Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[Br:42][C:43]1[CH:51]=[CH:50][C:46]([CH2:47][NH:48][NH2:49])=[CH:45][CH:44]=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:11]([NH:49][NH:48][CH2:47][C:46]1[CH:50]=[CH:51][C:43]([Br:42])=[CH:44][CH:45]=1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: NNCc1ccc(Br)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)NNCc1ccc(Br)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
N-(Methoxycarbonyl)-(L)-tert-leucine (J. Med. Chem., 41, 3387-3401, 1998) (1.74 g, 9.20 mmol) was dissolved in EtOAc (50 mL) and EDAC (1.94 g, 10.1 mmol), HOBT (1.37 g, 10.1 mmol), and NMM (1.11 mL, 10.1 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and then 4-bromo-benzylhydrazine (prepared as described in Zh. Org. Khim., 28, 43-50, 1992) (2.31 g, 11.5 mmol) in EtOAc (20 mL) was added and the stirring was continued over night. The reaction mixture was washed with saturated NaHCO3 (aq.), H2O and brine and then the organic phase was dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (silica, CHCl3/MeOH, 100:0-96:4) yielding the title compound (1.85 g, 54%) as a white solid.
Reaction SMILES: [OH:1]NC(=N)CC.C(C1N=C(C(C(NC(C(N[C:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[O:36])CS(CC2C=CC=CC=2)(=O)=O)=O)CC)=O)ON=1)C>>[N:37]1([C:35]([OH:36])=[O:1])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: CCc1noc(C(=O)C(CC)NC(=O)C(CS(=O)(=O)Cc2ccccc2)NC(=O)N2CCOCC2)n1
Reactant: CCC(=N)NO
Product: O=C(O)N1CCOCC1

Procedure:
By proceeding in a similar manner to that described in Example 20 above but using N-hydroxy-propionamidine instead of N-hydroxy-benzamidine in step 1, there was prepared morpholine-4-carboxylic acid {1-[1-(3-ethyl-[1,2,4]oxadiazole-5-carbonyl)-propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl}-amide. 1H NMR (DMSO): 8.73 (d, J=6.4 Hz, 1H), 7.40–7.33 (m, 5H), 7.01 (d, J=8 Hz, 1H), 4.88–4.82 (m, 1H), 4.71–4.65 (m, 1H), 4.47 (s, 2H), 3.57–3.24 (m, 10H), 2.81 (q, J=7.6 Hz, 2H), 1.99–1.88 (m, 1H), 1.75–1.64 (m, 1H), 1.26 (t, J=7.6 Hz, 3H), 0.92 (t, J=7.6 Hz, 3H). MS: (M++1) 522.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].CO[C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)=[O:15]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][O:6][C:14]([CH:16]1[CH2:17][CH2:18][CH:19]([C:22]([O:24][CH2:25][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:23])[CH2:20][CH2:21]1)=[O:15])[CH2:2][CH3:3]
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Reactant: CCCCCC(CO)CCC
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCCC(CCC)COC(=O)C1CCC(C(=O)OCC(CCC)CCCCC)CC1
Temperature: 185 °C

Procedure:
2-Propylheptyl alcohol (8.1 mol), dimethylcyclohexane-1,4-dicarboxylate (DMCD, cis 1.7%, trans 98.3%, Eastman, 3.0 mol) and tetraisopropyl titanate catalyst (0.85 g) were added to a 2.5 L reactor equipped with a stirrer and two condensers and heated to 185° C. Di(2-propylheptyl)cyclohexane-1,4-dicarboxylate (cis 3%, trans 97%) was obtained with a purity of 99.8% in the same manner as in Example 1.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:9]([NH:8][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[O:10][CH2:11][C:12]=2[CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Reactant: O=Cc1ccccc1
Product: c1ccc(CNc2ccc3c(c2)COC(NC2CCCCCC2)=N3)cc1
Yield: 96.2 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (200 mg, 0.77 mmol) and benzaldehyde (90 mg, 0.85 mmol) according to the procedure described for example 88. Obtained the title compound as a yellow oil (259 mg, 96%), MS (ISP) m/e=350.5 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:28]2[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=2[F:26])=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Product: Cc1ccc(-c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3sc4c(c23)CCCC4)c(F)c1

Procedure:
The title compound was prepared from Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 16, 100 mg, 212 μmol) and 2-(2-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 19, 99 mg, 424 μmol) using the same method as described in Example 44, Step 1 to yield 100 mg, 96%. Material obtained was a mixture of atropisomers, in a 2:1 ratio.
Reaction SMILES: OCCCC[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].NCCCC[CH2:50][CH2:51][OH:52]>>[OH:52][CH2:51][CH2:50][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12]
Reactant: NCCCCCCO
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCO)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using 6-aminohexanol in place of 8-aminooctanol. ES/MS calcd. for C31H35N4O6S+ 591.2. Found m/z=591.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.[Cu]I>[N:11]1([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 mL), were added 1,2,4-triazole (5 g, 75 mmol), Cs2CO3 (32.6 g, 100.5 mmol) and CuI (1.4 g, 10.1 mmol) and the resultant reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to ambient temperature and diluted with water (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. Purification by washing with diethyl ether afforded the title compound as a solid (5 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m/z 186.02 ([M−H]−).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C@H:3]([OH:17])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[O:9][CH2:8][CH2:7]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[F:25][C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([F:26])[CH:22]=1)[CH2:18][C@H:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[C@H:3]([OH:17])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[O:9][CH2:8][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@H]1CCOc2ccc(I)cc21
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN[C@H]1CCOc2ccc(I)cc21
Temperature: 0 °C

Procedure:
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-yl]amino}butan-2-ol (1 equiv) was dissolved in DCM with TEA (2 equiv) then cooled to 0° C. and treated with MsCl (1.25 equiv) while stirring. The reaction mixture was removed from the cold bath, brought to ambient temperature, then quenched with MeOH and concentrated. The residue was dissolved in EtOAc and washed with 1M HCl (2×10 mL). The organics were dried and concentrated and chromatographed over silica gel. 1H NMR (CD3OD) δ 7.74 (d, J=2.0 Hz, 1H), 7.53 (dd, J=2.0, 8.7 Hz, 1H), 6.88 (m, 2H), 6.77 (m, 1H), 6.67 (d, J=8.7 Hz, 1H), 4.23–4.39 (m, 2H), 4.25 (br m, 1H), 4.12 (m, 1H), 3.87 (td, J=3.1, 7.8 Hz, 1H), 3.29 (dd, J=3.5, 13.9 Hz, 1H), 3.11 (s, 3H), 3.05 (dd, J=3.2, 12.7 Hz, 1H), 2.98 (dd, J=7.9, 12.6 Hz, 1H), 2.74 (dd, J=11.0, 13.9 Hz, 1H), 2.14 (br m, 2H). MS (ESI+) calcd for C20H23F2IN2O4S m/z 553.38 (M+H)+. Found 553.4.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>>[ClH:1].[CH2:25]([N:12]1[CH2:13][CH2:14][C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[C@H:10]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:11]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCBr
Reactant: COc1ccc(OC[C@@H]2CNCC[C@H]2c2ccc(F)cc2)cc1
Agent: Cl
Product: CCCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc(OC)cc2)C1

Procedure:
(-)-trans-1-butyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride M.p. 163°-165° C. was prepared exactly as described in Example 1 from (-)-trans-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride and butyl bromide by refluxing for 120 hours.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].Cl[C:14]1[C:23]2[C:18](=[C:19]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>CN(C)C=O>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[CH:16][C:15]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:14]2[SH:10])=[O:34]
Reactant: [S-2]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a mixture of sodium sulfide nonahydrate (202 mg) in dimethylformamide (5 ml) was dropwise added 4-chloro-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (297 mg), and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added ice-water, and the mixture was adjusted to pH 3 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water to give 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonyl-4-mercaptoquinoline (260 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].Cl.[NH2:10][OH:11].C(N(CC)CC)C.Cl.C(N(CC)CC)C>CO>[OH:11][N:10]=[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)[NH2:2]
Reactant: NO
Reactant: N#Cc1cncnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=NO)c1cncnc1
Temperature: 0 °C
Yield: 52.2 %

Procedure:
5-Cyanopyrimidine (J. Org. Chem. 1962, 27, 2264) (0.64 g, 6.1 mmol) was dissolved in methanol (20 mL), the solution was cooled to 0° C. then hydroxylamine hydrochloride (0.42 g, 6.1 mmol) and triethylamine (0.84 mL, 6.1 mmol) were added and the mixture was heated to reflux overnight. The mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was pre-absorbed onto silica gel, and purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia—95:5:0.5 as eluant) to give a yellow solid which was contaminated with triethylamine hydrochloride. Recrystallisation from ethanol gave the title compound as a white solid (0.44 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:35])=[C:7]([NH:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:13][CH:12]=2)[CH:8]=1)#[N:2].C[Si]([N:40]=[N+:41]=[N-:42])(C)C.C([Sn](=O)CCCC)CCC>C(COC)OC>[CH3:35][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:42][N:41]=[N:40][N:2]=2)=[CH:8][C:7]=1[NH:9][C:10](=[O:34])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[N:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C#N)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: Cc1ccc(-c2nnn[nH]2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Yield: 80.9 %

Procedure:
A mixture of N-(5-cyano-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (273 mg, 0.600 mmol), prepared as described in Example 10, trimethylsilylazide (160 μL, 1.2 mmol), and dibutyltin oxide (36 mg, 0.060 mmol) in dimethoxyethane (6 mL) was reacted in the microwave reactor (120° C., 100 psi, 2). The reaction was then concentrated on a rotary evaporator and the residue was purified by preparative reverse phase HPLC to give N-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (242 mg, 81%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.91 (s, 1H), 8.20 (d, 2H), 8.13 (d, 1H), 8.03 (d, 2H), 7.91-7.79 (m, 5H), 7.67-7.63 (m, 3H), 7.53 (d, 1H), 7.42 (ddd, 1H), 2.36 (s, 3H). MS (EI) for C29H22N8O: 499.3 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:12]=2)=[N:8][C:7]=1[CH3:25])=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:13]2[CH:14]=[CH:15][C:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:25])[N:8]=3)=[N:12]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1sc(-c2ccn(CCc3ccc(F)cc3)n2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Yield: 86.8 %

Procedure:
A mixture of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid ethyl ester (0.5 g, 1.39 mmol) and NaOH (0.22 g, 5.57 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was heated to reflux for 16 hr. The reaction mixture was cooled to room temperature and neutralized with 5% HCl to pH 6. The precipitate was filtered and dried to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.40 g, 87%) as a yellow solid. MS (M+H)+=332; Rt=1.04 min.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:10](=[O:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([CH:14]([CH3:16])[CH3:15])[O:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[OH:5][C:4]1[CH:3]=[C:2]([CH3:1])[O:11][C:10](=[O:12])[C:9]=1[C:8](=[O:13])[CH:7]=[CH:6][CH:14]([CH3:15])[CH3:16]
Reactant: Cc1cc2c(c(=O)o1)C(=O)CC(C(C)C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.6 %

Procedure:
To a mixture of 450 mg of 2, 3-dihydro-7-methyl-2-(1-methylethyl)-4H,5H-pyrano[4,3-b]pyran-4,5-dione and 40 ml of 2-propanol, 400 mg of potassium carbonate were added and stirred at room temperature for 12 hours. The reaction mixture was then concentrated, and methyl t-butyl ether and 3% hydrochloric acid were added thereto. The separated organic layer was washed with saturated brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 340 mg of 4-hydroxy-6-methyl- 3-(4-methyl-2-pentenoyl)-2-pyrone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][C:12]([CH3:19])([CH3:18])[O:13][C:14]([CH3:17])([CH3:16])[CH:15]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>CCO.[Pd]>[CH3:18][C:12]1([CH3:19])[CH2:11][CH:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:15][C:14]([CH3:17])([CH3:16])[O:13]1
Reactant: [H][H]
Reactant: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccc(N)cn2)CC(C)(C)O1
Yield: 95 %

Procedure:
To a solution of 5-nitro-2-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-pyridine (as prepared in the previous step, 15.0 g, 57.1 mmol) in EtOH (60 mL) was added 10% Pd/C (7.00 g). The resulting mixture was hydrogenated at 50 psi of hydrogen pressure for 2 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to obtain a beige solid (12.7 g, 95%) which was directly used in next step without further purification. 1H-NMR (CDCl3; 400 MHz): δ 8.05 (br s, 1H), 6.98 (m, 2H), 3.59 (br s, 2H), 3.16 (m, 1H), 1.79 (m, 2H), 1.52 (m, 2H), 1.35 (s, 6H), 1.26 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C14H22N2O, 235.2 (M+H), found 235.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=2)=[CH:10][O:9][N:8]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:20]([C:17]2[CH:16]=[N:15][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[CH:19][N:18]=2)=[O:22])[CH2:25][CH2:24]1
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccccn2)cn1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cnc(OCc2conc2-c2ccccn2)cn1
Yield: 81 %

Procedure:
As described for example 19f, 5-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (84.7 mg, 2.8 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (SiO2, heptane:ethyl acetate 7:3 to 2:8, 78 mg, 81%) which was obtained as a white solid. MS: m/e=338.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH:35]([F:37])[F:36]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:35]([F:37])[F:36])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: FC(F)Cl
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of [8-chloro-3-(4-chlorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.080 g), N,N-dimethylformamide (2.0 mL) and potassium carbonate (0.080 g) at −80° C. was added chlorodifluoromethane (0.4 mL). The flask was sealed and the resulting mixture warmed to room temperature and then stirred at this temperature for 17 hours. The excess chlorodifluoromethane was allowed to evaporate and the residue diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a light brown solid, 0.10 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:17].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH2:14])=[O:17])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 78 °C
Yield: 101.3 %

Procedure:
To a solution of 4-benzyloxybenzonitrile (0.61 g, 2.91 mmol) in 15 ml of tert-butanol was added fine powder of KOH (1.22 g, 21.78 mmol) and the resulting reaction mixture was refluxed for 4 h at 78° C. After the completion of the reaction (TLC monitoring), added brine solution and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum, to get the product (0.67 g) that was used as such for the next step.
Reaction SMILES: [OH:1][CH:2]([C:6]([O:19]/[CH:20]=[CH:21]/[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[N:35](S(C)(=O)=O)[CH2:34][N:33]=1.Cl>CN(C=O)C.O>[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([O:1][CH:2]([C:6]([O:19]/[CH:20]=[CH:21]/[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])[N:33]=1
Reactant: O=C(O)C(O)C(O/C=C/Cc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1=CC(C)=NCN1S(C)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)nc(OC(C(=O)O)C(O/C=C/Cc2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
1.12 g (3 mmol) of 2-hydroxy-3-(3-phenyl-(2E)-propenoxy)-3,3-diphenylpropionic acid were added to a suspension of 432 mg (9 mmol, 50%) of NaH in 20 ml of DMF, and the mixture was stirred at room temperature for 10 minutes. 614 mg (3.3 mmol) of 4,6-dimethyl-1-methylsulfonylpyrimidine were added, and the mixture was stirred for 16 hours, then diluted with 200 ml of water, acidified with 1 N hydrochloric acid and extracted with ether. The ether phase was extracted with 1 N sodium hydroxide solution, the aqueous phase was again acidified, and the product was extracted with ether. The organic phase was dried over magnesium sulfate and filtered, and the solvent was distilled off. The residue was recrystallized from ether/hexane, and 927 mg (65%) of crystalline product were isolated.
Reaction SMILES: CN(C)[CH:3]=[C:4]([CH2:7][O:8][CH3:9])[CH:5]=[O:6].[OH-].[Na+].S(OC)([O:16][CH3:17])(=O)=O>CO.O>[CH3:17][O:16][CH:3]=[C:4]([CH2:7][O:8][CH3:9])[CH:5]=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: COCC(C=O)=CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC=C(C=O)COC
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of 3-(dimethylamino)-2-(methoxymethyl)-2-propenal, (E)-- and (Z)-- (53.06 g, 0.37 mol) and sodium hydroxide solution (29.7 g, 50%, 0.37 mol) in methanol (60 mL) is refluxed for 20 minutes and concentrated in vacuo to obtain a white solid. A solution of the solid in water (250 mL) is treated dropwise with dimethyl sulfate (46.75 g, 0.37 mol), stirred at room temperature for one hour and extracted with methylene chloride. The organic extract is dried over anhydrous sodium sulfate, concentrated in vacuo and distilled to give the title product as a colorless liquid (19.66 g, bp 80° C./0.5 mm Hg, 41% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[CH:11]=[C:10](C(OCC)=O)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:25])=[CH:10][C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(C)ccc2n(Cc2ccccc2)c1=O
Reactant: [OH-]
Agent: [Na+]
Product: Cc1ccc2c(c1)c(O)cc(=O)n2Cc1ccccc1

Procedure:
The product from Step (3) was dissolved in 2N sodium hydroxide (150 ml) and the solution was refluxed for 4 hours. Then the solution was cooled and acidified with mineral acid to pH3. The solid was filtered, dried and crystallized from ethyl acetate/hexane to give 1-benzyl-4-hydroxy-6-methyl-2(1H)-quinolinone (4,0 gm). That the expected product was obtained was confirmed by the spectral data: MS: m/e 265 (M+); NMR (DMSO): δ2.32 (s, 3H, CH3 -Ar), 5.43 (s, 2H, CH2 -Ar), 5.96 (s, 1H, =CH-), 11.48 (s, 1H, OH) ppm.