Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23].[H-].[Na+].Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23]
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 13.1 %

Procedure:
To a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.56 mmol) in DMF (4 mL), sodium hydride (60% dispersion in mineral oil, 34 mg, 0.84 mmol) was added. After 25 min, β-bromophenetole (0.15 mL, 1.1 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (17:3) and triturating with hexanes gave 35 mg (13%) of a white solid: mp 175.0-176.0° C.; 1H NMR (400 MHz, DMSO) δ 7.53 (d, J=8.8 Hz, 1H), 7.24 (m, 3H), 6.90 (t, J=7.6 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.81 (d, J=7.9 Hz, 2H), 4.60 (m, 2H), 4.17 (m, 2H), 3.67 (m, 2H), 3.61 (m, 2H), 3.14 (t, J=5.3 Hz, 2H), 1.41 (s, 9H); IR (diffuse reflectance) 2967, 2931, 1676, 1493, 1448, 1422, 1406, 1363, 1298, 1245, 1221, 1167, 1118, 754, 690 cm−1; MS (EI) m/z 474 (M+), 333, 95, 92, 79, 78, 76, 67, 64, 57, 55; HRMS (FAB) calcd for C25H28Cl2N2O3+H 475.1555, found 475.1559; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.47; H, 6.11; N, 5.84.
Reaction SMILES: C[C:2]1[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[C:7]([CH3:23])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:24][C:25]([S:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([F:27])[F:26].[CH3:38]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(#N)C>[CH3:38][C:5]1[CH:6]=[C:7]([CH3:23])[C:8]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:2][C:3]=1[NH:4][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[C:29]([S:28][C:25]([F:27])([F:26])[F:24])[CH:30]=1
Reactant: Cc1ccc(N)c(C)c1-n1ccn2nc(-c3cccnc3)cc12
Reactant: O=C(O)c1cccc(SC(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cccc(SC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
80 mg (0.264 mmol) of the compound of Example 11A and 62 mg (0.277 mmol) of 3-[(trifluoromethyl)sulphanyl]benzoic acid were dissolved in 2 ml of DMF, and 120 mg (0.316 mmol) of HATU and 60 μl (0.343 mmol) of N,N-diisopropylethylamine were added in succession. After about 16 h of stirring at RT, the reaction mixture was diluted with 1 ml of acetonitrile and separated into its components by preparative HPLC (Method 36). Pooling of the product fractions, evaporation and drying under high vacuum gave 89 mg (95% pure, 63% of theory) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][C:16](=[O:18])[CH2:15][C@H:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[O:18]=[C:16]1[CH2:17][C@@H:13]([CH:12]=[O:11])[C@H:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1
Reactant: O=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C[C@@H]1CC(=O)C[C@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
To a solution of oxalyl chloride (1.15 mL, 13.1 mmol) in methylene chloride (30 mL) at −70° C. was added dropwise DMSO (1.87 mL, 26.3 mmol). After 15 min, a solution of (+−)-trans-1-hydroxymethyl-4-oxo-2-phenylcyclopentane from Step C (1.0 g, 5.26 mmol) in methylene chloride (10 mL) was added. The reaction was stirred at −70° C. for 1.5 h and then DIPEA (9.25 mL, 53 mmol) in methylene chloride (10 mL) was added dropwise over 5 min. After a further 10 min, the mixture was allowed to warm to rt for 1 h and then diluted with methylene chloride and poured into dilute aq. HCl. The layers were separated. The aq. layer was reextracted with a second portion of methylene chloride and the organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC (30% ethyl acetate in hexanes) to give the title product (0.9 g) after vacuum drying.
Reaction SMILES: S([O-])(O)(=O)=O.[Na+].[CH2:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15]OC=C)[CH:8]1[O:10][CH2:9]1.C(=O)([O-])[OH:20].[Na+]>O>[CH2:7]([O:11][CH:12]([OH:20])[CH2:13][CH2:14][CH3:15])[CH:8]1[O:10][CH2:9]1
Reactant: O=C([O-])O
Reactant: C=COCCCCOCC1CO1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCCC(O)OCC1CO1
Yield: 94 %

Procedure:
A 1-L four-necked separable flask was charged with 5.0 g of sodium hydrogen sulfate and 140 g of pure water and then provided with a stirrer, a thermometer, an air-introducing tube, and a vacuum pump with a cooling trap. With stirring, 500 g of vinyloxybutyl glycidyl ether synthesized as described above was gradually added to the flask while the liquid temperature was controlled to be kept at 40° C. After the addition was completed, the pressure was reduced to 20 kPa. The mixture was continuously stirred for 1 hour while dry air was introduced at 100 ml/minute. The reaction liquid was then analyzed by gas chromatography. As a result, no peak was observed for vinyloxybutyl glycidyl ether, and thus, the reaction was completed. After 2.1 g of sodium hydrogen carbonate was added to neutralize the completed reaction liquid, the liquid was concentrated by removing water from the system by distillation using a rotary evaporator. After it was checked that the content of water in the system was 800 ppm or less, the liquid concentrate was filtered and then subjected to distillation (0.4 kPa, distillation temperature 82° C.) using a reduced-pressure distillation apparatus with a Vigreux column, so that butanediol glycidyl ether was obtained with a purity of 99% and a yield of 94%.
Reaction SMILES: OCCN[C:5](=[O:10])[C:6](F)(F)F.[C:11]1(C)[CH:16]=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1.C1C[O:25][CH2:24][CH2:23]1>>[C:24]([O:10][CH2:5][CH3:6])(=[O:25])[CH3:23].[CH3:15][CH2:16][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NCCO)C(F)(F)F
Product: CCCCCC
Product: CCOC(C)=O
Reaction time: 8 h
Yield: 48 %

Procedure:
Aldehyde 6 (2 g, 6.4 mmol, 1 equiv) and N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (7.37 g, 44.8 mmol, 7 equiv) were dissolved in dry THF (30 mL) followed by addition of p-Toluenesulphonic acid (0.21 g, 1.24 mmol, 0.16 equiv) and 5 Å molecular sieves (30 g). The reaction mixture was stirred overnight and quenched with triethylamine the next day. Molecular sieves from the reaction mixture were removed by filtering with a buckner funnel. A 150 mL portion of water was added to the filtrate and the reaction mixture was extracted with 5×150 mL portion of ethyl acetate. The ethyl acetate was evaporated and the yellow oil was loaded onto the silica gel column. The product was purified by eluting the column with 2/1 hexane/ethyl acetate, 1/1 hexane/ethyl acetate, 1/2 hexane/ethyl acetate and finally with ethyl acetate alone to afford light yellow colored solid. The product was recrystallized twice from ethyl acetate/hexane (1.9 g, 48% yield). Mp: 87.5-88.9° C. IR (cm−1): 3306 (b), 2886 (s), 1714 (s), 1564 (s), 1157 (s). 1H NMR (300 MHz, CDCl3): δ3.34 (s, 3 H), 3.36-3.65 (m, 8 H), 3.71-3.84-3.73 (m, 12 H), 3.79 (t, 2 H, J=4.8), 4.09 (t, 2 H, J=5.2), 5.49 (s, 1 H), 7.1 (m, 3 H,), 7.25 (m, 1 H), 9.85 (s, 1 H). 13C NMR (CDCl3) δ 42.60, 56.12, 61.34, 64.44, 69.31, 70.32, 70.75, 71.07, 71.67, 100.57, 114.82, 117.81, 121.57, 123.05, 129.15, 137.62, 156.40 (q, J=35), 164.2 (s). Calcd: [M+H]+ (C24H35O9F6N2) m/z=609.224. Found FAB-HRMS: [M+H]+=609.2246. Anal. Calcd: C, 47.37; H, 5.63; N, 4.60. Found C, 47.68; H, 5.32; N, 4.53.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:19](Cl)(Cl)(Cl)=[O:20].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:19]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:20])[C:13]1=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(N[C@H]1CCCNC1=O)OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(N[C@H]1CCCN(P(=O)(Nc2ccccc2)Nc2ccccc2)C1=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of (3S)-3-benzyloxycarbonylamino-2-piperidone (2.48 g, 9.99 mmol) in tetrahydrofuran (30 mL) was cooled at an external temperature of −78° C., followed by adding dropwise thereto an n-butyllithium-hexane solution (1.50 M, 6.5 mL, 9.75 mmol) over a period of 20 minutes, and the resulting mixture was stirred at the same temperature for 30 minutes. Subsequently, a solution of phosphorus oxychloride (1.53 g, 9.98 mmol) in tetrahydrofuran (3 mL) was added thereto and stirred for 20 minutes, after which aniline (d=1.022, 4.1 mL, 44.99 mmol) was added thereto and stirred for 1.5 hours.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[NH:23])[NH:20][O:21][CH3:22])[C:3]=1[S:24]([CH3:26])=[O:25].[CH3:27]C(C)([O-])C.[K+].IC>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:23][CH3:27])[NH:20][O:21][CH3:22])[C:3]=1[S:24]([CH3:26])=[O:25]
Reactant: CONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN=C(NOC)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 16 h
Yield: 25.3 %

Procedure:
A solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-4-methylsulfinyl-1H-pyrazole-3-carboximidamide (0.5 g) in anhydrous THF was stirred at 0-5° C. and potassium tert-butoxide (0.13 g) and iodomethane (0.081 ml) added. After three hours further potassium tert-butoxide (0.068 g) and iodomethane (0.08 ml) were added at 0-5° C. The mixture was stirred at this temperature for 16 hours, evaporated and the residue purified by chromatography on silica gel eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-N-methoxy-N′-methyl-4-methylsulfinyl-1H-pyrazole-3-carboximidamide (0.13 g), m.p. 139-142° C. Compound 50.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH2:22][CH:23]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:4]=1.[CH:38]([N:41]([CH:52]([CH3:54])[CH3:53])[CH2:42][CH2:43][NH:44][C:45](N1C=CN=C1)=[O:46])([CH3:40])[CH3:39]>>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[CH2:22][NH:21][C:5]2[N:4]=[C:3]([CH2:2][NH:1][C:45]([NH:44][CH2:43][CH2:42][N:41]([CH:52]([CH3:54])[CH3:53])[CH:38]([CH3:39])[CH3:40])=[O:46])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(CNc2nc(CN)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ccc(C)cc2)cc1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Product: Cc1ccc(C(CNc2nc(CNC(=O)NCCN(C(C)C)C(C)C)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from (2R,3R,4S,5R)-2-(2-(aminomethyl)-6-{[2,2-bis(4-methylphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (Preparation 60) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 27) using a similar procedure to that used in Example 36.
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:4][N:3]2[CH:15]=[CH:16][N:17]=[C:2]12.[I:18]N1C(=O)CCC1=O>CN(C)C=O>[I:18][C:15]1[N:3]2[C:2]([S:1][C:5]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)=[N:4]2)=[N:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(Nc2nn3ccnc3s2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nn3c(I)cnc3s2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 16 %

Procedure:
Imidazo[2,1-b][1,3,4]thiadiazol-2-yl-(4-methoxyphenyl)amine (0.455 g, 1.85 mmol) was dissolved in N,N-dimethylformamide (8 mL) and N-iodosuccinimide (2.03 mmol, 0.48 g) was added in one portion. The reaction mixture was stirred at room temperature for 22 hours in the absence of light. Solvent was evaporated and the residue was purified by column chromatography (Biotage™/Flash, silica, ethylacetate:dichloromethane 2:8 to 0:10) to give 0.11 g of (5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-(4-methoxyphenyl)amine as an off-white solid (16% yield).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1cccc(-c2cc3ncccc3c(Cl)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2cc3ncccc3c(Cl)n2)c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a solution of 5-chloro-7-(3-methoxyphenyl)-[1,6]naphthyridine (0.052 g, 0.2 mmol) in dichloromethane (2 mL) was added boron tribromide (1 M solution in dichloromethane, 0.4 mL, 0.4 mmol) at −78° C. The resulting mixture was slowly warmed to room temperature. The residue was quenched with water and neutralized with aqueous sodium carbonate. The aqueous solution was then extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a tan oil. Purification by flash chromatography eluting with hexanes/EtOAc (1:1) afforded the title compound as a yellowish solid (0.040 g). 1H NMR (DMSO-d6, 400 MHz) δ 9.70 (b, 1H), 9.19 (dd, 1H), 8.54-8.64 (m, 1H), 8.37 (s, 1H), 7.77(dd, 1H), 7.64 (m, 2H), 7.32 (t, 1H), 6.87 (m, 1H); MS (m/e) calculated for C16H13ClN2O 256, found 257.5 (M+H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].CO.[N:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[N+:27]=[N-:28]>CN(C)C=O.[Cu]I>[C:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:28]=[N:27][N:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[O:23])[CH2:8][C@@H:9]1[CH3:22])(=[O:21])[CH3:20]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: COC(=O)CN=[N+]=[N-]
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)nn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (408 mg, 1.298 mmol) in N,N-dimethylformamide (DMF) (8 mL) and methanol (0.9 mL) were successively added methyl azidoacetate (299 mg, 2.60 mmol) and copper(I) iodide (12.36 mg, 0.065 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 2 h then cooled to room temperature and partitioned between brine and AcOEt. The layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue on SP4 using a 25 G silica cartridge (gradient: 2 to 10% MeOH in DCM) gave methyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}acetate (468 mg, 1.046 mmol, 96%) as a viscous yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:6][CH2:5][O:4]1.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:37])=[O:36]>>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:1][CH2:2][C:3]1([CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:6][CH2:5][O:4]1)(=[O:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CN)CCCO1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CNS(=O)(=O)CCCCl)CCCO1

Procedure:
2-Aminomethyl-2-octadecylcarbamoyloxymethyltetrahydrofuran IVb2 is allowed to react and worked by the same procedure as described in (4). The summary of the experimental condition and the physical data of the prodcut are listed in the Table 7.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][NH:10][CH:11]=[C:5]2[N:4]2[C@H:12]3[CH2:17][CH2:16][CH2:15][C@H:13]3[N:14]=[C:3]12.Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:24][CH:25]=3)[CH:11]=[C:5]2[N:4]2[C@H:12]3[CH2:17][CH2:16][CH2:15][C@H:13]3[N:14]=[C:3]12
Reactant: CN1C(=O)c2c[nH]cc2N2C1=N[C@@H]1CCC[C@@H]12
Reactant: ClCc1ccc(-c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)cc2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
A suspension of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (140 mg, 0.61 mmol), 2-(4-(chloromethyl)phenyl)pyridine (0.12 g, 0.61 mmol) and cesium carbonate (400 mg, 1.22 mmol) in anhydrous DMF is stirred at room temperature overnight. The mixture is filtered through a 0.2 μL microfilter. The filtrate is purified by a semi-preparative HPLC to give 41 mg of pure product as off white solids. MS (ESI) m/z 398.2 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:29])[C@H:18]([NH2:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:30]([O-])(O)=[O:31].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:29])[C@H:18]([N:28]=[C:30]=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(C[C@@H](N)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C[C@@H](N=C=O)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 98 %

Procedure:
1-[2-(R)-Amino-3-(4-methoxyphenyl)-propionyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester hydrochloride (2.8 g) was dissolved in 30 mL of dichloromethane followed by addition of 30 mL of NaHCO3 solution (1M) under vigorous stirring. Triphosgene (0.6 g) in 6 mL of dichloromethane was added at 0° C. and the mixture was kept stirring for 0.25 h. The organic layer was separated and the solvent removed in vacuo to yield 1.20 g (98%) of the title compound as a yellow oil. (+)-APCI-MS: 409 (MH+).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C=O)C.[Br:15][C:16]1[C:17](=[O:42])[N:18]([CH2:33][C:34]2[CH:39]=[N:38][C:37]([CH2:40]O)=[CH:36][N:35]=2)[C:19]([CH3:32])=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]>ClCCl>[Br:15][C:16]1[C:17](=[O:42])[N:18]([CH2:33][C:34]2[CH:39]=[N:38][C:37]([CH2:40][Cl:3])=[CH:36][N:35]=2)[C:19]([CH3:32])=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CO)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CCl)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
Cyanurylchloride (0.42 g, 0.0023 mol) was added to DMF (0.52 mL) and stirred at room temperature for 15 min. Then added dichloromethane (15 mL) followed by the addition of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one 1.0 g, 0.0022 mol) and reaction mixture was stirred at room temperature under argon atmosphere. After 1 h, an additional 1.0 mL of DMF was added and the reaction was allowed to proceed for another hour, when a clear solution was obtained. The solution was diluted with dichloromethane (20 mL) and washed with water, dried (Na2SO4), and concentrated to dryness under reduced pressure. The residue was triturated with EtOAc, filtered, washed with EtOAc and dried to afford 0.79 g (77%) of the title compound as a pale yellow powder: 1H NMR (CD3OD/400 MHz) δ 8.66 (s, 2H), 7.73 (m, 1H), 7.05 (m, 2H), 6.56 (s, 1H), 5.52 (s, 2H), 5.33 (s, 2H), 4.74 (s, 2H), and 2.57 (s, 3H); ES-HRMS m/z 470.0051 (M+H C19H16N3O2BrClF2 requires 470.0077).
Reaction SMILES: Br[CH:2]1[CH:10]([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[C:3]1=[O:13].[C:14]([NH2:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:13])[N:22]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:21][CH:2]3[CH:10]([OH:11])[C:9]=2[CH:8]=1
Reactant: O=C1c2ccc(Cl)cc2C(O)C1Br
Reactant: NC(=S)c1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC1c2cc(Cl)ccc2C2(O)N=C(c3ccccc3)SC12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.6 g (2.3 mmol) of 2-bromo-5-chloro-3-hydroxyindan-1-one and 0.473 g (3.45 mmol) of thiobenzamide were dissolved in 5 ml of isopropanol. 0.478 ml (3.45 mmol) of triethylamine was added, and the mixture was then stirred at room temperature for 12 h and subsequently at 50° C. for 8 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel by initially using n-heptane/ethyl acetate 3/1 and then toluene/acetone 5/1. This gave 6-chloro-2-phenyl-8,8a-dihydroindeno[1,2-d]thiazole-3a,8-diol having a melting point of 151-153° C. (with decomposition).
Reaction SMILES: P(Cl)(Cl)([O:3][C:4]1C=CC=CC=1)=O.CO[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:4][O:3][C:21]1[CH:22]=[CH:14][C:15]([N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)=[CH:16][C:17]=1[C:18]([N:30]=[N+:31]=[N-:32])=[O:20]
Reactant: COc1ccc(C(=O)O)cc1N1CCN(C)CC1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(C)CC2)cc1C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 25 mmol (5.3 g) of phenyl dichlorophosphate in 100 ml of dichloromethane is added to a solution of 20 mmol (5 g) of 4-methoxy-3-(4-methyl-1-piperazinyl)benzoic acid (described in J. Med. Chem., 1994, 37, p.2255) and 50 mmol (3.25 g) of sodium azide in 4.05 ml of pyridine. After stirring for 12 hours at ambient temperature, the organic phase is washed with 100 ml of water, dried over magnesium sulphate and concentrated to yield the expected product.