Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH3:33][S-:34].[Na+].O>CC(O)C>[CH:18]1([CH2:17][S:14]([CH:11]2[CH2:12][CH2:13][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:2]=3[S:34][CH3:33])([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CSc1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Yield: 97.8 %

Procedure:
A solution of 2-chloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexylmethyl)-6-trifluoromethylnicotinamide (75 mg, 0.15 mmol) in propan-2-ol (5 ml) was treated with sodium thiomethoxide (21 mg, 0.30 mmol) and the mixture was heated under reflux for 4 hours. Water (1 ml) was added and the solvent was evaporated. The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and the layers were separated using a 5 micron PTFE frit and the filtrate was evaporated. The residue was purified by preparative plate chromatography eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band followed by trituration of the silica with ethyl acetate, filtration and evaporation gave a pale yellow foam (74 mg, 97%). 1H NMR δ (ppm)(CDCl3): 8.00 (1H, d, J=7.8 Hz), 7.41 (1H, d, J=7.8 Hz), 6.40 (1H, s), 3.64 (2H, d, J=6.3 Hz), 2.98-2.89 (3H, m), 2.63 (3H, s), 2.09-1.90 (6H, m), 1.46-1.16 (5H, m), 0.79-0.69 (3H, m), 0.55-0.51 (2H, m), 0.45-0.40 (2H, m), 0.09-0.06 (2H, m). MS (m/e)=505.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.N#C[Br:27]>O1CCCC1>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([Br:27])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: c1ccc(CSc2ncn(-c3ccccc3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1nc(SCc2ccccc2)nn1-c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
3-Benzylthio-1-phenyl-1,2,4-triazole (5 g) in dry tetrahydrofuran (50 ml) at -70° C. was treated dropwise with n-butyllithium (1.05 equivs). The solution was stirred at -70° C. for 10 minutes and cyanogen bromide (1.98 g) was added rapidly. The mixture was allowed to warm to room temperature and was then quenched with ethanol. The volatile materials were removed in vacuo, and the crude product was chromatographed on silica using dichloromethane to give 4.3 g of the desired product as a yellow oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[C@@H:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH2:1]([C@@H:8]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[C@@H:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc([C@@H]4CCN(C(=O)OC(C)(C)C)[C@H](Cc5ccccc5)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3ccc([C@@H]4CCN[C@H](Cc5ccccc5)C4)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of (2S,4R)-tert-butyl 2-benzyl-4-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.190 g, 0.387 mmol) in DCM (3 mL) was added TFA (1 mL) and the mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo and EtOAc (2 mL) was added to the residue. The precipitate was collected by filtration and washed with EtOAc (1 mL) and petroleum ether (2 mL) to give (R)-9-((2S,4R)-2-benzylpiperidin-4-yl)-1-methyl-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #109-2, Enantiomer 2, SFC (Table 1, Method 21) Rt=4.521 min, 0.190 g, 97%) as a solid. LC/MS (Table 1, Method 4) Rt=1.617 min; MS m/z: 391 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1.[CH:14]1([C:17](=O)[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1.C1C=CC=CC=1>C(O)(=O)C>[CH:14]1([C:17]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]3[C:2]([CH3:1])=[N:3][N:4]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)[C:5]=3[N:7]=2)[CH2:15][CH2:16]1
Reactant: Cc1cc(N)n(-c2ccncc2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2-c1ccncc1

Procedure:
The title compound was prepared in the same manner as described for intermediate 30 using 3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-amine (310 mg, 1.780 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (328 mg, 1.780 mmol), benzene (50 mL), and acetic acid (25 mL). The final product was collected as 3.71 (71% overall). LCMS E-S (M+H)=323.5 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.22 (m, 4 H), 1.41 (t, J=7.07 Hz, 3 H), 2.64-2.69 (m, 4 H), 4.47 (q, J=7.07 Hz, 2 H), 7.74 (s, 1 H), 8.27-8.36 (m, 2 H), 8.66-8.71 (m, 2 H).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH:13]=[CH:14][C:15]2[C:23]3[O:22][C:21]([CH3:25])([CH3:24])[CH2:20][C:19]=3[CH:18]=[C:17]([F:26])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:26][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:28][CH:27]=2)[C:23]2[O:22][C:21]([CH3:25])([CH3:24])[CH2:20][C:19]=2[CH:18]=1
Reactant: CC1(C)Cc2cc(F)cc(C=Cc3ccc(OCc4ccccc4)cc3)c2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Cc2cc(F)cc(CCc3ccc(O)cc3)c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 7-(4-(benzyloxy)styryl)-5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran (649) (207.7 mg, 0.583 mmol) in ethanol (6 mL) was added Pd/C (20 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, was filtered through a pad of celite and concentrated in vacuo to give 4-(2-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)phenol (650).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[N:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:6]([CH2:7][OH:8])[C:5]([O:12][CH3:13])=[N:4][C:3]=1[CH3:14]
Reactant: COC(=O)c1cc(F)c(C)nc1OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: COc1nc(C)c(F)cc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-fluoro-2-methoxy-6-methylnicotinate (19) (0.25 g, mmol) in MDC was added DIBAL-H in dropwise (2.5 ml, 1M in Toluene) at 0° C. The reaction mixture was stirred for 2 h at RT. Reaction was quenched with saturated ammonium chloride solution and extracted with DCM (2×50 ml). The combined organic layer was washed with water, brine and solvent was evaporated under reduced pressure to yield (5-fluoro-2-methoxy-6-methylpyridin-3-yl)methanol (20) as a liquid (0.2 g 90%).
Reaction SMILES: [OH-].[Na+].[N:3]1[C:7]2[C:8]3[C:13]([CH:14]=[CH:15][C:6]=2[S:5]C=1N)=[CH:12][CH:11]=[CH:10][CH:9]=3>O.C(O)CO>[NH2:3][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[SH:5]
Reactant: Nc1nc2c(ccc3ccccc32)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Nc1c(S)ccc2ccccc12
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a solution of 30.0 g sodium hydroxide in 30 ml of water and 180 ml of ethylene glycol was added 18.0 g (0.089 mol) of naphtho[1,2-d]thiazol-2-amine. The mixture was stirred and heated at reflux under nitrogen for 20 hours then diluted with 100 ml of water. After cooling to room temperature the mixture was extracted with ether (4×95 ml). The aqueous solution was cooled in an ice-bath and neutralized with acetic acid. The aqueous suspension was extracted with ether (3×175 ml). The combined ether solutions were washed with water and dried (MgSO4). Removal of the solvent gave a residue to which heptane (3×50 ml) was added and distilled off under reduced pressure to give 10.5 g (67%) of 1-aminonaphthalene-2-thiol. This compound is sensitive to air, and therefore was used immediately for the condensation with the glycidate. For analysis a sample of this compound was distilled at 110°-115° (0.05 mm), mp 36°-37°.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][CH2:3]1.[C:18]1([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:11][C:10]([O:9][C:7]([NH:6][C@@H:5]([CH2:4][CH2:3][C:2](=[O:1])[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:31]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:8])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Brc1cccc(OCc2ccccc2)c1
Product: COC(=O)[C@H](CCC(=O)c1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized (420 mg, 6%) following Description 6 from 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 3.69 g, 15.2 mmol) and 3-bromophenyl phenylmethyl ether (D48); Rt (HPLC): 6.2 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])[CH2:3][CH2:2]1.[Br:13][C:14]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:15]=1[O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](OS(C(F)(F)F)(=O)=O)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[Br:13][C:14]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:15]=1[O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([C:12]#[C:11][CH2:10][CH2:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1OS(=O)(=O)C(F)(F)F
Reactant: C#CCCCCN1CCOCC1
Product: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1C#CCCCCN1CCOCC1

Procedure:
Using an analogous procedure to that described in the second last paragraph of Note [115] above, 6-morpholino-1-hexyne was reacted with 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-trifluoromethanesulphonyloxyquinazoline to give 4-(2-bromo-4-fluorophenoxy)-6-methoxy-7-(6-morpholino-1-hexynyl)quinazoline, NMR Spectrum: (DMSOd6) 1.63 (m, 4H), 2.33 (m, 6H), 2.55 (m, 2H), 3.56 (m, 4H), 4.0 (s, 3H), 7.35-7.8 (m, 3H), 7.65 (s, 1H), 7.96 (s, 1H), 8.6 (s, 1H); Mass Spectrum: M+H+ 514 and 516.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.CCCCCC>C(OCC)(=O)C>[CH2:1]([S:8][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: SCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=Cc1ccc(SCc2ccccc2)cc1

Procedure:
Title product was prepared from benzyl mercaptan (145 mmol, 17.9 g) and 4-bromobenzaldehyde according to the method of Preparation 1 yielding 4 g of purified product following chromatography on silica gel using 9:1 hexane:ethyl acetate as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)[CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:26][CH2:25][CH2:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:13]([N:10]3[CH2:9][CH2:8][CH:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:35][CH:34]=4)[CH2:12][CH2:11]3)=[O:14])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2cc(C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCn1ccc2cc(C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of tert-butyl (2-(5-(4-(4-chlorophenoxy)piperidine-1-carbonyl)-1H-indol-1-yl)ethyl)carbamate (112 mg, 0.23 mmol, Step-1), trifluoroacetic acid (1.5 mL), and dichloromethane (1.5 mL) was stirred at room temperature for 1 hour. After concentration in vacuo, the residue was purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX) to give 83 mg (83% yield) of the title compound as yellow oil. 13 mg of this material was further purified by preparative LC-MS to give 6.6 mg (51% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]([C:29]([O:31]CC)=[O:30])=[C:26]([CH3:28])[N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+].CO>C1COCC1>[CH2:1]([O:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]([C:29]([OH:31])=[O:30])=[C:26]([CH3:28])[N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO[C@@H]1CN(c2nc(C)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCO[C@@H]1CN(c2nc(C)c(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 87.6 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(3-butoxy-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (120a) (0.34 g, 0.68 mmol), 2 N lithium hydroxide (5 mL, 10 mmol), methanol (3 mL) and THF (5 mL), to obtain 0.28 g of the title compound as a colorless solid (88%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C:16]([CH3:18])([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([NH2:21])=O)=[CH:6]3.C(N(CC)CC)C.O=P(Cl)(Cl)Cl>C(Cl)Cl>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[O:14][CH2:15][C:16]([CH3:18])([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:22])[C:5]([C:19]#[N:21])=[CH:6]3
Reactant: CC1(C)COc2c(F)c(F)c(N)c3c(=O)c(C(N)=O)cn1c23
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 0 °C
Yield: 94.6 %

Procedure:
A mixture of 11 (2.92 g, 9.44 mmol) and triethylamine (6.6 mL, 47 mmol) in CH2Cl2 (20 ml) was cooled to 0° C. and POCl3 (4.35 g, 28 mmol) was added drop wise with stirring. The mixture was stirred an additional 5 h at 0° C. During that time, the reaction mixture turned dark-brown. Upon completion of the reaction, the solvent was removed by evaporation. 70 mL of water were added and the mixture stirred at room temperature for 1 h. The precipitate that formed was collected by filtration and washed with water. The solid was dried under vacuum to yield 12 as a brown solid (2.6 g, 94%). This compound was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[C:26]([CH:30]=1)[C:27](O)=[O:28])(=[O:21])=[O:20]>>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:27]([C:26]3[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=[CH:24][C:25]=3[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[O:28])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Reactant: Fc1cc(N2CCNCC2)ccc1C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)c(F)c3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine (Example P) and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 514.5 MH+.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1)[C:3]([O:5][CH3:6])=[O:4].Cl(O)(=O)(=O)=O.C(=O)([O-])O.[Na+].C(O[C:30]([CH3:33])([CH3:32])[CH3:31])(=O)C>>[C:30]([O:1][CH:2]([C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)C(O)c1cn2ccccc2n1
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1cn2ccccc2n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 55 %

Procedure:
To a solution of methyl 2-hydroxy-2-{imidazo[1,2-a]pyridin-2-yl}acetate (25b) (153 mg, 0.74 mmol) in tert-butyl acetate (12 mL) at 0° C. was added perchloric acid (1.5 mL). The mixture was stirred at 0° C. for 15 minutes and at room temperature for 45 minutes before being poured into a saturated aqueous solution of sodium hydrogencarbonate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 50/50) to provide the desired product (25c) (108 mg, 0.41 mmol, 55%) as a colorless oil.
Reaction SMILES: [Na:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([OH:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C([O-])(=O)C.[Na+]>>[Na:1].[C:27]([O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([OH:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][CH:8]=1)(=[O:29])[CH3:28]
Reactant: O=S(=O)(O)Oc1ccc(C(c2ccc(O)cc2)c2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Na]
Product: CC(=O)Oc1ccc(C(c2ccc(OS(=O)(=O)O)cc2)c2ccccn2)cc1

Procedure:
100 g. 4-hydroxyphenyl-4-sulphoxyphenyl-(2-pyridyl)-methane sodium salt were treated with 400 ml. acetic anhydride and 100 g. anhydrous sodium acetate under conditions similar to those described in Example 4. The reaction mixture was filtered and the filtrate was concentrated at a reduced temperature and under reduced pressure. By subsequently adding excess diethyl ether, there was obtained a crystalline solid which was further purified with appropriate mixtures of ethanol and diethyl ether. A high yield of pure 4-acetoxyphenyl-4-sulphoxyphenyl-(2pyridyl)-methane sodium salt was thus obtained in the form of colourless crystals which melted at 142° - 143°C.
Reaction SMILES: C(OC([N:6]1[C:10]2[CH2:11][N:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH2:13][C:9]=2[C:8]([NH:24][C:25](=[O:45])[C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[C:28]([N:39]([CH2:41][CH2:42][O:43]C)[CH3:40])[CH:27]=2)=[N:7]1)=O)C>B(Br)(Br)Br.ClCCl>[F:23][C:19]1[CH:18]=[C:17]([S:14]([N:12]2[CH2:13][C:9]3[C:8]([NH:24][C:25](=[O:45])[C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)=[C:28]([N:39]([CH2:41][CH2:42][OH:43])[CH3:40])[CH:27]=4)=[N:7][NH:6][C:10]=3[CH2:11]2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)c(N(C)CCOC)c2)c2c1CN(S(=O)(=O)c1cccc(F)c1)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cccc(F)c3)C4)cc2N(C)CCO)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
A solution of 5-(3-fluoro-benzenesulfonyl)-3-[3-[(2-methoxy-ethyl)-methyl-amino]-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester (120 mg, 0.186 mmol) in 5 mL of 1M BBr3 in dichloromethane was stirred at room temperature for 24 h. The mixture was washed with saturated aqueous NaHCO3 and the combined organic layers were evaporated to dryness. The resulting crude (110 mg) was then dissolved in 4 mL of MeOH and 0.5 mL of triethylamine and the mixture was stirred at room temperature for 3 h. The solvent was removed and the final product was purified by flash column chromatography, using dichloromethane-methanol-aqueous ammonia 9:1:0.5 as eluant, affording 70 mg of yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23][CH3:24])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23]([CH3:24])=[O:38])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ncccn2)cc1Cl
Solvent: ClCCl
Product: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
In DCM (5 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (150 mg, 0.35 mmol). m-CPBA (3-chloroperbenzoic acid, 110 mg, 0.64 mmol) was added at 0° C. The reaction was conducted for 30 min at ambient temperature. Then the reaction mixture was washed with water and extracted with DCM. The organic phase was dried, and the solvent was removed by rotary evaporation. Purification was performed by silica gel column chromatography (DCM/methanol=50/1) to give solid 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulphinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (100 mg, 64% yield).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)[CH2:21]1
Reactant: Fc1cccc(C2CCCNC2)c1
Reactant: BrCC1COc2ccccc2O1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1cccc(C2CCCN(CC3COc4ccccc4O3)C2)c1
Temperature: 140 °C
Yield: 135.5 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (340 mg, 0.48 mmol), 3-(3-fluorophenyl)piperidine (323 mg, 2.50 mmol) and triethylamine (455 mg, 4.50 mmol) in acetonitrile (3 mL) was heated in a microwave reactor at 140° C. for 60 min. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 213 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[CH2:6][NH:7]C(=O)OC(C)(C)C)#[N:2].[ClH:26]>CCOCC>[ClH:26].[NH2:7][CH2:6][C:5]1[CH:15]=[CH:16][C:17]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC1(C)CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2C#N)CC1
Agent: Cl
Solvent: CCOCC
Product: CC1(C)CCN(c2ccc(CN)cc2C#N)CC1
Reaction time: 36 h

Procedure:
tert-Butyl 3-cyano-4-(4,4-dimethylpiperidin-1-yl)benzylcarbamate (250 mg, 0.73 mmol) was dissolved in Et2O (10 ml). HCl (2.0 M in Et2O)(10 ml) was added to the solution. The mixture was stirred for 36 h. The solvents were removed and the residue was used without further purification.