Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:3][CH:2]=1.Cl[S:21]([OH:24])(=[O:23])=[O:22].C(=O)=O.CO.[Na+:30].[Cl-]>ClCCl>[Na+:30].[CH:10]([O:9][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([C:14]2[CH:15]=[CH:16][C:17]([S:21]([O-:24])(=[O:23])=[O:22])=[CH:18][CH:19]=2)=[CH:2][CH:3]=1)=[O:13])([CH3:12])[CH3:11]
Reactant: CC(C)OC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)[O-])cc2)cc1
Temperature: -10 °C
Reaction time: 0.42 h
Yield: 92 %

Procedure:
A suspension of isopropyl biphenyl-4-ylcarbamate (256 g, 1 mol) in dichloromethane (2000 ml) was cooled to −10° C. and chlorosulfonic acid (350 g, 200 ml, 3 mol) was added dropwise with stirring within 25 min with gentle cooling using a dry ice-methanol bath. The internal temperature was kept below −4° C. Subsequently, the dry ice-methanol bath was replaced by an ice bath and the mixture was stirred at from 3° C. to 14° C. for 1.5 h. Afterward, chlorosulfonic acid (175 ml, 2.6 mol) was again added at from 2° C. to 3° C., the mixture was stirred again for 30 min and then worked up. To this end, a mixture of ice (5 kg), methylene chloride (1000 ml) and concentrated NaCl solution (1300 ml) was initially charged under vigorous stirring and the reaction mixture was added slowly. The precipitated solid was filtered off with suction and dried at 45° C. under reduced pressure. 329 g (92%) of 4′-isopropoxycarbonylaminobiphenyl-4-sulfonic acid sodium salt were obtained as a white, crystalline powder, m.p.>260° C.,
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:7]([O:9]CC)=O)=[CH:5][N:6]=1.[NH3:12]>CO>[Cl:1][C:2]1[S:3][C:4]([C:7]([NH2:12])=[O:9])=[CH:5][N:6]=1
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)s1
Solvent: CO
Product: NC(=O)c1cnc(Cl)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Dissolve ethyl 2-chlorothiazole-5-carboxylate (0.927 g, 4.84 mmol) in methanol. Cool the solution to 0° C., then bubble NH3 into the reaction mixture for 10 minutes. Then seal the reaction vessel and stir for 3 hours. Concentrate the reaction mixture to give the title product: 1H NMR (CDCl3): 8.21 (s, 1H), 8.19 (s, 1H), 7.77 (s, 1H); HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=6.9 min, 100% purity.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:48]([NH:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][C:56]1[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[C:57]=1[C:58]([O:60][CH3:61])=[O:59])=[O:49])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:33])[C:17](=[O:25])[C:18]([O:20]C(C)(C)C)=[O:19])=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3].C1(C=CC=C(O)C=1)O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:48]([NH:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][C:56]1[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[C:57]=1[C:58]([O:60][CH3:61])=[O:59])=[O:49])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]([C:17]([C:18]([OH:20])=[O:19])=[O:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([OH:34])=[O:33])=[CH:14][CH:15]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)NCCCCOc1cccc(O)c1C(=O)OC
Agent: Oc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)O)c2ccccc2C(=O)O)cc1)C(=O)NCCCCOc1cccc(O)c1C(=O)OC
Yield: 52 %

Procedure:
A mixture methyl 2-{4-[(N-[(allyloxy)carbonyl]-4-{{2-[(benzhydryloxy)carbonyl]phenyl}[tert-butoxy(oxo)acetyl]amino}-L-phenylalanyl)amino]butoxy}-6-hydroxybenzoate (89 mg, 0.10 mmol), 20 mg of resorcinol, and trifluoroacetic acid (1.5 mL) in methylene chloride (2.0 mL) was stirred for 5 hours, concentrated under reduced pressure. The crude product was purified on a Gilson preparative HPLC to provide the titled compound as a white powder (35 mg, 0.052 mmol, 52%). MS (ESI+) m/e 678 (M+H)+, 1H NMR (300 MHz, DMSO-d6) 1.40-1.66 (m, 4H), 2.68-2.83 (m, 1H), 2.83-2.98 (m, 1H), 2.98-3.15 (m, 2H), 3.72 (s, 3H), 3.90 (t, J=5.85 Hz, 1H), 4.09-4.12 (m, 1H), 4.33-4.41 (m, 2H), 5.08 (d, J=10.8 Hz, 1H), 5.18 (d, J=18.0 Hz, 1H), 5.70-5.90 (m, 1H), 6.47 (d, J=8.7 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.38-7.66 (m, 3H), 7.93-8.03 (m, 2H), 9.92 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)O
Reactant: Nc1cccc(F)c1
Solvent: O
Product: O=C(O)CCNc1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
To 3-fluoroaniline (5.0 g), water (50 ml) and acrylic acid (3.6 g) were added and heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was stirred for 3 days and further heated under reflux for 7 hours. After cooling at room temperature, the solvent was distilled off under reduced pressure. To the resulting residue, 8M aqueous sodium hydroxide and chloroform were added to separate the aqueous layer. The separated aqueous layer was adjusted to pH 3 with 12M aqueous hydrochloric acid under ice cooling, and then extracted with chloroform. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=4:1) to give 3-[N-(3-fluorophenyl)]aminopropionic acid (4.2 g) as a light-yellow powder. The compound thus obtained (3.8 g) was added to polyphosphoric acid (35g) heated at 130° C., followed by stirring for 1.5 hours. The reaction mixture was neutralized by addition of water and 8M aqueous sodium hydroxide under ice cooling, and then extracted with chloroform. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 4:1 to 2:1) to give the titled compound of low polarity, i.e., 7-fluoro-2,3-dihydro-1H-quinolin-4-one (810 mg) as a yellow powder. On the other hand, a yellow oil obtained as a compound of high polarity was crystallized from a mixture of n-hexane and diethyl ether to give the other titled compound, i.e., 5-fluoro-2,3-dihydro-1H-quinolin-4-one (110 mg) as a yellow powder.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[CH:5]=[N:4]1)[CH3:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:1]([N:3]1[N:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(2-ethyl-2H-1,2,3-triazol-4-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (2.10 g; compound B21) in DCM (50 ml) is reacted with trifluoroacetic acid (10 ml) according to the procedure described in example B43 to afford the title compound as a solid.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].[F:19][C:20]1[CH:27]=[C:26](F)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>O>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)=[CH:27][C:20]=1[F:19])#[N:23]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 100 °C
Yield: 66 %

Procedure:
A DMSO (25 mL, 0.1 M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 2,4-difluorobenzonitrile (348 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was purified via flash chromatography using 1:1 hexanes/EtOAc as the mobile phase. Isolated 530 mg (1.66 mmol, 66% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:15]Br>O.C(Cl)(Cl)Cl>[Br:15][C:8]1[C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C=O)c(Br)c(OC)c1OC
Yield: 98.2 %

Procedure:
To a stirred refluxing solution of 3,4,5-trimethoxybenzaldehyde (17.0 g, 86.6 mmol) in water (3 mL) and chloroform (100 mL) was added a solution of bromine (14.7 g, 92 mmol) in chloroform (30 mL) dropwise. The solution was heated under reflux overnight, cooled, washed with water (2×100 mL) and saturated aqueous sodium hydrogen carbonate (50 mL), dried over MgSO4, filtered and evaporated. The residual orange oil (27 g) crystallised on standing. The solid was washed with petroleum ether, b.p. 40-60° C., to obtain 2-bromo-3,4,5-trimethoxybenzaldehyde as white crystals (23.4 g, 98%); m.p. 69° C. (literature value 69.5-71° C., see Brown, E.; Robin, J.-P.; Dhal, R. Tetrahedron 1982, 38, 2569-2579); NMR Spectrum δH (300 MHz, CDCl3) 10.40 (1H, s, 1-CHO), 7.29 (1H, s, 6-H), 4.00 (3H, s, OCH3), 3.95 (3H, s, OCH3) and 3.93 (3H, s, OCH3); NMR Spectrum δC (75 MHz, CDCl3) 56.6, 61.6, 106.9, 126.1, 128.1, 149.2, 150.3, 152.8, 189.2; νmax/cm−1 (thin film) 2940, 2843, 1685 (C═O), 1588, 1480, 1460, 1386, 1317, 1196, 1161, 1134, 1103 and 1002 (data in accordance with published values, see Brown, E.; Robin, J.-P.; Dhal, R. Tetrahedron 1982, 38, 2569-2579); Rf(hexane-ethyl acetate 4:1) 0.50.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:27]([NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:28])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc(NCc2ccccc2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(=O)NNc1ccc(N(Cc2ccccc2)C(=S)Nc2ccccc2)cc1

Procedure:
1-Acetyl-2-(4-benzylaminophenyl)hydrazine (2.80 g, 0.011 mole) and phenylisothiocyanate (1.35 g, 0.01 mole) were mixed in ethanol (25 ml) and the resulting mixture was refluxed for 5 minutes. The mixture was chilled in ice and water was added to precipitate the product. The product oiled out of solution, but became crystalline upon standing and scratching. The solid was filtered off and washed with water, then ether. After drying the product was a pale yellow crystalline powder. Yield 3.0 g (77%), m.p. 114°-117° C.
Reaction SMILES: [F:1][C:2]([F:26])([CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[S:9]1(=[O:25])=[O:24])[C:3]([NH:5][CH3:6])=O.B.O1CCCC1.[ClH:33]>C(OCC)C>[ClH:33].[F:26][C:2]([F:1])([CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[S:9]1(=[O:24])=[O:25])[CH2:3][NH:5][CH3:6]
Reactant: CNC(=O)C(F)(F)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNCC(F)(F)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Reaction time: 2 h

Procedure:
To a stirred solution of 2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropanamide (ca. 1 mmol) at 0° C., was added borane-tetrahydrofuran complex (1 M in THF, 3 mL, 3 mmol). After stirring for 2 h, the mixture was quenched with dilute hydrochloric acid, basified (2 N NaOH) and extracted with ethylacetate. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography (hexanes: ethylacetate, gradient elution) to afford the crude product which was further purified by reverse phase hplc (Xterra RP18 19×150 mm, 5 u, 55% MeOH 45% H2O w/0.05% NH4OH, 20 mL/min). The residue obtained was dissolved in diethyl ether, treated with excess ethereal HCl and lyophilized to afford 2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].[CH2:61]([O:65]C=C)[CH2:62]CC.Cl>CN(C=O)C.O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:61]([C:21]1[CH:20]=[C:19]([C:4]2([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:13][CH:14]=3)[N:3]=[C:2]([NH2:1])[N:6]([CH3:7])[C:5]2=[O:8])[CH:24]=[CH:23][CH:22]=1)(=[O:65])[CH3:62]
Reactant: C=COCCCC
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (1.50 g, 3.66mmol), 1,3-bis(diphenylphosphino)propane (DPPP) (0.377 g, 0.915 mmol), K2CO3 (0.606 g, 4.39 mmol), Pd(OAc)2 (82 mg, 0.37 mmol) and n-butylvinylether (1.47 g, 14.6 mmol) in DMF/water (8 ml/0.8 ml) is heated in a microwave oven for 1 h at 120° C., cooled to room temperature, treated cautiously with 15 ml of 5% HCl, stirred at room temperature for 1 h, diluted with water, basified with aqueous K2CO3 and extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by SCX cartridge to give the title compound, 1.20 g (88% yield), identified by NMR and mass spectral analyses. 1H NMR (300 MHz,CDCl3) ppm 8.11 (t, 1 H), 7.87 (dt, 1 H), 7.72-7.80 (m, 1 H), 7.52 (d, 2 H), 7.44 (t, 1 H), 7.08 (d, 2 H), 6.49 (t, 1 H), 3.15 (s, 3 H), 2.59 (s, 3 H). MS [M+H]+ 374.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1.[ClH:29].CC(=O)OCC>CC(=O)OCC>[ClH:29].[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:28])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(C3CCNCC3)cc2)OC1(C)C

Procedure:
A solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (3.0 g, 7.75 mmol) and 10 mL of HCl-EA (5.0 N) in 20 mL of EA was stirred at room temperature for 2 hours. The volatiles were removed in vacuo to give 2.6 g of title compound. MS (m/z)=288 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[O:14]1[CH:18]=[CH:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[O:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 75.4 %

Procedure:
In 50 ml of pyridine were dissolved 2.5 g of 5-fluorouracil and 0.35 g of anhydrous aluminum chloride. To this solution were added 2.3 ml of 2,3-dihydrofuran and the mixture was reacted at 120° C. for 6 hours. A part of the reaction liquid was extracted and subjected to thin layer chromatography to observe the state of proceeding of the reaction whereby the composition of the product was 70% of the end product, 10% of by-products and less than 1% of unreacted 5-fluorouracil. The pyridine was distilled off from the reaction liquid and the residue was shaken with 50 ml of chloroform and a small amount of water and the mixture was separated. The chloroform layer was dried and the chloroform was distilled off. The precipitated crystals were collected by filtration, washed with ether and dried to obtain 2.9 g of 1-(2-tetrahydrofuryl)-5-fluorouracil in a yield of 75.4%, which had a melting point of 167°-168° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][C:5]=2[C:4]=1[NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>ClCCl>[CH:21]1([N:20]2[C:4]3[C:5]4[CH:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:17])[CH3:18])[C:6]=4[N:7]=[CH:8][C:3]=3[CH2:2][NH:1][C:27]2=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(CN)cnc21
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)CNC(=O)N3C1CCCCC1
Yield: 68.6 %

Procedure:
5-(Aminomethyl)-N-cyclohexyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-amine (127 mg, 0.339 mmol) in dichloromethane was stirred with 1,1′-carbonyldiimidazole (65.9 mg, 0.407 mmol) at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a colorless oil (93.2 mg, yield 69%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:6][CH:5]=1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28].CO>CN(C=O)C>[CH3:25][N:26]([CH3:30])[C:27]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:8][CH:9]=1)=[S:28]
Reactant: CN(C)C(=S)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)C(=S)Oc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A suspension of sodium hydride in mineral oil (0.44 g of 60%) in anhydrous DMF (10 mL) was cooled to 0° C. N-[4-(4-hydroxyphenyl)butyl]phthalimide (2.95 g, 10 mmol) dissolved in dry DMF (15 ml) was added into the mixture which was then stirred for 30 min at 0° C. and allowed to warm to room temperature over 1 h. To the mixture was added portionwise N,N-dimethylthiocarbamoyl chloride (1.35 g, 11 mmol) dissolved in DMF (10 ml). The newly formed mixture was stirred at room temperature overnight, then at 50° C. for 1 h, and was cooled back to room temperature, at which point methanol (10 mL) was added into the mixture. The solvent was removed under reduced pressure. The residue was purified by flash chromatography over silica gel (dichloromethane/hexane/ethyl acetate, 10:1:0.2, v/v) to give N-{4-[4-(dimethythiocarbamoyloxy)phenyl]butyl}phthalimide 34 (2.27 g, 59%) as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.72 (m, 4H), 2.66 (m, 2H), 3.33 (s, 3H), 3.45 (s, 3H), 3.70 (m, 2H), 6.96 (d, 2H), 7.18 (d, 2H), 7.71 (m, 2H), 7.84 (m, 2H). m/z (ESI) 383 [C21H22N2O3S+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]3[C:30](O)=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:33][N:34]1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.NO>CN(C=O)C>[OH:33][NH:34][C:30]([C@H:25]1[C@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:29][CH2:28][O:27][CH2:26]1)=[O:31]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCOCC3C(=O)O)cc2)c2ccccc2n1
Agent: CCN=C=N
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCOC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
To a solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid (0.280 g, 0.658 mmol) and 1-hydroxybenzotriazole (HOBT, 0.177 g, 1.32 mmol) in DMF (10 mL) was added 1-(3-dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.253 g, 1.32 mmol) at 0° C. The reaction mixture stirred at 0° C. for 10 min, then warmed to 25° C. over 1 h. After recooling the reaction to 0° C. hydroxylamine (50% by wt in water, 0.6 mL, 6.6 mmol) was added. The reaction was allowed to warm to 25° C. over 19 h. The DMF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL) and this mixture was then washed with saturated aqueous sodium bicarbonate (3×30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude solid (0.170 g) which was purified by Biotage Flash 40S chromatography, eluting with 4% methanol in ethyl acetate, to afford (3S,4R)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid hydroxyamide as an amorphous white solid (0.02 g, 6.6%) that was a 75.7:24.3 mixture of enantiomers, as determined by analytical chiral HPLC (Chiralpak IA column, 7:3 n-propanol/heptane, 1 mL/min, 254 nm). MS: 472 (M+H)+
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[C:6]1([CH:12]2[C:15]3([CH2:17][O:16]3)[O:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[OH:16][CH2:17][C:15]1([N:2]2[N:3]=[N:4][CH:5]=[N:1]2)[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][O:14]1
Reactant: c1nnn[nH]1
Reactant: c1ccc(C2COC23CO3)cc1
Solvent: C1CCOC1
Product: OCC1(n2ncnn2)OCC1c1ccccc1
Reaction time: 1 h
Yield: 41.2 %

Procedure:
1H-Tetrazole (0.078 g, 1.1 mmol) in dry THF (2 mL) was added dropwise to a stirred solution under N2 of 3-phenyl-1,5-dioxaspiro[3.2]hexane (0.15 g, 0.94 mmol) in dry THF (2 mL) at 0° C. The reaction mixture was stirred for 1 hour and then concentrated. The resultant yellow oil was purified by flash chromatography on silica gel (CH2Cl2/methanol 100:0 to 98:2) to provide 2-hydroxymethyl-3-phenyl-2-(tetrazol-2-yl)oxetane as a pale yellow oil (0.090 g, 42%): IR (CDCl3) 3436 (br), 2916, 1319, 1054, 953 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.42 (m, 5H), 5.37 (dd, J=8.6, 6.9 Hz, 1H), 5.16 (dd, J=8.6, 6.1 Hz, 1H), 5.08 (dd, J=6.2, 6.2 Hz, 1H), 4.21 (dd, J=13.5, 7.5 Hz, 1H), 4.17 (dd, J=13.5, 7.4 Hz, 1H), 1.86 (dd, J=7.4, 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.1, 133.2, 129.1, 128.5, 128.1, 100.9, 69.6, 62.6, 47.8; MS (EI) m/z 204 (M+—N2), 185, 173, 104 (100), 91, 78; Anal. calculated for C11H12N4O2: C, 56.89; H, 5.21; N, 24.12. Found: C, 56.76; H, 5.14; N, 23.78.