Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[C@H:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.O[NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[NH:20]>ClCCl>[NH2:8][CH:9]([CH2:15][CH3:16])[C@@H:10]([C:11]1[O:13][N:20]=[C:19]([CH:21]2[CH2:23][CH2:22]2)[N:18]=1)[OH:14]
Reactant: N=C(NO)C1CC1
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Solvent: ClCCl
Product: CCC(N)[C@H](O)c1nc(C2CC2)no1
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A solution of (S)-3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (2.00 g, 8.57 mmol) and N-hydroxy-cyclopropanecarboxamidine (1.03 g, 10.29 mmol) in dichloromethane (20 mL) was stirred at 0° C. and 1.25 equivalents of N-cyclohexylcarbodiimide-N′-methyl polystyrene (1.70 mmol/g, 6.30 g, 10.72 mmol) was added in portions. The reaction mixture stirred under nitrogen for three hours while warming to 15° C. The reaction mixture was filtered, the resin washed with dichloromethane and the filtrate evaporated under vacuum to dryness. [LC/MS m/z=338 (M+H+Na)].
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:31]3[C:26](=[CH:27][N:28]=[C:29]([NH:32][C:33](=[O:35])[CH3:34])[CH:30]=3)[CH2:25][O:24][C:21]=2[C:22]=1[CH3:23]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:20]2[C:31]3[C:26](=[CH:27][N:28]=[C:29]([NH:32][C:33](=[O:35])[CH3:34])[CH:30]=3)[CH2:25][O:24][C:21]=2[C:22]=1[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(Cl)c1C
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Product: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c1C
Yield: 11 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-7-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford (S)-tert-butyl(1-((2-acetamido-7-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (168 mg, 0.037 mmol, 11% yield) as a brown oil. LCMS (ESI) m/e 470.3 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method F): tR=0.96 min.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=[CH2:10])[C:7]([OH:9])=[O:8])(=[O:4])=[O:3]>CO.[Pd]>[CH3:10][CH:6]([CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:7]([OH:9])=[O:8]
Reactant: C=C(CS(C)(=O)=O)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(CS(C)(=O)=O)C(=O)O
Yield: 96.3 %

Procedure:
A solution of 2-(methylsulfonylmethyl) acrylic acid (700 mg, 4.26 mmol) in 20 mL of methanol was charged into a Fisher-Porter bottle along with 10% palladium on carbon catalyst under a nitrogen atmosphere. The reaction vessel was sealed and flushed five times with nitrogen and then five times with hydrogen. The pressure was maintained at 50 psig for 16 h and then the hydrogen was replaced with nitrogen and the solution filtered through a pad of celite to remove the catalyst and the filterate concentrated in vacuo to give 682 mg 96% of 2-(R,S)-methyl-3-methylsulfonyl propionic acid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([NH:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:23][N:22]([CH:24]3[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]3)[CH2:21]2)=[O:18])=[N:3]1.CC[N:35]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([NH:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:21][N:22]([CH:24]3[CH2:29][CH2:28][CH:27]([C:30]([NH2:35])=[O:31])[CH2:26][CH2:25]3)[CH2:23]2)=[O:18])=[N:3]1
Reactant: Cn1nc(NCC(=O)NC2CN(C3CCC(C(=O)O)CC3)C2)c2cc(C(F)(F)F)ccc21
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(C(N)=O)CC3)C2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{3-[2-(1-Methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetylamino]-azetidin-1-yl}-cyclohexane carboxylic acid (as prepared in the previous step, 100 mg, 0.22 mmol), EDCI (Aldrich, 65 mg, 0.33 mmol), HOBt (Aldrich, 45 mg, 0.33 mmol) and ammonia in THF (1N, Aldrich, 0.5 mL) in DCM (5 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel column chromatography using DCM: 7N NH3 in MeOH (10:1) as eluent to give the title compound as white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]O[Si](CC(C)C)(C)C.Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].[Mg].ClC1CCC=C1>O1CCCC1.O>[CH3:26][C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:5]1[CH2:4][CH2:3][CH:2]=[CH:6]1)([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCl
Reactant: CC(C)C[Si](C)(C)OCCCCCCl
Agent: ClC1C=CCC1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCC1C=CCC1
Temperature: 25 °C

Procedure:
All reactions are carried out under an inert atmosphere. The starting material, (5-chloro-1-pentyloxy)(2,2-dimethylethyl) dimethylsilane {[(5-chloropentyl)oxy](1,1-dimethylethyl)dimethylsilane} (534 g, 2.26 moles), diluted in tetrahydrofuran (500 ml), is added portionwise to a refluxing solution of tetrahydrofuran and granular magnesium (75 g). After the addition is complete the reaction is refluxed an additional 2 hours and the resultant Grignard salt is cooled to room temperature, cannulated into a three liter flask, and cooled to -20° C. A solution of Li2CuCl4 (6.4 mmoles) is added, followed by the dropwise addition of 3-chlorocyclopentene (219 g, 2.1 moles) cooled in a -20° C. dry ice/ethanol bath. After the addition is complete the mixture is warmed to room temperature. Water (500 ml) is added. The reaction mixture is extracted with hexane (3×400 ml). The organic layers are combined, washed with brine (2×500 ml) and dried over anhydrous sodium sulfate. The remaining solvent is removed under vacuum leaving a clear yellow oil. The crude product is fractionally distilled under reduced pressure leaving a clear, colorless oil (478 g, 1.78 moles), BP 96° C./0.3 mm.
Reaction SMILES: OC1CC(O)C(CC=CCCCC(OC)=O)C1COC(=O)NC1C=CC=CC=1.[CH2:29]([NH:36][C:37]([O:39][CH2:40][CH:41]1[CH:45]([O:46]C2CCCCO2)[CH2:44][CH:43]([O:53]C2CCCCO2)[CH:42]1[CH2:60][CH:61]=[CH:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[CH2:29]([NH:36][C:37]([O:39][CH2:40][CH:41]1[CH:45]([OH:46])[CH2:44][CH:43]([OH:53])[CH:42]1[CH2:60][CH:61]=[CH:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)CCCC=CCC1C(OC2CCCCO2)CC(OC2CCCCO2)C1COC(=O)NCc1ccccc1
Agent: COC(=O)CCCC=CCC1C(O)CC(O)C1COC(=O)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: COC(=O)CCCC=CCC1C(O)CC(O)C1COC(=O)NCc1ccccc1
Yield: 89.9 %

Procedure:
According to the procedures described for 3a the reaction of bis-THP ether 2b (240 mg, 0.42 mmol) and pyridinium p-toluenesulfonate (100 mg, 0.40 mmol) afforded 153.1 mg (90%) of the title compound after purification by flash column chromatography (silica gel, 1:1 hexane/EtOAc).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]2[O:19][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][N:10]=2)=[CH:17][CH:16]=1
Reactant: O=C(NNC(=O)c1ccc(Br)cc1)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1ccc(-c2nnc(-c3ccccc3)o2)cc1
Temperature: 100 °C

Procedure:
In a 300 mL three-necked flask were placed 19 g (60 mmol) of N′-benzoyl-4-bromobenzohydrazide and 100 mL of phosphoryl chloride. This mixture was stirred while being heated at 100° C. for 5 hours under a stream of nitrogen. After a predetermined time, the solid obtained by distilling off phosphoryl chloride from the mixture under reduced pressure was washed with a saturated aqueous sodium carbonate solution. The mixture was collected by suction filtration, and the collected solid was washed with methanol, so that 6.0 g of a white powder, which was a target substance, was obtained at a yield of 33%.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][C:4]2([O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]3[CH:16]=[CH:17][CH:18]=[C:7]23)[CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[ClH:33]>O1CCOCC1>[ClH:33].[NH:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]3[CH:16]=[CH:17][CH:18]=[C:7]23)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Yield: 76 %

Procedure:
A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, an addition funnel, a temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under nitrogen with a clear amber solution of tert-butyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate and (50 g, 0.15 mol) and toluene (250 mL). Stirring was commenced and the addition funnel was charged with (73 mL, 0.29 mol) of 4M HCl in 1,4-dioxane which was added dropwise over 10 minutes resulting in a very dark solution. The mixture was continued to stir at ambient temperature for 1 h before the reaction mixture was filtered to remove the residual solids. The filtrate was concentrated under reduced pressure to provide a solid which was triturated with diethyl ether (2×200 mL) and was then dried under vacuum to provide (31 g, 76%) of spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloride as an off-white solid. ESI-MS m/z calc. 240.1. found 241.3 (M+1)+. Retention time: 1.21 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 9.45 (s, 2H), 7.76-7.62 (m, 1H), 7.55 (dd, J=2.8, 1.3 Hz, 1H), 7.23-7.08 (m, 3H), 6.31 (t, J=3.2 Hz, 1H), 6.11 (dd, J=3.4, 1.3 Hz, 1H), 3.29-3.13 (m, 4H), 2.25 (td, J=14.4, 5.0 Hz, 2H), 2.09 (d, J=14.1 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:17])[C:13]([O:15]C)=[O:14])[CH:7]=[CH:6]2)#[N:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:17])[C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2)#[N:2]
Reactant: COC(=O)C(C)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(=O)O)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 60 °C
Yield: 99.6 %

Procedure:
To methyl 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]propanoate (0.055 g, 0.185 mmol) in 1:1 THF/MeOH (4 mL) was added 5N NaOH (0.185 mL) and the resulting mixture was heated to 60° C. for 30 min. The cooled mixture was partitioned between Et2O and 0.1N HCl. The separated organic portion was washed with brine, dried over Na2SO4, and filtered. Concentration afforded the title compound (0.052 g, 99% yield): MS (APCI) m/z 283 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C@@H:6]1[C:19]([O:21]C)=[O:20].[OH-].[Na+].[ClH:37]>CO>[ClH:37].[ClH:37].[OH:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C@@H:6]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSc4cccs4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of 0.45 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylate, 3.5 cm3 of methanol, and 0.54 cm3 of 5N aqueous sodium hydroxide was heated with stirring at a temperature in the region of 60° C. for 20 hours. After evaporating the solvents under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was taken up in 3 cm3 of a 6N aqueous hydrochloric acid solution. The solution was evaporated under the same conditions and then the residue obtained was triturated in a dichloromethane/methanol (90/10 by volume) mixture. The insoluble material was filtered off and washed with 2 times 1 cm3 of this mixture. The filtrate was dried over sodium sulfate and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 4° C. After drying in the air, 0.16 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of a beige solid which melts, with softening, at approximately 148° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[C:9]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([O:22]CC3C=CC=CC=3)=[CH:17][C:16]=2[O:30]CC2C=CC=CC=2)[O:8][N:7]=1)=[O:5])[CH3:2].B(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[C:9]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([OH:22])=[CH:17][C:16]=2[OH:30])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1NC(C)=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(Cl)c(O)cc2O)c1NC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-acetylamino-5-(2,4-bis-benzyloxy-5-chloro-phenyl)-isoxazole-3-carboxylic acid ethylamide (0.35 mmol) in DCM (10 ml) under inert atmosphere was cooled at 0° C. and BCl3 in DCM (1M, 1.05 mmol, 1.05 ml) was added dropwise. The reaction was stirred at 0° C. for 20 min, the cooling bath was then removed and the mixture stirred for a further 50 min. The mixture was cooled back and then quenched by cautious addition of saturated aqueous NaHCO3 solution (20 ml). The DCM was removed under vacuo and water (20 ml) was added. The mixture was then extracted with EtOAc (200 ml). The phases were separated and the organic phase was washed with water (2×30 ml), sat. aqueous NaCl solution (50 ml) and then dried and filtered. Solvent was removed under vacuo and the crude product purified by flash chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])(=[O:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1ccc(F)cc1F)c1ccccc1

Procedure:
2,4-Difluoro-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2,4-difluorobenzenesulfonylchloride (94 mg, 0.455 mmol) according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found: 509.1. Calcd 509.11. 1H-NMR δ 77.71-7.46 (m, 6H), 7.25-7.17 (m, 1H), 7.03-6.96 (m, 2H), 6.72 (dd, 1H), 6.44 (d, 1H), 3.20-3.16 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([O:26]C)=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCCP(=O)=O.[F:38][C:39]([F:43])([F:42])[CH2:40][NH2:41]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:28]([F:30])([F:31])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:41][CH2:40][C:39]([F:43])([F:42])[F:38])=[O:26])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: NCC(F)(F)F
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(bifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxylic acid (i.e. the product from Step C) (190 mg, 0.42 mmol), 4-(dimethylamino)pyridine (77 mg, 0.63 mmol), propylphosphonic anhydride (0.38 mL, 0.63 mmol, 50% in ethyl acetate) and 2,2,2-trifluoroethylamine (0.033 mL, 0.42 mL) in dichloromethane (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to give the title product, a compound of the present invention, as a white solid (71 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]([CH2:23][C:24]#[CH:25])[C:14]([NH:16][CH2:17][CH:18](OC)OC)=[O:15])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CC1C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:18]=[CH:17][NH:16][C:14](=[O:15])[C@H:13]2[CH2:23][C:24]#[CH:25])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(Cl)c(Cl)c1)C(=O)NCC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 19 h

Procedure:
A solution of (R)-2-(3,4-dichlorobenzenesulfonamido)-N-(2,2-dimethoxyethyl)pent-4-ynamide (36.7 g, 89.6 mmol) in 500 mL p-dioxane was treated with TsOH.H2O (5.11 g, 26.9 mmol). The reaction was heated to 60° C. for 7 h and then at 80° C. for 19 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with 400 mL EtOAc stirred with 400 mL 5% NaHCO3. The resulting precipitate was filtered and washed with H2O. The solid was suspended in hot EtOH and cooled to rt. The solid was collected by filtration, washed with EtOH and dried in vacuo to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]([N:10]2[C:14]3[CH:15]=[C:16]([F:28])[C:17]([S:19]([NH:22][C:23]4[S:27][N:26]=[CH:25][N:24]=4)(=[O:21])=[O:20])=[CH:18][C:13]=3[O:12][C:11]2=[O:29])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:30][N:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:28][C:16]1[C:17]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])=[CH:18][C:13]2[O:12][C:11](=[O:29])[N:10]([C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:33]4[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=4)[CH:3]=3)[CH3:9])[C:14]=2[CH:15]=1
Reactant: C[C@H](c1cccc(Br)c1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc21
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](c1cccc(-c2ccn(C)n2)c1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc21
Temperature: 90 °C

Procedure:
In a sealed vial, compound of Formula 28-2 (45 mg, 0.090 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21 mg, 0.10 mmol), PdCl2(dppf)-CH2Cl2 adduct (7.3 mg, 0.009 mmol), and cesium carbonate (88 mg, 0.270 mmol) were combined in dioxane (1 mL) and water (0.14 mL). The mixture was heated at 90° C. for 24 hours. The mixture was diluted with dioxane (4 mL), filtered through a celite pad, and the filtrate was concentrated. The resulting residue was purified by reverse phase HPLC (20-100% MeCN in water with 0.1% TFA, C18 column) to yield 28-3 as a white solid. 1H NMR δ (ppm)(DMSO-d): 8.50 (s, 1H); 7.74 (d, J=5.6 Hz, 1H); 7.63 (s, 1H); 7.52-7.46 (m, 5H); 7.41 (d, J=9.8 Hz, 1H); 6.40 (d, J=1.9 Hz, 1H); 5.65 (q, J=7.2 Hz, 1H); 3.79 (s, 3H); 1.91 (d, J=7.2 Hz, 3H). LRMS C21H18FN604S2 [M+H] calc 501.08, obs 501.0.
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C@H:16]([CH3:20])[C:17](O)=[O:18])[C:12]2=[O:21])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:29])=O>CN(C)C=O.ClCCl>[F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C@H:16]([CH3:20])[C:17]([Cl:29])=[O:18])[C:12]2=[O:21])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](C(=O)O)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C(=O)Cl)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R) -2-[3-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2,3-dihydro-2-oxo-1H-imidazol-1-yl]propanoic acid (1.5 g) and 3.8 ml of oxalyl chloride were added to 30 ml of dichloromethane, to which dimethylformamide (7 drops ) was added dropwise at room temperature. After the reaction solution was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure to give 1.5 g of (2R)-2-[3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,3-dihydro-2-oxo-1H-imidazol-1-yl]propanoyl chloride as a pale yellow oil. This product was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([Cl:23])=[O:19])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.400 g, 1.56 mmol) in CH2Cl2 (5 mL) at room temperature was added oxalyl chloride (0.86 mL, 1.7 mmol) followed by DMF (20 μL). Gas evolution was observed. After 30 minutes, the solution was concentrated in vacuo to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid chloride which was used without further purification.