Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][C:3]=1[CH3:11].NOS(O)(=O)=O.CO.[N:20]1C=CC=[CH:22][CH:21]=1>COC(OC)(N(C)C)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:10][N:20]=[C:21]([CH3:22])[N:9]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: c1ccncc1
Reactant: Cc1cc(C(N)=S)ccc1Br
Agent: COC(C)(OC)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1nsc(-c2ccc(Br)c(C)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromo-3-methylbenzenecarbothioamide (1.20 g) in dimethylacetamide dimethyl acetal (2 ml) and dichloromethane (30 ml) was stirred under nitrogen at room temperature for 7 h. The solvent was evaporated in vacuo to give a dark brown oil to which was added hydroxylamine-0-sulphonic acid (0.88 g), methanol (20 ml) and pyridine (0.83 ml) and the mixture stirred at room temperature under nitrogen for 16 h. After evaporation, aqueous potassium carbonate was added and the mixture was extracted with dichloromethane. The combined extracts were dried and evaporated to give a brown residue which was purified by column chromatography on silica eluting with hexane: ethyl acetate (4:1) to give the title compound as an orange solid (0.8 g).
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[CH3:18][C:19]1[CH:20]=[C:21]([C:25](=[O:27])[CH3:26])[CH:22]=[CH:23][CH:24]=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[NH:7]1[CH:8]=[CH:9][N:5]=[C:6]1[C:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH3:18])[CH:20]=1)([OH:27])[CH3:26]
Reactant: CC(=O)c1cccc(C)c1
Reactant: CCOC(OCC)n1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(C)(O)c2ncc[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of 1-(diethoxymethyl)-1H-imidazole (935 mg, 5.5 mmol) in anhydrous tetrahydrofuran (6 ml), at −78° C., was added n-butyllithium (2.5M in hexanes, 2.2 ml, 5.5 mmol). The mixture was allowed to warm to 0° C. and then added to a solution of 1-(3-methylphenyl)ethanone (670 mg, 5.0 mmol) in anhydrous tetrahydrofuran (5 ml), also at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 1 h. The mixture was poured into cold hydrochloric acid (4N, 10 ml) and stirred for 20 min. The mixture was adjusted to pH 7 by addition of sodium hydrogen carbonate and then extracted with dichloromethane. The combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (850 mg).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:27](=[O:28])[C:26]3[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:25]=3[Br:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Br)c(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)c1

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg) with 2-bromo-5-methoxybenzoic acid (21 mg) under the agency of HATU (68 mg) and N,N-diisopropylethylamine (32 l) in dichloromethane (4 ml) was performed according to the method described in example 11.,
Reaction SMILES: Cl.Br[C:3]1[C:4]2[N:5]([CH:10]=[CH:11][N:12]=2)[N:6]=[C:7]([Cl:9])[CH:8]=1.[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([O-:15])=[O:14].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[Cl:9][C:7]1[CH:8]=[C:3]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[C:4]2[N:5]([CH:10]=[CH:11][N:12]=2)[N:6]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
In a 2 dram reaction vial was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloric acid salt (0.5 g, 1.9 mmol) from Example I(1), step 1b, 4-nitroaniline (0.27 g, 1.9 mmol), 1.0 M potassium tert-butoxide in THF (7.6 ml, 7.6 mmol) and DMF (1.4 ml). Under N2, the reaction was stirred for 16 hr at 50° C. and the concentrated in vacuo. The resulting material was taken up in ethyl acetate and washed with H2O (2×50 ml) and then brine (1×20 ml). the organic layers were combined and dried over Na2SO4 and filtered. Following solvent evaporation, 0.42 g of crude 6-chloro-N-(4-nitrophenyl)imidazo[1,2-b]pyridazin-8-amine was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:54]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH3:37]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 55 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 284 mg mmole) of stearic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 305 mg (Yield: 55%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:26])[CH2:6][N:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[O:8])[CH2:4]1.[CH3:27][S:28][C:29](SC)=[CH:30][N+:31]([O-:33])=[O:32]>C(O)C>[F:16][C:11]1[C:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[C:9]([C:7]([N:5]2[CH2:6][C:3]([CH2:2][NH:1]/[C:29](/[S:28][CH3:27])=[CH:30]/[N+:31]([O-:33])=[O:32])([OH:26])[CH2:4]2)=[O:8])[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Solvent: CCO
Product: CS/C(=C\[N+](=O)[O-])NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
A solution of 3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (0.24 g, 0.5 mmol), prepared using procedures similar to those described in Example 3, and commercially available 1,1-bis(methylthio)-2-nitroethylene (0.083 g, 0.5 mmol) in ethanol (5 mL) was stirred at 70° C. for 16 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford 0.10 g, (39%) 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(Z)-1-(methylthio)-2-nitroethenyl]amino}methyl)azetidin-3-ol. MS (EI) for C20H18F3IN4O4S: 595 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][CH:29]([CH2:32][C:33]([OH:35])=O)[CH2:28][CH2:27]4)=[CH:22][C:21]=3[CH3:36])=[N:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:37]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:37]([N:44]1[CH2:49][CH2:48][N:47]([C:33](=[O:35])[CH2:32][CH:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][C:16]4[N:17]=[CH:18][C:13]([NH:12][S:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)(=[O:10])=[O:11])=[CH:14][CH:15]=4)=[C:21]([CH3:36])[CH:22]=3)[CH2:31][CH2:30]2)[CH2:46][CH2:45]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1cc(N2CCC(CC(=O)O)CC2)ccc1Oc1ccc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)cn1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCC(CC(=O)N3CCN(Cc4ccccc4)CC3)CC2)ccc1Oc1ccc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)cn1
Reaction time: 1 h

Procedure:
To a solution of (1-{4-[5-(3,4-dichlorobenzenesulfonylamino)pyridin-2-yloxy]-3-methylphenyl}piperidine-4-yl)acetic acid (1.70 g, 3.1 mmol) and 1-benzylpiperazine (0.71 g, 4.0 mmol) in DMF (40 mL) were added triethylamine (1.08 mL, 7.8 mmol) and diethyl cyanophosphonate (0.76 g, 4.3 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling. To this reaction solution was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1), after which the resulting product was recrystallized from ethanol, to thereby yield 1.61 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1.O.[OH-].[Na+]>CO.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[C:21]([F:22])([F:23])[F:24])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(COc2ccc(C(F)(F)F)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(COc2ccc(C(F)(F)F)c(Cl)c2)cc1
Temperature: 55 °C
Yield: 77.8 %

Procedure:
To a solution of ethyl 4-{[3-chloro-4-(trifluoromethyl)phenoxy]methyl}benzoate (Preparation 18, 125 mg, 0.35 mmol) in methanol (5.0 mL) was added water (2.0 mL) followed by sodium hydroxide (140 mg, 3.5 mmol). The reaction mixture was heated to 55° C. for 18 hours, then cooled and diluted with EtOAc (50 mL) and 2M HCl (50 mL). The aqueous layer was separated and washed with EtOAc (2×50 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to yield 4-{[3-chloro-4-(trifluoromethyl)phenoxy]methyl}benzoic acid as an off-white solid (90 mg, 78% yield). This solid was dissolved in dichloromethane (3 mL) then EDCI (344 mg, 1.79 mmol) and DMAP (88 mg, 0.70 mmol) were added, followed by the addition of N,N-dimethylsulfamide (86 mg, 0.70 mmol). The reaction was left to stir at room temperature for 2 hours. A solution of 2M HCl (10 mL) was added and the mixture separated using a phase separation cartridge. The organics were dried in vacuo to yield a solid which was triturated with heptane:IPA (4:1, 100 mL) and sonicated. The supernatant was decanted and the residue dried in vacuo to yield an off-white solid as the title compound (57 mg, 38% yield).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([Si:17]([C:20]1[C:25]([F:26])=[CH:24][N:23]=[C:22]([F:27])[C:21]=1[Cl:28])([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[C:35]([C:36](N(OC)C)=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C1COCC1>[Si:17]([C:20]1[C:21]([Cl:28])=[C:22]([F:27])[N:23]=[C:24]([C:36]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:37])[C:25]=1[F:26])([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1Cl
Reactant: CON(C)C(=O)c1cccnc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(C(=O)c2cccnc2F)nc(F)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (52.41 g, 72.59 mL, 517.9 mmol) in THF (967.3 mL) was cooled to −20° C. n-BuLi (2.5M in hexane) (198.5 mL of 2.5 M, 496.3 mmol) was added dropwise over 15 minutes via cannula maintaining the internal temperature below −15° C. The solution was warmed to 0° C. then immediately re-cooled to −90° C. A solution of tert-butyl-(3-chloro-2,5-difluoro-4-pyridyl)-dimethyl-silane (113.84 g, 431.6 mmol) in THF (85.35 mL) was added dropwise over 20 min via cannula at such a rate that the internal temperature was kept below −85° C. During addition the solution first changed to bright yellow then slowly became an orange coloured suspension. The reaction mixture was stirred at −85° C. for 1 h. A solution of 2-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (91.40 g, 496.3 mmol) in THF (85.35 mL) was added dropwise over 15 minutes via cannula at such a rate that the internal temperature was kept below −80.7° C. (ideally below −85° C.). The mixture turned dark orange brown after the addition. The mixture was stirred at −85° C. for 90 minutes after which time Lc/Ms indicated the reaction was complete. The cooling bath was removed and the mixture warmed to −50° C. Saturated ammonium chloride solution (400 mL) was added and the mixture allowed to warm up to RT. The mixture was diluted with ethyl acetate (1.5 L). The aqueous phase was separated and extracted with more ethyl acetate (300 ml). The combined organics were washed with brine (300 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to a brown oil. The crude was purified on silica gel (CombiFlash Companion XL, 1.5 kg column, 0.5-10% ethyl acetate in petroleum ether, 0-50% ethyl acetate in petroleum ether). This gave the title compound as a yellow oil which solidified on standing (159.6 g, 95%); 1H NMR (CDCl3) 0.60 (6H, d), 1.07 (9H, s), 7.47 (1H, m), 8.33 (1H, m), 8.52 (1H, m); 19F NMR (decoupled) −107.2, −72.4, −61.8; MS ES (+) 387.04 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17](=O)[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17](=[S:37])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)O[C@@H]1C[C@H](C(=O)NCc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1C[C@H](C(=S)NCc2ccc(Cl)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A mixture of purified (2R,4R)-tert-butyl-2-((4-chlorobenzyl)carbamoyl)-4-acetoxypyrrolidine-1-carboxylate from Step B (4.1 g, 10.3 mmol) and Lawesson's reagent (2.1 g, 5.15 mmol) in toluene (80 ml) was refluxed for 2 h under argon. The mixture was cooled to room temperature and then diluted with EtOAc (80 ml), treated with 1N NaOH (2×40 ml), dried over Na2SO4 and concentrated in vacuo. Flash chromatography purification (Hex/EtOAc gradient, 10-100% EtOAc) provided the desired product as a foamy white solid (1.8 g, 43%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:11])[NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19][C:20]([SH:23])(Cl)Cl>C(Cl)Cl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:20]([Cl:19])[S:23][N:11]=2)=[CH:5][CH:4]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1nc(-c2ccc(Br)cc2)ns1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
4-Bromobenzenecarboximidamide hydrochloride (1.00 g, 4.25 mmol), prepared in the previous step, was suspended in methylene chloride (25 mL) and triethylamine (6.1 mL, 42.5 mmol) was added and the mixture was cooled to 0° C. Perchloromethyl mercaptan (0.47 g, 4.25 mmol) was added slowly, the mixture was stirred for 30 min, warmed to 25° C. and stirred 4 h. The mixture was diluted with methylene chloride, filtered through the Celite™ reagent, and concentrated. Flash chromatography (2% acetone in hexane) afforded 3-(4-bromophenyl)-5-chloro-1,2,4-thiadiazole (327 mg, 28%). HRMS: calcd for C8H4BrClN2S, 273.89671; found (EI, M+.), 273.8968; Analytical HPLC: purity 100% at 210-370 nm, 11.2 min; 100% at 272 nm, 11.2 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:20]([CH3:27])([CH2:24][CH:25]=[CH2:26])[C:21]([OH:23])=O)[C:13]([O:18][CH3:19])=[CH:14][C:15]=2[CH3:17])[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[NH2:48])[C:43]#[N:44].N1C=CC=CC=1>C(Cl)Cl.C1COCC1>[NH2:48][C:47]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][C:40]=1[NH:39][C:21](=[O:23])[C:20]([C:12]1[C:13]([O:18][CH3:19])=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:27])[CH2:24][CH:25]=[CH2:26]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: C=CCC(C)(C(=O)O)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CCC(C)(C(=O)Nc1cc(C#N)ccc1N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To (±)-2-(1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)-2-methylpent-4-enoic acid (Example 156-D) (0.76 g, 2.035 mmol) in DCM (20.35 mL) was added DMF (7.88 μl, 0.102 mmol) and then oxalyl chloride (0.356 ml, 4.07 mmol). After 20 minutes the reaction was concentrated in vacuo. The crude product in THF (5 mL) was added to a mixture of 3,4-diaminobenzonitrile (0.48 g, 3.60 mmol) in THF (5 mL) and pyridine (0.494 ml, 6.11 mmol) at 0° C. After 10 minutes the reaction was stirred at room temperature. After 30 minutes the reaction was heated at 55° C. for 4 hours. At this point the volatiles were removed in vacuo and the crude product was absorbed onto silica to purify via FCC (0-50% EtOAc:heptanes) to obtain the title compound. MS (ESI+) m/z 489.5 (M+H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:8][C:9]([F:14])([F:13])[C:10](Cl)=[O:11]>>[F:8][C:9]([F:14])([F:13])[C:10]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)=[O:11]
Reactant: Oc1ccccc1
Reactant: O=C(Cl)C(F)(F)F
Product: O=C(c1ccc(O)cc1)C(F)(F)F

Procedure:
0.1 mol of phenol and 0.1 mol of trifluoroacetyl chloride are reacted analogously to Example 4 to give 4-trifluoroacetylphenol. The latter is esterified using carboxylic acids and DCC. With p-pentylbenzoic acid, 4-trifluoroacetylphenyl pentylbenzoate, mp. 27° C., Δε=26.7, is obtained.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:11])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[I-:12].[Na+]>CC(C)=O>[CH:6]1([CH2:5][C:4](=[O:11])/[CH:3]=[CH:2]/[I:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(/C=C/Cl)CC1CCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)CC1CCCC1

Procedure:
A solution of 57 g. of 1-chloro-4-cyclopentyl-trans-buten-3-one (Example 115) in 360 ml. of acetone containing 55 g. of sodium iodide is stirred at the reflux temperature for 18 hours. The resulting mixture is cooled, filtered and and the water liquor is taken to dryness. The residual oil is dissolved in ether washed successively with water, dilute sodium thiosulfate solution, and saturated sodium chloride solution, dried with anhydrous magesium sulfate and taken to dryness to give 87 g. (99%) of orange oil. Vapor phase chromatography shows one peak.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][C:12](=[O:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:11][O:14][C:12](=[O:41])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCC1(COCc2ccccc2)CC(=O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCC1(COCc2ccccc2)COC(=O)C1
Temperature: 25 °C

Procedure:
A stirred solution containing 2.27 g (5.1 mmol) of the compound prepared in (b) above and 2.2 g (12.75 mmol) of m-chloroperbenzoic acid in 30 ml of anhydrous methylene chloride was refluxed for 10 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature, washed with 10 ml of a 2M sodium bisulfite solution, washed twice with 10 ml of a 2M sodium bicarbonate solution and washed with 10 ml of brine, after which time it was dried over magnesium sulfate, filtered and evaporated to afford a colorless liquid. The liquid was then chromatographed on silica gel employing a mixture of petroleum ether and methyl-t-butyl ether in a ratio of 7:3 as the eluent to yield a colorless liquid.
Reaction SMILES: [CH:1](=[C:8]1[CH:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC=CC=1>[CH:1](=[C:8]1[CH:16]([NH:26][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccccc2)C(Br)c2ccccc21
Reactant: NC1CCCCCC1
Solvent: c1ccccc1
Product: O=C1C(=Cc2ccccc2)C(NC2CCCCCC2)c2ccccc21
Reaction time: 24 h
Yield: 81.8 %

Procedure:
2-Benzylidene-3-bromoindan-1-one 2 (299 mg, 1 mmol) was dissolved in benzene (10 mL). Cycloheptylamine (255 μL, 2 mmol) was added and reaction mixture was stirred for 24 h. Solvent was removed in vacuum and 5 (271 mg, 82%) was isolated as yellow crystals by column chromatography (Hexanes/EtOAc 9:1) followed by crystallization from dichloromethane with pentane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1nccnc1Cl
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1nccnc1Cl
Reaction time: 48 h

Procedure:
To a suspension of 3-chloropyrazine-2-carboxylic acid (10 g, 63 mmol) and cesium carbonate (31 g, 95 mmol) in DMF was added iodomethane (5.9 ml, 95 mmol). The solution was stirred for 48 hours. After that time, the reaction was removed from stirring, acidified to pH 5 with 1.0 N HCl and extracted five times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated, affording to target material as an orange oil. MS (ESI, pos. ion) m/z: 173.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34]I>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH3:34])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2S(C)(=O)=O)CC1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(S(C)(=O)=O)c1
Yield: 79 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-[4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)-2-methanesulfonylbenzoyl]piperazine-1-carboxylic acid tert-butyl ester (908 mg) described in Preparation Example 170 and methyl iodide (320 mg), the title compound (738 mg) was obtained.