Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([C:13]#[C:14][CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:27]>CO.[OH-].[OH-].[Pd+2]>[ClH:27].[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][NH2:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C#CCNC(=O)OCc2ccccc2)s1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(CCCN)s1
Reaction time: 16 h

Procedure:
To a solution of 5-(3-benzyloxycarbonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid tert-butyl ester (1.0 g, 2.69 mmol) in 15 mL MeOH and 2.69 mL 1N HCl (aq) was added Pd(OH)2 (1 g). The mixture was shaken in a Parr shaker under 45 psi H2 for 16 h. The catalyst was removed by filtration through Celite and additional Pd(OH)2 (1 g) was added. The reaction was shaken at 45 psi H2 for 6 h and the catalyst was removed by filtration through Celite. The solution was concentrated in vacuo. The residue was azeotroped with CCl4 and was triturated with Et2O to provide the title amine (360 mg).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2Br)=[N:2]1.C([Li])CCC.C[CH2:23][O:24]CC>CCCCCC>[O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:23]=[O:24])=[N:2]1
Reactant: Brc1ccccc1-c1noc2c1CCCC2
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=Cc1ccccc1-c1noc2c1CCCC2
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.1 g of 2-(4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl)-bromobenzene in 100 ml of ether at a temperature of -40° C. was added 11 ml of a 1.5M solution of butyllithium in hexane with magnetic stirring. The reaction was warmed to -20° C. and held at this temperature for 5 minutes. The lithio species was quenched by the addition of 1.3 ml of N,N-dimethylformamide. To the reaction was added 100 ml of saturated ammonium chloride and the solution was extracted with two 200 ml portions of ether. The combined organic layers were dried over sodium sulfate and evaporated to yield 3.5 g of 2-(4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl)-benzaldehyde, GC-M.S. (E.I.) (M/Z): 226 [M-H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Yield: 81 %

Procedure:
To 60 ml of dioxane were added 3.33 g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one and 3.40 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The mixture was refluxed for 12 hours. After water cooling, the precipitate was removed by filtration. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 2.68 g (yield: 81%) of 7-methylsulfonylamino-6-phenoxy4H-1-benzopyran-4-one [Compound No. 1].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:21])[N:15]3[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]3)=[O:10])=[C:4]([Cl:23])[CH:3]=1.[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:21])[N:15]3[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]3)([OH:10])[C:25]([F:27])([F:26])[F:24])=[C:4]([Cl:23])[CH:3]=1
Reactant: CC(C(=O)c1ccc(=O)n2ccccc12)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n2ccccc12)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 1-[2-(4-bromo-2-chloro-phenyl)-propionyl]-quinolizin-4-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a light yellow solid. MS (m/e)=460.2 [M+H+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:29][C:30]([F:35])([F:34])[C:31]([CH3:33])=[O:32]>O1CCCC1>[C:13]([C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:31]([OH:32])([CH3:33])[C:30]([F:35])([F:34])[F:29])=[CH:25][CH:26]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(C#Cc1ccc(C(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (99 mL, 0.87 mmol) in freshly distilled tetrahydrofuran (5 mL) was added a solution of n-butyllithium (326 mL of a 2.5M solution in hexanes, 0.81 mmol). The solution was stirred at -78° C. for 25 minutes before a tetrahydrofuran solution of 4-benzoylphenylethyne (120 mg, 0.58 mmol) was added. The reaction was kept at -78° C. for an additional 20 minutes before 1,1,1-trifluoroacetone (521 mL, 5.8 mmol) was added in one portion. After stirring at -78° C. for 15 minutes the reaction was quenched by pouring into a saturated NH4C1 solution. The product was extracted into diethyl ether. The combined ethers were dried and evaporated. The crude product was adsorbed onto silica gel and purified by chromatography, with ethyl acetate:hexanes as the eluent (gradient 1:9 to 1:3), to yield the title compound as a white solid after trituration with hexanes (80 mg, 43%); mp 94.5°-96.0° C.; 250 MHz NMR (CDCl3): 1.76 (s,3, CH3), 2.88 (s,1, OH), 7.46-7.64 (m,5, Ar), 7.77-7.79 (m,4, Ar); MS: m/z=319(M+ 1). Analysis for C18H13F3O2 : Calculated: C, 67.92; H, 4.14; Found: C, 68.16; H, 4.15.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].C(OC(C1[N:24](N)C(C(OCC)=O)=CC=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:24])[C:8]([CH3:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)n1N
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1C
Product: CCOC(=O)c1c(C)c(C(=O)OCC)n(N)c1C

Procedure:
Compound 409A was prepared from 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester by a route analogous to that used for the preparation of compound 406C.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[C:25]([F:26])[C:20]=2[O:19][N:18]=1.CN([CH:31]=[O:32])C.C(O)(=O)C>C1COCC1.CCOCC.CCOC(C)=O>[Cl:16][C:17]1[C:21]2[CH:22]=[C:23]([CH:31]=[O:32])[C:24]([F:27])=[C:25]([F:26])[C:20]=2[O:19][N:18]=1
Reactant: Fc1ccc2c(Cl)noc2c1F
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=Cc1cc2c(Cl)noc2c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 115.6 %

Procedure:
A solution of n-butyllithium (2.5 M in hexanes) (16.7 ml, 42 mmol) was added slowly to a solution of 2,2,6,6-tetramethylpiperidine (7.6 ml, 45 mmol) in THF (50 ml) cooled in a dry ice-acetone bath. The solution was warmed to 0° C. and re-cooled in a dry-ice acetone bath before transferring via syringe to a solution of 3-chloro-6,7-difluorobenzo[d]isoxazole (Intermediate 529, 5.64 g, 30 mmol) in THF (50 ml). After 1 hour stirring, DMF (1.0 ml, 13.2 mmol) was added all at once and the mixture was stirred with cooling in a dry-ice acetone bath for 45 min. The mixture transferred via cannula to a solution of acetic acid (6.8 ml, 119 mmol) in 100 ml Et2O and the mixture was warmed to room temperature. The mixture was diluted with EtOAc and washed with brine. The combined aqueous layers were extracted again with EtOAc, which was washed with brine. Drying (MgSO4) of the combined extracts and removal of solvent gave a brown oil that was chromatographed on silica gel (10% CH2Cl2 in hexanes followed by gradient elution to 100% CH2Cl2) to give 3.32 g of product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:40](=[O:42])[CH3:41])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC(COc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 18 h
Yield: 103.8 %

Procedure:
A solution of amine 84 (480 mg, 0.87 mmol) in DCM (8 mL) was treated with acetic anhydride (0.12 mL, 1.3 mmol) followed by DMAP (11 mg, 0.087 mmol). After 18 h, the solution was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 86 (537 mg, 100%) as a white foam that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.11-6.99 (m, 1H), 6.89 (br s, 1H), 6.74-6.67 (m, 1H), 6.61-6.56 (m, 1H), 4.77-4.69 (m, 1H), 4.63-4.57 (m, 2H), 4.39 (d, J=6.3 Hz, 1H), 4.10-3.95 (m, 2H), 3.82-3.67 (m, 2H), 3.54-3.48 (m, 1H), 3.45-3.36 (m, 1H), 2.87-2.79 (m, 4H), 2.44-2.38 (m, 1H), 2.23-2.08 (m, 6H), 1.65 (s, 1H), 1.49 (s, 9H), 1.32 (d, J=6.9 Hz, 3H), 0.99 (s, 9H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:19])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C

Procedure:
3-Bromo-4-chlorobenzoic acid (2.35 g, 10 mmol) was suspended in CH2Cl2 (50 mL) and stirred under argon at room temperature. Oxalyl chloride (2.53 g, 20 mmol) was added followed by DMF (10 μL). Gas evolution began, and the mixture was stirred until gas evolution ceased. The solvents were pumped off and toluene was added and stripped off to remove excess oxalyl chloride. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (10 mL). This was stirred for 30 min. The phases were separated and the organic washed 1× with brine dried over anhydrous Na2SO4, filtered, and evaporated. The residue was crystallized from EtOAc/hexane to give the title compound as a white crystalline solid. LC-MS m/z 233.7 (M+H)+, 1.54 min (ret time); mp 146-147° C.; analytical HPLC shows 100% purity, (ret time: 11.835 min).
Reaction SMILES: N([O-])=O.[Na+].CC(O[Na])=[O:7].[F:10][C:11]([F:29])([O:14][C:15]([F:28])([F:27])[C:16]([F:26])([F:25])[C:17]([F:24])([F:23])[O:18][C:19]([F:22])([F:21])[F:20])[CH2:12][OH:13]>CC1(C)N([O])C(C)(C)CCC1.C(O)(=O)C>[F:10][C:11]([F:29])([O:14][C:15]([F:27])([F:28])[C:16]([F:25])([F:26])[C:17]([F:23])([F:24])[O:18][C:19]([F:20])([F:21])[F:22])[C:12]([OH:7])=[O:13]
Reactant: OCC(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: CC(=O)O[Na]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Yield: 77.7 %

Procedure:
70 mL of acetic acid, 0.24 g sodium nitrite, TEMPO (0.18 g), CH3CO2Na (3.69 g) and 5 g of 2,2-difluoro-2-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-ethanol were placed in the reaction vessel described in example 17. The reaction was carried out and worked up as described in example 9. Distillation of the residue gave 4.05 g of the acid (20 mmHg, 65° C.). Yield: 78%.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)c1nc2ncccc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ncccc2n1-c1ccccc1
Temperature: 90 °C
Yield: 36.2 %

Procedure:
A mixture of (S)-1-(1-phenyl-1H-imidazo[4,5-b]pyridin-2-yl)ethylamine (330 mg, 1.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (460 mg, 1.94 mmol) and DIPEA (440 μL, 2.49 mmol) in n-butanol (2 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) and then crystallised from EtOAc and MeOH to afford 199 as a white solid (178 mg, 36%). LCMS (Method K): RT 2.72 min [M+H]+ 357.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.42 (1H, dd, J=4.73, 1.53 Hz), 8.20-7.94 (3H, m), 7.68 (2H, d, J=7.55 Hz), 7.63-7.48 (4H, m), 7.23 (1H, dd, J=8.06, 4.74 Hz), 5.51 (1H, br s), 1.60 (3H, d, J=6.85 Hz)
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([C:23]([O:25]C)=[O:24])=[O:22])=[CH:11][CH:10]=2)[C:6]2[C:27]([C:31]([O:33]CC)=[O:32])=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].O.[OH-].[Li+]>>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([C:23]([OH:25])=[O:24])=[O:22])=[CH:13][CH:14]=2)[C:6]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)C(=O)OC)cc3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1
Yield: 96.6 %

Procedure:
300 mg of ethyl 2-ethyl-1-[(2'-methoxalylbiphenyl-4-yl)methyl]benzimidazole-7-carboxylate [prepared as described in step (b) above] were subjected to hydrolysis using 134 mg of lithium hydroxide monohydrate in the same manner as described in Example 17(b), to give 264 mg of the title compound as a powder, melting at 278°-281° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].Cl.FC(F)(F)C1C=C(C2C=C(C([O-])=O)SN=2)C=CC=1>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)ns1
Agent: Cl
Agent: O=C([O-])c1cc(-c2cccc(C(F)(F)F)c2)ns1
Agent: [K+]
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)ns1
Yield: 85 %

Procedure:
A solution of 1.6 g. of methyl 3-(3-trifluoromethylphenyl)-5-isothiazolecarboxylate in 30 ml. of 95% alcohol containing 1.0 g. of potassium hydroxide was heated at reflux for one hour. The reaction mixture then was added to 50 g. of ice, and the aqueous solution was acidified by the addition of 12 N aqueous hydrochloric acid. The product which precipitated was collected by filtration and crystallized from toluene and hexane to provide 1.3 g. of 3-(3-trifluoromethylphenyl)-5-isothiazolecarboxylate acid. Yield 85%. M.P. 162.5°-164° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[SH2:13].[Na]>CN(C=O)C>[SH:13][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: NS(=O)(=O)c1cc(Cl)ccc1Cl
Reactant: S
Agent: [Na]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(Cl)ccc1S
Yield: 30.1 %

Procedure:
To 34.0 g (0.15 mol) of 2,5-dichloro-benzene sulfonamide in 200 mL of DMF was added 16.0 g (0.28 mol) of sodium hydrogensulfide. The mixture was refluxed for 18 hours, then cooled, concentrated, and the solids collected by filtration. The solids were dissolved in hot water, the pH adjusted to 4.0 and the precipitate filtered. This material was dried to yield 10.1 g of the title compound, mp 142°-144° C.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([NH2:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1.Br>C(O)(=O)C>[OH:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([NH2:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(CC(N)c2ccccc2)c1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: NC(Cc1cccc(O)c1)c1ccccc1
Yield: 79.9 %

Procedure:
A mixture of dl-2-(3-methoxyphenyl)-1-phenylethylamine hydrochloride (11.3 g), 48% hydrobromic acid (100 ml) and glacial acetic acid (30 ml) is refluxed for 4 hours. After the reaction, the solvent is distilled off. To the residue is added water and the mixture is made alkaline with ammonia and extracted with chloroform. The chloroform layer is dried over anhydrous potassium carbonate and the solvent is distilled off. To the residue is added ether. The precipitated crystals are separated by filtration and recrystallized from ethanol-ethyl acetate to give the desired compound (7.3 g), melting point: 179°-181° C.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[C:20]1([CH2:26][CH2:27][CH:28]=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:28]([OH:29])[CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: O=CCCc1ccccc1
Reactant: N#Cc1ccc(Cn2cncn2)cc1
Agent: [Li]CCCC
Product: N#Cc1ccc(C(C(O)CCc2ccccc2)n2cncn2)cc1

Procedure:
1-[1-(4-cyanophenyl)-2-hydroxy-4-phenylbutyl]-1,2,4-triazole is prepared by the method described in Example 1 starting from 1-(4-cyano-benzyl)-1,2,4-triazole (2.0 g, 0.0108 mol), n-BuLi (0.0108 mol) and 3-phenylpropionaldehyde (1.74 g, 0.013 mol). The product is purified by flash chromatography.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:18])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O-])([O-])=O.[K+].[K+].[Cl:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=1>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[C:3](=[O:18])[N:4]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([CH2:26][Cl:25])=[CH:28][CH:29]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1[nH]ccc(OCc2ccc(F)cc2F)c1Br
Reactant: ClCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1ccc(CCl)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one (0.60 g, 2.5 mmol) in DMF (40 mL) was added K2CO3 (0.70 g, 5.1 mmol) and α,α′-dichloro-p-xylene (0.53 g, 3.0 mmol), and the reaction mixture was stirred at 110° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with brine, and extracted with CHCl3 (4×100 mL). The combined organics were washed water and then brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 3-bromo-1-(4-chloromethylbenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as an off-white solid (0.49 g, 43%): 1H NMR (300 MHz, CDCl3) δ 7.54 (app q, J=8 Hz, 1H), 7.38-7.28 (m, 5H), 6.94 (td, J=8, 2 Hz, 1H), 6.85 (td, J=8, 2 Hz, 1H), 6.10 (d, J=9 Hz, 1H), 5.21 (s, 2H), 5.16 (s, 2H), 4.56 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[K+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1ncc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2ncc(F)cc2F)cc1
Reaction time: 18 h

Procedure:
To a solution of (3,5-difluoropyridin-2-yl)methanol (0.25 g, 0.7 mmol) in tetrahydrofuran (THF; 10 mL) was added potassium hydroxide (KOH; 0.14 g, 2.55 mmol) at RT, and the mixture was stirred for 15 min. p-Toluenesulfonyl chloride (0.42 g, 2.21 mmol) was added slowly at RT, and the reaction mixture was stirred for another 18 h. After complete consumption of the starting material (by TLC), the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with H2O (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 15% EtOAc/hexane afforded compound I-5 (0.18 g, 0.25 mmol, 35%) as colorless liquid. 1H NMR (500 MHz, CDCl3): δ 8.29 (s, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.20-7.16 (m, 1H), 5.20 (s, 2H), 2.45 (s, 3H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[SH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=2)([OH:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2Sc2cccc(F)c2)CC1

Procedure:
Prepared from 4-hydroxy-4-(2-mercapto-5-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester and 1-fluoro-3-iodo-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3([C:32]#[N:33])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClCCl.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3([CH:32]=[NH:33])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc2CSc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: N=CC1(CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc2CSc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(11-cyano-6,11-dihydrodibenzo[b,e]thiepin-11-yl)propyl]piperidin-4-ol (1.92 g) in dichloromethane (30 ml) at −78° C. was added 1M diisobutyl aluminum hydride dichloromethane solution (10 ml). The reaction mixture was warmed to room temperature, and stirred for 30 minutes. Water and dichloromethane were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give the titled compound (1.16 g).