Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1.ClCCl>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)(=[O:5])=[O:4]
Reactant: COC(=O)c1ccc2ccnc(O)c2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc2ccnc(OS(=O)(=O)C(F)(F)F)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
Trifluoromethanesulfonic anhydride (2.1 g) was added to a mixture of methyl 1-hydroxyisoquinoline-7-carboxylate (1.3 g), pyridine (587 mg), and dichloromethane (40 mL), followed by stirring at room temperature for 18 hours. The reaction mixture was diluted with water, extracted with chloroform, and the organic layer was concentrated under reduced pressure. The resulting residue was purified under silica gel column chromatography (chloroform/methanol) to obtain methyl 1-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-7-carboxylate (1.9 g).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH:5]1[CH:10]=[C:9]2[CH:11]([OH:19])[C:12]3[C:17]([O:18][C:8]2=[CH:7][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3>C(N(CC)CC)C>[CH3:1][NH:2][C:3]([O:19][CH:11]1[C:9]2[CH:10]=[CH:5][CH:6]=[CH:7][C:8]=2[O:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:4]
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)OC1c2ccccc2Oc2ccccc21
Reaction time: 0.67 h

Procedure:
Methyl isocynate (20 g.) is added slowly, with stirring, to a filtered solution of 30 g. of xanthydrol in 100 ml. of anhydrous triethylamine. After standing for 40 minutes in a 20° C. water bath, the mixture is filtered. The collected solid is washed with anhydrous diethyl ether and dried in vacuo to give 9-(N-methylcarbamoyloxy)xanthene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[NH:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[NH2:27][C:28]([NH2:30])=[O:29].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[NH:11][C:12]([C:13]1[CH:23]([C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[NH:27][C:28](=[O:29])[NH:30][C:14]=1[CH3:15])=[O:17]
Reactant: CC(=O)CC(=O)Nc1cc2cn[nH]c2cc1Cl
Reactant: NC(N)=O
Reactant: O=Cc1ccc(F)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2Cl)C(c2ccc(F)cc2)NC(=O)N1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
The product from Step (b) (0.100 g, 0.398 mmol, 1.00 equiv), 4-fluorobenzaldehyde (0.0430 mL, 0.398 mmol, 1.00 equiv), urea (36 mg, 0.60 mmol, 1.0 equiv), and ytterbium triflate (25 mg, 0.040 mmol, 0.10 equiv) and heated to 80° C. for 5.5 hours. The reaction was cooled to room temperature and water was added. The precipitate was collected by filtration and washed alternately with CH3CN and Et2O, affording 98 mg (62%) of the title compound. MS (ES+) m/e 400 [M+H].
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:5]2[N:10]=[C:9]([C:11]3[N:15]4[CH:16]=[CH:17][N:18]=[C:19]([N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)[C:14]4=[N:13][CH:12]=3)[CH:8]=[CH:7][N:6]=2)=[CH:30][CH:29]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5ccc(Cl)cc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and 4-chlorobenzylamine (228 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200˜300 mesh, eluting with dichloromethane:methanol, 30:1˜10:1) to afford the crude product (100 mg). The crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford (4-chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride. (Yield 38 mg, 21.8%). 1H NMR (300 MHz, CDCl3): δ 8.68 (s, 1H), 8.28 (s, 1H), 7.53 (d, 1H, J=6.9 Hz), 7.38-7.29 (m, 6H), 5.48-5.43 (m, 2H), 4.76 (brs, 2H), 3.68-3.61 (m, 4H), 3.34-3.27 (m, 4H), 2.89 (s, 3H). LC-MS: [M+H]+ 435.
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=[O:10])[C:7]([CH2:11][NH:12]C(=O)OC(C)(C)C)=[C:6]([CH3:20])[CH:5]=2)[CH2:3][CH2:2]1.CCOC(C)=O.[ClH:27].O1CCOCC1>CO>[ClH:27].[NH2:12][CH2:11][C:7]1[C:8](=[O:10])[NH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[CH3:20]
Reactant: Cc1cc(C2CC2)[nH]c(=O)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C2CC2)[nH]c(=O)c1CN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
1,1-Dimethylethyl [(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate (0.28 g, 1.006 mmol) was added to EtOAc (9 mL) and methanol (1.0 mL). The suspension was stirred at room temperature for 5 min, followed by addition of 4 M HCl in dioxane (5.03 mL, 20.12 mmol), and the contents were stirred at room temperature overnight. The volatiles were then removed in vacuo to afford a solid. The solid was triturated with ether, filtered, and dried in a vacuum oven at 45° C. for 4 h. The title compound was collected (0.22 g, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78-0.86 (m, 2H), 0.95-1.03 (m, 2H), 1.83 (tt, J=8.46, 5.05 Hz, 1H), 2.16-2.22 (m, 3H), 3.75 (q, J=5.47 Hz, 2H), 5.79 (s, 1H), 8.02 (br. s., 3H), 11.92 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[C@H:10]([N:14]([CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32](C(OC(C)(C)C)=O)[CH:31]=[CH:30]2)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:43])[C@H:10]([N:14]([CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C(=O)OC(C)(C)C)c2)[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccc3[nH]ccc3c2)[C@@H](C(=O)OCc2ccccc2)C(C)C)cc1
Yield: 75.4 %

Procedure:
A solution of 2(R)-[(N-tert-butoxycarbonylindol-5-ylmethyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (2.7 g. 4.45 mmol) and trifluoroacetic acid (5 mL) in methylene chloride (15 mL) was stirred for 2 h at room temperature. The organics were removed under vacuum and the residue was dissolved in ethyl acetate (80 mL) and the ethyl acetate layer was washed with 5% sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated to give a white foamy solid which was chromatographed on a silica gel column eluting with (5-100%) ethyl acetate/hexanes. This procedure gave 2(R)-[(1H-indol-5-yl-methyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (1.7 g) as a white foamy semi-solid, which was converted to 2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid by following the procedure described in Example 1, Step 6 above.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:20]=[C:19]([F:21])[C:18]3[O:17][C:16]4[C:11](=[CH:12][C:13]([C:22]5[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:14][CH:15]=4)[C@:10]4([N:33]=[C:32]([NH2:34])[CH2:31][O:30][CH2:29]4)[C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CCO.[Pd]>[F:21][C:19]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)[C@:10]3([N:33]=[C:32]([NH2:34])[CH2:31][O:30][CH2:29]3)[C:9]=2[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:20]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(C3CCOCC3)cc12
Reaction time: 48 h
Yield: 71.9 %

Procedure:
In a microwave vial, (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.040 g, 0.087 mmol) and Pd/C (10%, 0.055 g, 0.052 mmol) were suspended in EtOH (1.5 mL). A balloon full of hydrogen (˜1 L) was emptied into the vessel, venting through a needle, and the vessel was sealed. After 2 days, the mixture was filtered through Celite, rinsing with 5% MeOH-DCM. The filtrate was concentrated, and the residue was purified by chromatography (7.5% MeOH/DCM) to afford 29 mg of (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(tetrahydro-2H-pyran-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>CN(C)C=O>[C:1]1([CH:7]([CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)O[C@H]1CN2CCC1CC2
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)C(Cc1ccccn1)c1ccccc1
Yield: 35.9 %

Procedure:
A mixture of (R)-3-quinuclidinyl 2-phenylacetate (see Preparation 9) 1.23 g) and sodium hydride (165 mg of an 80% dispersion in oil) in dimethylformamide (10 ml) was stirred for 1/4 hour, treated with 2-picolyl chloride (0.64 g), stirred for 24 hours then partitioned between ethyl acetate and 10% aqueous potassium carbonate. The organic layer was dried over magnesium sulphate and the residue, after evaporation, was purified by chromatography on silica gel by gradient elution using chloroform plus methanol (0→10%) and aqueous ammonia (0→1%). Appropriate fractions were combined and evaporated to give the title compound as an oil (605 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O.[C:22]([O:26][C:27]([N:29]1[CH2:38][C:37]([CH3:40])([CH3:39])[C:36]2[C:31](=[CH:32][C:33]([NH2:41])=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:22]([O:26][C:27]([N:29]1[CH2:38][C:37]([CH3:40])([CH3:39])[C:36]2[C:31](=[CH:32][C:33]([NH:41][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[NH:12][CH2:11][C:7]3[C:6]4[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)c1ccccc1NCc1c[nH]c2c(F)cccc12
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3c[nH]c4c(F)cccc34)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[(7-fluoro-1H-indol-3-ylmethyl)-amino]-benzoic acid (Step A, 200 mg, 0.70 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (194 mg, 0.70 mmol), TBTU (247 mg, 0.80 mmol), and DIEA (0.25 mL, 1.4 mmol) in CH2Cl2 (5 mL) was stirred at RT under N2 atmosphere for 16 h. The mixture was diluted with CH2Cl2 (5 mL) and extracted with water (2×10 mL). The crude material was purified with flash chromatography (SiO2, 15% EtOAc/hexane) to give a yellow solid. MS (ES+) 543.1. (M+H)+. Calc'd for C32H35FN4O3-542.24.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>N1C=CC=CC=1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[C:3]([S:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A mixture of 4'-amino-3'-(2,4-difluorophenylthio)acetophenone (2.0 g) and methanesulfonyl chloride (1.0 g) in pyridine (20 ml) was stirred overnight at room temperature. The mixture was poured into cold diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give yellow crystals of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (1.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(/C=C/c2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a stirred solution of 2-[(E)-2-(3,5-dimethoxyphenyl)vinyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (1.10 g, 2.61 mmol) in tetrahydrofuran (8 mL)/methanol (10 mL), was added Pd/C (10% w/w, 580 mg, 0.545 mmol). The resulted mixture was stirred under H2 (45 psi) at ambient temperature. After 24 hours, the palladium catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to afford the desired product (1.05 g, 90%), which was used directly in the next step without further purification. LCMS calculated for C22H22N3O4S (M+H)+: m/z=424.2. Found: 424.2; 1H NMR (400 MHz, CDCl3): δ 8.18-8.15 (m, 3H), 7.97 (d, J=4.4 Hz, 1H), 7.63-7.59 (m, 1H), 7.53-7.48 (m, 2H), 6.80 (d, J=4.4 Hz, 1H), 6.34 (d, J=2.0 Hz, 2H), 6.30 (t, J=2.4 Hz, 1H), 3.73 (s, 6H), 3.19-3.15 (m, 2H), 3.02-2.98 (m, 2H) ppm.
Reaction SMILES: NOS(O)(=O)=O.C[N:8](C)[C:9](=[N:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1)=[S:13])[CH3:10].N1C=CC=CC=1>CO.C(O)C>[CH3:10][C:9]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[CH2:22][CH2:21]3)=[N:16][CH:15]=2)[S:13][N:8]=1
Reactant: CC(=NC(=S)c1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nc1)N(C)C
Agent: NOS(=O)(=O)O
Solvent: c1ccncc1
Solvent: CO
Solvent: CCO
Product: Cc1nsc(-c2ccc(N3CCN(c4cccc(C(F)(F)F)c4)CC3)nc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.5 %

Procedure:
A mixture of hydroxylamine-O-sulfonic acid (0.011 mol) in methanol (15 ml) was added at once to a mixture of intermediate 5 (0.01 mol) and pyridine (0.02 mol) in ethanol (40 ml). The mixture was stirred at room temperature for 90 minutes. The solvent was evaporated. The residue was dissolved in DCM, washed with water and an aqueous NaOH 0.1N solution, dried, filtered and the solvent was evaporated. The residue was taken up in methanol, filtered off and dried. The residue was taken up in acetonitrile (100 ml). The mixture was stirred and boiled until complete dissolution and then allowed to crystallize out. The precipitate was filtered off and dried, yielding 1.4 g (35%) of 1-[5-(3-methyl-1,2,4-thiadiazol-5-yl)-2-pyridinyl]-4-[3-(trifluoromethyl)-phenyl]-piperazine (compound 6).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].Cl.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C@H:31]2[CH2:36][CH2:35][NH:34][CH2:33][C@@H:32]2[OH:37])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C@H:31]2[CH2:36][CH2:35][N:34]([CH:2]3[CH2:6][CH2:5][N:4]([CH2:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=4)[C:3]3=[O:15])[CH2:33][C@@H:32]2[OH:37])=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O[C@H]1CNCC[C@@H]1c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(OCc5ccccc5)cc4)[C@@H](O)C3)C2=O)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 220 mg, 0.82 mmol), (3R,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-ol hydrochloride (262 mg, 0.82 mmol, from step G) and triethylamine (11 mL, 8.2 mmol) was stirred at 60° C. for 1 h, 80° C. for 1 h, 100° C. for 1 h and 120° C. for 1 h. The reaction mixture was then allowed to cool, diluted with 40 mL of water and extracted four times with 50 mL of chloroform. The combined organic layers were washed with 60 mL brine, dried over anhydrous sodium sulfate, filtered, and evaporated to yield 382 mg of 3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one which was used without further purification. LCMS (method J) (main component of a mixture) RT 2.23 min, m/z 471 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@@H:14]([NH:16][C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[OH:29])=[O:18])[CH2:13][C@H:12]1[C:30]1[O:31][CH:32]=[CH:33][N:34]=1)=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[O:31]1[CH:32]=[CH:33][N:34]=[C:30]1[C@H:12]1[NH:11][CH2:15][C@@H:14]([NH:16][C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[OH:29])=[O:18])[CH2:13]1
Reactant: O=C(N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1)c1ccc2ccccc2c1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H]1CN[C@H](c2ncco2)C1)c1ccc2ccccc2c1O
Reaction time: 16 h
Yield: 77.3 %

Procedure:
To a solution of (2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester (30 mg, 0.06 mmol) in methanol (2 mL) was added 20% Pd(OH)2 (20 mg) and the mixture was stirred at room temp. for 16 h. with a balloon containing H2 gas. The reaction mixture was then filtered and concentrated under reduced pressure to give 1-hydroxy-naphthalene-2-carboxylic acid ((3S,5S)-5-oxazol-2-yl-pyrrolidin-3-yl)-amide (15 mg) as a light brown liquid. MS calcd. for C18H18N3O3[(M+H)+] 324, obsd. 324.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([O-:3])[NH2:2].[C:6]1([C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:15][OH:16])[CH2:13]O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:15][O:16][S:1](=[O:4])(=[O:3])[NH2:2])[CH2:13][O:4][S:1](=[O:3])(=[O:5])[NH2:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCC(CO)(c1ccccc1)c1ccccc1
Reactant: NS(=O)(=O)[O-]
Product: NS(=O)(=O)OCC(COS(N)(=O)=O)(c1ccccc1)c1ccccc1

Procedure:
2,2-Diphenyl-1,3-bis-O-sulfamyl-1,3-propanediol is prepared in an identical manner as the sulfamate reported in Example 1 except for the use of 2,2-diphenyl-1,3-propanediol (87.7 g., 0.385 mol.) as the alkanediol.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][O:35][CH3:36])[C:26]([Cl:37])=[CH:25][C:24]=1[N+:38]([O-])=O)=[S:21].[NH4+].[Cl-]>[Fe].CCO>[NH2:38][C:24]1[CH:25]=[C:26]([Cl:37])[C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][O:35][CH3:36])=[CH:28][C:23]=1[NH:22][C:20](=[S:21])[NH:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[Cl:1])[CH2:6][NH:7][C:8]([C:10]1([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:12]1)=[O:9]
Reactant: COC[C@@H]1CCCN1c1cc(NC(=S)Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)c([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC[C@@H]1CCCN1c1cc(NC(=S)Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)c(N)cc1Cl
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of (S)—N-(4-chloro-3-(3-(4-chloro-5-(2-(methoxymethyl)pyrrolidin-1-yl)-2-nitrophenyl)thioureido)benzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (145 mg; 0.23 mmol), Fe (65 mg; 1.2 mmol), saturated aqueous NH4Cl-solution (3 mL) and EtOH (3 mL) was stirred at 90° C. for 2 h. The mixture was basicified to pH-9-10 and filtered through celite. The celite pad was washed with EtOH and EtOAc. The mixture was concentrated and the residue was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was washed with Et2O to give the sub-title compound.
Reaction SMILES: [CH2:1]([C:11]1[CH:26]=[CH:25][C:14]([C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+]>CO>[CH2:1]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(C(=O)CCCCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1
Yield: 46.8 %

Procedure:
Methyl 5-(4-n-decylbenzoyl)pentanoate (8 g) is added to a solution of 2N sodium hydroxide (40 ml) and methanol (100 ml). The mixture is refluxed 5 hours and the methanol is removed in vacuo. Water (50 ml) is added to the residue which is then filtered and acidified with dilute hydrochloric acid. Recrystallization from ethanol gives 5-(4-n-decylbenzoyl)pentanoic acid (3.6 g) as a white crystalline solid, m.p. 84°-85° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13](C)=[CH2:14]>>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[C:13]([CH3:14])[C:12]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:5]=1)=[O:8]
Reactant: C=C(C)C(=O)OCC
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Product: CCOC(=O)C(C)=Cc1ccc(C=O)cc1
Yield: 29.4 %

Procedure:
The procedure described in Example 28 is repeated, except that 8.23 g (0.05 mol) of p-formylbenzoyl chloride and 7.13 g (0.0625 mol) of ethyl methacrylate are used. After a reaction time of 2 hours at 120° C., 3.2 g (0.0147 mol) of ethyl p-formyl-α-methylcinnamate are obtained, corresponding to a yield of 29.4% of theory; boiling point 127°-131° C./7 Pa.