Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[N:8][C:9]=1[CH3:10])[CH2:2][CH3:3].O.[NH2:13][NH2:14]>C(O)C>[CH3:10][C:9]1[N:8]=[CH:7][N:6]=[C:5]([NH:13][NH2:14])[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: NN
Reactant: CCCc1c(C)ncnc1Cl
Solvent: CCO
Solvent: O
Product: CCCc1c(C)ncnc1NN
Temperature: 80 °C

Procedure:
A mixture of 5-propyl-4-chloro-6-methyl-pyrimidine (10 mmol) and hydrazine monohydrate (30 mmol) in ethanol (20 mL) is heated at 80° C. overnight. Solvent is removed in vacuo and the residue solid is in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH2:10].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2](/[CH:10]=[CH:9]/[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Brc1cncc(/C=C/c2ccncc2)c1
Yield: 36 %

Procedure:
A solution of 3,5-dibromopyridine (5.56 g, 23.4 mmol), 4-vinylpyridine (5.1 mL), palladium acetate (1.05 g), tri-o-tolylphosphine (5.00 g) and triethylamine (33 mL) in acetonitrile (100 mL) was heated overnight at 80° C. and concentrated. The residue was partitioned between 5% NaHCO3 and dichloromethane and filtered. The filtrate was separated and the organic layer was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4% methanol/dichloromethane to provide the desired product (2.18 g, 36%). (DCI/NH3) m/e 261, 263 (M+H)+.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:12])C>C(Cl)Cl>[N+:1]1([O-:12])[C:9]2[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OO
Reactant: c1cnc2c(c1)CCC2
Solvent: ClCCl
Product: [O-][n+]1cccc2c1CCC2
Reaction time: 12 h

Procedure:
N-oxide formation also was performed under the following conditions. To a 6,7-dihydro-5H-[1]pyrindine solution in DCM at 0° C. was added peracetic acid (3 mL, 32% in AcOH), and the reaction was slowly allowed to come to rt and stirred for 12 h. The reaction mixture was diluted with DCM (5 mL) and washed with water, aq NaHCO3, brine, then dried over Na2SO4, filtered and concentrated to afford desired 6,7-dihydro-5H-[1]pyrindine 1-oxide (0.6 g). LCMS (m/z): 136.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][C:9]1[CH:17]=[CH:16][C:12]([NH:13][CH:14]=[O:15])=[CH:11][CH:10]=1.Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[C@H:19]([CH3:25])[N:13]([CH:14]=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:4]2[NH:3][CH:7]=[CH:6][N:5]=2)=[CH:17][CH:16]=1)[CH3:24]
Reactant: O=CNc1ccc(Cc2ncc[nH]2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)N(C=O)c1ccc(Cc2ncc[nH]2)cc1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
In a 200 ml round-bottom flask is placed a solution of 8.0 g of p-(1-imidazolylmethyl)aniline prepared as described in Reference Example 3, and 30 ml of formic acid in 80 ml of toluene. The flask was fitted with a water separator, and the solution was refluxed for 4 hours. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 6.4 g of p-(1-imidazolylmethyl)-N-formylaniline as colorless prisms. M.P.: 121°-123° C. To a suspension of 0.48 g of 50% sodium hydride in 50 ml of dry dimethylformamide was added 2.01 g of the formylaniline and mixture was heated to 100° C. A solution of 1.81 g of ethyl α-bromopropionate in 30 ml of dry dimethylformamide was added to the mixture and the reaction mixture was heated at 100° C. for 16 hours. After removal of the solvent under reduced pressure, 50 ml of dichloromethane was added to the residue, and the solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 1.58 g of N-formyl-N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester as a pale brown oil. Then, a solution of 1.58 g of the resulting ester and 5 ml of concentrated hydrochloric acid in 50 ml of ethanol was stirred for 40 hours at room temperature. After concentration under reduced pressure, the residual solid was recrystallized from ethanol-diethyl ether to give 1.18 g of N-[p-(1-imidazolylmethyl)phenyl]alanine ethyl ester dihydrochloride as pale yellow crystals. M.P.: 154°-159° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C@@H:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 112.4 %

Procedure:
To a solution of (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.05 g, 4.54 mmol) in DMF (10 mL) at 0° C. were added N,O-dimethylhydroxylamine hydrochloride (1.36 g, 13.62 mmol), DIEA (3.9 mL, 22.7 mmol), HBTU (1.89 g, 4.99 mmol) and HOBt (0.67 g, 4.99 mmol). The resulting solution was warmed to rt and stirred until no starting material remained (˜2 h). The mixture was diluted with H2O (10 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with 1 N aq HCl (10 mL), 1 N aq NaOH (3×10 mL), water (2×10 mL) and brine (10 mL), and dried over Na2SO4. The solvent was removed under vacuum to give (R)-t-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.40 g, quant.), which was used for the next step without further purification; 1H NMR (400 MHz, CDCl3) δ: 4.36 (br, 1 H), 4.08 (m, 1 H), 4.00 (d, 1 H), 3.84 (m, 1 H), 3.76 (s, 3 H), 3.58 (m, 1 H), 3.20 (s, 3 H), 3.04 (m, 2 H), 1.44 (s, 9 H); MS m/z 297 (M+Na+).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][C:2]1=[O:9].F[B-](F)(F)F.[CH3:15][O+](C)C>ClCCl>[CH3:15][O:9][C:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][N:1]=1
Reactant: O=C1CCC=CCCN1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NCCC=CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a sample of 103 mg (0.822 mmol) of 1H,3H,4H,7H,8H-azocin-2-one in 5 mL of dichloromethane was added 183 mg (1.234 mmol) of trimethyloxonium tetrafluoroborate. The reaction was stirred at room temperature for 16 h, after which time it was diluted with 15 mL of methylene chloride and extracted twice with 5 mL of saturated aqueous NaHCO3 and once with 5 mL of brine. The organic layer was dried over MgSO4, filtered, and the concentrated under reduced pressure. The 8-methoxy-2H,3H,6H,7H-azocine thus produced (92 mg) was used without purification in the next reaction. 1H NMR (500 MHz, CDCl3): δ 5.82 (m, 1H), 5.69 (m, 1H), 4.22 (s, 3H), 4.04 (q, 2H, J=6 Hz), 3.03 (t, 2H, J=6 Hz), 2.73 (br apparent q, 2H, J=6 Hz), 2.63 (apparent q, 2H, J=6 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[CH:13]([S:17][CH:18](S(C)=O)C)[S:14]([CH3:16])=[O:15].CO>C1COCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[C:13](/[S:14]([CH3:16])=[O:15])\[S:17][CH3:18]
Reactant: COc1cccc(C=O)c1Cl
Reactant: CC(SC(C)S(C)=O)S(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(/C=C(\SC)S(C)=O)c1Cl

Procedure:
To a solution of 2-chloro-3-methoxybenzaldehyde (1.74 g, 10.0 mmol, 1.0 eq.) and methyl(methylsulfinyl)methyl sulfide (1.72 mL, 16.1 mmol, 1.6 eq.) in THF (9 mL), benzyltrimethylammonium hydroxide solution in methanol (2.3 mL, 10.0 mmol, 1.0 eq.) was added. The resulting solution was refluxed for 18 hours. The solvent was removed in vacuo. The residue was taken up in AcOEt and washed with 1M aq. HCl soln., water, and sat. aq. NaCl soln. The org. layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane+20% AcOEt to Heptane+65% AcOEt) to yield 2-chloro-1-((E)-2-methanesulfinyl-2-methylsulfanyl-vinyl)-3-methoxy-benzene as a pale orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.C1COCC1.O[Li].O.Cl>O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[NH:6]2
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
To a solution of ethyl 4,6-dichloro-1H-indole-2-carboxylate (I-1c: 50 g, 193.72 mmol) in a solvent mixture consisting of THF & water (1:1) (900 mL) was added LiOH.H2O (24.41 g, 581.7 mmol) and the reaction mixture stirred at room temperature for 18h. The solvent (THF) was distilled-off, the residue was diluted with water (400 mL) and acidified with 2N aqueous HCl to pH 6.0. The residue was extracted in to ethyl acetate (4×150 mL), combined organic layer washed with brine (350 ml), dried on anhydrous Na2SO4 and concentrated under reduced pressure to obtain 39 g (87.5%) of 4,6-dichloro-1H-indole-2-carboxylic acid (I-1d) as light brown solid.
Reaction SMILES: [C:1]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1([N:21]=[C:22]=[N:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CCCCCC>[CH:24]1([NH:23][C:22](=[N:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[O:14][N:13]=[C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: ON=C1CCCCCCCCCCC1
Solvent: CCCCCC
Product: C1CCCCCC(=NOC(=NC2CCCCC2)NC2CCCCC2)CCCCC1
Temperature: 50 °C
Reaction time: 23 h
Yield: 43.1 %

Procedure:
A mixture of cyclododecanone oxime (19.73 g, 100 mmol), dicyclohexylcarbodiimide (20.63 g, 100 mmol) and potassium-t-butylate (0.12 g) in hexane (75 ml) is stirred 23 h at 50° C. under argon. The mixture is then allowed to crystallize overnight at −18° C. The solid is filtered off and recrystallized from dichloromethane-hexane to afford 17.4 g of the title compound as white solid, mp. 108-111° C.
Reaction SMILES: COC1C=C([C:11](=O)[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3CCC[C@H:18]3[CH2:17]2)=O)C=CC=1OC.C(OC(N1CCCC[C@@H]1C(O)=O)=O)(C)(C)C.[F:42][C:43]1[CH:44]=[C:45]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[C:46]([CH2:48][CH2:49][C:50]([OH:52])=O)=[O:47]>>[F:42][C:43]1[CH:44]=[C:45]([C:46](=[O:47])[CH2:48][CH2:49][C:50]([N:19]2[CH2:20][CH2:21][N:16]3[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:17]3[CH2:18]2)=[O:52])[CH:53]=[CH:54][C:55]=1[O:56][CH3:57]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1F
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Agent: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Product: COc1ccc(C(=O)CCC(=O)N2CCN3CCCC[C@@H]3C2)cc1F

Procedure:
93 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using (R)-1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline and 3-(3-fluoro-4-methoxybenzoyl)propionic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=O.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:31][O:30][C:23](=[O:29])[CH2:24][C:25]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:26]=1[CH3:28]
Reactant: COC(=O)CCC(C)=O
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1OC
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCCC3
Yield: 80.2 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dimethoxyphenyl)methanone (0.317 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.330 g (80%) of the title compound as a yellow solid.
Reaction SMILES: O[C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1nc(O)c2c3c(sc2n1)CCCC3
Product: CCOC(=O)Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The ethyl 2-(4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate (9 g, 0.03078 mol) and phosphorous oxy-chloride (45 ml) was refluxed for 4 h. After completion of the reaction, it was concentrated under reduced pressure. The resulting residue was cooled to 0° C. To this, ice water (200 ml) was added and stirred for 30 min. Then it was basified with 25% aq. NH4OH solution slowly to pH=8. It was extracted with DCM (250 ml×3). Organic extracts were washed with water followed by brine. The separated organic layer was dried over anhydrous Na2SO4 and concentrated to get crude product. It was purified by column chromatography by using 100-200 mesh silica gel and DCM as eluent to give ethyl 2-(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate as yellow liquid. Yield—(7 g, 73.16%); 1H-NMR: (400 MHz, CDCl3); δ=4.22-4.16 (q, 2H), 4.02 (s, 2H), 3.06 (m, 2H), 2.85-2.84 (m, 2H), 1.93-1.83 (m, 4H), 1.26-1.23 (t, 3H); LC-MS [M+H]=310.9.
Reaction SMILES: [C@@H:1]12[O:6][C@@H:5]1[CH2:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]2.N1C=CC=CC=1.[FH:17]>ClC(Cl)C>[F:17][C@H:1]1[C@H:5]([OH:6])[CH2:4][C@@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: F
Reactant: COC(=O)C1C[C@@H]2O[C@@H]2C1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](O)[C@H](F)C1
Reaction time: 6 h

Procedure:
To a solution of methyl (1S,5R)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 2.110 mmol) in 3 ml of dichloroethane in a Teflon tube was added hydrogen fluoride-pyridine (0.190 ml, 2.110 mmol and allowed to stir at ambient for 6 hrs. Carefully poured onto 5 ml ice/NaHCO3 and extracted with three portions of DCM. Dried over sodium sulfate followed by Silica gel chromatgraphy with 30-50% Acetone-hexane to give title compound. 1H NMR (500 MHz, CDCl3) δ 1.96-2.03 (m, 1H), δ 2.12-2.32 (m, 3H), δ 2.38-2.52 (m, 1H), δ 3.12 (m, 1H), δ 3.72 (s, 3H), δ 4.34 (m, 1H), δ 4.86 (d of m, J=51.5 Hz, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[Cl-].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][Zn+])=[CH:30][CH:29]=1.O1CCCC1>CCOC(C)=O.[Cl-].[NH4+].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][C:2]2[CH:3]=[C:4]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[CH:30][CH:29]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Bis(tri-t-butylphosphine)palladium(0) (4.38 mg, 0.00857 mmol) and 4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine (0.075 g, 0.17 mmol) were combined in a dry round bottomed flask fitted with a stirbar and sealed with a septum. The flask was evacuated/refilled with nitrogen three times then a solution of 4-chlorobenzylzinc chloride in tetrahydrofuran (0.50M, 0.720 mL, 0.360 mmol) was added dropwise via a syringe. A nitrogen line was attached and the reaction was stirred at rt for 30 minutes, then at 60° C. for ˜2 hours. The reaction was cooled to rt, diluted with EtOAc and saturated ammonium chloride solution, then the mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted twice more with EtOAc. The organics were combined, washed with bicarbonate solution, then brine, then dried over sodium sulfate. The mixture was filtered then evaporated in vacuo and the residue was purified by column chromatography on silica, elution 100% hexane to 100% EtOAc to afford the title compound as a light yellow oil. Yield 63 mg (76% yield). LCMS: (FA) ES+, 483, 485.
Reaction SMILES: [O:1]=[CH: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].[P:13]([O-:20])([O-:19])([O:15]C(=O)C)=O.[Cl-].[Ca+2:22].[Cl-]>CC(C)=O>[P:13]([O:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][O:12][P:13]([O-:20])([O-:19])=[O:15])[OH:10])[OH:8])[OH:6])=[O:4])([O-:20])([O-:19])=[O:15].[Ca+2:22].[Ca+2:22]
Reactant: CC(=O)OP(=O)([O-])[O-]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)=O
Product: O=C(COP(=O)([O-])[O-])[C@@H](O)[C@H](O)[C@H](O)COP(=O)([O-])[O-]
Temperature: 30 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Propionibacterium freudenreichii IFO12425 was inoculated into 10 liters of a culture medium (pH: 6.5) containing 0.35% of glucose, 0.30% of peptone, 0.30% of yeast extract, and 0.05% of KH2PO4. This bacteria was cultured at 30° C. using a jar fermenter; 20 g of wet microorganisms were collected by centrifugation and immersed in acetone for 2 hours. Separately, 30 liters of tris-HCl solution prepared in the same manner as in Example 1 was placed in a 70-liter reaction vessel. To the tris-HCl solution was added 20 g of the acetone-treated microorganism body. The resulting solution was maintained at 30° C., and 20 liters of acetyl phosphate prepared as in the Reference Example was added in 5-liter portions. The reaction solution yielded 3.6 kg of dicalcium fructose-1,6-diphosphate salt following treatment with calcium chloride in the same manner as described in Example 1.
Reaction SMILES: C(OC([NH:8][C:9]([NH:32]C(OC(C)(C)C)=O)=[N:10][CH2:11][C:12]1[CH:16]=[C:15]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:21]([F:31])[CH:20]=2)[CH3:18])[O:14][N:13]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:31][C:21]1[CH:20]=[C:19]([CH:17]([C:15]2[O:14][N:13]=[C:12]([CH2:11][NH:10][C:9]([NH2:32])=[NH:8])[CH:16]=2)[CH3:18])[CH:24]=[CH:23][C:22]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(CN=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)no1
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(CNC(=N)N)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
The compound (1.24 g) obtained in Example 10 was dissolved in trifluoroacetic acid (10 ml), and the solution was stirred at room temperature for 2 hours and then the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was neutralized with a 1N aqueous sodium hydroxide solution, after which the organic layer was separated, washed with water, dried and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography to obtain the desired compound (562 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[C:30](Cl)[N:29]=[CH:28][N:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:35][NH2:36]>C(O)C>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[C:30]([NH:36][CH3:35])[N:29]=[CH:28][N:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CN
Reactant: O=C(N1CCN(c2cc(Cl)ncn2)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Solvent: CCO
Product: CNc1cc(N2CCN(C(=O)N3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)CC3)CC2)ncn1

Procedure:
A solution of 1-(4-triflouromethylphenylsulphonyl )-4-[1-(6-chloro-pyrimidin-4-yl)piperazin-4-ylcarbonyl]piperazine (26.0 g) in 33% methylamine in ethanol (400 ml) was heated at 110° C. in a Carius tube for 8 hours. The mixture was evaporated to dryness and the residue recrystallised from methanol to give, as a solid 1-(4-triflouromethylphenylsulphonyl)-4-[1-(6-metliylamino-pyrimidin-4-yl)piperazin-4-ylcarbonyl]piperazine (13.67 g), mp 230-231° C. Found C, 49.10; H, 4.90 and N, 19.00%. C21H26F3N7O3S requires C, 49.12; H, 5.10 and N, 19.09% NMR (CDCl3): 2.85 (d, 3H), 3.10 (m, 4H), 3.30 (m, 4H), 3.40 (m, 4H), 3.60 (m, 4H), 4.75 (m, 1H), 5.40 (s, 1H), 7.80 (d, 2H), 7.90 (d, 2H) and 8.15 (s, 1H); m/z 154 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[N:6]=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[N+:15]([O-])=O)[CH3:2]>CO.[Pd]>[NH2:15][C:4]1[C:5]([C:12]([NH2:14])=[O:13])=[N:6][N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Agent: [Pd]
Solvent: CO
Product: CCc1c(N)c(C(N)=O)nn1CCOC
Reaction time: 15 h

Procedure:
A mixture of 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide (20 g, 82.6 mMol) and 5%Pd/C (1 g) in methanol (200 mL) was pressurised at 50 psi/25° C. in a sealed vessel and stirred for 15 hours. At the end of the reaction the mixture was filtered through arbocel and the filter cake was washed with methanol. The methanolic solution was distilled at atmospheric pressure and replaced with ethyl acetate to a final volume of 100 mL. The cooled mixture was granulated at ambient temperature for 2 h filtered and washed with ethyl acetate (20 mL) to afford 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide as a white crystalline solid, 15 g, 88%. m.p.=131° C. Found: C, 50.75; H, 7.62; N, 26.38. C9H16N4O2 requires C, 50.94; H, 7.55; N, 26.42%.
Reaction SMILES: [CH:1]1([N:7]([CH3:32])[S:8]([CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH:17][C:16]=2[N+:29]([O-])=O)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S1C=CC=C1>CO.[Pd]>[CH:1]1([N:7]([CH3:32])[S:8]([CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH:17][C:16]=2[NH2:29])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C1CCCCC1)S(=O)(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CN(C1CCCCC1)S(=O)(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N

Procedure:
A mixture of 2-(5-benzoyl-2-nitro-benzylamino)-ethanesulfonic acid cyclohexyl-methyl-amide (0.009 mol) in methanol (150 mL) was hydrogenated with 10% Pd/C (1 g) as a catalyst in the presence of thiophene solution (1 mL). After uptake of H2 (3 equiv.), the catalyst was filtered off, and the filtrate was evaporated. The residue was purified by column chromatography over Biotage (eluent: 98:2 CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.