Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1C(C)=[N:4][O:5][C:6]=1[N:7]([CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1OC(=O)C)(=[O:10])=[O:9].C([SiH]([CH2:47][CH3:48])CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:47]([CH3:48])=[N:4][O:5][C:6]=1[N:7]([CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][CH:30]=1)(=[O:10])=[O:9]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc3ccccc3c2OC(C)=O)sc2ncccc12
Reactant: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cccc3ccccc23)sc2ncccc12
Yield: 65 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyi)-N-(methoxyethoxymethyl)-2-(α-acetoxynaphthylmethyl)thieno[2,3-b]pyridine-3-sulfonamide (97 mg, 0.16 mmoles), CH2Cl2 (3 ml), triethylsilane (0.25 ml, 1.6 mmoles) and boron trifluoride etherate (0.19 ml, 1.6 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 58 mg (66%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:27]C(OC(C)(C)C)=O)[C:8]([NH:10][C@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[CH2:13][CH2:14][CH:15]=[C:16]3[C:20]([O:22]C(C)(C)C)=[O:21])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:1]1([C@@H:7]([NH2:27])[C:8]([NH:10][C@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[CH2:13][CH2:14][CH:15]=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N[C@H]1C(=O)N2C(C(=O)OC(C)(C)C)=CCC[C@H]12)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N[C@@H](C(=O)N[C@H]1C(=O)N2C(C(=O)O)=CCC[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 70.9 %

Procedure:
In this Example, 280 mg. (0.59 mmole) of (±)-cis-7-[(R)-2-phenyl-2-t-butyloxycarbonylaminoacetamido]-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]oct-2-en-8-one obtained in Example 25 is dissolved in 2.5 ml of anhydrous methylene chloride and 2.5 ml of anisole, and 5.0 ml of trifluoroacetic acid is added under ice cooling. The mixture is allowed to stand for 4 hours and 50 minutes under ice cooling and is then concentrated. To the concentrated residue, 10 ml of ether is added and the mixture is stirred at room temperature for one hour to form a precipitate. The precipitate is collected by filtration to obtain 202 mg. (70.9%) of the desired compound as a pale yellow powder having the following properties.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[Cl:15][C:16]1[N:17]=[C:18](Cl)[C:19]2[CH:24]=[CH:23][NH:22][C:20]=2[N:21]=1>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([O:11][C:7]2[C:6]([CH3:12])=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:8]=2[CH3:10])[C:19]2[CH:24]=[CH:23][NH:22][C:20]=2[N:21]=1
Reactant: Cc1cc(C2CC2)cc(C)c1O
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a solution of 4-cyclopropyl-2,6-dimethylphenol (259 mg, 1.60 mmol) in THF (3 mL) at 0° C. was added NaH (64 mg, 1.60 mmol). The reaction mixture was stirred at room temperature for 30 min and a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.53 mmol) in THF (2 mL) was added to the mixture. The mixture was heated at 80° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with CHCl3 (3×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 79 mg (48%) of 2-chloro-4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidine as a tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][CH:16]=[CH:17][C:10]=23)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].CN(C)C=O.C(O)C>[Fe].O>[NH:15]1[C:11]2=[N:12][CH:13]=[CH:14][C:9]([O:8][C:7]3[CH:18]=[CH:19][C:4]([NH2:1])=[CH:5][CH:6]=3)=[C:10]2[CH:17]=[CH:16]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1

Procedure:
4-(4-Nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (84 mg), iron powder (160 mg), ammonium chloride (320 mg), dimethylformamide (4 ml), ethanol (2 ml) and water (2 ml) were stirred at 100° C. for 15 minutes. The mixture was filtered with celite, and then water and ethyl acetate were added for extraction. The organic layer was washed 5 times with aqueous ammonium chloride solution and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 230 mg of the target substance as a brown oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26].[CH:31](=O)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]3[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=3)[C:25]([O:27][CH3:28])=[O:26])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: CCCCCC=O
Reactant: CCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 60 °C
Yield: 131.4 %

Procedure:
To a solution of 4-[(4-ethylphenyl)ethynyl]benzaldehyde (530 mg; 2.26 mmol, intermediate which may be prepared according to methods disclosed in EP03103780.7) in toluene (35 mL) were added methyl 5-amino-2-fluorobenzoate (382 mg; 2.26 mmol) and AcOH (194 μL) and the reaction mixture was refluxed with azeotropic removal of water until complete consumption of, the aldehyde (determined by 1H NMR of aliquots). Toluene was concentrated under reduced pressure and the residue dissolved in DCE (25 mL). Hexanal (Aldrich, 818 μl; 6.79 mmol), acetic acid (194 μL) and sodium triacetoxyborohydride (1,4 g, 6.79 mmol) were added to the solution, which was then heated at 60° C. for 3 hrs. The reaction mixture was poured into a saturated solution of NaHCO3 and extracted twice with DCM. Combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated to give 1.4 g of a brown solid. Purification by flash chromatography using silica gel (EtOAc/c-Hex, gradient from 97:3 to 95:5) yielded to 330 mg (30%) of the title compound as a white solid. HPLC, Rt: 6.27 min (purity: 61%), LC/MS, M+(ESI): 472.2, 1H NMR (CDCl3) δ: 7.43 (t, J=7.7 Hz, 4H), 7.17 (m, 5H), 6.90 (t, J=10.7 Hz, 1H), 6.73 (m, 1H), 4.49 (s, 2H), 3.88 (s, 3H), 3.35 (t, J=7.8 Hz, 2H), 2.63 (qd, J=7.5 Hz, 2H), 1.61 (m, 2H), 1.28 (m, 6H), 1.22 (t, J=7.6 Hz, 3H), 0.85 (t, J=5.1 Hz, 3H).
Reaction SMILES: [C:1]12([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[Cl:24][C:25]1[C:26](=[O:32])[NH:27][N:28]=[CH:29][C:30]=1Cl>C(O)C>[C:1]12([N:11]3[CH2:16][CH2:15][N:14]([C:30]4[CH:29]=[N:28][NH:27][C:26](=[O:32])[C:25]=4[Cl:24])[CH2:13][CH2:12]3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C1CN(C23CC4CC(CC(C4)C2)C3)CCN1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]ncc(N2CCN(C34CC5CC(CC(C5)C3)C4)CC2)c1Cl
Yield: 73.7 %

Procedure:
A mixture of 1-(1-adamantyl)piperazine (2.2 g, 10 mmol), triethylamine (1.36 ml, 10 mmol) and 4,5-dichloro-3-oxo-2,3-dihydropyridazine (1.65 g, 10 mmol) in ethanol (25 ml) was heated under reflux for 5 hours. After cooling the precipitated solids were collected, washed with ethanol and dried to afford 2.57 g of the title compound, yield: 73.6%, mp. 292°-294° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CNc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (10.0 g, 53.9 mmol) and aniline (2.34 mL, 25.7 mmol) in ethanol (200 mL) was added acetic acid (7.35 mL, 128 mmol), followed by the portion-wise addition of sodium cyanoborohydride (4.84 g, 77 mmol). The resulting mixture was stirred at rt for 2.5 hrs and concentrated to vacuo. The residue was partitioned between ethyl acetate and saturated aq. NaHCO3, and the organic layer was dried over anhydrous Na2SO4. The drying agent was filtered off, and solvent was removed in vacuo to give a crude product that was purified by column chromatography on silica gel using a solvent gradient of 0-1% methanol in dichloromethane to give the title compound (5.7 g, 85%).
Reaction SMILES: C(N)(=N)C1C=CC=CC=1.[CH3:10][C@H:11]1[CH2:94]O[C@@:14]2(O[C@H:17]3[C@@H:19](O)[C@H:20]4[C@@H:25]5[CH2:26][CH2:27][C@H:28]6[CH2:33][C@@H:32]([O:34][C@@H]7O[C@H](CO)[C@H](O[C@@H]8O[C@H](CO)C(O)[C@H](O[C@@H]9OC[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O[C@@H]8O[C@H](CO)[C@H](O)[C@H](O[C@@H]9O[C@H](CO)[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O)[C@H](O)[C@H]7O)[C@H:31](O)[CH2:30][C@:29]6([CH3:89])[C@H:24]5[CH2:23][CH2:22][C@:21]4([CH3:90])[C@H:16]3[C@@H:15]2[CH3:92])[CH2:13][CH2:12]1>P([O-])([O-])([O-])=O>[CH3:94][CH:11]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:16]1[C@:21]2([CH3:90])[C@H:20]([C@H:25]3[C@H:24]([CH2:23][CH2:22]2)[C@:29]2([CH3:89])[C:28]([CH2:33][C@H:32]([CH2:31][CH2:30]2)[OH:34])=[CH:27][CH2:26]3)[CH2:19][CH2:17]1)[CH3:92])[CH3:10]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1[C@@H](O)[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[C@@H]6O[C@H](CO)[C@H](O[C@@H]7O[C@H](CO)C(O)[C@H](O[C@@H]8OC[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O[C@@H]7O[C@H](CO)[C@H](O)[C@H](O[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: N=C(N)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Human pancreas was received at autopsy. About 30 g of tissue in 10 mM phosphate, pH 6.0, 50 mM benzamidine, 0.5% digitonin were homogenized with a polytron, centrifugally pelleted (48,000×g, 30 min.) and the supernatant collected. The supernatant was centrifugally pelleted (100,000×g, 60 min.) again and the second supernatant was passed through glass wool and dialized overnight against 50 mM benzamidine, 10 mM phosphate, pH 6.8. The dialysate was loaded onto a hydroxylapatite column (2.6×10 cm) equilibrated with 50 mM benzamidine, 10 mM phosphate, pH 6.8. The column was washed with identical buffer, then developed with a linear gradient of 50 mM to 350 mM phosphate, pH 6.8, 50 mM benzamidine. The cholesterol esterase activity eluted at a conductivity of 20-22 mS/cm. These fractions were pooled and loaded onto an AcA34 column (Bio-Rad Laboratories, Inc., 2200 Wright Avenue, Richmond, Calif. 94804) (2.6×90 cm) equilibrated with 500 mM NaCl. 10 mM phosphate, pH 6.0. The fraction emerging at an apparent molecular weight of 350 kDa contained cholesterol esterase activity and was dialyzed against 10 mM phosphate, pH 6.0.
Reaction SMILES: [O:1]1[CH2:5]C[CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:18][C:17]([CH2:29][CH2:30][CH3:31])=[C:16]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].[H-].[Na+].ClCOCC>C(O)(=O)C>[CH2:2]([O:1][CH2:5][N:18]1[C:17]([CH2:29][CH2:30][CH3:31])=[C:16]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=2)[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]1[CH2:26][CH2:27][CH3:28])[CH3:3]
Reactant: C1CCOC1
Reactant: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(CCC)N1
Agent: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(CCC)N1COCC
Temperature: -20 °C

Procedure:
In 10 ml. of tetrahydrofuran was dissolved 0.5 g. of diethyl 4-(3-nitrophenyl)-2,6-dipropyl-1,4-dihydropyridine-3,5-dicarboxylate and after adding to the solution 0.2 g. of a 50% oil dispersion of sodium hydride, the mixture was stirred for 2 hours at room temperature. After cooling the mixture to -20° C., 0.5 ml. of chloromethoxyethane was added thereto and the mixture reacted for 1.5 hours at temperatures of from -20° C. to -10° C. After adding to the reaction product 0.5 ml. of glacial acetic acid and 20 ml. of water, the product was extracted three times each time with 5 ml. of ether at room temperature. The extracts were combined, washed with 5 ml. of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the ether was distilled away. The residue was subjected to a silica gel column chromatography, using a 10:1 benzene-acetone mixed solvent as an eluant, the effluent thus recovered was examined by a thin layer chromatography, and the effluent of the main fraction recovered was concentrated. By recrystallizing the residue formed from hexane, 0.4 g. of colorless acicular crystals of diethyl 1-ethoxymethyl-4-(3-nitrophenyl)-2,6-dipropyl-1,4-dihydropyridine-3,5-dicarboxylate melting at 109°-110° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:16]2[CH2:15][CH2:14][N:13]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[C@H:12]([CH3:11])[CH2:17]2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1c(Cl)nnc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)[C@H](C)C2)c1C
Temperature: 120 °C
Yield: 36.5 %

Procedure:
Combine 3,6-dichloro-4,5-dimethyl-pyridazine (100 mg, 0.554 mmol), (R)-2-methylpiperazine (85 mg, 0.831 mmol), potassium carbonate (383 mg, 2.77 mmol) and DMF (1 mL) in vial. Heat in the microwave at 120° C. for 3.25 h. Add 2-chloro-5-trifluoromethylpyridine (181 mg, 0.997 mmol) and heat at 180° C. for 30 min. The crude reaction is purified directly by flash chromatography on silica gel (0-40% EtOAc in heptanes) to afford the title compound as a light yellow solid (78 mg, 37%).
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].ClCCl.C(N(CC)CC)C.[CH2:28]([NH2:31])[C:29]#[CH:30]>O1CCCC1>[S:1]([NH:31][CH2:28][C:29]#[CH:30])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: C#CCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
234 mg of dansyl chloride (0.87 mmol) and 4.0 mL of anhydrous dichloromethane were placed in a 25 mL round-bottom flask equipped with a CaCl2 trap. 240 μL of triethylamine (1.73 mmol) and 330 μL of propargylamine (5.20 mmol) were added to the solution, which was then kept under stirring for 12 hours at room temperature. The residue obtained by distillation under reduced pressure was redissolved in some mL of tetrahydrofuran and the resulting mixture was filtrated. The evaporation of the solvent of the filtrated solution under reduced pressure affords the product in quantitative yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.C1(C(OC(C)(C)C)=O)CC1.BrCCCC[Cl:31].[Li+].CC([N-]C(C)C)C>>[Cl:31][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Reactant: ClCCCCBr
Agent: CC(C)(C)OC(=O)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)C1(CCCCCl)CC1

Procedure:
Compound 104a was prepared, likewise the procedure described for 103b, starting from t-butyl cyclopropanecarboxylate (Kohlrausch, K. W. F. et al. Z Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285) (12.5 g, 88 mmol), 1-bromo-4-chlorobutane (13.7 mL, 117 mmol) and LDA (prepared from BuLi (2.5M in hexanes, 37 mL, 92.5 mmol) and iPr2NH (12.3 mL, 88 mmol, distilled from NaOH)) to give, after purification by fractional distillation under reduced pressure, 104a (10.73 g 52%) as a colorless oil. bp: T=57-61° C. (p=0.001 mbar). 1H NMR: δ 3.52 (t, J=6.6 Hz, 2H), 1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 2H), 1.42 (s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR: δ 173.9, 80.0, 45.1, 33.6, 32.9, 28.2 (3×), 25.3, 24.2, 15.4 (2×). HRMS calcd for C12H22ClO2 (MH+): 233.1308, found: 233.1308.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7](/[C:10](=[N:18]/[NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])/[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O1CCCC1.[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=O)=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[Cl:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]2[N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[N:18]=[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)[C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)N1CCC(/C(Cc2ccncn2)=N/NS(=O)(=O)c2ccc(C)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nn(S(=O)(=O)c3ccc(C)cc3)c(-c3ccc(Cl)cc3)c2-c2ccncn2)CC1

Procedure:
This reaction was carried out in a 100 ml round bottom flask. N′-[(1E)-1-(1-acetylpiperidin-4-yl)-2-pyrimidin-4-ylethylidene]-4-methylbenzenesulfonohydrazide (7) (5g, 11 mmol) was charged to the reactor, followed by tetrahydrofuran (“THF”, 31 ml), which, in turn, was followed by 2.15 ml of triethylamine (“TEA”, 2.15 ml) and 4-dimethylaminopyridine (“DMAP”, 0.134 g). 4-Chlorobenzoyl chloride (8) (“4-CBC”, 2.09 ml) was then charged all at once while stirring the mixture. The reaction was brought to reflux. Liquid chromatography indicated that the reaction was complete in just over 1 hr. The solution was washed with saturated ammonium chloride (2×25 ml), and the THF was removed in vacuo to yield a yellow oil (11.18 g), which solidified upon sitting. Recrystallization from ethanol/water yielded 4.88 g of a white powder (76% yield). The product had the following characteristics: 1H NMR (CDCl3, 300 MHz) δ 9.20 (1H, s), 7.63 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.30 (2H, d, J=8.1 Hz), 7.29 (1H, s), 7.21 (2H, d, J=8.4 Hz), 6.64 (1H, d, J=5.1 Hz), 4.71–4.52 (1H, m), 4.01–3.82 (1H, m), 3.59–3.44 (1H, m), 3.28–3.08 (1H, m), 2.84–2.58 (1H, m), 2.46 (3H, s), 2.16 (3H, s), 2.02–1.62 (4H, m). 13C NMR (CDCl3, 75 MHz) δ 169.11, 158.91, 146.39, 136.80, 134.55, 132.01, 130.13, 129.19, 126.72, 34.91, 31.15, 22.01, 21.69.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16](O)=[O:17])[C:10]2=[O:34])[CH:4]=1)#[N:2].C([N:37](CC)CC)C.ClC(OCC)=O.[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16]([NH2:37])=[O:17])[C:10]2=[O:34])[CH:4]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ccc(S(=O)(=O)N(CC(N)=O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxynaphthalene-2-sulfonyl)amino]acetic acid (0.40 g, 0.80 mmol) in 6 mL of THF at -15° C. is added triethyl amine (0.10 g, 0.96 mmol) and ethyl chloroformate (0.09 g, 0.84 mmol). The solution is stirred for 1 hour. After this time, NH4OH (0.07 mL, 0.90 mmol) is added and the solution is allowed to warm to ambient temperatures. After 16 hours, the solution is diluted with EtOAc. The solution is washed with 1 N HCl, sat. NaHCO3 and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The title compound (0.28 g, 0.56 mmol) is obtained as a white foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[N:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[N:2]1)[CH3:16]
Reactant: c1cnc2[nH]ncc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2cccnc21
Temperature: 70 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 7-aza indazole (250 mg, 2.1 mmol) and ethyl bromoacetate (0.47 mL, 4.2 mmol) in DMF (8 mL) was added K2CO3 (1.16 gm, 8.4 mmol) and the resulting mixture stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic layer was washed with water (2×5 mL), brine (5 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified using silica gel column chromatography eluting with EtOAc:hexane 10:90 to afford the title compound as an off-white solid in 49% yield, 210 mg.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].[C:8](O)(=O)[CH3:9].O>C1(C)C=CC=CC=1>[CH:3]([C@H:2]1[CH2:6][O:7][C:8]([CH3:9])=[N:1]1)([CH3:5])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(C)[C@H](N)CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=N[C@@H](C(C)C)CO1
Reaction time: 24 h
Yield: 77.8 %

Procedure:
20 g (0.194 mol) valinol are dissolved with 11.64 g (0.194 mol) acetic acid in 60 ml toluol and cooked for 24 h under reflux in the water separator. After cooling the solution is extracted with 10% hydrochloric acid. The aqueous phase is neutralized with 40% sodium hydroxide solution and extracted with diethyl ether. The organic phase is dried via NaSO4 and the solvent removed. Distillation (112° C.) produces 19.2 g (78%) 4-(S)-isopropyl-2-methyloxazoline as a colourless oil.