Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1)=[O:10].Cl.[CH:30]1([NH:33][CH3:34])[CH2:32][CH2:31]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:33]([CH:30]2[CH2:32][CH2:31]2)[CH3:34])=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: CNC1CC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)nc1-c1ccc(OC(F)(F)F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.8 %

Procedure:
To a solution of 0.052 g of 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide in 2 ml dimethylsulfoxide was added at room temperature 0.024 g of cyclopropyl-methyl-amine hydrochloride and 0.04 ml N-ethyldiisopropylamine. The mixture was stirred at room temperature for 72 hours. The reaction mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic layer washed with 10% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel to yield 0.033 g (61% yield) of the title compound as colorless oil. MS (ISP) (M+H+)=451.1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH3:23].[CH2:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[CH3:25]>ClCCCl.ClCCl>[Br:11][C:12]1[C:13]([O:22][CH3:23])=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:16]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([CH2:24][CH3:25])=[CH:27][CH:28]=2)[CH:17]=1
Reactant: COc1cc(NC(C)=O)ccc1Br
Reactant: CCc1ccc(C(=O)O)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc(C(=O)c2cc(Br)c(OC)cc2NC(C)=O)cc1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (17 mL) and tin(IV) chloride (5 mL) are successively added to a suspension of N-(4-bromo-3-methoxy-phenyl)-acetamide (5.0 g) and 4-ethylbenzoic acid (4.4 g) in 1,2-dichloroethane at such a rate that the temperature maintains below 35° C. The resulting mixture is heated at reflux temperature overnight. Then, the mixture is diluted with dichloromethane and poured onto crushed ice. After stirring the aqueous mixture for 30 min, the organic phase is separated and washed with 10% NaOH in water and water. The organic phase is dried (sodium sulphate), the solvent is removed and the residue is triturated with methanol to give the product.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1Cl>COCCOC>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[O:4][CH2:1][CH:2]=[CH2:3]
Reactant: COCOc1cnccc1Cl
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCOc1ccncc1OCOC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
Under nitrogen atmosphere. 2-propen-1-ol (0.002 mol) was added dropwise to a stirred mixture of NaH 60% (0.002 mol) in DME (5ml). The mixture was stirred at room temperature for 15 minutes. A solution of 3-(methoxymethoxy)-4-chloropyridine (0.0017 mol) in DME (5 ml) was added dropwise. The resulting reaction mixture was stirred at reflux overnight. The mixture was washed with water and extracted with ethyl acetate. The organic layer was dried, filtered and evaporated till dryness. The residue was purified by open column chromatography (eluent: hexane/ethyl acetate 3/2; CH2Cl2/2-propanone 90/10; CH2Cl2/MeOH 96/4). The product fractions were collected and the solvent was evaporated, yielding 0.18 g of 3-(methoxymethoxy)-4-(2-propenyloxy)pyridine (intermediate 7).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[OH:6][C:7]1[CH:23]=[CH:22][C:10]([CH:11]=[C:12]2[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]2=[O:21])=[CH:9][CH:8]=1.[Cl-].[NH4+].CCCCCC>O1CCCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]([CH:12]2[C:13](=[O:21])[O:14][C:15]([CH3:20])([CH3:19])[O:16][C:17]2=[O:18])[C:1]#[C:2][CH3:3])=[CH:22][CH:23]=1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reactant: CC#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0.5M tetrahydrofuran solution of 1-propynylmagnesium bromide (800 mL) was added dropwise a solution of 5-(4-hydroxybenzylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dion e (47.3 g) obtained in Substep 1 in tetrahydrofuran (650 mL) under argon atmosphere at 11° C. over 40 minutes, followed by stirring the reaction mixture at room temperature for 1 hour. Then, to the reaction mixture were added successively aqueous ammonium chloride solution (34 g/l L) and hexane (1 L), followed by removing the organic layer. After adding saturated aqueous potassium hydrogen sulfate solution to the aqueous layer and adjusting a pH to 1, the aqueous layer was extracted with ethyl acetate twice. The organic layer was dried and concentrated to give 5-[1-(4-hydroxyphenyl)-but-2-ynyl]-2,2-dimethyl-[1,3]dioxan e-4,6-dione (54.8 g).
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[I:24]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([I:24])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc([Si](C)(C)C)cc2)C[C@@H]2CC[C@H]1N2C
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](c2ccc(I)cc2)C[C@@H]2CC[C@H]1N2C
Reaction time: 2 h

Procedure:
50 mg of 2β-carbomethoxy-3β-(4-trimethylsilylphenyl) tropane was dissolved in 5 ml of CCl4 at ambient temperature. To this was added 40 mg of iodine monochloride after which the solution was stirred for 2 h, then poured into 20 mL of 10% sodium thiosulfate (Reaction 7). The two phase solution was shaken until the dark color disappeared, made basic with saturated sodium bicarbonate, and the organic layer separated. The aqueous layer was extracted three times with 10 mL portions of CHCl3 and the combined organic layers were then washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in a small portion of ether and chromatographed using a flash SiO2 column (10"×1/2", ether/hexane 1/2) and the eluents concentrated to yield 53 mg of (91%) CIT. No isomerization of the ester moiety was detected by TLC or NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[NH2:27][CH:28]([C:34]([CH3:36])=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>ClCCl>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]1[O:8][C:34]([CH3:36])=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:27]=1
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: CCOC(=O)C(N)C(C)=O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C=Cc2ccccc2Cl)oc1C
Temperature: 25 °C

Procedure:
To a suspension of o-chlorocinnamic acid (9.1 g) in dichloromethane (200 ml) was added triethylamine (21 ml) for dissolution. With cooling with ice-sodium chloride and stirring, ethyl chlorocarbonate (5.0 ml) was added dropwise to the above-obtained solution, and the mixture was further stirred for 10 minutes. To the resulting mixed acid anhydride solution was added portionwise ethyl 2-aminoacetoacetate hydrochloride (9.05 g) and the mixture was stirred under cooling for 20 minutes and at room temperature for 40 minutes. The reaction mixture was washed with diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate and water in that order and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was dissolved in toluene (100 ml). Phosphorus oxychloride (14 ml) was added and the mixture was refluxed for an hour. The solvent and phosphorus oxychloride were distilled off under reduced pressure, and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was treated with isopropyl ether to give ethyl 2-(2- chlorostyryl)-5-methyl-4-oxazolecarboxylate as crystals; yield 6.4 g (44.1%). Recrystallization from ethanol gave yellow prisms melting at 99°-100° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([OH:29])[CH2:25]2)[C:21](=[O:30])[NH:20][C:19]2([C:31]([O:33]CC)=[O:32])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)[CH2:25]2)[C:21](=[O:30])[NH:20][C:19]2([C:31]([OH:33])=[O:32])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O)CC1C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3ccc([N+](=O)[O-])cc3)CN2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.7 %

Procedure:
To a mixture of (14-tert-butoxycarbonylamino-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid, ethyl ester (192 mg, 0.39 mmol; prepared in Ex. 25, step 3) in 3 mL of THF was added sodium hydride (50 mg, 60% in oil, 1.25 mmol). The mixture was stirred at rt for 5 min. then 1-fluoro-4-nitrobenzene (60 mg, 0.42 mmol) was added and stirring was continued at rt overnight. The reaction was quenched by adding 10 mL of water, and then 0.1 N hydrochloric acid was used bring the pH to 4. This acidic solution was then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to obtain 14-tert-butoxycarbonylamino-18-(4-nitrophenoxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid as a white solid (100 mg, 44%). LC-MS (YMC Xterra MS C18 S7 column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 4 min. Hold time: 1 min. Flow rate: 4 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.)(Retention time: 3. 17 min), MS m/z 587(M++1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH2:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[CH2:17][CH2:18][CH3:19]>>[CH2:16]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:15][C:13]2[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[N:11]3[N:12]=2)=[O:25])=[CH:27][CH:28]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1ccc(C(=O)O)cc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: CCCCc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and 4-butylbenzoic acid (80 mg; 0.45 mmol; 1.2 eq.) as a yellow foam (20 mg, 15%). HPLC, Rt: 4.45 min. (purity 82.6%). LC/MS, M+(ESI): 361.1, M−(ESI): 359.1.
Reaction SMILES: C(O)C.C(O[CH:7]=[C:8]([C:14]([CH3:16])=O)[C:9]([O:11]CC)=[O:10])C.Cl.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.[OH-].[Na+]>O>[CH3:16][C:14]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)[N:26]=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-n2ncc(C(=O)O)c2C)cc1
Yield: 57.7 %

Procedure:
To an ethanol (70 ml) and water (70 ml) solution of ethyl 2-(ethoxymethylene)acetoacetate (16.67 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), was added 4-methylphenylhydrazine hydrochloride (14.2 g) and the mixture was stirred at reflux temperature for 7.5 hours. Sodium hydroxide (8.5 g) was added and the mixture was further stirred at reflux temperature for an hour. After completion of the reaction, the solvent was evaporated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was washed with n-hexane to give the titled compound (11.17 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].ClC1C=CC=C2C=1C1C(=O)NC(NC(=O)C(C)(C)C)=[N:26][C:20]=1[NH:21]2.O.[OH-].[NH4+]>CS(C)(=O)=O>[NH2:21][C:20]1[NH:26][C:7](=[O:8])[C:6]2[C:5]3[CH2:12][CH2:13][CH2:14][CH2:15][C:4]=3[S:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: CS(C)(=O)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Temperature: 150 °C
Yield: 59.7 %

Procedure:
To a 50 mL flask was added 4 (225 mg, 1 mmol), 9 (452 mg, 4 mmol) in DMSO2 (500 mg) was heated at 150° C. for 2 h. The mixture was cooled to room temperature. 15 mL water was added and ammonium hydroxide was used to neutralize the suspension. The brown solid was obtained by filtration. Washed with water and dried. The solid was dissolved in methanol and silica gel was added. A dry silica gel plug obtained after evaporation. The plug was then loaded on the column and washed with 5% methanol in chloroform. The fractions containing the desired product (TLC) were pooled and evaporated to afford 132 mg (60%) of 10 as a white solid: 1H NMR (DMSO-d6) δ 1.71 (m, 4H), 2.60 (m, 2H), 2.72 (m, 2H), 6.38 (s, 2H), 10.72 (s, 1H). Anal. calcd for C10H11N3OS: C, 54.28; H, 5.01; N, 18.99; 0, 7.23; S, 14.49. Found: C, 53.45; H, 5.06; N, 18.26; S, 14.02.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1.[H-].[Na+].[O:25]([CH2:32][CH2:33]Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]([CH2:33][CH2:32][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:22]=1
Reactant: BrCCOc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(OCOC)cc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(CCOc1ccccc1)(Cc1ccc(OCOC)cc1)C(=O)OCC
Yield: 78.5 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using diethyl 2-(4-methoxymethoxybenzyl)malonate (1.58 g), which is the product of Reference example 3(b), sodium hydride (55% suspension in oil, 0.24 g) and 2-phenoxyethyl bromide (1.23 g) and the reaction mixture was treated to afford the desired compound (1.72 g) as a syrup.
Reaction SMILES: C(OP(CP(OCC)(=O)OCC)(=O)OCC)C.[H-].[Na+].[H][H].BrCCOCCN1C(=O)C2=CC=CC=C2C1=O.Cl.C([O:42][P:43]([CH:48]([P:64]([O:69]CC)(=[O:68])[O:65]CC)[CH2:49][O:50][CH2:51][CH2:52][N:53]1C(=O)C2=CC=CC=C2C1=O)(=[O:47])[O:44]CC)C.[Na]>O.C1(C)C=CC=CC=1>[NH2:53][CH2:52][CH2:51][O:50][CH2:49][CH:48]([P:43]([OH:44])(=[O:42])[OH:47])[P:64]([OH:68])(=[O:65])[OH:69]
Reactant: CCOP(=O)(OCC)C(COCCN1C(=O)c2ccccc2C1=O)P(=O)(OCC)OCC
Reactant: [H][H]
Agent: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: Cl
Agent: O=C1c2ccccc2C(=O)N1CCOCCBr
Solvent: Cc1ccccc1
Solvent: O
Product: NCCOCC(P(=O)(O)O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.73 g. (6 mmol) Methanediphosphonic acid tetraethyl ester is added dropwise to 144 mg. (6 mmol) sodium hydride in 5 ml. anhydrous toluene. After completion of the evolution of hydrogen, stirring is continued for 30 minutes and then 1.7 g. (6 mmol) N-(2-bromoethoxyethyl)-phthalimide (m.p. 83°-85° C.) is added dropwise thereto. The reaction mixture is stirred for 24 hours at ambient temperature, then mixed with water, the aqueous phase is adjusted to pH 5 with 2N hydrochloric acid and the organic phase is separated off, dried and evaporated. The residue is purified over 250 g. silica gel (elution agent: methylene chloride/methanol 4/1 v/v) to give 0.35 g. (12% of theory) 5-phthalimido-3-oxapentane-1,1-diphosphonic acid tetraethyl ester in the form of an oily substance. The ester is subsequently boiled under reflux for 12 hours with 10 ml. 6N hydrochloric acid and, after cooling, the precipitated phthalic acid is filtered off with suction. The residue is taken up in water, the solution is adjusted with 2N aqueous sodium hydroxide solution to pH 5 and mixed, while cooling with ice, with a large excess of methanol. The precipitate obtained is filtered off with suction and dried. There is obtained 0.125 g. (7.2% of theory) of the desired compound in the form of the monosodium salt containing 1 mole water of crystallisation; m.p.>300° C.; Mrel =0.30.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1nc(Br)cnc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1nc(-c2ccccc2)cnc1N
Temperature: 85 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
5-Bromo-3-methoxy-pyrazin-2-ylamine (A) (816 mg, 4 mmol) and phenyl boronic acid (732 mg, 6 mmol) in toluene (5 mL), ethanol (5 mL) and Na2CO3 (8 mmol, 1 M aqueous) was purged with nitrogen for 10 minutes, and was added PdCl2(PPh3)2(140 mg, 0.2 mmol). The reaction mixture was stirred at 85° C. for 4 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL). The solution was washed with brine (2×5 mL). The organic extracts was dried with MgSO4, then solvent was removed under vacuum. The residue was purified with flash column to give product B (660 mg, 82%) as yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.08 (1H, s), 7.92 (2H, d), 7.46 (3H, m), 4.94 (2H, bs), 4.12 (3H, s); MS: 202 (M+H+).
Reaction SMILES: Cl.O[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[Cl:14].[Cl-].[Al+3].[Cl-].[Cl-]>>[ClH:13].[Cl:13][C:9]1[C:8]([Cl:14])=[C:7]2[C:12]([CH2:3][CH2:4][NH:5][CH2:6]2)=[CH:11][CH:10]=1
Reactant: OCCNCc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Clc1ccc2c(c1Cl)CNCC2
Yield: 174.2 %

Procedure:
A mixture of 2.0 g (7.8 mm) of N-hydroxyethyl-2,3-dichlorobenzylamine hydrochloride and 5 g (37.5 mm) of aluminum chloride was reacted as above with the aluminum chloride additions at 0 time, 2 g; 1/2 hour, 1 g and 11/4 hour, 2 g to give 1.62 g (87.1%) of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride which is 97.93% pure by gas liquid chromatography.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C-:9]#[N:10].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.[Cu]I>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: [C-]#N
Reactant: Nc1cnc(Br)cn1
Agent: [Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(N)cn1
Temperature: 155 °C
Reaction time: 0.67 h

Procedure:
5-Bromo-pyrazin-2-ylamine was combined with copper (I) iodide (1.3 g, 6.9 mmol), potassium cyanide (0.44 g, 6.8 mmol), tetrakis (triphenylphosphine)palladium(0) (0.95 g, 0.83 mmol), and 18-crown-6 (0.058 g, 0.22 mmol) in DMF (15 mL). The resulting mixture was stirred for 40 min, then heated at reflux (155° C.) for 2 h. The reaction was cooled to room temperature, then allowed to stand overnight. The precipitate was separated by filtration and the filtrate was concentrated to dryness in vacuo. The orange-colored residue was taken up in EtOAc and hexanes and an initial precipitate was formed, then separated by filtration. Upon standing, additional precipitate formed in the mother liquor and was collected by filtration. The solids were combined to yield 0.10 g of a bright orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:27])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2c([C@@H]3C[C@H]3CNC(=O)C3CC3)cccn2n1
Yield: 65 %

Procedure:
To a solution of trans-1-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine (100 mg, 0.497 mmol) and triethylamine (83.2 μL, 0.596 mmol) in tetrahydrofuran (5 mL) was added cyclopropanecarbonyl chloride (49.6 μL, 0.547 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=35/65→90/10) to give the title compound (87.0 mg, yield 65%).
Reaction SMILES: CC(C)=O.[OH:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1.CC(O)C>O>[CH2:15]([O:14][C:12]([CH:9]1[CH2:10][CH2:11][C:6](=[O:5])[CH2:7][CH2:8]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C1CCC(O)CC1
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCOC(=O)C1CCC(=O)CC1
Reaction time: 0.33 h

Procedure:
120 ml of a Jone's reagent was added dropwise into a solution of 800 ml of acetone containing 81.1 g of ethyl 4-hydroxycyclohexane carboxylate over 30 minutes in an ice bath. After stirring at the same temperature for 20 minutes, 2-propanol was added thereto. The reaction solution was poured into water, followed by extracting with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed, to give 80.0 g of the target compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]1[S:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][C:23]#[N:24]>>[CH2:1]([N:8]1[C:12](/[CH:13]=[C:22](/[C:21]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=2)\[C:23]#[N:24])=[CH:11][N:10]=[C:9]1[S:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ncc(C=O)n1Cc1ccccc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cnc(SC)n2Cc2ccccc2)cc1OC
Yield: 92.4 %

Procedure:
1-Benzyl-2-(methylsulfanyl)-1H-imidazole-5-carbaldehyde (465 mg) was condensed with 3,4-dimethoxybenzyl cyanide (354 mg) through Method A (production step 2), to thereby yield the target product (yield: 723 mg, 92%).