Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:22][CH:21]=1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([NH:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:22][CH:21]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cnc(-c2ccncc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cnc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
To a solution of (S)-tert-butyl 1-oxo-3-phenyl-1-(2-(pyridin-4-yl)thiazol-5-ylamino)propan-2-ylcarbamate (0.448 g, 1.1 mmol) in DCM (10 ml, 155 mmol) was added TFA (3.00 ml, 39 mmol). The resulting mixture was allowed to stir at rt for 3 hours. Upon completion, the mixture was concentrated and the residue was purified by HPLC to give 165 mg of (S)-2-amino-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)propanamide 5.3E. 400 MHz 1H NMR (CD3OD) δ: 8.80 (d, J=8.0 Hz, 2H), 8.40 (d, J=8.0 Hz, 2H), 7.84 (s, 1H), 7.28-7.37 (m, 5H), 4.40 (dd, J=8.0, 8.0 Hz, 1H), 3.35 (obscured dd, 1H), 3.24 (dd, J=16.0, 8.0 Hz, 1H). LCMS (ES+) m/z 325.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[C:36]([O:40][C:41]([NH:43][C:44]([CH3:50])([CH3:49])[CH2:45][C:46](O)=[O:47])=[O:42])([CH3:39])([CH3:38])[CH3:37].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClC(Cl)C.CCOC(C)=O>[C:36]([O:40][C:41](=[O:42])[NH:43][C:44]([CH3:50])([CH3:49])[CH2:45][C:46]([N:23]1[CH2:22][CH2:21][CH:20]([C:18]2[CH:17]=[CH:16][C:15]([NH:26][C:27]([C:29]3[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=3)=[O:28])=[C:14]([C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=3)[CH:19]=2)[CH2:25][CH2:24]1)=[O:47])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.2 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 14, step (b), 40.0 mg, 0.0818 mmol), 3-tert-butoxycarbonylamino-3-methyl-butyric acid (J. Med. Chem., 34(2), 633-642, (1991), 21.4 mg, 0.0981 mmol) and PyBroP (55.0 mg, 0.0981 mmol) in dichloroethane (2 mL) was added DIEA (43 μL, 0.25 mmol) and the resulting mixture was stirred at RT for 1 day under Ar. The mixture was diluted with EtOAc (30 mL) and washed with H2O (2×10 mL), brine (10 mL), dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 10-40% EtOAc/hexane) to give 33.0 mg (70%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C32H42N6O4, 575.3 (M+H). found 574.8.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[N+:23]([O-])([OH:25])=[O:24].O.[OH-].[Na+]>C(O)(=O)C>[N+:23]([C:5]1[CH:4]=[CH:3][C:2]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[C:1]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2ccccc2OCCCN2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCCN2CCOCC2)c(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-[3-(Biphenyl-2-yloxy)-propyl]-morpholine (t, 500 mg, 1.46 mmol) was dissolved in 3 mL acetic acid and the reaction mixture was cooled in an ice bath. Concentrated nitric acid (3 mL) was added dropwise and the mixture was stirred for 15 minutes at 0° C., then at room temperature for one hour. The reaction was subsequently poured into 100 mL water and the pH of the reaction mixture was raised to >7 with 2N NaOH. The aqueous solution was extracted with ethyl acetate and dried. The solvent was then removed to afford 500 mg 4-[3-(5-nitro-biphenyl-2-yloxy)-propyl]-morpholine (u) which was used without further purification: m/e: 342.15, MS (ES+): 343.1; 1H NMR (500 MHz, CDCl3): 8.2-6.8 (m, 9H), 4.1(m, 2H), 3.7 (m, 4H), 2.5 (m, 6H) and 1.8 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:5]=[C:4]2[N:23]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[N:24]=[C:25]([CH2:26][CH:27]3[CH2:31][O:30]C(C)(C)[O:28]3)[C:3]=12.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[N:5]=[C:4]2[N:23]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[N:24]=[C:25]([CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[C:3]=12
Reactant: COc1ccc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COc1ccc(Cn2nc(CC(O)CO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
The above di-tert-butyl {4-chloro-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (22 g) was dissolved in methanol (400 ml). Pyridinium p-toluenesulfonate (10 g) was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and water (100 ml) was added to the resulting residue, followed by extraction with ethyl acetate (500 ml). The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (19.5 g, 95%) as an amorphous.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[O:26]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:29][CH2:28][CH2:27]1.Cl[C:37]1[S:41][N:40]=[C:39]([CH3:42])[N:38]=1>O1CCOCC1.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:42][C:39]1[N:38]=[C:37]([N:33]2[CH2:34][CH2:35][C:30]3([O:29][CH2:28][CH2:27][O:26]3)[CH2:31][CH2:32]2)[S:41][N:40]=1
Reactant: Cc1nsc(Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nsc(N2CCC3(CC2)OCCO3)n1
Temperature: 130 °C

Procedure:
To a prestirred solution (10 minutes at room temperature) of palladium(II) acetate (180 mg, 0.001 mmol) and 2-(dicyclohexylphosphino)biphenyl (572 mg, 0.002 mmol) in dioxane (10 mL) were added 1,4-dioxa-8-azaspiro(4,5)decane (1.3 mL, 10 mmol), 5-chloro-3-methyl-[1,2,4]thiadiazole (1.48 g, 11 mmol) and sodium tert-butylate (1.47 g, 15 mmol) and heated in the microwave at 130° C. for 15 minutes. The reaction mixture was diluted with half saturated brine, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate as eluent. The title compound was obtained as a light yellow solid (1.87 g, 77%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:25][S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:21](=[CH:22][CH:23]=2)[NH:24][N:39]=[C:25]3[S:26]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
A suspension of 4-[4-amino-3-(1-naphthylsulfonylmethyl)phenoxy]piperidin-1-ylcarboxylic acid benzyl ester (3.2 g, 6.0 mmol) in ethanol and 1.0 N HCl (155 mL) was heated to aid dissolution, treated slowly with sodium nitrite (0.67 g, 9.7 mmol) in water, stirred at ambient temperatures for one hour, basified with solid sodium carbonate, stirred at ambient temperature for 1 hour and concentrated in vacuo. The resultant residue was partitioned in ethyl acetate and brine. The phases were separated; the organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. This residue was purified by flash chromatography with 35-40% ethyl acetate in hexane and 100% ethyl acetate to give 4-[3-(1-naphthylsulfonyl)-1H-indazol-5-yloxy]piperidin-1-ylcarboxylic acid benzyl ester as a light orange foam, 1.79 g (55.9% yield), Mass spectrum (+EI, [M+H]+) m/z 542. 1HNMR (500 MHz, DMSO-d6): δ14.07 (s, 1H), 8.71-8.73 (m, 1H), 8.55 (dd, 1H, J=7.45 Hz and 1.22 Hz), 8.26 (d, 1H, J=8.29 Hz), 8.01-8.03 (m, 1H), 7.70-7.74 (m, 1H), 7.51-7.62 (m, 3H), 7.27-7.35 (m, 5H), 7.23 (d, 1H, J=2.20 Hz), 7.09 (dd, 1H, J=9.03 Hz and 2.32 Hz), 5.06 (s, 2H), 4.59-4.61 (m, 1H), 3.63-3.72 (m, 2H), 3.29-3.33 (m, 2H), 1.83-1.88 (m, 2H), 1.50-1.55 ppm (m, 2H
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:20]2[CH2:23][N:22]([CH3:24])[CH2:21]2)=[C:15]([N+:25]([O-])=O)[CH:14]=1.C(N(CC)CC)C.C1C=CC(O[C:48](OC2C=CC=CC=2)=[N:49][C:50]#[N:51])=CC=1>O1CCCC1.[Pt].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH:20]3[CH2:23][N:22]([CH3:24])[CH2:21]3)/[C:48](=[N:49]/[C:50]#[N:51])/[NH:25][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN1CC(Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])C1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CC(n2/c(=N/C#N)[nH]c3cc(/C=C4/c5ccc(F)cc5OCc5c(F)cccc54)ccc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 151.1 %

Procedure:
Dissolve [4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(1-methyl-azetidin-3-yl)-amine (4.23 mmol, 1.90 g), triethylamine (9.31 mmol, 1.30 mL) in tetrahydrofuran (20 mL), add 5% platinum on carbon (200 mg) and hydrogenate (50 psi) at 35° C. for one hour. Filter off the catalyst, rinse with pyridine (20 mL), add diphenyl N-cyanocarbonimidate (4.65 mmol, 1.11 g) and stir at room temperature overnight under nitrogen. Dilute with ethyl acetate, wash with 5% aqueous sodium bicarbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain approximately 3 g of an orange oil. Purify on an 80 g silica gel column eluting with 5% methanol in dichloromethane to obtain ˜930 mg of a yellow semi-solid. Dissolve in a minimum amount of methanol and let sit. White solids form. After 30 min filter off the solids and rinse with methanol to obtain the title compound as a white solid (815 mg, 41%). LC-MS m/z 470.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH2:13])=O)[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:13])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: NC(=O)c1cc(Br)c2c(c1)CCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(Br)c2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
7-Bromoindane-5-carboxamide (1.94 g, 8.1 mmol) was suspended in CH2Cl2 (50 mL) whereupon POCl3 (1.5 g, 9.8 mmol) was added. Triethylamine (3.5 g, 34.6 mmol), dissolved in CH2Cl2 (10 mL) was added during one minute and an exotermic reaction was observed. The mixture was stirred at room temperature for 30 min and then poured over ice (50 g). The remaining material in the flask was washed out using CH2Cl2 (50 mL) and water (25 mL). The organic layer was washed twice with brine, dried over Na2SO4 and then the solvent was evaporated. The solid residue was treated with cold methanol and then filtrated off. The material was washed with cold methanol and then dried. There was obtained 1.2 g (66%) of 7-bromoindane-5-carbonitrile as a solid material. 1H NMR (300 MHz, CDCl3): 2.1-2.2 (q, 2H), 2.9-3.1 (m, 4H), 7.4 (s, 1H), 7.6 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7].CI.[H-].[Na+].[C:25](OCC)(=O)C>C1COCC1.O>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:18])[CH3:19])[N:5]([CH3:25])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccn1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COC(=O)[C@H](CC(C)C)N(C)C(=O)OCc1ccccn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
N-(2-pyridinylmethoxycarbonyl)-L-leucine methyl ester (490 mg, 1.75 mmol) was dissolved in THF (7.0 mL) and methyl iodide (0.435 mL, 6.99 mmol) was added. The reaction mixture was cooled to 0° C. in a flask protected from moisture. Sodium hydride dispersion (236 mg, 2.62 mmol) was added cautiously and the suspension was stirred for 5 hours at room temperature. Ethyl acetate was then added, followed by water, dropwise. The solution was concentrated in vacuo, and the oily residue partitioned between ether and water. The organic layer was washed with saturated aqueous NaHCO3 and the combined aqueous extracts acidified to pH 3 with citric acid. The product was extracted with ethyl acetate, the extract was washed with water, 5% aqueous sodium thiosulfate and water, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate/hexane, 3:1) to give a yellow oil (235 mg, 46%). MS (ESI): 295.4 (M+H)+.
Reaction SMILES: COC1C=CC(C[S:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]4([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:25])[CH:10]=2)=CC=1.CS(O)(=O)=O>C(Cl)(Cl)Cl>[SH:8][C:9]1[C:14](=[O:15])[N:13]2[C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:17][C:18](=[O:19])[C:12]2=[C:11]([CH3:25])[CH:10]=1
Reactant: COc1ccc(CSc2cc(C)c3n(c2=O)C2(CCCCC2)NC3=O)cc1
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(S)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
6′-((4-Methoxybenzyl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-c]pyridine]-1′,5′-dione (3, 3.3 g, 8.59 mmol) was dissolved in chloroform (20 mL) and methanesulfonic acid (10 mL) was added. The reaction mixture was stirred at 50° C. for 16 h. After completion, solvent was evaporated under reduced pressure. Obtained crude was washed with water (50 mL) followed by ethyl acetate and then dried under reduced pressure to afford 6′-mercapto-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione as grey solid. Yield: 1.3 g, 59%; MS (ESI) m/z 265.6 [M+1]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Reactant: CCOC(=O)c1cc(Cl)nc(C)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc(C)n1
Yield: 21.4 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (94.7 mg, 0.29 mmol), ethyl 6-chloro-2-methylpyrimidine-4-carboxylate (56 mg, 0.28 mmol) (reference: Bioorganic and Medicinal Chemistry Letters; 14; 15; 2004; 3869-3874) and diisopropylethylamine (108 mg, 0.84 mmol), to obtain 27 mg of the title compound as a yellow brown oily substance (22%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[S:14][C:13]([NH2:16])=[N:12][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1COCC1.ClCCl>[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:16][C:13]2[S:14][C:15]3[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=3[N:12]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: COc1ccc(C2CCCCC2)c2sc(N)nc12
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 0.1 g (0.38 mMol) 7-cyclohexyl-4-methoxy-benzothiazol-2-ylamine in 3 ml THF were added 0.2 ml ethyl diisopropyl amine and 0.0865 g (0.46 mMol) 4-chloromethyl-benzoyl chloride, dissolved in 1 ml of dichloro methane. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated to dryness, the residue taken up in dichloro methane and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was triturated in ethyl ether, filtered and dried to yield 0.11 g (68%) of 4-chloromethyl-N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-benzamide as a light yellow foam. ES-MS m/e (%): 415 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[CH2:20][CH2:19]3)O1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:7][C:4]1[S:3][C:2]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[CH2:20][CH2:19]3)=[N:6][CH:5]=1
Reactant: Cc1cnc(Cl)s1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(-c2ccc3c(c2)CCC3=O)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
In a 200 mL flask, a mixture of 2-chloro-5-methylthiazole (1.00 g, 7.48 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 1.93 g, 7.48 mmol) and sodium carbonate (3.18 g, 30 mmol) was dissolved in 68 mL dioxane and 6.8 mL water. The solution was degassed for 15 minutes with nitrogen. Palladium tetrakis(triphenylphosphine) (174 mg, 0.15 mmol) was added and the solution was degassed for an additional 15 minutes. The reaction was heated under reflux for 16 hours. After cooling, the mixture was concentrated to dryness and the residue partitioned between ethyl acetate and water. The water layer was extracted once with ethyl acetate. The combined organic layers were washed twice with water, once with brine, and were dried over anhydrous sodium sulfate. Evaporation afforded the crude product as an orange solid (1.96 g). The material was suspended in a minimal amount of ethyl acetate and was stirred at room temperature for 16 hours. The resulting solid was filtered off and dried to afford the title compound as a brown solid (609 mg, 35%). MS (ES+) 230.2 (M+H+). 1H NMR (CDCl3) δ 2.53 (s, 3H), 2.71-2.75 (m, 2H), 3.18 (t, 2H), 7.56-7.57 (m, 1H), 7.76-7.79 (m, 1H), 7.85-7.89 (m, 1H), 8.02 (br S, 1H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([N:12]1[CH2:17][C:16](=[O:18])[N:15](C(=O)C)[CH2:14][C:13]1=[O:22])(=[O:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:9]([N:12]1[CH2:17][C:16](=[O:18])[NH:15]/[C:14](=[CH:1]\[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)/[C:13]1=[O:22])(=[O:11])[CH3:10]
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: O=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)N1CC(=O)N/C(=C\c2ccccc2)C1=O

Procedure:
To a solution of benzaldehyde 4 (0.54 g, 5.05. mmol) in DMF (5 mL) was added compound 1 (2.0 g, 10.1 mmol) and the solution was repeatedly evacuated in a short time to remove oxygen and flushed with Ar, followed by the addition of Cs2CO3 (1.65 g, 5.05 mmol) and the evacuation-flushing process was repeated again. The resultant mixture was stirred for 3.5 h at room temperature. After the solvent was removed by evaporation, the residue was dissolved in the mixture of EtOAc and 10% Na2CO3, and the organic phase was washed with 10% Na2CO3 again and saturated NaCl for three times, dried over Na2SO4 and concentrated in vacuo. The residual solid was recrystalized from MeOH-ether to obtain a off-white solid of 17; yield 1.95 g (79%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[Na+]>C(O)(=O)C.O>[I:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: [I-]
Reactant: Nc1ccc2c(c1)CCCC2=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2cc(I)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a stirred clear solution of 6-amino-3,4-dihydronaphthalen-1(2H)-one (15 g, 93 mmol) in acetic acid (150 mL) and water (150 mL) was added sulfuric acid (5.5 mL, 101 mmol) dropwise at 0° C. A solution of sodium nitrite (12.90 g, 187 mmol) in water (100 mL) was then added dropwise over 40 min at the same temperature. The mixture was stirred at 0° C. for 10 min before being added to a stirred solution of sodium iodide (55.8 g, 372 mmol) in water (600 mL) slowly over 2 h at 0° C. The resulting brown suspension was stirred at 0° C. for 30 min and at room temperature for 1 h. The mixture was extracted with ethyl acetate (400 mL, 2×100 mL). The combined ethyl acetate extracts were washed with water (60 mL), saturated aqueous Na2S2O3 solution until the brown color disappeared, and saturated aqueous K3PO4 (60 mL) solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Flash chromatography purification (330 g silica gel column, gradient elution from 5 to 15% ethyl acetate in hexanes) afforded 6-iodo-3,4-dihydronaphthalen-1(2H)-one (17.3 g, 63.6 mmol) as a solid. LC/MS M+1=273.