Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[O:14][CH2:13][C@H:12]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][N:11]3[CH2:10]2)=[CH:5][C:4]=1[O:26][CH3:27])#[N:2].[ClH:28]>O1CCOCC1>[ClH:28].[CH3:27][O:26][C:4]1[CH:5]=[C:6]([C@H:9]2[O:14][CH2:13][C@H:12]3[CH2:15][NH:16][CH2:17][CH2:18][N:11]3[CH2:10]2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: COc1cc([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc([C@@H]2CN3CCNC[C@@H]3CO2)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (3R,9aR)-3-(4-cyano-3-methoxyphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (120 mg, 0.321 mmol) was dissolved in 10 Ml of 4 M HCl in dioxane and stirred at room temperature for 8 h. The mixture was concentrated to ¼ the original volume and diluted with 10 Ml of diethyl ether. The precipitate was filtered and dried under high vacuum to offer amine HCl salt: NMR (DMSO-d6, Z (cis) isomer, 500 MHz) δ 7.77 (d, J=7.9 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J=7.9 Hz, 1H), 4.95 (bs, 1H), 4.08 (bs, 2H), 3.96 (s, 3H), 3.85-3.60 (bs, 3H), 3.58-3.34 (m, 6H); LC/MS: (IE, m/z) [M+1]+=274.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[NH3:27]>CO>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:27])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3F)oc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3F)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 62 %

Procedure:
Methyl 2-(2-fluoro-4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxylate (500 mg, 1.43 mmol) was added to ammonia in methanol (30 mL) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol and dried in vacuum to obtain 2-(2-fluoro-4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide as white solid (300 mg, yield 62%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.52-7.56 (t, J=7.6 Hz, 1H), 7.85-7.89 (m, 5H), 7.95-7.97 (d, J=8.4 Hz, 1H), 8.03-8.05 (m, 2H), 8.45-8.49 (t, J=7.6 Hz, 1H); 8.72-8.73 (d, J=4.4 Hz, 2H); LC-MS (ESI) m/z: 334 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:5]=[C:4]2[CH2:21][CH2:22][CH2:23][C:3]=12.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1>>[OH:33][CH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[N:5]=[C:4]3[CH2:21][CH2:22][CH2:23][C:3]=23)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)c3c(n2)CCC3)CC1
Reactant: Nc1ccc(CCO)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Nc3ccc(CCO)cc3)c3c(n2)CCC3)CC1
Yield: 39.5 %

Procedure:
Following general procedure B1, tert-butyl 4-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate (0.050 g, 0.15 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.030 g, 0.22 mmol) to afford the title compound (0.026 g, 40%) as an orange oil. MW=438.56. APCI MS m/z 439 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:10][C:11]([C:13]1[S:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:12])([CH2:7][O:8][CH3:9])[CH2:4][O:5][CH3:6].C(=O)([O-])[OH:20].[Na+].Cl[O-].[Na+]>O>[Cl:18][C:15]1[S:14][C:13]([C:11]([NH:10][C:3]([CH2:4][O:5][CH3:6])([CH2:7][O:8][CH3:9])[C:2]([OH:20])=[O:1])=[O:12])=[CH:17][CH:16]=1
Reactant: O=C([O-])O
Reactant: COCC(CO)(COC)NC(=O)c1ccc(Cl)s1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: COCC(COC)(NC(=O)c1ccc(Cl)s1)C(=O)O
Reaction time: 2 h

Procedure:
0.20 g (0.49 mmol) 5-chloro-thiophene-2-carboxylic acid(1-hydroxymethyl-2-methoxy-1-methoxymethyl-ethyl)-amide are dissolved at room temperature in 3 ml of water/3 ml acetonitrile and combined with 0.08 g (0.51 mmol) 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) and 0.13 g (1.55 mmol) sodium hydrogen carbonate. Then 1.5 ml (3.14 mmol) of 13% sodium hypochlorite is added dropwise and the mixture is stirred for 2 h. The reaction mixture is concentrated by evaporation i.vac. And purified by chromatography through RP material (Microsorb C18 Varian; eluant: water/acetonitrile/trifluoroacetic acid=90:10:0.1=>0:100:0.1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[C:30]([S:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[CH:29][N:28]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>C(O)(C)(C)C>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([S:31][C:30]2[C:23]3[C:22]([NH:1][C@H:2]([C:4]4[N:9]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:8](=[O:16])[C:7]5=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]5[N:5]=4)[CH3:3])=[N:27][CH:26]=[N:25][C:24]=3[N:28]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[CH:29]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1cccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(Cl)c23)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 35.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.22 mmol) was treated with 4-chloro-5-((3-methoxyphenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (109 mg, 0.26 mmol), N,N-diisopropylethylamine (195 μl, 1.12 mmol), cesium fluoride (41 mg, 0.27 mmol) and tert-butanol as a solvent according to the method described in Example 17. The crude was purified using SP1® Purification (0% to 50%, hexane-ethyl acetate) to give 51 mg (35% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[N:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].Cl.O1CCOCC1>C(Cl)Cl.C(Cl)(Cl)Cl>[ClH:34].[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[N:25]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-4-oxo-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methoxy-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (3.33 g, 6.16 mmol) in CH2Cl2 (21 mL) and add trifluoroacetic acid (7.25 mL). Stir for one hour at room temperature and then add 1 N NaOH to adjust to pH=8-10. Extract with EtOAc (3×50 mL) and wash with water (2×50 mL). Collect an off-white solid via vacuum filtration (2.15 g, 79%). Re-dissolve a portion of the crude material (300 mg, 0.68 mmol) in CHCl3 and add 4 N HCl/dioxane solution (about 200 μL). Remove the organic solvent via reduced pressure to dryness to give 316 mg of the titled compound. ES/MS m/z (35Cl) 442.0 [M+1]+.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[C:26]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].N1C=CN=C1.Cl>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C(O)C>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([N:34]2[C:21](=[O:22])[C:5]3[C:4]4[C:19]5[C:8](=[CH:7][CH:6]=3)[C:9]3[C:20]6[C:13]([CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=6[C:18]=5[CH:1]=[CH:2][C:3]=4[C:24]2=[O:23])=[CH:35][CH:36]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(N2C(=O)c3ccc4c5cccc6cccc(c7ccc(c3c47)C2=O)c65)cc1
Yield: 81.3 %

Procedure:
0.70 g (2.17 mmol) of perylene-3,4-dicarboxylic anhydride is mixed with 0.49 g (3.28 mmol) of 4-t-butylaniline, 3.00 g of imidazole and 0.10 g of zinc acetate dihydrate and the mixture is heated at 140°-150° C. for 5 h. While still hot, the mixture is treated with 100 ml of ethanol, and then 200 ml of 10% hydrochloric acid are added. The red suspension is heated until all the ethanol has evaporated, and the product is then filtered off with suction. The red-brown residue is boiled in 10% potassium carbonate solution, the solid residue is filtered off with suction while hot and rinsed several times with hot dist. water. The red residue is dried in a drying cabinet at 120° C. and then recrystallized by extraction with a toluene/methanol mixture to give 0.80 g (81%) of red N-(4-t-butylphenyl)perylene-3,4-dicarboximide which shows a red solid fluorescence. M.p. >330° C. Rf (CHCl3 /silica gel)=0.35.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[C:15]3[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][N:3]=1.O1CCOCC1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.N1C=CC=CC=1>ClS(O)(=O)=O>[N:34]1([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[C:15]4[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:6]=2)(=[O:10])=[O:9])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNCC1
Reactant: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)Cl
Agent: O=S(=O)(O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Nc1ncc(-c2ccc3nccc(-c4ccncc4)c3c2)cc1S(=O)(=O)N1CCCCC1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a cold (5° C.) solution of the 0.456 M solution of 2-amino-5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinesulfonyl chloride (2 mL, 0.912 mmol) in chlorosulfonic acid from above was added anhydrous dioxane (1 mL) and piperidine (1.8 mL, 18.24 mmol). After 30 minutes of stirring, pyridine (1 mL, 12.3 mmol) was added and the reaction mixture stirred for an additional hour at room temperature. The reaction mixture was concentrated in vacuo, the residue dissolved in CH2Cl2 and the pH adjusted to 14 using 6 N NaOH (aq). The solution was extracted with CH2Cl2 (×4) and the combined organic layers dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified twice by silica gel chromatography (0-5% MeOH in EtOAC) to give the title compound as a pale yellow solid (269 mg, 66% yield). MS(ES)+ m/e 446.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Li+]>C(O)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)=[O:30])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(C(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (430 mg, 0.95 mmol) in ethanol (10 mL) and water (2 mL) was treated with lithium hydroxide (46 mg, 1.9 mmol). The reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was then concentrated in vacuo to remove methanol. The resulting aqueous residue was diluted with water (20 mL) and then washed ethyl acetate (1×20 mL). The aqueous layer was then acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (3×40 mL). The combined organic layers were then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-5-carboxylic acid (386 mg, 96%) as a white solid which was used without further purification: mp 172-176° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:39]=[C:38]([O:40][CH3:41])[C:37]([F:42])=[CH:36][C:11]=1[C:12]([CH:14](C(OCC)=O)[C:15]([O:17][CH:18](C1C=CC=CC=1)[C:19]1C=CC=CC=1)=[O:16])=[O:13].FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:39]=[C:38]([O:40][CH3:41])[C:37]([F:42])=[CH:36][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13]
Reactant: CCOC(=O)C(C(=O)OC(c1ccccc1)c1ccccc1)C(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Yield: 94.2 %

Procedure:
In 2 ml of anisole was dissolved 200 mg of diphenylmethyl ethyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoylmalonate, and 2 ml of trifluoroacetic acid was added thereto with ice-cooling, after which the resulting mixture was subjected to reaction at the same temperature for 10 minutes. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 120 mg (yield 94.3%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate.
Reaction SMILES: C1([CH2:7][CH2:8][CH2:9][N:10]([CH2:28][CH2:29][CH:30]=[CH2:31])[CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]3[C:22]([CH3:27])=[N:23][CH:24]=[C:25]([CH3:26])[C:14]=23)CCCCC1.C(C(C)CN(CCCC#C)CCC1C2C(=CC=CC=2)N2C(C)=NC=C(C)C=12)C.CC(C)=CCN(CC(C)C)CCC1C2C(=CC=CC=2)N2C(C)=NC=C(C)C=12>>[CH2:28]([N:10]([CH2:9][CH:8]=[CH2:7])[CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]2[C:22]([CH3:27])=[N:23][CH:24]=[C:25]([CH3:26])[C:14]=12)[CH2:29][C:30]#[CH:31]
Reactant: C=CCCN(CCCC1CCCCC1)CCc1c2ccccc2n2c(C)ncc(C)c12
Agent: C#CCCCN(CCc1c2ccccc2n2c(C)ncc(C)c12)CC(C)CC
Agent: CC(C)=CCN(CCc1c2ccccc2n2c(C)ncc(C)c12)CC(C)C
Product: C#CCCN(CC=C)CCc1c2ccccc2n2c(C)ncc(C)c12

Procedure:
N-(3-cyclohexylpropyl)-N-(3-butenyl)-1,4-dimethylpyrimido[1,6-a]indole-5-ethanamine, N-(2-ethylpropyl)-N-(4-pentynyl)-1,4-dimethylpyrimido[1,6-a]indole-5-ethanamine, and N-(3-methyl-2-butenyl)-N-(2-methylpropyl)-1,4-dimethylpyrimido[1,6-a]indole-5-ethanamine.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[K+:21].O.C(O)(C)C>CO>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2].[K+:21]
Reactant: CCOC(=O)c1ccc(N2CCN(CC)CC2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: CCN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Yield: 97.5 %

Procedure:
To a solution of 69.81 g of ethyl 6-(4-ethyl-1-piperazinyl)pyridine-3-carboxylate in 280 ml of methanol were added 37 g of potassium hydroxide and a small volume of water and the mixture was heated under reflux for one hour. To the reaction solution were added methanol and isopropyl alcohol, the crystal thus precipitated out was recovered by filtration and then dried under reduced pressure to afford 70.65 g of the title compound as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=NN(C)C=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][N:18]1C(B2OC(C)(C)C(C)(C)O2)=C[CH:20]=[N:19]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:19]([CH3:20])[N:18]=[CH:17][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ESI-MS (m/z): 217 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)#[N:25].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine -2,4-dione (35 mg) was dissolved in DMF (0.4 mL) and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-cyanobenzyl bromide (25 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 24 mg of white crystals.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:11](C(C)=O)([CH3:13])=[O:12]>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:12])[CH3:13].[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(=O)C(C)=O
Agent: [Co+2]
Agent: C1C2CC3CC1CC(C2)C3
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 0.3 mol of adamantane, 1.8 mol of biacetyl, 1.5 mmol of cobalt (II) acetate, and 300 ml of acetic acid was stirred at 60° C. under an oxygen atmosphere (1 atm) for 4 hours. The reaction mixture was concentrated to about 20% by weight, extracted with ethyl acetate, dried and washed with hexane to give 1-acetyladamantane in yield of 52% at a conversion rate from adamantane of 87%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=3[C:15]=2[NH:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:10])=[N:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]3[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=3[C:15]=2[NH:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)CCCC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Methyl 5-[(2-{[(5-chloropyridin-2-yl)amino]-carbonyl}benzofuran-3-yl)amino]-5-oxopentanoate (4.44 g) obtained in Example 9(1) is suspended in methanol (50 ml), and thereto is added 2N aqueous sodium hydroxide solution (30 ml) under ice-cooling followed by stirring at room temperature for 2 hours. After evaporating methanol under reduced pressure, the residue is diluted with water and washed with diethyl ether. The separated aqueous layer is acidified with 10% hydrochloric acid under ice-cooling, and the precipitates are collected by filtration. The resulting solid materials are washed successively with water, ethanol and diethyl ether, and dried to give the title compound (3.99 g). ESI-MS M/Z:400/402[M−H]−
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:20]1[CH2:23][C:22](=O)[CH2:21]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O.C(O)(=O)C>[O:20]1[CH2:23][CH:22]([N:17]2[CH2:18][CH2:19][CH:14]([N:11]3[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]3)[CH2:15][CH2:16]2)[CH2:21]1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C3COC3)CC2)CC1
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
In a 100 ml round-bottom flask 2 g (7.42 mmol) of 1-boc-4-(piperidin-4-yl)-piperazine and 1.07 g (14.85 mmol) of 3-oxetanone were dissolved in 30 ml of dichloromethane. 3.16 g (22.27 mmol) of sodium sulfate were added and the reaction was stirred for 10 min. Subsequently, 2.203 g (10.39 mmol) of sodium triacetoxyborohydride were added and the reaction was stirred for 5 min. pH was adjusted to 5-6 with acetic acid and the reaction was stirred over night. Then, 50 ml of water were added and the resulting two phases were separated. The organic phase was washed twice with water dried over MgSO4, filtered and evaporated. The resulting solid was digested in methyl-tert-butyl ether, filtered off, washed with 10 ml of methyl-tert-butyl ether and dried. Flash chromatography (silica gel/gradient from 0 to 20% methanol in dichloromethane) yielded 650 mg of the title compound as a yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:20])=[CH:13][C:3]=1[CH2:4]P(=O)(OCC)OCC.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.[H-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:20])=[CH:13][C:3]=1[CH:4]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1
Reactant: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])cc1F)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(F)c([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
Diethyl 2,5-difluoro-4-nitrobenzylphosphonate (0.67 g, 2.17 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.43 g, 2.17 mmol) were stirred in tetrahydrofuran (8.3 mL) and cooled in an ice bath. Sodium hydride (0.133 g, 2.82 mmol) was added then the reaction was taken off ice bath and stirred for 4 hours at room temperature. The reaction was quenched with water and extracted with dichloromethane, dried (magnesium sulphate), filtered and evaporated under reduced pressure. The crude material was purified by silica chromatography using a dichloromethane solvent system. The solid obtained was triturated with heptane to give the title compound as a yellow solid (0.24 g). 1H NMR (CDCl3, 400 MHz): δ 7.80 (dd, 1H), 7.12 (dd, 1H), 6.24 (s, 1H), 3.54 (t, 2H), 3.45 (t, 2H), 2.40 (t, 2H), 2.56 (t, 2H), 1.48 (s, 9H)
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].F[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[N:11][C:12]([CH3:18])=[N:13]2>CN(C)C=O>[CH3:18][C:12]1[N:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[CH:17][C:8]=2[O:3][CH2:2][CH2:1][OH:4])[N:13]=1
Reactant: Cc1ncc2c(F)cccc2n1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc2c(OCCO)cccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.4 %

Procedure:
To a solution of ethylene glycol (3.05 mL, 55.6 mmol) in N,N-dimethylformamide (50 mL) at room temperature was added sodium hydride (60% dispersion in oil, 0.30 g, 7.50 mmol) portion-wise. The reaction mixture was allowed to stir at room temperature for 30 minutes. A solution of 5-fluoro-2-methylquinazoline (2.22 g, 55.6 mmol) in N,N-dimethylformamide (5 mL) was added and the reaction mixture heated at 85° C. for 14 h. The mixture was allowed to cool to room temperature, quenched by the addition of water and concentrated in vacuo. Chromatography of the residue on SiO2 eluting with 40% ethyl acetate in dichloromethane to ethyl acetate gave the title compound as a yellow solid (0.39 g, 10%).