Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][NH2:29])=[N:26][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([NH:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][N:26]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Reactant: Cc1ccc(CN)nc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3cc(Br)co3)c2C#N)nc1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(5-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. 387 (M{81Br}+H+, 100), 385 (M{79Br}+H+, 95).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:1][C:2]1([CH2:3][CH2:4][CH:5]=[CH2:6])[O:10][CH2:9][CH2:8][O:7]1
Reactant: C=CCCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCCC1(C)OCCO1
Yield: 46.4 %

Procedure:
In a 200 mL RB flask, 5-hexen-2-one (37.18 g, 0.3788 mol) was mixed with ethylene glycol (23.49 g, 0.3788 mol), 0.72 g p-toluenesulfonic acid monohydrate and 40 mL toluene. A graduated water collector and a reflux condenser were connected to the flask. The mixture was refluxed overnight. The reaction was completed as shown by the amount of water collected (ca. 7 mL). After evaporation of toluene, the mixture was distilled under reduced pressure to gave 25 g of pure product. 1H NMR (CDCl3): δ 1.31 (s, 3H, —CH3); 1.72 (m, 2H, CH2═CHCH2CH2—); 2.13 (m, 2H, CH2═CHCH2CH2—); 3.92 (m, 4H, —OCH2CH2O—); 4.95 (m, 2H, CH2═CH—); 5.80 (m,1H, CH2═CH—).
Reaction SMILES: [C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25])([O-:16])=[O:15]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:28][CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15])[C:24]([CH3:25])([CH3:26])[CH3:27])=[O:11]
Reactant: CC(C)(C)C(O)c1ccccc1[N+](=O)[O-]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
Under a nitrogen atmosphere, (1S)-camphanic acid chloride (3.37 g, 15.6 mmol) was added to a solution of (RS)-1-(2-nitrophenyl)-2,2-dimethyl-1-propanol (2.71 g, 13 mmol) and DMAP (80 mg, 0.65 mmol) in anhydrous pyridine (50 mL). The mixture was stirred for 24 hours at room temperature. Solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (50 mL), washed with 0.5 M HCl (20 mL) twice followed with saturated NaHCO3 solution (20 mL). The organic phase was dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield (RS)-1-(2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (4.11 g, 81%, 1:1 mixture of diastereomers) as a yellow solid. 1H NMR (400 MHz, CDCl3) for diastereomers: δ 7.91 (m, 1 H, Ph-H), 7.62 (m, 2 H, Ph-H), 7.46 (m, 1 H, Ph-H), 6.66 and 6.62 (2 s, 1 H, Ph-CH), 2.38 (m, 1H), 2.10-1.9 (m, 2H), 1.71 (m, 1H), 1.13, 1.11, 1.08, 1.04, 1.03, 0.87 (6s, 9 H, CH3×3), 0.97 (s, 9 H, (CH3)3C).
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[C@@H:26]([F:38])[C@@H:25]2[OH:39])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Si:42](O[C@@H]1[C@@H](CO)O[C@@H](N2C=C(C)C(=O)NC2=O)C1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>>[Si:42]([O:39][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[C@H:26]1[F:38])([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2F)c(=O)[nH]c1=O

Procedure:
This compound is prepared from 1-[2-deoxy-5-O-(4,4'-dimethoxytrityl)-2-fluoro-β-D-arabinofuranosyl]-thymine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilylthymidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C1([Hg][C:23](Br)([Br:25])[F:24])C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:23]2([Br:25])[F:24])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=CSc1ccc(F)cc1
Reactant: FC(Br)(Br)[Hg]c1ccccc1
Product: CCOC(=O)C1C(Sc2ccc(F)cc2)C1(F)Br
Reaction time: 0.5 h

Procedure:
Ethyl 3-(4-fluorophenylthio)-2-propenoate can also be combined with phenyl(dibromofluoromethyl)mercury, in 1:1 ratio, and heated at 80°, with stirring for 30 min, to give ethyl 3-(4-fluorophenylthio)-2-bromo-2-fluorocyclopropanecarboxylate.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:35]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:59]([C:60]([NH2:62])=[O:61])=[C:51]3[NH:52][C:53]4[CH2:58][CH2:57][NH:56][CH2:55][C:54]=4[N:50]3[N:49]=2)=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([N:56]1[CH2:57][CH2:58][C:53]2[NH:52][C:51]3[N:50]([N:49]=[C:48]([C:45]4[CH:44]=[CH:43][C:42]([O:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:47][CH:46]=4)[C:59]=3[C:60]([NH2:62])=[O:61])[C:54]=2[CH2:55]1)=[O:8]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CCNC3
Reactant: CN(C)C/C=C/C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C/C=C/C(=O)N1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (147 mg, 0.88 mmol), HATU (611 mg, 1.6 mmol) and TEA (328 mg, 3.2 mmol) in 50 mL of DCM was stirred at RT for about 2 hr before 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide (300 mg, 0.8 mmol) was added. The mixture was stirred at RT overnight. TLC and LCMS analysis showed that starting material was consumed. To the reaction were added 100 mL of water and 50 mL of DCM. Aqueous phase was further extracted with 50 mL of DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated to get crude product which was chromatographed on 5 g of silica gel using DCM/MeOH (20/1 to 10/1) as eluant to afford 145 mg (37%) of (E)-7-(4-(dimethylamino) but-2-enoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide, which was dried by lyophilization. 1H NMR (400 MHz, DMSO-d6 at 80° C.) δ 11.52 (s, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.42 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.12-6.99 (m, 4H), 6.78-6.56 (m, 2H), 6.22 (s, 2H), 4.75 (s, 2H), 3.89 (t, J=5.6 Hz, 2H), 3.12 (d, J=5.6 Hz, 2H), 2.80-2.72 (m, 2H), 2.22 (s, 6H). MS (ESI) m/e [M+1]+ 484.9.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[C:19]#[N:20])#[CH:13]>>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:13]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=2)[C:19]#[N:20])=[CH:6][CH:5]=1
Reactant: C#Cc1ccc(OC)c(C#N)c1
Reactant: FC(F)Oc1ccc(I)cc1
Product: COc1ccc(C#Cc2ccc(OC(F)F)cc2)cc1C#N

Procedure:
The title compound was prepared in substantially the same manner as described in Example 12, step 3 starting from 1-Difluoromethoxy-4-iodo-benzene (0.17 g, 0.64 mmol), and 5-Ethynyl-2-methoxy-benzonitrile (0.10 g, 0.64 mmol), and was obtained as a light brown solid, (0.170 g, 89%), identified by NMR and mass spectral analyses. MS (APPI+): 299 (M+)
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O>>[CH:2]12[CH:1]3[CH2:7][CH:4]([CH2:5][CH:6]3[O:9][C:8]1=[O:10])[CH2:3]2
Reactant: O=C(O)C1CC2C=CC1C2
Agent: O=S(=O)(O)O
Product: O=C1OC2CC3CC1C2C3
Temperature: 0 °C
Reaction time: 240 h
Yield: 89.2 %

Procedure:
The carboxylic acid (51 g) prepared in Example 1 was slowly added with stirring to sulfuric acid (500 ml, 75 percent by volume). The exothermic reaction that ensued was controlled by an ice-water bath. The reaction subsided after several minutes and the resulting dark solution was then kept at room temperature for about 10 days. The solution was then poured into ice-water (150 ml) and the product then extracted with diethyl ether (three 200-ml portions). The combined extracts were washed with saturated sodium bicarbonate solution (200 ml). The ether was evaporated yielding 45.5 g of 6-oxatricyclo[3.2.1.13,8 ]nonan-7-one which was about 91 percent of theory. The product was identified by GC-mass spectrometric, infrared and melting point analysis.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O.O1CCCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: NCCCCC(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.00 g 5-aminopentanoic acid and 3.62 g of sodium carbonate in 30 ml of water was cooled to 0° C. and 4.41 g of 9-fluorenylmethyl chloroformate in 10 ml of tetrahydrofuran was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was then diluted with water and washed with ether. The aqueous solution was cooled to 0° C. and adjusted to pH 2 with 3N hydrochloric acid. The resulting white solid was collected by filtration and dried to give N-(9-fluorenylmethoxycarbonyl)-5-amino-pentanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][N:19]([CH3:21])[CH3:20])[C:15]([O-:17])=O)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].CCN=C=NCCCN(C)C.[CH:34]1[CH:35]=[CH:36][C:37]2N(O)N=[N:40][C:38]=2[CH:39]=1.NC1C=CC=CC=1>CN(C=O)C>[NH:40]([C:15](=[O:17])[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=1)[CH2:18][N:19]([CH3:21])[CH3:20])[C:38]1[CH:39]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(C)CC(C(=O)[O-])c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [K+]
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CC(C(=O)Nc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h

Procedure:
Crude potassium 2-[4-(tert-butoxycarbonyl)phenyl]-3-(dimethylamino)propanoate (925 mg, ˜2.79 mmol), EDCI (803 mg, 4.19 mmol), and HOBT (491 mg, 3.63 mg) were combined in DMF (15 mL) and stirred for 5 minutes before adding aniline (331 μL, 3.63 mmol). The reaction was stirred at room temperature for 3 h. Additional EDCI (200 mg) was added, and the reaction was stirred for another 3 h. The mixture was concentrated and purified by reverse phase HPLC (50-95% MeCN/water). The resulting residue was dissolved in EtOAc, neutralized with sat. NaHCO3, washed with brine, dried (MgSO4), and concentrated to give tert-butyl 4-{2-anilino-1-[(dimethylamino)methyl]-2-oxoethyl}benzoate as a white solid. 1H NMR (CDCl3) δ 7.97 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.21 (dd, J=8.5, 7.3 Hz, 2H), 6.77 (t, J=7.3 Hz, 1H), 6.72 (d, J=7.9 Hz, 2H), 4.22 (dd, J=8.8, 5.0 Hz, 1H), 3.80 (dd, J=13.8, 9.1 Hz, 1H), 3.40 (dd, J=13.6, 4.8 Hz, 1H), 2.95 (s, 3H), 2.74 (s, 3H), 1.58 (s, 9H). MS (ESI) calcd [M+H]+ 369.2, found 369.2.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][OH:11]>N1C=CC=CC=1.O>[CH3:1][S:2]([O:11][CH2:10][CH2:9][CH:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3]
Reactant: CCCC(CO)CCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC(CCOS(C)(=O)=O)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulphonyl chloride (16.95 g) was added dropwise to a stirred solution of 3-hydroxymethylhexan-1-ol (8.94 g) in pyridine (39.5 g), maintaining the temperature at less than 5° C. Following the addition, the reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with water and extracted with dichloromethane. The extracts were washed successively with water, dilute hydrochloric acid (X 2), water, aqueous sodium bicarbonate, and water, then dried over magnesium sulphate and concentrated to give 3-methanesulphonyloxymethylhex-1-yl methanesulphonate. (16.13 g, 83%) as a yellow oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([OH:11])[CH2:9]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OCCCCO)(=[O:16])C(C)=C>>[C:1]([O:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC(O)CC
Reactant: C=C(C)C(=O)OCCCCO
Product: C=C(C)C(=O)OCC(O)CO

Procedure:
2-hydroxybutyl methacrylate; 4-hydroxybutyl methacrylate;
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(N[S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])C=CC=CC=1>C1COCC1>[C:13]([N:20]1[CH2:25][CH2:24][C:23]([O:26][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[CH:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 90 %

Procedure:
To a stirring solution of diisopropylamine (38.7 mL, 275 mmol) in THF (900 mL) at 0° C. was added dropwise via an addition funnel a solution of n-BuLi in hexanes (1.6 MN 171.5 mL, 276 mmol). After 25 min, the solution was cooled to −78° C. To this solution was added dropwise via an addition funnel a solution of 1-Boc-4-piperidinone (50 g, 250.9 mmol) in THF (300 mL). After 30 min, a solution of N-phenyltrifluoromethanesulfonamide (95.9 g, 268.5 mmol) in THF (300 mL) was added and the solution was warmed to 0° C. After 3 h, the solvents were evaporated in vacuo and the residue was loaded into a silica gel column with a minimal amount of dichloromethane and eluted with 5% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 74.84 g (90%) of a light yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]O.S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:3]2[C:2]([F:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([F:13])[C:4]=2[CH2:5][Cl:27])[CH2:15][CH2:16]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)CC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CCl)CC1
Temperature: 0 °C

Procedure:
To a solution of 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol (8.5 g) in chloroform (85 ml) is added thionyl chloride (2.7 ml) at room temperature. The mixture is stirred at the same temperature for 30 mintues, and the reaction mixture is poured into ice water, and then neutralize with sodium hydrogen carbonate and extracted with diethyl ether. The extract is dried over magnesium sulfate, and then the solvent is distilled off to give 2-(4-ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5-nitrobenzyl chloride (8.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH2:20])[CH3:19])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[NH:33][CH:34]=[N:35]2>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH:20][C:31]1[N:39]=[CH:38][N:37]=[C:36]3[C:32]=1[N:33]=[CH:34][NH:35]3)[CH3:19])=[CH:7]2
Reactant: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N)s1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)Nc2ncnc3[nH]cnc23)s1
Temperature: 130 °C

Procedure:
To a stirred solution of (1S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)-quinolin-3-yl)ethanamine (9 mg, 30 μmol) in 1-butanol (1.5 mL) was added huenig's base (6 μl, 35 μmol) and 6-chloropurine (5 mg, 30 μmol). The reaction was heated to 130° C. for 16 hours and then cooled to room temperature. The crude reaction mixture was purified by reverse phase HPLC (gradient: 20% water in acetonitrile to 85% water in acetonitrile) to give N-((S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.62 (1H, s), 8.05 (1H, s), 7.83-7.89 (2H, m), 7.53-7.57 (1H, m), 2.89 (3H, s), 1.83 (3H, d, J=6.6 Hz). Mass Spectrum (ESI) m/e=423.1 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:20][C:21]([F:24])([CH3:23])[CH3:22])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:18])[C:9]=2[N:19]=1)(=O)C.N.C(Cl)Cl>CO>[NH2:18][C:10]1[C:9]2[N:19]=[C:6]([CH2:5][OH:4])[N:7]([CH2:20][C:21]([F:24])([CH3:23])[CH3:22])[C:8]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(=O)OCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(F)Cn1c(CO)nc2c(N)nc3cccnc3c21
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A solution of [4-amino-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate (1.13 g, 3.41 mmol) dissolved in 10 mL of methanol was treated with 10 mL of a 7% solution of ammonia in methanol. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The resulting solid was treated with H2O and the mixture was heated to reflux for 15 minutes. The mixture was cooled and the resulting light-yellow solid was isolated by filtration. The light-yellow, solid was then treated with 20 mL of CH2Cl2 and the mixture was stirred rapidly for several minutes. The mixture was filtered and the resulting white solid was washed with several portions of cold CH2Cl2 and dried with suction. Crystallization from ethanol/H2O gave 477 mg of [4-amino-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol as fluffy cream colored crystals, mp 240-241° C. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (dd, J=1.5, 4.3 Hz, 1H), 7.93 (dd, J=1.5, 8.4 Hz, 1H), 7.46 (dd, J=4.3, 8.4 Hz, 1H), 6.92 (s, 2H), 5.62 (t, J=5.8 Hz, 1H), 5.33 (br s, 2H), 4.83 (d, J=4.7 Hz, 2H), 1.33 (d, J=20.3 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 154.3, 152.7, 143.1, 140.8, 134.2, 133.4, 133.2, 128.7, 122.5, 96.8 (d, J=170 Hz), 56.7 (d, J=9.5 Hz), 52.7 (d, J=21.4 Hz), 24.5; MS (ESI) m/z 290 (+H)+; Anal. calcd for C14H16FN5O: C, 58.12; H, 5.57; N, 24.21. Found: C, 58.19; H, 5.54; N, 24.16.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12]C(=O)C)[N:10]=[C:6]2[N:5]=[C:4]([CH2:16][O:17]C(=O)C)[CH:3]=1.NC(N)=[S:23]>C(O)C>[OH:12][CH2:11][C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH2:16][OH:17])[CH:3]=[C:2]([SH:23])[N:7]2[N:8]=1
Reactant: NC(N)=S
Reactant: CC(=O)OCc1cc(Cl)n2nc(COC(C)=O)nc2n1
Solvent: CCO
Product: OCc1cc(S)n2nc(CO)nc2n1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
In 300 ml of ethanol was dissolved 14 g of 7-chloro-2,5-bis(acetoxymethyl)-s-triazolo[1,5-a]pyrimidine, and 10.7 g of thiourea was added thereto and the mixture was refluxed for 10 minutes. After removing ethanol from the reaction mixture, the residue was dissolved in 230 ml of a 5 % potassium hydroxide. The mixture was stirred for 30 minutes, ice-cooled and adjusted to pH 2 with 2N hydrochloric acid. Precipitated crystal was collected by filtration, washed with water and dried to obtain 7.16 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=C(O)C=[CH:27][CH:28]=1.S(=O)(=O)(O)O.P(Cl)(Cl)(Cl)=O>>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:19]3[C:18](=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[O:17][C:15](=[O:16])[CH:14]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1cn(Cc2ccccc2)cn1
Reactant: COc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3cn(Cc4ccccc4)cn3)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1 mmol of ethyl 3-(1-benzyl-1H-imidazol-4-yl)-3-oxopropionate and 1 mmol of 3-methoxyphenol [150-19-6] is admixed dropwise at 0° C. with 0.5 ml of concentrated sulphuric acid. 0.25 ml of phosphoryl chloride is added and the reaction mixture is stirred at room temperature for 17 hours. It is poured into a 1:1 mixture of ice and saturated, aqueous sodium hydrogen carbonate solution and extracted with chloroform (3×). The combined organic phases are dried over sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:22][SiH:23]([Cl:25])[Cl:24]>>[CH2:14]([Si:23]([Cl:25])([Cl:24])[Cl:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 94.6 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 0.95 g (7.5 mmol) of benzyl chloride, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.6 g of benzyltrichlorosilane (bp; 140-2° C./10 mmHg, yield; 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:25](=[O:26])[NH:24][CH2:22][CH3:23])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 50 °C
Reaction time: 10 h
Yield: 77 %

Procedure:
5-Chloro-3-(4-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) was dissolved in dry pyridine (15 ml) and the solution was cooled. After ethyl isocyanate (0.9 g) was dropwise added to the solution, the resultant was stirred for 10 hours at 50° C. Pyridine was evaporated off under vacuum from the reaction mixture and the residue was recrystallized from ethanol to yield the title compound as colorless crystals (3.0 g). mp 210°-211° C.