Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH:9]([CH3:13])[C:10]([CH3:12])(O)[C:4]=2[CH:3]=1>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[C:9]([CH3:13])=[C:10]([CH3:12])[C:4]=2[CH:3]=1
Reactant: CC1c2ccccc2Sc2ccc(Br)cc2C1(C)O
Agent: O=S(=O)(O)O
Product: CC1=C(C)c2cc(Br)ccc2Sc2ccccc21

Procedure:
A suspension of 7.7 g of 2-bromo-10,11-dimethyl-11-hydroxy-10,11-dihydro-dibenz[b,f]thiepine in 40 ml of 20% sulfuric acid is refluxed for 36 hours, with rapid stirring. The mixture is then cooled and extracted with three times 50 ml of ether. The ether extracts are combined, washed with water until neutral, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in 32 ml of 20% ethanolic potassium hydroxide solution and the solution is refluxed for 40 hours. It is then concentrated to dryness under reduced pressure and the residue is extracted with 100 ml of ether. The ether solution is washed with 20 ml of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in 300 ml of methanol, a small amount of insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. 2-Bromo-10,11-dimethyl-dibenz[b,f]thiepine is obtained in the form of yellowish crystals; melting point 108°-111°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9](O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([I:45])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: II
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1CCC(I)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) stirred solution of 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (1.0 g, 5.80 mmol) in 1:2 CH2Cl2/CCl4 (52 ml) is added triphenylphosphine (1.82 g, 6.96 mmol), imidazole (473 mg, 6.96 mmol), and iodine (1.79 g, 7.08 mmol). The reaction is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of saturated sodium thiosulphate (c.a. 50 ml) and stirred until the solution becomes clear. The layers are separated and the aqueous layer is extracted with CH2Cl2 (3×30 ml). The combined organic phases are washed with sodium thiosulphate (30 ml), brine (30 ml), dried with anhydrous MgSO4, filtered and evaporated at reduced pressure to an oily solid. Purification by dry flash chromatography, Keiselgel 15-40 grade silica, eluting with 3% ethyl acetate/iso hexane yields the title compound as a clear colourless oil.
Reaction SMILES: [NH:1]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:1]([CH:8]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Reactant: c1ccc(NC2CCNC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CCN2CCC(Nc3ccccc3)C2)cc1
Yield: 71.6 %

Procedure:
3-Anilinopyrrolidine (0.67 g) and 2-(4-fluorophenyl)ethyl p-toluenesulfonate (1.2 g) were dissolved in acetonitrile (20 ml), and potassium carbonate (2 g) was added. The mixture was refluxed for 3 hours, and after the completion of the reaction, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with an aqueous potassium carbonate solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=20:1). The obtained eluate was concentrated to give 3-anilino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.83 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][C:10]=1[S:13]([CH3:16])(=[O:14])=[O:15])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
10.8 g (0.045 mol) of methyl 2,3-dimethyl-4-methanesulfonylbenzoate was dissolved in 80 ml of carbon tetrachloride, and 8.3 g (0.047 mol) of N-bromosuccinimide and 0.1 g of benzoyl peroxide were then added, followed by stirring for 3 hours under heating reflux. After the solution was allowed to cool, insoluble substance was removed by filtration, and the resulting filtrate was washed with an aqueous sodium hydrogen bisulfite solution, and then dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure, the residue was purified through silica gel column chromatography to obtain 6.2 g of methyl 3-bromomethyl-4-methanesulfonyl-2-methylbenzoate in a state of crystals. Yield=43.4%.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[C:8]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:38])[C:30]([CH2:36][CH3:37])=[C:31]([C:34]#[N:35])[C:32]=1I)=[O:27])[CH3:24]>[Pd].C(O)C>[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:38])[C:30]([CH2:36][CH3:37])=[C:31]([C:34]#[N:35])[C:32]=1[C:11]1[CH:12]=[CH:13][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][CH:10]=1)=[O:27])[CH3:24]
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: 80 °C
Yield: 88.7 %

Procedure:
Charge deionized water (0.50 L), potassium carbonate (66.3 grams, 0.48 mol), and 4-biphenyl boronic acid (62.4 grams, 0.315 mol) and ethanol (1.4 L) to a 3 L 3-neck reaction flask equipped with a mechanical stirrer, condenser, heating mantle, thermocouple, and nitrogen inlet. Stir the mixture to dissolve the solids. Add 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (Preparation 38), additional ethanol (0.90 L) and stir the mixture while the flask is inerted with nitrogen. Add palladium black to the reaction mixture and heat the mixture to reflux at 80° C. Stir the reaction mixture at reflux for 70 minutes. Add ethyl acetate (0.50 L) and filter the mixture through Whatman® GF/F to remove palladium black. Concentrate the filtrate to about 0.6 L by distillation and filter the resulting suspension to collect the precipitate. Rinse the filter cake with ethanol (0.441 L) and vacuum-dry to afford 95.6 grams of the title compound in 88.7% yield.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8]([OH:10])=O)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH2:27]([NH2:32])[CH2:28][CH2:29][CH2:30][CH3:31].CCOCC>C(OCC)(=O)C>[CH2:27]([NH:32][C:8](=[O:10])[CH2:7][CH:6]([N:5]1[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]2[C:4]1=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: CCCCCN
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCNC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
By following the procedure of Example 46 utilizing 3-phthalimido-3-(3,4'-dimethoxyphenyl)propionic acid and amylamine (1.0 equiv) to afford 2.15 g (84%) of crude product. The crude product was dissolved in 150 mL of ethyl acetate and then 50 mL of ether was added and the mixture stirred for 1 hour. The resulting slurry was filtered and the solid dried in vacuo to afford 1.28 g (50%) yield of 3-phthalimido-3-(3',4'-dimethoxyphenyl)propionic amylamide as a white powder: mp 140.5°-142.1° C.; 1H NMR (DMSO-d6, 250 MHz), d 8.05 (t, 1 H, J=5 Hz), 7.85 (m, 4 H), 7.03 (br s, 1 H), 6.90 (m, 3 H), 5.68 (t, 1 H, J=8 Hz), 3.73 (s, 3 H), 3.71 (s, 3 H), 3.19 (d, 2 H, J=8 Hz), 2.8-3.1 (m, 2 H), 0.9-1.3 (m, 6 H), 0.74 (m, 3 H); 13C NMR (DMSO-d6) δ 168.8, 167.7, 148.5, 148.3, 134.5, 131.5, 131.2, 123.1, 119.5, 111.6, 111.1, 55.4, 50.6, 38.2, 37.4, 28.7, 28.3, 21.7, 13.7; Anal. Calcd. for C24H28N2O5. Theoretical: C, 67.9; H, 6.65; N, 6.60. Found: C, 67.84; H, 6.70; N, 6.57.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([Cl:19])=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(-c2cccc(F)c2)nc1
Yield: 99.3 %

Procedure:
6-(3-Fluorophenyl)-3-pyridinecarboxylic acid (82 mg, 0.376 mmol) was stirred in dioxane (4 mL) and thionyl chloride (0.137 mL, 1.88 mmol) added dropwise. The reaction mixture was heated at reflux for 40 min then concentrated in vacuo to give 6-(3-fluorophenyl)-3-pyridinecarbonyl chloride as a white solid (0.088 g) which was used directly in step 2.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[C:3]#[CH:4].[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>>[C:13]([O:1][CH:2]([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[C:3]#[CH:4])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C#CC(O)COC1CCCCO1
Solvent: c1ccncc1
Product: C#CC(COC1CCCCO1)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
3-Hydroxy-4-(tetrahydro-2-pyranyloxy)-butyne (8.0 g, 0.047 mole) was mixed with acetic anhydride (10 g, 0.098 mole) and pyridine (8 g, 0.098 mole). The solution was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The extract was sequentially washed with 10% hydrochloric acid (10 ml×5), saturated sodium bicarbonate aqueous solution (10 ml×5) and water (50 ml×3). The extract was dried over anhydrous magnesium sulfate, concentrated and separated by silica gel chromatography, eluted with n-hexane/ethyl acetate (5:1) to give colorless oil (9.0 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16])([O-])=O.CO.N.[H][H]>[Pd].O>[CH3:16][O:15][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: CCC(=O)Nc1ccc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O
Product: CCC(=O)Nc1ccc(OC)c(N)c1
Reaction time: 1 h

Procedure:
114 parts of 2-nitro-4-propionamidoanisole, 160 parts of methanol, 2.5 parts of a 30% aqueous solution of ammonia and 1 part of a 50% suspension of palladium on activated charcoal, moist with water, in 2 parts of water are charged to an autoclave equipped with an aerating stirrer. The autoclave is pressurised with hydrogen and, at a pressure of 18 bar and a temperature of 80° C., hydrogenation is carried out for 1 hour. 2-Methoxy-5-propionamidoaniline is obtained in quantitative yield in a purity of >97% (analysis by liquid chromatography).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1cccc(-c2ccccc2)c1

Procedure:
3-Bromophenol (1.0 g, 5.78 mmol), phenylboronic acid (1.4 g, 11.48 mmol), potassium carbonate (2.0 g, 14.47 mmol), and PdCl2(PPh3) (1/200 eq.) were added to a solution of dioxane/H2O (20 mL/5 mL). The resulting solution was refluxed for 16 h. The reaction mixture was then partitioned between Et2O and water, and the aqueous phase was extracted with Et2O. The combined organic layer was evaporated to dryness and purified by flash column chromatography (ethyl acetate/hexanes=1/9) to give TC-IV-119 (1.02 g, 100%) as a transparent oil.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C@H:8]2[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]2)=[CH:4][C:3]=1[CH:17]([F:19])[F:18].[Li]CCCC.CN([CH:28]=[O:29])C.[NH4+].[Cl-]>C1COCC1>[F:18][CH:17]([F:19])[C:3]1[CH:4]=[C:5]([O:6][CH2:7][C@H:8]2[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]2)[CH:15]=[CH:16][C:2]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: CC1(C)OC[C@H](COc2ccc(Br)c(C(F)F)c2)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2ccc(C=O)c(C(F)F)c2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
To a solution of (S)-4-((4-bromo-3-(difluoromethyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (65; 3 g, 0.089 mol) in THF (30 ml) was added n-BuLi (2.5M solution in hexane, 3.9 ml, 0.097 mol) at −78° C. The mixture was stirred at the same temperature for 1 h and DMF (0.929 g, 0.103 mol) was added dropwise. After stirring at −78° C. for an additional 20 min, saturated aqueous NH4Cl (30 ml) was added. The resulting reaction mixture was warmed to room temperature and extracted with Et2O (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether/EtOAc=5:1) to afford the titled compound, namely (S)-2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzaldehyde 66 (1.83 g, 72%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([I:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:15][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:37]([I:39])=[CH:38][C:30]=1[NH:29][S:26]([C:22]1[C:19]2=[N:20][S:21][N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:27])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1
Reactant: COC(=O)C(N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride (prepared as in Example 2, Part A) and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid as in Example 1, Part C. HPLC: RT=10.50 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 691.35; m/z found, 689/691 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.34 (s, 1H), 8.36 (dd, J=7.1, 0.9, 1H), 8.23 (dd, J=8.8, 0.9, 1H), 8.08 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.36-7.30 (m, 2H), 7.14 (d, J=2.0, 1H), 6.95 (d, J=8.3, 1H), 6.90 (dd, J=8.2, 2.0, 1H), 6.53 (d, J=7.0, 1H), 4.94 (q, J=5.6, 1H), 3.82 (s, 3H), 3.25-3.10 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1
Reactant: CN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C(O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-fluorophenyl 1-methylpiperidin-4-yl methanone 1.10 g (5 mmol) in 30 ml methanol was added in small portions sodium borohydride 0.378 g (10 mmol). The reaction mixture was stirred at room temperature for two hours, concentrated, added water and extracted with methylene chloride 2×50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 1.0 g of desired product in 90% yield.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:29][CH2:30][CH2:31][NH:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+]>COCCOC>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][CH2:31][CH2:30][NH:29][C:15]2[N:14]3[N:13]=[C:12]([CH:9]4[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:41])=[O:3])[CH2:7][CH2:8]4)[N:20]=[C:19]3[CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:16]=2)=[N:34][CH:35]=1)#[N:40]
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(CC(=O)O)CC4)nn23)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
105 mg (0.18 mmol) of ethyl-{4-[5-({2-[(5-cyanopyridin-2-yl)amino]ethyl}amino)-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]piperidin-1-yl}acetate (Example 57A) were dissolved in 1,2-dimethoxyethane (7.5 ml), water (5 ml) and 31 mg (0.76 mmol) of sodium hydroxide were added and the reaction mixture was stirred at RT for 16 h. The mixture was then concentrated by lyophilization. This gave, after purification of the residue by preparative HPLC (Method 11), 65 mg (65% of theory) of the product as a solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: Nc1nnn[nH]1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Nc3nnn[nH]3)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (500 mg; 1.2 mmol; 1 eq), is dissolved in anhydrous DCM (30 ml). The reaction is put under nitrogen. Triethylamine (0.34 ml; 2.41 mmol; 2 eq) and 5-amino-1H-tetrazole (204.6 mg; 2.41 mmol; 2 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (550 mg; 64%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: CC(C)(C)N
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(Br)ccc1C(=O)NC(C)(C)C

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-methylbenzoic acid and tertiarybutylamine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][NH:6]1)=[O:4].C(N(CC)CC)C.[CH:15]([S:18](Cl)(=[O:20])=[O:19])([CH3:17])[CH3:16]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:18]([CH:15]([CH3:17])[CH3:16])(=[O:20])=[O:19])=[O:4]
Reactant: COC(=O)C1CN1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of aziridine-2-carboxylic acid methyl ester (0.5 g) in dichloromethane (20 ml) at 0° C. were added triethylamine (0.95 g) and isopropylsulfonyl chloride (1.38 g). The mixture was warmed to room temperature and stirred for 3.5 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with brine. The organic phase was dried (MgSO4), filtered and evaporated to give the crude 1-(propane-2-sulfonyl)-aziridine-2-carboxylic acid methyl ester as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH:22][C:23](=[O:33])[CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:31][C:29]1[CH:30]=[C:25]([CH2:24][C:23]([NH:22][CH2:21][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:33])[CH:26]=[C:27]([F:32])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)Cc2cc(F)cc(F)c2)(c2ccc(I)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1cc(F)cc(F)c1)NCC1(c2ccc(I)cc2)CCNCC1
Yield: 50 %

Procedure:
To a stirred solution of 4-{[2-(3,5-difluoro-phenyl)-acetylamino]-methyl}-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.09 g, 0.16 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added TFA (0.5 mL, to give a 25% v/v solution). The mixture was stirred at room temperature for 3 h at which time TLC (4:1 hexanes/EtOAc) showed no starting material left. The solvent was removed by rotary evaporation and the resulting liquid was evaporated from toluene (2×10 mL) then diluted with EtOAc (100 mL) and washed with 10% aqueous NaHCO3 solution (2×50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and dried under high vacuum for 1 h to yield 4-{[2-(3,5-difluoro-phenyl)-acetylamino]-methyl}-4-(4-iodo-phenyl)-piperidine as a reddish solid (0.038 g, ˜0.08 mmol). MS (ESI): 471.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(F)ccc(N)c1Nc1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a solution of (3-fluoro-2-methyl-6-nitro-phenyl)-pyridin-2-yl-amine (2 g, 8.1 mmol) in EtOAc (25 mL) was added palladium on carbon (200 mg, 10% by wt) and the reaction mixture stirred at RT under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the title compound as a white solid (1.7 g, 100%). 1H NMR 400 MHz δ (CDCl3): 8.19-8.11 (1H, m), 7.42 (1H, ddd, J=8.8, 7.1, 2.0 Hz), 6.86 (1H, t, J=8.9 Hz), 6.69 (1H, dd, J=6.9, 5.1 Hz), 6.61 (1H, dd, J=8.8, 5.4 Hz), 6.16 (1H, d, J=8.3 Hz), 6.07 (1H, br s), 3.76 (2H, br s), 2.10 (3H, d, J=1.9 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[O:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:16][OH:17])[O:11][CH2:12][C:13]([OH:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(COCc1ccccc1)OCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COC(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1-O-Benzyl-3-t-butyldimethylsilyl-2-O-carboxymethylglycerol (5 g) was dissolved in methanol (50 ml), and a solution of 85% potassium hydroxide (7 g) in water (50 ml) was added thereto. The mixture was stirred at room temperature for 60 hours to complete the reaction.