Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]2[CH:30]=[N:31][NH:32][C:26]=2[CH:25]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:23][C:24]1[N:29]=[CH:28][C:27]2[CH:30]=[N:31][N:32]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[C:26]=2[CH:25]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC(O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC(O)C1
Temperature: 100 °C
Yield: 69.8 %

Procedure:
To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (800 mg, 2.16 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (330 mg, 2.16 mmol) in 1,4-dioxane (25 mL) was added CuI (164 mg, 0.86 mmol), N1,N2-dimethylethane-1,2-diamine (240 mg, 2.7 mmol), and K2CO3 (894 mg, 6.48 mmol). The mixture was heated at 100° C., which was monitored by LCMS. After completion of the reaction, it was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using DCM:MeOH (20:1˜10:1) as eluting solvents to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate as yellow solid (671 mg, 70%). MS (ESI) m/z: 445 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].N1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>ClCCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: O=C(Cl)CCCl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of 4-bromo-3-chloroaniline (6.0 g, 29.1 mmol) and pyridine (3.45 g, 43.6 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (5.53 g, 43.6 mmol) drop wise at 15° C. After stirring for 2 hr at room temperature, the mixture was washed with water and then 2 N aq. hydrochloric acid. The organic layer was dried over anhy. Na2SO4, and after filtration, the solvent was removed under reduced pressure. The product N-(4-bromo-3-chloro-phenyl)-3-chloro-propionamide (8.20 g, 95% yield) was obtained as oil. MS: 298.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3=CCCC3)c3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Yield: 97.4 %

Procedure:
In a 3 gallon autoclave, charge 4-(3-Cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acid methyl ester (475 g), ethyl acetate (2.5 L), absolute ethanol (2.5 L) and 10% Pd—C (45 g, w/w) under 35 psi hydrogen at ambient temperature for 5 hours. Filter the crude reaction over Hyflo. Concentrate the filtrate under vacuum to give a light yellow solid (465 g) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([F:11])=[CH:4][C:3]=1[F:12].[Li]CCCC.[B:18](OC)([O:21]C)[O:19]C>C1COCC1>[CH2:9]([O:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([F:12])=[C:2]([B:18]([OH:21])[OH:19])[CH:7]=1)[CH3:10]
Reactant: CCOc1cc(Br)c(F)cc1F
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)c(F)cc1F
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To 97D (670 mg, 2.83 mmol) in THF (10 mL) was added n-BuLi (1.6M in hexane, 2.3 mL) at −78° C. After stirring for 15 min, trimethyl borate (0.634 mL) was introduced. The mixture was stirred from −78° C. to rt for 5 h before it was quenched by 1N HCl. It was extracted with ethyl acetate. The organic extract was washed with saturated Na2S2O3, brine and dried over MgSO4. The crude product was purified by column chromatography to give 97E (400 mg, 70% yield) as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:11](O)(=[O:13])C.C(OC=O)=O.O>O1CCCC1>[CH:11]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:13]
Reactant: CC(=O)O
Reactant: NC1Cc2ccccc2C1
Agent: O=COC=O
Solvent: O
Solvent: C1CCOC1
Product: O=CNC1Cc2ccccc2C1

Procedure:
To a solution of 2-aminoindan (19.95 g) in tetrahydrofuran is added an solution of 2M acetic acid-formic acid anhydride in tetrahydrofuran under ice cooling, and the mixture is reacted at room temperature. To the reaction mixture is added water, and then, the solvent is distilled off, and the residue is extracted with ethyl acetate. After distilling off the solvent, the residue is recrystallized from ethyl acetate - n-hexane to give 2-formylaminoindan (19.02 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:40][CH2:41][CH2:42]Br.O>CN(C)C=O.CO.C(Cl)Cl>[Br:40][CH2:41][CH2:42][O:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([NH:20][C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: BrCCBr
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
4.14 g of potassium carbonate were added at room temperature over 3 minutes under an argon atmosphere to a mixture of 4.94 g of the syn isomer of ethyl 2-hydroxyimino-2-(2-tritylamino-4-thiazolyl)-acetate in 10 ml of dimethylformamide and after stirring the mixture at 20° C. for 20 minutes, 8.65 ml of 1,2-dibromoethane were added thereto. The mixture was stirred for 30 hours and was then poured into a mixture of 100 ml of distilled water and 20 ml of methylene chloride. The decanted aqueous phase was extracted with methylene chloride and the combined organic phases were washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with benzene containing 5% of ether to obtain a first fraction which was dissolved at 50° to 60° C. in methanol and crystallized at 0° C. to 5° C. The mixture was vacuum filtered to obtain 1.16 g of syn isomer of ethyl 2-(2-bromoethoxyimino)-2-(2-tritylamino-4-thiazolyl)-acetate in the form of a cream white product melting at 117° C. There was obtained a homogenous fraction of 1.258 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](O)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B#B.[H][H].Cl.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: [H][H]
Agent: B#B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (16.7 g, 69.0 mmol) in THF (100 mL) was added diborane (151 mL, 1.0 M solution in THF) over a period of 10 min at 0° C. Hydrogen gas was rapidly evolved and after gas evolution had ceased the reaction was stirred at room temperature for 1 h. The reaction mixture was again cooled to 0° C., and 1 M aqueous HCl was added dropwise to the reaction mixture with further evolution of hydrogen. Addition of HCl was continued until the evolution of hydrogen had almost ceased. The mixture was then stirred for 10 min and made basic (pH 13-14) by the addition of 1 M NaOH solution. The aqueous solution was extracted with ethyl acetate, the organic phase washed with brine, dried and concentrated under reduced pressure to yield 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (15.2 g, 97%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[O:16][C:15]([C:17]2([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:14][C:13]=1[CH3:24])=O)C.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH3:24][C:13]1[N:14]=[C:15]([C:17]2([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O:16][C:12]=1[CH2:10][OH:9]
Reactant: CCOC(=O)c1oc(C2(C)CCCCC2)nc1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C2(C)CCCCC2)oc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
0.30 g Lithium aluminum hydride was dissolved in 10 ml dry tetrahydrofuran. 2.0 g 4-Methyl-2-(1-methyl-cyclohexyl)-oxazole-5-carboxylic acid ethyl ester, dissolved in 20 ml tetrahydrofuran, were added. The reaction mixture was stirred at room temperature over a period of one hour, then 50 ml ethyl acetate and 50 ml saturated ammonium chloride solution were added to the ice cooled mixture. The reaction mixture was extracted five times with portions of 60 ml of ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to provide 1.54 g [4-Methyl-2-(1-methyl-cyclohexyl)-oxazol-5-yl]-methanol as an oil.
Reaction SMILES: [N:1]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].CCN(C(C)C)C(C)C.Cl.[Cl:27][C:28]1[CH:39]=[CH:38][C:31]2[NH:32][C:33]([C@@H:35]([NH2:37])[CH3:36])=[N:34][C:30]=2[CH:29]=1>CN(C=O)C>[Cl:27][C:28]1[CH:39]=[CH:38][C:31]2[NH:32][C:33]([C@@H:35]([NH:37][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][C:2]4=[O:7])=[CH:16][CH:15]=3)[CH3:36])=[N:34][C:30]=2[CH:29]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(N2CCOCC2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CCOCC2=O)cc1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
254 mg (1.15 mmol) 4-(morpholin-3-on-4-yl)-benzoic acid (prepared by synthesis sequence analogously to Example 30a, 2d and 21a) are placed in 5 ml DMF and 428 mg (1.0 mmol) PfTU and 514 μl (3.0 mmol) DIPEA are added. After stirring at ambient temperature for 10 minutes 232 mg (1.0 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine-hydrochloride are added and the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is filtered through basic aluminium oxide and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/methanol 100:0->90:10), the corresponding fractions are evaporated down i. vac., the residue is dissolved in acetonitrile/water and lyophilised.
Reaction SMILES: [CH3:1][NH:2][CH3:3].N.[C:5]([CH2:10][C:11]1[O:12][C:13]([SH:16])=[N:14][N:15]=1)(OCC)=[O:6]>>[CH3:1][N:2]([CH3:3])[C:5]([CH2:10][C:11]1[O:12][C:13]([SH:16])=[N:14][N:15]=1)=[O:6]
Reactant: CCOC(=O)Cc1nnc(S)o1
Reactant: CNC
Agent: N
Product: CN(C)C(=O)Cc1nnc(S)o1

Procedure:
Substitution of dimethylamine in the procedure of Example 17 in place of ammonia in the reaction with 2-carbethoxymethyl-1,3,4-oxadiazole-5-thiol gives 2-(N,N-dimethylcarbamoylmethyl)-1,3,4-oxadiazole-5-thiol.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.S(=O)(=O)(O)O.B(OC)(OC)OC>[Cl-].[Zn+2].[Cl-].C(OC)(=O)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: COC(C)=O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of methyl acetate were added 1.41 g of 7-ACA, 3.0 g of zinc chloride, 0.29 ml of concentrated sulfuric acid and 3.13 ml of trimethyl borate. The mixture was heated at 30° C. for 6 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.86 g. The yield of the desired product was 69%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C:19]([OH:21])=O)[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C:19]([NH:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:21])[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCN(CC(=O)O)C1)c1cccc(Cl)c21
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCN(CC(=O)Nc3cccnc3)C1)c1cccc(Cl)c21
Yield: 39.8 %

Procedure:
To a dry roundbottom flask add [3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-piperidin-1-yl]-acetic acid (50 mg, 0.11 mmol), 3-amino-pyridine (16 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol), 1-hydroxy-7-azabenzotriazole (23 mg, 0.17 mmol), 4-dimethylamino-pyridine (2 mg, 0.01 mmol), and dimethylformamide (3 mL). Stir the reaction under nitrogen, and add triethylamine (30 μL, 0.22 mmol) dropwise. Stir the solution under nitrogen at room temperature overnight. Concentrate the mixture, partition between 20% isopropanol/chloroform and water, and separate. Wash the organic layer with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–0.5% methanol/chloroform) to give 19.8 mg of the title compound as an orange solid, 33% yield. 1H NMR: consistent with structure. MS (ion spray) 452 (M+).
Reaction SMILES: [OH-].[Na+].C1(C)C=CC=CC=1.[OH:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH3:19])[C:13]([CH3:21])([CH3:20])[CH2:12]1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:19][N:14]1[C:13]([CH3:21])([CH3:20])[CH2:12][CH:11]([O:10][CH2:22][CH:24]2[O:26][CH2:25]2)[CH2:16][C:15]1([CH3:17])[CH3:18]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C(C)(C)CC(OCC2CO2)CC1(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
300 g (7.5 mol) of sodium hydroxide are dissolved in 300 g of water under an argon atmosphere in a 2.51 sulfonation flask fitted with mechanical stirrer, condenser and 500 1 dropping funnel. 750 ml of toluene, 48.4 g (0.15 mol) of tetrabutylammonium bromide and 257 g (1.5 mol) of 4-hydroxy-1,2,2,6,6-pentamethylpiperidine are added. 347 g of epichlorohydrin (3.75 mol) are added dropwise at 60° C. over the course of 1.5 hours, and the mixture is subsequently stirred at the same temperature for a further 4 hours. The reaction solution is poured in 3 l of ice water, and the organic phase is separated off, dried using sodium sulfate and evaporated. The residue is distilled at 0.05 mmHg over a Vigreux column, and the fraction of boiling point 71°-72 C. is collected.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][NH:19][C@H:20]([P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24])[CH3:21])[CH:5]=1)([O-:3])=[O:2].[CH2:28](I)[CH3:29].CCN(C(C)C)C(C)C>C(#N)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[N:11]2)=[C:6]([CH2:18][N:19]([CH2:28][CH3:29])[C@H:20]([P:22](=[O:27])([O:23][CH3:24])[O:25][CH3:26])[CH3:21])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN[C@@H](C)P(=O)(OC)OC)c2nc1OC
Reactant: CCI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)[C@@H](C)P(=O)(OC)OC
Temperature: 55 °C
Reaction time: 18 h

Procedure:
3.4 g (8.5 mmol) of dimethyl (R)-N-(7-nitro-2,3-dimethoxyquinoxalin-5-ylmethyl)-α-aminoethylphosphonate, 8.9 ml (7.5 eq.) of ethyl iodide and 20.9 ml (14.5 eq.) of Hunig's base are mixed in 18 ml of acetonitrile and stirred at 55° C. for 18 hours. The reaction mixture is evaporated and slurried with ethyl acetate. The deposited solid is filtered off and washed with ethyl acetate. The title compound is obtained in the form of a yellow resin after evaporation of the filtrate and column chromatography using ethyl acetate/methanol (95:5) as eluent.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[CH:25]=[CH:26]/[C:27]2[N:41]=[C:30]3[CH:31]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH2:32][CH2:33][CH2:34][N:29]3[N:28]=2)[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1.O.C(OCC)(=O)C>C(Cl)Cl>[C:1]1([S:7]([N:38]2[CH2:39][CH2:40][CH:35]([CH:31]3[CH2:32][CH2:33][CH2:34][N:29]4[N:28]=[C:27](/[CH:26]=[CH:25]/[C:15]5[CH:16]=[CH:17][C:18]([N:19]6[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]6)=[C:13]([O:12][CH3:11])[CH:14]=5)[N:41]=[C:30]34)[CH2:36][CH2:37]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCNCC2)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(S(=O)(=O)c3ccccc3)CC2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
TEA (20 μl) and benzenesulfonyl chloride (8 μl) were added to a solution of racemic 2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained in Examples 118 and 119 (20 mg) in methylene chloride (1 ml), and the reaction solution was stirred at room temperature for 40 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 24 mg of racemic 8-(1-benzenesulfonylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the racemate was separated by CHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the title optically active compound with a retention time of 24 minutes and positive optical rotation (7.3 mg; 100% ee) and the title optically active compound with a retention time of 29 minutes and negative optical rotation (7.4 mg; >98% ee).
Reaction SMILES: [CH3:1][C:2]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].ClC1N=NC(C2C=CC(C(C)(C3C=CC(OCC4C=CC=CN=4)=CN=3)C(C)C)=CC=2)=CC=1.Cl[C:61]1[N:62]=[N:63][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:65][CH:66]=1.CC(C1C=CC(OCC2C=CC=CN=2)=CN=1)(C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)C(C)C.ClC1N=NC(Cl)=CC=1>>[CH3:1][C:2]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([C:6]1[CH:7]=[CH:8][C:9]([C:61]2[N:62]=[N:63][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:65][CH:66]=2)=[CH:10][CH:11]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CC(C)C(C)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(O)cn1
Agent: CC(C)C(C)(c1ccc(-c2ccc(Cl)nn2)cc1)c1ccc(OCc2ccccn2)cn1
Agent: CC(C)C(C)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCc2ccccn2)cn1
Agent: Clc1ccc(Cl)nn1
Product: CC(C)C(C)(c1ccc(-c2ccc(C(F)(F)F)nn2)cc1)c1ccc(O)cn1

Procedure:
Compound 8b was prepared from 8a following procedures similar to those described for preparing compound 5b substituting compound 8a and 3-chloro-6-trifluoromethylpyridazine for compound 5a and 3,6-dichloropyridazine, respectively. m/z (ES) 402 (MH)+
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Br[C:43]1[C:44]([CH:53]2[CH2:55][CH2:54]2)=[C:45]([F:52])[C:46]([OH:51])=[C:47]([CH:50]=1)[CH:48]=[O:49]>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].O.C1(C)C=CC=CC=1>[CH:53]1([C:44]2[C:43]([CH:1]3[CH2:3][CH2:2]3)=[CH:50][C:47]([CH:48]=[O:49])=[C:46]([OH:51])[C:45]=2[F:52])[CH2:55][CH2:54]1
Reactant: OB(O)C1CC1
Reactant: O=Cc1cc(Br)c(C2CC2)c(F)c1O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc(C2CC2)c(C2CC2)c(F)c1O
Reaction time: 15 h
Yield: 89.1 %

Procedure:
Cyclopropylboronic acid (1.72 g), a 2 M aqueous sodium carbonate solution (13 mL), tris(dibenzylideneacetone)dipalladium(0) (0.611 g), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.548 g) were added at room temperature to a toluene (50 mL) solution of 5-bromo-4-cyclopropyl-3-fluoro-2-hydroxybenzaldehyde (1.73 g), and the mixture was stirred at 100 C for 15 hours in an argon atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.31 g)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5](Br)=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH:5]([N:1]=[N+:2]=[N-:3])=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCC=CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCC=CN=[N+]=[N-]
Temperature: 80 °C
Yield: 56.4 %

Procedure:
To do this, sodium azide (2.781 g, 43 mmol) was dissolved in 170 ml of dimethylformamide (DMF). 5 ml of undecenyl bromide (36 mmol) were added, with stirring, to the reaction medium, which was subsequently heated at 80° C. for 24 hours. The mixture was left to cool to ambient temperature, and then 100 ml of water were added portionwise. An extraction with ethanol (3×100 ml) was subsequently carried out, and the organic phase was then washed with water (3×100 ml) and dried over sodium sulfate (Na2SO4). Finally, the solvent was evaporated off and 2.58 g of undecenyl azide (20.3 mmol; yield 60%) were isolated in the form of a pale yellow-colored transparent oil.