Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][Si:10]([CH3:14])([CH3:13])[C:11]#[CH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.C1CCCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][Si:10]([C:11]#[C:12][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Oc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(O)c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-3-hydroxy-pyridine and 2.3 mL (16.2 mmol) 1-trimethylsilyl-ethyne using 66 mg (0.3 mmol) CuI, 303 mg (1.2 mmol) triphenylphosphine, 243 mg (0.3 mmol) PdCl2(PPh3)2 and 19 mL (139 mmol) triethylamine in 20 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate and small amounts of cyclohexane, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using DCM/MeOH gradient. Yield: 2.0 g (91%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>[OH:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Oc1cccc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.491 g (4.5 mmol) 3-aminophenol is heated under nitrogen atmosphere for 1 h at 90° C. and for 3 h at 120° C. The reaction mixture is then taken up in a mixture of 30 ml acetate and 20 ml 20% aqueous potassium carbonate solution while stirring for about 4 h, and the filtration material is digested for 20 min in 20 ml of boiling methanol. After cooling to RT, filtration, washing of the filter residue with methanol, and drying under HV (8 h, 130° C.), title compound is obtained with a water content of 1.94%; m.p. 217-219° C.; ESI-MS: (M+H)+=329.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=3)=[CH:17][CH:16]=2)[CH:11]=[C:12](I)[N:13]=1.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(=O)([O-])[O-].[K+].[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=3)=[CH:17][CH:16]=2)[CH:11]=[C:12]([C:33]2[CH:34]=[CH:35][S:31][CH:32]=2)[N:13]=1
Reactant: OB(O)c1ccsc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(I)nc3-c3cccc(Cl)c3Cl)cc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(-c4ccsc4)nc3-c3cccc(Cl)c3Cl)cc2)c1
Temperature: 120 °C

Procedure:
Into a 5 mL microwave vial was weighed 220 mg (0.39 mmol) of 2-(2,3-di-chlorophenyl)-4-iodo-1-(3′-(methylsulfonyl)biphenyl-4-yl)-1H-imidazole, 108 mg (0.84 mmol) of thiophen-3-ylboronic acid 25 mg (31 μmol) of PdCl2(dppf)-CH2Cl2. The mixture was taken up in 1,2-dimethoxyethane (2 mL), and treated with 400 μL (0.1.4 mmol) of 3.5M aqueous potassium carbonate. The mixture was heated in the Biotage Initiator microwave reactor for 30 minutes at 120° C. LC/MS at this time showed a large peak for the product and some smaller impurity peaks. The reaction mixture was diluted with EtOAc, treated with some decolorizing carbon and Na2SO4. The mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was concentrated in vacuo to afford a dark brown oil. The crude product was adsorbed onto silica, loaded onto the top of a 12 g silica column and eluted with a gradient from 0% to 100% EtOAc in hexane. The main product peak was collected and concentrated in vacuo to afford a brown powder that was impure. This impure product was further purified by reverse phase prep HPLC (3 injections). (Phenomenex Axia Gemini C18 30×100 mm 5 μm, A=H2O with 0.1% trifluoroacetic acid, B=acetonitrile with 0.1% trifluoroacetic acid, 17 minute gradient from 30% B to 100% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3×), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting 2-(2,3-dichlorophenyl)-1-(3′-(methylsulfonyl)biphenyl-4-yl)-4-(thiophen-3-yl)-1H-imidazole was isolated as a white powder, yield: 89.8 mg (44%) 1H NMR (400 MHz, CDCl3): δ 8.14-8.12 (m, 1H), 7.96-7.92 (m, 1H), 7.87-7.83 (m, 1H) 7.73-7.70 (m, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.61-7.57 (m, 2H), 7.55-7.50 (m, 2H), 7.49-7.46 (m, 2H), 7.40-7.37 (m, 1H), 7.32-7.25 (m, 4H); 3.10 (s, 3H), MS (ES): 525.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH2:13])=[S:12])([CH3:3])[CH3:2].Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17]>>[CH:19]([CH:15]1[S:12][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[N:13][C:16]1=[O:17])([CH3:21])[CH3:20]
Reactant: CC(C)c1ccccc1NC(N)=S
Reactant: CC(C)C(Br)C(=O)O
Product: CC(C)c1ccccc1NC1=NC(=O)C(C(C)C)S1

Procedure:
Synthesis was performed from N-(2-isopropylphenyl)thiourea and 2-bromo-3-methylbutyric acid according to Method C1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([O:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1)=[O:9].[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)CC>[F:13][C:2]1[N:7]=[C:6]2[C:8]([O:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1)=[O:9]
Reactant: O=C1OC(=O)c2nc(Cl)ccc21
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCC#N
Product: O=C1OC(=O)c2nc(F)ccc21
Reaction time: 10 h

Procedure:
A mixture of 36.7 g (0.2 mol) of 6-chloropyridine-2,3-dicarboxylic anhydride, 17.4 g (0.3 mol) of potassium fluoride and 1 g of 18-crown-6 in 200 ml of propionitrile were stirred for 10 hours while refluxing. After cooling, the reaction mixture was filtered with suction and the residue was washed with methylene chloride. The filtrate was evaporated down under reduced pressure and stirred with a 2:1 methyl tert-butyl ether/pentane mixture, and the product was filtered off with suction and dried. 25.3 g (76% of theory) of the title compound of melting point 106° C. (decomposition) were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:22][CH2:21][CH2:20][CH2:19][OH:23])[CH:7]=1
Reactant: OCCCO
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii), 3 g) and propane-1,3-diol (1.1 g) in THF (50 ml) was added NaH (390 mg) slowly and the reaction was then allowed to stir at room temperature for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow oil. Yield 2.9 g
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])=[C:6]([CH3:11])[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: COc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Temperature: 100 °C
Yield: 89.7 %

Procedure:
A mixture of 3-methyl-4-bromobenzoic acid methyl ester (2.0 g, 8.7 mmol), 2-methoxyphenyl boronic acid (1.32 g, 8.7 mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25 mL), was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol), the reaction mixture was heated at 100° C. overnight. After cooling, the reaction was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography with a solvent gradient from 20% to 50% dichloromethane in hexane gave 2.0 g of product as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]=[CH2:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].[OH-].[Na+].C1(O)C=CC=CC=1.Cl[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl>C(O)C.O>[CH2:25]([O:26][CH2:27][CH2:28][O:13][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:10][CH:11]=[CH2:12])[CH3:24]
Reactant: C=CCc1cccc(CC=C)c1O
Reactant: ClCCOCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: O
Solvent: CCO
Product: C=CCc1cccc(CC=C)c1OCCOCC
Yield: 69 %

Procedure:
2,6-Diallylphenol (5.2 g, 0.03 mol) was diluted with 95% ethanol (50 ml). Sodium hydroxide (1.4 gm, 0.03 mol) was added to the phenol solution followed by 2-chloroethylether (3.8 gm, 0.035 mol). The reaction mixture was refluxed for 48 hrs, cooled, diluted with water, extracted with hexane and dried over MgSO4. Filtration of the MgSO4 and evaporation of the hexane gave 5.1 g of 2,6-diallylphenyl ethoxyethyl ether. MS m/z 246 (M+ calcd for C16H22O2=246). H NMR (300 MHz, CDCl3) d 1.30 (3, t, CH3), 3.40–3.55 (4, m, CH2 allyl), 3.65–3.75 (2,q, OCH2 methyl), 3.80 (q, 2, OCH2), 4.00(q, 2, OCH2), 5.05–5.25 (m, 4, CH2 vinyl), 5.90–6.20 (m, 2, CH vinyl), 7.05–7.20 (m, 4, CH2 vinyl), 7.05–7.20 (m, 3, aromatic). Oxidation of the product as described in Example 1 gave 2,6-di-(2,3-epoxypropyl)phenyl ethoxyethyl ether as an oil. MS m/z 278 (M+ calcd for C16H22O4=278). H NMR (300 MHz, CDCl3) d 1.25 (t, 3, CH30, 2.65–2.85 (m, 4, epoxypropyl CH2), 2.90–3.15 (m, 4, epoxypropyl CH2), 3.21–3.35(m, 2, epoxypropyl CH), 3.65 (q, 2, OCH2), 3.80 (q, 2, OCH2), 4.00 (q, 2, OCH2), 5.33 (s, 3, OCH3), 7.05–7.33 (m, 3, aromatic).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1ccc(C(=O)c2ccc(C#N)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(C#N)cc1

Procedure:
A solution of 0.5 g. (0.0017 mole) of ethyl 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetate in 3 ml. ethanol is brought to reflux and 1.7 ml. of 1N sodium hydroxide solution is added dropwise. The mixture is refluxed for 3 minutes, and the ethanol is then evaporated in vacuo. The residue is diluted with water and acidified with dilute hydrochloric acid. A white solid precipitates, 5-(p-cyanobenzoyl)-1-methylpyrrole-2-acetic acid, which is collected by filtration and dried, m.p. 196-198° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)(O)=[O:2].[BH4-].[Na+].Cl>O1CCCC1>[Cl:10][C:6]1[CH:5]=[C:4]([CH2:1][OH:2])[CH:9]=[CH:8][N:7]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Yield: 86.7 %

Procedure:
4-Carboxy-2-chloropyridine (78.7 g) is added slowly to a suspension of sodium borohydride (28.4 g) in tetrahydrofuran (750 ml) under nitrogen atmosphere, and thereto is added dropwise boron trifluoride ether complex (123 ml). The mixture is reacted at room temperature for six hours. To the mixture is added a 6 M hydrochloric acid (960 ml), and the mixture is concentrated under reduced pressure to remove the solvent. The resultant is basified with sodium hydroxide, and extracted with chloroform. The chloroform layer is washed with a saturated aqueous sodium hydrogen carbonate solution, dried and concentrated under reduced pressure to remove the solvent to give 2-chloro-4-hydroxymethylpyridine (62.2 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]1[CH:5]=[C:6]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)[C:7]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]=2[CH:14]=1)[CH3:2].CO.[OH-].[Li+].Cl>O1CCCC1.CCOC(C)=O.O>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([CH3:30])[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[C:7]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][C:8]=2[CH:14]=1)[CH3:32]
Reactant: CCOC(=O)C(C)Cc1ccc(OCc2cc(N(CC)CC)cc3c2OC(C)(C)C3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)c1cc(COc2ccc(CC(C)C(=O)O)cc2)c2c(c1)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 3-(4-((5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoate (110) (78 mg, 0.17 mmol), diethylamine (0.08 mL, 0.78 mmol), [1,1′-biphenyl]-2-yldi-tert-butylphosphine (16 mg, 0.052 mmol), tris(dibenzylideneacetone) dipalladium (47.6 mg, 0.052 mmol), and sodium t-butoxide (25 mg, 0.26 mmol) in toluene (2 mL) was heated in a pressure tube at 80° C. overnight. Water was added and the reaction was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%) to give ethyl 3-(4-((5-(diethylamino)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoate. The ester was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (3 mL). Lithium hydroxide was added and the reaction was stirred at room temperature for 24 hours. The mixture was acidified with 1M HCl and diluted with EtOAc (3 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 3-(4-((5-(diethylamino)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoic acid (118). 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.18 (s, 1H), 7.09 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 5.04 (s, 2H), 3.84-3.47 (m, 2H), 3.34-3.09 (m, 2H), 3.06 (s, 2H), 3.01-2.89 (m, 1H), 2.78-2.57 (m, 2H), 1.51 (s, 6H), 1.18 (d, J=6.7 Hz, 3H), 1.07 (t, J=6.9 Hz, 6H). LC-MS ESI m/z: found 410.4 [M−H]−.
Reaction SMILES: Br[Si:2]([CH3:5])([CH3:4])[CH3:3].C([O:8][P:9]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])[O:10]CC)C>>[CH3:3][Si:2]([O:8][P:9]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])[O:10][Si:2]([CH3:5])([CH3:4])[CH3:3])([CH3:5])[CH3:4]
Reactant: CCOP(=O)(OCC)c1ccc(F)cc1
Reactant: C[Si](C)(C)Br
Product: C[Si](C)(C)OP(=O)(O[Si](C)(C)C)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
Bromotrimethylsilane (15.3 mL, 0.116 mol) was added dropwise to 4-fluorophenyl-phosphonic acid diethyl ester (8.95 g, 38.58 mmol) stirred in a reaction flask chilled to 0° C. The resulting solution was allowed to warm to ambient temperature and stirred for an additional hour. The mixture was then concentrated by rotary evaporation yielding crude 4-fluorophenyl-phosphonic acid bis(trimethylsilyl) ester which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10].C(N(CC)CC)C>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ncc(I)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(Br)nc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
2-Bromo-5-iodopyrimidine (1.2 g, 4.2 mmol) was dissolved under nitrogen in 25 ml THF. Bis-(triphenylphosphine)-palladium(II)dichloride (300 mg, 420 μmol, 0.1 equiv.), ethynyltrimethylsilane (540 mg, 0.77 ml, 5.48 mmol, 1.3 equiv.), triethylamine (0.85 g, 1.17 ml, 8.4 mmol, 2 equiv.) and copper(I)iodide (40 mg, 210 μmol, 0.05 equiv.) were added and the mixture was stirred for 4 hours at 50° C. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 2-bromo-5-trimethylsilanylethynyl-pyrimidine (0.75 g, 70% yield) was obtained as a yellow solid, MS: m/e=255/257 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5]1=[N:6][C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:8][C:9]=2[NH2:15].[NH2:21][CH2:22][CH2:23][OH:24]>C(#N)C>[NH2:15][C:9]1[N:8]=[C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:6]=[C:5]2[C:10]=1[N:11]=[C:12]([O:13][CH3:14])[N:4]2[CH2:3][CH2:2][NH:21][CH2:22][CH2:23][OH:24]
Reactant: NCCO
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCBr)c2n1
Solvent: CC#N
Product: CCCCOc1nc(N)c2nc(OC)n(CCNCCO)c2n1
Temperature: 70 °C

Procedure:
To the compound obtained by Example 2-39 step (i) (300 mg) in acetonitrile (5 ml) was added 2-aminoethanol (265 mg) and heated at 70° C. for 24 hours. The reaction mixture was purified by column chromatography (ethyl acetate:7N ammonia-methanol 95:5) to give the titled compound. Yield: 295 mg (100%).
Reaction SMILES: Cl[CH2:2][CH:3]=O.C(=O)(O)[O-].[Na+].[I:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[CH:15]=[CH:14]2>O1CCOCC1>[I:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]1[CH:2]=[CH:3][N:21]=[C:16]1[CH:15]=[CH:14]2
Reactant: Nc1ccc2cc(I)ccc2n1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1ccc2c(ccc3nccn32)c1
Temperature: 80 °C

Procedure:
To chloroacetaldehyde (50 wt %, 460 mg, 2.92 mmol) and sodium bicarbonate (613 mg, 7.3 mmol) was added 6-Iodo-quinolin-2-ylamine (390 mg, 1.46 mmol) in 1,4-dioxane (5 mL). The mixture was heated to 80° C. overnight, and then cooled to room temperature. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (50-100% EtOAc in hexanes) to obtain the desired product, 1g.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([O:21]C(=O)C)[CH:18]=[CH:19][CH:20]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Oc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(O)c1
Reaction time: 4 h

Procedure:
To a stirred solution of the title A compound, acetic acid 3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl ester (3.92 g, 12.14 mmol) in methanol (15 mL) is added sodium hydroxide (0.97 g, 24.27 mmol) in water (15 mL) at RT. The reaction mixture is stirred for 4 h. The reaction mixture is concentrated at reduced pressure, poured into water, the aqueous layer is separated, washed with ethyl acetate twice, acidified with concentrated HCl and extracted three times with ethyl acetate. The combined ethyl acetate extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenol as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.[CH3:9][O:10][N:11](C)[C:12]([C@@H]1C[C@H]1C)=O>>[CH3:9][O:10][N:11]([CH3:12])[C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:8]
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1C
Product: CON(C)C(=O)[C@@H]1CCCO1

Procedure:
(2S)-Tetrahydrofuran-2-carboxylic acid was converted to the product using the method described for the synthesis of (1R,2R)—N-methoxy-N,2-dimethylcyclopropanecarboxamide (C79) in Example 20. The resulting product was used in the next step without further purification. Yield: 24.6 g, ≦0.153 mol, ≦90%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C(CCl)c1cccc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21)c1cccc(F)c1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 2-chloro-1-(3-fluoro-phenyl)-ethanone gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]([OH:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCCCCCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)CCCCCCC(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of 0.8 g of 1-(3,4-dibenzyloxyphenyl)-1,8-nonanedione and 10 ml of tetrahydrofuran was added to a solution of 0.1 g of lithium aluminum hydride in 50 ml of ether under ice-cooling followed by stirring for 2 hours at room temperature. Then, 50 ml of toluene was added to the reaction mixture and the mixture was acidified by the addition of diluted hydrochloric acid. The toluene layer was collected, washed with an aqueous 5% sodium hydrogencarbonate solution, washed with water, dried over anhydrous magnesium carbonate, and concentrated under reduced pressure to provide 0.8 g of 1-(3,4-dibenzyloxyphenyl)-1,8-nonanediol as an oil.