Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+:2].CS(C)=O.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([OH:15])=[O:14]>COCCOC>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([O-:15])=[O:14].[Na+:2]
Reactant: O=C(O)Cc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COCCOC
Product: O=C([O-])Cc1cccs1

Procedure:
To a suspension of 1.9 g. of sodium hydride (63% content) in 60 ml. of a mixture of dimethyl sulphoxide and 1,2-dimethoxyethane (2:1), there were added dropwise 3.7 ml. of thiolacetic acid at 0° C. with stirring under an atmosphere of nitrogen to give a sodium thiolacetate solution. To the reaction solution thus obtained, there was added a solution of 8.4 g. of methyl 9α,11α-bis-(p-toluenesulphonyloxy)-15α-(2-tetrahydropyranyloxy)-prosta-cis-5,trans-13-dienoate (prepared as described in Reference Example 5) in 30 ml. of a mixture of dimethyl sulphoxide and 1,2-dimethoxyethane (2:1) at 0° C., and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was then poured into 500 ml. of ice-water, extracted with ethyl acetate, and the extract washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel, first using a mixture of benzene and ethyl acetate (20:1) as eluent to give 5 g. of the title compound contaminated with by-products, and then by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (5:1) as eluent to give 2.35 g. of the title compound having the following physical characteristics:
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Br.Br[CH2:54][C:55]1[C:56]([Cl:61])=[N:57][CH:58]=[CH:59][CH:60]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:54][C:55]3[C:56]([Cl:61])=[N:57][CH:58]=[CH:59][CH:60]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: Clc1ncccc1CBr
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: Br
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3cccnc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 3-(bromomethyl)-2-chloropyridine hydrobromide and isolated as light brown gum. MS (m/e): 388.3 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 28 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a Pyrex round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 4.9 g of 1-benzyl-3,4-epoxypyrrolidine (yield 28.0%) was obtained and 11.9 g (yield 75.0%) of 1-benzyl-3-pyrroline was recovered.
Reaction SMILES: C1C(C(OO)=[O:8])=CC=CC=1.[CH3:11][C:12]1[CH:17]2[C:18]([CH3:20])([CH3:19])[CH:15]([CH2:16]2)[CH2:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:19][C:18]1([CH3:20])[CH:17]2[C:12]3([CH3:11])[O:8][CH:13]3[CH2:14][CH:15]1[CH2:16]2
Reactant: O=C(OO)c1ccccc1
Reactant: CC1=CCC2CC1C2(C)C
Solvent: ClC(Cl)Cl
Product: CC1(C)C2CC3OC3(C)C1C2
Temperature: -15 °C
Reaction time: 1 h

Procedure:
550 ml of a 23.3% (151 g) chloroform solution of 100% perbenzoic acid, are loaded into a glass reactor vessel of 2 l capacity, externally cooled to -15° C. Over a period of around 2 hours 150 g of 95% α-pinene are dripped in, maintaining the temperature between -5° C. and -2° C. The solution is then stirred for 1 hour, lowering the temperature to -10° C. At this temperature the perbenzoic acid which has precipitated out is filtered off. The chloroform solution obtained is washed with a small quantity of a 20% alkaline solution of sodium carbonate (Ha2CO3), in order to eliminate the contained residual benzoic acid. The process is then completed as in example 2a.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2NN=[N:26][N:25]=2)=[CH:20][CH:19]=1.N1C=CC=CC=1>O>[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:7][C:6]([C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])=[N:26][N:25]=2)=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: c1cc(C2OCCO2)ccc1-c1nnn[nH]1
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1nnc(-c2ccc(C3OCCO3)cc2)o1
Yield: 77.2 %

Procedure:
A mixture of 2-nitrobenzoyl chloride (0.190 g), 5-[4-(1,3-dioxolan-2-yl)phenyl]-1H-tetrazole (0.200 g) and pyridine (5 ml) was heated under reflux for 1 hr. After cooling, water was added to the reaction mixture, and the crystals were collected by filtration, and dissolved in ethyl acetate. This solution was washed with 1 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with hexane to give 2-[4-(1,3-dioxolan-2-yl)phenyl]-5-(2-nitrophenyl)-1,3,4-oxadiazole (0.240 g, yield 77%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 88–89° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:26][C:27](OC(C)=O)=[O:28]>N1C=CC=CC=1>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:27](=[O:28])[CH3:26])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H]1C[C@H](NC2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](N(C(C)=O)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Methyl(2S,4S)-1-BOC-4-[(4,4-dimethylcyclohexyl)amino]pyrrolidine-2-carboxylate (1.01 g, 2.84 mmol) obtained in Step A, was dissolved in pyridine (5 mL), and Ac2O (1.34 mL, 14.20 mmol) was added thereto at room temperature. The reaction solution was heated to 90° C. and was stirred for 2 hours. After the reaction was completed, CuSO4.5H2O aqueous solution was added and the solution was extracted with EtOAc. The extracted organic solution was dried over MgSO4 and concentrated in vacuo. The obtained residue was purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (0.98 g, 87%).
Reaction SMILES: [NH2:1][NH2:2].[N:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[CH2:11][C:12](=O)[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCO>[N:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:1]=[N:2][C:12]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:20])[CH2:17][CH2:18]3)=[CH:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=2)=[CH:7][CH:8]=1
Reactant: NN
Reactant: O=C(CC(C(=O)c1ccncc1)c1cccc(C(F)(F)F)c1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3cccc(C(F)(F)F)c3)c(-c3ccncc3)nn2)CC1
Reaction time: 4 h
Yield: 36.8 %

Procedure:
Under Ar, hydrazine (0.5 mL, 0.51 g, 15.9 mmol) was added to a solution of 34 (3.3 g) in EtOH (75 mL). After 4 h, the solution was concentrated to dryness and the residue treated with toluene (60 mL) dioxane (60 mL) and DDQ (0.8 g, 3.5 mmol). After 15 h, the reaction was concentrated to dryness. The residue was chromatographed on a Still column (50 mm) and the product eluted with 100% EtOAc to yield 1.2 g of 35.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:5]2.C(N(CC)CC)C.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH:32]=[CH2:33]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([O:15][C:14]([NH:13][CH2:12][C@H:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2](/[CH:33]=[CH:32]/[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:3]=2)[O:8]1)=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NC[C@H]1CCc2cc(I)ccc2O1)OCc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc2c(c1)CC[C@H](CNC(=O)OCc1ccccc1)O2
Temperature: 25 °C
Yield: 94.5 %

Procedure:
Palladium acetate (224 mg, 1 mmol) was added to a mixture of the carbamate of Example 11 (4.2 g, 10 mmol), triethylamine (2.1 mL, 15 mmol), and t-butyl acrylate (1.76 mL, 12 mmol) in acetonitrile (50 mL) previously degassed with argon for 20 minutes. The resulting mixture was heated at gentle reflux for 26 hours. It was cooled to room temperature. The catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and filtered over a pad of silica gel. Removal of solvent in vacuo afforded the product as an oil (4.0 g, 95%): 1H NMR (CDCl3) δ1.50 (s, 9H), 1.70 1.85 (m, 1H), 200 (m, 1H), 2.80 (m, 2H), 3.40(m, 1H), 3.65 (m, 1H), 5.12 (s, 2H), 5.25 (m, 1H), 6.21 (d, J=15.3 Hz,1H), 6.76 (d, J=8.4 Hz, 1H), 7.20-7.40 (m, 7H), 7.49 (d, J=15.9 Hz, 1H); CI-MS m/z 424 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]#[C:22][CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1C#CC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethynyl)piperidine-1-carboxylate (0.0982 g, 0.197 mmol) in methylene chloride (5 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperidin-4-ylethynyl)benzofuran-3(2H)-one (0.0392 g, 50%).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[C:19]([O:23][C:24](=[O:28])[C@H:25]([CH3:27])[NH2:26])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:19]([O:23][C:24](=[O:28])[C@@H:25]([NH:26][CH:14]1[CH2:15][CH2:16][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:12][CH2:13]1)[CH3:27])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](NC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
To a solution of N-Cbz-4-piperidinone (3.497 g, 15.0 mmol) in dichloroethane (100 mL) was added L-alanine tert-butyl ester hydrochloride (2.731 g, 15.03 mmol) and sodium triacetoxyborohydride (6.47 g, 30.5 mmol). The mixture was stirred for 20 hours at room temperature, then quenched by the addition of saturated ammonium chloride (100 mL). The mixture was poured into ethyl acetate (500 mL), washed with water (2 times 100 mL), dried (MgSO4) and concentrated to yield the desired product (5.30 g, 97% yield). LC/MS: m/z 325.25 [M+H]+
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([N:14]([CH2:18][CH2:19]O)[CH2:15][CH2:16]O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:19][CH2:18][N:14]([CH2:15][CH2:16][Cl:23])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NCCOCc1ccccc1)N(CCO)CCO
Solvent: ClCCl
Product: O=C1N(CCCl)CCN1CCOCc1ccccc1

Procedure:
To 3-benzyloxypropionic acid (129.6 g) in ether (310 ml) and N,N-dimethylformamide (4 ml) was added thionyl chloride (155 ml). The solution was refluxed for 2 hours, and solvents and excess thionyl chloride were removed by evaporation in vacuo. Yield 132 g of 3-Benzyloxypropionic acid chloride as an oil. To an ice cooled solution of the thus prepared acid chloride (132 g) in acetone (450 ml) was added a cold solution of sodium azide (48.5 g) in water (200 ml) at 5° C. After additional stirring at 5° C. for 30 minutes, the mixture was poured into water and toluene, and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine. After drying (magnesium sulfate) the solution was heated slowly to 85° C. on a steam bath until evolution of nitrogen ceased. The solvent was removed in vacuo leaving 108.4 g of 2-benzyloxyethylisocyanate as an oil. A mixture of 2-benzyloxy-ethylisocyanate (10 g) and diethanolamine (5.72 g) in dichloromethane (60 ml) was refluxed for 2.5 hours. After cooling to room temperature, the solution was washed with brine. Drying (magnesium sulfate) and evaporation of the solvent yielded 11.4 g of N-(2-benzyloxyethyl)-N',N'-di-(2-hydroxyethyl)-urea as an oil. A solution of the urea derivative (11.4 g) in dichloromethane (55 ml) was cooled to 5° C., and thionyl chloride (8.3 ml) was added at a temperature below 10° C. After the addition the mixture was refluxed for 1 hour and then left over night at room temperature. The solution was washed with cold sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,1,1-trichloroethane and refluxed for 3 hours. After cooling the solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo, yielding 6.6 g of the title compound 22a as an oil.
Reaction SMILES: CC1C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].N1C=CC=CC=1.CC1C=CC(S(OCCCCC#C)(=O)=O)=CC=1.[O:42]=[CH:43][C:44]1[CH:52]=[CH:51][C:49](O)=[C:46]([O:47][CH3:48])[CH:45]=1>C(Cl)Cl>[CH2:12]([O:18][C:49]1[CH:51]=[CH:52][C:44]([CH:43]=[O:42])=[CH:45][C:46]=1[O:47][CH3:48])[CH2:13][CH2:14][CH2:15][C:16]#[CH:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: C#CCCCCO
Agent: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCCCCOc1ccc(C=O)cc1OC
Yield: 61.5 %

Procedure:
4-Methylbenzenesulfonyl chloride (2.9 g, 15 mmol), 5-hexyn-1-ol (1.1 mL, 10 mmol) and pyridine (1.6 mL, 20 mmol) in CH2Cl2 (10 mL) were treated according to Procedure 4 giving hex-5-ynyl 4-methylbenzenesulfonate (2.1 g, 83%) as a colourless oil. Vanillin (0.84 g, 5.6 mmol) was alkylated with hex-5-ynyl 4-methylbenzenesulfonate (2.1 g, 8.3 mmol) according to Procedure 4 and the crude product was recystallised from EtOAc/petrol to provide 4-(hex-5-ynyloxy)-3-methoxybenzaldehyde (0.80 g, 62%) as a colourless crystalline solid; mp 67-68° C.; δH (400 MHz, CDCl3) 1.74 (p, J=7.0 Hz, 2H, CH2), 1.97 (t, J=2.8 Hz, 1H, C≡CH), 2.02 (p, J=7.0 Hz, 2H, CH2), 2.30 (td, J=7.0, 2.8 Hz, 2H, CH2C≡CH), 3.92 (s, 3H, OCH3), 4.14 (t, J=7.0 Hz, 2H, OCH2), 6.97 (d, J5,6=8.0 Hz, 1H, H5), 7.41 (s, 1H, H2), 7.43 (d, J5,6=8.0 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 18.1, 24.9, 27.9, 56.0, 68.5, 68.8, 83.9, 109.3, 111.4, 126.7, 130.0, 149.9, 154.0, 190.9; vmax 1029, 1269, 1584, 1681, 2956, 3246 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:15][CH2:16][CH2:17][OH:18])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH:8]1[CH2:9][CH2:10][CH:11]([CH3:14])[CH2:12][CH2:13]1)[CH2:15][CH2:16][CH2:17][O:18][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCCO)[C@H]1CC[C@H](C)CC1
Reactant: Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC(N(CCCOc2ccccc2)C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 51.5 %

Procedure:
(3-Hydroxy-propyl)-(trans-4-methyl-cyclohexyl)-carbamic acid tert-butyl ester (1.5 g, 5.53 mmol) and phenol (0.52 g, 5.53 mmol) in dry THF (15 mL) was added DEAD (1.06 g, 6.08 mmol) and resin bound triphenyl phosphine (polystyrene, 2% cross linking, loading=3 mmol/g, 2.76 g). The reaction mixture was gently stirred for 18 h before the resin was filtered off and washed with THF (2×15 mL). The fitrate was concentrated in vacuo and the resulting residue was purified (SiO2, 0-20% EtOAc in heptane) to give 0.99 g of (4-methyl-cyclohexyl)-(3-phenoxy-propyl)-carbamic acid tert-butyl ester. This was dissolved in DCMTFA ((3:1), 16 mL) and the mixture was stirred for 18 h before the solvent was removed in vacuo to give 0.75 g of the TFA salt of (4-methyl-cyclohexyl)-(3-phenoxy-propyl)-amine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[CH2:12]1[CH2:21][O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13]1>>[CH2:12]1[CH2:21][O:20][C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:3]=[C:4]([CH3:11])[C:5]4[N:6]([CH:8]=[N:9][N:10]=4)[N:7]=3)[CH2:16][CH2:15]2)[O:13]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1cc(Cl)nn2cnnc12
Product: Cc1cc(N2CCC3(CC2)OCCO3)nn2cnnc12

Procedure:
reacting 6-chloro-8-methyl-1,2,4,triazolo[4,3-b]pyridazine with 4,4-ethylenedioxypiperidine to give 6-(4,4-ethylenedioxy-1-piperidinyl) -8-methyl-1,2,4-triazolo[4,3-b]pyridazine;
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)C=C.CN(C)[C:18]1[CH:23]=CC=C[CH:19]=1>>[CH2:23]([C:15]1[CH:14]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:4])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=[CH2:19]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C(=O)OCC)cc1
Product: C=CCc1cc(C(=O)OCC)ccc1O
Temperature: 25 °C

Procedure:
A mixture of 82.3 g (0.899 mole) ethyl 4-allyloxybenzoate in 100 ml N,N-dimethylaniline was stirred under nitrogen while heating at reflux for 2 days. The resulting mixture was cooled to room temperature, the solvent distilled in vacuo, the residue taken up in ethyl ether, washed three times with 1N hydrochloric acid and extracted with 1N sodium hydroxide solution. The alkaline extract was acidified to pH 3.0, extracted with ethyl ether and the extracts dried (MgSO4). Evaporation of solvent provided 47.1 g of the desired product as a solid, TLC with 1.5:1 isopropyl ether/hexane gave one spot, Rf 0.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1OCCCC)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:18]>O1CCCC1.CO>[NH2:18][C:7]1[C:8](=[O:11])[C:9](=[O:10])[C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1c(N)c(=O)c1=O
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Preparation A: A solution of 1,2-dibutoxy-1-cyclobutene-3,4-dione (6.09, 0.027 mole) in 40 mL of tetrahydrofuran was cooled to 5° C. in an ice-water bath and treated dropwise over a period of 9 minutes with a solution of 1.8 mL of concentrated ammonium hydroxide in a mixture of 8 mL of tetrahydrofuran and 1 mL of methanol. After stirring at 5° C. for 30 minutes and at ambient temperature for 90 minutes the mixture was concentrated under reduced pressure to a slurry. A small amount of Skellysolve B was added and the product was collected by filtration after 16 hours of standing at 0° C. to give 3.26 g of the title compound. A sample (8.54 g) was partly dissolved in acetone, filtered and cooled to give 4.51 g of purified title compound; mp=165.5°-168° C. (clear melt).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=2)[C:22]([C:24](=[CH:27]NC2C=CC=CC=2)[C:25]#[N:26])=[O:23])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[NH2:26][C:25]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:27][C:24]=1[C:22](=[O:23])[C:21]1[CH:35]=[CH:36][CH:37]=[C:19]([O:18][CH2:17][CH2:16][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:20]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(OCCN2CCOCC2)c1
Reactant: NNc1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: Nc1c(C(=O)c2cccc(OCCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-fluorophenylhydrazine (1.0 g, 6.8 mmol) and 2-[3-(2-morpholin-4-ylethoxy)-benzoyl]-3-phenylaminoacrylonitrile (2.0 g, 5.3 mmol) in ethanol (30 ml) was heated at reflux under a nitrogen atmosphere. After 6 h, the reaction mixture was cooled to room temperature and diluted with water. The product was extracted into ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (elution gradient: CH2Cl2-3% MeOH/CH2/Cl2) gave 5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole which was converted to the hydrochloride salt (0.7 g, mpt. 191.6-192.5° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[I:11]N1C(=O)CCC1=O>C(O)(=O)C>[I:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1Cc2ccccc2N1
Solvent: CC(=O)O
Product: O=C1Cc2cc(I)ccc2N1
Temperature: 10 °C
Yield: 58 %

Procedure:
2-Oxindole (82.9 g) was suspended in 630 mL acetic acid and the misture was mechanically stirred and cooled to 10° C. in an ice water bath. Solid N-iodosuccinimide (175 g) was added in portions over 10 minutes. After the addition was complete the mixture was stirred for 1 hour at 10° C. The suspended solid which was always present became very thick at this time. The solid was collected by vacuum filtration, washed with 100 mL of 50% acetic acid in water and then with 200 mL of water and sucked dry for 20 minutes in the filtration funnel. The product was dried under vacuum to give 93.5 g (36%) of 5-iodo-2-oxindole containing about 5% 2-oxindole by proton NMR.