Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([NH:9][C:10]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[N:13]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:12](=[O:26])[N:11]=1)[CH2:2]2.C(N(CC)CC)C.Cl[CH2:35][C:36]1[CH:44]=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1>CN(C=O)C>[O:40]1[C:39]2[CH:43]=[CH:44][C:36]([CH2:35][N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH2:2][CH:3]([NH:9][C:10]3[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=5)[N:13]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:12](=[O:26])[N:11]=3)[CH2:4]4)=[CH:37][C:38]=2[O:42][CH2:41]1
Reactant: O=c1nc(NC2CC3CCC(C2)N3)c2cc(Cl)ccc2n1CC(F)(F)F
Reactant: ClCc1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1nc(NC2CC3CCC(C2)N3Cc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 50 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
To a solution of 4-(8-aza-bicyclo[3.2.1]oct-3-ylamino)-6-chloro-1-(2,2,2-trifluoro-ethyl)-1H-quinazolin-2-one (149 mg, 0.320 mmol) in DMF (10 mL) was added triethylamine (0.3 mL) and 5-Chloromethyl-benzo[1,3]dioxole (0.061 mL, 0.480 mmol). The solution was heated to 50° C. and stirred for 6 hrs. The reaction was partitioned between ethyl acetate and water and the organic phase was washed an additional 2× with water and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash chromatography (gradient elution: 0→20% MeOH/dichloromethane) to provide 99 mg white solid (60%). 1H NMR (300 MHz, CDCl3) δ ppm 2.10 (m, 4H), 2.32 (m, 2H), 3.56 (m, 3H), 3.77 (s, 2H), 4.87 (m, 2H), 5.96 (s, 2H), 6.77 (d, J=8.0 Hz, 1H), 6.83 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 7.17 (m, 2H), 7.56 (dd, J=2.3, 8.9 Hz, 1H), 7.91 (s, 1H); MS (ESI+Q1MS) m/z 522 [M+2H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][C@H:35]1[O:40][C@@H:39]([CH3:41])[CH2:38][NH:37][CH2:36]1>>[CH3:41][C@H:39]1[O:40][C@@H:35]([CH3:34])[CH2:36][N:37]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:38]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4C[C@@H](C)O[C@@H](C)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cis-2,6-dimethylmorpholine. ES-MS m/e (%):
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]=[CH:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1)(=[O:30])=[O:29].Cl>O1CCOCC1.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([S:28]([C:31]3[CH:32]=[CH:33][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 71.8 %

Procedure:
To a suspension of 1-bis(4-fluorophenyl)methyl piperazine (0.47g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (50 mL), the pH of the medium was brought to 4 with 2 N HCl, and extracted with ethyl acetate. The extract was washed successively with water, brine, and dried (Na2SO4). The solvent was removed and the crude product was crystallized from dioxane to give the title compound (0.58 g, 63%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 2.19-2.50 (4H, m, overlapped with a signal of DMSO); 2.80-3.12 (4H, m); 4.42 (1H, s); 6.78 (1H, d, J=16.0 Hz); 7.11 (4H, t, J=9.0 Hz); 7.41 (4H, dd, J=8.6 and 5.6 Hz); 7.72 (1H, d, J=16.0 Hz); 7.78 (2H, d, J=8.2 Hz); 8.00 (2H, d, J=8.2 Hz); 12.68 (1H, br s).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH3:2].Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH2:29][CH:28]=[CH2:27])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH3:2]
Reactant: CCc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(CC)cc13
Reaction time: 2 h

Procedure:
To a stirred solution of 3-Ethylmorphinan.HCl 46 (3 mg, 0.01 mmol) in dry DMF (0.6 mL) was added potassium carbonate (5 mg, 0.036 mmol), allyl bromide (5.0 μL, 0.060 mmol) sequentially and the mixture was refluxed. After 2 h, the mixture was dried over anhydrous MgSO4, filtered, and concentrated. Column chromatography of the product gave -2 mg of white solid. 1H NMR (300 MHz, CDCl3) δ 6.89˜7.16 (3H, m); 5.80 (1H, d); 5.16˜5.30 (2H, m); 4.00˜4.30 (1H, dd); 3.68 (2H, t); 3.66 (1H, m); 3.15 (1H, br); 2.68 (2H, m); 2.50 (2H, m); 2.38 (1H, m); 1.10˜1.70 (13H, m).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[CH2:10]=[O:11]>CC(C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([CH2:10][OH:11])[CH:7]=1
Reactant: C=O
Reactant: FC(F)(F)c1c[nH]cn1
Solvent: CC(C)=O
Product: OCn1cnc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
The mixture of 1.80 g of 4-(trifluoromethyl)-1H-imidazole, 0.78 g of paraformaldehyde was stirred at 140° C. for 4 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered, and then the filtrate was concentrated under reduced pressure to obtain 2.16 g of 4-(trifluoromethyl)-1H-imidazole-1-ylmethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[C:17]([O:26][CH3:27])[CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[C:17]([O:26][CH3:27])[CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C(C)(C)CO)c(OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1C(C)(C)CO
Temperature: 70 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
A mixture of the methyl 6-chloro-5-(4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylate (25 mg, 0.064 mmol), 2.4 ml of methanol (2.4 mL), and 0.8 mL of 1M aqueous solution of sodium hydroxide (0.8 mL, 0.8 mmol) was stirred at 70° C. for 24 hours—the starting material is consumed by TLC and LCMS. The reaction mixture was cooled to room temperature, diluted with 1M solution of potassium bisulfate (1 mL) and the obtained mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and loaded on silica gel. A silica gel column was equilibrated with 30% ethyl acetate in heptane. Chromatography on this column, eluting with a solution of 3% of acetic acid and 30% of ethyl acetate in heptane gave the title compound (18 mg, 73% yield). MS (ES−) 372.1 (M−H)− Retention time:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:19]=O)[CH:8]=[CH:9][CH:10]=1.[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(-c2c(C=O)cccc2OC)c1
Reactant: NCCCN1CCCC1=O
Product: COC(=O)Cc1cccc(-c2c(CNCCCN3CCCC3=O)cccc2OC)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and 1-(3-aminopropyl)-2-pyrrolidinone.
Reaction SMILES: [CH2:1]([C:11]1[O:12][CH2:13][CH2:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH2:16]([O:18][SiH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:17]>>[CH2:16]([O:18][Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:11]1[O:12][CH2:13][CH2:14][N:15]=1)[CH3:17]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCCCCCC1=NCCO1
Product: CCO[Si](CCCCCCCCCCC1=NCCO1)(OCC)OCC

Procedure:
wherein 2-(9-decenyl)-1,3-oxazoline is reacted with triethoxysilane to form 2-[10-(triethoxysilyl)decyl]-1,3-oxazoline.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([O:33][C:34](=[O:37])[CH2:35]Br)[CH3:32]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[C:7]=2[O:24][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Temperature: 80 °C

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (250 mg, 0.766 mmol) in acetonitrile (20 mL) was added potassium carbonate (312 mg, 2.3 mmol) and ethylbromoacetate (256 mg, 1.533 mmol) and the reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure to afford Ethyl 2-(2-(cyclopropylmethoxy)-3-methoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)acetate as a crude product which was used as such in further reaction (300 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[O:21]=[C:19]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:23])[F:22])=[N:4]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: C1CCNCC1
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCCC1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and piperidine using a similar procedure to that described for Example 2, product further purified by mass directed auto-prep.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][C:11]=1[O:20][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 18 h

Procedure:
Benzyl bromide (21.4 ml) was added to a stirred mixture of 2-bromo-4-trifluoromethylphenol (46.4 g) and potassium carbonate (39 g) in DMF (200 ml). After 18 h, the mixture was partitioned between diethylether and water, the organic layer washed with water, 2M sodium hydroxide solution, water, dried and the solvent evaporated under reduced pressure. Yield 58.7 g
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[CH:19]=[C:20]([CH:23]=O)[S:21][CH:22]=3)=[N:13][C:12]([CH:25]([CH3:27])[CH3:26])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>C(O)CO.O>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[CH:19]=[C:20]([CH3:23])[S:21][CH:22]=3)=[N:13][C:12]([CH:25]([CH3:27])[CH3:26])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(c(-c3csc(C=O)c3)n1)CCN(Cc1ccccc1)C2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1cc(-c2nc(C(C)C)nc3c2CCN(Cc2ccccc2)C3)cs1
Temperature: 200 °C
Reaction time: 6 h
Yield: 65.9 %

Procedure:
To a solution of the product of Step A (0.230 g) in ethylene glycol was added hydrazine hydrate (0.1 mL). The mixture was heated at 200° C. for 1 h, then KOH (0.150 g) was added and the heating continued for 6 h. The mixture was allowed to cool then was diluted with water and extracted with Et2O. The combined organic extracts were dried and concentrated to 0.210 g of pale yellow solid. Chromatography on SiO2 (EtOAc/hexanes) afforded 0.146 g of the title compound. MS (ESI): exact mass calcd. for C22H25N3S, 363.18; found m/z 364.4 [M+H]+. 1H NMR (MeOH-d4): 7.85-7.84 (m, 1H), 7.65-7.63 (m, 2H), 7.56-7.55 (m, 3H), 7.37-7.36 (m, 1H), 4.60 (br s, 2H), 4.44 (br s, 2H), 3.46-3.32 (m, 2H), 3.22-3.17 (m, 1H), 2.55 (s, 3H), 1.34 (d, J=7.2, 6H).
Reaction SMILES: Cl.[NH:2]1[CH2:16][CH2:15][CH2:14][C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.[O:41]=[C:42]([CH2:46][CH2:47][CH3:48])[C:43](O)=[O:44]>ClCCl>[O:41]=[C:42]([CH2:46][CH2:47][CH3:48])[C:43]([N:2]1[CH2:16][CH2:15][CH2:14][C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])=[O:44]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCCC(=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
8.8 g benzyl prolinate hydrochloride, 9.78 g dicyclohexylcarbodiimide and 6.12 g diisopropylethylamine were reacted together in 50 mL dichloromethane at 0°. 5.51 g 2-oxopentanoic acid in 10 mL dichloromethane was added dropwise at 0°. The pH of the reaction was adjusted to between 8 and 9 with diisopropylethylamine. The reaction mixture was stirred for four hours at 0°, then room temperature overnight. The next day, the reaction mixture was filtered, concentrated to dryness, and partitioned between ethyl acetate and water. The organic layer was washed with 5% sodium bisulfate, 5% sodium bicarbonate, and saturated sodium chloride solutions, and dried with magnesium sulfate. The organic layer was concentrated to give a yellow oil. The oil was then passed through a silica gel column and eluted with ethyl acetate/hexane (4:6) and ethyl acetate/hexane (1:1). Benzyl N-(2-oxopentanoyl)prolinate, [α]D25 -56.9, was isolated.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1>>[CH3:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)=[O:18])=[CH:15][CH:16]=1
Reactant: Ic1ncn2ccsc12
Reactant: Cc1ccc(C=O)cn1
Product: Cc1ccc(C(=O)c2ncn3ccsc23)cn1
Yield: 82.8 %

Procedure:
7-(6-Methylpyridin-3-yl)carbonylimidazo[5,1-b]-thiazole (885 mg) was prepared in the same manner as in step a) of Synthesis Example 3, except that 1.10 g of 7-iodoimidazo[5,1-b]thiazole and 532 mg of 2-methylpyridine-5-aldehyde were used as the starting compounds.
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([O-:16])=[O:15])=[CH:12][N:13]=2)[CH:10]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=2)[CH:10]=1
Reactant: CC(=O)CCc1ccc2ncc(C(=O)[O-])n2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Temperature: 50 °C

Procedure:
A stirring mixture of ethyl 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylate (77) (190 mg, 0.730 mmol) and 2N LiOH (0.2 mL) in THF:MeOH (4:1, 3 mL) was heated at 50° C. for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially reduced. The resulting solid was collected by vacuum filtration and washed with excess water. Crude 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (78) was dried and used in the next step without further purification. MS m/z 233.08 (M+1)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]([F:21])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:13]2[CH:14]=[C:15]([F:21])[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[Cl:11])[CH:7]=[CH:6][N:5]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
Sodium hydride (60% in mineral oil) (0.620 g, 15.5 mmol) was placed in a 100 mL round bottom flask under argon. Dry DMF (30 mL) was added, followed by portion wise addition of 2-chloro-4-hydroxypyridine (1.339 g, 10.33 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then slowly warmed to RT. A solution of 5-chloro-2,4-difluoronitrobenzene (2 g, 10.33 mmol) in DMF (4.4 mL) was added to the suspension, and the mixture was placed in a 90° C. oil bath to heat for 15 hours under argon. The reaction mixture was then cooled to RT and diluted with ethyl acetate (100 mL), washed with 10% aqueous LiCl (3×100 mL) and brine (2×100 mL), dried (MgSO4) and purified via silica gel chromatography (ethyl acetate/hexanes) to yield 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine as a bright yellow oil (1.415 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.56 (dd, 1H), 8.35 (dd, 1H), 7.88 (dd, 1H), 7.32 (dd, 1H), 7.18 (m, 1H); MS (ESI) m/z: 303.0 (M+H+).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][C:31]([CH3:36])=[CH:30]4)=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:56]1([CH2:61][CH2:62][CH2:63]O)[CH2:60][CH2:59][CH2:58][CH2:57]1>C(Cl)Cl>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:26][C:20]1[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:63][CH2:62][CH2:61][N:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)=[CH:17][CH:18]=3)[N:23]=[CH:22][N:21]=1)=[CH:35][CH:34]=2
Reactant: Cc1cc2cc(Oc3ncnc4cc(O)ccc34)ccc2[nH]1
Reactant: OCCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2cc(Oc3ncnc4cc(OCCCN5CCCC5)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Diisopropyl azodicarboxylate (146 mg, 0.72 mmol) was added to a solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.34 mmol), triphenyl phosphine (189 mg, 0.72 mol), and 3-pyrrolidinopropan-1-ol (89 mg, 0.686 mmol), (J. Org. Chem. 1988, 53, 3164), in methylene chloride (2.5 ml). After stirring overnight at ambient temperature, the solid was filtered. The filtrate was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by ethyl acetate/methylene chloride/methanol (4/5/1), methylene chloride/methanol (9/1) and 3N ammonia in methanol/methylene chloride (1/9). After removal of the solvent, the residue was triturated with ether, filtered, and dried under vacuum to give 4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline (49 mg, 35%).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]>C(O)(=O)C>[Br:1][CH2:11][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3])=[O:12]
Reactant: CC(=O)c1ccccc1Br
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1Br
Temperature: 25 °C

Procedure:
Bromine (40.3 g, 0.25 mol) was added dropwise to a solution of 2′-Bromoacetophenone (50.0 g, 0.25 mol) in acetic acid (500 ml) over 1.5 hours at 15-20° C. The solution was then allowed to warm to room temperature and concentrated under reduced pressure to yield a crude product that was used without further purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO>[F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH2:33])[CH2:10][CH2:9]2
Reactant: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Yield: 49.7 %

Procedure:
To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one (1 g, 2.39 mmol) in CH3OH (10 mL) were added ammonium acetate (1.84 g, 23.9 mmol) and sodium cyanoborohydride (NaCNBH3; 0.44 g, 7.17 mmol,) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with H2O and saturated aqueous sodium bicarbonate (satd aq NaHCO3) solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (500 mg, crude): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.71 (s, 2H), 4.78 (m, 1H), 4.2 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 1.60 (m, 2H); ESIMS m/z 419.02 ([M+H]+); IR (thin film) 2924, 1552, 1112, 807 cm−1.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[OH:9][C:10]([CH3:18])([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][SH:12].C(NC(C)C)(C)C>>[CH3:3][C:2]1([CH2:4][C:5]([OH:7])=[O:6])[S:12][CH2:11][C:10]([CH3:18])([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9][C:1]1=[O:8]
Reactant: CC1=CC(=O)OC1=O
Reactant: CCCCCC(C)(O)CS
Solvent: CC(C)NC(C)C
Product: CCCCCC1(C)CSC(C)(CC(=O)O)C(=O)O1

Procedure:
Analogously to Example 1, from citraconic acid anhydride and 2-hydroxy-2-methylheptane-1-thiol in the presence of diisopropylamine and the usual working up of the reaction mixture, 3,6-dimethyl-2-oxo-6-pentyl-1,4-oxathiane-3-acetic acid is obtained. Using chromatographic purification it can be separated into two isomers:
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[CH3:20][O:19][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][C:15]=1[CH3:18]
Reactant: COc1c(C)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
To 80 mg of 4-methoxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butyl ester was added 2 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 3 h. When the reaction was done, the solvents were removed under vacuum and the residue was triturated with hexane/dichloromethane. Filtration of the suspension gave 55 mg of 4-methoxy-3,5-dimethyl-benzofuran-2-carboxylic acid as a pale brown solid.