Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].Cl[C:5]1[C:6]([C:11]#[N:12])=[N:7][CH:8]=[CH:9][CH:10]=1.CN(C=O)C.[H-].[Na+]>O>[CH2:1]([S:3][C:5]1[C:6]([C:11]#[N:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: N#Cc1ncccc1Cl
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.9 mL of ethanethiol was added to a mixture of 1.39 g of 3-chloropyridine-2-carbonitrile and 10 mL of DMF, 0.52 g of 60% sodium hydride (oil-based) was added to the reaction mixture under ice cooling, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 1.52 g of 3-ethylsulfanylpyridine-2-carbonitrile.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:21](=[O:23])[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 5 h

Procedure:
To a solution of 1-benzylpiperidin-4-amine (10 g) in dichloromethane (80 ml), cooled to 5° C., was added pyridine (5.1 ml) followed by acetyl chloride (4.5 ml) and the resulting mixture was stirred for 5 hours. The reaction mixture was washed with 1N NaOH (×2) and then the organic layers were dried and evaporated to dryness to give a solid which was recrystallised from ethyl acetate to give N-(1-benzylpiperidin-4-yl)acetamide. Yield 8.8 g. NMR (d6 DMSO): 1.4 (m, 2H), 1.7 (m, 2H), 1.8 (s, 3H), 2.0 (m, 2H), 2.75 (m, 2H), 3.45 (s, 2H), 3.55 (m, 1H), 7.3 (m, 5H), 7.75 (d, 1H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19].[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][NH:23][C:22]1=[O:27].NCCN>O1CCOCC1.[Cu]I>[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[C:22]1=[O:27]
Reactant: Cc1cc([N+](=O)[O-])ccc1I
Reactant: CN1CCCNC1=O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: Cc1cc([N+](=O)[O-])ccc1N1CCCN(C)C1=O
Temperature: 110 °C
Reaction time: 19 h

Procedure:
16.1 g (76.1 mmol) of potassium phosphate and 0.362 g (1.90 mmol) of copper(I) iodide are initially charged, and the apparatus is baked out and then flushed with argon. 10.0 g (38.1 mmol) of 1-iodo-2-methyl-4-nitrobenzene, 6.51 g (57.0 mmol) of 1-methyltetrahydropyrimidin-2(1H)-one and 0.394 g (3.80 mmol) of N,N′-dimethylenediamine in 200 ml of dioxane are added, and the mixture is stirred at 110° C. After 19 h, after cooling, the mixture is filtered with suction through kieselguhr and then washed three times with 100 ml of ethyl acetate. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel (2:1→1:1 cyclohexane/ethyl acetate). This affords 5.94 g (63% of theory) of the desired compound.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].[CH3:16][CH2:17][CH2:18]CCCC=CCCC.IC(C)C>C(#N)C.C(OCC)C>[C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][CH:17]([CH3:18])[CH3:16])=[O:14])[CH2:5]1)#[N:2]
Reactant: CCCC=CCCCCCC
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Solvent: CCOCC
Solvent: CC#N
Solvent: CC(C)I
Product: CC(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 0.6 g (3 mmol), in acetonitrile, 2 mL, is added 1,8-diazabicyclo5.4.0]-undec-7-ene (DBU), 0.45 mL (3 mmol), and 2-iodopropane, 0.33 mL (3.3 mmol). The solution is stirred overnight at room temperature, diluted with diethyl ether, washed with brine, and dried (magnesium sulfate). Flash chromatography provides 0.55 g of (±)-cis-1-methylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane4-acetate.
Reaction SMILES: [NH:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].OS(O)(=O)=O>C(Cl)(Cl)Cl>[C:4]([O:11][C:10]([CH:2]1[CH2:3][CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[NH:1]1)=[O:12])([CH3:9])([CH3:5])[CH3:3]
Reactant: O=C(O)C1CC2CCCCC2N1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CC2CCCCC2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 200 %

Procedure:
Octahydro-indole-2-carboxylic acid 11b (5.0 g, 29.5 mmol, purchased from Bachem) was suspended in 200 mL of CHCl3 then cooled in a dry ice/acetone bath. H2SO4 (120 uL/mmol) was added followed by bubbling in excess isobutylene. The mixture was sealed and the ice bath removed. The mixture was stirred at RT for 12 hours. The reaction mixture was carefully unsealed after cooling and concentrated. EtOAc was added and washed with saturated sodium bicarbonate soln, brine, dried over sodium sulfate, then filtered and concentrated to give octahydro-indole-2-carboxylic acid tert-butyl ester 12b (6.65 g, 29.5 mmol, 100%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2ccccc2n1
Product: Cc1cc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (30 mL) was added to 4-hydroxy-2-methylquinoline (10 g), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium carbonate solution was added to the residue under ice-cooling. The mixture was extracted with ethyl acetate. The extract was washed with brine, and concentrated under reduced pressure to give 4-chloro-2-methylquinoline (11.2 g) as a black oil.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[NH2:7])#[N:3].[N:17]([O-])=O.[Na+]>>[C:2]([C:4]1[CH:5]=[C:6]([NH:7][NH2:17])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])#[N:3]
Reactant: O=N[O-]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)COc1ccc(NN)cc1C#N
Yield: 88.9 %

Procedure:
To an aqueous solution (33 ml) of 3-cyano-4-neopentyloxyaniline hydrochloride (21 g) were added sodium nitrite (6.7 g), stannous chloride dihydrate (59.5 g) and con. hydrochloric add (100 ml) with stirring under ice-cooling. After the completion of the reaction, precipitated crystals were collected by filtration The crystals were added to water, and the mixture was neutralized with aqueous sodium hydroxide solution, extracted with a mixed solvent of toluene and tert-butanol, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 17 g of 3-cyano-4-neopentyloxy-phenylhydrazine.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([CH2:12][CH2:13][C:14]([OH:16])=O)[CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[F:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C@H:40]([NH2:42])[CH3:41])=[CH:32][CH:31]=1>CN(C=O)C>[F:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C@H:40]([NH:42][C:14](=[O:16])[CH2:13][CH2:12][C@@H:4]2[CH2:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)[CH3:41])=[CH:32][CH:31]=1
Reactant: C[C@@H](N)c1ccc(F)c2ccccc12
Reactant: O=C(O)CC[C@H]1CC(=O)c2ccccc2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)CC[C@@H]1CC(=O)c2ccccc2C1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To the stirred solution of (R)-3-(4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoic acid (0.8 g, 3.67 mmol) (Crude) in dry DMF (15 mL), CDI (0.713 g, 4.40 mmol) was added. The reaction mixture was stirred at RT for 0.5 h. Then (R)-1-(4-fluoronaphthalen-1-yl)ethanamine (0.832 g, 4.40 mmol) was added and the reaction mixture was stirred at RT for 2 h. After completion of reaction ice was added to reaction mixture, solid precipitated out was filtered through Buchner funnel to get title compound (830 mg, 58.1%); m/z 390.54. Crude was taken without purification for next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH:13]([CH3:15])[CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: Cc1csc2c(NC(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 443 mg (7.5 mmol) of isopropylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/6) to give 636 mg (yield: 82.4%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1Br.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(OC)ccc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1cc(OC)ccc1-c1ccc(F)cc1
Yield: 63 %

Procedure:
Methyl-2-bromo-5-methoxybenzoate (15.1 g; 0.062 mol), 4-fluorobenzene boronic acid (9.98 g; 0.0713 mol), and tris (dibenzylideneacetone)dipalladium (0) (1.0 g) were dissolved in 100 mL dimethoxyethane (DME) and 100 mL 2N sodium carbonate and stirred at reflux overnight. The reaction mixture was cooled, the DME removed in vacuo, and the resulting oil partitioned between methylene chloride and water. The aqueous layer was extracted further with methylene chloride and the combined organic extracts dried over magnesium sulfate and concentrated in vacuo. Purification of the crude material by silica gel column chromatography (gradient elution with ethyl acetate/hexane) provided 5-methoxy-[2-(4-fluorophenyl)] benzoic acid methyl ester as a colorless oil (63%). The ester (8.6 g) was hydrolyzed in refluxing 1N sodium hydroxide (72 mL) and ethanol (250 mL). The reaction mixture was cooled and extracted with ethyl acetate. The aqueous layer was then acidified, extracted with EtOAc and the extracts concentrated to afford pure 5-methoxy-[2-(4-fluorophenyl)] benzoic acid in 86% yield. The acid (6.9 g; 0.03 mol) was dissolved in 50 mL thionyl chloride and refluxed overnight. The thionyl chloride was removed in vacuo to afford 2-fluoro-7-methoxy fluorenone quantitatively as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:15][NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[CH:26])=[CH:19][C:18]=3[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)=O)[CH:9]=2)[N:4]=1.[O-:38][C:39]#[N:40].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:15][N:16]3[C:17]4[C:18](=[CH:19][C:20]([O:23][CH2:24][C:25]#[CH:26])=[CH:21][CH:22]=4)[C:27]([C:29]4[CH:34]=[CH:33][C:32]([CH:35]([CH3:36])[CH3:37])=[CH:31][CH:30]=4)=[N:40][C:39]3=[O:38])[CH:9]=2)[N:4]=1
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2ccc3nc(OC)c(OC)nc3c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccc2nc(OC)c(OC)nc2c1
Reaction time: 2 h

Procedure:
To a solution of 52 mg (0.105 mmol) {2-[(2,3-dimethoxy-quinoxalin-6-ylmethyl)-amino]-5-prop-2-ynyloxy-phenyl}-(4isopropyl-phenyl)-methanone in 1 ml acetic acid is added 14 mg (0.210 mmol) sodium cyanate. After stirring for 2 h the solvent is removed in vacuo and the residue is partitioned between CH2Cl2 and water. The organic layer is extracted with 2 M sodium hydroxide and evaporated. Purification of the crude product by flash-chromatography (ethyl acetate/hexanes 9:1) affords a yellow oil.
Reaction SMILES: [N-]=[N+:2]=[N-:3].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C>O.C(O)C>[N+:2](=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([O:24][CH2:25][CH3:26])=[O:23])=[N-:3]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A mixture of sodium azide (683 mg, 10.5 mmol), p-toluenesulfonyl chloride (2.0 grams, 10.5 mmol), and 70% aqueous ethanol (30 mL) was stirred at room temperature for 1 hour. Diethyl malonate (1.62 mL, 10.0 mmol) and triethylamine (1.46 mL, 10.5 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours and then poured into deionized water (200 mL). The mixture was extracted with petroleum ether. The extracts were combined and decanted from the solid that formed. The petroleum ether solution was washed with a saturated aqueous sodium chloride solution. The organic solution was dried using anhydrous magnesium sulfate, filtered, and concentrated to give 1.65 grams of diethyl 2-diazomalonate as a yellow oil. IR (KBr): 2138, 1757, 1735, 1320, 1092 cm-1. Decomposition temperature: 175° C. (by DSC).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]1[CH:9]([OH:10])[CH2:8][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:6]1[CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)C>[OH:4][CH:5]1[CH:9]([OH:10])[CH2:8][CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:3])=[O:18])[CH:6]1[CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(O)CCC1C(CCCCCCC(=O)O)CC(O)C1O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC(O)CCC1C(CCCCCCC(=O)OC)CC(O)C1O
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A solution of diazomethane (60 mg.) in diethyl ether (10 ml.) was added to 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoic acid (0.3 g.; prepared as described in Example 1(q)) and the reaction mixture was left to stand for one day at room temperature. The polymethylenes formed as by-products of the reaction were removed by filtration and the filtrate was washed with dilute aqueous sodium carbonate solution. Evaporation of the ethereal solution gave crude methyl 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate (0.26 g.), νmax 3450 cm-1, 1730 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.C(OC(=O)[N:33]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[C:34]1[S:35][C:36]([CH:40]=O)=[C:37](Cl)[N:38]=1)(C)(C)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:40][C:36]3[S:35][C:34]([NH:33][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=4)=[N:38][CH:37]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1nc(Cl)c(C=O)s1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Fc1ccc(CNc2ncc(Cc3c[nH]c4ncc(Cl)cc34)s2)cc1
Temperature: 0 °C
Yield: 51.1 %

Procedure:
To a solution of 5-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (626, 300 mg, 0.69 mmol) in tetrahydrofuran (10 mL) at −20° C. was added dropwise iso-propyl-magnesium chloride (2M in tetrahydrofuran, 0.44 mL, 0.88 mmol). The reaction mixture was allowed to warm to 0° C. over 10 minutes and then cooled to −40° C. To this reaction mixture was added a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (625, 211 mg, 0.63 mmol) in tetrahydrofuran (5 mL). The reaction mixture was allowed to warm to 0° C. over 30 minutes and then quenched with brine (50 mL). The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude material which was purified by silica gel column chromatography (0-30% ethyl acetate/heptane) to provide the desired compound as a foam (120 mg, 30%), consistent with structure by 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:17][CH2:18][C@@H:19]([OH:37])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[C:29]=2[CH3:36])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:17][CH2:18][C@@H:19]([OH:37])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[C:29]=2[CH3:36])[CH2:23][CH2:22]1)=[O:8]
Reactant: Cc1c(OC2CCN(C[C@H](O)CN)CC2)ccc(Cl)c1Cl
Reactant: COC(=O)c1ccc(Cl)c(OCC(=O)O)c1
Product: COC(=O)c1ccc(Cl)c(OCC(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3C)CC2)c1

Procedure:
Prepared as for Example 15 Step 2 using [2-Chloro-5-(methoxycarbonyl)-phenoxy]acetic acid and (2R)-1-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]propan-2-ol to yield the subtitle compound as a colourless oil (0.084 g).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[OH:20])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31].[CH3:32][CH:33](O)[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[O:20][CH:33]([CH3:34])[CH3:32])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31]
Reactant: CC(C)O
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3O)c(=O)c1Cl)C2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Oc1cnccc1CNC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(3-hydroxypyridin-4-yl)methyl]acetamide (26.6 mg, 0.06 mmol) in tetrahydrofuran (1 mL) was mixed with 2-propanol (10.9 mg, 0.18 mmol), triphenylphosphine (23.6 mg, 0.09 mmol) and diethyl azodicarboxylate in toluene (2.2 M, 0.04 mL, 0.09 mmol) at 0° C. and stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate/methanol 20/1) to give the desired product (4.48 mg, 15%).
Reaction SMILES: [CH2:1]([CH:6]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH:15]([O:17][CH2:18][CH3:19])=[CH2:16]>C(OCC)C.P(=O)(O)(O)O>[CH2:15]([O:17][CH:18]([O:8][C:7](=[O:9])[CH:6]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])[CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH3:19])[CH3:16]
Reactant: C=CCCCC(CCCC=C)C(=O)O
Reactant: C=COCC
Agent: O=P(O)(O)O
Solvent: CCOCC
Product: C=CCCCC(CCCC=C)C(=O)OC(C)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-pentenyl)-6-hepteneoic acid (1 eq.) in diethyl ether (20 mL) was slowly added via a Pasteur pipette to a precooled (0° C.) solution of ethyl vinyl ether (excess, usually >4 eq.) and phosphoric acid (cat., 1 drop from capillary pipette) in diethyl ether (10 mL). The solution was stirred cold for 30 minutes under argon, and then warmed to room temperature for 3 days. Basic alumina (˜1 g) was added to the reaction mixture and stirred for five minutes. After filtration and solvent removal, 1-ethoxyethyl-2-(pent-4-enyl)hept-6-enoate was isolated as 7.3 g (99.0% yield) of colorless oil with no further purification required. 1H NMR (CDCl3): δ (ppm) 1.22 (t, 3H) 1.30-1.55 (br, 9H), 1.62 (m, 2H), 2.05 (q, 4H), 2.36 (m, 1H), 3.53 (d, 1H), 3.71 (m, 1H), 4.97 (m, 4H), 5.82 (m, 2H), 5.94 (q, 1H); 13C NMR (CDCl3): δ (ppm) 15.24, 21.14, 26.86, 26.89, 31.91, 32.10, 33.76, 45.98, 64.77, 96.33, 114.92, 138.56, 176.17. In like manner 1,2-(7-octenyl)-9-deceneoic acid was converted into 1-ethoxyethyl-2-(oct-7-enyl)dec-9-enoate (99.1% yield). 1H NMR (CDCl3): δ (ppm) 1.16-1.53 (br, 24H), 1.61 (m, 2H), 2.04 (q, 4H), 2.34 (m, 1H), 3.53 (m, 1H), 3.71 (m, 1H), 4.97 (m, 4H), 5.81 (m, 2H), 5.95 (q, 1H); 13C NMR (CDCl3): δ (ppm) 15.24, 21.13, 27.59, 27.65, 29.03, 29.15, 29.58, 32.52, 32.71, 33.94, 46.30, 64.72, 96.22, 114.41, 139.27, 176.42. In like manner to Example 1, 2-(10-undecenyl)-12-trideceneoic acid was converted into 1-ethoxyethyl-2-(undec-10-enyl)tridec-12-enoate (98.4% yield). 1H NMR (CDCl3): δ (ppm) 1.16-1.53 (br, 36H), 1.60 (m, 2H), 2.04 (q, 4H), 2.33 (m, 1H), 3.54 (m, 1H), 3.71 (m, 1H), 4.97 (m, 4H), 5.81 (m, 2H), 5.95 (q, 1H); 13C NMR (CDCl3): δ (ppm) 15.24, 21.13, 27.59, 27.65, 29.03, 29.15, 29.58, 32.52, 32.71, 33.94, 46.30, 64.72, 96.22, 114.41, 139.27, 176.42.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CN(C=O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:17]=[CH:18][C:3]([CH2:2][N:29]3[CH2:28][CH2:27][N:26]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30]3)=[CH:4][CH:5]=2)=[N:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CCl)cc2)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-chloromethylphenoxy)-5-nitropyridine (12.32 g, 47 mmol) in DMF (120 mL) were added triethylamine (19.4 mL, 140 mmol) and t-butyl piperazine-1-carboxylate 11.27 g, 61 mmol), and the resulting solution was stirred for 3 hours at 50° C. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 11.26 g of the title compound.