Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([NH2:11])=[CH:4][C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.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>[CH3:12][C:3]1[CH:4]=[C:5]([NH2:11])[C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:2]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(N)c2c(c1Br)CCO2
Reactant: OB(O)c1ccncc1
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: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N)c2c(c1-c1ccncc1)CCO2
Temperature: 135 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-5-methyl-2,3-dihydrobenzofuran-7-amine (1e) (0.80 g, 3.5 mmol), pyridin-4-ylboronic acid (0.86 g, 7 mmol), Cs2CO3 (2.84 g, 8.7 mmol), Pd(PPh3)4 (0.40 g, 0.346 mmol) and water (7 mL) in DMF (35 mL) was stirred at 135° C., under N2 for 1 h. It was cooled to ambient temperature, poured into water (50 mL), extracted with EtOAc (150 mL), washed with water, brine, dried and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (20:1 to 5:1 to 1:1) to give the title compound (1f) as a yellow solid. MS-ESI (m/z): 227 (M+1)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](F)[N:21]=1.O>C1COCC1>[F:19][C:20]1[N:21]=[C:22]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13])[CH:23]=[CH:24][CH:25]=1
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1COc1cccc(F)n1
Reaction time: 3.25 h
Yield: 78.1 %

Procedure:
NaH (7.0 g, 60% oil dispersion, 0.176 mol) was added portionwise over five minutes to a stirred slurry of 2-(hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (35.8 g, 0.161 mol) in 700 mL THF. After the resulting mixture was stirred for 3.25 hours, 2,6-difluoropyridine (15.4 g, 0.134 mol) was added neat over a 20 minute period, and the mixture was stirred overnight at room temperature. Water (250 mL) was added, THF was removed in vacuo, and the aqueous residue was extracted three times with 250 mL CH2Cl2. The combined extracts were washed with brine (250 mL), filtered through Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (5% CH3CN in CH2Cl2) to yield 2- [[[6-fluoro-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-benzeneacetamide (33.2 g, 78%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[O:28][CH:29]([CH3:31])[CH3:30])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:29]([O:28][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=2)[CH2:7]1)=[O:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(C(F)(F)F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(C(F)(F)F)cc3C2)c1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
The mixture of 2-(2-isopropoxy-3-methyl-benzoylamino)-5-trifluoromethyl-indan-2-carboxylic acid ethyl ester (94) (690 mg, 1.5 mmol) and KOH (1.5 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved. The resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until pH˜4. The precipitate is filtered to give a pure product (95) as a pale brown solid (495 mg, 78%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[C:32]1([CH3:41])[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(OCC)(=O)C>COCCOC.O.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>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([CH3:41])=[CH:33][CH:34]=2)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
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: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.069 g; 0.181 mmol) in a mixture of DME-water (3:1) (1 mL) were added potassium carbonate (0.100 g; 0.723 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol) and 4-tolylboronic acid (0.049 g; 0.361 mmol). The solution was stirred for 30 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-40%) in heptane furnished 0.043 g (44%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32]([Cl:34])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-]>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:21][C:22]([C:24]2[CH:33]=[C:32]([Cl:34])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC)NC(=O)c2cc(Cl)c3ccccc3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(Cl)c3ccccc3n2)CC1
Reaction time: 2 h
Yield: 111.9 %

Procedure:
A solution of 4-ethoxycarbonyl-1-(1-amino-3-(methoxycarbonyl)propyl)carbonylpiperazine (0.97 g, 3.23 mmol), 2-carboxy-4-chloroquinoline (0.67 g, 3.23 mmol), EDCl (0.68 g, 3.55 mmol) and HOBT (0.48 g, 3.55 mmol) was combined in 30 mL of THF. The reaction mixture was stirred overnight at ambient temperature. The reaction was diluted with ethyl acetate and washed with water. The organic layer was concentrated to give a dark oil (0.87 g) that was purified by flash chromotography through silica gel with 2:1 ethyl acetate-hexanes to provide 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (0.46 g). A solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (0.15 g, 0.313 mmol) was dissolved in 5 mL THF and LiOH (0.25 M, 1.9 mL, 0.47 mmol) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated to an oil, acidified with 10% HCl, extracted into ethyl acetate, and concentrated to provide pure 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-chloroquinoline, (167 mg); NMR 1.20 (t, 3), 1.90 (m, 1), 2.05 (m, 1), 2.35 (m, 2), 3.35–3.60 (m, 8), 3.65 (m, 2), 4.05 (q, 2), 5.07 (m, 1), 7.95 (m, 1), 8.02 (m, 1), 8.23 (s, 1), 8.30 (m, 1), 8.98 (m, 1) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34]CC)=[O:33]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:12]([F:15])([F:14])[F:13])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([OH:34])=[O:33]
Reactant: O=C(O)Cc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)Cc3ccc(F)cc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 2-(4-fluoro-2-(trifluoromethyl)phenyl)acetic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=1.88, min, m/z=486, 484
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:8][C:7](=[O:9])[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][N:4]=1.C([O:23][CH2:24][CH3:25])(=O)C>CO.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[N:4]([O:23][CH:24]([C:25]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:7](=[O:9])[CH:8]=1)=[O:1]
Reactant: COc1ccc(COC2=CN=C(CO)CC2=O)cc1
Reactant: CCOC(C)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Product: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(C=O)cc2=O)cc1

Procedure:
In 300 ml of anhydrous methanol is suspended 6 g of 2-hydroxymethyl-5-p-methoxybenzyloxy-4-pyridone, and 15 g of active manganese dioxide is added thereto. The reaction is performed under heating at a refluxing temperature for 30 minutes. At the end of the reaction, the manganese dioxide is removed by filtration, and the filtrate is condensed under reduced pressure. The residue is dissolved in 150 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and condensed under reduced pressure to give the title compound (5.63 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:6][C:5]=1[O:20][CH3:21].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH:28]=1.Cl>CN(C)C=O.O>[CH3:21][O:20][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])[CH:8]=[CH:9][C:4]=1[O:3][CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH:28]=1
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Sodium hydride (60% in oil, 0.32 g) was added, at 0° C., to a solution of 5-[3-(4-hydroxy-3-methoxyphenyl]propyl]-2,4-oxazolidinedione (1.0 g) in N,N-dimethylformamide (DMF) (20 ml). The mixture was stirred for one hour at room temperature. To the reaction mixture was then added 4-chloromethyl-2-[(E)-styryl]oxazole (0.87 g), which was stirred for 3.5 hours at 90° C. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to yield 5-[3-[3-methoxy-4-[2-[(E)-styryl]-4-oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione (1.1 g, 66%). The product was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.178-179° C.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH:44]([CH:54]=O)[CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:38][CH:37]=1)#[N:35].O>CCCCCC.C1COCC1>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH:44](/[CH:54]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:38][CH:37]=1)#[N:35]
Reactant: CCOC(=O)CCCCC(C=O)CCc1ccc(C#N)cc1
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
15.91 ml (25.45 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added to a solution of 5.066 g (10.91 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 38 ml of anhydrous THF at 0° C. Then, at this temperature, 2.740 g (9.09 mmol) of ethyl 8-(4-cyanophenyl)-6-formyloctanoate from Example 86A, dissolved in 38 ml of THF, are slowly metered in. After the reaction solution has been warmed to room temperature it is stirred for 12 hours and, after addition of some water, concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 2.30 g (5.88 mmol, 63% yield) of a colorless solid are obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([O:6][CH3:18])=[O:5]
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C[C@H](N)c1ccccc1

Procedure:
2.3 g (11.65 mmol) of (S)-3-amino-3-phenylpropionic acid are introduced in 100 ml of methanol and admixed with a catalytic amount of concentrated sulfuric acid (0.02 eq.). The reaction mixture is heated at reflux for 24 h and then concentrated. The crude product can be used without further purification in the next stage.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[C:13](=[O:15])=[O:14].[CH3:16][Si:17]([CH3:20])([CH3:19])Cl>CCOCC>[CH3:16][Si:17]([O:14][C:13](=[O:15])[N:3]([O:4][CH3:5])[CH3:2])([CH3:20])[CH3:19]
Reactant: O=C=O
Reactant: C[Si](C)(C)Cl
Reactant: CNOC
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CON(C)C(=O)O[Si](C)(C)C
Yield: 82 %

Procedure:
49 g (0.5 mole) of methyl-methoxyamine hydrochloride, 101 g (1 mole) of triethylamine in 250 ml of dry ether is treated with carbon dioxide in the same apparatus and under the same conditions as described in Example 1a. When the carbon dioxide absorption has been ceased, 54 g (0.5 mole) of trimethylchlorosilane is added to the reaction mixture over about 1 hour. Following the same procedure as in Example 1a. 73.2 g (82%) of N-methoxy,N-methylcarbamic acid trimethylsilyl ester are obtained. B.p.: 38-41° C./2.5 mbar.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]=[C:10]([O:26][CH3:27])[CH:9]=1)=[O:7].[CH2:28](OCC)[CH3:29].C([Mg]I)C.[Cl-].[NH4+]>O1CCCC1>[OH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]=[C:10]([O:26][CH3:27])[CH:9]=1)[CH2:28][CH3:29]
Reactant: CCOCC
Reactant: COc1cc(OCc2ccc3ccccc3c2)cc(C(=O)c2nccs2)c1
Agent: CC[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1cc(OC)cc(OCc2ccc3ccccc3c2)c1)c1nccs1
Yield: 55 %

Procedure:
A solution of the ketone so obtained (1.2 g) in tetrahydrofuran (20 ml) was added to a diethyl ether solution of ethylmagnesium iodide [prepared from iodoethane (0.6 ml) and magnesium turnings (0.154 g) under diethyl ether (10 ml)] and the mixture was heated to reflux for 15 minutes. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3×15 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (17/3 v/v) to give 2-[1-hydroxy-1-[3-methoxy-5-(naphth-2-ylmethoxy)phenyl]propyl]thiazole (0.72 g, 55%), m.p. 105° C. (recrystallised from a mixture of petrol (b.p. 60°-80° C.) and ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10]Cl.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C(#N)C>[CH2:14]([O:13][P:12]([CH2:10][C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[OH:1])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: O=Cc1ccc(O)c(CCl)c1
Reactant: CCOP(OCC)OCC
Solvent: CC#N
Product: CCOP(=O)(Cc1cc(C=O)ccc1O)OCC
Temperature: 25 °C

Procedure:
0.1 mole 4-Hydroxy-3-chloromethylbenzaldehyde was stirred in 75ml acetonitrile and 0.1 mole triethyl phosphite was added dropwise into the stirring suspension. After all the triethyl phosphite had been added, the reaction was refluxed for 4 hours. The reaction was then cooled to room temperature. The reaction solution was then filtered and the acetonitrile was removed on a rotary evaporator leaving behind a solid. This was recrystallized from THF:hexanes in a -20° C. freezer. The product was isolated on a buchner funnel and washed with -20° C. THF. mp 88°-88.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([OH:7])[CH2:5][OH:6].[CH3:8][C:9]1([CH3:33])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]4)[S:24][CH:25]=3)[CH:12]=[CH:11][C:10]1=2.Cl>>[CH3:8][C:9]1([CH3:33])[CH2:18][CH2:17][C:16]([CH3:19])([CH3:20])[C:15]2[CH:14]=[C:13]([C:21]3[N:22]=[C:23]([N:26]4[CH2:31][CH2:30][CH:29]([NH:1][CH2:2][CH2:3][C@@H:4]([OH:7])[CH2:5][OH:6])[CH2:28][CH2:27]4)[S:24][CH:25]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21
Reactant: NCC[C@@H](O)CO
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCC[C@@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously starting from 22 mg (0.21 mmol) of (R)-4-aminobutane-1,2-diol and 80 mg (0.21 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(C(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
The title product was prepared from (4-hydroxy-phenyl)-phenyl-methanone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (36%, colorless oil). HPLC-MS: m/z=332.2 (M+1); Rt: 4.42 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21]C)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)C1C=CC2OCOC=2C=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:18]=[CH:19][C:20]2[O:21][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1OC
Product: COc1ccc(C(=O)c2ccc3c(c2)OCO3)cc1OC

Procedure:
1-(3,4-Dimethoxybenzoyl)-3,4-methylenedioxybenzene was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (1.3 mL, 10 mmol), aluminum chloride (1.5 g, 11 mmol) and piperonyloyl chloride (1.9 g, 10 mmol) with a reaction time of 2.5 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) to afford 1.99 g (69%) of the product as a white solid: mp 164-165° C.; 1H NMR (CDCl3) δ 7.46-7.26 (m, 4 H), 6.95-6.82 (m, 2 H), 6.06 (s, 2 H), 3.96 (s, 3 H), 3.94 (s, 3 H); 13C NMR (CDCl3) δ193.9, 152.7, 151.0, 148.9, 147.8, 132.4, 130.6, 126.1, 124.8, 112.2, 109.9, 109.7, 107.6, 101.7, 56.0, 56.0; Anal. Calcd for C16H14O5. Theoretical: C, 67.13; H. 4.93. Found: C, 66.86; H, 5.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[ClH:21].[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][O:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:13]=1
Reactant: ClCCCCBr
Reactant: Cc1cc(O)cc(-c2ccc(F)cc2)n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(OCCCCCl)cc(-c2ccc(F)cc2)n1
Product: Cl
Yield: 47.7 %

Procedure:
A mixture of 2.5 g of 2-(4-fluorophenyl)-4-hydroxy-6-methylpyridine, 3.16 g of 1-bromo-4-chlorobutane, 1.7 g of silver carbonate, and 100 ml of toluene was refluxed for 40 hours. This reaction mixture was filtered to remove insolubles and the filtrate was concentrated. The residue was purified with silica gel column chromatography to provide 1.45 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:28][C:29]1[C:30]([F:43])=[C:31]([NH:35]C(=O)OC(C)(C)C)[CH:32]=[CH:33][CH:34]=1.Cl.ClC1C=C(NC2C3C(=CC(OC4CCNCC4)=C(OC)C=3)N=CN=2)C=CC=1F>>[ClH:1].[Br:28][C:29]1[C:30]([F:43])=[C:31]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1F
Reactant: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: COc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC1CCNCC1
Agent: Cl
Product: COc1cc2c(Nc3cccc(Br)c3F)ncnc2cc1OC1CCNCC1

Procedure:
tert-Butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with tert-butyl (3-bromo-2-fluorophenyl)carbamate using an analogous process to that described in Example 22 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(3-bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride; 1H NMR Spectrum: (DMSO d6) 1.85-2.1 (m, 2H), 2.1-2.32 (m, 2H), 3.0-3.35 (m, 4H), 4.02 (s, 3H), 4.83-5.0 (m, 1H), 7.3 (dd, 1H), 7.5-7.65 (m, 2H), 7.75 (dd, 1H), 8.45 (s, 1H), 8.8(s, 1H), 9.15 (bs, 2H), 11.86 (s, 1H); Mass Spectrum: (M+H)+ 447.12.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[O:8]2)=[CH:4][C:3]=1[N+:19]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[F:1])[CH:6]=[C:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[O:8]1
Reactant: O=C1OC(=Cc2ccc(F)c([N+](=O)[O-])c2)C2=C1CCCC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(C=C2OC(=O)C3=C2CCCC3)ccc1F
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 2A (2.25 g) and ammonium chloride (0.83 g) in ethanol (35 mL) and water (25 mL) at 70° C. was treated with iron powder (4.35 g), stirred for 3 hours and filtered through diatomaceous earth (CELITE™, World Minerals, Santa Barbara, Calif.) with hot ethanol. The filtrate was concentrated, and the concentrate was stirred with water for 30 minutes and filtered. The solid was washed with water and dried.