s, 1H), 5.65-5.64 (m, 1H), 5.10-5.07 (m, 1H), 5.03 (s, 2H), 3.87-3.85 (m, 1H), 1.93-1.88 (m, 1H), 1.57 (d, J=6.8 Hz, 3H), 1.08-1.06 (m, 2H), 0.81-0.77 (m, 2H). MS: Calcd.: 393; Found: [M+H]+ 394.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[N:9][CH:10]=1.[C:23]1([C:29]2[C:33]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][NH:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:23]1([C:29]2[C:33]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:31]([CH2:4][C:5]3[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)=[CH:7][CH:6]=3)[N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 2-(5-chloromethyl-2-pyridyloxymethyl)quinoline (498 mg), ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (428 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-phenyl-1-[6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (651 mg, yield: 76%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Cl.[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:8]([N:19]2[CH2:20][CH2:21][CH:16]([C:15]([F:23])([F:22])[F:14])[CH2:17][CH2:18]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from 4,5-dichloro-2-nitro-aniline (500 mg, 2.4 mmol), 4-trifluoromethyl-piperidine hydrochloride (550 mg, 2.9 mmol) and K2CO3 (830 mg, 6.0 mmol) in DMSO (10 mL) in analogy to example 3, step (a).
Reaction SMILES: C[O-].[Na+].[Na].[C:5](OC)(=[O:9])[C:6]([CH3:8])=O.[S:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>CO>[OH:9][C:5]1[C:6]([CH3:8])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[S:12][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CSCC(=O)OC
Reactant: COC(=O)C(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sc(C(=O)OC)c(O)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of sodium methoxide from sodium (5.4 g) in methanol (100 ml) was added a solution of methyl pyruvate (24 g) and dimethyl thiodiacetate (41.83 g) in methanol (50 ml). The reaction was stirred at room temperature for 2 days, and then added to ice water (500 ml). After neutralization with 5N HCl and extraction with chloroform, the organics were washed with brine, dried over anhydrous magnesium sulphate, filtered and the solvent evaporated to give a solid, m.p 95°-97° ex methanol.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH:9](Cl)[CH2:10][C:11](Cl)(Cl)[CH3:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+]>C(O)C>[C:10]([C@H:9]1[C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]1([CH3:16])[CH3:1])#[C:11][CH3:12]
Reactant: CCOC(=O)CC(C)(C)C(Cl)CC(C)(Cl)Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC#C[C@H]1[C@H](C(=O)OCC)C1(C)C
Yield: 67.8 %

Procedure:
Hereinafter, the present invention is explained in more detail below referring to production example and reference examples but the present invention should not be limited in the following examples. Example 1 (preparation example of the present compound) A mixture solution of 27.5 g of ethyl 3,3-dimethyl-4,6,6-trichloroheptanoate and 204 g of a 20% ethanol solution of sodium ethoxide was stirred under reflux for 48 hours. The reaction solution was poured into ice and extracted with 500 ml of ethyl acetate 3 times. The combined extract was washed with 500 ml of water twice, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was distilled under reduced pressure to afford 11.6 g of ethyl trans-3-(1-propynyl)-2,2-dimethylcyclopropanecarboxylate (yield: 64%).