Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=1.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:17]/[C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:18])=[C:5]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=1
Reactant: COc1ccc(C=O)c(-c2cccs2)c1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1ccc(/C=C/C(=O)c2ccc(C(=O)O)cc2)c(-c2cccs2)c1
Yield: 61 %

Procedure:
The title compound was prepared by condensing 4-methoxy-2-thiophen-2-yl-benzaldehyde (Ex-34A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 61% yield, m.p. 209–211° C. 1H-NMR (300 MHz, d6-DMSO): 8.14 (m, 3H), 8.04 (d, 2H, J=9.2 Hz), 7.89 (d, 1H, J=15.5 Hz), 7.76 (d, 1H, J=15.5 Hz), 7.70 (d, 1H, J=5.0 Hz), 7.18 (dd, 1H, J=5.6 and 3.6 Hz), 7.11 (d, 1H, J=2.1 Hz), 7.05 (dd, 1H, J=8.8 and 1.8 Hz), 6.98 (d, 1H, J=1.8 Hz), 3.83 (s, 3H). MS m/z=364 ([M]+, 100%). HRMS (EI) Calcd. for C21H16O4S: 364.0769. Found: 364.0761.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[PH:10](=[O:13])([OH:12])[OH:11].[CH2:14]([C:16]([CH2:44][CH3:45])([C:18](=O)[C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)[CH3:17])[CH3:15]>C(O)C>[PH:10](=[O:11])([OH:13])[OH:12].[CH2:14]([C:16]([CH2:44][CH3:45])([C:18](=[N:2][OH:3])[C:19]1[N:23]=[CH:22][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)[CH3:17])[CH3:15]
Reactant: CCC(C)(CC)C(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NO
Agent: Cl
Agent: O=[PH](O)O
Solvent: c1ccncc1
Solvent: CCO
Product: CCC(C)(CC)C(=NO)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
Hydroxylamine hydrochloride (0.29 g), then pyridine (7.7 ml), was added under nitrogen to a stirred solution of diethyl 3-oxo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 42) in ethanol (20 ml). The mixture was stirred at room temperature for three hours, then evaporated under reduced pressure. The residue was treated with water, basified to pH 8 with 1M sodium hydroxide solution, and extracted with chloroform. The organic layers were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-oximino-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.90 g, m.p. 190°-192° C.), probably as a single geometric isomer of unknown configuration. NMR (CDCl3): δ1.2(6H,t), 1.95-2.1(2H,m), 3.05(2H,m), 3.95(4H,m), 7.1-7.3(15H,m), 8.0(1H,s), 9.1(1H,br).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6].O>C(O)(=O)C>[C:5]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[C:19]([N+:1]([O-:4])=[O:2])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCC2(CC1)Cc1ccccc1O2
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCC2(CC1)Cc1cc([N+](=O)[O-])ccc1O2
Temperature: 100 °C

Procedure:
3.8 g of nitric acid (sp gr 1.42) in 30 ml of glacial acetic acid is added dropwise to a stirred solution of 4.7 g of 2,3-dihydro-1'-acetylspiro[benzofuran-2,4'-piperidine] in 65 ml of glacial acetic acid. After total addition, the reaction mixture is slowly heated to 100° C. over a 2 hour span and then cooled and poured into 500 ml of water. The diluted mixture is extracted with chloroform and the chloroform extracts are washed sequentially with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and then dried. The chloroform is removed under reduced pressure. The residue is triturated with ether causing an orange precipitate, which is collected and recrystallized first from an ethyl alcohol-ether mixture and then from ethyl alcohol to provide the product, 2,3-dihydro-1'-acetyl-5-nitrospiro[benzofuran-2,4'-piperidine], mp 149°-150° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:28])=[C:11]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([CH3:27])[CH:17]=3)[N:12]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)CCC.[C:48]1(C)C=CC=CC=1>>[CH3:48][O:26][C:24](=[O:25])[CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:3][CH:4]=3)[S:9][C:10]=2[CH3:28])=[CH:17][C:18]=1[CH3:27]
Reactant: Cc1cc(OCCc2nc(-c3ccc(Br)cc3)sc2C)ccc1CCC(=O)O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccn4)cc3)sc2C)cc1C
Temperature: 25 °C

Procedure:
3-(4-{2-[2-(4-Bromo-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid (100 mg, 0.21 mmol) is dissolved in anhydrous toluene (1 mL), degassed, and filled with nitrogen three times. Palladium tetrakis triphenyl phosphine [Pd(PPh3)4, 21 mg, 0.0021 mmol] is added, and the degassing procedure is repeated. 2-tributylstannylpyridine (63 uL, 0.25 mmol) is then added via syringe and the reaction is heated to reflux. The reaction is monitored by HPLC. Upon complete consumption of starting material, the reaction is allowed to cool to room temperature and diluted with ethyl acetate. Celite is added and the mixture is filtered and rinsed with more ethyl acetate and water. The solution is further diluted with water and the two phases are separated. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester is obtained after column chromatography.
Reaction SMILES: C(=O)(O)[O-].[Na+].[I-:6].[Na+].Br[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CC(C)=O>[I:6][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: [I-]
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(CI)OCC

Procedure:
To a solution of sodium bicarbonate (426.2 g, 5074 mmol) in acetone was added sodium iodide (760.3 g, 5074 mmol) and 2-bromo-1,1-diethoxyethane (500 g, 2537 mmol). The reaction mixture was allowed to reflux for 8 hours. The reaction mixture was then filtered and the solvent evaporated. Ether was added and the reaction mixture filtered again. The ether was evaporated, leaving the title compound, 2-iodo-1,1-diethoxyethane, as an oil, which was further purified by column chromatography.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([CH3:6])[CH3:5].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[C:11]([CH3:20])[N:10]=1.[CH2:21](O)C>>[CH3:20][C:11]1[N:10]2[CH:2]=[C:3]([C:4]3([CH3:6])[CH2:21][CH2:5]3)[N:8]=[C:9]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=1
Reactant: CCOC(=O)c1cc(C)nc(N)c1
Reactant: CC(C)C(=O)CBr
Reactant: CCO
Product: CCOC(=O)c1cc(C)n2cc(C3(C)CC3)nc2c1
Temperature: 25 °C
Yield: 21 %

Procedure:
1-Bromo-3-methylbutan-2-one (4.43 g, 26.8 mmol) was dissolved in ethanol (10 mL), and the solution was stirred under heat and reflux for 2 days after adding ethyl 2-amino-6-methylpyridine-4-carboxylate (3.00 g, 16.7 mmol). The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate after adding a sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20→65/35) to give ethyl 5-methyl-2-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-7-carboxylate (835 mg, yield 21%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:47]([NH:51][C:52]([C@@H:54]1[CH2:59][NH:58][CH2:57][CH2:56][NH:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].C(N(C(C)C)CC)(C)C>C(O)CC(C)C>[NH3:1].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:58]2[CH2:57][CH2:56][NH:55][C@H:54]([C:52](=[O:53])[NH:51][C:47]([CH3:49])([CH3:48])[CH3:50])[CH2:59]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CC(C)(C)NC(=O)[C@@H]1CNCCN1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC
Product: N
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A mixture of 0.36 g of 4amino-2-chloro6,7-dimethoxyquinazoline, 1.08 g of (S)-N-tert-butyl-2-piperazinecarboxamide bis-(1S)-(+)-10-camphorsulfonate, prepared as described in U.S. Pat. No. 5,700,364, and 0.94 ml of diisopropylethylamine in 10 ml of isoamyl alcohol was heated at reflux for 9 h. After cooling to room temperature, the solvent was evaporated in vacuo and 50 ml of dichloromethane was added to the residue. The mixture was washed with water (3×20 ml), 5% aqueous Na2CO3 (30 ml), water (3×20 ml), dried (Na2SO4) and evaporated to dryness. The residue was purified by flash chromatography eluting with chloroform:2N methanolic ammonia 100:3 to give 0.173 g (30%) of the desired compound.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[CH3:5][O:6][C:7]1[C:8]([OH:22])=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[C:8]([O:22][CH:2]([CH3:4])[CH3:3])=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OC(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
2-Iodopropane (0.5 ml, 0.005 mol) was added to a suspension of methyl 3,4-dimethoxy-2-hydroxy-6-nitrobenzoate (1 g, 0.0039 mol) and sodium carbonate (1.6 g, 0.015 mol) in dimethylformamide (15 ml) and the reaction stirred at 60° C. for 2 hours. On cooling, the reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was further extracted with ethyl acetate (2×25 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound as a crystalline solid (1.1 g, 74%). 1H-NMR (CDCl3): δ=1.28 (6H, d), 3.94 (9H, m), 4.72 (1H, m), 7.49 (1H, s).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])([CH3:20])[C:18]#[N:19])[C:11]=1[CH3:30]>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([C:21]2[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])([CH3:20])[C:18]#[N:19])[C:11]=1[CH3:30])[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(C(C)(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc(C(C)(C#N)c2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 145.8 %

Procedure:
To a solution of 3-pentanol (140 mg, 1.59 mmol) in 2 ml of dry THF was added sodium hydride (60% in oil, 38 mg) and the mixture was stirred at room temperature for 5 minutes. 2-(6--Choro-2,5-dimethylpyrimidin-4-yl)-2-(2,4,6-trimethylphenyl)-propionitrile (100 mg, 0.319 mmol) was added to the reaction mixture, and the resulting mixture was heated at reflux for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a brown oil (170 mg). The residue was purified through chromatotron using 20% ethyl cetate in hexane as eluent to give a mixture of two isomers as a yellow glass form and oth having a M+ of 365 from GC/Ms. 1H NMR (CDCl3) δ6.8 and 6.76 (s, 2H), 4.08 and 3.96 (m, 1H), 3.25 and 3.22 (s, 3H), 2.36 and 2.30 (s, 3H), 2.21, 2.20 and 2.06 (s, total of 9H), 1.5-1.7 (m, 4H), 1.04 (s, 3H), 0.96 and 0.90 (t, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Br.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:12][O:13][CH3:14])[CH:4]=1
Reactant: COc1cccc(O)c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 3-(methyloxy)phenol (10.38 g, 84 mmol) in tetrahydrofurane (100 ml, SCRC) was added NaH (60% wt., 1.824 g, 76 mmol, Aldrich) portionwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and bromomethyl methyl ether (9.5 g, 76 mmol, SCRC) was then added. The resulting mixture was stirred at room temperature for 2 hours and water (50 ml) was added. The reaction mixture was extracted with ethyl acetate (2 times 50 ml, SCRC) and the combined organic layers were dried over sodium sulphate, evaporated. The residue was purified by column chromatography on silica gel (EtOAc: PE=1:100) to afford the title compound (10.2 g) as a colorless liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[S:9].[C:23](=O)([O-])[O-].[K+].[K+].IC.CS(C)=O>C(OCC)(=O)C>[CH3:23][S:9][C:8](=[N:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)Nc2ccccn2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSC(=Nc1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
Part B: A mixture of tert-butyl 4-(pyridin-2-ylcarbamothioyl)piperazine-1-carboxylate (15.30 g, 47.5 mmol), potassium carbonate (13.10 g, 95.0 mmol), iodomethane (3.00 mL, 47.5 mmol), and DMSO (200 mL) was stirred at 25° C. for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water (×4) and brine, dried over anhyd. sodium sulfate, filtered, and concentrated to provide tert-butyl 4-(methylthio(pyridin-2-ylimino)methyl)piperazine-1-carboxylate (12.00 g) as a waxy solid; 1H NMR (300 MHz, CDCl3) δ 8.25 (m, 1H), 7.63 (m, 1H), 6.88 (m, 2H), 3.70 (m, 4H), 3.52 (m, 4H), 2.04 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[N:17]=1)=[O:15])[CH3:12]>CCN(CC)CC.C(Cl)Cl>[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:19]=[C:18]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:35][CH:36]=2)[N:17]=1)=[O:15])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 23.7 %

Procedure:
Phenyl sulfonyl chloride (0.02 ml, 1.3 eq.), Et3N (1 drop) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (40 mg, 1 eq.) in CH2Cl2 (2 ml) and the mixture was reacted overnight at r.t. The reaction mixture was extracted with EA and washed with brine. The crude was purified by chromatography to give a product (13 mg, 23.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:18]=[C:17]([N:19]2[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])[CH2:20]2)[CH:16]=[C:15]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[C:40](F)[CH:39]=2)[N:14]=1.O.[NH2:48][NH2:49]>C(O)C>[NH2:45][C:44]1[C:41]2[C:40](=[CH:39][C:38]([C:15]3[N:14]=[C:13]([NH:12][CH2:11][C:4]4[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=4[O:2][CH3:1])[N:18]=[C:17]([N:19]4[C@H:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][C@H:21]([C:29]([NH:31][CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)=[O:30])[CH2:20]4)[CH:16]=3)=[CH:43][CH:42]=2)[NH:49][N:48]=1
Reactant: NN
Reactant: COc1ccc(CNc2nc(-c3ccc(C#N)c(F)c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2nc(-c3ccc4c(N)n[nH]c4c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To cis-1-[2-({[2,4-bis(methyloxy)phenyl]methyl}amino)-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (304 mg, 0.48 mmol) in ethanol (6 mL) was added hydrazine monohydrate (0.47 mL, 9.5 mmol), and the reaction mixture was stirred overnight at 100° C. into a sealed tube. The reaction was allowed to cool to room temperature and poured onto water (˜200 mL). A white precipitate was formed. The mixture was filtered, and the solid was air dried for 2 hours to afford the title compound (270 mg) as a white solid. LC-MS (ES) m/z=653 [M+H]+.
Reaction SMILES: [Br:1]Br.[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>CO.CCOCC>[Br:1][CH2:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: CC(=O)CCCCCCCc1ccccc1
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: O=C(CBr)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (5.21 g, 0.033 mol) was added to a solution of 9-phenylnonan-2-one (7.12 g, 0.033 mol) in dry methanol (75 ml) and stirred for 2 hours at room temperature. Water (50 ml) was added and stirring continued for 18 hours at room temperature. Ether (175 ml) and water (100 ml) were added, the organic layer washed with dil. NaHCO3, water (×2), dried (MgSO4) and evaporated under reduced pressure to an oil (5.39 g). Petroleum ether (40° C.-60°C., 50 ml) was added and the mixture cooled to -10° C. and filtered. The solid obtained was re-dissolved in ether (40 ml) and evaporated under reduced pressure to an oil (4.06 g) which was was further purified by flash chromatography on silica gel using hexane/ethyl acetate to give 1-bromo-9-phenylnonan-2-one a pale yellow solid (3.80 g, 39%).
Reaction SMILES: NC1C=CC=CC=1[N:8]1[C:12](=[O:13])[CH:11]([CH2:14][C:15]([OH:17])=O)[S:10][CH:9]1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[2H][C:26]1[C:31]([2H])=[C:30]([NH2:33])[C:29]([NH2:34])=[C:28]([2H])[C:27]=1[2H].Cl.CN(C)CCCN=C=NCC.CC#N>C(Cl)Cl.CN(C=O)C>[NH2:33][C:30]1[CH:31]=[CH:26][CH:27]=[CH:28][C:29]=1[NH:34][C:15](=[O:17])[CH2:14][CH:11]1[S:10][C:9]([NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:8][C:12]1=[O:13]
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Reactant: Nc1ccccc1N1C(=O)C(CC(=O)O)SC1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)CC1SC(Nc2ccccc2)=NC1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
N-(2-Aminophenyl)-2-(2-anilino-4-oxo-4,5-dihydro-1,3-thiazol-5-yl)acetic acid, prepared using method 2 above, (30 mg, 1 eq) was dissolved in a mixture of DCM/DMF (2 mL/2 mL) and O-phenylenediamine (15 mg, 1.1 eq), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 30 mg, 1.3 eq) were then added sequentially. The reaction mixture was stirred 40° C. for 2 h. Separated between DCM and H2O, the organic layer concentrated to give a crude orange brown oil used directly in the next step: HPLC 43%, RT=0.93 min (System B, 2-95% MeCN over 2 min); MS [M+H]m/z=341.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH2:12])=[O:11].[C:13]([CH2:15][C:16](O)=[O:17])#[N:14].CS(Cl)(=O)=O.O.C(O)(C)C>CN(C)C=O>[C:13]([CH2:15][C:16]([NH:12][C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:11])=[O:17])#[N:14]
Reactant: N#CCC(=O)O
Reactant: NC(=O)Nc1ccc(I)cc1F
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)O
Product: N#CCC(=O)NC(=O)Nc1ccc(I)cc1F
Temperature: 25 °C

Procedure:
To a mixture of (2-fluoro-4-iodophenyl)-urea 78 (21.7 g) and cyanoacetic acid 73 (7.88 g) in N,N-dimethylformamide (108 ml) was added, and methanesulfonyl chloride (7.17 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 2 hrs, and water-isopropyl alcohol [1:2 (volume ratio), 210 ml] was added dropwise. The mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration and washed with water to give 1-(2-cyanoacetyl)-3-(2-fluoro-4-iodophenyl)-urea 79 (wet crystals), which was used for the next reaction in the form of wet crystals.
Reaction SMILES: [N:1]([CH:4]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[C:8]2[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:20][N:18]1[CH2:17][CH2:16][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:6]([CH2:5][CH:4]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[NH2:1])[C:7]=2[CH2:19]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CN(C)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CN(C)CC1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 3.4 %

Procedure:
To a solution of 9-(2-azido-2-(pyridin-4-yl)ethyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (800 mg, 2.3 mmol) in ethanol-water (9 mL:1 mL) were added zinc dust (600 mg, 9.2 mmol) and ammonium chloride (490 mg, 9.2 mmol) and the reaction mixture stirred at 85° C. for 45 min. The reaction mixture was filtered and the filtrate concentrated. The residue was basified with aqueous ammonia and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to yield 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(pyridin-4-yl)ethanamine (25 mg). The racemate can be further separated into the optically active forms by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (s, 2H), 7.62 (bs, 2H), 7.23 (s, 1H), 7.0 (d, 1H), 6.98 (d, 1H), 4.9 (m, 1H), 4.8-4.58 (m, 3H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.6-3.4 (m, 2H), 3.1 (bs, 4H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH2:11][CH:12]=O.C(=O)([O-])O.[Na+]>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:11]=[CH:12][N:9]=[C:5]2[CH:4]=1
Reactant: COc1ccnc(N)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccn2ccnc2c1
Yield: 45 %

Procedure:
A stirred suspension of 4-methoxypyridin-2-ylamine (4.50 g, 36.3 mmol), chloroacetaldehyde (8.54 g of a 50 wt % solution in water, 54.4 mmol) and sodium hydrogencarbonate (6.09 g, 72.6 mmol) in ethanol (70 ml) was heated under reflux for 4 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and evaporated to give an orange oil. Purification by silica gel chromatography eluting with 2% methanol in dichloromethane gave 7-methoxyimidazo[1,2-α]pyridine (2.40 g, 45%) as a brown oil. 1H NMR (400 MHz, CDCl3) δH 3.85 (3H, s), 6.50 (1H, d, J 7), 6.88 (1H, s), 7.41 (1H, s), 7.48 (1H, s), 7.92 (1H, d, J 7).