Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]=[C:3]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]1[C:16]2[C:3](=[CH:2][C:25]3[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:28]=[CH:29][CH:30]=3)[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[O:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: BrC=C1c2ccccc2Oc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3Oc3ccccc32)c1
Temperature: 95 °C
Yield: 2.8 %

Procedure:
Mix 9-Bromomethylene-9H-xanthene (400 mg, 1.46 mmol), N-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (413 mg, 1.39 mmol), and Na2CO3 (2M/water, 1.74 mL, 3.48 mmol) in dioxane (10 mL) and sparge with nitrogen for 10 min. Add Pd(PPh3)4 (81 mg, 0.070 mmol), seal vial, and heat to 95° C. overnight. Concentrate and dilute with water (3 mL) and ethyl acetate (10 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge. Elute, collect, and concentrate 50 mL ethyl acetate. Purify on silica gel (20-40% ethyl acetate/hexanes), then re-purify by semi-prep reverse-phase HPLC (10-95% CH3CN/H2O, 0.1% TFA added) to afford 14 mg (3%) of the title compound as a yellow solid. MS [ES] 364 (M+H), 362 (M−H); HPLC shows 97% purity; 1H-NMR (CDCl3) δ 7.78 (d, 1H, J=7.5 Hz), 7.39-7.14 (m, 10H), 6.91 (s, 1H), 6.85 (t, 1H, J=7.5 Hz), 6.53 (s, 1H), 3.01 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(OCc2ccc(F)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(OCc4ccc(F)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (53 mg, 0.30 mmol) was reacted with 4-[2-amino-4-(4-fluoro-benzyloxy)-phenylsulfanyl]-phenol (102 mg, 0.30 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (115 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3H) 5.11 (s, 2 H) 6.26 (d, J=6.99 Hz, 1 H) 6.65 (d, J=8.46 Hz, 2 H) 7.10 (d, J=8.82 Hz, 2 H) 7.15-7.27 (m, 4 H) 7.49 (m, J=5.88 Hz, 2 H) 7.81 (d, J=8.46 Hz, 1 H) 8.40 (d, J=6.98 Hz, 1 H) 8.98 (d, J=8.46 Hz, 1 H) 9.78 (s, 1 H) 11.03 (br s,1 H) 14.36 (br s, 1 H); MS (ESI+) m/z, 484 (M+H−TFA)+; (ESI−) m/z, 482 (M−H−TFA)−.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:35])([CH3:34])[C@H:10]([NH:15][C:16]([C:18]1[S:22][C:21]2[CH:23]=[C:24]([C:27]#[C:28][C@@H:29]3[CH2:31][C@H:30]3[CH2:32][OH:33])[CH:25]=[CH:26][C:20]=2[CH:19]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:8][C:9]([CH3:35])([CH3:34])[C@H:10]([NH:15][C:16]([C:18]1[S:22][C:21]2[CH:23]=[C:24]([C:27]#[C:28][C@@H:29]3[CH2:31][C@H:30]3[CH2:32][OH:33])[CH:25]=[CH:26][C:20]=2[CH:19]=1)=[O:17])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](NC(=O)c1cc2ccc(C#C[C@@H]3C[C@H]3CO)cc2s1)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@@H](NC(=O)c1cc2ccc(C#C[C@@H]3C[C@H]3CO)cc2s1)C(C)(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a stirring solution of (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.3) in methanol (10 mL) was added 4N HCl in dioxane (10 mL) and the reaction was stirred at room temperature for 2 hr, then at 4° C. overnight. The reaction mixture was concentrated under reduced pressure to yield a residue, which was partitioned between water and MTBE. The aqueous layer was basified with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-amino-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.4, 880 mg, 2.2 mmol, 67%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH:17]1([CH2:22][CH2:23]CS([O-])(=O)=O)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH2:23][CH2:22][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=S(=O)([O-])CCCC1CCCC1
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cc(I)c(OCCC2CCCC2)c(I)c1
Temperature: 65 °C
Yield: 72.2 %

Procedure:
To a stirred mixture of 2,4,6-triiodophenol (20.36 g, 43.2 mmol) and milled anhydrous potassium carbonate (7.2 g, 52.2 mmol) in 75 ml of dry dimethylformamide was added dropwise over 10 minutes, a solution of 2-cyclopentylethylmethanesulfonate (8.2 g, 42.7 mmol) in 10 ml of dimethylformamide. The mixture was heated at 65° C. under argon overnight and the solvent was then removed under vacuum. The resulting amber residue was partitioned between ethyl acetate (200 ml) and water (30 ml). The aqueous layer was further extracted with ethyl acetate (2×250 ml) and the combined ethyl acetate extracts were treated with decolorizing carbon, dried over magnesium sulfate and passed through a short pad of basic alumina. The filtrate was evaporated under vacuum to give 17.5 g (73%) of the desired product as an amber oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[N+:12]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>CCO>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:12]
Reactant: COc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: COc1c(N)cccc1N
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A 2 L round bottomed flask was charged with 23 g (116 mmol) 2-methoxy-1,3-dinitrobenzene and 261 g (1.16 mol) tin chloride dihydrate. 160 mL EtOH was added, and the resulting suspension was stirred at 70° C. for 90 min. In the beginning, the reaction is very exothermic be careful! The solvent was removed and the reaction mixture was diluted with H2O and slowly added to about 500 mL of a 10 M NaOH solution. The suspension was cooled down to RT and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The product was obtained as red oil and used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=[O:12].[CH3:16][CH:17](C(O)=O)C(O)=O.Cl>C(N(CC)CC)C>[O:12]=[C:11]([C:3]1[C:2]([C:14]([OH:13])=[O:15])=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][CH3:17]
Reactant: CC(C(=O)O)C(=O)O
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CCC(=O)c1cc2ccccc2cc1C(=O)O
Yield: 56.3 %

Procedure:
A mixture of 2,3-naphthalenedicarboxylic anhydride (35.5 g), methylmalonic acid (25 g) and triethylamine (250 ml) was stirred and refluxed for 8 hr. The cooled reaction mixture was poured onto 10% hydrochloric acid (2 liter) and the aqueous slurry was extracted with chloroform (1.5 liter). The dried (magnesium sulphate) extract was evaporated to dryness to give an oil which was recrystallised from light petroleum (b.p. 60°-80°)/chloroform to give 3-(1'-oxopropyl)naphthalene-2-carboxylic acid (23 g, m.p. 147°).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]2)=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Li+].C1COCC1.Cl>O>[F:26][C:22]1([F:25])[CH2:23][CH2:24][N:20]([C:18]([C:16]2[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=2)[C:4]([OH:27])=[O:3])=[O:19])[CH2:21]1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N2CCC(F)(F)C2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)N2CCC(F)(F)C2)c1
Yield: 104.1 %

Procedure:
Stir a solution of 5-(3,3-difluoropyrrolidine-1-carbonyl)-N-methyl-N-propyl-isophthalamic acid ethyl ester (270 mg, 0.71 mmol), 1 N lithium hydroxide (1.1 mL, 1.1 mmol) and THF (2.0 mL) at room temperature for 4 h. Add 10 mL water, acidify with 1 N HCl (2 mL), extract with dichloromethane (3×10 mL), dry (sodium sulfate) and concentrate to give the title compound (262 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH2:32]=[O:33].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[OH:1][C:2]1[C:3]([C:11]2([CH2:32][OH:33])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: COC(=O)c1ccccc1CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A solution of methyl 2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate (17.1 g, 40.0 mmol) and paraformaldehyde (10.3 g, 330 mmol) in THF (500 mL) was degassed by bubbling through argon for 2 hours. To this solution was added lithium diisopropylamide solution (45.1 mL, 2 M solution, 90.0 mmol) slowly at −78° C. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonium chloride solution. The mixtrue was concentrated in vacuo to remove THF followed by the addition of ethyl acetate (500 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was recrystallized from ethyl acetate/hexanes to give the title compound (13.7 g, 75%): 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.95 (dd, 1H), 7.53-7.33 (m, 3H), 7.08-6.82 (m, 4H), 6.53 (d, 1H), 6.25 (s, 1H), 5.93-5.86 (m, 2H), 5.31-5.07 (m, 3H), 4.26-4.17 (m, 1H), 4.00-3.92 (m, 1H), 3.88 (s, 3H); MS (ES+) m/z 448.3 (M+1).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH3:13].[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[CH3:13])=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: Cc1nc2ccccc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1nc2ccccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-Amino-2-methyl-4(3H)-quinazolinone and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.74 (m, 9H), 1.94-1.98 (m, 3H), 2.13 (d, J=1.7 Hz, 1H), 2.39 (s, 3H), 7.50-7.56 (m, 1H), 7.63-7.65 (m, 1H), 7.82-7.88 (m, 1H), 8.11 (dd, J=8.1, 1.0 Hz, 1H), 10.87 (s, 1H) ppm; MS (DCI/NH3) m/z 352 (M+H)+; Elemental Analysis: Calculated for C20H25N3O2.H2O: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.16; H, 7.40; N, 11.40.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].Cl[Si:7]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:24][CH:25]([F:27])[F:26])=[C:19]([F:28])[CH:18]=2)[CH2:9][CH2:8]1>C1COCC1>[F:28][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH:10]2[CH2:11][CH2:12][Si:7]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]2)[CH:22]=[C:21]([F:23])[C:20]=1[O:24][CH:25]([F:27])[F:26]
Reactant: Fc1cc(CCCCC2CC[Si](Cl)(c3ccccc3)CC2)cc(F)c1OC(F)F
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCC[Si]1(c2ccccc2)CCC(CCCCc2cc(F)c(OC(F)F)c(F)c2)CC1

Procedure:
50 ml (0.13 mols) of a THF solution of 2.5M of propylmagnesium bromide was dropped in a mixed solution of 44.5 g (0.1 mol) of 1-chloro-1-phenyl-4-(4-(3,5-difluoro-4-difluoromethoxyphenyl)butyl)-1-silacyclohexane and 300 ml of THF. After ordinary after-treatments, 4-(4-(3,5-difluoro-4-difluoromethoxyphenyl)butyl)-1-phenyl-1-propyl-1-silacyclohexane was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Reactant: C1COCCN1
Product: c1ccc(COc2ccc3c(c2)OC[C@@H](c2ccccc2)[C@H]3c2ccc(OCCCCN3CCOCC3)cc2)cc1

Procedure:
From (+,−) cis 7-Benzyloxy-4-[4-(4-chlorobutyloxy)-phenyl]-3-phenyl-chroman (300 mg, 0.60 mmol) and morpholine (240 mg, 3 mmol). Reaction time 4 days. The evaporated product was crystallised from ether-petrolether, and further purified by silica column chromatography using methanol-methylene chloride (1+19) as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1)(=[O:14])[CH3:13].Cl>>[C:12]([N:15]1[CH2:16][CH2:17][CH:18]([C:21](=[O:22])[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:19][CH2:20]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Reaction time: 8 h
Yield: 34 %

Procedure:
To a stirred and warm (40° C.) mixture of 600 parts of bromobenzene and 223 parts of aluminum chloride were added portionwise 168.8 parts of 1-acetyl-4-piperidinecarbonyl chloride. Upon completion, stirring was continued for 1 hour at 50° C. and overnight at room temperature. The reaction mixture was poured onto a mixture of 1500 parts of crushed ice and hydrogen chloride. The whole was stirred thoroughly. The precipitated product was filtered off, washed with 2,2'-oxybispropane and dissolved in a mixture of 2250 parts of trichloromethane and 200 parts of water. The layers were separated. The organic layer was dried, filtered and evaporated. The solid residue was suspended in 280 parts of 2,2'-oxybispropane. The product was filtered off and dried, yielding 94 parts (34%) of 1-acetyl-4-(4-bromobenzoyl)piperidine; mp. 120° C. (intermediate 15).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH2:14][O:15][CH2:16][C:17]=3[C:18](OC)=[O:19])[CH:8]=2)=[N:3]1.C[O-].[Na+].C([NH2:28])=O>>[C:18]([C:17]1[CH2:16][O:15][CH2:14][C:13]=1[C:9]1[CH:8]=[C:7]([C:4]2[O:5][CH2:6][C:2]([CH3:22])([CH3:1])[N:3]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:19])[NH2:28]
Reactant: COC(=O)C1=C(c2cccc(C3=NC(C)(C)CO3)c2)COC1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: CC1(C)COC(c2cccc(C3=C(C(N)=O)COC3)c2)=N1
Temperature: 100 °C

Procedure:
A mixture of 4,4-dimethyl-2-[3-(4-methoxycarbonyl-2,5-dihydrofuran-3-yl)phenyl]-4,5-dihydrooxazole (1.92 g) and sodium methoxide (0.96 g) in formamide (70 ml) was heated at 100° C. for three hours. The reaction mixture was cooled to room temperature and was poured onto ice-water. The product was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and acetone (5:1). The fractions containing the desired product were collected and evaporated in vacuo to give 2-[3-(4-carbamoyl-2,5-dihydrofuran-3-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](N1C=CN=C1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>C1COCC1>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[O:18])[N:27]([CH2:26][C:25]([F:29])([F:28])[F:24])[C:1]2([OH:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(O)(c2ccccc2)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a suspension of N-(2-benzoyl-4-chlorophenyl)-1H-imidazole-1-carboxamide (39.3 g, 120.5 mmol) in THF (200 mL) was added 2,2,2-trifluoroethylamine (14.0 g, 141.0 mmol). The reaction was heated to 50° C. for 16 h. A second portion of 2,2,2-trifluoroethylamine (3.6 gm, 36.4 mmol) was added and warming continued at 50° C. for 3 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The light yellow oil was partitioned between n-butyl chloride (500 mL) and aqueous 10% citric acid (300 mL) with vigorous stirring. The resulting precipitate was collected by vacuum filtration and placed under vacuum alongside P2O5 for 16 h to give 35.4 g (82.4%) of 6-chloro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid. 1H NMR (CDCl3, 400 MHz) 8.41 (brs, 1H); 7.47 (d, J=8.06 Hz, 2H); 7.36 (m, 3H); 7.27 (m, 1H); 7.21 (dd, J=2.26 Hz and 8.52 Hz, 1H); 6.76 (d, J=8.52 Hz, 1H); 4.37 (m, 1H); 3.55 (m, 1H); 3.25 (s, 1H). MS (Electrospray): m/z 357.0 (M+H).
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[CH3:3][C:2]1([CH3:10])[CH2:4][CH2:5][C:6]([CH3:8])([CH3:7])[C:15]2[CH:16]=[C:11]([OH:17])[CH:12]=[CH:13][C:14]1=2
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 2,5-dichloro-2,5-dimethyl-hexane (Intermediate 1, 97 g, 0.53 mol) and phenol (50 g, 0.53 mol) in CHCl3 (500 mL) at 0° C. was added AlCl3 (71 g, 0.54 mmol) portionwise. After stirring for 2 h at 0° C., the mixture was poured onto ice and was extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Recrystallization of the resulting solid from Et2O-hexane (1:1) gave the title compound as off-white crystals (95.7 g, 89%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Cl:15][C:16]1[C:17](I)=[N:18][CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[C:17]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1cccnc1I
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncccc1Cl
Yield: 78 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (64 mg, 0.35 mmol) was converted [using 3-chloro-2-iodopyridine (prepared according to Eur. J. Org. Chem. (24), 4181, 2002) instead of 2-chloro-4-iodopyridine] to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 81 mg, 78%) which was obtained as a light yellow solid. MS: m/e=295.2/297.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:7][NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([I:18])=[CH:11][N:10]=1)[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:7][NH:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([I:18])=[CH:11][N:10]=1)[CH3:2]
Reactant: CCOc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(OC)nc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1cc(CNc2ncc(I)cc2N)ccc1OCc1ccc(OC)nc1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a stirred suspension of N-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3-nitropyridin-2-amine (4.34 g, 8.09 mmol) in acetic acid (25 mL) was added iron powder (2.26 g, 40.46 mmol). The reaction mixture was heated to 90° C. After 15 min, the reaction mixture became a gray-brown suspension. The mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL). The mixture was filtered through Celite with the aid of additional ethyl acetate (50 mL). The filtrate was washed with water (2×50 mL) and then with 1N sodium hydroxide solution (3×50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 3.99 g (97%) of N2-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodopyridine-2,3-diamine as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[CH2:12][C:13]#[C:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:19]([O:18][C:17](=[O:23])[NH:16][CH2:15][C:14]#[C:13][CH2:12][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)NCC#CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC#CCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.51 g), tert-butyl (4-chlorobut-2-yn-1-yl)carbamate (2.60 g), cesium carbonate (4.80 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→33:67) to give the title compound (2.61 g) as an orange oil.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]([NH2:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C(O)C>[CH2:22]([NH:25][S:18]([C:4]1[CH:5]=[C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])[CH:7]=[CH:8][C:3]=1[Cl:2])(=[O:20])=[O:19])[CH:23]=[CH2:24]
Reactant: C=CCN
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCNS(=O)(=O)c1cc(C2(O)CSC(=NC)N2C)ccc1Cl

Procedure:
8.7 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of allyl amine and 4 g of triethyl amine in 50 ml of ethanol and worked up. The water was decanted and the amorphous end product was crystallized under diethyl ether. Colorless solid body, melting point: 146° C. (decomposition).