Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CC(O)=O.[CH2:19]([CH2:23][C:24](=O)[CH3:25])[C:20]([CH3:22])=O>C1CCCCC1.C(Cl)Cl>[C:11]([C:9]1[CH:8]=[CH:7][C:5]([N:6]2[C:24]([CH3:25])=[CH:23][CH:19]=[C:20]2[CH3:22])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(=O)CCC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: Cc1ccc(C)n1-c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 48.6 %

Procedure:
To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (00.1 mL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The reaction mixture was heated at 120° C. for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH2Cl2 (10 mL) and sequentially washed with a 1N HCl solution (15 mL), a 1N NaOH solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiO2; gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) Rf 0.67; 1H NMR (CDCl3) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J=2.4 Hz, 1H); CI-MS m/z 273 ((M+H)+, 50%).
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:36][C:37]1[CH:44]=[C:41]([CH:42]=O)[C:40]([O:45][CH3:46])=[CH:39][CH:38]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:46][O:45][C:40]1[CH:39]=[CH:38][C:37]([Br:36])=[CH:44][C:41]=1[CH2:42][CH:6]=[CH:5][CH2:4][O:3][CH3:2]
Reactant: COc1ccc(Br)cc1C=O
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COCC=CCc1cc(Br)ccc1OC
Reaction time: 0.75 h

Procedure:
251.1 g of 3-methoxypropyltriphenylphosphonium bromide are added to a solution, stirred at 5°, of 110.8 g of sodium bis(trimethylsilyl)amide in 1200 ml of tetrahydrofuran. The reaction mixture is further stirred for 45 minutes at 0° and then a solution of 100 g of 5-bromo-o-anisaldehyde in 1000 ml of tetrahydrofuran is added dropwise thereto. The reaction mixture is stirred for a further 1 hour at 0°. Then, at 0° C., 1 litre of a saturated ammonium chloride solution is added dropwise. After concentration, the residue is extracted 4 times with ethyl acetate. The organic phases are washed with water and saturated sodium chloride solution and concentrated by evaporation. The residue is purified by FC (500 g of silica gel, hexane/ethyl acetate=5:1). Distillation under a high vacuum yields the title compound: Rf (hexane/ethyl acetate=4:1)=0.61.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:13]2)[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[Cl:29][C:30]1[CH:31]=[C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:33]=[CH:34][C:35]=1C(O)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C(Cl)Cl>[Cl:29][C:30]1[CH:31]=[C:32]([C:39]2[CH:40]=[CH:41][C:42]([C:6]([N:8]3[CH2:9][CH:10]4[CH:14]([CH2:13][N:12]([C:16]5[N:17]=[CH:18][CH:19]=[CH:20][N:21]=5)[CH2:11]4)[CH2:15]3)=[O:7])=[CH:43][CH:44]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ncccn3)CC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2cccc(Cl)c2)cc1)N1CC2CN(c3ncccn3)CC2C1
Temperature: 25 °C

Procedure:
A solution of 5-pyrimidin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (0.70 g, 2.4 mmol) and CH2Cl2 (20 ml) was treated with trifluoroacetic acid (TFA, 10 ml) and maintained at room temperature for 3 hours. The resulting solution was concentrated, and the residue was dissolved in CH2Cl2 (5 ml) and added to a solution of 3-chloro-biphenyl-4-yl-carboxylic acid (0.62 g, 2.6 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 1.0 g, 2.6 mmol), diisopropylethylamine (1.5 ml, 8 mmol), and CH2Cl2 (20 ml). The resulting solution was maintained at room temperature for 2 hours, diluted with EtOAc, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The solid residue was recrystallized from methyl alcohol to afford the final product as white needles: 1H NMR (CD3OD): δ 8.32 (d, J=4.8 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.67 (s, 1H), 7.63 (d, J=8.5 Hz, 2H), 7.60-7.50 (m, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.40-7.37 (m, 1H), 6.63 (t, J=4.8 Hz, 1H), 3.96 (dd, J=7.8, 12.8 Hz, 1H), 3.86 (ddd, J=3.0, 7.2, 10.6 Hz, 2H), 3.76 (dd, J=7.5, 11.6 Hz, 1H), 3.65-3.58 (m, 2H), 3.51 (dd, J=5.1, 11.3 Hz, 1H), 3.43 (dd, J=4.7, 11.7 Hz, 1H), 3.21-3.07 (m, 2H). 13C NMR (100 MHz, CD3OD): δ 171.8, 161.4, 159.1, 143.5, 142.9, 137.0, 136.0, 131.6, 129.0, 128.2, 128.1, 126.6, 110.9, 54.5, 51.9, 51.7, 51.1, 43.9, 42.0; LRMS m/z 405 (M+H)+; Anal. calcd for C23H21ClN4O: C, 68.23; H, 5.23; N, 13.84. Found: C, 68.01; H, 5.23; N, 13.60.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1.C=O.[OH-].[CH3:20][N+](C)(C)CC1C=CC=CC=1>O1CCCC1.CO>[CH2:20]=[C:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[CH:10]=[CH:11][N:12]2[C:3]([S:2][CH3:1])=[N:4][N:5]=[C:6]12
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: C=O
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C1c2ccccc2C=Cn2c(SC)nnc21

Procedure:
To 4.6 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 60 ml of tetrahydrofuran was added 2.4 g of paraformaldehyde together with 4.0 ml of a 40% solution of trimethylbenzylammonium hydroxide in methanol. After refluxing the mixture for 30 minutes, the solvent was evaporated off. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over Na2SO4. The solvent was then evaporated off and the residual crystals were collected by filtration, washed with isopropyl alcohol and dried. The above procedure provided 11-methylene-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethyl acetate yielded colorless needles melting at 121°-122° C.
Reaction SMILES: [CH2:1]([C:12]1[CH:17]=[CH:16][N+:15]([O-])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:19]([N:21](CC)CC)C>C(#N)C>[C:19]([C:16]1[CH:17]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:13]=[CH:14][N:15]=1)#[N:21]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCc1cc[n+]([O-])cc1
Solvent: CC#N
Product: CCCCCCCCCCCc1ccnc(C#N)c1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a solution of 5.00 g (20 mmol) of 4-n-undecylpyridine N-oxide and 4.04 g (40 mmol) of triethylamine dissolved in 20 ml of acetonitrile was dropwise added 7.92 g of trimethylsilylanilide while stirring at room temperature. After the dropwise addition, the mixture was refluxed for 22 hours, concentrated under a reduced pressure, then dissolved in diethyl ether and washed with saturated sodium hydrogen carbonate solution. The product was dried over anhydrous aqueous sodium sulfate and concentrated under a reduced pressure, followed by separation by silica gel column chromatography (ethyl acetate:hexane=1:9) to give the desired product of 3.95 g (solidified) (yield 76.2%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(C(C)C)CC)(C)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:25][CH2:26][C:27]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1CNC(=O)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (2.0 g, 9.3 mmol) and diisopropylethylamine (5 mL) in DCM (30 mL) was added 2-chloroacetyl chloride (1.2 g, 10.6 mmol) dropwise at 0° C. The mixture was stirred at room temperature overnight. Then the mixture was quenched with water (30 mL) and extracted with DCM (5×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was used directly for the next reaction. MS (ESI): 291, 293 (MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.O>O1CCCC1.C(OCC)(=O)C>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cncn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (4.63 g, 0.12 mol) in tetrahydrofuran (150 ml) was added 1,2,4-triazole (8.0 g, 0.12 mol) at room temperature under nitrogen. The mixture was cooled to 0° C. and 2-(trimethylsilyl)ethoxymethylchloride (20.5 ml, 0.12 mol) added dropwise. The mixture was stirred at room temperature overnight, water (100 ml) was added and the mixture diluted with ethyl acetate. The organic layer was dried ((MgSO4) and evaporated in vacuo and the residue distilled to give the title-compoud (14.6 g, 63%), bp 110° C. at 5mm Hg; 1H NMR (250 MHz, CDCl3) δ 0.01-0.03 (9H, s, 3 of CH3), 0.93 (2H, m, CH2), 3.63 (2H, m, CH2), 5.52 (2H, s, CH2), 7.99 (1H, s, Ar—H), 8.26 (1H, s Ar—H).
Reaction SMILES: [CH:1]([N:5]([CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([N:12]=O)=[C:8]([CH3:14])[CH:7]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C1C(=NNC2C=CC(/C=C/C3C=CC(NN=C4C=CC(=O)C=C4)=CC=3S([O-])(=O)=O)=C(S([O-])(=O)=O)C=2)C=CC(=O)C=1.[Na+].[Na+]>CO.Cl.[Fe]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:15][CH3:16])=[CH:7][C:8]=1[CH3:14]
Reactant: CCC(C)N(CC)c1ccc(N=O)c(C)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: CCC(C)N(CC)c1ccc(N)c(C)c1
Reaction time: 3 h

Procedure:
A suspension of iron powder (8.34 g) in methanol (60 ml) and hydrochloric acid (20 ml) was stirred at reflux for 15 mins. A solution of the product from Stage 1d (11 g) in methanol (60 ml) was added dropwise over 15 mins and refluxing continued for 3 hours. Sodium carbonate was added until no soluble iron remained and the solution was alkaline to Brilliant Yellow paper. The hot reaction mixture was filtered and the solvent removed under reduced pressure to give the product as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:32]1[C:36](=[O:37])[CH:35]=[CH:34][C:33]1=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([N:32]1[C:33](=[O:38])[CH2:34][CH:35]([S:12][C:10]2[CH:9]=[C:8]([CH3:13])[C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=2)[C:36]1=[O:37])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Reactant: CCCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN1C(=O)CC(Sc2cc(C)c(N)c(C(C)(C)C)c2)C1=O
Yield: 56.4 %

Procedure:
A stirred solution of 2.8 g (14 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline, 5.0 g (14 mmol) of N-octadecylmaleimide and 0.1 g (1 mmol) of triethylamine in 50 mL of toluene is heated at 50° C. for 18 hours. The solvent is removed in vacuo and the residue is purified by preparative HPLC (silica gel, 4:1, heptane:ethyl acetate eluent) to give 4.3 g (55%) of the title compound as a caramel-colored liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])O[C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:4].C(O)(=O)C.[CH2:24]([NH2:27])[CH:25]=[CH2:26].Cl>O.CO>[CH2:24]([N:27]1[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:25]=[CH2:26]
Reactant: C=CCN
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)oc(C)cc1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: C=CCn1c(C)cc(=O)c(C(=O)OC)c1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
10 gms of 3-methoxycarbonyl-6-methyl-2-(4'-chlorophenyl)-4-pyrone, 1.65 gms glacial acetic acid and 100 mls of methanol are mixed in 500 ml flask fitted with a magnetic stirring bar and sidearm additionl funnel. 6.15 gms of allylamine are slowly added (one hour addition time). Three hours later 20 mls of water and 8 mls of concentrate HCl are added. This reaction mixture is allowed to stand at room temperature for one hour, then is poured into 400 mls of water and extracted with methylene chloride (2×100 mls). Removal of the solvent yields 10 gms of crude methyl 1-allyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([CH3:14])=[C:9]([OH:13])[C:10]=2[CH3:12])[O:5][C:4]([CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=2)([CH3:16])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CN(C)C=O>[OH:13][C:9]1[C:10]([CH3:12])=[C:11]2[C:6](=[C:7]([CH3:15])[C:8]=1[CH3:14])[O:5][C:4]([CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=1)([CH3:16])[CH:3]=[CH:2]2
Reactant: Cc1c(C)c2c(c(C)c1O)C(O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
A mixture of 140 mg of 5-[4-(4,6-dihydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 30), 10 mg of p-toluenesulfonic acid, 10 ml of benzene and 0.5 ml of dimethylformamide was heated under reflux for 1 hour. The reaction solution was cooled, washed with a saturated aqueous solution of sodium bicarbonate and then with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound, softening at 173°-176° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[CH2:21][CH2:22][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24].[I-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:24][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:21][N:4]1[CH2:5][CH2:6][C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH:2]([CH3:1])[CH2:3]1
Reactant: CC1CNCCC1(C)c1cccc(-c2c[nH]nn2)c1
Reactant: OC(CCCl)c1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCC(O)c2ccccc2)CCC1(C)c1cccc(-c2c[nH]nn2)c1
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 50 mg, 0.20 mmol) in N,N-dimethylformamide (6 mL) was added commercially available 3-chloro-1-phenyl-1-propanol (33 mg, 0.21 mmol), sodium iodide (15 mg) and aqueous sodium hydrogencarbonate (25 mg, 0.29 mmol). The resultant mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled, poured onto saturated aqueous sodium hydrogencarbonate solution (100 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to give an off-white gum. The crude product was purified by column chromatography on a 5 g silica Waters Sep-Pak3 eluting with dichloromethane and then dichloromethane:methanol (5:95) to give the title compound as a clear oil (19 mg, 25%).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][CH2:41][N:42]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[N:42]1([CH2:41][CH2:40][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:37][CH:38]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: ClCCN1CCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCCCCC3)cc2)c1
Yield: 28.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 1-(2-chloroethyl)azepane (23 mg) according to an analogous synthetic method to Example 404 and purified by NH silica gel column chromatography (hexane-ethyl acetate system), the title compound (9 mg) was obtained.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.P(Br)(Br)[Br:25].N1C=CC=CC=1>CCOCC>[Br:25][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(Br)c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 116.7 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (1.0 g), phosphorus tribromide (0.70 g) and pyridine (0.05 g) in dry ether was stirred at 0° C. for 15 hours. The reaction mixture was quenched with water and extracted with ether. The organic extracts were dried (anhydrous magnesium sulphate), filtered and the solvent evaporated yielding 4-[bromo-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 299, 1.18 g) as a yellow oil: NMR: (CDCl3) 1.1(4H,m) 1.9(1H,m) 6.9(1H,s) 7.9(1H,m) 8.0(1H,s) 8.15(2H,m).
Reaction SMILES: CC1C=CC(C)=CC=1[C@@H](NCCC1(O)CCC2(OCC(C)(C)CO2)CC1)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:42]=1[C@@H:48]([N:50]1[CH2:55][CH2:54][C:53]2([CH2:67][CH2:66][C:58]3(OCC(C)(C)C[O:59]3)[CH2:57][CH2:56]2)[O:52][C:51]1=[O:68])[CH3:49]>>[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:42]=1[C@@H:48]([N:50]1[CH2:55][CH2:54][C:53]2([CH2:56][CH2:57][C:58](=[O:59])[CH2:66][CH2:67]2)[O:52][C:51]1=[O:68])[CH3:49]
Reactant: Cc1ccc(C)c([C@H](C)N2CCC3(CCC4(CC3)OCC(C)(C)CO4)OC2=O)c1
Agent: Cc1ccc(C)c([C@H](C)NCCC2(O)CCC3(CC2)OCC(C)(C)CO3)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: Cc1ccc(C)c([C@H](C)N2CCC3(CCC(=O)CC3)OC2=O)c1

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(2,5-dimethyl-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-1-(2,5-dimethyl-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound, too. Yield: 49% of theory; Mass spectrum (ESI+): m/z=316 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.47 (d, J=7.2 Hz, 3H), 1.79-2.00 (m, 5H), 2.05-2.13 (m, 1H), 2.15-2.25 (m, 2H) superimposed by 2.20 (s, 3H) and 2.22 (s, 3H), 2.44-2.55 (m, 2H), 2.70-2.78 (m, 1H), 3.16-3.24 (m, 1H), 5.48 (q, J=7.2 Hz, 1H), 7.02 (dm, J=7.8 Hz, 1H), 7.08 (broad s, 1H), 7.12 (d, J=7.8 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[Br:11].[F-:12].[Na+].[F-:14].[K+]>C1S(=O)(=O)CCC1>[F:12][C:2]1[CH:10]=[CH:9][C:5]([C:6]([F:14])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: [F-]
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Agent: [K+]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: O=C(F)c1ccc(F)c(Br)c1
Yield: 79 %

Procedure:
1,270 g (5 moles) of 4-chloro-3-bromo-benzoyl chloride, 1,150 g of tetramethylenesulphone and 315 g (7.5 moles) of anhydrous sodium fluoride were warmed for 5 hours to 210° C., while stirring. Thereafter, 435 g (7.5 moles) of anhydrous potassium fluoride, suspended in 1,150 g of tetramethylenesulphone, were added to the reaction mixture, and the latter was stirred for a further 7 hours at 210° C. The subsequent distillation gave 873 g (79% of theory) of 4-fluoro-3-bromobenzoyl fluoride (a starting material for Example 19).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:7]=1
Reactant: Oc1ncc(Br)cn1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1ncc(Br)cn1CCN1CCOCC1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
To a solution of 5-bromo-2-hydroxypyrimidine (1.00 g, 5.75 mmol) in DMF (19 mL) was added sodium iodide (1.29 g, 8.6 mmol), cesium carbonate (4.68 g, 14.4 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.18 g, 6.32 mmol) and the reaction mixture was stirred at 60° C. for 2.5 h. The solution was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography, eluting with gradient of methanol (5-15%) in dichloromethane to give title compound 413 (1.29 g, 78% yield). MS (m/z): 288.1 (50%) (M+H), 290.0 (50%) (M+H). 1H NMR (DMSO-d6) δ (ppm): 8.61 (d, J=3.3 Hz, 1H), 8.46 (d, J=3.3 Hz, 1H), 3.93 (t, J=5.9 Hz, 2H), 3.51 (t, J=4.5 Hz, 4H), 2.57 (t, J=6.1 Hz, 2H), 2.45-2.39 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14]>CN(C=O)C>[Cl:14][C:10]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Cc1csc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1csc2c(Cl)ncnc12
Temperature: 110 °C
Yield: 81 %

Procedure:
7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (9 g, 54.2 mmol), DMF (1 mL), POCl3 (80 mL) were mixed and refluxed for 4 hours at 110° C. The reaction solution was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was added with toluene, and further concentrated under reduced pressure. The resulting residue was neutralized with sodium bicarbonate, subjected to extraction with ethyl acetate, dried, and filtered to obtain the title compound (8.1 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[Br:11].[H-].[Na+].S(OC)(O[CH3:19])(=O)=O.Cl>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH3:19])[CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: COC(=O)c1cc(O)ccc1Br
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(OC)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Compound of example 152 (6.5 g, 28.1 mmol) was dissolved in dry 1,4-dioxane (50 mL) under dry N2 atmosphere. To this solution, NaH (50%, 3.37 g, 70.20 mmol) was added in portions at 25° C. and the mixture was stirred for 10 min. Dimethyl sulfate (4 mL, 5.31 g, 40.48 mmol) was added and the reaction mixture was stirred at 50° C. for 1 h. It was poured into ice water, acidified using 6N HCl and extracted using EtOAc (3×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4), concentrated and purified using a silica gel column and 5% EtOAc in petroleum ether (60-80° C.) as eluant to obtain the title compound.