Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=[N:9][OH:10])[C:6](=[O:8])[CH3:7])[CH3:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:10][N:9]=[C:5]([C:6](=[O:8])[CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:11])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOCc1ccc(F)cc1)C(C)=O
Yield: 95.9 %

Procedure:
Ethyl2-hydroxyimino-3-oxobutyrate (syn isomer, 40.0 g.), 4-fluorobenzyl chloride (43.6 g.), N,N-dimethylformamide (60.0 ml), potassium carbonate (52.0 g.) and ethyl acetate (60.0 ml.) were treated in a conventional manner to give ethyl 2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn isomer, 64.4 g.).
Reaction SMILES: O.C([O:4]CC)C.[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])Cl)(=[O:11])[C:8]([CH3:10])=[CH2:9]>C1COCC1>[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[OH:4])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: CCOCC
Reactant: C=C(C)C(=O)OCCC[Si](C)(C)Cl
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCC[Si](C)(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Deionized water (100 mL) and diethyl ether (200 mL) were added to a single-neck 500 mL round-bottom flask fitted with a magnetic stirrer. The flask was cooled in an ice bath to 0° C. The flask was fitted with a dropping funnel and a mixture of (10 g, 0.045 mol) of 3-methacryloxypropyl dimethylchlorosilane and 50 mL of anhydrous THF was added to the flask. The reaction was stirred for one hour at 0° C. The organic layer was separated and dried over anhydrous sodium sulfate and filtered. The solvent was evaporated on a rotovap to give 3-methacryloxypropyl dimethylhydroxysilane in 9.0 g quantity, 99% yield as a clear, colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[NH2:12]
Reactant: COCSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: COCSc1ccc(N)c(N)c1

Procedure:
1.2 G. 1-amino-2-nitro-4-methoxymethylthiobenzene is reduced in 80 ml. methanol and 20 ml. water at reflux with 2.4 g. iron powder and 0.6 g. ferrous sulfate. The mixture is filtered and concentrated. The residue is recrystallized from cyclohexane, yielding pure 1,2-diamino-4-methoxymethylthiobenzene.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([F:30])[CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([F:30])[CH:20]=3)=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C#N)c1ccc(CN)cc1F
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3cccc(C#N)c32)cc1F

Procedure:
2-(7-cyano-1H-benzimidazol-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-fluorobenzyl]acetamide is synthesized according to example 14 with (7-cyano-1H-benzimidazol-1-yl)acetic acid (150 mg, 0.746 mmol) prepared according to scheme 3, 2-[4-(aminomethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (205 mg, 0.896 mmol) prepared according to scheme 8, Et3N (250 μL, 1.79 mmol) and HATU (341 mg, 0.896 mmol) in DMF (3.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (50 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA). Yield=21 mg as TFA salt, 0.043 mmol, 6%); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.62-1.71 (m, 6H), 4.32 (d, J=5.86 Hz, 2H), 5.26 (s, 2H), 7.13-7.25 (m, 2H), 7.29-7.41 (m, 2H), 7.71 (d, J=7.42 Hz, 1H), 8.00 (d, J=8.01 Hz, 1H), 8.36 (s, 1H), 8.84-8.93 (m, 1H). MS [M+H], calcd: 376.2. found: 376.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]([CH3:11])=[CH2:10])=[CH:4][CH:3]=1.[CH2:13]=[CH:14][O:15]CCOCCOCCOC=C>C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:11][C:9](=[CH2:10])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:13][CH:14]=[O:15]
Reactant: C=COCCOCCOCCOC=C
Reactant: C=C(C)C(O)c1ccc(C)cc1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Product: C=C(C)C(CC=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
(3E)-(4-Methylphenyl)-2-methyl-2-propen-1-ol (17.33 g, 0.102 mol), tri (ethylene glycol) divinyl ether (Aldrich 98%, 20.5 g, 0.102 mol) and mercury(II) acetate (1 g, 0.003 mol) were heated together under nitrogen at 155-160° C. (bath temperature) for 3 hours. After cooling to room temperature, the reaction was diluted with heptanes, washed with water (3 times). Each aqueous phase was re-extracted with heptanes. Combined extracts were dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with heptanes and the solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate (11:1) followed by bulb-to-bulb distillation (81° C./0.002 mbar). 8.71 g of the desired product were obtained (yield=43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27]([CH:29]4[CH2:30][CH2:31]4)=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Br)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 1-(4-bromophenyl)-4-chloro-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 469.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:24].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[O:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:20]([Cl:19])[CH:21]=2)=[CH:27][CH:28]=1)#[N:2]
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)propanoate (360 mg, 1.44 mmol) from Step A and 3,4-dichloro-N-(4-hydroxyphenyl)benzamide (488 mg, 1.73 mmol) from Step B in DMSO (4 ml) was added K2CO3 (240 mg, 1.73 mmol). The reaction was stirred 125° C. overnight, then cooled to ambient temperature and diluted with EtOAc and 10% aqueous sodium carbonate. The aqueous phase was extracted with EtOAc and the combined organics washed with 10% aqueous sodium carbonate and brine, dried over MgSO4, concentrated and purified on a Biotage Horizon (40+M 5% to 50% B:EtOAc, 21 ml-1008 ml). The appropriate fractions were then combined and concentrated to give tert-butyl 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoate (0.476 g, 0.797 mmol, 55%). 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.84 (bs, N—H), 7.72 (d, J=9.3 Hz, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.60 (m, 2H), 7.42 (d, J=8.6 Hz, 1H), 7.11 (d, J=7.7, 2H), 6.83 (d, J=8.7 Hz, 1H), 3.61 (q, J=7.1 Hz, 1H), 1.45 (d, J=7.5 Hz, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[C:9]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(N=C=NC2CCCCC2)CCCCC1.CO>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:19](=[O:20])[C@H:17]([CH3:18])[NH:16][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: COCCOCCO
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CO
Product: COCCOCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(2-Methoxyethoxy)ethanol (1.28 g, 10.5 mmol), 4-N,N′-(dimethyl)aminopyridine (128 mg, 1 mmol) and N-Boc-(L)-alanine (2 g, 10.5 mmol) were dissolved in freshly distilled CH2Cl2 (25 mL). The reaction mixture was cooled to 0° C. (ice bath) and dicyclohexylcarbodiimide (DCC, 2.39 g, 1.1 mmol) was added portionwise. The reaction mixture was stirred for 1 h at 0° C. and then warmed up to room temperature over 2 h. The dicyclohexyl urea was filtered off, washed with ethyl acetate (2×20 mL) and the solvents evaporated. Column chromatography (SiO2, 0.060-0.200 mm/1% MeOH in CH2Cl2) yielded compound 2a as a colorless to pale yellow oil (2.40 g, 8.3 mmol, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][CH2:31][CH2:32]Cl>CN(C=O)C.CCOC(C)=O>[Cl:30][CH2:31][CH2:32][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2[O:10][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:13][C:12]=2[C:14]([NH2:16])=[O:15])=[CH:22][CH:21]=1
Reactant: ClCCCl
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.100 g, 0.316 mmol) in DMF (5 ml) were added potassium carbonate (0.220 g, 1.58 mmol) and 1,2-dichloroethane (0.50 m, 6.32 mmol). The reaction was heated to 130° C. via microwave irradiation and held at that temperature for 1 hour. The reaction was then diluted with EtOAc, washed with water and brine and dried over Na2SO4 before being concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 0-50% EtOAc in hexane as eluant to afford 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.11 g, 0.29 mmol, 92%) as a white solid. LCMS (1) 2.25 min; m/z (ES+) 379/381.
Reaction SMILES: C[C@H]1OC(=O)[C@H]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)N(C)C(=O)[C@H](C)NC(=O)C([C@H](C(C)C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2N(C[C@H](O)C2)C(=O)[C@@H](CC(C)C)NC(=O)[C@H]1NC(C1N=CC=CC=1O)=O.CC1[O:96][C:94](=[O:95])[CH:93](C2C=CC=CC=2)[N:92](C)[C:90](=O)C(C)NC(=O)C(C(C(C)C)C)N(C)C(=O)CN(C)C(=O)C2N(CC(O)C2)C(=O)C(CC(C)C)NC(=O)C1NC(C1N=CC=CC=1O)=O.C[C@H]1OC(=O)[C@H]2CSC(C(NCC=CC=C[C@@H](O)C[C@@H](O)CC3OC=C(C(N2)=O)N=3)=O)=CC1>>[C:34]1([N:92]([CH2:93][C:94]([OH:96])=[O:95])[CH3:90])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)CC1NC(=O)C(NC(=O)c2ncccc2O)C(C)OC(=O)C(c2ccccc2)N(C)C(=O)C(C)NC(=O)C(C(C)C(C)C)N(C)C(=O)CN(C)C(=O)C2CC(O)CN2C1=O
Reactant: CC(C)C[C@H]1NC(=O)[C@@H](NC(=O)c2ncccc2O)[C@@H](C)OC(=O)[C@H](c2ccccc2)N(C)C(=O)[C@H](C)NC(=O)C([C@@H](C)C(C)C)N(C)C(=O)CN(C)C(=O)[C@H]2C[C@@H](O)CN2C1=O
Agent: C[C@@H]1C/C=C2\SC[C@@H](NC(=O)c3coc(n3)C[C@H](O)C[C@H](O)/C=C\C=C/CNC2=O)C(=O)O1
Agent: C[C@@H]1CC=C2SC[C@@H](NC(=O)c3coc(n3)C[C@H](O)C[C@H](O)C=CC=CCNC2=O)C(=O)O1
Product: CN(CC(=O)O)c1ccccc1

Procedure:
In addition the identity of neoviridogrisein IV with viridogrisein was further confirmed by IR, UV, NMR and mass spectrometry, thin layer chromatography, hydrolysate analysis and antimicrobial spectrometry. On the other hand, the griseoviridin preparation obtained in Example 5 was crystallized in warm methanol to yield needle crystals. Then a part of the needle crystals were compared and identified with an authentic preparation of griseoviridin by IR, UV, NMR and mass spectrometry, thin layer chromatography, elementary analysis and other physico-chemical properties.
Reaction SMILES: O1[C:6](=[O:7])[CH2:5][O:4][CH2:3][C:2]1=[O:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH3:17].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C(OC)(C)(C)C.O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:2](=[O:8])[CH2:3][O:4][CH2:5][C:6]2=[O:7])=[CH:12][C:11]=1[CH3:17]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=C1COCC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(N2C(=O)COCC2=O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
[1,4]Dioxane-2,6-dione (312 mg, 2.69 mmol) was added to a solution of 4-bromo-3-methyl-phenylamine (500 mg, 2.69 mmol) in tBuOMe (7.0 ml), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. Acetic anhydride (4.0 ml, 42.3 mmol) and sodium acetate (35 mg, 0.427 mmol) were added to the resulting residue, and the mixture was heated with stirring at 60° C. for three hours. Water was added to the reaction solution, and collection by filtration and trituration with water gave 4-(4-bromo-3-methyl-phenyl)-morpholine-3,5-dione (577 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:13].[BH4-].[Na+].Cl>CO>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][CH:5]2[OH:13]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(C)c2c1SCCC2O
Reaction time: 2 h
Yield: 9.7 %

Procedure:
In a 100-ml eggplant type flask, 5.0 g (18.4 mmol) of 6-bromo-5,8-dimethylthiochroman-4-one as a halogenated thiochroman-4-one compound was dissolved in 30 ml of methanol, and 0.35 g (9.2 mmol, 0.5 equivalent) of sodium borohydride as a reducing agent was added at room temperature. The reaction mixture was stirred for 2 hours, then, diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then solvent was distilled off to give 0.49 g (yield 95%) of 6-bromo-5,8-dimethylthiochroman-4-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][Si](C(C)C)(C(C)C)C(C)C)[N:10]([C:30]([C:32]3[C:37]([F:38])=[CH:36][C:35]([F:39])=[CH:34][C:33]=3[F:40])=[O:31])[N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2SC(C3C=CC=C(OC)C=3O[Si](C(C)C)(C(C)C)C(C)C)N(C(C3C(F)=CC(F)=CC=3F)=O)N=2)=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:10]([C:30]([C:32]3[C:37]([F:38])=[CH:36][C:35]([F:39])=[CH:34][C:33]=3[F:40])=[O:31])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Oc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [F-]
Product: O=C(c1c(F)cc(F)cc1F)N1N=C(c2ccc(F)cc2)SC1c1ccccc1O

Procedure:
[5-(4-Fluoro-phenyl)-2-(2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (41 μmol), prepared in a similar manner as described for [5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone in example 3, is treated with tetrabutylammonium fluoride (1.0 M in THF) (48 μmol) at room temperature for 40 minutes. The solvent is removed in vacuo and dried over MgSO4 to yield [5-(4-fluoro-phenyl)-2-(2-hydroxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone to be used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12.[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Reactant: OB(O)c1cccc(F)c1F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(-c4cccc(F)c4F)ccnc32)cc1

Procedure:
A mixture of Example 220C (750.0 mg, 1.409 mmol), (2,3-difluorophenyl)boronic acid (267 mg, 1.690 mmol), bis(triphenylphosphine)palladium(II)dichloride (39.5 mg, 0.056 mmol), and 1M sodium carbonate (1409 μL, 1.409 mmol) in 10 mL 1,2-dimethoxyethane/ethanol/water (7:2:3) was heated in a Biotage Initiator microwave reactor at 150° C. for 15 minutes. The mixture was concentrated, treated with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was washed with water, dried over magnesium sulfate, filtered, concentrated and purified on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (7:3 to 6:4) to give the title compound. MS (ESI+) m/z 566.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][C:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH:24]1[C:23]2[C:17]([NH:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:32][CH2:33][CH3:34])[C:4]([OH:35])=[O:3])=[CH:12][CH:11]=3)=[N:18][C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[S:21][C:22]=2[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC2=Nc3ccccc3Sc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCNC2=Nc3ccccc3Sc3ccccc32)cc1)C(=O)O
Yield: 92.8 %

Procedure:
3-(4-[2-(Dibenzo[b,f]-1,4-thiazepin-11-ylamino)-ethoxy]-phenyl)-2-ethoxy-propanoic acid ethyl ester (1.6 g, 3.26 mmol) was dissolved in ethanol (30 ml) and 20% sodium hydroxide (3 ml) was added. After 6 days ethanol was evaporated in vacuo, water (50 ml) and acetic acid (3 ml) were added, the product was filtered off and dried yielding 1.4 g (87%) of the title compound as hydrate. 1H NMR (250 MHz, DMSO-d6) δ7.3-7.6 (m, 6 H), 7.10-7.25 (m, 3 H), 6.82-7.15 (m+bs, 4-5 H), 4.26 (bt, J=4.9 Hz, 2 H), 3.88 (dd, J=7.6 Hz and 4.2 Hz, 1 H), 3.78 (bs, 2 H), 3.54 (m)+3.25 (m), 2 H; 2.91 (bdd, 1 H), 2.70-2.82 (m, 1 H), 1.03 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([NH2:35])[N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]([NH2:35])[N:27]=2)[N:11]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: Nc1nc(NCCNCc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
Using the procedure described above, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-nitro-6-amino-pyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl {2-[(5-nitro-6-amino(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[OH-].[Li+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 6-(tert-butyloxycarbonylaminomethyl)nicotinate from Example G3 (1.56 g, 5.84 mmol) in THF (20 ml) and water (5 ml) was added lithium hydroxide monohydrate (0.37 g, 8.76 mmol). The mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The aqueous residue was acidified by addition of 1M citric acid solution and extracted with chloroform/IPA (3 times). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated in vacuo to give a white solid; yield 1.38 g (94%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20][C:21]1[S:22][C:23]2[C:29]([N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>ClCCl.C([O-])(O)=O.[Na+]>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20]([C:21]1[S:22][C:23]2[C:29]([N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCN(CCC)c1cccc2nc(Sc3ccc(C)cc3C)sc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(CCC)c1cccc2nc(S(=O)c3ccc(C)cc3C)sc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
3-Chloroperoxybenzoic acid (MCPBA) (20 mg, 0.0810 mmol) was added to a solution of 2-[(2,4-dimethylphenyl)thio]-N,N-dipropyl-1,3-benzothiazol-7-amine (30 mg, 0.0810 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 18 h and diluted with saturated NaHCO3. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to afford 16 mg of the title compound.
Reaction SMILES: [C:1]([C:9](=[CH:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[C:10]([O:12]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:9]1[C:10](=[O:12])[C:22]2[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=CNc1ccccc1OC)C(=O)c1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc2c(=O)c(C(=O)c3ccccc3)c[nH]c12
Yield: 93.5 %

Procedure:
Ethyl 2-benzoyl-3-(2-methoxyphenylamino)acrylate (6.0 g, 0.018 mol) was added in portions to boiling diphenyl ether (100 ml) and heated under reflux for 45 minutes. The reaction mixture was allowed to cool and diluted with petroleum ether to afford the crystalline 3-benzoyl-8-methoxy-4(1H)-quinolone (4.7 g, 91%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[S:27]=[C:28]1[NH:32][C:31](=[O:33])[CH2:30][S:29]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:30]3[S:29][C:28](=[S:27])[NH:32][C:31]3=[O:33])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: O=C1CSC(=S)N1
Product: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2-thioxo-thiazolidin-4-one following General Procedure C.