Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([O:19]/[C:20](/[C:29]([O:31]CC)=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[O:7][C@H:6]1[CH2:34][O:35]C(=O)C)(=O)C.O[Li].O>C1COCC1.O>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1/[CH:21]=[C:20](\[O:19][C@@H:8]1[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:5]([OH:4])[C@H:6]([CH2:34][OH:35])[O:7]1)/[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
The ester C4 (20 mg, 0.037 mmol) was dissolved in THF (0.4 mL) and added a solution of LiOH H2O (8.86 mg, 0.37 mmol) in water (0.3 mL). The reaction mixture was stirred at room temperature for one hour and then acidified until pH<3 with Dowex 50-X8 resin, filtered and concentrated, and the residue was purified by preparative HPLC using acetonitrile-water as an eluent. After freeze drying, the final product was isolated in 87% yield: 1H NMR (400 MHz, MeOH-d4): δ 8.31 (t, J=7.1 Hz, 1H), 7.24 (dd, J=13.6, 5.8 Hz, 1H), 7.14 (s, 1H), 7.07 (t, J=7.6 Hz, 1H), 7.03-6.96 (m, 1H), 5.17 (d, J=7.4 Hz, 1H), 3.66 (dd, J=12.0, 2.2 Hz, 1H), 3.52 (dd, J=12.0, 5.2 Hz, 1H), 3.41-3.23 (m, 3H), 3.17-3.11 (m, 1H); 13C NMR (101 MHz, MeOH-d4): δ 166.72, 161.83 (d, 1JC,F=249.7 Hz), 144.28, 132.66, 131.71, 125.15, 122.48, 115.93 (d, 1C), 115.78 (d, 1C), 102.66, 78.59, 78.07, 75.64, 71.35, 62.50; ESI-HRMS m/z: calcd for C15H17FO8Na+: 367.0800. found 367.0800.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([Si:16]([CH:29]=[CH2:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH2:15]>>[C:8]1([P:7]([CH2:30][CH2:29][Si:16]([CH2:14][CH2:15][P:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C[Si](C=C)(c1ccccc1)c1ccccc1
Reactant: c1ccc(Pc2ccccc2)cc1
Product: c1ccc(P(CC[Si](CCP(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
About 2 moles of diphenyl phosphine were added sequentially to one mole of divinyl diphenyl silane to yield mostly the desired diadduct which crystallized on standing; recrystallization from heptane provided the pure product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([CH:14]=[O:15])[S:12][CH:13]=1.[C:16]([Mg]Br)#[CH:17]>CCCCCC.C(OCC)(=O)C>[C:16]([CH:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:10]=1)[OH:15])#[CH:17]
Reactant: O=Cc1nc(COC2CCCCO2)cs1
Reactant: C#C[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#CC(O)c1nc(COC2CCCCO2)cs1

Procedure:
The product was prepared starting with the product of Stage B and ethynyl magnesium bromide using the procedure of Example 1 to obtain the desired product with a Rf=0.11 (hexane-ethyl acetate (7-3)).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Brc1ccccn1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(-c2ccccn2)cc1
Temperature: 90 °C

Procedure:
Pd(PPh3)4 (0.404 gm, 0.35 mmol) was added to a degassed solution of 4-cyanobenzene boronic acid (1.029 g, 7 mmol) and 2-bromopyridine (1.11 g, 7 mmol) in 75 mL acetonitrile. 0.4 M sodium carbonate solution (35 mL) was added to the reaction mixture and the resulting solution was refluxed at 90° C. under Ar for 24 hours (progress of reaction was monitored by TLC). The reaction mixture was cooled and aqueous layer was separated. The organic layer containing the product and spent catalyst was mixed with silica gel (15 g) and concentrated to dryness. The 4-(2-pyridyl)-benzonitrile was isolated by column chromatography (0.850 g, 68%). LCMS: MH+=181; 1H NMR (CDCl3) δ 8.85 (d, 1H), 8.7 (dd, 1H), 7.9 (dd, 1H), 7.75 (d, 2H), 7.7 (d, 2H), 7.4 (dd, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1.[Li]CCCC.[C:25]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH3:18][C:14]1([CH3:19])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:35]3([OH:38])[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[CH2:13]1
Reactant: CC1(C)CCCN(CCCOc2ccc(I)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCCN(CCCOc2ccc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-{3-[(4-iodophenyl)oxy]propyl}-3,3-dimethylpiperidine (for example as prepared for Intermediate 2) (3 g, 8.02 mmol) in anhydrous THF (30 ml) was cooled to −78° C. under nitrogen and treated with nBuLi (1.6M solution in hexanes, 6.02 ml, 9.63 mmol), after 0.5 h, a solution of N-Boc-4-oxopiperidine (commercially available, for example from Aldrich) (1.99 g, 10 mmol) in THF (10 ml) was added dropwise. The mixture was allowed to warm up to room temperature and was stirred overnight. The mixture was quenched with ammonium chloride solution and extracted with EtOAc, dried over magnesium sulphate, filtered and concentrated. The resulting residue was purified by FlashMaster II chromatography using a 100 g cartridge, eluting with 100% cyclohexane for 5 minutes, 100% cyclohexane to 100% EtOAc over 15 minutes, 100% EtOAc to 100% DCM in 5 minutes and 100% DCM to 30% MeOH (containing 1% of triethylamine) in DCM over 40 minutes then held constant for 5 min, monitoring at 254 nm to afford the title compound (1.25 g). LCMS RT=2.48 min, ES+ve m/z 447 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CNC(=O)Cc1ccc(N)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CNC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 46 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) and 2-(4-aminophenyl)-N-methylacetamide (0.164 g, 1.0 mmol) was heated for 3 h at 150° C., then toluene added and the mixture continued heating for an additional 3 h. After this time, the mixture was purified by silica gel chromatography eluting with methylene chloride and methanol. The resulting solid was further purified by reverse phase preparative HPLC and then converted to the HCl salt to afford the title compound (0.065 g, 50%) as a white solid. MW=391.89. 1H NMR (DMSO-d6, 500 MHz) δ 14.07 (br s, 1H), 9.82 (s, 1H), 8.04-8.03 (m, 1H), 7.90-7.89 (m, 1H), 7.71-7.58 (m, 3H), 7.38-7.34 (m, 4H), 7.01 (s, 1H), 3.44 (s, 2H), 3.18-3.14 (m, 2H), 2.93 (t, J=7.3 Hz, 2H), 2.59 (d, J=4.6 Hz, 3H), 2.27-2.21 (m, 2H); ESI MS m/z 392 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]Br.CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 180 °C
Yield: 30 %

Procedure:
To a mixture of 2-methylindole (3.28 g, 25 mmol), 4-benzyloxy iodobenzene (7.76 g, 25 mmol), potassium carbonate (2.65 g, 25 mmol), and N-methylpyrrolidinone (250 mL) was added copper (I) bromide (0.5 g, 3.5 mmol). The stirred solution was heated to 180° C. and maintained for 18 hr. The reaction mixture was cooled, poured onto ice and extracted with ethyl acetate. After washing the organic layer with water and brine, and drying over anhydrous MgSO4 the solvent was removed to yield a dark liquid. Purification by silica gel chromatography (2% ethyl acetate-hexanes) provided the title compound as a white solid (30%): mp 95-96° C.; 1H NMR (DMSO-d6): δ 2.24 (3H, s), 5.19 (2H, s), 6.38 (1H, s), 6.93-7.04 (3H, m), 7.20 (2H, d, J=11.9 Hz), 7.23 (2H, d, J=3.1Hz), 7.32-7.53 (8H, m); MS m/z (M+H)+ 314: Anal. for C22H19NO 0.1H2O: Calc'd: C, 83.83; H, 6.14; N, 4.44. Found: C, 83.84; H, 6.18; N, 4.29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.[NH2:16][CH2:17][CH:18](O)[CH3:19]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: CC(O)CN
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Solvent: C1CCOC1
Product: Cc1c[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 150 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
A mixture of 5-(2-chlorophenyl)cyclohexane-1,3-dione (2.0 g), 3-aminopropan-2-ol (0.88 g), molecular sieves 4A (12 g) and tetrahydrofuran (30 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (40 ml). To the solution were added 2-bromomesitylene(1.8 g), tetrakistriphenylphosphine palladium (0.26 g) and potassium carbonate (2.5 g), and the mixture was stirred at 150° C. for 5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindol-4-one (1.3 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:36]([CH:38]1[O:40][CH2:39]1)Br>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:36][CH:38]5[CH2:39][O:40]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]([CH3:28])=[C:10]([CH3:29])[N:9]=2)[S:5][C:6]=1[CH3:7]
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
4-[2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinolin-7-ol (compound 455) (41 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (42 mg) and epibromohydrin (0.03 ml) were added to the supension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (44 mg, yield 94%).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[NH:11](CCO)[CH2:12][CH2:13][OH:14]>C(O)CCC>[OH:14][CH2:13][CH2:12][N:11]1[CH2:10][CH2:9][O:8][C:1](=[O:7])[C:2]1=[O:4]
Reactant: OCCNCCO
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCCCO
Product: O=C1OCCN(CCO)C1=O
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
A 4(2-hydroxyethyl)morpholine-2,3-dione was prepared by charging 125 g diethyl oxalate and 80 g n-butanol into a suitable reaction vessel and heated to 22° C. under nitrogen blanket. A mixture of 89.9 g diethanolamine and 72 g n-butanol was slowly charged into the reaction vessel while maintaining the reaction mixture below 50° C. After stirring for 30 minutes, the reaction mixture was refluxed for one hour and then allowed to stand at room temperature for 16 hours. The product was collected by filtration and the solid was washed twice with diethyl ether and dried under nitrogen to give 100 g (73.4% yield) of white crystals with 83.3° C.-84.4° C. melting point. IR (Nujol mull) 1759 (ester carbonyl), 1684 (amide carbonyl) cm−1. 1H NMR (500 MHz, acetone-d6) δ 4.592 (approx. triplet, 2H, J=5.0 Hz, ring CH2O), 3.903 (approx. triplet, 2H, J=5.0 Hz, ring CH2N), 3.767 (t, 2H, J=5.5 Hz, CH2OH), 3.597 (t, 2H, J=5.5 Hz, chain CH2N). 13C NMR (500 MHz, D2O) δ158.514 (ester C═O), 155.338 (amide C═O), 67.036 (ring CH2O), 60.399 (CH2OH), 51.034 (ring CH2N), 47.600 (chain CH2N).
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:19](=[O:32])[N:18]=3)[CH2:13][CH:12]=2)=[CH:7][CH:6]=1.B(Br)(Br)Br>O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][N:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:24]5[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=5)=[CH:28][CH:29]=4)[C:19](=[O:32])[N:18]=3)[CH2:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Cn2cnc(N3CC=C(c4ccc(F)cc4)CC3)nc2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(OCc2ccc(O)cc2)cc1
Yield: 28.3 %

Procedure:
To a dichloromethane solution (8.0 mL) of 4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1-(4-methoxybenzyl)-1,3,5-triazin-2(1H)-one (200 mg, 0.510 mmol) synthesized in Reference Synthesis Example 352, boron tribromide (1.53 mL, 1.53 mmol) was added at 0° C. and the resultant mixture was stirred at room temperature for 1 day. After the completion of the reaction, to the reaction solution, water was added and extraction with chloroform from the reaction solution was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (chloroform/ethyl acetate→methanol/ethyl acetate) to obtain the title compound (35.0 mg, yield: 18%) of Synthesis Example 483a and the title compound (7.15 mg, yield: 3%) of Synthesis Example 483b.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[Si]([O:27][K])(C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([OH:27])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2c(Cl)nnc(Cl)c2-c2ccc(Cl)cc2)cc1
Reactant: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Product: Oc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a round bottom flask was added 3,6-dichloro-4,5-bis(4-chlorophenyl)pyridazine (1000 mg, 2.710 mmol), THF (20 ml) and TMSOK (869 mg, 6.775 mmol). The reaction was stirred at 80° C. for 8 hrs. After this time, the reaction mixture was concentrated. The residue was diluted with water (15 ml). The pH of the resulting solution was adjusted to 4 using 1N HCl. During addition, a solid precipitated. The solid was collected by filtration to give product 6-chloro-4,5-bis(4-chlorophenyl)pyridazin-3-ol as white solid (760 mg, 80% yield). HPLC retention time (method A) 3.535 min; LCMS (M+H)=351.1.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].Br[CH:9]([CH2:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][CH2:15][CH2:16][N:4]1[C:5](=[O:6])[CH2:7][NH:1][C:2]1=[S:3])[CH3:14]
Reactant: CCOC(=O)C(Br)CC
Reactant: O=C1CNC(=S)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1C(=O)CNC1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
As depicted in Scheme 40 below, 2-thiohydantoin (1.4 grams, 12 mmol) was dissolved in DMF (50 ml) and ethyl bromobutyrate (0.48 ml, 3.4 mmol, 0.28 molequivalents) and K2CO3 (2.07 grams, 15 mmol, 1.5 molequivalents) were added thereto. The mixture was stirred at room temperature for 2 hours and then additional ethyl bromobutyrate (0.48 ml, 3.4 mmol, 0.28 molequivalents) was added and the reaction mixture was stirred for 16 hours until all starting material was consumed, as indicated by TLC. Thereafter methylene chloride was added followed by addition of water, the organic phase was extracted, the aqueous layer was washed 5 times with methylene chloride and the combined organic phase was washed 10 times in order to remove residual DMF, dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford a black oil. The crude product was purified by liquid chromatography using silica gel 60 (230-400 mesh) and a 6:4 hexane:methylene chloride mixture, a 5.8:4:0.2 hexane:methylene chloride:ethyl acetate mixture, a 5.5:4:0.5 hexane:methylene chloride:ethyl acetate mixture, a 5:4:1 hexane:methylene chloride:ethyl acetate mixture, a 4:4:2 hexane:methylene chloride:ethyl acetate mixture and a 3:4:3 hexane:methylene chloride:ethyl acetate mixture, sequentially, as eluents. Pure 4-(5-oxo-2-thioxo-imidazolidin-1-yl)-butyric acid ethyl ester (884 mg, 32% yield) was obtained as a yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1.[CH:43]([NH2:46])([CH3:45])[CH3:44]>>[CH:43]([NH:46][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1)([CH3:45])[CH3:44]
Reactant: CC(C)N
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(Br)c2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(NC(C)C)c2)cc1

Procedure:
Analogously to Example 125a, 0.510 g of tert-butyl 3-(3-bromobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.086 ml of isopropylamine are reacted. The title compound is obtained as a yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.18.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]#[C:30][CH3:31]>CN(C)C=O.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][C:7]2([O:20][CH:3]([CH2:2][OH:1])[CH2:4][N:5]([CH2:28][C:29]#[C:30][CH3:31])[CH2:6]2)[CH2:12][CH2:11]1)=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(CO)O2
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCN1CC(CO)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 45 °C
Yield: 70.3 %

Procedure:
Tert-butyl 10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.35 g, 4.71 mmol), K2CO3 (3.26 g, 23.6 mmol) and 1-bromobut-2-yne (495 μL, 5.66 mmol) were combined in N,N-dimethylformamide (15 mL) and heated for 48 h at 45° C. under nitrogen. The reaction mixture was diluted with ethyl acetate (150 mL) and filtered. The filtrate was washed with water, 50% saturated sodium bicarbonate solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The desired fractions obtained from silica gel chromatography (5-20% methanol/dichloromethane) were combined and concentrated, then brought up in ethyl acetate, filtered and concentrated in vacuo to provide tert-butyl-8-but-2-ynyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.12 g, 3.31 mmol, 70%). ESI-MS m/z calc. 338.2. Found 339.3 (M+1)+; Retention time: 0.86 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[N:15][OH:16]
Reactant: COc1cccc2c1CCCC2=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc2c1CCCC2=NO
Yield: 79.5 %

Procedure:
17.7 g (0.1 mole) of commercial 5-methoxy-1-tetralone (from Aldrich), 18.4 g (0.26 mole) of hydroxylamine hydrochloride and 22.6 g of sodium bicarbonate (0.26 mole), in 450 ml of methanol and 80 ml of water, are refluxed for 36 hours. The solvent is then removed on a rotary evaporator, the residue is thoroughly stirred with water and the precipitate is filtered off, dried and recrystallized from toluene. 15.2 g of 5-methoxy-tetralone-1-oxime (79.6% yield), of melting point 158°-159° C., are obtained.
Reaction SMILES: [CH3:1][C:2]([NH:12][C:13](=O)[CH:14]=[CH2:15])([CH3:11])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:17]([CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)#[N:18]>>[NH2:18][CH2:17][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:15][CH2:14][CH2:13][NH:12][C:2]([CH3:11])([CH3:1])[CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:24]=1
Reactant: N#CCc1c[nH]cn1
Reactant: C=CC(=O)NC(C)(C)COc1ccccc1
Product: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1

Procedure:
The title compound was prepared in a similar manner to the Example immediately above from N-(1,1-dimethyl-2-phenoxyethyl)acrylamide and 4-cyanomethyl-imidazole.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1>[Pt](=O)=O.CO>[F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([NH2:10])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1cc(F)c(F)cc1N
Reaction time: 5 h
Yield: 81.4 %

Procedure:
Into a Parr bottle were placed 4,5-difluoro-2-nitroaniline (5.00 g, 28.72 mmol), platinum (IV) oxide (0.31 g, 1.13 mmol) and methanol (60 mL). The bottle was flushed three times with hydrogen and was finally pressurized to 45 psig with hydrogen. The bottle was shaken for 5 h, after which time it was depressurized and the contents were poured into a separatory funnel containing ethyl acetate (300 mL) and water (300 mL). The organic layer was collected and washed with saturated aqueous brine solution (100 mL), dried over magnesium sulfate and the solvents were removed under reduced pressure using a rotary evaporator to leave 3.37 g (81%) of a brown solid. MS (Ca): m/z 145 (M+1).