Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:20])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:15]=1)[C:9]([O:11]C)=[O:10].Cl>O.O1CCCC1>[F:4][CH:5]([F:20])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][N:17]([CH3:18])[CH3:19])[CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(CN(C)C)cc(C(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc(C(=O)O)cc(C(F)F)c1
Reaction time: 3.5 h
Yield: 100.7 %

Procedure:
Lithium hydroxide, monohydrate (65.2 mg, 1.55 mmol) in water (0.7 mL) was added to a solution of methyl 3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoate (45 mg, 0.13 mmol, from Step C) in tetrahydrofuran (2 mL). Upon stirring for 3.5 hours, the mixture was treated with 1N HCl to adjust the pH to 7, then THF was removed by rotary evaporation. Acetonitrile was added to make a 1:1 ACN:water mixture, the mixture was filtered, and the filtrate was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as a white solid (0.030 g, 100%). 1H NMR (300 MHz, DMSO-d6): δ 7.95 (s, 2H), 7.50 (s, 1H), 7.05 (t, 1H), 3.44 (s, 2H), 2.15 (s, 6H); LCMS (M+H)+: 230.1.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.[NH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[OH:32]>>[OH:32][C@@H:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[NH:26][C:2]1[N:3]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: O=c1c2c(ncn2Cc2ccccc2)nc(Cl)n1Cc1ccccc1
Reactant: N[C@@H]1CCC[C@H]1O
Product: O=c1c2c(ncn2Cc2ccccc2)nc(N[C@@H]2CCC[C@H]2O)n1Cc1ccccc1

Procedure:
Treat 2-chloro-1,7-bis(phenylmethyl)purin-6-one with trans-2-aminocyclopentanol as described in Preparative Example 5 to give the title compound, a tan solid. FAB MS: M+1=416.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Cl)cc2)CC1
Product: Clc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chlorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44]O)[CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44][NH:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])[CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(C)(N)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4cccc(OCCO)c4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: NCCO
Product: CC(C)(CO)NCCOc1cccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[3-(2-hydroxyethoxy)phenyl]ethyl}benzofuran and 2-amino-2-methyl-1-propanol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[C:21](F)=[CH:22][C:23]([F:33])=[C:24]([CH:32]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CC(C)([O-])C.[K+]>CS(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:21]2[C:20]([Cl:19])=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[C:23]([F:33])[CH:22]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 20 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
A mixture of 1-benzhydrylazetidin-3-ol (500 mg, 2.08 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (568 mg, 2.29 mmol) and potassium tert-butoxide (349 mg, 3.12 mmol) in DMSO (30 mL) was stirred at 20° C. for 1 h. The mixture was quenched with water and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to get the target compound (700 mg, 72%) which was used in the next step without further purification. LCMS (ESI) m/z: 468.2 [M+H]+.
Reaction SMILES: [Na].[CH:2]([O:5][C:6]1[N:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)([CH3:4])[CH3:3].C([O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=O)C.Cl>C(O)C>[CH:2]([O:5][C:6]1[N:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]2[C:19](=[O:18])[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cccs1
Reactant: CC(C)Oc1ccc2c(n1)CC(=O)N2
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(C)Oc1ccc2c(n1)C(C(=O)c1cccs1)C(=O)N2
Temperature: 25 °C
Yield: 44.7 %

Procedure:
Pellets of sodium metal (250 mg, 11 mmole) were added to dry ethanol (10 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, solid 5-isopropoxy-4-azaoxindole (419 mg, 2.22 mmol) was added followed by ethyl-2-thiophene carboxylate (0.59 mL, 688 mg). The mixture was heated at reflux overnight and then cooled to room temperature. After pouring into ice/water, the mixture was acidified using 1N HCl solution and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography on silica gel eluting successively with chloroform and 49:1 chlorform/methanol. All fractions containing the desired product were combined and concentrated. The residue was again subjected to flash chromatography on silica gel eluting with chloroform. Fractions containing only the desired product were combined and concentrated to give 5-isopropoxy-3-(2-thenoyl)-4-azaoxindole as a yellow gum (300 mg, 45%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:21])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([F:20])[CH:13]=2)=[O:8])C.[OH-].[Na+]>O1CCCC1.CO>[F:20][C:14]1[CH:13]=[C:12]2[C:17]([C:18]([OH:19])=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:22])=[O:3])=[O:8])[C:10](=[O:21])[S:11]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2ccc(F)cc2sc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNC(=O)c1c(O)c2ccc(F)cc2sc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
[(7-Fluoro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (150 mg, 0.461 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL). 1N Sodium hydroxide (1.85 mL) was added to the solution and the reaction was stirred overnight (18 h) at ambient temperature. The reaction was concentrated in vacuo and the residue dissolved in water, treated with 1N HCl to pH 3 to precipitate the product, which was collected via filtration and dried to yield [(7-fluoro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (100 mg, 75%.) MS ESI(−) m/e: 296.23 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN.O.Cl>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Yield: 69.6 %

Procedure:
5-(4-Nitrophenyl)-2-(1H)-pyrazinone (0.1 g) was warmed with hydrazine hydrate (1 ml) in 50% aqueous ethanol (2.5 ml). Water (about 3 ml) was added sufficient to provide a clear solution. The mixture was allowed to cool slightly and 10% Palladium on charcoal (0.01 g) added as a slurry in a small amount of water. The well-stirred mixture was re-heated for 2 minutes, stirred without heating for 2 minutes, cooled and filtered. The filtrate was evaporated under reduced pressure to give a residue which was suspended in a little water. Dilute hydrochloric acid was added to pH6; the pale yellow solid was collected and washed with water to afford 5-(4-aminophenyl)-2(1H)-pyrazinone (0.06 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:14]3[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=3[F:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Product: Fc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-fluoro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-fluoro-5-trifluoromethylphenylboronic acid in a manner analogous to Example 2c (0.150 g, 22%). MP=88-89° C. MS=317 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].O.[NH2:19][NH2:20]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7]([NH:19][NH2:20])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccnc(NN)c1Oc1cc(Cl)cc(Br)c1
Temperature: 100 °C

Procedure:
To a solution of 3-(3-bromo-5-chlorophenoxy)-2-chloro-4-methylpyridine (121 mg, 0.363 mmol) in DMSO (1 mL) was added hydrazine hydrate (177 μL, 3.63 mmol) and the mixture was heated at 100° C. for 18 hours. The mixture was then purified on a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA) to give the title compound. LRMS (M+1)=329.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([O:19][NH:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH2:12]([O:19][N:20]([CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[C:10]([NH:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[S:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cccc(F)c1N=C=S
Reactant: O=C1c2ccccc2C(=O)N1CCNOCc1ccccc1
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCN(OCc1ccccc1)C(=S)Nc1c(F)cccc1F

Procedure:
A solution of 19.68 g of 2,6-difluorophenylisothiocyanate and 34.1 g of N-{2-[N-(benzyloxy)amino]ethyl}phthalimide in 150 ml of benzene is heated to boiling under reflux for 6 hours. The cooled solution is separated from a slight precipitate and then evaporated in vacuo. The residual oil crystallizes from isopropyl ether. There is obtained 1-(benzyloxy)-3-(2,6-difluorophenyl)-1-(2-phthalimidoethyl)-2-thiourea of melting point 141°-143° (ether/methylene chloride).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.O=S(Cl)[Cl:14]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1F
Solvent: ClCCl
Product: O=C(Cl)Cc1ccccc1F

Procedure:
To a solution of 2-fluorophenylacetic acid (450 g, 3.0 mol) in CH2Cl2 (900 mL) is added SOCl2 (714 g, 6 mol) dropwise. After addition is complete, the reaction mixture is heated to reflux for 2 hours. Subsequently, the solvent is removed in vacuo after which vacuum distillation of the resulting oil provides 2-fluorobenzeneacetyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:9][C:8]([C:7]1[CH:6]=[C:5]([C:11]([O:13][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])[CH:4]=[C:3]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:2]=1[O:1][CH2:14][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1cc(C(=O)O)c(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Compound 13 (22.6 g, 0.1 mol), benzyl chloride (57 g, 0.46 mol) and anhydrous potassium carbonate (120 g, 0.87 mol) were mixed in dry DMF (500 mL). The mixture was heated at 75° C. while stirring under nitrogen overnight. TLC confirmed that the reaction was complete. The reaction mixture was cooled, filtered, and the filtrate was evaporated to remove the volatiles. The residue was dissolved in 1 L of recycling [?] methylene chloride and a silica gel plug was used to remove some impurities with low Rf. The fully benzyl-protected product was obtained as a thick, yellow oil after removing the solvent: raw yield 53 g (90%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:15][CH2:16]O>>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:15][CH3:16])=[O:9])[CH2:4][CH2:3]1
Reactant: NC1CCC(C(=O)O)CC1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCC(N)CC1
Temperature: 80 °C

Procedure:
To an ice-cold solution of 4-aminocyclohexanecarboxylic acid (5.0 g, 34.92 mmol) in EtOH (20 mL) was added thionyl chloride (7.60 mL, 104.76 mmol). The mixture was heated at 80° C. for 3 h. The solvent was evaporated in vacuo to obtain i (7.23 g). 1H NMR (400 MHz, DMSO-d6): δ 4.19 (q, J=7.20 Hz, 2H), 3.71 (m, 1H), 2.71 (m, 1H), 2.06 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.55 (m, 2H), and 1.25 (t, J=7.20 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:39][S:40]([NH:43][C:44]1[CH:45]=[CH:46][C:47]2[O:52][CH2:51][CH:50]([CH2:53][NH2:54])[O:49][C:48]=2[CH:55]=1)(=[O:42])=[O:41]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][NH:54][CH2:53][CH:50]1[CH2:51][O:52][C:47]2[CH:46]=[CH:45][C:44]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:55][C:48]=2[O:49]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccc(NS(C)(=O)=O)cc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
5-Methoxyindole-3-butyric acid (0.75 g, 3.2 mmole), 1-hydroxybenzotriazole hydrate (0.52 g, 3.8 mmole) and 1,3-diisopropylcarbodiimide (1.2 ml, 7.6 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (0.9 g, 3.2 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using first ethyl acetate and then 2.5% methanol in ethyl acetate as eluants. Fractions were concentrated and washed with a minimum amount of THF to remove a byproduct and to give 1.2 g (79%) of the desired product, (7-methylsulfonyl amino-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-yl)-butanamide, as a oily white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])(=[O:12])=[O:11].Br[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:21][C:22]([OH:24])=[O:23])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: COc1ccccc1NS(=O)(=O)c1ccccc1C
Reactant: CC(C)(C)OC(=O)CBr
Product: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of N-(2-methoxy-phenyl)-2-methyl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH:13]=C)[CH2:9][CH2:8][N:7]1[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:5])[CH3:2].CC[OH:25]>Cl.[Zn]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH:13]=[O:25])[CH2:9][CH2:8][N:7]1[C@@H:15]([CH3:16])/[C:17](/[CH3:22])=[CH:18]/[CH:19]=[CH:20]\[CH3:21])=[O:5])[CH3:2]
Reactant: CCO
Reactant: C=CCC[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(=O)OCC
Agent: Cl
Agent: [Zn]
Product: C/C=C\C=C(/C)[C@H](C)N1CC[C@@H](CCC=O)[C@H]1C(=O)OCC
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
(2S,3R)-3-But-3-enyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid ethyl ester (1.0 g, 3.32 mmol) is dissolved in EtOH (10 mL) with HCl (0.5 mL, 37%), and cooled to −70° C. Ozone gas is bubbled though the solution for about 10 min or until the solution is turned very light blue color. The nitrogen gas is bubbled though the solution for 15 min to remove excess ozone in the solution. To the cool solution is added Zn dust (0.43 g. 6.6 mmol) and HCl (0.5 mL, 37%), and stirred at r.t. for 20 min. After filtration the solution is diluted with 50 mL of CH2Cl2 and washed with saturated NaHCO3 (10 mL) and 2×20 ml of water. After dried and concentrated, a colorless liquid (1.0 g) is obtained without further purification for next step reaction. (NMR and MS data confirmed, U-4117-51-30).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[SH:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:49][O:48][C:46](=[O:47])[CH2:45][CH2:44][S:43][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)c(Oc2ccccc2)c1
Temperature: 95 °C
Yield: 69.1 %

Procedure:
A 1 L flask was charged with tert-butyl 4-(5-(5-bromo-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (Example 4, Step D, 24.4 g, 45.8 mmol), N-ethyl-N-isopropylpropan-2-amine (16.0 mL, 91.7 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (1.33 g, 2.29 mmol), and dioxane (450 mL). Nitrogen was bubbled through the solution for 30 minutes. Methyl 3-mercaptopropanoate (5.46 mL, 50.4 mmol) and Pd2dba3 (1.05 g, 1.15 mmol) were added and the reaction was heated at 95° C. overnight. The reaction was cooled to ambient temperature and the resultant solids were filtered through celite. The filtrate was concentrated and purified on silica (30 to 40% EtOAc in hexanes) to afford tert-butyl 4-(5-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (18.1 g, 69.1% yield) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:12][C:13](O)=[O:14])([CH3:11])[CH2:8][CH2:7][C:6]=2[CH:16]=1.S(Cl)([Cl:19])=O>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:12][C:13]([Cl:19])=[O:14])([CH3:11])[CH2:8][CH2:7][C:6]=2[CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(CC(=O)O)CCc2cc(Cl)ccc2O1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC1(CC(=O)Cl)CCc2cc(Cl)ccc2O1

Procedure:
To a solution composed of 2.89 g of (6-chloro-3,4-dihydro-2-methyl-2H-benzopyran-2-yl)acetic acid, 2 drops of N,N-dimethylformamide and 50 ml of benzene was added 0.9 ml of thionyl chloride and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure to remove the low-boiling substances. The above procedure gave (6-chloro-3,4-dihydro-2-methyl-2H-benzopyran-2-yl)acetyl chloride in a quantitative yield of 3.1 g.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=2)[C:10]([CH2:25][C:26]([NH:31][C:32](=[O:34])[CH3:33])([CH2:29][OH:30])[CH2:27][OH:28])=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:28][CH2:27][C:26]([NH:31][C:32](=[O:34])[CH3:33])([CH2:29][OH:30])[CH2:25][C:10]1[C:11]2[C:16](=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)[NH:8][CH:9]=1
Reactant: CCCCCCCCc1ccc2c(CC(CO)(CO)NC(C)=O)cn(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc2c(CC(CO)(CO)NC(C)=O)c[nH]c2c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Compound 29 (200 mg, 0.46 mmol) is added to methylene chloride (10 mL) and the solution is cooled to −40° C. Trifluoroacetic acid (3.0 mL) is added and the reaction is stirred for 1 hour maintaining the temperature. The reaction is quenched with methanol (10 mL) at −40° C. and then partitioned between methylene chloride (25 mL) and aqueous sodium hydroxide (1.0 N, 25 mL). The aqueous layer is back extracted with methylene chloride (2×10 mL) and the combined organic layers are washed with aqueous sodium hydroxide (1.0 N, 3×10 mL), then brine and dried over MgSO4. The organic layer is evaporated to dryness and the residue purified using silica gel chromatography with methanol (10%)-methylene chloride (90%) to give compound 30.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:19])=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)Nc1ccc(N)cc1
Solvent: CC(=O)O
Product: CCOC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(4-Amino-phenyl)-carbamic acid ethyl ester (118 g, 0.65 mol) is dissolved in glacial acetic acid (2.0 L) under nitrogen and the mixture is heated to 90° C. Phthalic anhydride (102.0 g, 0.69 mol) is added portionwise over 30 minutes and the reaction is kept at 90° C. for 2 hours. The mixture is allowed to cool to ambient temperature and the precipitated solid is filtered off. The solid is washed on the filter with water (2 L) followed by diethylether (3 L) and then dried in vacuo. Yield 127 g (62%) title compound as white crystalline compound. LC/MS (m/z) 311.3 (MH+); tR=2.57 min. 1H NMR (DMSO-d6): 1.26 (t, 3H); 4.15 (q, 2H); 7.34 (dd, 2H); 7.58 (dd, 2H); 7.90 (ddd, 2H); 7.95 (ddd, 2H); 9.80 (s, 1H, NH).