Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18][CH3:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18][CH3:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2nnnc2SC)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2nnnc2SC)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine methyl 2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoate (0.51 g, 1.81 mmol) and lithium hydroxide (0.065 g, 2.71 mmol) and tetrahydrofuran/water (5 mL/5 mL). Heat to reflux. After 1 hour, cool to ambient temperature, separate the layers, and extract the organic layer 2 times with 1 M aqueous sodium hydroxide solution. Combine the aqueous layers and extract with diethyl ether. Acidify the aqueous layer using aqueous 1 M hydrochloric acid solution to give the title compound.
Reaction SMILES: [CH:1]#[C:2][CH2:3][C@@H:4]([NH2:8])[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.O>[CH:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:21]([NH:8][C@H:4]([CH2:3][C:2]#[CH:1])[C:5]([OH:7])=[O:6])(=[O:23])=[O:22]
Reactant: C#CC[C@@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of d-propargylglycine (32.10 g, 88.46 mmol), Na2CO3 (20.62 g, 194.6 mmol), and benzenesulfonyl chloride (18.74 g, 106.2 mmol) in p-dioxane/H2O (1:1, 200 ml) was stirred overnight at rt. The reaction mixture was concentrated and the ph adjusted to 4.0 with 10% hcl. The aqueous layer was extracted with CHCl3 (3×), dried over mgso4, and concentrated to give the title compound. 1H NMR (400 mhz, CDCl3): δ 2.04 (s, 1h), 2.65 (s, 3h), 2.71 (m, 2h), 4.11 (m, 1h), 5.61 (d, 8.4 hz, 1h), 7.61 (m, 3h), 7.88 (m, 2h).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([C:16](OC)=[O:17])[CH2:15][CH:14]=[CH:13][CH2:12]1)=O>O1CCCC1.C1(C)C=CC=CC=1>[OH:8][CH2:9][C:11]1([CH2:16][OH:17])[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: COC(=O)C1(C(=O)OC)CC=CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC1(CO)CC=CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
The desired diol was prepared via LAH reduction of the corresponding diester 2. To a flame dried round-bottomed flask was placed lithium aluminum hydride (LAH, Aldrich, 95%, 6.99 g, 175 mmol) and anhydrous tetrahydrofuran (THF, 235 mL). The resulting suspension was cooled to 0° C. and then a solution of the dimethyl diester 2 in 58 mL of anhydrous THF was added dropwise via an additional funnel. The resulting mixture was allowed to stir at 0° C. for 4 hours while monitored by TLC. The reaction mixture was then carefully quenched by sequential addition of 6 mL of water, 6 mL of 3 N aqueous solution of NaOH and 17.5 mL of water. The resulting mixture was allowed to slowly come to room temperature and then filtered through a bed of celite. The resultant solid cake was washed repeatedly with refluxing THF (total of 250 mL). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford alight yellow oil which was dissolved in 10 mL of refluxing toluene and the water was azeotropically removed, removal of the remaining toluene gave an off-white solid, which was recrystallized from refluxing toluene. The desired diol 3 was obtained as white needles in 86.2% yield, Mp (DSC) 81.21° C.; 1H-NMR (CD13, 300 MHz) δ5.59 (s, 2H), 3.73 (s, 2H), 3.63 (s, 4H), 2.16 (s, 4H); 13C-NMR (CD13, 300 MHz) δ128.69, 69.19, 47.53, 38.61; FT-IR (CH2Cl2) (cm−1) 3323, 3055, 2918, 2846, 1619, 1442, 1419, 1357, 1266, 1114, 1093, 1025, 955, 909, 896.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([C:7]([O:9][C@@H:10]2[CH2:15][C@@H:14]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[O:13][C@@:12]([O:36]C)([C@@H:21]3[CH2:25][S:24][C:23](=[O:26])[N:22]3CC3C=CC(OC)=CC=3)[CH2:11]2)=[O:8])=[CH:5][CH:4]=1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][C@@H:10]2[CH2:15][C@@H:14]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[O:13][C@@:12]([OH:36])([C@@H:21]3[CH2:25][S:24][C:23](=[O:26])[NH:22]3)[CH2:11]2)=[O:8])=[CH:38][CH:39]=1
Reactant: C=CCCC[C@@H]1C[C@@H](OC(=O)c2ccc(OC)cc2)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: C=CCCC[C@@H]1C[C@@H](OC(=O)c2ccc(OC)cc2)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl 4-methoxybenzoate was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[I-].[Na+].[OH-].[Na+].Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(O)(CC)(C)C.C1(C)C=CC=CC=1>[C:14]1([C:12](=[O:13])[CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1c[nH]nn1
Reactant: O=C(CCl)c1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCC(C)(C)O
Product: O=C(Cn1ccnn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
1,2,3-Triazole (1689 mg, 24.45 mmol), sodium iodide (2443 mg, 16.3 mmol) and sodium hydroxide (978 mg, 24.45 mmol) were added to t-amyl alcohol (6.5 ml), and the mixture was refluxed under stirring for 1 hour. 2-Chloro-1-phenylethanone (2520 mg, 16.3 mmol) was dissolved in t-amyl alcohol (13 ml) and added dropwise over 1 hour. The mixture was refluxed under stirring for 1 hour. The mixture was cooled to room temperature, toluene (50 ml) was added. The mixture was washed with water (50 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2→1/4) to give 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone (1.38 g) as brown crystals (yield 45%). 1-Phenyl-2-(2H-1,2,3-triazol-2-yl)ethanone (550 mg) was obtained as yellow crystals (yield 18%). 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:45])[S:35]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)(=[O:36])=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)S(=O)(=O)c3ccc(Cl)cc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(N(C)S(=O)(=O)c3ccc(Cl)cc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-6-(N-4-chlorobenzenesulphonyl-methylamino)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:12])[CH2:8][CH2:9]2)=[CH:5][C:4]=1[C:13]([NH2:15])=[O:14].C([O:20][N:21]=O)CCC.Cl>CO>[OH:20][N:21]=[C:8]1[C:7](=[O:12])[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([C:13]([NH2:15])=[O:14])[CH:5]=2)[CH2:9]1
Reactant: COc1cc2c(cc1C(N)=O)C(=O)CC2
Reactant: CCCCON=O
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1C(N)=O)C(=O)C(=NO)C2
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 6-Methoxy-3-oxo-indan-5-carboxylic acid amide (3 g, 14.6 mmol) in the methanol (50 ml) was added n-butylnitrite (1.8 ml, 16.06 mmol), followed by concentrated HCl (1.2 ml). The solution was stirred at r.t overnight during which time a precipitate was formed. The precipitate was collected and dried to yield product as a yellow solid (2.78 g, 81.37%). LC-MS: m/e 235(MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:24]=1)[C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.12 g) and ethyl bromoacetate (0.31 mL), ethyl 2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}pyrazol-1-yl)acetate (0.66 g) was obtained. This compound was dissolved in ethanol (20 mL), and 1 mol/L-aqueous sodium hydroxide solution (1.22 mL) was added. The mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1 mol/L-hydrochloric acid (1.22 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. By the reaction and treatment of the obtained residue in the same manner as in Example 17 (0.58 g), 2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}pyrazol-1-yl)acetic acid (0.23 g) was obtained. melting point: 180-182° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[O:20][CH3:21])=[O:11].[OH-].[Na+]>CO.O>[CH3:21][O:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[C:10](=[O:11])[CH:9]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(38) To a solution of benzaldehyde (295 mg, 2.77 mmol) and 2,6-dimethoxyacetophenone (500 mg, 2.77 mmol) in 4.1 ml of methanol was added 0.1 ml of 40% sodium hydroxide in water at 10° C. After stirring for 3 hour at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 371 mg (49.9%) of white flakes: mp 125.5-126.6° C. (lit. mp 123-124° C., Kuck and Grutzmacher, Org. Mass. Spect., 1978, 13, 90-102). 1H NMR (250 MHz) δ 7.55-7.51 (m, 2 H), 7.39-7.30 (m, 5H), 7.00-6.94 (d, 1 H), 6.64-6.61 (d, 2 H), 3.79 (s, 6 H); 13C NMR (62.7 MHz) 213.8, 176.1, 163.9, 153.4, 149.4, 149.0, 147.4, 147.3, 147.0, 122.6, 74.5 ppm.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:34]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Agent: Cl
Product: C[C@H](O)C(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([O:19][N:20]=[C:21]([NH2:23])[CH3:22])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]2[O:19][N:20]=[C:21]([CH3:22])[N:23]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(N)=NOC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Solvent: Cc1ccccc1C
Product: Cc1noc([C@@H]2CCCCN2S(=O)(=O)c2ccc(F)cc2)n1

Procedure:
The title compound was prepared by a similar method to Preparation 6 from N′1-[((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)oxy]ethanimidamide [see Preparation 82] and xylene. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 80:20, by volume, hexane:ethyl acetate in 10% increments, to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine as an oil.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)=[CH:13][C:12]=1[NH:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40](O)([CH3:42])[CH3:41])[CH:35]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)=[CH:13][C:12]=1[NH:32][C:33](=[O:44])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:7])([CH3:42])[CH3:41])[CH:35]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cccc(C(C)(C)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cccc(C(C)(C)F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., a solution of 34 μl (0.258 mmol) of diethylaminosulphur trifluoride (DAST) in 0.5 ml of anhydrous dichloromethane was added dropwise to a solution of 100 mg (0.215 mmol) of the compound of Example 141 in 4.5 ml of anhydrous dichloromethane. The reaction mixture was stirred at −78° C. for 1 h, about 5 ml of saturated aqueous sodium bicarbonate solution were then added and the mixture was warmed to RT. The mixture was diluted with about 10 ml of water and extracted three times with in each case about 10 ml of dichloromethane. The combined organic extracts were washed once with saturated aqueous sodium chloride solution and dried over magnesium sulphate. After filtration and evaporation, the residue obtained was separated into its components by preparative HPLC (Method 9). Evaporation of the product fractions and drying of the residue under high vacuum gave 40 mg (39% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Li]CCCC.CCOCC.[C:36](=[O:38])=[O:37].OS([O-])(=O)=O.[K+]>C1COCC1.O>[C:36]([C:9]1[S:10][C:6]2[CH2:5][CH2:4][N:3]([CH2:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:2](=[O:1])[C:7]=2[CH:8]=1)([OH:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sccc3C2=O)CC1
Reactant: O=C=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sc(C(=O)O)cc3C2=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of 2-4 (3.65 g, 0.01 moles) in THF (100 ml) was treated at -78° with n-BuLi (in hexane) and stirring was continued for 30 minutes. This was then poured into a slurry of Et2O/CO2 and this was stirred for 0.5 hours. A solution of 10% KHSO4 was added, and after stirring for 10 minutes, the reaction mixture was diluted with H2O. The organic phase was separated, washed with H2O, brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with CHCl3 (95)/MeOH(5) to give pure 2-5, Rf 0.5.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:28](=[O:35])[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH2:27])[CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:13][CH:12]=1)=[O:7])(C)(C)C.C(O)(=O)C.[CH:40]1[C:52]2[CH:51]([CH2:53]OC(ON3C(=O)CCC3=O)=O)[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>O.O1CCOCC1>[CH:40]1[C:52]2[CH:51]([CH2:53][O:5][C:6]([NH:8][C@H:9]([C:28](=[O:35])[N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17](=[CH2:27])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=3)=[O:7])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1
Reactant: C=C(CCC(=O)OC(C)(C)C)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: C=C(CCC(=O)O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (S)-4-(4-(2-((tert-butoxycarbonyl)amino)-3-oxo-3-(piperidin-1-yl)propyl)phenyl)pent-4-enoate (Compound SP415) (0.50 g, 1.03 mmol) was suspended in acetic acid (7.0 ml, 122.28 mmol) and water (7.0 ml), and the suspension was stirred with heating at reflux for 8 hours. The same reaction was additionally carried out four times. The reaction solutions were combined and concentrated under reduced pressure, and the resulting residue was suspended in a 10% aqueous sodium carbonate solution (38 ml). A solution of N-(9-fluorenylmethoxycarbonyloxy)-succinimide (1.65 g, 4.89 mmol) in 1,4-dioxane (19.0 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made acidic by adding acetic acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate=100:0-40:60) to afford the title compound SP416 (1.60 g, 56.3%).
Reaction SMILES: Cl.O.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=3)[N:22]=2)[CH2:12][CH2:11]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Solvent: O
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccccc4Cl)CC3)nn12

Procedure:
A mixture of 1-(2-chlorophenyl)piperazine hydrate hydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2-chlorophenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C@@H:7]2[CH2:9][C@H:8]2[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:20][O:21][NH2:22]>CO>[CH3:20][O:21][N:22]=[C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CON
Reactant: CC(=O)[C@@H]1C[C@H]1c1ccc(Cl)s1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
To a stirred solution of trans 1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethanone (1.0 g; 5.0 mmol) in methanol (10 ml) at ambient temperature was added pyridine (0.85 ml; 10.3 mmol) and methoxyamine hydrochloride (0.86 g; 10.3 mmol). The reaction mixture was stirred for 20 hours at ambient temperature then poured on water (50 ml) and extracted with dichloromethane (3×20 ml). Combined organic layers were dried over anhydrous sodium sulphate. The solvent was removed in vacuo to afford 1.0 g (92% of theory) of trans 1-[2-(5-Chloro-thiophen-2-yl)-cyclopropyl]-ethanone O-methyl-oxime as an E/Z mixture in form of a clear oil.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH3:8][CH:9]([CH3:28])[C:10]([O:12][CH:13]([O:17][C:18](ON1C(=O)CCC1=O)=[O:19])[CH:14]([CH3:16])[CH3:15])=[O:11]>>[C:10]([O:12][CH:13]([O:17][C:18]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:19])[CH:14]([CH3:15])[CH3:16])(=[O:11])[CH:9]([CH3:28])[CH3:8]
Reactant: NC1(C(=O)O)CC1
Reactant: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Product: CC(C)C(=O)OC(OC(=O)NC1(C(=O)O)CC1)C(C)C
Yield: 51.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (121 mg, 1.2 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanoate (301 mg, 1.0 mmol) were reacted to provide 148 mg (51% yield) of the title compound (2) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 127.4-129.0° C. 1H NMR (CDCl3, 400 MHz): δ=6.59 (d, 1H), 5.68 (br s, 0.3H), 5.39 (s, 0.7H), 2.58 (m, 1H), 2.01 (m, 1H), 1.61 (m, 2H), 1.30 (m, 2H), 1.19 (d, 3H), 1.18 (d, 3H), 0.99 (d, 6H). MS (ESI) m/z 305.20 (M+NH4)+; 310.15 (M+Na)+; 286.21 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[CH2:9]([N:13]1[CH:17]=[CH:16][N:15]=[N:14]1)[CH2:10][C:11]#[CH:12].C(N(CC)CC)C.C(Cl)(Cl)Cl>CN(C=O)C.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[N:6][CH:7]=1
Reactant: C#CCCn1ccnn1
Reactant: Brc1cnc(I)nc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1cnc(C#CCCn2ccnn2)nc1
Reaction time: 3 h

Procedure:
5-Bromo-2-iodo-pyrimidine (1.14 g, 4.0 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (0.533 g, 4.4 mmol) and triethyl amine (NEt3) (2 ml) are dissolved in DMF (1 ml) and copper iodide (CuI) (0.38 g, 0.2 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min bis(triphenylphosphine) palladium(II) dichloride (0.140 g, 0.2 mmol) is added and stirring is continued for 3 h at r.t. Chloroform (300 ml) is added; the mixture is washed with 1N HCl and water, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash column chromatography (chloroform (100%)->ethyl acetate (100%)) yielding 5-bromo-2-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrimidine as a beige solid. Yield 0.96 g (86%).