Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].[BH4-]>C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)=Cc1ccc(CO)cc1

Procedure:
To a suspension of 10.0 g of 50% sodium hydride (dispersion in mineral oil) in freshly distilled dimethoxyethane (DME, 350 ml) stirred under nitrogen at 10° is added 53.6 ml of triethyl 2-phosphonopropionate in ca. 40 minutes. The mixture is stirred for 0.5 hour at 10° and for an additional 1.5 hours during which time the temperature is allowed to rise to room temperature. This solution is transferred under nitrogen by cannula to a 500 ml addition funnel and is added dropwise to a solution of terephthalaldehyde (33.53 g) in dry DME (475 ml) over a period of 1 hour at 22°-34°. After addition is complete the reaction mixture is stirred mechanically at room temperature for 2 hours, poured into 1 L of water and extracted with 4×500 ml of ether. The ether extract is washed with a saturated sodium chloride solution (700 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil which partially crystallizes on standing. This crude mixture is purified by suspending in petroleum ether and ethyl acetate (93:7). The filtrate, after removal of unreacted dialdehyde, is concentrated in vacuo to give a mixture which is further purified by high pressure liquid chromatography (using petroleum ether/ethyl acetate 93:7). There is obtained pure ethyl 4-formyl-α-methylcinnamate. A solution of the aldehyde (34.80 g) in 820 ml of absolute ethanol is treated with 12.11 g of granular sodium borohydride at room temperature under nitrogen. The resulting mixture is stirred at room temperature for 3 hours (or until all borohydride has dissolved) and then concentrated to ca. 200 ml volume, diluted with 400 ml of water, and extracted with 3×200 ml of ether. The ether extract is washed with 100 ml of water and brine (100 ml), is dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuo to give ethyl 3-(p-hydroxymethylphenyl)-2-methylacrylate. To a solution of this product in 350 ml of methylene chloride is added at room temperature 11.53 ml of thionyl chloride dropwise over 25 minutes. The clear, colorless solution is stirred for 2 hours. The solution is washed with 100 ml of water, 200 ml of saturated sodium bicarbonate, 100 ml of water, and 100 ml of brine. The organic layer after drying and removal of solvent yields ethyl 3-(p-chloromethylphenyl)-2-methylacrylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH:12](OC)=[O:13]>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][NH:1][CH:12]=[O:13]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: COC=O
Product: CO[Si](CCCNC=O)(OC)OC
Reaction time: 3 h

Procedure:
A mixture of 7 parts (39 mmol.) of 3-aminopropyltrimethoxysilane and 20 parts (330 mmol.) of methyl formate was heated under reflux in a nitrogen atmosphere. The reaction was monitored by gas chromatography and was found to be complete after 3 hours. Volatiles were then removed in vacuum, yielding the desired N-(3-trimethoxysilylpropyl)formamide.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][CH2:26][OH:27])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][CH2:26][OH:27])[CH:13]=[N:12]2)[C:8]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C@@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)[N:36]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2CCO)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4ccccc4CCO)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-{4-[2-(2-hydroxy-ethyl)-phenoxy]-6-oxo-6H-pyridazin-1-yl}-propionic acid (Intermediate 79) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded impure 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-{4-[2-(2-hydroxy-ethyl)-phenoxy]-6-oxo-6H-pyridazin-1-yl}-propionamide as a white foam as a mixture of diastereomers (0.70 g, 95%).
Reaction SMILES: B(Br)(Br)[Br:2].[C:5]1([CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[Br:2][CH:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][OH:16]
Reactant: BrB(Br)Br
Reactant: OCCCCC(O)c1ccccc1
Solvent: ClCCl
Product: OCCCCC(Br)c1ccccc1
Reaction time: 1 h

Procedure:
Boron tribromide (1.2 mL, 12.69 mol) was slowly added to a dichloromethane solution (40 mL) of 1-phenylpentane-1,5-diol (1.89 g, 10.52 mmol) at 0° C. The reaction mixture was stirred for one hour and quenched with water. The aqueous layer was extracted with dichloromethane (3×10 mL), and the combined organics were dried (magnesium sulfate). The residue was purified by column chromatography on silica gel, eluting with 0-100% ethyl acetate/hexanes to give the title compound as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 1.33-1.44 (m, 1H), 1.52-1.70 (m, 2H), 1.90-2.00 (m, 1H), 2.13-2.22 (m, 1H), 2.27-2.36 (m, 1H), 3.65 (t, J=6.3 Hz, 2H), 4.96 (dd, J=6.9, 8.0 Hz, 1H), 7.24-7.30 (m, 1H), 7.33 (t, J=7.8 Hz, 2H), 7.39 (d, J=7.1 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH2:14][OH:15])[CH:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+].[H][H]>[Pd].CO>[OH:15][CH2:14][CH2:13][N:6]1[CH:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[NH:8][C:7]1=[O:12]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)N1CCO
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2ccccc2C(c2ccccc2)N1CCO
Yield: 91 %

Procedure:
A mixture of 14 parts of 6-chloro-3,4-dihydro-3-(2-hydroxyethyl)-4-phenyl-2(1H)-quinazolinone, 5 parts of sodium acetate and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is stirred in 2,2'-oxybispropane. The solid product is filtered off and stirred in 200 parts of water. It is filtered off again and dried, yielding 11.2 parts (91%) of 3,4-dihydro-3-(2-hydroxyethyl)-4-phenyl-2(1H)-quinazolinone; mp. 141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][C:18]([NH:20][C:21]1[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27](Cl)=[O:28])=[CH:23][CH:22]=1)=[O:19]>>[Cl:16][CH2:17][C:18]([NH:20][C:21]1[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:15][CH2:14]2)=[O:28])=[CH:23][CH:22]=1)=[O:19]
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(Cl)C=Cc1ccc(NC(=O)CCl)cc1
Product: O=C(CCl)Nc1ccc(C=CC(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 7, 1-[2-(4-chlorophenyl)ethyl]piperazine and 4-chloroacetylaminocinnamic acid chloride are reacted to form 1-{3-[4-(N-chloroacetylamino)phenyl]prop-2-en-1-on-yl}-4-[2-(4-chlorophenyl)ethyl]piperazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:6]([CH3:7])[CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].C1COCC1>[OH-].[Na+]>[CH3:16][C:2]1([CH3:1])[CH:6]([CH3:7])[CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CCCC1CCC(C)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CCC(CCCC(=O)O)C1(C)C
Temperature: 110 °C
Yield: 87.6 %

Procedure:
Ethyl 4-(2,2,3-trimethylcyclopentyl)butanoate (5 g, 22 mmol) was added to THF (25 ml) into a round bottom flask. Aqueous 1 N NaOH (25 ml) was then added to the flask and the reaction mixture was refluxed at 110° C. for 8 h. Upon completion of the reaction, the reaction mixture was diluted with 1 N NaOH (25 ml) and the aqueous layer washed twice with MTBE (50 ml×2). The aqueous layer was treated with aqueous 1.0 N HCl until it reached a pH of about 3 (for example from 2 to 4), then extracted three times with AcOEt (50 ml×3). The combined AcOEt extracts were concentrated in vacuo and purified via flash column chromatography with (0-40% gradient) to give 4-(2,2,3-trimethylcyclopentyl)butanoic acid as a colorless oil (3.82 g, 87%). The NMR data is indicated below.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9](=[O:48])[N:8]2[N:49]=[C:50]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH:51]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>CC(C)=O>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:25][N:26]=[N:27][N:28]=3)=[CH:16][CH:17]=2)[C:9](=[O:48])[N:8]2[N:49]=[C:50]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH:51]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3ccccc3)nn2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: CCCCc1nc2cc(-c3ccccc3)nn2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 64.8 %

Procedure:
A solution of 800 mg of the product of Example 7 in 100 ml of acetone containing 3 drops of 5% HC1 is refluxed for 16 hours. The reaction mixture is concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 70% ethyl acetate-hexanes to give 350 mg of the desired product as a solid. M+H 503
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=4[CH3:33])[N:14]=3)=[CH:9][C:8]=2I)[CH2:3]1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].C(NC(C)C)(C)C>O1CCOCC1.[Cu](I)I.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:1][C:2]1([F:35])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=4[CH3:33])[N:14]=3)=[CH:9][C:8]=2[C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH2:3]1
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(N3CCC(F)(F)C3)c(I)c2)n1
Reactant: C#C[Si](C)(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(N3CCC(F)(F)C3)c(C#C[Si](C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a solution of 61 mg (0.10 mmol) of tert-butyl 3-(4-(5-(6-(3,3-difluoropyrrolidin-1-yl)-5-iodopyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from EXAMPLE 34) in 5.0 mL of 1,4-dioxane were added 1 mg (0.005 mmol) of copper(II) iodide, 20 mg (0.21 mmol) of (trimethylsilyl)acetylene, 12 mg (0.12 mmol) of diisopropylamine, and 2.6 mg (0.005 mmol) of bis(tri-tert-butylphosphine)palladium(0). The mixture was stirred at rt for 16 h and concentrated. Chromatography on a Biotage 25S cartridges using 9:1 v/v hexanes/EtOAc as the eluant afforded 43 mg of a yellow solid as the title compound: 1HNMR (500 MHz, CDCl3) δ 0.26 (s, 9H), 1.45 (s, 9H), 2.46 (m, 2H), 2.58 (t, J=7.8, 2H), 2.66 (s, 3H), 2.96 (t, J=7.8, 2H), 4.15 (t, J=7.3, 2H), 4.32 (t, J=13, 2H), 7.18 (s, 1H), 7.19 (s, 1H), 8.01 (m, 1H), 8.34 (d, J=2.3, 1H), 8.88 (d, J=2.3, 1H).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:36][C:37]1[O:38][C:39](=[O:43])[O:40][C:41]=1[CH3:42].CCOC(C)=O>CN(C=O)C>[CH3:42][C:41]1[O:40][C:39](=[O:43])[O:38][C:37]=1[CH2:36][O:12][C:11](=[O:13])[C@H:10]([OH:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid (500 mg, 1.0 mmol, 1.0 eq.) was dissolved in dry DMF (10.0 mL). The solution was cooled to 0° C. and dicesium carbonate (465 mg, 1.4 mmol, 1.1 eq.) was added. The mixture was stirred for 30 minutes and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (212 mg, 1.4 mmol, 1.1 eq.) was added. The resulting mixture was stirred for an additional 1 hour at 0° C., then warmed to room temperature while stirring. The mixture was further stirred overnight. EtOAc (20 mL) was added, followed by washing with saturated aqueous NaCl (100 mL). The product was dried under vacuum and purified using reverse phase chromatography (10-70% MeCN/H2O; 0.05% TFA over 70 minutes) to yield (2R,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester. This material was dissolved in 4N HCL in dioxane and stirred for 2 hours at room temperature. The material was dried under vacuum then azeotroped with toluene to yield (2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester, which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:27][OH:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>N1C=CC=CC=1>[OH:28][NH:27][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([CH2:16][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:18][CH:19]=1
Reactant: NO
Reactant: O=C(O)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(NO)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Yield: 16.7 %

Procedure:
Title compound 496 (332 mg, 1.014 mmol), hydroxylamine hydrochloride (85 mg, 1.217 mmol), BOP (583 mg, 1.318 mmol), triethylamine (0.424 mL, 3.04 mmol) and pyridine (7 mL) were stirred together at room temperature for 1 hour. All solvents were then removed under reduced pressure, and the residue was diluted with ethyl acetate and brine. Following extraction with ethyl acetate, the combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was then purified by column chromatography on silica gel using 50-100% EtOAc/hexanes as the eluent to afford title compound 497 (0.058 g, 17%) as a white solid. 1H NMR (CD3OD) δ (ppm): 7.66-7.62 (m, 3H), 7.50-7.38 (m, 5H), 7.28-7.23 (m, 1H), 7.17-7.08 (m, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.65 (d, J=0.6 Hz, 1H), 5.51 (s, 2H). MS (m/z): 343.5 (M+H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.[C:33]([NH:37][S:38]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)(=[O:40])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([NH:37][S:38]([C:41]1[CH:42]=[CH:43][CH:44]=[C:45]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:23][CH2:22][CH:21]([N:24]6[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]6)[CH2:20][CH2:19]5)=[CH:14][C:13]=4[O:31][CH3:32])=[N:9]3)=[CH:4][CH:3]=2)[CH:46]=1)(=[O:40])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Yield: 50.6 %

Procedure:
Following the procedure of example 532 (D), (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.050 g, 0.00010 mol) and 3-t-Butylsulfamoylphenylboronic acid (0.028 g, 0.00011 mol) were reacted. Purification by prep plate chromatography gave N-tert-Butyl-3-(2-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide as a tan solid (0.032 g, 51%). MP: 214-216° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 8.96 (s, 1H), 8.54 (s, 1H), 8.35-8.34 (d, 1H), 7.80 (t, 1H), 7.78-7.77 (d, 1H, J=2.88 Hz), 7.66 (t, 1H), 7.58 (s, 1H), 7.20-7.19 (d, 1H, J=4.80 Hz), 6.97-6.96 (d, 1H, J=4.72 Hz), 6.66 (s, 1H), 6.62-6.60 (d, 1H), 3.83 (s, 3H), 3.73-3.70 (d, 2H), 2.70-2.63 (m, 2H), 2.38-2.25 (m, 4H), 2.14 (s, 3H), 1.89-1.81 (d, 2H), 1.60-1.45 (q, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[C:3]=1[O:21][CH3:22].[OH-].[Na+].[CH:25](O)=O>C=O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:25])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[C:3]=1[O:21][CH3:22]
Reactant: O=CO
Reactant: COc1cc2c(c(Cl)c1OC)CCNCC2c1ccccc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(c(Cl)c1OC)CCN(C)CC2c1ccccc1

Procedure:
A solution of 3.7 g of 6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 15 ml of formic acid and 10 ml of formaldehyde is refluxed for 18 hours. The reaction mixture is evaporated to dryness, 20 ml of 6N hydrochloric acid is added and the solution is again evaporated to dryness to give a liquid. The latter is treated with 20 ml of 10% sodium hydroxide solution and the mixture is extracted with ether. The dried extract is evaporated to give 6-chloro-7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]C>CO>[C:1]([O:7][CH2:8][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCO
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)CC(C)=O
Temperature: 165 °C
Reaction time: 8 h

Procedure:
Introduced into a reactor equipped with a stirrer mechanism, a Vigreux column with a column head and a reflux condenser are 464 g (4 moles) of methyl acetoacetate and 186 g of dodecyl alcohol. The temperature of the reaction medium is progressively raised to 165° C. and the methanol having formed is distilled until the reaction is terminated, that is to say, for about 8 hours. The methyl acetoacetate excess is eliminated under a reduced pressure of 8 mm Hg and the crude dodecyl acetoacetate is recovered, and this will be used as such for the preparation of the corresponding dihydropyridine derivative (Example 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]1)=[O:7].N1(CCN)CCC[CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:14][CH2:22][CH2:13][CH2:12]1)=[O:7]
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1[N+](=O)[O-]
Reactant: NCCN1CCCC1
Product: COc1cc(C(=O)NCCN2CCCC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 9.28 mmol scale utilising 2-pyrrolidin-1-ylethanamine (Aldrich; 1.06 g, 9.28 mmol), as a brown solid (2.3 g, 85%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([CH:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)([CH3:12])[CH3:11].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:14]2[CH:13]([C:10]([F:9])([CH3:12])[CH3:11])[CH2:17][O:16][C:15]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(F)C1COC(=O)N1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(F)C1COC(=O)N1c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To the solution of 2,4-dichloropyrimidine (150 mg, 1.006 mmol) and 4-(2-fluoropropan-2-yl)oxazolidin-2-one (148 mg, 1.01 mmol) in DMF (4.5 mL), sodium hydride (60% wt. 89 mg, 2.21 mmol) was added to give a pale yellow mixture. The mixture was stirred at room temperature for 2 hr, diluted with EtOAc and stirred for additional 30 min. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane=0/100 to 80/20] providing 3-(2-chloropyrimidin-4-yl)-4-(2-fluoropropan-2-yl)oxazolidin-2-one (150 mg) as a brown solid. MS m/z 260.1 (M+H)+; Rt-0.72 min. 1H NMR (400 Mhz, CDCl3) δ ppm 8.51 (d, J=5.9 Hz, 1H), 8.17 (d, J=5.9 Hz, 1H), 5.14 (dd, J=17.4, 8.0 Hz, 1H), 4.66 (d, J=9.4 Hz, 1H), 4.43-4.52 (m, 1H), 1.42-1.52 (m, 3H), 1.30-1.40 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=2)=[CH:6][N:7]=1.[CH3:24]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC>[Cl:14][C:13]1[C:8]([C:5]2[N:4]=[C:3]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:2]([CH3:24])=[N:7][CH:6]=2)=[CH:9][C:10]([F:15])=[N:11][CH:12]=1
Reactant: Fc1cc(-c2cnc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 191.6 %

Procedure:
3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.0275 g, 0.077 mmol), methylboronic acid (0.014 g, 0.231 mmol), and sodium carbonate (0.100 ml, 0.200 mmol, 2M aq solution) were dissolved in DME (1.0 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf).CH2Cl2 adduct (0.013 g, 0.015 mmol). The reaction mixture was then heated in the microwave at 105° C. for 20 min. More of the above reagents in the same amounts were added to the reaction mixture and heating in the microwave was continued at 115° C. for 20 min. The reaction mixture was allowed to cool to ambient temperature. It was then filtered through a pad of Celite. The filtrate was concentrated in vacuo to yield 0.0497 g of a mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-3-methyl-N-((tetrahydro-2H-pyran-4-yl)pyrazine-2-amine and 6-(2-fluoro-5-methylpyridin-4-yl)-3-methyl-N-((tetrahydro-2H-pyran-4-yl_methyl)pyrazine-2-amine.
Reaction SMILES: C(O[CH:5]([CH3:8])[CH:6]=O)(=O)C.[C:9]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:13][C:11]1[O:12][C:5]([CH3:8])=[CH:6][C:10]=1[C:9]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: CC(=O)OC(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cc(C(=O)Nc2ccccc2)c(C)o1

Procedure:
A solution of 24 parts of α-acetoxypropionaldehyde, 35.4 parts of acetoacetanilide and 2 parts of p-toluenesulfonic acid in 100 parts of benzene is kept for 3 hours at 40° C and then boiled under reflux for 1 hour. Adopting the isolation procedure described in Example 1 there is obtained 41.8 parts of 2,5-dimethylfuran-3-carboxanilide having a melting point of 92° to 93° C.