Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[C:13]([OH:31])=[CH:14][C:15]2[CH2:16][CH2:17][C@@H:18]3[C@@H:27]([C:28]=2[CH:29]=1)[CH2:26][CH2:25][C@@:23]1([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]1[OH:30])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:9]([O:11][C:12]1[C:13]([O:31][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:15]2[CH2:16][CH2:17][C@@H:18]3[C@@H:27]([C:28]=2[CH:29]=1)[CH2:26][CH2:25][C@@:23]1([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]1[OH:30])[CH3:10]
Reactant: CCOc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1cc2c(cc1OCc1ccccc1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 109.7 %

Procedure:
Benzyl bromide (4.5 g, 38 mmol) was added to a suspension of 2-ethoxy-β-estra-3,17β-diol (2) (4.5 g, 13 mmol) and potassium carbonate (8.6 g, 62 mmol) in anhydrous ethanol (100 mL) under argon atmosphere at 0° C. The resulting mixture was stirred at 100±5° C. for 7-8 h. The solvent was evaporated under reduced pressure and the residue was diluted with water, and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic solution was washed with water (100 mL), sodium bicarbonate (120 mL), brine (100 mL), and dried over sodium sulfate. The ethyl acetate layer on evaporation under reduced pressure gave a viscous oil (5.8 g), which was used as such without any further purification in the next step: 1H NMR, (CDCl3) δ 7.35 (s, 5 H), 6.75 (s, 1 H) 6.65 (s, 1 H), 5.5 (s, 1 H), 4.55 (s, 2 H), 4.04 (q, J=6.4, 2 H), 3.5 (t, J=8.5 Hz, 1 H), 2.75 (m, 3 H), 2.20-1.95 (m, 6 H), 1.90-1.80 (m, 2 H), 1.75-1.5 (m, 2 H), 1.45-1.1 (m, 7 H, 0.85 (s, 1 H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].Br[CH2:19][C:20]([NH2:22])=[O:21]>CC#N>[C:16]([C:8]1[C:9]([C:12]([F:15])([F:13])[F:14])=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]([CH2:1][CH3:2])=[CH:11]2)#[N:17]
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: NC(=O)CBr
Solvent: CC#N
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(N)=O
Temperature: 90 °C
Yield: 376.3 %

Procedure:
2-Ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.004 g, 0.018 mmol) Cs2CO3 (0.051 g, 0.16 mmol), and 2-bromoacetamide (0.022 g, 0.16 mmol) were combined in CH3CN (3 mL) and heated at 90° C. under N2 for 1 hr. Extraction with Et2O and washing with water and brine was followed by drying (Na2SO4), filtration, and concentration in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.020 g): MS (ESI): m/z 296 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.Cl.[CH3:29][CH:30]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:31](O)=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:29][CH:30]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:31]([O:1][C:2]1[C:11]2[C:10]3[CH:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C:9]=3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1)=[O:32]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(C)CCC1
Reactant: CC(CCN1CCOCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)C(C)CCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2C(C)CCC1

Procedure:
A mixture of 1.2 g. (3.24 mmole) of 1-hydroxy-3-(3-methyl-2-octyl)-7,8,9,10-tetrahydro-6,6,10-trimethyl-6H-dibenzo[b,d]pyran, 0.73 g. (3.24 mmole) of 2-methyl-4-morpholinobutyric acid hydrochloride, 0.71 g. (3.46 mmole) of dicyclohexylcarbodiimide and 50 ml. of methylene chloride was stirred at room temperature for 16 hrs. The reaction mixture was cooled and the byproduct of dicyclohexylurea was removed by filtration. The solvent was evaporated to give a foamy residue which was chromatographed using activated magnesium silicate and methanol/chloroform solvent mixtures. The fractions were monitored by thin layer chromatography and the desired material was obtained from the 2% methanol/chloroform fractions. The appropriate fractions were collected and evaporated to give 0.9 g. (51%) of light purple gum.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].N1C=CC=CC=1.[CH3:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](Cl)=[O:42]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:41]([C:40]4[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=4[CH3:38])=[O:42])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(NC(=O)c2ccccc2C)cc1OC
Reaction time: 16 h

Procedure:
0.46 g of the compound prepared in Example 5 step B), 20 ml of DCM and 0.5 g of pyridine were mixed at 20° C. and 0.18 g of 2-methylbenzoyl chloride in 10 ml of DCM was then added. The reaction mixture was stirred for 16 hours and then concentrated under vacuum. The residue was washed with water, with 1N hydrochloric acid, with 10% sodium carbonate and then with water. It was dried over sodium sulfate and the solvent was then evaporated off to dryness to give the expected product in the form of a white solid, which crystallized from isopropyl ether. m=0.3 g. M.p.=180° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:15]([O:19]C)(=[O:18])[CH:16]=[CH2:17]>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][CH2:17][CH2:16][C:15]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: C=CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(OCCC(=O)O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (350 mg, 2.0 mmol) and NaH (6 mg of a 60% dispersion in mineral oil, 0.15 mmol) was warmed until effervescence had ceased. The mixture was stirred at ambient temperature for 15 min, then methyl acrylate (940 μL, 10.5 mmol) was added. After 3 h, the reaction was diluted with Et2O (50 mL), before being washed with H2O (10 mL) and brine (10 mL) then dried (MgSO4). The Et2O solution was filtered and evaporated, then EtOAc (15 mL) was added. The solvents were removed, then more EtOAc (15 mL) was added, before being evaporated off again to ensure that no methyl acrylate remained. The residue was dissolved in MeOH (3 mL), before being treated with 2 M NaOH (2.0 mL). After 1 h, the MeOH was removed, then H2O (12 mL) and Et2O (10 mL) were added. The Et2O layer was extracted further with H2O (8 mL), then the combined aqueous extracts were acidified to pH 2 with 2 M HCl and the resulting mixture extracted with EtOAc (50+40 mL). The combined organic extracts were washed with brine and dried (MgSO4). Filtration, solvent evaporation and column chromatography (IH-EtOAc, 1:1) gave the title compound: δC (CDCl3): 28.1, 34.8, 56.3, 63.9, 68.0, 79.9, 156.4, 176.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][N:15]=[C:16]=[O:17]>C(OCC)(=O)C>[CH3:14][NH:15][C:16](=[O:17])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NC)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 10 g of ethyl 2-aminothiazol-4-ylglyoxylate. 7 g of methyl isocyanate and 200 ml of ethyl acetate. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [Cl:1][C:2]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([O:26][CH3:27])=[O:25])[N+:18]=1[O-:28])(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:2][Cl:1])=[N+:18]([O-:28])[C:19]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(Cl)ccc(C(Cl)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[n+]1[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(Cl)ccc(CCl)[n+]1[O-]
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A mixture of di-tert-butyl chloro[5-chloro-6-(methoxycarbonyl)-1-oxidopyridin-2-yl]malonate (19.65 g, 45.0 mmol), trifluoroacetic acid (41 mL) and dichloromethane (82 mL) was refluxed for 2.5 hours, cooled and then concentrated to dryness. The crude residue was taken up in xylene and the mixture heated at reflux until carbon dioxide was no longer given off. The reaction mixture was then cooled to room temperature and ethyl ether added followed by a small amount of saturated NaHCO3 solution. The organic was separated and the aqueous layer was saturated with brine and extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated to dryness. The crude product was purified by column chromatography (20-50% ethyl acetate in hexane) to give methyl 3-chloro-6-(chloromethyl)pyridine-2-carboxylate 1-oxide (7.11 g, 30.1 mmol) as a brown solid; 1H NMR (CDCl3): δ 7.60 (d, 2H), 7.40 (d, 2H), 4.80 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: Cl.[NH2:2]O.[C:4](/[N:12]=[C:13](\SC)/[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([C:22]2[C:23](=[O:34])[N:24]([CH3:33])[C:25]3[C:30]([CH:31]=2)=[CH:29][N:28]=[C:27]([CH3:32])[CH:26]=3)[CH:16]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCO>[CH3:33][N:24]1[C:25]2[C:30](=[CH:29][N:28]=[C:27]([CH3:32])[CH:26]=2)[CH:31]=[C:22]([C:17]2[CH:16]=[C:15]([NH:14][C:13]3[N:12]=[C:4]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[O:11][N:2]=3)[CH:20]=[CH:19][C:18]=2[CH3:21])[C:23]1=[O:34]
Reactant: CS/C(=N\C(=O)c1ccccc1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4ccccc4)n3)ccc1C)c(=O)n2C
Temperature: 80 °C

Procedure:
Hydroxylamine hydrochloride (35 mg, 0.5 mmol) and EtOH (1 mL) were added to the crude 21 (0.05 mmol). The mixture was heated at 80° C. for 2 h. After filtration, the mixture was purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-phenyl-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one A7. 1H NMR (400 MHz, d4-MeOH) δ 9.03 (s, 1H), 8.12 (s, 1H), 8.1 (d, J=1.5 Hz, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7.65 (d, J=6.2 Hz, 1H), 7.59 (d, J=6.3 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.5 (d, J=2.4 Hz, 1H), 7.43 (dd, J=8.3, 2.5 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 2.83 (s, 3H), 2.18 (s, 3H). MS m/z 424.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[S:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].O1CCOCC1>[F:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][C:5]([C:15]2[S:16][CH:17]=[C:13]([CH3:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1csc(B(O)O)c1
Reactant: OCCc1cc(I)cnc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1csc(-c2cnc(F)c(CCO)c2)c1
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
To a microwave tube was added 2-(2-fluoro-5-iodopyridin-3-yl)ethanol (0.09 g, 0.3 mmol), 4-methylthiophen-2-ylboronic acid (0.2 g, 1 mmol), palladium fibrecatalyst (0.010 mg, 10% wt), potassium carbonate (2 M, 0.3 mL, 0.7 mmol), and dioxane (3 mL). The vial was sealed and placed into CEM microwave for 20 min. at 150° C., with 80 Watts of power via Powermax. The reaction mixture was partitioned between water/CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using SiO2 chromatography with hexane:acetone (90%:10%) to afford the product as colorless liquid (65 mg). MS (ESI pos. ion) m/z (MH+): 238.3. Calc'd exact mass for C12H12FNOS: 237.1. 1H NMR (300 MHz, Chloroform-d) δ ppm 1.54-1.64 (m, 1 H) 2.30 (s, 3 H) 2.94 (t, J=6.36 Hz, 2 H) 3.95 (q, J=6.24 Hz, 2 H) 6.92 (s, 1 H) 7.11 (s, 1 H) 7.84 (d, J=9.06 Hz, 1 H) 8.27 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[Br:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35].C(Cl)Cl>C(OCC)(=O)C>[Br:23][C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([C:2]([CH3:1])([S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)(=[O:5])=[O:6])[CH3:3])[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2Br)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a 10 ml vial was loaded 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (60 mg, 0.179 mmol), diisoprpoylethylamine (0.093 ml, 0.54 mmol), 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (87 mg, 0.27 mmol), N,N-dimethylaminopyridine (4.4 mg, 0.036 mmol) and 1 ml methylene chloride. The resulting reaction solution was stirred at room temperature for one hour. It was diluted with 20 ml ethyl acetate, washed sequentially with 20 ml 1N HCl, 20 ml 10% KOH and 20 ml brine. Organics were dried over sodium sulfate, filtered and concentrated to give 91 mg white solid. A fraction of this crude product (20 mg) was further purified on a reverse phase column eluted with water/acetonitrile gradient solvent to give 16 mg desired product as fluffy white solid after lyophilizing.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C=O)C>O>[CH2:12]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[S:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(SCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 35.5 g (115.2 mmol) 2-bromo-5-nitro-O-benzylphenol, 26.3 g (190 mmol) potassium carbonate, 15 mL (127 mmol) benzyl mercaptan, and 200 mL DMF were stirred at room temperature 18 h. TLC analysis indicated a complete reaction, so the thick reaction mixture was transferred to a 2 L Erlenmeyer containing 1 L water and the resulting mixture was stirred in a ice/water bath 30 min. The precipitate was filtered, washed with three 300 mL portions of water, dried at 40° C. 18 h under vacuum to give 2-benzyloxy-4-nitro-S-benzylthiophenol 40.5 g (115.2 mmol, 100%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([NH:15][C:16]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=O)=[O:17])=[CH:13][N:12]=[C:11]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[N:10]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([N:15]2[C:16](=[O:17])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[CH:13][N:12]=[C:11]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[N:10]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2-{N-[4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]carbamoyl}benzoic acid was heated to 120° C. in acetic acid for four hours and then concentrated in vacuo to obtain 2-[4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]isoindoline-1,3-dione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[S:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:33]=3)[S:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(C)c1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)cs2)c1
Yield: 44.9 %

Procedure:
2-Chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-isopropyl phenyl boronic acid (42 mg, 0.26 mmol) to give the title compound (28 mg, 45%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[CH:22][NH:21][N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(F)c1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(F)c(F)c3)nc12
Yield: 42.3 %

Procedure:
Reaction of 1-(3,4-difluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (252 mg, 1.0 mmol), prepared from commercially available 3,4-difluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (137 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[C:4](/[C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)=[N:5]\[O:6][CH2:7][CH2:8][CH3:9].[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[CH3:1][O:2][C:3](=[O:16])/[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:19](=[O:20])[CH2:18][Cl:17])[S:13][CH:14]=1)=[N:5]\[O:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCO/N=C(\C(=O)OC)c1csc(N)n1
Reactant: O=C(Cl)CCl
Product: CCCO/N=C(\C(=O)OC)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a solution of 5.0 g of 2-(2-amino-4-thiazolyl)-(Z)-2-(n-propoxyimino)acetic acid methyl ester in 35 ml of N,N-dimethylacetamido is added dropwise under ice-cooling and stirring 3.25 g of chloroacetyl chloride in the course of 10 minutes. The mixture is stirred for one hour at room temperature, then poured into 200 ml of ice-water, whereupon an oily product separates out, which is left standing to crystallize. The crystals are collected by filtration, washed with water and dried to yield 6.35 g (96.7%) of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(n-propoxyimino)-acetic acid methyl ester, m.p. 100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:15][Mg]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)([OH:9])[CH3:15])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1nccs1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(O)(c1ccc(F)cc1)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4-fluorophenyl)(thiazol-2-yl)methanone (1.05 g, 5.07 mmol) in diethyl ether (50 mL) and was cooled to 0° C., treated with methylmagnesium bromide (1.85 mL, 3.0 M in Et2O, 5.57 mmol) and stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, extracted with diethyl ether (2×30 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as an oily brown residue (1.052 g, 93% yield). MS (M+H)+ 224.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23](O)=[O:24])[N:21]=1)=[CH:5]2.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: C1CCNCC1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)N1CCCCC1
Yield: 57 %

Procedure:
The compound (40 mg, 0.11 mmol) prepared in Example 27 and piperidine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (27 mg, Yield 57%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 2 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (582 mg, 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>[Ni](Cl)Cl>[CH2:16]([O:15][P:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2)([O:18][CH2:19][CH3:20])=[O:21])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Agent: Cl[Ni]Cl
Product: CCOP(=O)(OCC)c1ccc2c(c1)C=CC(C)(C)O2
Temperature: 180 °C

Procedure:
16 g of 6-bromo-2,2-dimethyl-2H-chromene are dissolved in 100 ml of triethyl phosphite. 2 g of nickel chloride are added and the mixture is refluxed at 180° C. for 24 hours in an autoclave. After the remaining triethyl phosphite has been concentrated, the expected product distills at 130°-140° C. under 0.1 mm Hg. 11.5 g are collected.