Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]([O:29][N:30]=C(C)C)=[C:24]([C:26](=O)[CH3:27])[CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(O)C>[CH3:42][C@@H:37]1[CH2:36][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:25][C:24]3[C:26]([CH3:27])=[N:30][O:29][C:23]=3[C:22]=2[F:34])[CH2:40][C@H:39]([CH3:41])[O:38]1
Reactant: CC(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1ON=C(C)C
Agent: Cl
Solvent: CCO
Product: Cc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Yield: 39 %

Procedure:
To a stirred solution of 1-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-3-fluoro-2-(propan-2-ylideneaminooxy)phenyl)ethanone (Intermediate 32, 77 mg, 0.13 mmol, crude reaction product from above reaction) dissolved in ethanol (5 ml) was treated with 5 ml of 5% aqueous HCl at 75° C. for 2 hours. Reaction quenched with 10% aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer washed with water, dried, and concentrated. The residue purified over a silica gel flash column (elution with 50-70% EtOAc in hexanes) to give the title compound (15 mg, 39%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[N:32]([CH3:33])[C:31]5[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=5[N:29]=4)[CH:23]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:38]CCl>Cl.CCOCC>[ClH:38].[CH3:33][N:32]1[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]=[C:28]1[C:24]1[CH:23]=[C:22]([N:18]2[CH2:19][CH2:20][CH2:21][C@H:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:17]2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1c(-c2cccc(N3CCC[C@H](C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)C3)c2)nc2ccccc21
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: Cn1c(-c2cccc(N3CCC[C@H](C(=O)N4CCNCC4)C3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Method A—Step b To a mixture of 4-{(S)-1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.04 g, 0.08 mmol) in dichloromethane (0.5 mL), 2M HCl in Et2O (2 mL) was added and the resulting mixture was stirred overnight at room temperature. Solvent was removed to get 0.04 g of the title compound as hydrochloride salt with quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1.BrBr.[OH-].[K+].Cl.[CH3:32][C:33]([OH:35])=O>>[OH:9][C:5]1[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:33](=[O:35])[CH3:32]
Reactant: CC(=O)O
Reactant: COc1cccc(OC)c1-c1c[nH]c2ncc(-c3cccc(O)c3)cc12
Agent: BrBr
Agent: Cl
Agent: [K+]
Product: COc1ccc(C(C)=O)c(O)c1-c1c[nH]c2ncc(-c3cccc(O)c3)cc12
Temperature: 70 °C
Reaction time: 6 h
Yield: 20 %

Procedure:
To 3-[3-(2,6-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol (12 mg, 0.0346 mmol) was added 0.5 mL of 33 wt % bromine in AcOH. The mixture was stirred at 70° C. for 6 h, then it was treated with 1.2 mL 50 wt % of aqueous KOH and it was further stirred at room temperature for 3 days, then at 80° C. for 3 hours. The mixture was acidified to pH4 with 1N aqueous HCl and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of methanol/dichloromethane afforded 1-{2-hydroxy-3-[5-(3-hydroxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]-4-methoxy-phenyl}-ethanone as a white solid (2.6 mg, 20% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.65 (s, 3H), 3.85 (s, 3H), 6.72 (dd, J=2.5, 8.5 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 6.99 (t, J=2.0 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.54 (d, J=2.5 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 8.00 (d, J=9.0 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 9.49 (s, 1H), 11.9 (s, 1H), 13.0 (s, 1H). MS: m/z 375 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][CH:17]([CH3:20])[C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH3:16][CH:17]([CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:18]#[N:19]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C#N)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C#N)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.050 g, 0.26 mmol), 3-chloro-2-methylpropanenitrile (27 uL, 0.28 mmol, Aldrich, Cat. No. 150428), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) in a sealed reaction vial was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 41 mg product. It was directly used in the next step reaction without further purification.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[C:6]3[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)[CH2:13][CH2:14]1
Reactant: O=c1[nH]ccc2scc(Br)c12
Reactant: C1COCCN1
Product: O=c1[nH]ccc2scc(N3CCOCC3)c12
Yield: 42.7 %

Procedure:
3-Bromothieno[3,2-c]pyridin-4(5H)-one from Example 202.3 (411 mg, 1.786 mmol) and morpholine 81501 mg, 17.23 mmol) were stirred in a microwave for 3 h at 220° C. The mixture was poured onto water and extracted with DCM. The organic phase was concentrated and the residue was recrystallized from EA to give 180 mg (yield: 42.6%) of the title compound.
Reaction SMILES: [NH:1]1[C:5]([C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)=[CH:10][CH:9]=2)[CH3:7])=[CH:4][N:3]=[N:2]1.CC[O:26]C(C)=O>>[F:22][C:20]([F:23])([F:21])[C:18]1[N:19]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C@H:6]([C:5]3[N:1]([OH:26])[N:2]=[N:3][CH:4]=3)[CH3:7])=[CH:9][CH:10]=2)[S:16][CH:17]=1
Reactant: CCOC(C)=O
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1cnn[nH]1
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1cnnn1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of N-{4-[(1R)-1-(1H-1,2,3-triazol-5-yl)ethyl]phenyl}-4-(trifluoromethyl)-1,3-thiazol-2-amine (0.06 g, 0.18 mmol) in EtOAc (10 ml) m-CPBA (43 mg, 0.25 mmol) was added and the resulting mixture stirred at room temperature overnight. EtOAc (10 ml) was added and the organic layer was washed with water (2×10 ml) and dried over anhydrous Na2SO4 to give, after solvent evaporation, a crude which, by purification by flash chromatography (EtOAc/CH3OH 7:3) afforded the pure 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1H-1,2,3-triazol-1-ol (9) (0.025 g, 0.072 mmol) as a transparent oil (40%). [α]D=−19 (c=1; CH3OH); 1H-NMR (CD3OD): δ 9.40 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.35 (d, 2H, J=7 Hz), 7.15 (s, 1H), 7.40 (s, 1H), 3.70 (q, 1H, J=7 Hz), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:5][CH:6]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:19]2([CH3:20])[CH:14]([CH:15]([O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])=[CH2:4].C(O)(=O)C(C(C(O)=O)O)[OH:36]>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[O:1]1[C@@:3]([CH2:4][OH:36])([CH2:5][CH:6]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28])[CH2:7][CH2:8][C@H:9]([C@@H:11]2[C@:19]3([CH3:20])[CH:14]([CH:15]([O:21][Si:22]([CH3:23])([CH3:24])[CH3:25])[CH2:16][CH2:17][CH2:18]3)[CH2:13][CH2:12]2)[CH3:10])[CH2:2]1
Reactant: C=C(CO)CC(CC[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C)O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: C[C@H](CCC(C[C@@]1(CO)CO1)O[Si](C)(C)C(C)(C)C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -20 °C
Yield: 94 %

Procedure:
A 20 ml amount of dichloromethane was placed in a 200 ml eggplant-shaped flask, 1.36 ml of titanium tetraisopropoxide was added, then the solution was cooled to −20° C. and stirred. Thereafter, 1.05 g of D(−)-diethyl tartrate dissolved in 5 ml of dichloromethane and the solution stirred at −25° C. for 20 minutes was placed and then, 2.14 g of the compound (4-10), (7R)-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-octene, dissolved in 10 ml of dichloromethane, was added, then the solution was stirred for 30 minutes. Further, 4.3 ml of t-butyldiperoxide was added and the solution was stirred at the same temperature for 30 minutes. The reaction solution was poured into 20 ml of a 10% aqueous solution of tartaric acid, the solution was stirred at that temperature for 30 minutes and at room temperature for 1 hour, then separation was performed and extraction performed from the aqueous layer by dichloromethane. The organic layer was washed by a 10% aqueous solution of tartaric acid and saturated saline and was dried over anhydrous magnesium sulfate. After filtration by Celite, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 50 ml of ether, 18 ml of 1N sodium hydroxide was added, then the solution was stirred under ice cooling for 1 hour. After separation, extraction was performed from the aqueous layer by ether. The organic layer was washed with saturated saline, then was dried over anhydrous magnesium sulfate, then filtered by Celite. The filtrate was concentrated under reduced pressure to obtain 2.40 g of a crude product. This was purified by a silica gel column (IR-60, 200 g, hexane/ethyl acetate=15/1 to 4/1) to obtain the desired product (4-11), (7R, 2R)-1,2-epoxy-2-hydroxymethyl-4-(t-butyldimethylsilyloxy)-7-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-octane in an amount of 2.08 g (yield 94%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH2:25][C:26]([C:29](O)=[O:30])=[N:27][N:28]=2)[CH:19]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:29]([C:26]3[CH:25]=[C:24]([C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)[NH:28][N:27]=3)=[O:30])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)[nH]n3)n2)cc1Cl
Yield: 3.6 %

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.361 g, 1.463 mmol), 5-Pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.305 g, 1.610 mmol), DIPEA (0.382 ml, 2.195 mmol), HOBt (0.297 g, 2.195 mmol) and EDCI (0.421 g, 2.195 mmol) using the method of Example 75(b) affording 0.022 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.71 (m, 2H), 4.38 (t, 2H), 6.97 (m, 1H), 7.23 (m, 1H), 7.48 (m, 1H), 7.86 (m, 2H), 7.97 (m, 1H), 8.09 (m, 1H), 8.17 (m, 1H), 8.40-8.71 (m, 2H), 8.98 (m, 1H), 13.82 (m, 1H).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1.Cl>O>[CH2:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][OH:12])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC[C@H]1CC[C@H](CO)CC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
55 g (0.30 mol) of trans-4-butylcyclohexane carboxylic acid was dispersed in 200 c; of toluene and stirred. 250 cm3 (0.90 mol) of a 70% NaAlH2 (OC2H4OCH3)2 solution was added drop-wise to the solution at a rate to gently reflux the toluene. After the drop-wise addition was completed, the resulting mixture was stirred over a hot water bath at 90° C. for 3 hours. The solution was cooled to room temperature and, while stirring, 10 cm3 of water and 300 cm3 an aqueous 15% hydrochloric acid solution were added drop-wise while stirring. The oily layer was separated out and the aqueous layer was extracted with toluene. The two layers were combined and washed with an aqueous 15% hydrochloric acid solution and water. The toluene was distilled off the washed mixture. The oily residue was distilled in a vacuum (b.p. 100° C./2 mmHg) to yield 37 g (0.11 mol) of trans-4-butylcyclohexyl methanol.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:60][C:61]1[S:62][CH:63]=[CH:64][N:65]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[C:8]([NH:60][C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionic acid (100 mg, 0.29 mmol) in dry N,N-dimethylformamide (2 ml,) was treated with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol), N,N-diisopropylethylamine (61 μL, 0.35 mmol), and 2-aminothiazole (45 mg, 0.44 mmol). The reaction mixture was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was poured into a mixture of water and ethyl acetate (1:1), and the layers were separated. The organic layer was washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-thiazol-2-yl-propionamide (92 mg, 74%) as a white foam: mp 202-204° C.; FAB-HRMS m/e calcd for C27H26N2OS (M+H)+ 427.1844, found 427.1837.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:17][N:16]=[N:15]4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1>CO.[Pd]>[C:19]([C:18]1[N:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[CH:2][CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)[N:15]=[N:16][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cnnn1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cnnn1-c1nc2c(s1)CCOc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A suspension of 8-bromo-2-(5-tert-butyl-[1,2,3]triazol-1-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (101 mg, 0.25 mmol) and 10% Pd/C (250 mg) in MeOH (5 mL) was stirred at RT under a hydrogen atmosphere for 16 h. The reaction mixture was flushed with nitrogen, filtered through Celite, washed with ethyl acetate and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give 434 as a white solid (54 mg, 66%). LCMS (Method C): RT=13.19 min, [M+H]+=327. 1H NMR (CDCl3): 8.30 (1 H, dd, J=7.9, 1.8 Hz), 7.55 (1H, s), 7.29 (1 H, m), 7.17-7.12 (1 H, m), 7.08 (1 H, dd, J=8.0, 1.4 Hz), 4.43 (2 H, t, J=5.1 Hz), 3.39 (2 H, t, J=5.1 Hz), 1.55 (9 H, s).
Reaction SMILES: I[CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:11]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:19]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CC(C)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Mix ethyl 4-iodo-3-methylbutyrate (4.61 g, 0.18 mol), dibenzylamine (35.5 g, 0.18 mol), potassium carbonate (24.9 g, 0.18 mol) and ethanol (114 mL dried over 4A molecular sieves). Reflux for 24 hours then stir at room temperature for 48 hours. Add methylene chloride (100 mL) and filter. Evaporate the filtrate to a residue and purify by silica gel chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[Cl:11])[C:5](O)=[O:6].S(Cl)([Cl:16])=O.S(=O)=O.Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[Cl:11])[C:5]([Cl:16])=[O:6]
Reactant: COc1cc(C(=O)O)cc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=S=O
Solvent: c1ccccc1
Product: COc1cc(C(=O)Cl)cc(Cl)c1Cl

Procedure:
3,4-Dichloro-5-methoxybenzoic acid (22.1 g., 0.1 mole) is heated with thionyl chloride (15 g., 0.125 mole) in benzene (100 ml.) until evolution of sulfur dioxide and hydrogen chloride ceases. The benzene and excess thionyl chloride are evaporated and the solid residue is used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:42][O:41][C:35]1[CH:34]=[C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1cc(OC)cc(C(=O)CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3cc(OC)cc(OC)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(3,5-dimethoxyphenyl)ethanone (1 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.19 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (1.14 g, 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][NH:17][C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19]>>[CH3:16][NH:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:22][CH2:21]1)=[O:19]
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CNC(=O)C1CCNCC1
Product: CNC(=O)C1CCN(C(=O)c2cnoc2-c2ccc(C)cc2)CC1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and piperidine-4-carboxylic acid methylamide (8.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.1 mg). HRMS calcd for C18H21N3O3: 327.1583, found 327.1580.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[N+:25]([O-])([OH:27])=[O:26].[K+].[Br-]>C(O)(=O)C>[OH:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[C:11]([N+:25]([O-:27])=[O:26])[S:12][C:4]=2[CH:3]1[NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Oc2ccsc2C(NC(=O)c2ccc([N+](=O)[O-])cc2)C1O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(NC(=O)c2ccc([N+](=O)[O-])cc2)C1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(4-nitrobenzamido)-7H-thieno[3,2-b]pyran (1.5 g, 4.30 mmol) was treated with 90% nitric acid (2.5 mL, 53.5 mmol) in acetic acid (25 mL) and stirred at 15°-20° C. for 0.5 h. The resultant solution was poured into ice water 100 mL and extracted with 10% isopropanol in dichloromethane. The dichloromethane solution was washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by medium pressure chromatography using 2% methanol in dichloromethane as the eluant, to give the product, 0.489 g (29%), as a yellow solid: mp 221°-225° C. dec; IR (KBr): 3345, 1647 and 1602 cm-1 ; MS: m/z 394 (MH+); 1H NMR (DMSO-d6): δ1.26(s, 3H), 1.45(s, 3H), 3.90(dd, J=8.8 Hz and J=5.9 Hz, 1H, simplifies to d, J=8.8 Hz with D2O), 4.98(dd, J=7.6 Hz and J=8.8 Hz, 1H, simplifies to d, J=8.8 Hz with D2O), 6.01(d, J=5.9 Hz, 1H exchanges with D2O), 7.75(s, 1H), 8.14(d, J=8.8 Hz, 2H) 8.37(d, J=8.8 Hz, 2H) and 9.38(d, J=7.6 Hz, 1H, exchanges with D2O).
Reaction SMILES: [Na].[S:2](=[CH:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH3:12])[N:7]=1)(=[O:4])=[O:3].[CH3:13]I>>[CH3:13][N:10]1[CH:9]=[C:8]([CH3:12])[N:7]=[C:6]([CH:5]=[S:2](=[O:3])=[O:4])[CH2:11]1
Reactant: Cc1cncc(C=S(=O)=O)n1
Reactant: CI
Agent: [Na]
Product: CC1=CN(C)CC(C=S(=O)=O)=N1

Procedure:
4.0 g of 2-sulfonylmethyl-6-methylpyrazine sodium salt (2900) was added to a solution of 15 ml methyl iodide/30 ml methanol and the mixture refluxed for 4 days. It was then cooled and filtered. The solid was chromatographed (Biogel P-2/water) and freeze-dried to give 3.4 g of product (3000). It was recrystallized from propanol/water, m.p.>280° (dec.). UV H2O max: 288 (3.92).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:19]([CH2:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>C1COCC1.C(OCC)(=O)C>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:27]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(CC(C(=O)c1ccccc1)C(=O)c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I, 3.00 g), dibenzoyl methane (II, 2.30 g), and DBU (0.25 ml) are heated to 50° in THF (20 ml) for 15 min. The reaction mixture is cooled, diluted with ethyl acetate, filtered through magnesium sulfate and concentrated under reduced pressure. The concentrate is chromatographed eluting with ethyl acetate, ethyl acetate/acetone (1/1). The appropriate fractions are pooled and concentrated to give the title compound, MS (m/e) 524 (M+), 419, 387, 373, 268 and 224; IR (neat) 2982, 1736, 1696, 1674, 1594, 1580, 1448, 1392 and 1253 cm-1 ; NMR (CDCl3) 8.07, 7.58, 7.46, 6.18, 4.17, 2.65 and 1.29 δ.