Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]([O:19][CH3:20])[C@H:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[I:18])[N:8]=1.[CH3:24][O:25]C(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.[Cl-].[NH4+]>ClCCl>[CH3:1][O:2][C:3]1[C@@H:4]([CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]([O:19][CH3:20])[C@H:7]([CH2:9][C:10]2[CH:15]=[C:14]([CH:24]=[O:25])[C:13]([O:16][CH3:17])=[CH:12][C:11]=2[I:18])[N:8]=1
Reactant: COC(Cl)Cl
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccc(OC)cc1I
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(C=O)c(OC)cc1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
Formylation of compound 21 by dichloromethyl methyl ether in the presence of stannic chloride was carried out by a known method [(A. H. Lewin, S. R. Parker, N. B. Fleming, and F. Carroll, “Formylation of Arenes by α,α-Dichloromethyl Methyl Ether. An Improved Experimental Procedure” Org. Prep. Proced. Int., 10, pp 201-204 (1978)]. The pyrazine derivative 21 (100 mg, 0.23 mol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to 0° C. and a 1M solution of SnCl4 (2.6 mL, 2.6 mol) was added drop wise under argon. After completion of the addition of SnCl4, 1,1-dichloromethyl methyl ether (0.21 mL, 2.32 mmol) was added drop wise to the reaction mixture. The solution turned from light yellow to greenish brown upon the addition of the dichloro derivative. The resulting mixture was stirred for 45 min at 0° C. A saturated solution of ammonium chloride (2 mL) was added to quench the reaction and the light brown suspension that resulted was stirred for 30 min at room temperature. The mixture was then extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated, resulting in an oily product. Flash chromatographic purification of this product provided pure 2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(2′-iodo-4′-methoxy-5′-formylbenzyl)-(2R,5S)-pyrazine (22) as a yellow oil (51 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 70 °C
Yield: 78.4 %

Procedure:
A stirred mixture of 10.0 g (0.063 mole) of 3-fluoro-4-nitrophenol, 17.0 g (0.090 mole) of 4-fluorophenylmethyl chloride, and 12.42 g (0.090 mole) of anhydrous potassium carbonate in 80 mL of methyl ethyl ketone was heated at 70° C. for approximately 17 hours. The reaction mixture was then cooled and filtered and the filtrate evaporated under reduced pressure, leaving 13.10 g of 4-fluorophenylmethyl 3-fluoro-4-nitrophenyl ether as a solid; m.p. 90°-91° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>ClCCl.O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:12]2[CH:13]=[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)[CH:10]=[N:11]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CSc1nccc(-c2cn[nH]c2)n1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3ccnc(SC)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (200 mg, 1 mmol) in dichloromethane (3 mL) and H2O (1 mL) was added 4-methoxybenzylchloride (200 mg, 1.28 mmol) at 0° C. The mixture was stirred at RT overnight. The organic layer was separated, washed with brine and concentrated in vacuo to give crude 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.50, (d, J=5.4 Hz, 1H), 8.16 (s, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 5.30 (s, 2H), 3.72 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z: 313 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=1>>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[N:19]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCNCC1
Reactant: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)NC1CCN(c2cccc(Cl)n2)CC1
Reaction time: 40 h
Yield: 78.6 %

Procedure:
A suspension of 175.5 g of 4-acetamidopiperidine, 269.7 g of potassium carbonate and 182.5 g of 2.6-dichloropyridine in 1600 ml of n.penytylic alcohol is heated at reflux with stirring for 40 hours. The reaction mixture is cooled, the solvent is removed under reduced pressure and the residue is taken up with 100 mlof water. The solid product is extracted with 2000 ml of methylene chloride, the organic phase is washed with water, it is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is taken up with 1200 ml of diisopropylic ether, stirred for 30 minutes, filtered and washed with diisopropylic ether. 246 g of 4-acetamido-1-(6-chloro-2-pyridyl)piperidine are obtained; m.p. 153° to 155° C.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:7]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[CH:13][N:12]([CH:23]([CH3:25])[CH3:24])[C:8]=2[N:9]=[CH:10][N:11]=1>ClCCl>[NH2:5][C:6]1[C:7]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[CH:13][N:12]([CH:23]([CH3:25])[CH3:24])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: COc1ccc(-c2cn(C(C)C)c3ncnc(N)c23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccc(O)cc2)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of boron tribromide (14.4 ml of a 1M solution in dichloromethane) was added dropwise to a stirred solution of 4-amino-7-isopropyl-5-(4-methoxyphenyl) pyrrolo[2,3-d]pyrimidine (1.35 g) in dichloromethane (100 ml) at -10° C. under nitrogen. The reaction mixture was allowed to warm to 0° C. and stirred at this temperature for one hour. Additional boron tribromide (9.6 ml of a 1M solution in dichloromethane) was added at -10° C. and the mixture was allowed to warm to 0° C. and stirred for a further hour. The reaction mixture was quenched by the dropwise addition of saturated sodium bicarbonate solution (50 ml). The mixture was allowed to stand overnight and the dichloromethane layer separated off. Insoluble material at the interface was removed by filtration and dried to yield 4-amino-5-(4-hydroxyphenyl)-7-isopropylpyrrolo-[2,3-d]pyrimidine. The structure was confirmed by 1H nmr.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>CN(C)C=O>[C:14]1([NH:13][CH2:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl bromoacetate (4.0 ml) and aniline (2.28 ml) in 25 ml of dry dimethylformamide was added sodium acetate (2.05 g). The reaction was stirred at room temperature overnight and extracted from water with three portions of ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The volatiles were removed, and the residue was purified by flash column chromatography on silica gel (eluting with 10% ethyl acetate/hexane) to yield 4.54 g of benzyl N-phenylglycinate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]1([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C=O>[C:19]1([C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cccc(-c3ccccc3)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 72.2 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.22 g of 3-phenylphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.25 g of 4-(3-phenylphenoxy)-6-(2-butynyloxy)pyrimidine (the present compound (69)).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10](=[O:25])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](OCC)=[O:27].[O-]CC.[Na+]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH:8]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:12]([CH2:11][C:10](=[O:25])[C:9]2=[CH:26][OH:27])[CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 94 %

Procedure:
9-(4-Chloro-benzenesulfonyl)-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (6) (2.49 g, 6.45 mmol) was dissolved in THF/ethanol (14 mL, 1/1, v/v). Ethyl formate (5.19 mL, 64.53 mmol) was added followed by sodium ethoxide (6.2 mL of 21% solution in ethanol). The resulting mixture was heated to 60° C. for 30 minutes after which the solution was cooled to room temperature and quenched by the addition of saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic phases were dried (Na2SO4); filtered and concentrated under vacuum to yield 2.51 g (94%) of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (7) as a yellow oil. Retention time (min)=2.017, method [1], MS (ESI) 414.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:34]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH:22]=[O:34])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COC(=O)c1c(C=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Temperature: 100 °C

Procedure:
To a 25 mL round bottom flask was added methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (0.17 g, 0.382 mmol), selenium dioxide (0.085 g, 0.765 mmol) and dioxane. The reaction mixture was heated at 100° C. overnight, cooled to RT, and filtered through a bed of Celite 545, which was rinsed with MeOH. The solvent was removed to give the title compound as yellowish-brown foam, which was used in the next step without further purification (245 mg).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.Cl>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:19]1([N:14]2[CH2:15][CH2:16][N:11]3[N:10]=[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:18]=[C:12]3[C:13]2=[O:17])[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: O=C1NCCn2nc(COc3ccccc3)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2cc(COc3ccccc3)nn2CCN1C1CC1
Temperature: 95 °C
Reaction time: 16 h
Yield: 16.4 %

Procedure:
Copper(II) acetate monohydrate (83 mg, 041 mmol) was added to a mixture of 2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.1 g, 0.41 mmol), cyclopropylboronic acid (35 mg, 0.41 mmol) and DMAP (75 mg, 0.617 mmol) in toluene (1 mL). The mixture was stirred at 95° C. for 16 hours. The mixture was stirred at 95° C. for 24 hours more. The reaction was allowed to room temperature and was poured into a 1N solution of HCl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo. The desired product was triturated with diethyl ether to yield 5-cyclopropyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (19 mg, 16% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 0.68-0.79 (m, 2H), 0.89-1.00 (m, 2H), 2.74-2.82 (m, 1H), 3.74-3.82 (m, 2H), 4.30-4.37 (m, 2H), 5.08 (s, 2H), 6.93 (s, 1H), 6.94-6.97 (m, 1H), 6.98-7.02 (m, 2H), 7.26-7.31 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[F:8][C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12].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>CN(C=O)C.CCOC(C)=O>[F:8][C:9]1[C:17]([C:18]([F:21])([F:19])[F:20])=[N:16][CH:15]=[CH:14][C:10]=1[C:11]([N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)=[O:12]
Reactant: O=C1CCNCC1
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)c2ccnc(C(F)(F)F)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of piperidin-4-one (1 g, 10 mmol) and 3-fluoro-2-(trifluoromethyl)isonicotinic acid (2.32 g, 11.1 mmol) in DMF (20 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (5.62 g, 12.7 mmol) and triethylamine (4.43 mL, 31.8 mmol). The mixture was stirred at room temperature overnight and diluted with EtOAc. The solution was washed with brine, dried with sodium sulfate, filtered and concentrated. Purification on silica gel with 50-100% EtOAc/hexanes gave 2.1 g (70% yield) of the title compound. LC/MS found: 291.2 (M+1)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[Br:14][C:15]1[N:16]=[C:17](Br)[C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1.O>CN(C=O)C>[Br:14][C:15]1[N:16]=[C:17]([N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1
Reactant: c1cc(-c2ncc[nH]2)ccn1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cn2ccnc2c(-n2ccnc2-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Sodium hydride (NaH) (730 milligrams (mg) of a 95% dispersion in mineral oil) is added to a solution of 4-(1H-Imidazol-2-yl)-pyridine (4.0 g) in N,N,-dimethylformamide (DMF) (150 ml) and the mixture is stirred at room temperature (rt) for 0.5 hr. A solution of 6,8-dibromoimidazo[1,2-a]pyrazine (3) (7.63 g) in DMF (10 ml) is added. The mixture is stirred at room temperature (rt) for 16 hr. Water (50 ml) is added and the mixture is extracted with ethyl acetate (3×70 ml); extracts are washed with water (2×50 ml) and brine (1×50 ml), dried over sodium sulfate (Na2SO4), and evaporated in vacuo. Purification on SiO2 (5% MeOH, DCM) yielded 6-Bromo-8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazine (4) (4.08 g) as an off-white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)=[CH:10][CH:9]=1.S(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:12]1([C:11]2[CH:23]=[CH:24][C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:25])[CH3:1])=[CH:9][CH:10]=2)[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: O=S(Cl)Cl
Reactant: C[Si](C)(C)CCOCOc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCOc1ccc(C2(Cl)OC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Distilled THF (10 mL) was added to 2-[4-(2-trimethylsilanylethoxymethoxy)-benzoyl]benzoic acid (1.86 g, 5 mmol) followed by thionyl chloride (0.43 mL, 6 mmol) and 3 drops of DMF. The system was stirred at room temperature under nitrogen for 2 h and monitored by TLC. The solvent was removed to give 3-chloro-3-[4-(2-trimethylsilanylethoxymethoxy)phenyl]-3H-isobenzofuran-1-one as a clear oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([Cl:3])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1sccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1sccc1Cl
Temperature: 25 °C

Procedure:
Excess thionyl chloride (3.5 ml, 48.0 mmoles) was added to 0.85 g (5.2 mmoles) of 3-chloro-2-thiophenecarboxylic acid (prepared according to Corral, C., et al., Heterocycles 23:1431 (1985)) dissolved in 50 ml of toluene and stirring at room temperature. After addition the solution was refluxed for 3 hours to form 3-chloro-2-thiophenecarbonyl chloride. Concentration of the reaction solution gave the acid chloride as a white solid. The acid chloride was then dissolved in 4 ml of N,N-dimethylformamide and slowly added to a cooled (ice/water bath) stirring solution of 5-chloro-2-oxindole-1-carboxamide (1.0 g, 4.71 mmoles) and 4-(N,N-dimethylamino)pyridine (1.3 g, 10.5 mmoles) in 10 ml of N,N-dimethylformamide. After 45 minutes the solution was allowed to warm to room temperature and after 2 hours was worked-up by pouring into a mixed ice/6N hydrochloric acid solution. A yellow precipitate formed. The precipitate was filtered, washed with water and dried to give 1.3 g of impure product as a yellow solid. Recrystallization with acetic acid/heptane (2:1) gave 0.77 g (2.2 mmoles) of pure title compound as yellow needles, m.p. 222-224° C. Total yield of product was 42%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH3:25])[C:12]=2[C:16]([O:18]C)=[O:17])[C:7]1=[O:28].[OH-].[K+].O1CCCC1CO.O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH3:25])[C:12]=2[C:16]([OH:18])=[O:17])[C:7]1=[O:28]
Reactant: CNCCCCn1c(C(=O)OC)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: CNCCCCn1c(C(=O)O)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 50 °C

Procedure:
Methyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.18 g, 0.38 mmol) and potassium hydroxide (0.17 g, 2.3 mmol) in a mixture of 1:1:1 v/v/v tetrahydrofuran-methanol-water (4.5 mL) was heated at 50° C. overnight. The reaction mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and dilute hydrochloric acid. The aqueous extract was concentrated under vacuum to provide the title compound as hydrochloride salt. This was used in the following step without further purification. ES MS M+1=452
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[O:16])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1.C[Si]1(C)CC[Si](C)(C)[N:32]1[CH2:38][CH2:39][CH2:40][Mg]Cl>C1COCC1>[NH2:32][CH2:38][CH2:39][CH2:40][C@:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[OH:16]
Reactant: C[Si]1(C)CC[Si](C)(C)N1CCC[Mg]Cl
Reactant: Cc1cccc(-c2c(Cl)cccc2C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Solvent: C1CCOC1
Product: Cc1cccc(-c2c(Cl)cccc2[C@](O)(CCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-(6-chloro-3′-methylbiphenylcarbonyl)piperidine-1-carboxylate (800 mg, 1.94 mmol) in anhydrous THF (15 mL) cooled to −78° C. was added dropwise a solution of 2 M (3-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)propyl)magnesium chloride in THF (0.968 mL, 1.94 mmol). After addition, the reaction mixture was allowed to warm slowly to room temperature while stirring overnight. The mixture was quenched with satd aq NH4Cl (15 mL) and extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and concentrated to give crude (R)-tert-butyl 3-((S)-4-amino-1-(6-chloro-3′-methylbiphenyl-2-yl)-1-hydroxybutyl)piperidine-1-carboxylate (900 mg), which was used in the next step without further purification.
Reaction SMILES: O=[C:2]([CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:17]=[CH2:18])[CH:13]=2)[C:8]1=[O:19])[C:3]([O:5][CH3:6])=[O:4].Cl.[NH2:21]O>CO>[CH:17]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8]1[O:19][N:21]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[C:7]=1[CH2:16][CH2:15]2)=[CH2:18]
Reactant: C=Cc1ccc2c(c1)CCC(C(=O)C(=O)OC)C2=O
Reactant: NO
Agent: Cl
Solvent: CO
Product: C=Cc1ccc2c(c1)CCc1c(C(=O)OC)noc1-2
Yield: 35 %

Procedure:
A mixture of methyl 2-oxo-2-(1-oxo-6-vinyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetate (Preparation 45A, 180 mg, 0.697 mmol) and hydroxylamine hydrochloride (145 mg, 2.091 mmol) in methanol (3 mL) was stirred at reflux for 60 min. The reaction mixture was allowed to stir at room temperature overnight. The product crystallized from solution upon stirring at room temperature. The solid was collected by vacuum filtration and dried to give methyl 7-vinyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (65 mg, 0.244 mmol, 35.1% yield over two steps) as yellow solid. The compound had an HPLC ret. time=1.05/2.0 min. (condition E); MS:(M+H)=256.2.