Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C@H:13]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=1)[CH3:14].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([C:4]([NH:12][C@H:13]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:17][CH:16]=2)[CH3:14])=[O:6])=[CH:7][C:8]([Cl:11])=[CH:9][N:10]=1
Reactant: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a stirred solution of 2,5-dichloronicotinic acid (Syn. Commun. 1989, 19, 553–9, 1.92 g, 10 mmol) and tert-butyl 4-[(1S)-1-aminoethyl]benzoate (example 44 step 3, 2.02 g, 9.1 mmol) in dichloromethane (20 mL) were successively added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.59 g, 13.5 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (2.07 g, 13.5 mmol), and triethylamine (4 mL). After being stirred overnight, the reaction was quenched by the addition of saturated sodium bicarbonate aqueous solution (100 mL). The aqueous layer was extracted with dichloromethane (50 mL×3) and the combined organic layers were washed with brine (100 mL), dried (sodium sulfate), and evaporated. The remaining residue was purified by flush column chromatography on silica gel (100 g) eluting with dichloromethane/ethyl acetate (20/1) to afford 2.51 g (70%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.41 (1H, d, J=2.6 Hz), 8.09 (1H, d, J=2.6 Hz), 7.99 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz), 6.81 (1H, d, J=7.2 Hz), 5.33 (1H, dq, J=7.2, 7.0 Hz), 1.62 (3H, d, J=7.0 Hz), 1.58 (9H, s).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2]1.[NH2:7][C@H:8]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[CH:16][C:17]([Cl:22])=[N:18][C:19]=3[CH:20]=2)[O:11][C:10]([CH3:25])([CH3:24])[C@@H:9]1[OH:26].Cl([O-])(=O)(=O)=O.[Li+].C(OCC)(=O)C>O1CCOCC1>[Cl:22][C:17]1[CH:16]=[C:15]([CH3:23])[C:14]2[CH:13]=[C:12]3[O:11][C:10]([CH3:24])([CH3:25])[C@H:9]([OH:26])[C@@H:8]([NH:7][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH3:6])[C:21]3=[CH:20][C:19]=2[N:18]=1
Reactant: CCCC1CO1
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3N
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(O)CN[C@H]1c2cc3nc(Cl)cc(C)c3cc2OC(C)(C)[C@@H]1O
Temperature: 70 °C
Reaction time: 25 h
Yield: 59 %

Procedure:
Under nitrogen stream, 1,2-epoxypentane (71 μL, 0.682 mmol) was added to a solution of (3R*,4S*)-4-amino-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (100 mg, 0.343 mmol) and lithium perchlorate (36 mg, 0.343 mmol) in dioxane (0.50 mL) at room temperature, and the resulting mixture was stirred at 70° C. for 25 hours. Upon the completion of the reaction, ethyl acetate was added thereto, the resulting reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/1) to obtain the aimed product (yield: 59%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)[OH:13]>O>[Cl:11][C:5]1[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2](=[O:13])[NH:3][N:4]=1
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(Cl)n[nH]c1=O

Procedure:
27 g of 3,6-dichloro-pyridazine-4-carboxylic acid were stirred at 50° C. for 6 h in a. 1:1 mixture of concentrated sulphuric acid and water. The pure product crystallized after cooling off the reaction mixture and was filtered.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH3:17])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C(N)CCC.[C:23]([C:27]#[CH:28])([CH3:26])([CH3:25])[CH3:24]>[Cu]I.O1CCCC1>[ClH:1].[CH3:24][C:23]([CH3:26])([CH3:25])[C:27]#[C:28]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH3:17])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CN(C/C=C/Cl)Cc1cccc2ccccc12
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Solvent: CCCCN
Solvent: C1CCOC1
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 89 %

Procedure:
To 33 ml of tetrahydrofuran were added 5.40 g (22 mmol) of (E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine, 210 mg (1.1 mmol) of copper (I) iodide and 356 mg (0.31 mmol) of tetrakis (triphenylphosphine)palladium, and further, 4.35 ml (44 mmol) of n-butylamine and 2.83 ml (23.1 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated and the residue was subjected to silica gel chromatography (n-hexane-n-hexane/ethyl acetate=9/1→4/1). The desired fractions were put together and concentrated under reduced pressure. The oily residue was dissolved in 6 ml of ethanol and 6 ml of 23% hydrogen chloride methanol solution was added thereto. The solvent and excess hydrogen chloride were distilled off. The resulting crystals were suspended in diisopropyl ether, filtered, washed with diisopropyl ether and dried to obtain 6.41 g (yield: 89%) of the above identified compound as white crystalline powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[N:3][CH:4]=1)[CH3:17]
Reactant: CCO
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(O)nc1
Yield: 80 %

Procedure:
To a 100 mL three-necked flask, 0.84 g (0.006 mol) of 6-hydroxynicotinic acid, 30 mL of anhydrous ethanol were added, 3 mL of concentrated sulfuric acid was added dropwise slowly, refluxed overnight, evaporated under vacuum to remove excessive ethanol, the residue was poured into water, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate, dried with anhydrous sodium sulfate, and concentrated to obtain 0.8 g of 6-hydroxy-nicotinic acid ethyl ester. Yield: 80%.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.C(Cl)(=O)OCC.[C@@H:49]1([N:58]2[CH:65]=[CH:64][C:62]([NH2:63])=[N:61][C:59]2=[O:60])[O:55][C@H:54]([CH2:56][OH:57])[C@@H:52]([OH:53])[C@@H:50]1[OH:51]>O1CCCC1.CN(C)C=O>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33]([NH:63][C:62]4[CH:64]=[CH:65][N:58]([C@@H:49]5[O:55][C@H:54]([CH2:56][OH:57])[C@@H:52]([OH:53])[C@@H:50]5[OH:51])[C:59](=[O:60])[N:61]=4)=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)Nc5ccn([C@@H]6O[C@H](CO)[C@@H](O)[C@@H]6O)c(=O)n5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
To a solution of N-(cholest-5-en-3β-oxycarbonyl)glycine (2.74 g) and triethylamine (0.78 ml) in tetrahydrofuran (40 ml) was added dropwise ethyl chlorocarbonate (0.61 g) at -15° C., and the reaction mixture was stirred for 20 minutes at -15° C. To the reaction mixture a solution of 1-β-D-arabinofuranosylcytosine (1.37 g) in dimethylformamide (30 ml) was added dropwise at -15° C. to -10° C. After the addition, the mixture was stirred for one hour at 5° C. and then for 30 minutes at room temperature. The reaction mixture was concentrated in vacuo. The residue was washed with methanol and dried to afford a crude reaction product, which was purified by silica gel column chromatography to yield N4 -[N-(cholest-5-en-3β-oxycarbonyl)glycyl]-1-β-D- arabinofuranosylcytosine (1.8 g) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(OCC)=O)[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][O:10][C:9]([CH3:12])([CH3:13])[O:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1COC(C)(C)OC1
Yield: 53 %

Procedure:
To the solution of 2,2-dimethyl-[1,3]dioxane-5,5-dicarboxylic acid diethyl ester (19.75 g, 75.96 mmol) in dimethyl sulfoxide (80 ml) was added sodium chloride (4.4 g, 75.76 mmol) and water (2 ml). The reaction was refluxed for 7 h. After such time, it was poured into saturated sodium chloride solution (500 ml) and extracted with ether (4×200 ml). The combined organics were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residual oil was distilled under reduced pressure. Three fractions collected between 100° C. and 120° C. were combined to afford 2,2-dimethyl-[1,3]dioxane-5-carboxylic acid ethyl ester (7.58 g, 53%) as a clear oil (J. Org. Chem. 1986, 51, 2637) 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.1 Hz, 3H, CH3), 1.41 (s, 3H, CH3), 1.44 (s, 3H, CH3), 2.74-2.85 (m, 1H, CH), 3.96-4.30 (m, 6H, 3×OCH2).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[O:23][C:22]([C:24]([NH:26][C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)=[O:25])=[N:21][N:20]=1.C(N(CC)CC)C>CN(C=O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[O:23][C:22]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:35][CH2:34]3)=[N:29][CH:28]=2)=[O:25])=[N:21][N:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCN(C(=O)Oc3ccccc3)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Reaction time: 2 h
Yield: 30.6 %

Procedure:
Phenyl chloroformate (0.036 mL, 0.29 mmol) was added to a mixture of 5-[(2-fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41, 100 mg, 0.26 mmol) and triethylamine (0.07 mL, 0.52 mmol) in DMF (1.5 mL). The mixture was stirred for 2 h then directly purified by reverse phase HPLC eluting with a gradient of acetonitrile/water containing 0.2% TFA to give the title compound (40 mg, 31%) as a solid; 1H NMR δ 10.95 (1H, s), 10.73 (1H, s), 8.50 (1H, s), 8.05-7.95 (2H, m), 7.45-7.10 (8H, m), 6.90 (1H, d), 3.80-3.60 (8H, m); MS m/e MH+ 504.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][C:5](=[O:7])[CH2:4][CH:3]1[C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.Br.Br.[NH2:39][C@H:40]([C:47]([N:49]1[CH2:56][CH2:55][CH2:54][C@H:50]1[C:51]([NH2:53])=[O:52])=[O:48])[CH2:41][C:42]1[N:46]=[CH:45][NH:44][CH:43]=1>CN(C=O)C.C(N(CC)CC)C>[CH3:11][C:2]1([CH3:1])[CH2:6][C:5](=[O:7])[CH2:4][CH:3]1[C:8]([NH:39][C@H:40]([C:47]([N:49]1[CH2:56][CH2:55][CH2:54][C@H:50]1[C:51]([NH2:53])=[O:52])=[O:48])[CH2:41][C:42]1[N:46]=[CH:45][NH:44][CH:43]=1)=[O:10]
Reactant: CC1(C)CC(=O)CC1C(=O)O
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)CC1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Yield: 56.1 %

Procedure:
In DMF (2 ml) was dissolved 2,2 dimethyl-4-oxocyclopentanecarboxylic acid [W. H. Perkin, jun., J. F. Thorpe, J. Chem. Soc., 79, 729 (1901)] (100 mg), and HOBT (108 mg) was added to the solution, followed by addition of DCC (145 mg) under cooling at 0° C. The mixture was stirred at 5° C. over night. After addition of L-histidyl-L-prolinamide dihydrobromide (265 mg) followed by addition of triethylamine (0.134 ml), the mixture was stirred at 5° C. for 4 days. After the resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure to dryness and the residue was subjected to silica gel column chromatography. The fractions eluted by chloroform:methanol:ammonia water (90:10:2) were combined and concentrated to dryness to give the title compound (140 mg) was obtained as powders.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[CH3:71][NH:72][C@@H:73]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:74]>CN(C=O)C>[CH3:71][N:72]([C@@H:73]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:74])[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:25]([F:28])([F:27])[F:26])=[N:5]3)[CH2:15][CH2:14]2)[CH:17]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Reactant: CN[C@H](C)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(C(=O)N(C)[C@H](C)c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a solution of 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid (320 mg, 0.80 mmol) in DMF (8 mL) was added diisopropylethylamine (1.01 mL, 4.85 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (0.41 g, 0.89 mmol) at RT. After stirring for 15 min. at RT, Methyl-((R)-1-phenyl-ethyl)-amine (0.132 g, 0.80 mmol) was added to the reaction mixture. After stirring for 2 h at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (20 mL), washed with aq. sat. sodium bicarbonate solution (30 mL) and the aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with 1M HCl solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2) to give N-methyl-3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-N—((R)-1-phenyl-ethyl)-benzamide (170 mg, 41%). 1H-NMR (400 MHz, d6-DMSO): δ=1.55 (d, 3H), 1.62-1.71 (m, 1H), 1.82-1.89 (m, 2H), 1.99 (s, 3H), 2.22 (s, 3H), 2.54-2.73 (m, 3H), 2.81-2.90 (m, 1H), 3.12-3.21 (m, 1H), 3.99-4.04 (m, 1H), 4.46-4.52 (m, 1H), 5.19-5.38 (m, 2H), 6.50 (s, 1H), 7.12-7.41 (m, 9H). MS: m/z=513 (M+1)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C>[CH:23]1([CH2:22][N:8]([C:6]2[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH3:1])[N:7]=2)[C:9](=[O:11])[CH3:10])[CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCC1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CC1CCC1)c1ccc([N+](=O)[O-])c(C)n1
Temperature: 80 °C

Procedure:
N-(6-Methyl-5-nitro-pyridin-2-yl)-acetamide (0.5 g) was taken in 5 mL anhydrous DMF. 3 eq of K2CO3 and 3 eq of bromomethyl-cyclobutane were added and heated at 80° C. for 24 h. Water was added to the reaction and the mixture extracted with EtOAc (2×10 mL). The organic layer was washed with water and brine and dried over Na2SO4. Solvent was concentrated and the residue was purified over silica to give N-Cyclobutylmethyl-N-(6-methyl-5-nitro-pyridin-2-yl)-acetamide LCMS (m/z): 264.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:42]3[CH2:43][CH2:44][N:39]([C:36](=[O:38])[CH3:37])[CH2:40][CH2:41]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1
Product: Cl

Procedure:
1-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1-acetyl-piperazine in an analogous manner as described in example 25. LR-MS: 621.4 [(M+H)+]
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH:15]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:17])[CH3:16]>ClCCl>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:18]([CH:15]([CH3:17])[CH3:16])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[CH3:24]
Reactant: CCOC(=O)CNC(C)C
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CCOC(=O)CN(c1ncc(C(=O)OC)cc1[N+](=O)[O-])C(C)C
Temperature: 25 °C
Yield: 79.6 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2 g, 9.23 mmol) was added to ethyl 2-(isopropylamino)acetate (5.0 g, 34.5 mmol) neat while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one h and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified via column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield the title compound (2.39 g, 83%) as a yellow oil. [M+H] calc'd for C, 14; H, 19; N, 3; O, 6, 326; found, 326.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][N:4]=1.CC(OC(C)=O)=O.C1C(=O)N([Br:25])C(=O)C1.O>CC(O)=O>[Br:25][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[N:6][C:7]=1[O:9][CH3:10]
Reactant: COc1cc(OC)ncn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ncnc(OC)c1Br
Temperature: 100 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
To the solution of 4,6-dimethoxypyrimidine (5 g, 35.7 mmol) in HOAc (20 mL) at room temperature under argon was added Ac2O (4.6 g, 44.6 mmol). The resulting solution was heated at 100° C. for 10 min and then NBS (7.9 g, 44.6 mmol) was added. Heating was continued at 100° C. for 5 h. Analysis by HPLC/MS indicated that the reaction was complete. After the reaction mixture was cooled to room temperature, water (50 mL) was added. The resulting precipitate was collected by filtration and further washed with water (15 mL×3), then dried under vacuum. The title compound (7.5 g) was obtained as a white solid. 1H NMR (CDCl3): δ 4.05 (s, 6H), 8.32 (s, 1H). 13C NMR (CDCl3): δ 55.2, 89.0, 154.9, 166.8.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C:22]1(OC)[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3].C(Cl)Cl.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>CC#N>[CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C@H:22]1[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3]
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1C1(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 4 h

Procedure:
To a cooled solution (−15° C.) of (3R,4S,5S,6R)-2-(2-(allyloxymethyl)-4-chloro-5-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol in 1:1 CH2Cl2:CH3CN was added triethylsilane followed by addition of BF3.Et2O at a rate such that the temperature was maintained between −15° C. and −10° C. under argon. The reaction mixture was stirred for 4 h prior to being quenched by satd NaHCO3. It was evaporated and the residue was partitioned between EtOAc and water. The organic layer was separated, washed 2× with brine and dried over Na2SO4. Concentration gave a residue, which was purified by preparative TLC (EtOAc:MeOH=20:1, Rf=0.6) to yield 58 mg of title compound as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.46 (s, 1H), 7.35 (s, 1H), 7.04 (s, 4H), 5.92-5.86 (m, 1H), 5.25 (dd, J=17.2 Hz, 1.6 Hz, 1H), 5.09 (dd, J=10.4 Hz, 1.6 Hz, 1H), 4.68 (m, 3H), 4.48 (d, J=9.2 Hz, 1H), 4.05-3.86 (m, 4H), 3.83 (dd, J=12.4 Hz, 2.4 Hz, 1H), 3.71-3.62 (m, 2H), 3.50-3.46 (m, 1H), 3.26-3.22 (m, 1H), 2.78-2.74 (m, 1H), 1.13 (d, J=7.2 Hz, 6H); LC-MS (m/z) 463 [(M+1)+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([CH3:23])=[O:22]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:9]([OH:10])[CH2:20][C:21](=[O:22])[CH3:23])[CH:11]=[CH:12][CH:13]=2)=[CH:2]1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(-c2ccsc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)CC(O)c1cccc(-c2ccsc2)c1
Reaction time: 8 h

Procedure:
300 mg of 3-(3-thienyl)benzaldehyde was dissolved in 3 ml of acetone, and 441 mg of potassium carbonate was added. The mixture was sirred overnight at room temperature, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by medium-pressure liquid chromatography [hexane/ethyl acetate =3/1] to give 1-[3-(3-thienyl)-phenyl]-3-oxo-1-butanol as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([S:5]([N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])([CH3:4])[CH3:3].F[C:20](F)(F)[C:21]1C=CC(C=O)=C[CH:22]=1.C([Mg]Br)C=C>C(Cl)Cl>[CH3:4][C:2]([S:5]([NH:7][CH:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)[CH2:22][CH:21]=[CH2:20])=[O:6])([CH3:1])[CH3:3]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)S(=O)N=Cc1ccc(C(F)(F)F)cc1
Agent: C=CC[Mg]Br
Solvent: ClCCl
Product: C=CCC(NS(=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-N-{[4-(trifluoromethyl)phenyl]methylene}propane-2-sulfinamide (prepared according to the procedure described in Example 99 step 1, using 4-(trifluoromethyl)benzaldehyde) (5 g, 0.18 mol) was dissolved in CH2Cl2 and the solution cooled to −50° C. Allylmagnesium bromide (10.8 mL, 2M in THF, 0.22 mol) was added dropwise and the resulting solution was stirred at 0° C. for 30 min. The mixture was quenched with NH4Cl and diluted with water and was extracted with CH2Cl2. The organic layer was separated and was washed with brine, then dried (MgSO4) and concentrated in vacuo to give the product as a 3:2 mixture of diastereoisomers.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([I:12])=[CH:8][N:7]3[CH:13]=2)[CH2:3][CH2:2]1.[C:14]([O-])(=[O:16])C.[Na+].C=O>CC(O)=O>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([I:12])=[CH:8][N:7]3[C:13]=2[CH2:14][OH:16])[CH2:3][CH2:2]1
Reactant: CC(=O)[O-]
Reactant: Ic1ccc2nc(C3CC3)cn2c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1c(C2CC2)nc2ccc(I)cn12
Temperature: 50 °C

Procedure:
To a solution of 2-cyclopropyl-6-iodoimidazo[1,2-a]pyridine (1.5 g) in AcOH (20 ml) were added sodium acetate (2.39 g) and 40% aqueous formaldehyde solution (4 ml), and the mixture was heated at 50° C. for 6 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo.