Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:4][C:3]=1[CH3:18].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH:35]([C@@H:38]1[CH2:42][O:41][C:40](=[O:43])[NH:39]1)([CH3:37])[CH3:36]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:39]2[C@H:38]([CH:35]([CH3:37])[CH3:36])[CH2:42][O:41][C:40]2=[O:43])=[O:17])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(CCCCCCCC(=O)O)ccc1F
Reactant: CC(C)[C@@H]1COC(=O)N1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(CCCCCCCC(=O)N2C(=O)OC[C@H]2C(C)C)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a cooled (−10° C.) solution of 8-(4-fluoro-3-methylphenyl)octanoic acid (0.486 g, 1.926 mmol) in 15 mL of THF, were added stepwise triethylamine (0.69 mL, 4.952 mmol) and pivaloyl chloride (0.23 mL, 1.889 mmol). The reaction mixture was stirred at −10° C. for 1 h and then LiCl (0.080 g, 1.889 mmol) and (R)-4-iso-propyloxazolidin-2-one (0.237 g, 1.834 mmol) were added stepwise. After being warmed slowly to room temperature and stirred for overnight, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with saturated NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.547 g, 82% yield). GC-MS: tR=6.9 min; m/z 363 (M+).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:6]2.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:45]I>C1COCC1>[I:45][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:6]2
Reactant: II
Reactant: O=[N+]([O-])c1cc(CO)cc2cc(-c3ccccc3)[nH]c12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CI)cc2cc(-c3ccccc3)[nH]c12
Reaction time: 2 h

Procedure:
5-Hydroxymethyl-2-phenyl-7-nitro-1H-indole (804 mg, 3 mmol) prepared in Step A of Example 29 was dissolved in THF (10 mL), and imidazole (408 mg, 6 mmol) and triphenylphosphine (1.52 g, 6 mmol) were added thereto. Iodine (453 mg, 3.9 mmol) was added to the mixture, which was then stirred for 2 h. After completion of the reaction, the reaction mixture was filtered through a cellite, and the product was used in the next reaction without further purification.
Reaction SMILES: [CH:1]12[CH:6]([N:7]3[C:11](=[O:12])[C:10]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)([CH2:13][C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[NH:9][C:8]3=[CH:26][C:27]([C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=3)=[O:28])[CH:5]1[CH2:4][NH:3][CH2:2]2.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:37]1([S:43]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[N:7]3[C:11](=[O:12])[C:10]([CH2:19][C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)([CH2:13][C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[NH:9][C:8]3=[CH:26][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=3)=[O:28])[CH2:2]2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccsc3)C(=O)N2C2C3CNCC32)cc1
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccsc3)C(=O)N2C2C3CN(S(=O)(=O)c4ccccc4)CC32)cc1

Procedure:
According to the procedure of Example 13, the title compound of 37A (60 mg, 0.12 mmol) and benzenesulfonyl chloride (0.023 ml, 0.18 mmol) were reacted to generate the title compound as a white solid (58 mg, 0.091 mmol, 76% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[C:20]2[C:15](=[C:16]([C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=2)[O:14][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:12]1.Cl.[N:35]1([CH2:40][C:41]2[N:46]=[C:45]([NH2:47])[CH:44]=[CH:43][CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1.O>CC#N>[O:10]=[C:11]1[C:20]2[C:15](=[C:16]([C:21]([NH:47][C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([CH2:40][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[N:46]=3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[O:14][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:12]1
Reactant: Nc1cccc(CN2CCCC2)n1
Reactant: O=C(Cl)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: O=C(Nc1cccc(CN2CCCC2)n1)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Temperature: 60 °C
Yield: 39.7 %

Procedure:
DIPEA (125 mL, 0.705 mmol) was added to a solution of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromene-8-carbonyl chloride 37 (83 mg, 0.235 mmol) and 6-(pyrrolidin-1-ylmethyl)pyridin-2-amine hydrochloride 49 (75 mg, 0.353 mmol) in CH3CN (15 mL). The reaction mixture was heated at 60° C. for 12 h, cooled to room temperature and poured into H2O. The mixture was extracted with CH2Cl2. The combined organics were dried (MgSO4) and concentrated. The crude residue was purified by MPLC eluting with CH2Cl2/MeOH (0-10%) to give Compound 243 (46 mg, 40% yield). MS (ESI) calcd for C27H22F3N3O3: 493.16. found: 494 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:6](=[O:18])[CH2:5]2.[H-].[Na+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[C:6](=[O:18])[CH:5]2[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1
Reactant: CCOC(OCC)N1C(=O)Cc2cc(Br)ccc21
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2cc(Br)ccc21
Reaction time: 2 h
Yield: 73.2 %

Procedure:
5-Bromo-1-diethoxymethyloxindole (942 mg, 3 mmol) and sodium hydride (138 mg, 5.8 mmol, pre-washed with petroleum ether) were added successively to a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (269 mg, 1 mmol), (prepared as described for the starting material in Example 2), in THF (25 ml) at ambient temperature. After stirning for 2 hours at ambient temperature, the volatiles were removed by evaporation and the residue dissolved in methylene chloride. The solution was washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and the solvent evaporated. The residue was purified by column flash chromatography using an increasingly polar mixture of methylene chloride and ethyl acetate followed by a 7/3 mixture of methylene chloride/acetonitrile as eluent. The purified product was triturated with ether, collected by filtration, washed with a 1/1 mixture of ether/petroleum ether and dried under vacuum to give 4-(5-bromo-1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (400 mg, 73%) as a yellow-orange solid.
Reaction SMILES: I[C:2]1[C:3]([NH:14][C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:23][C:24]1[N:29]=[C:28]([S:30][CH3:31])[N:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=1.[F-].[Cs+].O1CCOCC1>O.[Cu]I.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>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([NH:14][C:3]2[C:2]([C:26]3[N:25]=[C:24]([CH3:23])[N:29]=[C:28]([S:30][CH3:31])[N:27]=3)=[CH:7][N:6]=[C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:4]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Nc2nc(N3CCOCC3)ncc2I)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)nc(SC)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(N3CCOCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 140 °C
Yield: 35.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-iodo-N-(6-methoxypyridin-3-yl)-2-morpholinopyrimidin-4-amine (118 mg, 0.286 mmol), 2-methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazine (123 mg, 0.286 mmol), copper(I) iodide (11 mg, 0.057 mmol), cesium fluoride (87 mg, 0.571 mmol), tetrakis(triphenylphosphine)palladium(0) (33.0 mg, 0.029 mmol) and dioxane (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-2-morpholinopyrimidin-4-amine (43 mg, 0.101 mmol, 35.3% yield). 1H NMR (300 MHz, CDCl3) δ 11.63 (s, 1H); 9.41 (s, 1H); 8.38 (d, J=1.90 Hz, 1H); 7.90 (dd, J=8.77, 2.34 Hz, 1H); 6.78 (d, J=8.77 Hz, 1H); 3.96 (s, 3H); 3.88 (s, 4H); 3.65-3.81 (m, 4H); 2.60 (s, 3H); 2.58 (s, 3H). m/z (ESI, +ve ion) 427.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:19].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:20]([NH:27][CH2:17][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][C:3](=[O:19])[N:2]([CH3:1])[C:6]=3[CH:7]=2)[CH:16]=[N:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(=O)oc2ccc(-c3cncc(C=O)c3)cc21
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1c(=O)oc2ccc(-c3cncc(CNCc4ccccc4)c3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-pyridine-3-carbaldehyde (100 mg, 0.39 mmol), Benzylamine (46.4 mg, 0.43 mmol), acetic acid (50 uL) and sodium triacetoxyborohydride (25 0 mg, 1.18 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 2 h. The mixture was quenched with NaHCO3 (saturated solution) and extracted with CH2Cl2 (20 mL×3). The combined extracts were washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the residue was obtained as yellow solid. ESI-MS m/z: 346.1 [M+1]+, Retention time 1.11 min.
Reaction SMILES: C(O[N:4]=[C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:13]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]=1[NH2:12])[NH2:6])C.CO.[C:24](=S)=[S:25]>>[CH:9]1[N:10]([C@@H:13]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]2[C:7](=[C:5]([NH2:6])[NH:4][C:24]([N:12]=2)=[S:25])[N:8]=1
Reactant: S=C=S
Reactant: CCON=C(N)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
0.45 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide O-ethyl-oxime was dissolved in 8 ml of an aqueous solution containing 7 ml of methanol, and 2 ml of carbon disulfide was added to the solution. The resulting mixture was allowed to react in an autoclave at 120° C for 6 hours under autogenous pressure (about 10 Kg/cm2). The reaction mixture was concentrated to dryness, and the residue was dissolved in water. The aqueous solution was adjusted to a pH of 2 with hydrochloric acid, and the crystals thus precipitated were filtered to obtain 2-thioadenosine, which was then dissolved in aqueous ammonia, filtered and again adjusted to a pH of 2 with hydrochloric acid to obtain 0.355 g of pure 2-thioadenosine having a melting point of 199° C (with decomposition) in a 75% yield.
Reaction SMILES: C(O[C:6]([CH2:8][O:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([C:19]2[C:20](=[O:30])[N:21]([CH3:29])[C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:24]=2)=[CH:12][CH:11]=1)=[O:7])CCC.[H][H].C(O)(=O)C.O>C(OCC)(=O)C.[Pd]>[O:7]=[C:6]1[NH:16][C:15]2[CH:14]=[C:13]([C:19]3[C:20](=[O:30])[N:21]([CH3:29])[C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][N:24]=3)[CH:12]=[CH:11][C:10]=2[O:9][CH2:8]1
Reactant: CCCCOC(=O)COc1ccc(-c2ncc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cnc(-c2ccc3c(c2)NC(=O)CO3)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
Then, 0.24 g of 10% palladium/carbon was added to a solution of 1.25 g of 3-[4-(butoxycarbonylmethoxy)-5-nitrophenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine in 36 ml of ethyl acetate under an atmosphere of nitrogen, which was then replaced with hydrogen under a pressure of 1 atm., and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite and concentrated. To the crude product obtained was added 2.0 ml of acetic acid, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, water, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.45 g (yield, 48%) of 3-(3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-1; m.p., 191.1° C.).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][C:18](=[CH:21][C:22]#[N:23])[CH2:17][CH2:16]1.Cl.C(=O)(O)[O-].[Na+]>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:16][CH2:17][C:18](=[CH:21][C:22]#[N:23])[CH2:19][CH2:20]1
Reactant: COCOc1ccc(C2CCC(=CC#N)CC2)c(OCOC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N#CC=C1CCC(c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a round bottomed flask was added (±)-{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetonitrile (141 mg) and methanol (5 ml). The reaction mixture was stirred, the solution was heated under reflux temperature and aqueous hydrochloric acid (5 ml, 1.0M) was added slowly. Heating was continued for 1 hr and the reaction mixture was allowed to cool to room temperature prior to the addition of saturated aqueous sodium bicarbonate solution (12 ml). The reaction mixture was partitioned between ethyl acetate (30 ml) and water (10 ml). The aqueous layer was extracted with ethyl acetate (3×15 ml) and the combined organic layers washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:1, v/v) to afford the title compound (90 mg, 88%) as a white solid. m/z (ES−) 228 (M−H+); δH (CD3OD) 1.56-1.68 (2H, m), 2.02-2.14 (2H, m), 2.33-2.48 (2H, m), 2.57 (1H, m), 3.01 (1H, m), 3.14 (1H, m), 5.31 (1H, s), 6.27 (1H, dd), 6.32 (1H, d), 6.80 (1H, d).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)C>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][N:30]=[N+:31]=[N-:32])[CH2:22][CH2:21]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: [N-]=[N+]=NC[C@H]1CCc2cccc(-c3ccccc3Cl)c2O1
Yield: 83.4 %

Procedure:
A solution of [(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.24 g, 0.56 mmol) and sodium azide (0.15 g, 2.24 mmol) in anhydrous dimethyl sulfoxide (10 mL) was heated to 70° C. under nitrogen for 15 hours. The cooled reaction mixture was then diluted with diethyl ether (50 mL), washed with water (5×25 mL) and saturated brine (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 0.14 g (82%) of {[(2R)-8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}azide as a colorless oil that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])C(O)=C([CH:9]=1)C=O.Br[CH:15]([C:21]([O:23][CH2:24][CH3:25])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:24]2[O:23][CH:21]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:25]=2[CH:9]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1cc(Br)cc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1coc2c([N+](=O)[O-])cc(Br)cc12

Procedure:
A mixture of 5-bromo-2-hydroxy-3-nitrobenzaldehyde (8.9 g, 36.2 mmol), diethyl bromomalonate (6.3 mL, 37.3 mmol) and potassium carbonate (4.6 g) in butanone (50 mL) was heated a reflux for 4 h. The mixture was cooled, filtered and evaporated to give the crude product which was recrystallized from ethanol. Yield: 6.6 g (58%) of a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (t, J=7.0 Hz, 3H) 4.35 (q, J=7.1 Hz, 2H) 7.83 (s, 1H) 8.39 (d, J=2.0 Hz, 1H) 8.43 (d, J=2.0 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]([CH2:26][CH2:27][CH3:28])[C:14](=[O:25])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:16]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>C(OCC)(=O)C.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]([CH2:26][CH2:27][CH3:28])[C:14](=[O:25])[N:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[N:16]=2)=[CH:5][CH:4]=1
Reactant: CCCn1c(CCCc2ccc(OC)cc2)nn(Cc2ccc(C)cc2)c1=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCn1c(CCCc2ccc(O)cc2)nn(Cc2ccc(C)cc2)c1=O
Temperature: 180 °C
Yield: 90.1 %

Procedure:
5-[3-(4-Methoxyphenyl)-propyl]-2-(4-methylbenzyl)-4-propyl-2,4-dihydro-[1,2,4]triazol-3-one (0.770 g, 2.03 mmol) and excess pyridine hydrochloride were melted together for 2 hours with stirring at 180° C. After cooling to room temperature, the contents were diluted in ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organics were washed with 5 N HCl (50 mL), saturated aq. NaCl (25 mL), dried (MgSO4), filtered and concentrated to afford the title compound as a yellow oil (0.670 g, 1.83 mmol, 90%): 1H NMR (DMSO-d6) δ 9.13 (s, 1 H), 7.10 (q, 4H, J=3.0 Hz), 6.79 (AB, 4H, J=8.5 Hz), 4.77 (s, 2H), 2.5 (t, 2H, J=7.5 Hz), 2.46 (t, 2H, J=7.5 Hz), 2.24 (s, 3H), 1.79 (m, 2H), 1.51 (m, 2H), 0.79 (t, 3H, J=7.5 Hz); 13C NMR (DMSO-d6) δ 156.1, 154.1, 146.8, 137.2, 135.1, 132.1, 129.9, 129.7, 128.1, 115.7, 48.3, 42.8, 34.1, 28.2, 24.7, 22.5, 21.3, 11.5; IR (CHCl3) 3007, 2937, 1690, 1515, 1463 cm−1. Exact Mass Calcd. for C22H28N3O2: 366.2182. Found: 366.2191.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[C:17]([NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH2:17][NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CNC(Cc2ccc(OCc3ccccc3)cc2)C(=O)NCCN2CCCCC2)cc1
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNC(CNCCN2CCCCC2)Cc2ccc(OCc3ccccc3)cc2)cc1
Yield: 20.2 %

Procedure:
A solution of 700 mg (1.36 mmol) 3-(4-benzyloxy-phenyl)-2-(4-tert-butyl-benzylamino)-N-(2-piperidin-1-yl-ethyl)-propionamide (Example 13) in 28 mL dry THF was treated portionwise with 258 mg (6.80 mmol) lithium tetrahydriodoaluminate, and the resulting suspension was heated under reflux for 24 hours. The mixture was then carefully quenched with 0.35 mL H2O and filtered, and the resulting solids were washed with THF. The filtrate was diluted with 30 mL H2O, and the THF removed under reduced pressure. The aqueous layer was extracted with three 40 mL portions of ethyl acetate. The combined organic extracts were washed with 100 mL each of saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulphate, and concentrated at reduced pressure to give an amber oil. The oil was purified by column chromatography on silica gel (230-400 mesh) using 20% methanol in chloroform as eluant to give 141 mg (20%) of the title compound as a viscous, pale yellow liquid.
Reaction SMILES: [CH2:1]([C:3]1[O:8]C(C)(C)[O:6][C:5](=O)[CH:4]=1)[CH3:2].[CH3:12][NH2:13].Cl>C1(C)C(C)=CC=CC=1>[CH3:12][NH:13][C:5](=[O:6])[CH2:4][C:3](=[O:8])[CH2:1][CH3:2]
Reactant: CCC1=CC(=O)OC(C)(C)O1
Reactant: CN
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCC(=O)CC(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-ethyl-2,2-dimethyl-4H-1,3-dioxin-4-one (10.0 g, 64.0 mmol) in 20 ml of xylene was bubbled with methylamine gas at 110° C. for 3 hrs. After cooling to room temperature, 5.3 ml of 1N HCl aqueous solution was added and the mixture was stirred at r.t. for 2 hrs. The organic layer was separated, the water layer was extracted by Et2O (3×30 ml). The organic layers were combined and dried (Na2SO4). After evaporation of solvent, N-methyl propionylacetamide was obtained as a colorless oil (4.25 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.CCOCC.CCCCCC>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:12](=[O:14])[CH2:11][CH2:10][S:9]2)=[CH:7][CH:8]=1
Reactant: COc1cccc(SCCC(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc2c(c1)SCCC2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
The acid from Step 1 (2.55 g, 12 mmol) was dissolved in trifluoroacetic acid (10 mL), treated with trifluoroacetic anhydride (5 mL) and stirred at room temperature (10 minutes). The reaction was poured into 10% Na2 CO3 (60 mL), extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give a red oil which was passed through a column of silica gel with 50% ether/hexane to give 7-methoxythiochroman-4-one as an orange solid (1.18 g, 51%): mp 49°-51° C.; 1H NMR (CDCl3) 300 MHz 8.06 (d, J=8.9 Hz, 1H) 6.72 (m, 2H) 3.83 (s, 3H) 3.20 (m, 2H) 2.95 (m, 2H). Mass spectrum: M+H=195.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].[NH:19]([C:26]1[O:27][C:28]2[CH:34]=[C:33]([O:35][CH2:36][C:37](O)=[O:38])[CH:32]=[C:31](OC)[C:29]=2[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH:19]([C:26]1[O:27][C:28]2[CH:34]=[C:33]([O:35][CH2:36][C:37]([NH:16][C:14]3[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([O:9][CH2:8][CH:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[CH:15]=3)=[O:38])[CH:32]=[CH:31][C:29]=2[N:30]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(OCC(=O)O)cc2oc(Nc3ccccc3)nc12
Reactant: COC(=O)CC(C)COc1cc(N)ccc1OC
Product: COc1ccc(NC(=O)COc2ccc3nc(Nc4ccccc4)oc3c2)cc1OCC(C)CC(=O)O

Procedure:
Methyl 3-methyl-4-(2-methoxy-5-aminophenoxy)butyrate and 2-anilino-4-methoxy-6-carboxymethoxybenzoxazole were coupled together using the method described in example 1 g above.