Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[N:19][O:20][CH3:21])[C:16]([OH:18])=O)[N:14]=1)=[O:8].[NH2:22][CH:23]1[C:38](=[O:39])[N:25]2[C:26]([C:35]([OH:37])=[O:36])=[C:27]([CH2:30][S:31][C:32](=[O:34])[CH3:33])[CH2:28][S:29][C@H:24]12>C(Cl)Cl.C(N(CC)CC)C>[C:32]([S:31][CH2:30][C:27]1[CH2:28][S:29][C@@H:24]2[CH:23]([NH:22][C:16](=[O:18])[C:15]([C:13]3[N:14]=[C:10]([NH:9][C:7](=[O:8])[CH2:6][Cl:5])[S:11][CH:12]=3)=[N:19][O:20][CH3:21])[C:38](=[O:39])[N:25]2[C:26]=1[C:35]([OH:37])=[O:36])(=[O:34])[CH3:33]
Reactant: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(NC(=O)CCl)n1
Reaction time: 0.25 h

Procedure:
3.8 ml of thionyl chloride and 26 ml of methylene chloride were added at 0° C. under nitrogen to a mixture of 15.3 g of the syn isomer of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetic acid in 80 ml of methylene chloride and after standing at 0° C. for 15 minutes, 7 ml of triethylamine were added thereto. A mixture of 14.4 g of 7-amino-3-acetylthiomethyl-ceph-3-eme-4-carboxylic acid in 100 ml of methylene chloride and 14 ml of triethylamine were added to the mixture at 0° C. under nitrogen and the temperature was allowed to return to 20° C. The mixture was stirred for an hour and was then evaporated to dryness at 30°-35° C. under reduced pressure. The residue was taken up in 250 ml of water and the solution was raised through carbon black. 50 ml of 2 N hydrochloric acid were added thereto and the mixture was vacuum filtered. The product was washed with water and the raw product was suspended in 80 ml of ethanol. 7 ml of triethylamine were added thereto at 5° C. and 15 ml of 4 N sulfuric acid were added thereto all at once with stirring at 5° C. After standing for 15 minutes, the mixture was vacuum filtered and the product was empasted with ethanol, then with ether and was dried under reduced pressure to obtain the syn isomer of 3-acetylthiomethyl-7-[{2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CCN(C(C)C)C(C)C.[NH2:24][CH2:25][CH2:26][OH:27]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:24][CH2:25][CH2:26][OH:27])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Fluoro-3-nitro-benzoic acid methyl ester (3 g, 15.64 mmol) was dissolved in DMF (20 ml) and DIPEA (5.8 g, 18.07 mmol) was added. 2-Aminoethanol (1.1 g, 18.07 mmol) was then added slowly by maintaining the temperature <20° C. Stirring continued at ambient temperature for 1 h. After checking the completion of reaction by TLC, the reaction mixture was added onto the ice cold water. The yellow solid which separated out was filtered, washed with cold water and finally washed with hexane affording 3.3 g (92%) of 4-(2-hydroxyethylamino)-3-nitro-benzoic acid methyl ester. 1H NMR (300 MHz, CDCl3) δ 3.5 (q, 2H), 3.7 (q, 2H), 3.9 (s, 3H), 5.1 (t, 1H), 7.2 (d, 1H), 8.0 (d, 1H), 8.6 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][C@@H:13]([CH2:17][C@H:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[O:19][CH3:20])[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:33]O>>[CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][C@@H:13]([CH2:17][C@H:18]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[O:19][CH3:20])[C:14]([O:16][CH3:33])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H](C[C@H](CC=CCOCc1ccccc1)C(=O)O)c1ccc(F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](CC=CCOCc1ccccc1)C[C@@H](OC)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of ((S)-6-(benzyloxy)-2-((R)-2-(4-fluorophenyl)-2-methoxyethyl)hex-4-enoic acid in 10 mL methanol was added concentrated H2SO4 (150 μL) at room temperature and the resulting solution stirred for 8 h. The reaction mixture was concentrated under reduced pressure, the residue treated with water, and the mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×30 mL) and dried over Na2SO4. The product was isolated by flash column chromatography eluting with 0% to 20% ethyl acetate/hexane gradient solvent to give 494 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:20])([CH3:19])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][N:8]=1)=[O:5].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=1.CCN(CC)CC.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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>[F:21][C:22]1[CH:23]=[C:24]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]([O:2][CH3:1])([CH3:20])[CH3:19])=[N:8][CH:9]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COC(C)(C)C(=O)Nc1ccc(C#C[Si](C)(C)C)cn1
Reactant: Fc1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(C)(C)C(=O)Nc1ccc(C#Cc2cccc(F)c2)cn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
2-Methoxy-2-methyl-N-(5-trimethylsilanylethynyl-pyridin-2-yl)-propionamide (Example 13, step 2) (90 mg, 0.31 mmol) was dissolved in THF (8 ml). 1-Fluoro-3-iodobenzene (83 mg, 0.37 mmol, 1.2 equiv.), Et3N (130 μl, 0.93 mmol, 3 equiv.), bis-(triphenylphosphine)-palladium(II)dichloride (11 mg, 15 μmol, 0.05 equiv.) and copper(I)iodide (1.8 mg, 10 μmol, 0.03 equiv.) were added under nitrogen and the mixture was heated to 70° C. TBAF 1M in THF (370 μl, 0.37 mmol, 1.2 equiv.) was added dropwise at 70° C. The reaction mixture was stirred for 1 hour at 70° C., filtered through celite and the filtrate evaporated to dryness. The crude product was purified by flash chromatography with a silica gel column eluting with heptane:ethyl acetate 100:0->90:10. The desired N-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-2-methoxy-2-methyl-propionamide (64 mg, 66% yield) was obtained as a yellow oil, MS: m/e=313.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[N:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:38]=[N:37][C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Clc1cc(Oc2cnc3ccccc3n2)ncn1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cnc5ccccc5n4)ncn3)CC1)C(=O)N2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
24 mg (0.087 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 20 mg (0.077 mmol) 2-(6-chloro-pyrimidin-4-yloxy)-quinoxaline and 0.050 mL (0.29 mmol) DIPEA were combined in 1.0 mL DMF and stirred overnight at 90° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O-:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na+]>CN1C(=O)CCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:19][CH:18]=1)([CH3:21])[CH3:22]
Reactant: [O-]c1ccccc1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(Oc3ccccc3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 100 mg, 0.302 mmol) and sodium phenoxide (70 mg, 605 mmol) in NMP (3 mL) was stirred at room temperature overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 40-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (44 mg, 37%). 1H NMR (DMSO-d6) δ: 11.11 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H), 7.41-7.68 (m, 7H), 7.17 (s, 1H), 6.51 (d, J=2.3 Hz, 1H), 3.94 (br. s., 1H), 1.43 (s, 6H). ESI-MS: m/z 389.0 (M+H)+.
Reaction SMILES: C([C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:11][CH:10]=2)(=O)CCC.NC1C(C)=CC=CC=1>O1CCOCC1>[C:19]([O:18][CH2:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:15]2)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCC(=O)c1c(Cl)c2cc(COC(=O)c3ccccc3)ccc2[nH]c1=O
Solvent: Cc1ccccc1N
Solvent: C1COCCO1
Product: O=C(OCc1ccc2ncccc2c1)c1ccccc1
Yield: 108.9 %

Procedure:
3-butyryl-4-chloro-6-benzoyloxymethylquinolone (10 g, 30 mmol) and o-toluidine (3.7 ml, 35 mmol) were heated together under reflux in 1,4-dioxan (150 ml) for 1.5 hours. The solvent was evaporated and the residue dissolved in chloroform, washed with 2 M HCl, sodium hydrogen carbonate solution (x2) and brine, dried, filtered and evaporated to an oil which immediately crystallized to give 3-butyryl-4-2-methylphenylamino)-6-benzoyloxymethyl quinoline (8.6 g, 66%), m.p. 142° C.-4° C.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=1.[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[Na+].[H-].[Na+]>O.CN(C=O)C>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:3]2[N:2]=[N:1][C:5]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)=[N:4]2)=[CH:28][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(-c2nn[nH]n2)c(N)n1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nnn(Cc3ccc(OCc4ccccc4)cc3)n2)c(N)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
3-(2H-tetrazol-5-yl)-pyridin-2,6-diamine (60 mg) described in Manufacturing Example 7-3, 4-benzyloxybenzyl chloride (79 mg), sodium iodide (51 mg), NaH (14 mg, 60% in oil), and DMF (0.69 mL) were stirred for 10 minutes at 60° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated and purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1, then ethyl acetate). Ethyl acetate-hexane was added to the residue thus obtained, and the solids were filtered off to obtain the titled compound (26 mg).
Reaction SMILES: Cl.[CH3:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH2:12][C:13]#[N:14])[CH:8]=[C:9]([Cl:11])[CH:10]=1>C1(C)C=CC=CC=1>[ClH:4].[Cl:4][C:5]1[CH:6]=[C:7]([CH2:12][C:13](=[NH:14])[O:3][CH3:2])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CO
Reactant: N#CCc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=N)Cc1cc(Cl)cc(Cl)c1
Yield: 722.6 %

Procedure:
Hydrogen chloride was passed through a mixture of toluene (485 mL), methanol (16.8 g, 0.112 mol) and 3,5-dichlorophenylacetonitrile (100 g, 0.107 mol) at 25° C. When the hydrogen chloride uptake ceased, the mixture was sparged with nitrogen for 30 min. The mixture was filtered and the collected solid washed with toluene (150 mL) and dried overnight in a vacuum oven (50° C. at 25 in. Hg) to yield an off-white solid (98.4 g, 72%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]1[NH:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[C:8]1=[O:15])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][CH2:6][CH:7]1[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)[C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[C:8]1=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OCC1NC(=O)C(C)(C)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 5-(tert-butoxymethyl)-3,3-dimethylpyrrolidine-2,4-dione (1.20 g), 4-bromo-2-chlorobenzonitrile (1.46 g), cesium carbonate (2.75 g), tris(dibenzylideneacetone)dipalladium(0) (258 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (488 mg), and in the same manner as in Reference Example 3, the title compound was obtained as colorless crystals (yield: 1.59 g, 81%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[CH:15][N:16](/[CH:18]=[CH:19]\[C:20]([O:22]C(C)C)=[O:21])[CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.O[Li].O.Cl>C1COCC1.C(OCC)(=O)C.CCCCCC>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:14]=[CH:15][N:16](/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21])[CH:17]=2)[CH:4]=[C:3]([C:2]([F:1])([F:27])[F:26])[CH:8]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reaction time: 3.5 h
Yield: 44.8 %

Procedure:
In a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet, thermometer pocket and stopper, (Z)-isopropyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)-1H-imidazol-1-yl)acrylate (2) (1.0 g, 1.0 eq.) was dissolved in THF: H2O (20 mL, 1:1, 20V). To this reaction mixture LiOH.H2O (0.535 g, 5.0 eq.) was added at 0° C. This reaction mixture was stirred for 3-4 h and progress of the reaction was followed by TLC using 20% ethyl acetate/n-hexane as mobile phase. Reaction mixture was acidified using dilute HCl. The reaction mixture was extracted with EtOAc (3×20 mL). The combined organic layers was washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure by rotary evaporation to afford 0.4 g of crude compound which was used for next step without purification.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)(=[NH:3])[NH2:2].[CH3:14][CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17].C[O-].[Na+]>C(O)C>[O:9]1[C:8]2[CH:12]=[CH:13][C:5]([CH2:4][C:1]3[N:2]=[C:16]([OH:17])[C:15]([CH3:14])=[C:21]([OH:22])[N:3]=3)=[CH:6][C:7]=2[O:11][CH2:10]1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: N=C(N)Cc1ccc2c(c1)OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)nc(Cc2ccc3c(c2)OCO3)nc1O

Procedure:
To ethanol (350 mL) was added 5-(amidino)methyl-1,3-benzodioxolane (50 g, 0.23 mol), diethyl methylmalonate (50 mL), and sodium methoxide (120 mL of 25 wt % in methanol). After refluxing for 5 hours, the solvent was removed in vacuo. The residue was dissolved in water, washed with ethyl acetate, treated with charcoal, and acidified with 6 N HCl. The resulting solid was collected by filtration, washed with water, CH3CN and ethyl ether to give 54 g of 2-[(1,3-benzodioxol-5-yl)methyl]-4,6-dihydroxy-5-methylpyrimidine.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li]C.CCOCC.C([Cu])#N.[CH:19]([CH:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH:24]=[CH:23]1)([CH3:21])[CH3:20]>[H-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].Cl[Ni]Cl.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].[Cu]>[CH:1]([CH:23]1[CH:22]([CH:19]([CH3:21])[CH3:20])[CH2:27][CH2:26][C:25](=[O:28])[CH2:24]1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)C1C=CC(=O)CC1
Reactant: C#CCCCCCC
Agent: Cl[Ni]Cl
Agent: N#C[Cu]
Agent: [Cu]
Solvent: CCOCC
Product: CCCCCCC=CC1CC(=O)CCC1C(C)C
Temperature: -78 °C
Yield: 77.5 %

Procedure:
A 10 mL round-bottom flask equipped with a stir bar was charged with zirconocene chloride hydride (0.305 g, 1.07 mmol) and sealed with a septum. The flask was evacuated with a vacuum pump and purged with argon, the process being repeated 3 times. THF (4 mL) was injected and the mixture stirred to generate a white slurry which was treated via syringe with 1-octyne (0.115 g, 1.04 mmol). The mixture was stirred for 15 minutes to yield a yellow-to-green solution which was cooled to -78° C. and treated via syringe with ethereal MeLi (0.63 mL, 1.01 mmol) to generate a dark red solution. At the same time, NiCl2 (68 mg, 0.52 mmol) was placed in a 5 mL round bottom flask and purged as above with Ar to which was added 1 mL THF via syringe. This solution was then cooled to -78° C. where it was treated with MeLi in Et2O (0.98 mL, 1.574 mmol) and then warmed to about -20° C. for 10 minutes to generate a dark brown solution. It was then cooled again to -78° C. Concurrently, CuCN (9.3 mg, 0.104 mmol) was placed in a 10 mL round-bottom flask equipped with a stir bar and sealed under septum. The flask was warmed slightly to generate a clear solution of Me2Cu(CN)Li2, then cooled to -78° C. At -78° C. and by cannula the solution of NiMe3Li was added to the Me2Cu(CN)Li2 solution. The solution of the zirconocene was added via cannula to the resulting Me2Cu(CN)Li2 /NiMe3Li solution, thereby providing a reaction mixture comprising 20 mol-% of copper per mole of substrate enone. The mixture was stirred for 15 minutes at -78° C. to provide a dark brown solution, which was treated with 4-isopropyl-2-cyclohexenone (77 μL, 0.5 mmol) added slowly as a neat liquid over 70 minutes. After stirring for 1.5 hours, the mixture was quenched with 5 mL of 10% NH4OH in saturated NH4Cl. The product was extracted with 3×20 mL of ether and dried over Na2SO4. The solution was then filtered through fritted filter paper and the solvent removed in vacuo. The resulting residue was submitted to flash chromatography on silica gel (Petroleum Ether/Ethyl Acetate, 40/1) to give a 77% yield (97.1 mg) of 3-(1-octen-1-yl)-4-isopropylcyclohexanone as a colorless oil giving satisfactory IR, NMR, MS and HRMS data.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:21][CH2:20][C:5]2[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=2[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:31])=[CH:25][CH:24]=1
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccc(Cl)cc1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C(#N)C.[Cl:11][CH2:12][C:13](Cl)=[O:14]>ClCCCl>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)=[O:14]
Reactant: Nc1cncnc1
Reactant: O=C(Cl)CCl
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(CCl)Nc1cncnc1
Temperature: 80 °C

Procedure:
5-Aminopyrimidine (450 mg) was suspended in DCE (2 mL) and acetonitrile (2 mL) in a microwave vial. Chloroacetyl chloride (0.377 mL) was added with stirring. The vial was sealed and the reaction mixture was heated in the microwave at 80° C. for 5 minutes. The solid was filtered off, washed with acetonitrile (2×5 mL), DCE (2×5 mL) and pentane (2 ×30 mL) and then partioned between saturated sodium bicarbonate and DCE (50 mL/50 mL) ensuring the aqueous layer was still basic. The organic layer was separated and the aqueous layer was extracted with DCE (2×75 mL). The combined organic layer was dried over magnesium sulfate and evaporated to give the sub-titled compound (200 mg) as a yellow solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[N:17]=[C:16]([C:18](OCC)=[O:19])[CH:15]=[C:14]([CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:13]=1>ClCCl>[Cl:11][C:12]1[N:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:14]([CH2:23][O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:13]=1
Reactant: CCOC(=O)c1cc(COCC(F)(F)F)nc(Cl)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Diisobutyl aluminum hydride (1.21 mL, 1M solution in hexane, 1.22 mmol), was added dropwise to a solution of ethyl 2-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carboxylate (242 mg, 0.81 mmol) in dry dichloromethane (10 mL) under nitrogen at −78° C. The mixture was stirred at −78° C. for 1 h. Diisobutyl aluminum hydride solution (1 mL) was added and the mixture was stirred for 15 minutes. The mixture was quenched with methanol and allowed to reach ambient temperature. Water (10 mL) and dichloromethane were added, the pH of the water phase was adjusted to 6 by addition of acetic acid. The mixture was filtered through a pad of silica gel and sodium bicarbonate. The water phase was extracted with 5% solution of methanol in dichloromethane (3×10 mL). The combined organic phase was dried over sodium sulfate and concentrated in vacuum to yield the title product, 216 mg (100%).
Reaction SMILES: [CH:1]1([CH2:9]Br)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.CC(C)([O-])C.[K+]>C(O)CCC>[CH:1]1([CH2:9][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: BrCC1C=CCCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: C1=CC(Cn2ccnc2)CCCCC1

Procedure:
2-Cyclooctenylmethyl bromide (0.7 g; 0.0035 mole) as just made was added dropwise to a refluxing solution of imidazole (0.24 g; 0.0025 mole) and potassium tertiary butoxide (0.39 g; 0.0035 mole) in dry butanol under nitrogen. After addition the mixture was stirred under reflux for 1 hour. Pure product was obtained as described in Example 4, b.p. 108°-110°/0.02 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:16][CH2:17][CH2:18][C:19]1[O:20][C:21]([CH3:24])=[CH:22][CH:23]=1.[Mg].[BH4-].[Na+].Cl>CCOCC.CC(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH2:14])[CH2:16][CH2:17][CH2:18][C:19]3[O:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: Cc1ccc(CCCBr)o1
Agent: Cl
Agent: [BH4-]
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(CCCC(N)C2(c3ccc(Cl)c(Cl)c3)CCC2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3,4-Dichlorophenyl)cyclobutanecarbonitrile (8 g) was added to the Grignard reagent prepared by the reaction under argon of 2-(3-bromopropyl)-5-methylfuran (10 g) and magnesium (1.1 g) in ether (20 ml). The mixture was stirred for 16 hours at ambient temperature. A suspension of sodium borohydride (3 g) in propan-2-ol (100 ml) was added and the mixture heated under reflux for 4.75 hours and then allowed to cool. The mixture was added to water with cooling and excess 2N hydrochloric acid added. The aqueous acid layer was extracted with ether and the extract washed with 1N aqueous sodium hydroxide solution, dried and evaporated to yield 1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-(5-methyl-2-furyl)butylamine.