Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>CN(C=O)C>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(O)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCCl)cc1
Temperature: 40 °C
Yield: 47 %

Procedure:
A solution of 3-[(4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one (0.945 g, 3.75 mmol) in 20 mL DMF is treated with potassium carbonate (777 mg, 1.5 equiv.) and 1-bromo-4-chlorobutane (1.1 equiv.). The reaction mixture is heated to 40° C. for 3 h. The reaction mixture is partitioned between EtOAc and water. The organic layer is collected and washed sequentially with H2O (1×), saturated aqueous NaHCO3 solution (1×), and brine (1×). The organic phase is dried and concentrated to give a solid. The solid is triturated with MeOH and collected by filtration to give the named compound as yellow solid (600 mg, 47%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([NH:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=O)[CH:18]=2)=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59]>CN(C=O)C>[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]([N:60]1[CH2:61][CH2:62][N:63]([C:25](=[O:27])[CH2:24][C:23]([NH:22][C:19]2[CH:18]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=3)[O:21][N:20]=2)=[O:28])[CH2:64][CH2:65]1)=[O:59]
Reactant: O=C(O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1cc(-c2ccc(F)cc2)on1
Reaction time: 0.03 h
Yield: 28.5 %

Procedure:
DIPEA (57 mg, 0.078 mL, 0.45 mmol) was added dropwise to N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid (40 mg, 0.15 mmol) in DMF (2 mL) followed by EDCI (35 mg, 0.18 mmol) and HOBT (24 mg, 0.18 mmol). After 2 minutes, (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (55 mg, 0.18 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was quenched with cold water and was then extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by preparative HPLC afforded 22 mg (28.27% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-3-oxo-propionamide. LC/MS [M+H]+: 515.07, 96.02%. 1H NMR (300 MHz, DMSO-d6): δ 11.4-11.2 (m, 1H), 7.8 (m, 2H), 7.6 (d, 1H), 7.4-7.2 (m, 5H), 7.1 (t, 2H), 6.6 (d, 1H), 4.1-3.9 (m, 2H), 3.8-3.2 (m, 10H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=2[O-:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(-c2ccccn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
3-chloroperbenzoic acid (19 g) was added portionwise to an ice-cold solution of 2-phenylpyridine (10 g) in DCM (30 ml). The mixture was allowed to warm to RT and was stirred at RT for 4 h. 100 ml of a NaHCO3 solution were added to the reaction mixture and the phases were separated. The aq. phase was further extracted with DCM and the combined org. phases were washed with an aq. NaHSO3 (40%) solution and evaporated off. Recrystallisation (EA) afforded 8.77 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1.[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>C(#N)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([O:13][S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: NS(=O)(=O)Cl
Reactant: Cc1nccn1-c1cccc(O)c1
Solvent: CC#N
Product: Cc1nccn1-c1cccc(OS(N)(=O)=O)c1
Yield: 31.6 %

Procedure:
A slurry of 8.7 g (0.05 mole) of 3-(2-methyl-1H-imidazol-1-yl)phenol in 150 ml of acetonitrile was treated with a solution of 0.05 mole of sulfamoyl chloride in 20 ml of acetonitrile. The mixture dissolved and slowly deposited off-white crystals over the period of 24 hr. The precipitate was collected and triturated with hot absolute ethanol. The slurry was cooled and the precipitate was collected and dried to give 4.0 g (32%) of off-white powder, monohydrochloride, mp 197°-200° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:41][C:42]1[C:43]([CH:49]=O)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1>CO>[CH3:41][C:42]1[C:43]([CH2:49][N:24]([CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=3)=[O:32])=[CH:18][CH:19]=2)[CH2:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc(C)cc3C)Cc3nccn3C)cc2)cc1
Yield: 88.1 %

Procedure:
The compound (155 mg) obtained in Example 15-5 was dissolved in anhydrous methanol (3.0 ml) and added with sodium cyanoborohydride (33.7 mg), acetic acid (0.50 ml), and the compound (58.0 mg) obtained in Example 15-6, and the whole was stirred at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution, followed by stirring for a while. Then, the solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (174 mg) of the subject compound as a white solid.
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]([NH:12][CH:13]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[C:23]=1[CH3:29])=[O:20])[CH2:14][CH2:15][S+](C)C)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Br:28][C:24]1[C:23]([CH3:29])=[C:22]([N:21]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:19]2=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(Br)cccc1NC(=O)C(CC[S+](C)C)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c(Br)cccc1N1CCC(NC(=O)OCc2ccccc2)C1=O
Reaction time: 4.5 h
Yield: 93.8 %

Procedure:
Step 3 A solution of racemic (3-(benzyloxycarbonylamino)-4-(3-bromo-2-methylphenylamino)-4-oxobutyl)dimethylsulfonium iodide (1.96 g, 3.30 mmol) in anhydrous DMSO (33 mL) was stirred at rt and treated with cesium carbonate (2.69 g, 8.26 mmol) in 3 portions over 25 min. After 4.5 h, the mixture was diluted with EtOAc, washed three times with water and twice with brine, dried and concentrated to provide racemic benzyl 1-(3-bromo-2-methylphenyl)-2-oxopyrrolidin-3-ylcarbamate as a tan solid (1.248 g, 94%). 1H NMR (400 MHz, chloroform-d) δ 7.52-7.58 (1H, m), 7.30-7.40 (5H, m), 7.10 (2H, d, J=5.1 Hz), 5.47 (1H, br. s.), 5.15 (2H, s), 4.39 (1H, ddd, J=10.6, 8.3, 5.2 Hz), 3.72 (1H, td, J=9.9, 6.4 Hz), 3.60 (1H, t, J=9.4 Hz), 2.27 (3H, s), 2.11-2.26 (2H, m). Mass spectrum m/z 425, 427 (M+Na)+.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:26]O>>[CH3:26][O:13][C:12](=[O:14])[CH2:11][N:10]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=1)(=[O:9])=[O:8]
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CN(c1ccccc1)S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene-4-sulfonyl)phenylglycine was esterified with thionyl chloride in methanol to give N-(toluene-4-sulfonyl)phenylglycine methyl ester. This was then taken up in dry acetone (50 mL) with iodomethane (1.1 eq, 1.88 mL) and K2CO3 (1.1 eq, 4.10 g). The solution was refluxed overnight. The solvent was evaporated under reduced pressure. EtOAc was added and the organic layer was washed with brine. The organic layer was dried over MgSO4. The solvent was evaporated under reduced pressure. The resulting ester was hydrolyzed using the procedure described in Method 6 to yield N-(Toluene-4-sulfonyl)-N-methylphenylglycine, which was coupled with L-phenylalanine ethyl ester using the procedure described in Method 3 to yield the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.CCN(CC)CC.[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30](Cl)=[O:31])=[CH:24][CH:23]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:30]([O:29][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[O:31])[CH2:2]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of tert-butyl(S)-piperidin-3-ylcarbamate (1.0 g, 5.0 mmol) and Et3N (0.76 mL) in CH2Cl2 was added Cbz-Cl (50% solution in toluene, 5.49 mmol, 0.78 mL) at 0° C. The reaction mixture was then warmed to rt and stirred for 3 h, diluted with CH2Cl2 (50 mL) and washed with water (3×5 mL). The organic layer was then dried over Na2SO4 and concentrated in vacuo to give (1.5 g, 89%) of the titled compound which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 7.35-7.38 (m, 5H), 5.13-5.12 (d, 2H), 4.61 (bs, 1H), 3.73-3.67 (m, 2H), 3.51-3.46 (m, 2H), 3.26-2.23 (m, 2H), 1.86-1.80 (m, 2H), 1.66-1.50 (m, 1H), 1.42 (s, 9H). LC-MS: m/z [M-100]=235 & [M+23]=357.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11]Br.[F:18][C:19]([F:34])([F:33])[C:20]1[C:24]2[CH:25]=[CH:26][C:27]([OH:32])=[C:28]([CH2:29][CH2:30][CH3:31])[C:23]=2[O:22][N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:32][C:27]1[CH:26]=[CH:25][C:24]2[C:20]([C:19]([F:34])([F:33])[F:18])=[N:21][O:22][C:23]=2[C:28]=1[CH2:29][CH2:30][CH3:31]
Reactant: COC(=O)Cc1ccc(NCCCBr)c(Cl)c1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCNc2ccc(CC(=O)OC)cc2Cl)ccc2c(C(F)(F)F)noc12

Procedure:
Using the method in example 17 step D substituting Methyl 3-chloro-4-(3-bromopropylamino)phenylacetate and 3-trifluoromethyl-7-propyl-6-hydroxybenz-[4,5]-isoxazole as the starting materials, the titled compound was obtained.
Reaction SMILES: [OH-:1].[Na+].[C:3]([N:7]=[N:8][C:9](Cl)([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4]>C(O)(C)(C)C>[C:3]([N:7]=[N:8][C:9]([OH:1])([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)(C)N=NC(C)(C)Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)N=NC(C)(C)O

Procedure:
2-t-butylazo-2-hydroxypropane was prepared by reacting aqueous sodium hydroxide and 2-t-butylazo-2-chloropropane in t-butyl alcohol. The 2-t-butylazo-2-hydroxypropane was isolated by diluting the alcohol solution with water and extracting with pentane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[CH:8]=[C:7]([C:16](OCC)=[O:17])[C:6]2=[O:21].[NH3:22]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[CH:8]=[C:7]([C:16]([NH2:22])=[O:17])[C:6]2=[O:21]
Reactant: CCOC(=O)c1cn(C)c2cc(OC)c(OC)cc2c1=O
Reactant: N
Solvent: CCO
Product: COc1cc2c(=O)c(C(N)=O)cn(C)c2cc1OC
Temperature: 25 °C

Procedure:
A mixture of ethyl 6,7-dimethoxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (4.0 g) and ethanol saturated with ammonia (200 ml) was heated at 100° in a stainless steel pressure vessel for 20 hours, then cooled to ambient temperature. The mixture was evaporated and the residue purified by high pressure liquid chromatography on silica using dichloromethane IMS 96.5:3.5 as the eluent. The resulting product was recrystallised from IMS to give the novel compound 6,7-dimethoxy-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, m.p. 323°-325° (dec).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:25]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([F:25])=[O:16])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a cooled (-15° C.) solution of t-butoxycarbonylisoleucine (0.482 g, 2 mmol) and pyridine (0.16 ml) in methylene chloride (5 ml) is dropped cyanuric fluoride (0.9 ml) and the mixture is stirred at -15° C. for 1 hour. The reaction mixture is diluted with methylene chloride and ice, and filtered on Celite. The filtrate is diluted with ice water and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonylisoleucine fluoride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:14]=[N:13][CH:12]([NH:15][CH3:16])[NH:11][C:10]1=[O:17].[CH3:18][S:19]([OH:22])(=[O:21])=[O:20]>O>[CH3:18][S:19]([OH:22])(=[O:21])=[O:20].[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH:14]=[N:13][C:12]([NH:15][CH3:16])=[N:11][C:10]1=[O:17]
Reactant: CNC1N=CN(c2c(C)cccc2C)C(=O)N1
Agent: CS(=O)(=O)O
Solvent: O
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Yield: 94.3 %

Procedure:
A solution of 6.0 g (0.026 moles) of 1-(2,6-dimethylphenyl)-4-methylamino-dihydro-1,3,5-triazin-2-one in 100 ml iPA was prepared with warming. To the warm solution was added 2.0 ml (0.031 moles) of methane-sulfonic acid. The mixture became hot and crystals of white crystalline solid began to form almost immediately. The mixture allowed to cool to room temperature in tap water and filtered. The solution was washed with iPA EtOH to give 8.00 g of product which was dried overnight at 50°-60° C. in a vacuum. Obtained 8.0 g of 1-(2,6-dimethylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one methanesulfonate after drying.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)[CH:16]=[N:15][CH:14]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc(F)c(Cl)c3)n2)c1
Yield: 4.7 %

Procedure:
Using Method K. 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 3-chloro-4-fluoroaniline (42 mg, 0.29 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 80° C. for 12 hours. The same workup as for Method K and a combination of column chromatography and preparative TLC furnished 4 mg of title compound. Yield: 4.7%. 1H NMR (250 MHz, DMSO-d6) δ 2.09 (s, 3 H), 7.38 (d, 1 H, J=9.5 Hz), 7.46 (d, 1 H. J=7.9 Hz), 7.61 (d, 1 H, J=7.9 Hz), 7.72 (d, 1 H, 7.5 Hz), 7.86-7.91 (m, 1 H), 8.00-8-04 (m, 1H), 8.18 (s, 1 H), 8.40 (bs, 1 H), 8.48 (s, 1 H), 9.80 (s, 1 H), 10.08 (s, 1 H); m/z 357.2 [(M+H)+, calcd for C18H14ClFN4O 356.1].
Reaction SMILES: [N+]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:11]1([C:9]2[S:10][C:6]3[C:7]([N:8]=2)=[CH:17][CH:18]=[C:4]2[C:5]=3[CH2:19][C:20](=[O:22])[NH:21]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1c([N+](=O)[O-])ccc2nc(-c3ccccc3)sc12
Reactant: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2c(ccc3nc(-c4ccccc4)sc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (6-nitro-2-phenyl-benzothiazole-7-yl)-acetonitrile (40 mg 0.23 mmol) (Starting Material 8) was suspended in concentrated H2SO4 /H2O (1/1, 2 mL) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. Subsequently, to a solution of the crude acid in acetic acid (3 mL) heated at reflux was added excess zinc dust (88.4 mg, 1.36 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-thiazolo[5,4-e]indol-7-one. (Yield 12 mg, 33%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:14][CH2:13][O:12][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[O:5][CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[OH:12][CH2:13][CH2:14][CH:3]1[CH2:2][O:1][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[O:5][CH2:4]1
Reactant: OCC1CCOC2(CCCCC2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: OCCC1COC2(CCCCC2)OC1

Procedure:
A solution of 9-hydroxymethyl-7,12-dioxaspiro[5,6]dodecane of the formula V (4 g) of the drawings in benzene (15 ml) was stirred at 10° C. for 5 hr with anhydrous p-toluenesulphonic acid (0.2 g). The reaction mixture was made alkaline by adding TEA and water. The benzene layer was separated and the aqueous layer extracted with benzene. The combined benzene solution was dried over K2CO3 and evaporate to a residue (4 g). It was chromatograped on silicagel using chloroform-methanol mixture as eluent to give 9-(2-hydroxyethyl)-7, 11-dioxaspiro[5,5]undecane of formula VI (2.8 g) (70%) of the drawings as colorless viscous liquid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=O.[NH2:15][C:16](=[S:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([C:3]2[N:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:22][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1nc(-c2cccc(C(F)(F)F)c2)cs1
Temperature: 80 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
To 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (14 g, 41 mmol) was added ethyl amino(thioxo)acetate (5.0 g, 38 mmol), and the mixture was stirred at 80° C. for 3 hr. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by recrystallization (ethyl acetate) to give the title compound (5.6 g, 49%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:20][C:21]#[N:22]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[C:20](=[CH:6]/[C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3][CH2:1][CH3:2])/[C:21]#[N:22])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOc1ccc([N+](=O)[O-])cc1C=O
Product: CCOc1ccc([N+](=O)[O-])cc1/C=C(\C#N)c1ccc(OC)c(OC)c1
Yield: 45.1 %

Procedure:
2-Ethoxy-5-nitrobenzaldehyde (390 mg) and 3,4-dimethoxybenzyl cyanide (354 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (319 mg, yield: 45%).
Reaction SMILES: O[C:2]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23]([N:25]5[CH2:30][CH2:29][O:28][CH:27]([CH2:31][OH:32])[CH2:26]5)=[N:22][C:21]4=[O:33])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:36]([F:39])([F:38])[F:37])[CH:6]=1)([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[OH:32][CH2:31][C@@H:27]1[O:28][CH2:29][CH2:30][N:25]([C:23]2[S:24][C:20](=[CH:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:10]([CH2:9][C:8]3[CH:34]=[CH:35][C:5]([C:2]([CH3:4])=[CH2:3])=[CH:6][C:7]=3[C:36]([F:37])([F:39])[F:38])[N:11]=[CH:12]4)[C:21](=[O:33])[N:22]=2)[CH2:26]1
Reactant: CC(C)(O)c1ccc(Cn2ncc3cc(C=C4SC(N5CCOC(CO)C5)=NC4=O)ccc32)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)c1ccc(Cn2ncc3cc(C=C4SC(N5CCO[C@@H](CO)C5)=NC4=O)ccc32)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
A solution of 5-{1-[4-(1-Hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-2-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one (400 mg, 0.71 mmol) in dichloromethane (2 mL) was treated with TFA (2 mL). The reaction mixture was stirred at room temperature for 1.5 hour and partitioned between water and dichloromethane. The dichloromethane layer was washed with aqueous saturated sodium carbonate, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (90% ethyl acetate in Heptane) to yield the title compound as a solid (94 mg, 24% yield).