Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:7][C:6]2C=CC([N+]([O-])=O)=C[C:5]=2NC1=O.[NH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=1[OH:28]>>[Cl:24][C:22]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]2[O:28][CH2:5][C:6](=[O:7])[NH:17][C:18]=2[CH:23]=1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Product: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1

Procedure:
This compound was prepared using the general procedure described for 2,2-Dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one above except 2-amino-4-chloro-5-nitrophenol was used as starting material.
Reaction SMILES: C(O[C:5]([CH3:8])([CH3:7])[CH3:6])(=O)C.[CH2:9]([O:11][C:12](=[O:36])[CH:13]([OH:35])[C:14]1[C:15]([CH3:34])=[N:16][C:17]2[S:18][C:19]3[CH2:20][O:21][CH2:22][CH2:23][C:24]=3[C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[CH3:10].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:11][C:12](=[O:36])[CH:13]([O:35][C:5]([CH3:8])([CH3:7])[CH3:6])[C:14]1[C:15]([CH3:34])=[N:16][C:17]2[S:18][C:19]3[CH2:20][O:21][CH2:22][CH2:23][C:24]=3[C:25]=2[C:26]=1[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)[CH3:10]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Tert-Butyl acetate (0.8 mL) was added to a solution of hydroxy-(2-methyl-4-p-tolyl-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl)-acetic acid ethyl ester (100 mg, 0.252 mmol) in dichloromethane (0.8 mL) followed by concentrated sulphuric acid (40 μL) and the reaction stirred at room temperature for 2 hours. Sodium bicarbonate solution (10% aqueous, 2 mL) was added and the reaction evaporated in vacuo until only the aqueous remained. The aqueous was extracted with ethyl acetate (2 mL) and the organic layer washed with brine (1 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with 0-30% ethyl acetate/heptanes to afford a colourless solid (66 mg, 45%). LCMS (12 min acidic) 7.25 min, ES+/AP+ 454 (MH+) 1HNMR (400 MHz, CDCl3) δ ppm 0.98 (s, 9H), 1.20 (t, 3H), 1.55-1.65 (m, 2H), 2.43 (s, 3H), 2.77 (s, 3H), 3.57-3.61 (m, 1H), 3.78-3.82 (m, 1H), 4.06-4.20 (m, 2H), 4.79-4.82 (m, 2H), 7.16 (d, 2H), 7.32 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:15]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: CI
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(Br)ccc31)CCCC2
Yield: 91.1 %

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 6-bromo-2,3,4,9-tetrahydro-1H-carbazole (1.501 g, 6 mmol) was reacted with k-t-butoxide (0.707 g, 6.3 mmol) and methyl iodide (0.894 g, 6.3 mmol) in DMF (15 ml) to give the desired product (1.443 g, 5.463 mmol, 91%) as an off-white solid, mp 70-73° C. 1H NMR (DMSO-d6) δ 1.73-1.77 (m, 2H), 1.82-1.87 (m, 2H), 2.58 (t, J=6.1 Hz, 2H), 2.70 (t, J=6.1 Hz, 2H), 3.58 (s, 3H), 7.13 (dd, J=1.7, 8.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H); [EI], m/z 263/265 (M)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.CCN(CC)CC.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>C1COCC1>[CH3:20][Si:21]([CH3:23])([CH3:22])[O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Oc1ccc(-c2cccs2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-thienyl)phenol in anhyd. THF (10 mL) was added Et3N (0.9 mL, 6.5 mmol), followed by TMSCl (0.4 mL, 3.2 mmol). The reaction mixture was stirred at room temperature overnight, then filtered and concentrated under reduced pressure to give 2-(4-trimethylsilyloxyphenyl)thiophene: TLC (20% EtOAc/hex) Rf 0.69. This material was used without further purification.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].NC1[NH:15][C:16]2C=C[CH:20]=[CH:19][C:17]=2N=1>C(#N)C>[N:15]1[C:16]2[CH:17]=[CH:19][CH:20]=[CH:12][C:11]=2[NH:10][C:9]=1[NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CC#N
Product: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Yield: 73.3 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (8.91 g, 50 mmol) and 2-aminobenzimidazole (6.66g, 50 mmol) in acetonitrile (50 mL) was stirred at room temperature for 19 hours. The resulting precipitate was collected by filtration to provide 8.92 g (73%) of the titled product: IR (KBr, cm-1) 3058, 2621, 1623, 1580, 1509, 1469, 1445, 1355, 1290, 1252, 1212, 1153, 1099, 1081, 1048, 925, 898, 746, 659; 1H NMR (300 MHz, DMSO-d6) δ 13.24 (br s, 2H), 8.52 (s, 1H), 7.87 (s, 1H), 7.57 (m, 2H), 7.33 (m, 2H), 6.96 (s, 1H); MS (FAB) m/e 244 (M+1); UV (EtOH) 351 nm (ε=18204), 283 nm (ε=13099), 227 nm (ε=17339), 204 nm (ε=31915).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(C(F)(F)F)c4)cc3CC[C@@H]12
Yield: 74.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 180 mg (77%) of the title compound as an amorphous foam. mp 64°-87°. FDMS: m/e=373. α[D]589 =+64.42 (c=1.04, chloroform).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([CH3:12])[C:3]=1[I:13].C([Mg]Cl)(C)C.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.[NH4+].[Cl-]>CCOCC.C1COCC1>[I:13][C:3]1[C:4]([CH3:12])=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[B:19]([OH:24])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(I)c(I)c(C)c1OC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(B(O)O)c(I)c(C)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of 1,2-diiodo-4,5-dimethoxy-3-methylbenzene (Example 5(b), 2.0 g, 4.95 mmol) in 120 mL of a mixture of THF and Et2O (1:1) was added dropwise at −78° C., isopropylmagnesium chloride (2 M in THF, 2.72 mL, 5.44 mmol). After the mixture was stirred for 2 h at that temperature, B(OiPr)3 (10.50 ml, 14.84 mmol) was added. The solution was warmed to room temperature overnight; then a saturated solution of NH4Cl was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times), dried over Na2SO4 and concentrated. To the concentrated sample, hexane was added and the resulting precipitate was isolated to give 0.90 g of the pure product (56%).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43](=[O:50])[NH:42][CH:41]=1>>[CH3:38][N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:15][C:14]([C:40]4[C:49]5[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=5)[C:43](=[O:50])[NH:42][CH:41]=4)=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: O=c1[nH]cc(Br)c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Product: CN(C)C1CCN(Cc2cc3nc(-c4c[nH]c(=O)c5ccccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 4-bromoisoquinolin-1(2H)-one were reacted to give 217. LCMS m/z: 505.7 (MH+)
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:25]=[CH:26][CH:27]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2cccc(Cl)c2)nc1
Yield: 60.3 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 2-(3-chlorophenyl)ethylamine (560 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (738 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH2:25][OH:26])[CH:27]=[CH:28][CH:29]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CO)c1
Reactant: COc1cccc(CCCNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CCCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
To a solution of 2,5-dichloro-N-[3-(3-methoxyphenyl)propyl]pyrimidin-4-amine (0.70 g, 2.2 mmol) and 3-aminobenzyl alcohol (0.38 g, 3.0 mmol) in 1,4-dioxane (19.1 mL) was added p-toluenesulfonic acid monohydrate (0.16 g, 0.82 mmol). The mixture was heated at 100° C. for 16 hours and the reaction was complete. After cooling, the mixture was filtered under vacuum. The cake was washed with cold EtOAc and then H2O to give the desired product as an off-white powder (0.71 g, 79%). LCMS for C21H24ClN4O2 (M+H)+: m/z=399.1.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].[OH-].[Na+]>CO>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C=CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCn1cc(C)c(=O)[nH]c1=O

Procedure:
Thymine (14 g, 0.11 mol) was suspended in methanol. Methyl acrylate (39.6 mL, 0.44 mol) was added, along with catalytic amounts of sodium hydroxide. The solution was refluxed in the dark for 45 h, evaporated to dryness in vacuo, and the residue dissolved in methanol (8 mL) with heating. After cooling in an ice bath, the product was precipitated by addition of ether (20 mL), isolated by filtration, washed with ether (3×15 mL), and dried over sicapent, in vacuo. Yield: 11.23 g (48%). M.p. 112°-119° C. Anal. for C9H12N2O4, found (calc.) C: 51.14 (50.94) H: 5.78 (5.70) N: 11.52 (13.20). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11]I.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CC(C)=O>[C:13]1(=[O:23])[N:17]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: ICCCCC=CCCCCI
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCC=CCCCCN1C(=O)c2ccccc2C1=O

Procedure:
The 1,10-Diiodo-dec-5-ene (1 equiv.) is dissolved in anhydrous acetone at ambient temperature followed by the addition of potassium phthalimide (4. equiv.). The reaction mixture is stirred until completion, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified via silica gel chromatography to afford 1,10-dipthalimido-dec-5-ene.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][O:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=[N:18][C:14]=3[CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(/C=C/COCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)C=CC=CC=1>C(O)(=O)C.O>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][O:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[NH:16][CH:17]=[N:18][C:14]=3[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C/c1ccccc1)\COCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: C(=C/c1ccccc1)\COCC1CCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C1
Solvent: O
Solvent: CC(=O)O
Product: C(=C/c1ccccc1)\COCC1CCc2[nH]cnc2C1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of (E)-5-(3-phenylallyloxymethyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and (E)-5-(3-phenylallyloxymethyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (501 mg, 0.98 mmol) was dissolved in a mixture of acetic acid (5.0 ml) and water (0.6 ml). The reaction mixture was stirred for 2 hours at 90° C. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 179 mg of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5].[NH2:10][C:11]1[N:16]=[C:15](Cl)[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][C:20]=2[F:28])=[C:13]([CH3:29])[N:12]=1>CN1C(=O)CCC1.O>[NH2:10][C:11]1[N:16]=[C:15]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][C:20]=2[F:28])=[C:13]([CH3:29])[N:12]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CC#N)cc1F
Reactant: CCCC[C@H](N)CCO
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Temperature: 150 °C
Reaction time: 8 h

Procedure:
(S)-3-Aminoheptan-1-ol (0.135 g) was added to a stirred solution of the product from step (iii) (0.12 g) in NMP (2 mL). The mixture was heated at 150° C. for 48 h, and then at 170° C. for a further 8 h. The mixture was allowed to cool, diluted with water (10 mL) and the aqueous extracted with EtOAc. The combined organic phase was dried and evaporated. The crude product was purified by column chromatography, to give the subtitle compound, 0.11 g.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: BrCCCCBr
Reactant: CCOC(=O)C(C)C
Product: CCOC(=O)C(C)(C)CCCCBr

Procedure:
Using ethyl isobutyrate and 1,4-dibromobutane, the title compound was produced in the same manner as in Reference Example 6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[C:10]3[C:7](=[CH:2][CH:3]=[CH:4][CH:9]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCCCCC
Reactant: Brc1ccc(I)cc1
Product: Brc1ccc(-c2cccc3ccccc23)cc1

Procedure:
An Rf value of the objective substance by a silica gel thin layer chromatography (TLC) (developing solvent, hexane) was 0.38 and that of 4-bromoiodobenzene was 0.57.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:10]1([OH:18])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[CH3:17].FC(F)(F)C(O)=O>CCOCC>[CH3:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[O:18][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(O)c1C
Reactant: CC(C)(C)N1CC(O)C1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(OCC(O)CNC(C)(C)C)c1C
Temperature: 130 °C

Procedure:
A mixture of 4.8 parts of 1-(tert.-butyl)-3-azetidinol, 6.1 parts of 2,3-xylenol and 1.4 parts of trifluoroacetic acid was heated at 130° C. for 12 hours. The reaction mixture was cooled and dissolved in 100 parts of ether, and the solution was washed three times with 50 parts of 2N-sodium hydroxide aqueous solution and extracted three times with 2N-hydrochloric acid aqueous solution. The extract was washed twice with 50 parts of ether and made alkaline by addition of 2N-sodium hydroxide solution. The extraction was conducted three times with 50 parts of ether, and the extract was condensed and distilled under reduced pressure to yield 3.2 parts of 1-(2',3'-dimethylphenyloxy)-3-(tert.-butylamino)-2-propanol having a melting point of 57° C. and a boiling point of 134°-136° C. under 0.7 mm Hg.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)[S:9][CH:10]=1)(=[O:5])[CH3:4].[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:32]=1[CH:33]=O>CO.O>[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:32]=1/[CH:33]=[CH:4]/[C:3]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:26])([F:28])[F:27])=[N:20]3)[CH2:15][CH2:16]2)[S:9][CH:10]=1)=[O:5]
Reactant: CC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: O=Cc1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)/C=C/c3c(F)cccc3F)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, a solution of sodium hydroxide (19 mg) in methanol (0.25 ml) and water (0.05 ml) was added to a solution of 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (190 mg) and 2,6-difluorobenzaldehyde (67 mg) in methanol (0.12 ml). The reaction mixture was stirred at room temperature overnight. After aqueous work-up, the mixture was extracted with ethyl acetate and the extracts were dried with sodium sulphate and concentrated under reduced pressure. The residue was purified chromatographically. This gave (2E)-3-(2,6-difluorophenyl)-1-[2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]prop-2-en-1-one (160 mg).
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[CH2:13]([C:17]1[C:21]([CH2:22]Cl)=[C:20]([CH3:24])[O:19][N:18]=1)[CH2:14][CH2:15][CH3:16]>CN(C=O)C.O>[CH2:13]([C:17]1[C:21]([CH2:22][N:6]2[C:2](=[O:12])[C:3]3[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]2=[O:7])=[C:20]([CH3:24])[O:19][N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1noc(C)c1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1noc(C)c1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 78 %

Procedure:
Phthalimide potassium was suspended in DMF (35 mL) and the reaction mixture heated to 90° C. A solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (970 mg, 5.2 mmol) in DMF (25 mL) was added. After 45 min the reaction mixture was cooled, evaporated and the residue obtained was diluted with water then extracted with ether. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 0 to 50% ethyl acetate in heptane) to give the title compound (1.21 g, 78%) as an off white solid that was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+]>COCCOC.[Cl-].[Na+].O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Brc1ccc(Sc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 2,5-dibromopyridine (12.0 g) and thiophenol (5.46 mL) in DME (50 mL) was added sodium tert-butoxide (5.35 g) at room temperature and the mixture was stirred at 100° C. for 15 h. The reaction mixture was poured into brine, extracted with EtOAc, washed with brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc 30:1) to give 5-bromo-2-(phenylsulfanyl)pyridine (13.69 g) as an oil.
Reaction SMILES: Cl.[CH3:2][C@@H:3]([NH2:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[C:16]([NH:24][C:25]([NH:8][C@H:3]([CH3:2])[C:4]([F:7])([F:6])[F:5])=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C[C@@H](N)C(F)(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=S)NC(=O)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Dissolve (R)-1-methyl-2,2,2-trifluoroethylamine hydrochloride (3.73 g, 25 mmol) in chloroform (50 mL) containing triethylamine (3.5 mL, 25 mmol). Cool to 0° C. in an ice bath and dropwise add benzoyl isothiocyanate (3.35 mL, 25 mmol) over 10 min. Warm the mixture to room temperature and stir overnight. Concentrate in vacuo and purify by chromatography on silica gel (200 g) eluting with hexane/EtOAc (19:1 to 4:1 over 40 min; 50 mL/min) to afford the desired intermediate as a light yellow oil (6.2 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].CS(O[CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)(=O)=O.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][O:26][C:23]1[N:22]=[CH:21][C:20]([CH2:19][N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=3)[CH:9]=[CH:10]2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: COc1ccc(COS(C)(=O)=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3ccc(OC)nc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (0.54 g, 3.1 mmol) and (6-methoxypyridin-3-yl)methyl methanesulfonate (0.73 g, 3.4 mmol) in DMF (15 mL) was added NaH (0.9 g, 3.7 mmol). After stirring at room temperature for 1 hr, the solution was diluted with ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was subjected to flash chromatography (40% ethyl acetate/hexane) to provide 0.68 g (75%) of methyl 1-((6-methoxypyridin-3-yl)methyl)-1H-indole-6-carboxylate as a colorless oil.