Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:21])=[C:14]([C:19]#[N:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.[NH2:30][OH:31]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:21])=[C:14]([C:19](=[N:30][OH:31])[NH2:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:22]=1
Reactant: N#Cc1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of 3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzene-carbonitrile (250 mg, 0.74 mmol, 1 equiv.), Na2CO3 (181 mg, 1.70 mmol, 2.3 equiv.) and hydroxylamine hydrochloride (103 mg, 1.48 mmol, 2 equiv.) in absolute EtOH (5 ml) was stirred at 70° C. for 8 h. Excess Na2CO3 (181 mg, 1.70 mmol, 2.3 equiv.) and hydroxylamine hydrochloride (103 mg, 1.48 mmol, 2 equiv.) were added and the heating continued for 1 h. The reaction mixture cooled at room temperature, diluted with water (40 ml) and extracted with CH2Cl2 (3×60 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness under reduced pressure, to give 201 mg (73% yield) of the desired product. Mp 169-170° C., HPLC (Gemini C18, 50×4.6 mm): m/z 370 [M+H]+, Rt=3.82 min.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]\[C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]\[C:60]([CH3:70])([O:62][Si:63]([CH2:66][CH3:67])([CH2:68][CH3:69])[CH2:64][CH3:65])[CH3:61])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CBr
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 97.8 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (Z)-l-bromo-4-methyl-4-triethylsilyloxy-2-pentene (125 mg, 0.428 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (80.7 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[C:8]([CH2:20][NH2:21])=[CH:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=1)[C:8]([CH2:20][NH:21][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)cc(F)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1cc(F)cc(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(3,5-difluorophenyl)-quinolin-3-yl)methanamine (0.105 g, 0.345 mmol), 6-chloropurine (0.064 g, 0.41 mmol, 1.2 eq) and DIEA (0.70 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(3,5-difluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=76 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) 8 ppm 8.48 (s, 1 H), 8.35 (s, 1 H), 8.24 (s, 1 H), 7.86-7.94 (m, 2 H), 7.52-7.61 (m, 1 H), 7.27-7.35 (m, 2 H), 6.96-7.06 (m, 1 H), 4.73 (d, J=5.71, 2 H), Mass Spectrum (ESI) m/e=423 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[SH:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>CC(=O)CC>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[S:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: CCOP(=O)(CS)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OCC

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (569 mg, 1.57 mmol), potassium carbonate (303 mg, 2.36 mmol), diethyl sulfhydrylmethylphosphonate (405 mg, 2.20 mmol) and 2-butanone (5 ml) is heated under reflux for 5 hours. The reaction mixture is then filtered, and the filtrate is concentrated to dryness and purified by prep. TLC to give diethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylthiomethylphosphonate. NMR (CDCl3) δ 5.87 (m, 4H, OCH2CH3), 6.90 (d, 2H, 14 Hz, SCH2 --P) and 8.63 ppm (t, 6H, OCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)([Cl:10])[Cl:9])[N:3]=1.CO.Cl.ClC1C=CC=C(CCl)N=1>[Fe].C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([Cl:10])[Cl:9])[N:3]=1
Reactant: Clc1cccc(C(Cl)(Cl)Cl)n1
Agent: [Fe]
Agent: Cl
Agent: ClCc1cccc(Cl)n1
Solvent: ClCCl
Solvent: CO
Product: Clc1cccc(C(Cl)Cl)n1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
Into a 250 milliliter (ml) flask fitted with a condenser, magnetic stirrer and dropping funnel were added 46.2 grams (g) (0.20 mole) of 2-chloro-6(trichloromethyl)pyridine, 30 g of methanol and 9.1 g (0.16 mole) of 20 mesh iron filings. The mixture was heated to 70° C. and 30 g of concentrated hydrochloric acid was added thereto over a 5 minute period. A slight exotherm occurred and the mixture was heated and maintained under reflux (83°-86° C.) for 1 hour. The reaction mixture was cooled to 45° C., and 50 ml of methylene chloride was added thereto. The mixture was filtered through diatomaceous earth and the filter cake washed thoroughly with water and then with methylene chloride. The filtrates were combined and the methylene chloride phase separated from the water phase. The product from a second run was combined with the above product mix and the mixture concentrated to a pot temperature of 95° C. at 15 millimeters of mercury (mm Hg). This residue was present in an amount of 74.5 g and melted at 48°-52° C. Analysis by gas-liquid chromatography (glc) showed a yield of 90.1 percent 2-chloro-6-(dichloromethyl)pyridine, 3.7 percent 2-chloro-6-(chloromethyl)pyridine and 1.7 percent 2 -chloro-6-(trichloromethyl)pyridine. The 2-chloro-6-(dichloromethyl)pyridine was recovered by recrystallization from heptane and melted at 53.3°-54.0° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH:17]=[CH:18][C:19]2=[O:29])[CH2:11]1.O>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:5][C:4]([Si:1]([CH3:3])([CH3:2])[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH:17]=[CH:18][C:19]2=[O:29])[CH2:11]1)([CH3:7])[CH3:6]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]32)C1

Procedure:
Add t-butyldimethylsilyl chloride (5.49 g, 36.4 mmol), 4-dimethylaminopyridine (0.21 g, 1.74 mmol) and triethylarmine (5.32 mL, 38.14 mmol) to a stirred solution of 3β-hydroxyandrosta-5,15-dien-17-one (M81, 10.00 g, 34.8 mmol) in anhydrous DMF (175 mL) under nitrogen. Stir the resultant suspension at room temperature for 3 days and then pour into rapidly stirred water (750 mL). Filter the resultant suspension and crystallize the white solid to give 3β-[[(1,1-dimethylethyl)dimethylsilyl]oxy]androst-5,15-dien-17-one (M82).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Sc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
The product of Example 237A (0.301 g, 1.22 mmol), 4-mercaptophenol (0.184 g, 1.46 mmol, 1.2 eq) and cesium carbonate (0.952 g, 2.92 mmol, 2.4 eq) in dimethylformamide (10 mL) was heated in a 100° C. oil bath for 3 hours and then cooled to room temperature. Water (20 mL) was added and the mixture was stirred at room temperature for 2 hours, and the resulting solid was isolated by vacuum filtration and dried to provide the title compound (0.405 g, 94%) as a yellow solid.
Reaction SMILES: BrCCCCCC1[O:11]N=C(C)C=1.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[O:21]CCN=2)[CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[C:15]=1[OH:28].BrC1C=C(C=C([N+]([O-])=O)C=1O)C(NCCO)=O.CO.[C:48]([O:51][CH:52]([CH3:54])[CH3:53])(=[O:50])[CH3:49].OC1C=CC(C(O)=O)=CC=1[N+]([O-])=O>>[Br:13][C:14]1[C:15]([OH:28])=[C:16]([N+:25]([O-:27])=[O:26])[CH:17]=[C:18]([CH:19]=1)[C:20]([OH:21])=[O:11].[C:48]([O:51][CH:52]([CH3:54])[CH3:53])(=[O:50])[CH3:49]
Reactant: O=[N+]([O-])c1cc(C2=NCCO2)cc(Br)c1O
Reactant: Cc1cc(CCCCCBr)on1
Agent: O=C(NCCO)c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Solvent: CO
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1cc(Br)c(O)c([N+](=O)[O-])c1

Procedure:
Intermediates: 5-(5-bromopentyl)-3-methylisoxazole and 2-bromo-4-(4,5-dihydro-2-oxazolyl)-6-nitrophenol. The latter, a bright yellow solid, was prepared by cyclization of 3-bromo-4-hydroxy-N-(2-hydroxyethyl)-5-nitrobenzamide, yellow solid, m.p. 163°-164° C. (from methanol-isopropyl acetate). The latter was in turn prepared by bromination of 4-hydroxy-3-nitrobenzoic acid to form 5-bromo-4-hydroxy-3-nitrobenzoic acid, m.p. 233°-234° C. (yellow solid from isopropyl acetate), esterification to the corresponding methyl ester, m.p. 128°-130° C. (yellow solid from carbon tetrachloride) and reaction of the latter with 2-hydroxyethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:32][CH2:33][C:34](=N)OCC.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>ClCCCl>[Cl:32][CH2:33][C:34]1[N:12]([C@H:13]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 99.9 %

Procedure:
tert-Butyl (4S)-4-[(3-aminoquinolin-4-yl)amino]-5-[(methylsulfonyl)amino]pentylcarbamate (7.13 g, 16.3 mmol) was dissolved in 100 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (7.73 g, 48.9 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated NaHCO3 solution and 200 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (4S)-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-5-[(methylsulfonyl)amino]pentylcarbamate (8.08 g) as an orange foam. The crude material was used in the next step without further purification.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19][OH:20])=[CH:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([O:25]CC)=[O:24])[O:3]1.[OH-].[Na+]>CO.C1COCC1>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19][OH:20])=[CH:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([OH:25])=[O:24])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=N)NO)s3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ncc(C(=N)NO)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude ethyl 2-(1-hydroxy-6-(5-(N-hydroxycarbamimidoyl)thiazol-2-yloxy)-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (10 mL, 1:1) was added aqueous NaOH solution (200 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified with 1N HCl to pH 5 and then concentrated. HPLC purification gave desired product as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.2 (b, 2H), 9.20 (b, 1H), 7.70 (s, 1H), 7.37 (d, J=2 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 5.48 (dd, J=9.2, 2 Hz, 1H), 3.02 (dd, J=15.6, 2.4 Hz, 1H), 2.26 (s, 3H), 2.28 (dd, J=15.6, 9.6 Hz, 1H). 2 protons assumed to be exchanged with solvents. MS (ESI) m/z=364 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Cl:27]N1C(C)(C)C(=O)N(Cl)C1=O.[OH-].[Na+]>O1CCCC1.CCCCC>[Cl:27][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)nc2)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (3.6 g, 10 mmol) in tetrahydrofuran (200 ml) was cooled to −78° C. Tert-butyllithium (14.7 ml, 1.5 M) in pentane was added during 10 min, followed by stirring for 5 min at −78° C. 1,3-Dichloro-5,5-dimethylhydantoin (1.97 g, 10 mmol) was added in small portions. The mixture was stirred for 0.5 min. Aqueous sodium hydroxide was added (100 ml, 4 M), and the reaction was allowed reach room temperature. The mixture was extracted twice with diethyl ether (100 ml) Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as free base. Yield 1.7 g, 55%.
Reaction SMILES: [OH-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.Cl>CN(C)C=O.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C

Procedure:
2.7 g (67.5 mmol) of powdered NaOH are introduced into 10.8 g (675 mmol) of diethyl malonate in 30 ml of dimethylformamide at room temperature, with cooling, a solution of 5 g (31 mmol) of 2-chloro-5-nitropyridine in dimethylformamide is then added dropwise and the mixture is stirred at room temperature until the reaction is complete. For working up, the mixture is poured onto 500 ml of water and acidified with concentrated HCl and the precipitate is filtered off with suction and rinsed with petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:18][CH3:19])=[O:9])=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(Cl)cc1
Reaction time: 96 h
Yield: 93 %

Procedure:
A solution of 4-chlorophenoxyacetic acid (Aldrich) (18.62 g, 99.8 mmoles) and concentrated sulfuric acid (Fisher) (2.5 mL) in ethanol (170 mL) was refluxed with stirring under a Drierite tube for 96 hours. The reaction solution was cooled in an ice-bath, and the volatiles were removed by spin evaporation in vacuo to a volume of about 100 mL. The liquid was dissolved in dichloromethane (225 mL) and washed with a solution of 5% aqueous sodium bicarbonate (4×100 mL) and finally with brine (1×50 mL). The solution was dried over sodium sulfate and spin evaporated in vacuo to give 19.97 g (93% yield) of ethyl 4-chlorophenoxyacetate as an amber liquid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](I)[CH:7]=1)=[O:4].[CH2:15]=[C:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21].CC([O-])=O.[K+]>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](/[CH:15]=[C:16]2\[C:17](=[O:21])[O:18][CH2:19][CH2:20]\2)[CH:7]=1)=[O:4]
Reactant: O=C(Nc1cccc(I)c1)C(F)(F)F
Reactant: C=C1CCOC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1OCC/C1=C/c1cccc(NC(=O)C(F)(F)F)c1
Temperature: 110 °C
Yield: 80.9 %

Procedure:
The reaction mixture of 2,2,2-trifluoro-N-(3-iodophenyl)acetamide (160 mg, 0.52 mmol), 3-methylenedihydrofuran-2(3H)-one (62 mg, 0.63 mmol), Pd(OAc)2 (33 mg, 0.015 mmol) and KOAc (200 mg, 2.04 mmol) in NMP (2 mL) was degassed and heated to 110° C. for 12 hrs. The mixture was extracted with EtOAc and washed with H2O, brine, dried over MgSO4, filtered, concentrated in reduced pressure to dryness, and recrystallized in MeOH to give desired intermediate (Z)-2,2,2-trifluoro-N-(3-((2-oxodihydrofuran-3(2H)-ylidene)methyl)phenyl)acetamide (120 mg). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.4 (s, 1H), 7.96 (s, 1H), 7.74 (dt, J=7.6, 1.6 Hz, 1H), 7.51 (7, J=7.6 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.47 (dt, J=7.6, 1.6 Hz, 1H), 7.38 (t, J=2.8 Hz, 1H), 4.43 (t, J=7.2 Hz, 2H), 3.24 (dt, J=2.8, 7.2 Hz, 2H). MS (ESI) m/z=284 (M−1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]=[N:9][C:8]=2[C:19]([F:22])([F:21])[F:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:27]Br.C(N(C(C)C)CC)(C)C>C(#N)C>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:27][N:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:10]=[N:9][C:8]([C:19]([F:22])([F:21])[F:20])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)[CH2:18][CH2:17]1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)cc1-c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(F)cc(CN2CCN(c3cc(-c4ccccc4)c(C(F)(F)F)nn3)CC2)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A mixture of 4-phenyl-6-piperazin-1-yl-3-trifluoromethyl-pyridazine (E1) (0.050 g, 0.16 mmol), 3,5-difluorobenzyl bromide (0.031 ml, 0.24 mmol) and diisopropylethylamine (0.056 ml, 0.32 mmol) in acetonitrile (2 ml) was stirred at 100° C. for 10 min., under microwave irradiation. The solvent was evaporated in vacuo and then, dichloromethane and ammonium chloride (10% aqueous solution) were added. The mixture was filtered through a diatomaceous earth cartridge. The solvent was then evaporated in vacuo and the residue was purified by CC-TLC (centrifugal circular thin-layer chromatography) on a chromatotron (a preparative, centrifugally accelerated, radial, thin-layer chromatograph). The crude product was crystallised from diethyl ether/heptane to yield E3 (0.037 g, 52%) as a solid. C22H19F5N4 requires 434. Found 435 (MH+).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@H:15]3[CH2:17][O:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([C:27]1([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([C:27]1([OH:33])[CH2:32][CH2:31][N:30]([CH2:17][C@@H:15]([OH:16])[CH2:14][O:13][C:12]2[CH:18]=[CH:19][C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][CH:11]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(COc2ccc(OC[C@H]3CO3)cc2)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Solvent: CCO
Product: O[C@@H](COc1ccc(OCc2ccccc2)cc1)CN1CCC(O)(Cc2ccccc2)CC1
Yield: 86.3 %

Procedure:
(R)-{[4-(Phenylmethoxy)phenoxy]methyl}-oxirane (0.55 g, 2.2 mmol) and 4-benzyl-4-hydroxy-piperidine (0.49 g, 2.4 mmol) were dissolved in ethanol (10 ml) and refluxed for 2 h. After evaporation of the solvent, the residue was chromatographed over silica gel (ethyl acetate-MeOH, 9:1) to give (R)-4-benzyl-1-[3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-piperidin-4-ol (0.85 g, 88%) as colorless oil. MS: m/e=448.5 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.Cl.[CH3:11][C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][C@H:12]2[CH3:11])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Temperature: 120 °C
Yield: 75.1 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (500 mg, 3.05 mmol) in CH3OH (10 mL) were added (3R)-3-methylmorpholine hydrochloride (441 mg, 3.2 mmol) and triethylamine (1.28 mL, 9.2 mmol), and the reaction mixture was heated in a microwave at 120° C. for 35 minutes. Side-product started to form. An additional 0.5 eq of (3R)-3-methylmorpholine hydrochloride and 0.2 mL of triethylamine were added, and the mixture was heated in an oil bath at 50° C. for 3 days and in a microwave at 100° C. for 3 hours. The mixture was cooled down, evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organics were washed with water and brine, dried (MgSO4), filtered, and evaporated. The resulting material was triturated with Et2O and dried in vacuo to afford the title compound (524 mg). LC-MS (ES) m/z=229, 231 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:17]1([C:23]2[S:27][C:26]([CH2:28][C:29]([OH:31])=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[N:12]1([C@@H:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:3]2[N:2]([CH3:1])[C:29](=[O:31])[CH2:28][C:26]2[S:27][C:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:24][CH:25]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)s1
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN(C(=O)Cc1ccc(-c2ccccc2)s1)[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Yield: 68.6 %

Procedure:
Using the procedure of Step C of Example 1, 0.432 g of the product of Step B of Example 1, 0.567 g of 5-phenyl-2-thiophene-acetic acid and 0.422 g of carbonyldiimidazole were reacted to obtain 0.571 g of trans-(±)- N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-5-phenyl-2-thiophene-acetamide and then 0.457 g of its hydrochloride melting at ≃249° C.