Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH:20]1([N:17]2[CH2:18][CH2:19][N:14]([C:11]3([CH2:23][NH:24][C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:15][CH2:16]2)[CH2:21][CH2:22]1
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Through a solution of N-((1-benzyl-4-(4-cyclopropylpiperazin-1-yl)-piperidin-4-yl)methyl)-2,2,2-trifluoroacetamide (5.4 mmol) in methanol (30 ml) was passed argon gas for 10 min. Then acetic acid (855 μl) and Pd(OH)2 (40% by weight) were added to the reaction mixture and it was stirred at room temperature for 16 h under an atmosphere of H2 by using a hydrogen balloon. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness to yield the desired product which was used in the next step without further purification. Yield: 90%.
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](C(C)C)[C:37]=1CC(O)=O)(C)C>>[CH:5]1([CH:13]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:14]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:4]1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Product: CC(C)c1ccc(C(=O)C(c2ccccc2)C2CCCCC2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with α-phenylcyclohexanecarboxylic acid, mp 127°-137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:13])[CH2:10][CH2:11][CH3:12].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: Nc1ccc(O)cc1
Reactant: CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc(O)cc1

Procedure:
4-aminophenol (550 mg; 5 mmol) is added to a solution of butyric acid (1.4 mL; 15 mmol) in DCM (20 mL) at room temperature and stirred vigorously. To this solution DCC (2.48 g; 12 mmol) is added followed by DMAP (24 mg) and the contents stirred overnight at room temperature. The reaction mixture is then filtered and washed with DCM. The filtrate is concentrated and redissolved in methanol, added with 10% aqueous sodium bicarbonate solution and stirred vigorously until diacylated byproduct disappeared (as detected by LC-MS) to yield 4-butyramidophenol as the only product. The product was used for further transformation without further purification.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>O1CCOCC1>[CH3:19][C:16]1[CH:17]=[CH:18][C:10]2[NH:9][C:2](=[O:3])[O:13][C:12](=[O:14])[C:11]=2[CH:15]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Yield: 94.1 %

Procedure:
Trichloromethyl chloroformate (36.27 mL, 300 mmol) was added to a stirred solution of Compound 10 (41.3 g, 273 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h. The solution was cooled in ice bath and the solids formed were filtered. The solids were washed by ether and dried under vacuum at room temperature to yield 45.5 g (94%) of white solids. M.P. 257° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 7.06 (d, J=8.6 Hz, 1H), 7.56 (dd, J=8.6, 1.8 Hz, 1H), 7.71 (d, J=1.1, 1H), 11.63 (s, 1H). EIMS (neg. mode) m/z 176 (M−1), 152 (M+23). Anal. (C9H7NO3) C, H, N.
Reaction SMILES: [CH2:1]([Si:3]([CH2:6][CH3:7])(Cl)[Cl:4])[CH3:2].[CH3:8][N-:9][CH3:10].[Li+]>O1CCCC1>[CH3:8][N:9]([Si:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[Cl:4])[CH3:10]
Reactant: CC[Si](Cl)(Cl)CC
Reactant: C[N-]C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](Cl)(CC)N(C)C
Reaction time: 1 h

Procedure:
One mole of diethyldichlorosilane can be dissolved in one liter of tetrahydrofuran, or similar solvent, under an atmosphere of nitrogen, and one mole of lithium dimethylamide can be slowly added with stirring over a one hour period, then stirred overnight. All of the volatiles can be vacuum transferred off and fractionally distilled to yield the product, dimethylaminodiethylchlorosilane. This product can be dissolved in tetrahydrofuran, or similar solvent, under a nitrogen atmosphere. One mole of water can be dissolved in 100 ml of tetrahydrofuran, or similar solvent, and can be added slowly over a one hour period at zero degrees centigrade. The resulting mixture can be filtered, and the filtrate fractionally distilled to give the product, dimethylaminodiethylsilanol. One equivalent of this product can be dissolved in tetrahydrofuran, or in a similar solvent, and treated with one equivalent of n-butyl lithium solution. The mixture can be cooled to zero degrees centigrade, and one equivalent of copper chloride can be added over 30 minutes. The mixture would be allowed to warm to room temperature, filtered, solvent stripped away, and the resulting mixture can be heated under vacuum to distill out the product, [Cu—NMe2-SiEt2-O—Cu—NMe2-SiEt2-O—Cu—].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:26][O:27][C:28]([C:30]1[CH:31]=[N:32][C:33](Cl)=[N:34][CH:35]=1)=[O:29].N12CCN(CC1)CC2>C(N(CC)CC)C>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[N:32][C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[N:34][CH:35]=1)=[O:29]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
In analogy to Example 163, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with methyl-2-chloropyrimidine-5-carboxylate in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as a colorless solid. MS (m/e)=512.2 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]1)=O>>[CH2:49]([N:46]1[CH2:47][CH2:48][N:43]([CH2:41][CH2:40][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:37][CH:38]=2)[CH2:44][CH2:45]1)[CH3:50]
Reactant: CCN1CCN(C(=O)CCl)CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: CCN1CCN(CCOc2ccc(CCCCNc3cc(OC)ccc3C3CCc4cc(O)ccc4C3)cc2)CC1
Yield: 52.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-(4-ethylpiperazin-1-yl)ethanone (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [N:1]1([CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCCC1>[CH:25]1([C:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:11]2[N:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:8]=[CH:9][N:10]=2)[OH:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: c1ncn(CN2CCCC2)n1
Reactant: O=C(c1ccccc1)C1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ncnn1CN1CCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1-(pyrrolidin-1-ylmethyl)-1H-1,2,4-triazole (Preparation 16, 12.0 g, 78.84 mmol) was dissolved in tetrahydrofuran (120 mL) and the solution cooled to −78° C. n-Butyl lithium (2.5M in hexanes, 34.7 ml, 86.7 mmol) was then added dropwise over 30 mins. After warming to room temperature and stirring for 1 hour the reaction mixture was cooled to −78° C. and a solution of cyclohexyl(phenyl)methanone (16.3 g, 86.7 mmol) in tetrahydrofuran (30 mL) added dropwise. After warming to room temperature over 18 hr, water (100 ml) was added and the solvent removed in vacuo. The residue was partitioned with ethyl acetate (200 ml), the aqueous phase separated and re-extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over magnesium sulphate, filtered and the solvent removed in vacuo to furnish the title compound as a yellow oil, in 100% yield, 27.28 g.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH3:13])[N:3]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:13])[N:3]=[C:2]2[Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccc2c(c1)c(I)nn2C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
3-iodo-5-methoxy-1-methyl-1H-indazole (0.355 g, 1.23 mmol) was dissolved in THF (3.00 mL). The yellow solution was cooled to −16° C. (NaCl/ice bath), isopropylmagnesium chloride 2M in THF (690 μL, 1.38 mmol.12) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min where a solid precipitated. Then, tributylchlorostannane (461 mg, 384 μL, 1.42 mmol.15) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum to give crude 5-methoxy-1-methyl-3-(tributylstannyl)-1H-indazole, which was used directly in the next step without further purification. The crude mass exceeded the expected amount so the yield was assumed to be quantitative.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:32])=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: O=C(CCl)c1ccccn1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)c3ccccn3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with commercially available 2-chloro-1-pyridin-2-yl-ethanone gave the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:16]O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(I)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 25 g (100.8 mmol) of 3-iodobenzoic acid in 250 mL of methanol under argon was added 1.2 mL (23.2 mmol) of concentrated H2SO4 and the mixture was heated to reflux for 24 h. The solution was concentrated to 150 mL, gravity filtered to remove any insoluble material, scratched with a glass rod, and allowed to cool slowly. After cooling to RT the flask was allowed to stand in the refrigerator for a few days. The solid was collected and washed with ice cold methanol and dried under high vacuum at RT for 2 days to provide 25.7 g (97%) of a light violet colored solid. mp 40°-41° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([CH2:24][CH3:25])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)=O>ClCCCl.C(O)(=O)C>[O:18]=[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C@@H:16]([NH:15][CH2:26][C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:35]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[C:29]=12)[CH2:24][CH3:25]
Reactant: CC[C@H](N)C(=O)N1CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC[C@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
A mixture of sodium triacetoxyborohydride (279 mg, 1.315 mmol) and (S)-2-amino-1-(pyrrolidin-1-yl)butan-1-one (123 mg, 0.789 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (200 mg, 0.657 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (83 mg, 28.4%). [M+H] calc'd for C23H32N4O5, 445; found, 445.5.
Reaction SMILES: [C:1]([C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>CCO>[C:2]1([C:1]2[N:20]=[N:19][C:15]([OH:17])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=23)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)O
Solvent: O
Solvent: CCO
Product: Oc1nnc(-c2ccccc2)c2cccnc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 3-benzoylpicolinic acid (0.272 g, 0.120 mmol) and hydrazine hydrate (0.17 mL, 0.37 mmol) in EtOH (3.3 mL) was stirred at 80° C. overnight, concentrated, diluted with saturated aqueous NaHCO3, extracted with CH2Cl2, dried (Na2SO4), and concentrated to give the title compound as a white solid (0.28 g, 0.12 mmol). 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.10 (dd, 1H), 8.09 (dd, 1H), 7.88 (dd, 1H), 7.54-7.63 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH:11](Br)[F:12])=[CH:6][CH:5]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23](=[S:25])[NH2:24])[CH2:19][CH2:18]1>C(O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:24]=[C:23]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)[S:25][C:11]=2[F:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)C(F)Br)cc1
Reactant: CN1CCN(C(N)=S)CC1
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(N3CCN(C)CC3)sc2F)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
4-(2-Bromo-2-fluoro-acetyl)-benzoic acid methyl ester (1.18 mmol) and 4-methyl-piperazine-1-carbothioic acid amide (1.18 mmol) were dissolved in ethanol (10 mL). The reaction was heated at reflux for 2 h. The reaction was cooled to RT causing the product to precipitate. The product was collected by filtration and washed with cold ethanol. The product was given an aqueous sodium bicarbonate work up to yield the title compound as a colourless oil (74%). MS (ES+) 337 (M+H, 100%).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:25][NH:26][O:27][CH3:28].Cl>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:7](=[O:9])[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCC1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
A solution of 2.0 mL (15.9 mmol) of cyclopentylacetic acid in 80 mL of CH2Cl2 at 0° C. was treated with 3.7 mL (33.6 mmol) of N-methyl-morpholine and 2.2 mL (16.9 mmol) of isobutyl chloroformate. After stirring for 20 min, 1.61 g (16.5 mmol) of N,O-dimethyl-hydroxylamine.HCl was added. The reaction was warmed to rt and stirred for 3 h. The reaction was partitioned between 200 mL of EtOAc and 200 mL 2.0 N HCl. After separating the phases, the organic layer was washed with 200 mL of 1.0 N NaHCO3, dried over Na2SO4 and concentrated. Flash chromatography on silica gel using 4:1 v/v hexanes/EtOAc afforded 2.28 g (83%) of the title compound as a colorless oil. RF: 0.27 (4:1 v/v hexanes/EtOAc). 1H NMR (300 MHz): δ 1.12-1.23 (m, 2H), 1.51-1.89 (m, 6H), 2.28 (m, 1H), 2.44 (d, J=7.5, 2H), 3.18 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CO>[CH2:22]([N:29]1[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:10](=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=2)[C:8]1=[O:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1oc(=O)c2ccc(F)cc2c1-c1ccccc1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 76.1 %

Procedure:
A mixture of 6-fluoro-4-phenylisocoumarin-3-carboxylic acid (300 mg), benzylamine (230 mg), triethylamine (0.3 ml) and methanol (3 ml) was stirred at 50° C. for 36 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N-Hydrochloric acid-ethyl acetate solution (3 ml) was added to the residue at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the obtained crystals were washed with (diisopropyl ether) to give the title compound, 2-benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].CN(CCN(C)C)C.[Li].[I:23]I>O1CCCC1.C(OCC)C>[I:23][C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1]
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1cnccc1I
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A solution of 2,2-dimethyl-N-pyridin-3-ylpropanamide [(1 g, 5.61 mmol), J. Org. Chem, 48(20), 3401;1998]in tetrahydrofuran (10 mL) and diethyl ether (30 mL) was cooled to −78° C. and TMEDA (2.1 mL, 14 mmol) and nbutyl lithium (1.6M in hexane, 8.8 mL, 14 mmol,) were added dropwise. The mixture was stirred for 15 minutes and was then warmed to −10° C. and stirred for a further 2 hours. The reaction mixture was again cooled to −78° C. and a solution of iodine (3.56 g, 14 mmol) in tetrahydrofuran (10 mL) was added dropwise. The resulting slurry was stirred at −78° C. for 2 hours. The mixture was warmed to 0° C. and was quenched with saturated aqueous sodium thiosulfate solution (50 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 50:50 afforded the title compound as a yellow solid in 38% yield, 655 mg.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:54]([C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:62][C:61]3[CH:63]=[CH:64][C:58]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:59][CH:60]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)cc1
Temperature: 50 °C
Reaction time: 17.5 h
Yield: 82.2 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 0.9 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 7 minutes 4-tert-butylaniline (0.024 mL, 0.15 mmol) was added and the reaction continued at room temperature for 17.5 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an EtOAc/hexane mixture to give the title compound as an off-white solid (33 mg, 81%). 1H NMR (DMSO-d6) δ: 10.08 (s, 1H), 8.13 (s, 1H), 7.65-7.70 (m, 2H), 7.50 (s, 1H), 7.32-7.40 (m, 4H), 7.21 (dt, J=7.0, 2.4 Hz, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 1.28 (s, 9H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc(Oc2ccc(C=O)cc2)cc1
Yield: 84.9 %

Procedure:
A mixture of 4-methoxyphenol (1.0 g, 0.00806 mol), 4-bromobenzaldehyde (1.49 g, 0.00805 mol), CuO (0.64 g, 0.00805 mol), potassium carbonate (1.11 g, 0.00803 mol) in pyridine (100 mL) was refluxed for 60 h. The reaction mixture was filtered into ice/water and the product was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), concentrated and chromatographed with CH2Cl2 to afford 1.56 g (85%) of 4-(4-methoxyphenoxy)benzaldehyde.