Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[N:6]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.[Cl-].[Zn+2].[Cl-].CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1)[N:6]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:5]2=[O:20]
Reactant: Cc1nc(C=O)cs1
Reactant: Cc1ncccc1-n1c(C)nc2ccc(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2cccnc2C)cs1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
Anhydrous zinc chloride (2.7 g, 20 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (150 mL) was then added. To this mixture was added 6-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (2.6 g, 10 mmol), acetic anhydride (2.8 mL, 30 mmol), and 2-methylthiazole-4-carboxaldehyde (3.7 g, 30 mmol). The reaction was refluxed 2 hours, cooled to ambient temperature, and diluted with water. Sodium carbonate was added until the mixture was basic. The mixture was repeatedly extracted with chloroform. The combined chloroform layer was washed with water and brine and finally dried over sodium sulfate and concentrated to leave a dark residue. This residue treated with methanol and concentrated (effectively azeotroping residual chloroform from the residue) and this process was repeated to leave a brown solid. The solid was triturated with ether (twice), filtered and dried to afford 3.1 g (82%) of 6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:10][C:6]=2[CH:5]=1.[Cl-].[Mg+2].[Cl-]>O>[CH3:23][C:17]1[CH:16]=[N:15][C:14]([CH2:13][S+:11]([O-:12])[C:9]2[NH:8][C:7]3[CH:24]=[CH:25][C:4]([O:3][CH3:2])=[CH:5][C:6]=3[N:10]=2)=[C:19]([CH3:20])[C:18]=1[O:21][CH3:22]
Reactant: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Cl-]
Agent: [K]
Agent: [Mg+2]
Solvent: O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Potassium salt of (S)-5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]1-H-benzimidazole (Esomeprazole potassium) (5.2 gm) was dissolved in water (75 ml). To this solution, was added magnesium chloride solution (1.4 gm in 50 ml water), and then the contents were stirred for 1 hour at 25° C. The solid precipitated was filtered, washed with water and dried under vacuum for 12 hours at 40° C. to obtain 4.0 gm of esomeprazole magnessium dihydrate (enantiomeric excess: 99.7%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[C:19]#[CH:20]>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:21][CH2:18][C:19]#[CH:20])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: C#CCN
Solvent: CC#N
Product: C#CCN=C(NC#N)NCCSCc1[nH]cnc1C
Yield: 116.4 %

Procedure:
A mixture of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methyl isothiourea (3.00 g, 0.0111 mole) and propargyl amine (2.50 g, 0.045 mole) in acetonitrile (60 ml) was stirred at reflux for 65 hours, and then was heated in a stainless steel pressure vessel at 120°-130° for 38 hours. The reaction mixture was cooled, decanted from a tar, and then evaporated to leave a gum (3.57 g). This material was placed on silica gel (100-200 mesh) and eluted with a mixture of methylene chloride (97 parts) and methanol (3 parts). The product obtained from a middle fraction was crystallized by trituration under acetonitrile, and then was recrystallized from acetonitrile to yield the title compound (0.236 g; 7.7%); m.p. 146°-149.5°.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:27]([C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2ccc3ccccc3c2)c2cc3c(cc21)OCO3
Yield: 60 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (226 mg) and 2-naphthaldehyde (152 mg) by the procedure described in example 10 in 60% yield, mp: 186-178° C. 1H NMR (CDCl3): 7.86-7.75 (m, 4H), 7.52-7.42 (m, 3H), 6.70 (s, 1H), 6.32 (s, 1H), 5.91 (d, J=1.3, 1H), 5.88 (d, J=1.3, 1H), 5.47 (s, 1H), 5.16 (br s, 1H), 4.45 (m, 1H), 1.58 (m, 6H). Anal. calcd. for C22H20N2O3: C, 73.32; H, 5.59; N, 7.77. Found: C, 73.10; H, 5.49; N, 7.62.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:5]OS(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)[CH2:4][O:3]1.[OH:19][C:20]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:21]=1[C:22]([NH:24][CH3:25])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][O:30][C:28]2[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[C:20]([O:19][CH2:1][C@:2]3([CH3:5])[CH2:4][O:3]3)[CH:29]=2)=[CH:37][CH:36]=1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: CNC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(OCc2ccc(OC)cc2)cc1OC[C@]1(C)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of [(2S)-2-methyloxiran-2-yl]methyl3-nitrobenzenesulfonate (133 mg, 0.487 mmol), 2-hydroxy-4-[(4-methoxybenzyl)oxy]-N-methylbenzamide (140 mg, 0.487 mmol) and cesium carbonate, Cs2CO3, (198 mg, 0.608 mmol) in dimethylformamide (5 mL) was kept on stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-60% ethyl acetate in petroleum ether) to give the subtitled compound (130 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described for Intermediate 14. LC (method 2): tR=1.23 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:21])[C@@H:10]([CH2:15][O:16]C(C)(C)C)[NH:11][C:12](=[O:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl>[CH2:1]([NH:8][C:9](=[O:21])[C@@H:10]([CH2:15][OH:16])[NH:11][C:12](=[O:14])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@H](COC(C)(C)C)C(=O)NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of N-benzyl-O-tert-butyl-N2-acetyl-D-serinamide (0.5 g) and dichloromethane (10 mL), aq. HCl 35% (5 mL) was added. The solution was stirred for 2 hours at room temperature for completion of reaction and after workup and crystallization gave solid 0.21 g N-benzyl-N2-acetyl-D-serinamide.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:12]2[NH:13][CH:14]=[CH:15][C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>[OH-].[Na+]>[NH:13]1[CH:14]=[CH:15][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[C:5]([CH2:4][C:3]([OH:16])=[O:2])[C:12]1=2
Reactant: COC(=O)CC1=CC=CC=Cc2cc[nH]c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC1=CC=CC=Cc2cc[nH]c21

Procedure:
A suspension of ±1H-cycloocta[b]pyrrole-9-acetic acid methyl ester, decahydro-2-oxo-, (3aα, 9β, 9aα)-; ±1H-cycloocta[b]pyrrole-9-acetic acid methyl ester, decahydro-2-oxo, (3aα, 9α, 9aα)-; 1H-cycloocta[b]pyrrole-9-acetic acid methyl ester, decahydro-2-oxo, (3 aα, 9β, 9aβ) - (3.0 g, 0.013 mol) in 2N NaOH (6.5 ml) is stirred until hydrolysis is complete. The basic solution is treated with 2N HCl (6.5 ml). The solution is cooled and the product is separated by filtration. After drying in vacuo ±1H-cycloocta[b]pyrrole-9-acetic acid, decahydro-2-oxo-, (3aα, 9β, 9aα)-; ±1H-cycloocta[b]pyrrole9-acetic acid, decahydro-2-oxo-, (3aα, 9α, 9aα)-; ±1H-cycloocta[b]pyrrole-9-acetic acid, decahydro-2-oxo(3aα, 9β, 9aβ)- are isolated as a crystalline solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][F:20]>CO>[F:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][CH2:8][OH:7]
Reactant: FCCCCCCCC/C=C\CCOC1CCCCO1
Solvent: CO
Product: OCC/C=C\CCCCCCCCF
Temperature: 45 °C
Yield: 84.3 %

Procedure:
To a solution of 12-fluoro-(Z)-3-dodecen-1-yl tetrahydropyranyl ether (0.5242 g, 1.83 mmol) (prepared as in Example 5 above) in methanol (10 ml) is added Dowex resin (0.5 g) and the mixture is heated at 45° C. overnight (Bongini et. al., Synthesis, 618, 1979). The resin is then filtered off and the solvent is removed in vacuo. The crude product is purified by flash chromatography using hexane/ethyl acetate (93:7, v/v) to give 12-fluoro-(Z)-3-dodecen-1-ol (312 mg, 83%) as a clear colorless oil: Rf=0.36, hexane/ethyl acetate (7:3, v/v); IR (film ν3100-3550 (OH), 3000 (C=CH); and H NMR (CDCl3) δ1.25-1.75 (m, 12H), 2.15 (m, 2H), 2.35 (br q, J=6 Hz, 2H), 3.65 (t, J=9 Hz, 2H), 4.41(dt, J=48 Hz, 6 Hz, 2H), 5.46 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([CH2:19][N:20]([CH3:25])[CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:16][CH:17]([CH2:19][N:20]([CH3:25])[CH:21]2[CH2:22][O:23][CH2:24]2)[CH2:18]1
Reactant: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC1CNC1)C1COC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-[(methyl(oxetan-3-yl)amino)methyl]azetidine-1-carboxylic acid tert-butyl ester (330 mg, 1.29 mmol) in dichloromethane (12 mL) The resulting reaction mixture was stirred at RT for 1.5 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford (Azetidin-3-ylmethyl)methyl(oxetan-3-yl)amine as colourless oil (180 mg, 90%). 1H NMR (400 MHz, CDCl3): δ 4.64 (2H, t, J=6.59 Hz), 4.57 (2H, t, J=6.31 Hz), 3.72 (2H, t, J=7.87 Hz), 3.58-3.49 (1H, m), 3.37 (2H, t, J=7.22 Hz), 2.92-2.82 (1H, m), 2.44 (3H, m), 2.06 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:29]3[CH2:30][CH2:31][N:26]([CH2:25][C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)[CH2:27][CH2:28]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: c1coc(CN2CCNCC2)c1
Reactant: O=C(Cl)N1Cc2ccccc2Sc2ccc(Cl)cc21
Product: O=C(N1CCN(Cc2ccco2)CC1)N1Cc2ccccc2Sc2ccc(Cl)cc21

Procedure:
The title compound of Example 105 is reacted with the product of Example 63 by the method of Example 4. Following chromatographic separation, the title product is obtained.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC(C(OCC)=O)C1.[S:31]1C=CC=C1CC(Cl)=O>>[S:31]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:2][C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)=[O:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(C(=O)Cc2cccs2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl nipecotate (201.8 mg; 1.28 mmol) and commercially available 2-thiopheneacetyl chloride (158 μl; 1.28 mmol). The crude product was distilled at 225° C./0.1 torr, giving ethyl 1-(2-thiopheneacetyl)-3-piperidinecarboxylate (250.5 mg) as a yellow oil, which solidified on standing. MS m/z (positive ion) 304 (M+Na+; 60), 282 (MH+; 100).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:6]2[C:2]([CH3:1])=[CH:3][C:4]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:16][CH:17]=4)[N:8]=3)=[N:5]2)=[CH:26][CH:27]=1
Reactant: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a mechanically stirred solution of 5-(5-methyl-1H-pyrazol-3-yl)-3-[4-(trifluoromethoxy)-phenyl]-1,2,4-oxadiazole (Intermediate C, 60 mg, 0.193 mmol) and 1-(bromomethyl)-4-chlorobenzene (53 mg, 0.215 mmol) in dry THF (2 mL) was added potassium tert-butoxide (24 mg, 0.213 mmol) at a temperature of 0° C. The cooling bath was removed, and the reaction mixture was stirred at rt over night. After the addition of DMF (1 mL), the complete reaction mixture was subjected to preparative HPLC affording the title compound in pure form (68 mg, 81%): 1H NMR (400 MHz, CDCl3) 8.25 (d, 2H), 7.33 (d, 2H), 7.31 (d, 2H), 7.11 (d, 2H), 6.82 (s, 1H), 5.42 (s, 2H), 2.27 (s, 3H); ES-MS m/z 435, HPLC RT (Method K) 1.63 min.
Reaction SMILES: CC1C=CC(C(O)=O)=CC=1.C(ON1C(=O)C2=CC=CC=C2C1=O)(=O)C1C=CC=CC=1.O=O.[C:33](O)(=[O:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1>[Ti].O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[C:38]([C:37]1[CH:41]=[CH:42][C:34]([CH:33]=[O:43])=[CH:35][CH:36]=1)([OH:40])=[O:39]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: [Ti]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(C(=O)O)cc1
Yield: 63.2 %

Procedure:
In a 500-ml titanium autoclave, 15.36 g (0.113 mol) of p-toluic acid, 0.301 g (1.13 mmol) of N-benzoyloxyphthalimide, 0.112 g (0.45 mmol) of cobalt(II) acetate tetrahydrate, 0. 277 g (1.13 mmol) of manganese(II) acetate tetrahydrate and 104 g of acetic acid were placed, the resulting mixture was stirred at 190° C. in an atmosphere of a mixture of oxygen and nitrogen gases (1:1) [4 MPa (gauge pressure)] for 1 hour and thereby yielded terephthalic acid in a yield of 63.2% with a conversion from p-toluic acid of 67.4%. A small amount of 4-carboxybenzaldehyde was by-produced.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br>>[CH3:25][O:26][C:27](=[O:30])[CH2:28][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COC(=O)CBr
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 28.1 %

Procedure:
The title compound (0.09 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 2-bromoacetic acid methyl ester (1.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C16H18ClN3O2, 319.11. found, m/z 320.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.31 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 4.93 (s, 2H), 3.56 (s, 3H), 3.27-3.25 (br m, 2H), 3.19-3.17 (br m, 2H), 3.04-3.03 (br m, 2H), 2.90-2.88 (br m, 2H).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11](=[CH:17][N:18](C)C)[C:12]2=O)[CH2:9]1)C1C=CC=CC=1.[C:21]([NH:25]N)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([N:25]1[N:18]=[CH:17][C:11]2[CH:10]3[CH2:15][CH:13]([CH2:14][NH:8][CH2:9]3)[C:12]1=2)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NN
Reactant: CN(C)C=C1C(=O)C2CC1CN(Cc1ccccc1)C2
Product: CC(C)(C)n1ncc2c1C1CNCC2C1

Procedure:
Following the method described in Example 14, 3-benzyl-7-dimethylaminomethylene-3-aza-bicyclo[3.2.1]octan-6-one and t-butyl hydrazine were converted to the title compound in 7.5% overall yield. APCl MS m/z 206.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:30][CH2:29][C@@H:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:30][CH2:29][C@@H:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
2.10 g (4.19 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoate (racemate) in 6 ml of dichloromethane and 6.23 ml (83.8 mmol) of TFA were reacted according to General Method 6A. Yield: 2.10 g (quant.)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C(N(CC)CC)C.C(O)(=O)C>C(#N)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])=[O:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccc(Cl)cc1C(=O)NC1CCC(=O)NC1=O
Temperature: 150 °C
Yield: 44 %

Procedure:
A stirred mixture of 5-chloroisatoic anhydride (0.51 g, 2.5 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (0.42 g, 2.5 mmol), triethylamine (1.8 mL, 12.7 mmol), and acetic acid (1.5 mL, 25.3 mmol) in acetonitrile (5 mL) was heated at 150° C. in a microwave oven for 5 miutes. The suspension was filtered and washed with water (50 mL) and ethyl acetate (20 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-chloro-benzamide as a white solid (0.31 g, 42% yield): 1H NMR (DMSO-d6) δ 1.91-2.12 (m, 2H, 2CHH), 2.50-2.56 (m, 1H, CHH), 2.72-2.80 (m, 1H, CHH), 4.71-4.76 (m, 1H, NCH), 6.58 (brs, 2H, NH2), 6.74 (d, J=8 Hz, 1H, Ar), 7.19 (dd, J=2, 9 Hz, 1H, Ar), 7.58 (t; J=2 Hz, 1H, Ar), 8.62 (d, J=8 Hz, 1H, NH), 10.86 (s, 1H, NH); 13C NMR (DMSO-d6) δ 23.99, 30.89, 49.00, 114.62, 117.60, 118.04, 127.25, 131.63, 148.61, 167.37, 172.20, 172.93; LCMS: MH=282, 284.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c[nH]c(=O)c2ccc(F)cc12
Product: COC(=O)c1cnc(Cl)c2ccc(F)cc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To methyl 6-fluoro-1oxo-1,2-dihydroisoquinoline-4-carboxylate (756 mg), phosphoryl chloride (5 ml) was added, and the mixture was stirred at 100° C. for one hour. The resulting solution was returned to room temperature, and evaporated under reduced pressure to remove the solvent. To the resulting crude product, saturated sodium bicarbonate water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent to give methyl 1-chloro-6-fluoroisoquinoline-4-carboxylate (792 mg) as a brown solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:9][C:7]=2[CH:8]=1)=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:2]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:9][C:7]=2[CH:8]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C(N)=O)cc3c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C#N)cc3c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The tert-butyl 4-[2-(aminocarbonyl)-1-benzofuran-5-yl]piperazine-1-carboxylate (85 mg, 0.246 mmol) was dissolved in 5 mL of DCM and cooled to 0° C. under nitrogen. Triethylamine (0.075 mL, 0.541 mmol) was added, followed by trifluoroacetic anhydride (0.038 mL, 0.271 mmol). The reaction was stirred for 1 hour, then was diluted with additional 20 mL of DCM and washed with water (2×40 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford tert-butyl 4-(2-cyano-1-benzofuran-5-yl)piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1>C(O)C.[Pd]>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
300 mg of 4-fluoro-2-nitrophenol was dissolved in 3 ml of ethanol, and 120 mg of 10% palladium/carbon was added and stirred under hydrogen atmosphere at room temperature for 1 hour. After the insoluble matter was filtered off, the filtrate was distilled off under reduced pressure to yield 211 mg of the title compound.
Reaction SMILES: O[C:2]1([C:28]([F:31])([F:30])[F:29])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:28]([F:30])([F:29])[F:31])[N:3]=[C:4]2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(-c3cccs3)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(-c3cccs3)cc2)cc1
Yield: 63.9 %

Procedure:
A mixture of 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-[4-(2-thienyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.345 g, 0.74 mmol) and p-toluenesulfonic acid monohydrate (0.035 g) in toluene (40 mL) was heated to reflux for 7 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in CH2Cl2 (50 mL) and the whole washed with water, aqueous NaHCO3 (30 mL), and brine. After dried over Na2SO4, and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (2/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.212 g, 63.9% yield).