Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[CH:25]=[CH:24][C:11]([C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH3:36]>CC(C)=O>[CH2:35]([O:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[CH:25]=[CH:24][C:11]([C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1)=[O:6])[CH3:36]
Reactant: CCI
Reactant: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)c1
Yield: 83.7 %

Procedure:
To a solution of 1-[4-(3-hydroxybenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.4 g) in acetone (5 ml) are added potassium carbonate (0.22 g) and ethyl iodide (0.34 g), and the mixture is refluxed for 5 hours. Then, acetone is distilled off under reduced pressure and water is added to the residue. The precipitated crystal is collected by filtration, and recrystallized from methanol to give 1-[4-(3-ethoxybenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.36 g) as white powder, m.p. 170.5°-171.5° C.
Reaction SMILES: Cl[C:2]1[C:3](I)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1.[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([C:3]2[CH:2]=[CH:22][C:6]3[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:9][C:5]=3[CH:4]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(I)c(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)ccc21
Temperature: 150 °C

Procedure:
A 2 mL Biotage™ microwave vial was charged with 6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (Intermediate 5, 49.0 mg, 0.100 mmol), biphenyl-4-boronic acid (24.0 mg, 0.120 mmol) and Pd(PPh3)4 (5.8 mg, 5 mol %) following by dioxane (1.0 mL) and 1M aqueous K2CO3 (120 uL). The resulting suspension was heated in a microwave synthesizer (Biotage Initiator™) at 150° C. for 10 min. The microwave procedure was repeated two more times, before each irradiation additional Pd(PPh3)4 (2.9 mg, 2.5 mol %) was added. The reaction mixture was then diluted with EtOAc (5 mL), filtered and the resulting solution was evaporated to dryness in vacuo to give brown oil. The oil was dissolved in ACN and passed through a Thiol StratoSphere™ SPE cartridge (Polymer Labs). The solvent was evaporated to dryness in vacuo to give crude product as colorless oil which was used in the next step without further purification. LR-MS (API-ES): calculated C26H29ClN2O3SSi 512.1, observed m/e 513.0 (M+H)+, 485.0, 455.0 (Rt 3.91 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:20]([NH2:22])[CH3:21]>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:22][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1nnsc1-c1cccnc1Cl
Reactant: CCN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCNc1ncccc1-c1snnc1-c1cccnc1Cl
Temperature: 105 °C
Yield: 66.3 %

Procedure:
A mixture of 4, 5-di-(2-chloropyridin-3-yl)-1, 2, 3-thiadiazole (1.823 g), and ethylamine (0.61 g) in dioxane (9 mL) was heated at 105° C. in a sealed tube 3 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel gave 4-(2-chloropyridin-3-yl)-5-(2-ethylaminopyridin-3-yl)-1, 2, 3-thiadiazole (1.243 g) as an oil.
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[CH2:7][CH2:8][N:9]([CH2:20][CH2:21][C:22](=O)[NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].B.C(Cl)Cl>O1CCCC1>[CH2:24]([NH:23][CH2:22][CH2:21][CH2:20][N:9]([CH2:8][CH2:7][CH2:6][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNC(=O)CCN(CCC(=O)NCCCC)S(=O)(=O)c1ccc(C)cc1
Agent: B
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCNCCCN(CCCNCCCC)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
Dissolve N-butyl-3-[(2-butylcarbamoyl-ethyl)-(toluene-4-sulfonyl)-amino]-propionamide (10 mmol) prepared in example 9, Scheme VI, step C in tetrahydrofuran (50 mL). Cool the solution to 0° C. and add borane (20 mmol, 1M solution in tetrahydrofuran. Heat the reaction to reflux for 18 hours. After cooling, dilute the reaction with methylene chloride (200 mL), rinse with water (100 mL), brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide N,N-bis-(3-butylamino-propyl)-4-methyl-benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(3-chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 475) in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone. 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=8.7 Hz, 2H), 7.91 (s, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.68 (m, 1H), 7.57 (m, 1H), 7.41 (m, 1H), 7.38 (m, 1H), 5.65 (s, 2H), 4.51 (t, J=6.6 Hz, 2H), 2.70 (br s, 1H), 1.87 (t, J=6.6 Hz, 2H), 1.20 (s, 6H); MS (DCI/NH3) m/z 463 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:46][O:47][CH2:48][CH2:49][CH2:50][NH2:51]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:51][CH2:50][CH2:49][CH2:48][O:47][CH3:46])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: COCCCN
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCCNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, 3-methyoxypropylamine (12 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-{1-[2-(3-methoxy-propylcarbamoyl)-ethyl]-1H-pyrazol-3-yl}-propionamide (16 mg, 27%) as a white solid: ESI-LRMS m/e calcd for C25H35ClN4O5S [M+] 538.2, found 539.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.21 (m, 2H, CH2), 1.43-1.97 (m, 10H, 5×CH2), 2.17-2.28 (m, 1H, CH), 2.61 (t, J=6.3 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.27-3.34 (m, 2H, CONCH2), 3.31 (s, 3H, OCH3), 3.41-3.46 (m, 2H, OCH2), 3.55 (t, J=7.5 Hz, 1H, CH), 4.30 (t, J=6.3 Hz, 2H, NCH2), 6.19 (brm, 1H, NH), 6.60 (d, J=2.3 Hz, 1 H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 8.08 (d, Jo=8.2 Hz, 1H, Ar), 8.13 (s, 1H, NH).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2N.N([O-])=[O:16].[Na+].O>C(O)(=O)C>[OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:9](=[O:16])[NH:8][CH:7]=[N:6][C:5]1=2
Reactant: O=N[O-]
Reactant: CC(O)Cn1cnc2c(N)ncnc21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(O)Cn1cnc2c(=O)[nH]cnc21
Reaction time: 3 h

Procedure:
9-(2-Hydroxy-1-propyl)adenine (I, 4.0 g, 20.7 mmol) was suspened in 50% acetic acid (20 ml) and sodium nitrite (4 g, 58 mmol), was slowly added. The mixture was stirred at 25° for 3 hr. The resulting solution was evaporated to dryness and isopropanol added; this operation was repeated once. The solid residue was boiled in isopropanol and filtered. The filtrate was evaporated and crystallized by addition of acetone. Recrystallization was made from iso-propanol/methanol (98:2); a colorless crystalline product was obtained. Yield 3.3 g (82%); M.P. 244°-250°; uv (H2O; pH 5.5), λmax 250 nm.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:26](O)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[C:33]([O:32][C:30]([NH:29][C:23]1([C:26](=[O:27])[NH:1][C@H:2]([C:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[CH2:3][CH2:4][OH:5])[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: N[C@@H](CCO)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 155 %

Procedure:
(S)-3-amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 47) (1.09 g, 5.87 mmol) was added in one portion to 1-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylic acid (Intermediate 70) (2.022 g, 5.87 mmol) and DIPEA (3.08 mL, 17.61 mmol) in DMA (20 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.456 g, 6.46 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated then triturated with diethyl ether to afford crude (S)-tert-butyl 4-(tert-butoxycarbonylamino)-4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)piperidine-1-carboxylate (4.66 g, 155%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([O:25]C)=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1.Cl.O1CCOCC1.[H][H]>[Pd].CO>[NH:3]1[CH2:4][CH2:5][CH2:6][N:1]=[C:2]1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:28]=[CH:27][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([OH:25])=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)CC1Cc2ccc(OCCCNC3=NCCCN3)cc2CNC1=O
Reaction time: 18 h

Procedure:
A mixture of methyl (±)-8-[3-(pyrimidin-2-ylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.36 g, 0.94 mmol), 4 M HCl in dioxane (0.25 mL, 1 mmol), 10% palladium on charcoal (0.24 g, 0.24 mmol), and MeOH (5 mL) was stirred under a balloon of hydrogen. After 18 hr, the mixture was filtered and the filtrate was concentrated. The residue was partitioned between EtOAc and aqueous K2CO3. A solid precipitated, which was collected by filtration and dried to give the title compound as a white solid: MS m/e 375.4 (M+H)+. Anal. Calcd for C19H26N4O4.2.5 H2O: C, 54.40; H, 7.45; N, 13.35. Found: C, 54.68; H, 7.12; N, 13.39.
Reaction SMILES: COS([O-])(=O)=O.C[S+](C)C1C=CC(O[C:16](=[O:36])[C@H:17]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=CC=1.[NH:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41].C(N(CC)CC)C.Cl>O>[CH2:22]([O:21][C:19]([NH:18][C@H:17]([C:16]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41])=[O:36])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C[S+](C)c1ccc(OC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)cc1
Agent: COS(=O)(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1

Procedure:
In 30 ml of water was dissolved 5.47 g of benzyloxycarbonylphenylalanine p-dimethylsulfoniophenyl ester methylsulfate obtained by a synthesizing method according to Synthetic Example 5, and 20 ml of an aqueous solution of 1.15 g of proline and 1.4 ml of triethylamine was added dropwise thereto while stirring. The reaction mixture was further stirred for 12 hours at room temperature, adjusted to pH 2 by adding 2% HCl, and extracted twice with 50 ml of ethyl acetate. The ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure, and the resultant residue was recrystallized by adding ether. This crystalline product indicated only the peak of the desired product by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:48])[CH2:26][C@@H:27]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:48])[CH2:26][C@@H:27]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH2:28])=[O:21])[CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CCOC(=O)[C@H](CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H](N)CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.7 %

Procedure:
To a solution of the material from Step 3 (476 mg, 0.706 mmol) in dichloromethane (3 mL) at 0° C. were added anisole (0.232 mL, 2.119 mmol) and TFA (0.653 mL, 8.48 mmol). The reaction mixture was stirred at room temperature for 3 hours, poured into saturated aqueous NaHCO3, and extracted with dichloromethane (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to afford 370 mg of the title compound a colorless foam. LCMS (M+1)=474.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:25]1[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[N:28]=[C:27]([S:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[F:43])[N:26]=1>O1CCOCC1.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]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:25]2[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[N:28]=[C:27]([S:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=3[F:43])[N:26]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-(aminosulfonyl)-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from step i) (0.29 g), tris(dibenzylideneacetone)dipalladium (0) (67 mg), 2-dicyclohexylphosphiiao-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (35 mg), cesium carbonate (0.36 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-ethoxy-pyrimidine (the product from example 14, step i) (0.23 g) in dioxane (5 mL). Purification was by column chromatography on silica using EtOAc/isohexane (1:9 to 1:3 gradient) as eluent to give the subtitle compound as a yellow oil. Yield: 0.25 g
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.Cl.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][NH2:19]>CCO>[NH2:9][C:8]1[N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[N:19]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: N#Cc1cnn(-c2ccccc2Cl)c1N

Procedure:
At RT, 2-(ethoxymethylene)malononitrile (5.77 g, 47.2 mmol) was added in portions to a stirred suspension of 1-(2-chlorophenyl)hydrazine hydrochloride (8.05 g, 45.0 mmol) and TEA (6.58 ml, 47.2 mmol) in absolute EtOH (56 mL). The mixture was heated to reflux for 1 h. The volatile solvents were removed under reduced pressure. The brown reside was dissolved in EtOAc, washed with water followed by saturated NaHCO3 solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-amino-1-(2-chlorophenyl)-1H-pyrazole-4-carbonitrile as a rusty crystalline solid. MS (ESI, pos.ion) m/z: 219.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+]>CC(CC(C)C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:26][CH2:27][CH2:28][C:29](=[O:30])[C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(OCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=C(CCCCl)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C(CCCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1)c1cccs1

Procedure:
A mixture of 1.67 g (0.005 mol) 1-(2-[bis(4-fluorophenyl)-methoxy]ethyl)piperazine, (U.S. Pat. No. 1545094), 1.89 g (0.010 mol) 3-chloropropyl-2-thienyl ketone, 1.52 g (0.011 mol) potassium carbonate and 30 ml methylisobutyl ketone was stirred and heated to reflux for 45 h. The reaction mixture was then evaporated in vacuo. The residue was redissolved in dichloromethane (1 00 ml) and washed twice with water (100 ml). The organic layer was then separated and dried with sodium sulfate. Evaporation in vacuo left a brown syrup. This was redissolved in dry ether and precipitated as the dihydrochloride with gaseous hydrogen chloride. The precipitate was collected by filtration and recrystallized from isopropanol. White crystals, m.p. 185°-88° C. (0.98 g=35%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:30][C@H:31]2[CH2:35][CH2:34][NH:33][CH2:32]2)=[C:14]([CH:29]=1)[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[O:16])#[N:9]>N1C=CC=CC=1>[C:1]([N:33]1[CH2:34][CH2:35][C@H:31]([NH:30][C:13]2[CH:12]=[CH:11][C:10]([C:8]#[N:9])=[CH:29][C:14]=2[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:16])[CH2:32]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@H]2CCNC2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@H]2CCN(C(C)=O)C2)cc1OC
Temperature: 25 °C
Yield: 69.8 %

Procedure:
Acetic anhydride (64 mg) was added to a solution of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (80 mg) in pyridine (1 mL). The mixture was stirred for an hour at ambient temperature. The mixture was partitioned between ethyl acetate and 1% hydrochloric acid. The organic layer was washed with an aqueous saturated sodiunn bicarbonate solution and brine. The resultant was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a thin layer chromatography developed with 5% methanol in chloroform to give (S)-2-(1-acetylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (62mg) as amorphous powders.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Br:15])[C:8]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[K+].Cl>O1CCCC1.CO.O>[Br:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[C:8]2[C:16]1[CH2:20][C:19]([C:25]2[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=2)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccc(Br)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccc(Br)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of 8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid methyl ester (Example 8.1) (400 mg) in tetrahydrofuran (3.5 ml) was added a solution of potassium hydroxide (1.9 g) in methanol (3.5 ml) and water (3.5 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then acidified by addition of aqueous hydrochloric acid (4N) and the mixture extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (3×10 ml) and brine, dried over sodium sulfate and concentrated to give 8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid (342 mg). LC-MS: RT=2.41 min, [M−H]−=532/534, Method A.