Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Br[C:6]1[N:10]([C@@H:11]2[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1>C(Cl)Cl>[Cl:23][C:21]1[C:20]([Cl:24])=[CH:19][C:9]2[N:10]([C@@H:11]3[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:6]([NH:4][CH2:1][CH:2]=[CH2:3])=[N:7][C:8]=2[CH:22]=1
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: C=CCN
Solvent: ClCCl
Product: C=CCNc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 83.1 %

Procedure:
Following General Procedure V, allylamine (Aldrich, 5 mL, 66.64 mmol), and 2-bromo-5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (250 mg, 0.65 mmol) reacted for 92 h. Purification on a silica gel column with 1:25 methanol:CH2Cl2 gave the title compound (195 mg, 0.54 mmol, 84%); MS (EI): m/z (rel. intensity) 358 (0.05, M+); 1H NMR (DMSO-d6) δ7.41 (s, 1H, Ar—H), 7.36 (s, 1H, Ar—H), 7.10 (t, 1H, NH, J=11.2 Hz), 5.94 (m, 1H, CH), 5.70 (d, 1H, CH, J=6.5 Hz), 5.25 (m, 3H, overlapping OH and CH2), 5.09 (d, 1H, OH, J=8.8 Hz), 4.35 (m, 1H, CH), 3.98 (m, 2H, CH2), 3.92 (m, 1H, CH), 3.81 (m, 1H, CH), 1.38 (d, 3H, CH3, J=6.5 Hz).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]([CH2:31][CH3:32])[C:27]([NH:29][CH3:30])=[O:28])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[Li+].[OH-].Cl>O1CCOCC1>[CH2:31]([N:26]([CH2:25][C:16]1[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:15]=1[C:7]1[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:6]=1)[C:27]([NH:29][CH3:30])=[O:28])[CH3:32]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)NC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)cc(C(F)(F)F)c1)C(=O)NC

Procedure:
To [2′-(1-ethyl-3-methyl-ureidomethyl)-5,4′-bis-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.18 mmol) was added 1:1 1N aqueous LiOH:1,4-dioxane (2 mL), and the reaction was stirred at room temperature for 30 minutes. 10% Aqueous HCl was added to acidify the solution to pH 3, and the mixture was extracted with EtOAc. The crude material was purified by silica gel chromatography to give the title compound. M+H is 463.
Reaction SMILES: [F:1][CH2:2][C:3](OCC)=O.[H-].C([Al+]CC(C)C)C(C)C.[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[F:1][CH2:2][CH:3]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CF
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCOC(=O)C=CCF
Reaction time: 0.5 h

Procedure:
Ethyl 2-fluoroacetate (21.0 g) in CH2Cl2 (200 mL) at −78° C. was treated dropwise over 45 min with a 1.0 M solution of diisobutylaluminum hydride in CH2Cl2 (200 mL) maintaining the internal temperature below −70° C. Stirring was continued at −78° C. for 30 minutes and then (carbethoxymethylene)triphenylphosphorane (70.0 g) was added in one portion. The reaction mixture was allowed to slowly reach room temperature while stirring overnight. It was then quenched with methanol, filtered and concentrated to give the product as a mixture of isomers (E/Z=3:1).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][CH:23]([CH2:25]O)[OH:24]>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][CH2:25][CH:23]([OH:24])[CH2:22][OH:21])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: OCC(O)CO
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO
Temperature: 50 °C

Procedure:
A mixture of oleic acid (1.5 g=5.32 mmoles), glycerol (0.57 g=6.2 mmoles), water (70 μl) and potato protein extract (100 mg) was stirred at 50° C. and a vacuum (<50 mbar) was applied to the system using an oil pump to remove water from the mixture. For comparison a similar reaction was run without vacuum in a stoppered tube. Samples were taken from the reaction mixtures periodically for analysis by GC. Progress curves for the reactions are given in FIG. 2. In the reaction cariied out under vacuum 4.43 mmoles of MG and 0.10 mmoles of DG were formed after 72 hours. 87% of the oleic acid was converted into acylglycerols. In the comparison reaction after 72 hours 3.51 mmoles of MG and 0.14 mmoles of DG were formed. The final conversion of oleic acid into acylglycerols was 71%.
Reaction SMILES: C([Li])CCC.[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]([CH:27]=[O:28])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CON(C)C(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH:24]([CH3:25])[CH3:26])[C:22]([C:27](=[O:28])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
n-Butyllithium (3.12 ml of 1.6 M solution in hexane, 5.0 mmol) was added to a stirred solution of 2-anilino-4-(2-formyl-1-isopropylimidazol-5-yl)pyrimidine (Example 10; 558 mg, 2.0 mmol) in anhydrous THF (20 ml) cooled to −70° C. The mixture was stirred for 30 minutes and then N-methoxy-N-methylbenzamide (660 mg, 4.0 mmol) was added and the reaction mixture was allowed to warm and stirred at ambient temperature for 18 hour. The reaction mixture was quenched with water (20 ml), and extracted with EtOAc (4×25 ml). The organic extracts were washed with brine (2×50 ml), dried and the volatiles removed by evaporation and the residue triturated with ether and the solid collected by filtration to give the title compound (303 mg, 43%) as a pale yellow crystalline solid. NMR (CDCl3): 1.55-1.70 (m, 8H), 5.52-5.68 (sept, 1H), 6.99 (d, 1H), 7.09 (dt, 1H), 7.18 (br s, 1H), 7.30-7.40 (m, 2H), 7.45-7.54 (m, 2H), 7.55 (s, 1H), 7.56-7.62 (m, 3H), 8.09 (d, 2H), 8.49 (d, 1 H); m/z 384.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH2:7][OH:8])[NH2:6].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][C:4](=[O:3])[CH:5]([NH2:6])[CH2:7][OH:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Product: NC(CO)C(=O)NCc1ccccc1
Yield: 34.2 %

Procedure:
To a stirred methanolic solution (250 mL) of L-serine methyl ester hydrochloride ((S)-6) (20.00 g, 128 mmol) was added benzylamine (55.9 mL, 512 mmol), and then the reaction solution was heated at reflux (18 h). The solvent was removed under reduced pressure, the insoluble salts were filtered, and the excess benzylamine was removed under high vacuum (Kugelrohr). The residue was dissolved in H2O (100 mL), and the product was extracted with CHCl3 (8×200 mL). The organic layers were combined and dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was triturated with Et2O (150 mL) and filtered to give 8.50 g (34%) of the product as a white solid: mp 76-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:48][CH:49]1[CH:56]2[CH2:57][C:52]3([OH:59])[CH2:53][CH:54]([CH2:58][CH:50]1[CH2:51]3)[CH2:55]2>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:48][CH:49]1[CH:50]2[CH2:58][CH:54]3[CH2:53][C:52]([OH:59])([CH2:57][CH:56]1[CH2:55]3)[CH2:51]2)=[O:10]
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: CC(C)(CCOc1ccc(Cl)cc1Cl)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CCOc1ccc(Cl)cc1Cl)C(=O)NC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred solution of 4-(2,4-dichloro-phenoxy)-2,2-dimethyl-butyric acid (250 g, 0.902 mmol, prepared in a similar way as described in J. Am. Chem. Soc. 89, 2500-1 (1967)) in dry DMF (3 mL) was added HOBt (180 mg, 1.173 mmol) and EDAC (225 mg, 1.173 mmol). After stirring for 1 hr at room temperature, DIPEA (306 μL) and 4-amino-adamantan-1-ol (181 mg, 1.082 mmol) were added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were removed in vacuo and the residue was purified using prep. HPLC/MS affording 153 mg (40%) of the title compound as a solid. 1H NMR (400 MHz, CDCl3) □ 1.34 (s, 6H), 1.52 (q, 4H), 1.69-1.79 (m, 4H), 1.87 (d, 2H), 2.02-2.16 (m, 5H), 2.57 (br.s., 1H), 3.95-4.02 (m, 1H), 4.05 (t, 2H), 6.02 (d, 1H), 6.83 (d, 1H), 7.17 (dd, 1H), 7.35 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][N:5]([CH3:23])[C:6](=[O:22])[CH2:7][C:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:10])[CH3:9].[CH3:25][I:26]>C(O)C>[I-:26].[CH2:14]([O:13][C:12]([NH:11][C:8]([CH3:10])([CH3:9])[CH2:7][C:6]([N:5]([CH2:4][CH2:3][N+:2]([CH3:25])([CH3:1])[CH3:24])[CH3:23])=[O:22])=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CI
Reactant: CN(C)CCN(C)C(=O)CC(C)(C)NC(=O)OCc1ccccc1
Solvent: CCO
Product: CN(CC[N+](C)(C)C)C(=O)CC(C)(C)NC(=O)OCc1ccccc1
Product: [I-]
Temperature: 50 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
Benzyl 4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl-4-oxobutan-2-ylcarbamate (2.08 g, 6.2 mmol) was dissolved in a solution of ethanol (4 ml) and methyl iodide (30 ml). The mixture was stirred at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo and dissolved in water. The aqueous mixture was washed with ethyl acetate. The washed aqueous mixture concentrated in vacuo to give 2.19 g (74%) of 2-(3-(benzyloxycarbonylamino)-N,3-dimethylbutanamido)-N,N,N-trimethylethanaminium iodide. MS (ESI+) calculated for C19H32N3O3+: 350.24, Found: 350.2 (M+).
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[CH:29][C:28]([I:31])=[C:27]([Cl:32])[CH:26]=4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[Cl:32][C:27]1[CH:26]=[C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:34])=[O:3])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[N:18][CH:19]=2)=[O:33])[CH:30]=[CH:29][C:28]=1[I:31]
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(I)c(Cl)c4)cn3)CC2)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c1
Product: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(I)c(Cl)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(3-Chloro-4-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared by the hydrolysis of 4-{4-[5-(3-chloro-4-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester with LiOH monohydrate in manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid, above. The product was obtained after suspension in small volume of EtOAc and filtration. HRMS m/z calcd for C23H20N4O3ClI [M+H]+: 563.0342. Found: 563.0343.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:28])[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:26]=2)=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-N-(4-hydroxyphenyl)-2-oxoacetamide (Example 199, 0.40 g, 1.05 mmol), methyl bromoacetate (0.18 g, 1.15 mmol) and potassium carbonate (0.29 g, 2.1 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 35:65) to give the title compound (0.32 g, 67%) as a colorless amorphous.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]1[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=1>C(O)C>[F:9][C:10]1[C:11]([C:18]([F:21])([F:19])[F:20])=[CH:12][C:13]([C:16]([NH2:17])=[O:2])=[N:14][CH:15]=1
Reactant: N#Cc1cc(C(F)(F)F)c(F)cn1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)c(F)cn1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To 12 ml of ethanol were added 1.01 g of sodium bicarbonate and 0.83 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.6 g of 5-fluoro-4-trifluoromethylpyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 2 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.4 g of 5-fluoro-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[C:15]([Cl:27])[CH:14]=1.[CH3:28][O:29][CH:30](OC)[CH2:31]OC>>[Cl:27][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][CH2:31][CH2:30][O:29][CH3:28])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: COCC(OC)OC
Reactant: Nc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Product: COCCNc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 43, 6-amino-4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-[3-chloro-4-(2-pyridylmethoxy)anilino]-6-(2-methoxyethylamino)quinazoline in 67% yield;
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1)[CH3:2].[Br:14]Br>C(Cl)Cl>[Br:14][C:4]1[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:7][C:3]=1[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Product: CCc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a solution of 5-ethyl-3-phenyl-1H-pyrazole (10.0 g, 58.1 mmol) in DCM (150 mL) was added dropwise bromine (9.28 g, 58.1 mmol) at 0° C. The reaction was stirred at that temperature for 30 min and continued for 2 h at room temperature and then quenched with aqueous Na2SO3 solution (10% w/w, 10 mL). DCM was removed and the residue was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow liquid (9.5 g). LCMS m/z=250.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.58 Hz, 3H), 2.66 (q, J=7.58 Hz, 2H), 7.40-7.56 (m, 3H), 7.82 (d, J=7.58 Hz, 2H), 13.15 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[C:12]3[C:24]2[N:29]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[CH:27]=[N:26][CH:25]=2)[CH:6]=[N:7][CH:8]=1.Cl>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:24]2[CH:25]=[N:26][CH:27]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)[N:29]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(-c2ccc3c(c2)c(-c2cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n2)nn3C2CCCCO2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cncc(-c2ccc3[nH]nc(-c4cncc(O[C@@H]5CCCNC5)n4)c3c2)c1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl (3R)-3-((6-(5-(5-methoxy-3-pyridinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.062 g, 0.106 mmol) and HCl (5 M in i-PrOH, 2.114 mL, 10.57 mmol, Acros) in 1 ml of MeOH and 1 mL of DCM was heated at reflux for 30 min. The crude reaction was cooled to RT and concentrated to a yellowish-green solid that was slurried with a 1/1 mixture of DCM/MeOH (2 mL) and applied to a pre-washed (5 mL MeOH) of Si-propylsulfonic acid (Silicycle, Cat# R51230B). The column was washed with MeOH (10 mL). The compound was released with 15 mL of 2 M NH3 in MeOH to afford 5-(5-methoxy-3-pyridinyl)-3-(6-((3R)-3-piperidinyloxy)-2-pyrazinyl)-1H-indazole as an off-white foam. MS (ESI, pos. ion) m/z: 403.1 (M+1).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:22]1[C:26]([CH3:27])=[N:25][N:24]=[N:23]1)[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:28][CH2:29][CH2:30][CH2:31][S:32](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:34])=[O:33]>>[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:21][CH2:20][CH:19]([N:22]1[C:26]([CH3:27])=[N:25][N:24]=[N:23]1)[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:34])=[O:33]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)n1nnnc1C
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)n1nnnc1C

Procedure:
3-Hexadecylthio-2-(5-methyl-1H-tetrazol-1-yl)propylamine IVi1 is allowed to react and worked up by the same procedure as described in (4). m.p. 62°-62.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(CC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1ccc(C(=O)O)cc1Cl
Yield: 86.8 %

Procedure:
A solution of ethyl 3-chloro-4-(2-methylpropyl)benzoate (D23) (1.76 g, 7.33 mmol), and aqueous sodium hydroxide (2M, 3.70 mL, 7.4 mmol) in ethanol (30 mL) was heated at 40° C. for 3 h. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL), the latter acidified with 2M HCl (4 mL). The aqueous layer was extracted with ethyl acetate (100 mL) and the combined organic extracts dried (phase separator) and concentrated in vacuo to give the title compound as a white solid (1.35 g, 6.36 mmol). δH (d6-DMSO, 400 MHz): 13.20 (1H, br. s), 7.89 (1H, d), 7.82 (1H, dd), 7.44 (1H, d), 2.64 (2H, d), 1.94 (1H, m), 0.89 (6H, d). MS (ES): C11H1335ClO2 requires 212; found 211 (M−H+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][C@H:21]([OH:36])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>O1CCCC1>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([O:23][CH2:22][C@H:21]([OH:36])[CH2:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:29][CH:28]=1
Reactant: O[C@@H](CCc1cccnc1)COc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 88 %

Procedure:
Diethyl azodicarboxylate (0.123 ml) was added to a stirring solution of (2S)-4-(3-pyridyl)-1-[(4-phenyl)phenoxy]-butan-2-ol (0.25 g), triphenylphosphine (0.262 g) and benzoic acid (0.122 g) in tetrahydrofuran (10 ml) at 0° C. and the resulting solution was stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was redissolved in methanol (20 ml) and water (5 ml). Solid potassium hydroxide (0.112 g) was added and the reaction stirred for 2 hours before being poured into a solution of saturated aqueous sodium hydrogencarbonate. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.22 g) as a solid that was recrystallised from ethyl acetate:hexane.
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11]([NH2:13])=[S:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][I:15]>CO>[IH:15].[C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[NH:13])[S:12][CH3:14])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(N)=S)n[nH]1
Reactant: CI
Solvent: CO
Product: CSC(=N)Nc1cc(C(C)(C)C)[nH]n1
Product: I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
270 mg (1.4 mmol) (5-tert-butyl-1H-pyrazole-3-yl)-thiourea were dissolved in 2 ml methanol, methyl iodide (202 mg, 1.4 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, dichloremethane was added to the residue and the mixture was stirred at room temperature. The solid was suction-isolated and dried (0.43 g).