Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:9])C1C=CC=CC=1.Cl.[NH2:18][N:19]1[CH2:24][CH:23]=[CH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([NH:18][N:19]2[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24]2)=[O:9])=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: NN1CC=CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccncc1)NN1CC=CCC1
Yield: 45.9 %

Procedure:
A solution of 4-(phenoxycarbonylamino)pyridine (4.284 g), N-amino-1,2,3,6-tetrahydropyridine hydrochloride (4.038 g) and triethylamine (3.036 g) in chloroform (70 ml) was refluxed for 20 hours. After evaporation of chloroform, the residue was extracted with ethyl acetate (200 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (52 g) using chloroform to give N-[(4-pyridylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (2.005 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[O:20][N:19]=[C:18]([CH3:21])[C:17]=4[CH:22]=3)[C:11](=[O:24])[C:10](=O)[CH:9]2[C:26](=O)[CH2:27][CH3:28])=[CH:4][CH:3]=1.[NH:30]([CH2:32][CH2:33][OH:34])[NH2:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:26]([CH2:27][CH3:28])=[N:31][N:30]([CH2:32][CH2:33][OH:34])[C:10]=3[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[O:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)=[CH:6][CH:7]=1
Reactant: NNCCO
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c3onc(C)c3c2)C1c1ccc(Cl)cc1
Product: CCc1nn(CCO)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3onc(C)c3c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 78 using 5-(4-chlorophenyl)-1-(3,7-dimethylbenzo[d]isoxazol-5-yl)-4-propionylpyrrolidine-2,3-dione (Step 79.1) and 2-hydrazinylethanol. The crude material was purified by silica gel chromatography (hexane/EtOAc/MeOH 90:10:1 to 50:50:5 to 0:10:1). tR: 1.10 min (LC-MS 2); ESI-MS: 451 [M+H]+ (LC-MS 2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][CH:10]=1.[Br:16]N1C(=O)CCC1=O>O1CCCC1>[Br:16][C:9]1[CH:10]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[NH:7][C:8]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1csc(-c2ccc(-c3cccs3)[nH]2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Brc1cc(-c2cccs2)[nH]c1-c1cccs1
Reaction time: 4 h
Yield: 46.6 %

Procedure:
To a solution of 2,5-dithienylpyrrole (130 mg, 0.56 mmol) in 2.5 mL of anhydrous tetrahydrofuran cooled to -78° C. was added N-bromosuccinimide (99.68 mg, 0.56 mmol). After addition was complete the cooling bath was removed and the reaction mixture was allowed to stand in a -20° C. freezer for 4 hours, during which the solution became a brown color. The reaction mixture was concentrated under reduced pressure, carbon tetrachloride was added to precipitate the succinimide, and this mixture was filtered. The filter cake was washed with additional chloroform, the combined filtrates were concentrated, and the resulting oil was chromatographed on silica gel (50 g). Elution with hexane-ethyl acetate, 4:1, furnished 81 mg (46%) of 3-bromo-2,5-dithienylpyrrole.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]2[CH2:23][CH2:24][CH2:25][N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH2:17][CH2:18]2)[CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2]>C(C(O)=O)(F)(F)F.C(Cl)Cl>[C:27]([CH2:26][N:16]1[CH2:15][CH2:14][CH2:13][N:12]2[CH2:25][CH2:24][CH2:23][N:19]([CH2:20][CH2:21][CH2:22][N:9]([CH2:8][C:1]([OH:3])=[O:2])[CH2:10][CH2:11]2)[CH2:18][CH2:17]1)([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CN1CCCN2CCCN(CCCN(CC(=O)OC(C)(C)C)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCCN2CCCN(CCCN(CC(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 3373.4 %

Procedure:
Compound 15 (1.23 g, 2.62 mmol) was dissolved in a 1:1 (vol:vol) mixture of CF3CO2H (TFA) and CH2Cl2 (45 mL). The mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give an oily residue which was triturated with Et2O to provide white solid 16 (31.505 g, 98% yield) (2 equiv TFA calculated on the basis of mass).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[NH:16][N:15]=[C:14]2[CH3:20].C1C(=O)N([I:30])C(=O)C1>CC(O)=O.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([I:30])[CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[NH:16][N:15]=[C:14]2[CH3:20]
Reactant: Cc1n[nH]c(=O)c2c(Nc3ccccc3Cl)c(F)c(F)cc12
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1n[nH]c(=O)c2c(Nc3ccc(I)cc3Cl)c(F)c(F)cc12
Temperature: 85 °C
Yield: 18.5 %

Procedure:
A mixture of 8-(2-chlorophenylamino)-6,7-difluoro-4-methyl-2H-phthalazin-1-one (30 mg, 0.093 mmol) and NIS (24 mg, 0.11 mmol) in AcOH-THF (2 mL/0.5 mL) was heated at 85° C. for 3 minutes The reaction mixture was concentrated in vacuo and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 15% EtOAc in hexanes) to afford 8-(2-chloro-4-iodophenylamino)-6,7-difluoro-4-methyl-2H-phthalazin-1-one (7.7 mg, 17%). MS APCI (−) m/z 446, 448 (M-, Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.96 (s, 1H), 7.86 (s, 1H), 7.60 (d, 1H), 7.53 (dd, 1H), 6.94 (t, 1H), 2.47 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([S:21][C:22]([F:25])([F:24])[F:23])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].O.S>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([S:21][C:22]([F:25])([F:24])[F:23])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[S:28])[CH3:6]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(SC(F)(F)F)c(OC)ccc12
Agent: S
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CN(C)C(=S)c1cccc2c(SC(F)(F)F)c(OC)ccc12
Yield: 73.4 %

Procedure:
N-[[6-Methoxy-5-(trifluoromethylthio)-1-naphthalenyl]carbonyl]-N-methylglycine methyl ester (2.0 g, 5.4 mmoles) was dissolved in dry pyridine (40 ml). Phosphorus pentasulfide (2.37 g, 10.7 mmoles) was added to the pyridine solution. The mixture was heated at refluxed for 4 hr and then poured into warm water at 50° to 80° C. (caution: evolution of copious quantities of H2S). The mixture was extracted with ethyl acetate. The extract was washed successively with 3 N aqueous HCl, water, a saturated aqueous solution of NaHCO3, water and brine, dried (MgSO4) and concentrated to dryness. The residue was recrystallized from ethanol-water to give 1.6 g of the title compound; mp 121°-123° C.; NMR (CDCl3) δ 3.00 (s, 3H), 3.75 (s, 3H), 4.00 (s, 3H), 4.35 and 4.5 (d, 2H), 7.0-8.5 (m, 5H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:53][C:54]1[N:59]=[CH:58][N:57]=[C:56]2[N:60]([C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[C:64]=3[Cl:70])[N:61]=[CH:62][C:55]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[C:51]([C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])[C@@H:41]([O:53][C:54]2[N:59]=[CH:58][N:57]=[C:56]3[N:60]([C:63]4[CH:68]=[CH:67][CH:66]=[C:65]([Cl:69])[C:64]=4[Cl:70])[N:61]=[CH:62][C:55]=23)[CH2:40][O:39][CH2:38][CH2:37][OH:36])=[N:46][CH:47]=1)#[N:52]
Reactant: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NC(=O)[C@H](COCCO)Oc2ncnc3c2cnn3-c2cccc(Cl)c2Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (0.701 mL, 0.70 mmol) was added dropwise to a stirred solution of (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-cyanopyridin-2-yl)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (440 mg, 0.58 mmol) in THF (15 mL) over a period of 1 minute. The resulting solution was stirred at ambient temperature for 3 hours. Saturated ammonium chloride (20 mL) was added to the reaction mixture which was then diluted with EtOAc (25 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were concentrated to remove most of the MeCN and then EtOAc was added. The organic phase was washed sequentially with saturated NaHCO3 and water the organic layer was evaporated to dryness to afford the product (240 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 2.37 (1H, s), 3.81-3.62 (4H, m), 4.14 (2H, m), 6.00 (1H, t), 7.44-7.28 (2H, m), 7.60 (1H, dd), 7.90 (1H, dd), 8.29 (1H, dd), 8.36 (1H, s), 8.49 (1H, dd), 8.52 (1H, s), 9.26 (1H, s); m/z (ES+) (M+H)+=514; HPLC tR=2.13 min.
Reaction SMILES: [Si](OC[CH2:10][C:11]([CH2:21]C=C)([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]#[N:13])(C(C)(C)C)(C)C.ClCCl.[Mn]([O-])(=O)(=O)=O.[K+].S([O-])([O-])=O.[Na+].[Na+].[C:39]([OH:42])(=[O:41])[CH3:40]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[O-2].[O-2].[Mn+4].C(OCC)(=O)C.CCCCCC.O>[C:12]([C:11]1([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:21][O:42][C:39](=[O:41])[CH2:40][CH2:10]1)#[N:13]
Reactant: CC(=O)O
Reactant: C=CCC(C#N)(CCO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Mn+4]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#CC1(Cc2ccccc2)CCC(=O)OC1
Reaction time: 18 h

Procedure:
Combine 2-(2-(t-butyldimethylsilyloxy)ethyl)-2-allyl-3-phenylpropionitrile (1.19 g) and dichloromethane (25 mL) and water (25 mL). Add tetrabutyl ammonium bromide (0.01 g) and acetic acid (8.0 mL). Add potassium permanganate (2.24 g) portionwise over 2 hours. After 18 hours, add sodium sulfite to dissolve the precipitated manganese dioxide. Separate the layers and adjust the pH of the aqueous layer to about 2 using aqueous 1 M hydrochloric acid solution. Extract the aqueous layer three times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give 4-cyano-4-phenylmethyl-δ-valerolactone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12.CC(C)([O-])C.[Na+].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CN(C=O)C>[Br:17][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])=[C:3]2[CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a stirring mixture of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (5.84 g, 18.53 mmol) in THF (110 mL) and DMF (55 mL) was added sodium tert-butoxide (4.45 g, 46.3 mmol) and benzenesulfonyl chloride (4.75 mL, 37.1 mmol). The resulting mixture was stirred at RT for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (ca. 150 mL) and extracted with DCM (80 mL×3). The combined organic layers were dried and concentrated. The residue was purified via normal phase chromatography, eluting with 0-30% ethyl acetate in DCM, to give the title compound (6.27 g). LCMS (A) m/z: 455/457 [M+1]+, Rt 1.35 min (acidic).
Reaction SMILES: [CH2:1]([C@@:4]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].N.C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl>CO.CCOC(C)=O.CN(C=O)C>[CH2:1]([C@@:4]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:31])=[O:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C(=O)O)cc2)C(=O)O1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C(N)=O)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoic acid (12 mg, 0.03 mmol), ammonia in methanol (c.a. 7N, 1 mL, excess), HATU (12 mg, 1.1 equiv.), and DIEPA (11 μL, 2 equiv.) were mixed in 4:1 CH2Cl2 and DMF (2 mL). The mixture was stirred overnight at rt, diluted with EtOAc (5 mL), washed with 5% aq HCl (2×2 mL). The organic layer was concentrated and purified by prep HPLC to afford 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzamide (2 mg, 17.5%) product. LC-MS Method 1 tR=1.4 min, m/z=383 (M+1); 1H NMR (CDCl3) 7.55 (d, 2H), 7.25 (t, 2H), 7.03 (t, 2H), 6.94 (d, 2H), 6.03 (br d, 2H), 5.68 (m, 2H), 5.05 (dd, 2H), 2.95 (m, 1H), 1.54 (d, 3H).
Reaction SMILES: [C:1]1([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[OH:13][CH:8]([C:7]([CH3:15])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:14])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=O)C(C)(C)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)C(C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Following a procedure found in the literature (Ferguson, C. G.; Money, T.; Pontillo, J.; Whitelaw, P. D. M.; Wong, M. K. C. Tetrahedron. 52(47), 1996, 14661-14627) a solution of methyl 3-phenyl-3-methyl-2-oxobutanoate (2.5 g, 12 mmol, from Reference Example 36) in methanol (144 mL) is cooled to 0° C. (ice water bath). Sodium borohydride (0.21 g, 5.5 mmol) is added in three portions over 3 minutes. The reaction mixture is stirred at 0° C. for 10 minutes and then at room temperature for 30 minutes. The reaction mixture is quenched by the addition of 10% aqueous hydrochloric acid solution until pH=6 and then extracted thrice with diethyl ether. The combined extracts are washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfite, and concentrated under reduced pressure to give a light blond liquid, which is combined with the crude material from another reaction. The combined crude material is subjected to flash chromatography to (silica gel, hexanes/ethyl acetate) and provided 2.4 g (80% combined yield) of a clear, colorless oil. TOF MS (ES+): (M+H)=209.1
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:21]1[CH:35]=[CH:34][C:24]([CH2:25][N:26]2[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[O:33]=[S:29]1(=[O:32])[CH2:30][CH2:31][N:26]([CH2:25][C:24]2[CH:34]=[CH:35][C:21]([NH:1][C:2]3[S:3][C:4]([C:10]4[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=4)=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])=[CH:22][CH:23]=2)[CH2:27][CH2:28]1
Reactant: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Product: CS(=O)(=O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)s2)cc1

Procedure:
2-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}amino)-5-[4-(methyl sulfonyl)phenyl]thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[4-(methylsulfonyl)phenyl]thiophene-3-carboxamide (149 mg, 0.503 mmol) and 4-(4-bromobenzyl)thiomorpholine 1,1-dioxide (153 mg, 0.503 mmol) as the starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Oc1ccc(SC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 276.2 %

Procedure:
To a solution of 4-hydroxythiophenol (10 g, 79 mmol) and p-toluenesulphonic acid (100 mg) in dichloromethane (100 ml) was added dihydropyran (16.7 g, 19.8 mmol) and the mixture stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and the residue dissolved in THF (100 ml) and 0.5 M sulphuric acid (20 ml). The mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (200 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica eluting with 25% diethyl ether in hexane afforded the title compound as a white solid (11.5 g, 66%).
Reaction SMILES: [NH:1]1[CH2:3][C@H:2]1[C:4]([OH:6])=[O:5].[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17])([O-:9])=[O:8].[OH-].[Na+]>CC(C)=O>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N@:1]1[CH2:3][CH:2]1[C:4]([OH:6])=[O:5])(=[O:18])=[O:17])([O-:9])=[O:8]
Reactant: O=C(O)[C@@H]1CN1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)C1C[N@@]1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 2 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
The liquid reaction mixture containing 9.21 g (106 mmol) of (S)-aziridine-2-carboxylic acid obtained in Example 1 was cooled to 2° C. and 150 mL of acetone was added thereto at an internal temperature of 2 to 5° C. While maintaining this solution at an internal temperature of −6 to −2° C., a mixture of 26.9 g (121 mmol) of 2-nitrobenzenesulfonyl chloride with 50 mL of acetone was added thereto over 1 hour. Then the reaction was continued as such for additional 2 hours. During the reaction, a 30 wt. % aqueous solution of sodium hydroxide was added to maintain the reaction system at pH 10.0 to 10.5 The obtained liquid reaction mixture contained 26.9 g (99 mmol) of (S)-N-2-nitrobenzenesulfonyl-aziridine-2-carboxylic acid (yield: 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:11])[CH2:9][OH:10].N1C=CN=C1.[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.CN(C)C=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:11])[CH2:9][O:10][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC(O)c1ccccc1Br
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC(O)c1ccccc1Br)(c1ccccc1)c1ccccc1
Reaction time: 19 h
Yield: 68.5 %

Procedure:
To a stirred solution of 1-(2-bromophenyl)ethane-1,2-diol (step 1, 5.01 g, 22.6 mmol) and in dichloromethane (20 mL) and imidazole (2.31 g, 33.9 mmol) in N,N-dimethylformamide (20 mL) was added tert-butyldiphenylsilyl chloride (6.53 g, 23.8 mmol) at 0° C. and the mixture was stirred for 19 h at the same temperature. The reaction mixture was diluted with toluene/ethyl acetate (1/3), then washed with water for three times and brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/ethyl acetate (10/1) to afford 7.05 g (68%) of the title compound as a colorless syrup:
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[N+:17]([O-:18])=[C:16]3[CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[N:14]2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:25](I)[CH3:26].O>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[N+:17]([O-:18])=[C:16]3[CH2:19][CH2:20][CH2:21][CH2:22][C:15]3=[N:14]2)=[CH:11][C:5]2[N:6]([CH2:25][CH3:26])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc2N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)COc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21
Temperature: 40 °C

Procedure:
To a solution of 2-(7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl)-4,5,6,7-tetrahydro-1,2,3-benzotriazole-1-oxide (0.5 g) in dimethylformamide (5 ml), sodium hydride (0.1 g) and then ethyl iodide (0.3 g) were added, followed by heating at 40° C. for 2 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, dried and recrystallized from a mixture of acetonitrile and isopropanol (1:10) to give Compound No. 2 (0.4 g). m.p., 143°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[C:6]([NH2:30])[CH:5]=1.[CH3:32][CH:33]([CH3:37])[C:34](Cl)=[O:35]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[C:6]([NH:30][C:34](=[O:35])[CH:33]([CH3:37])[CH3:32])[CH:5]=1
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(N)cc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1
Product: COC(=O)c1cc(NC(=O)C(C)C)cc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1

Procedure:
Prepared by general procedure E but using 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-3-aminobenzoic acid methyl ester instead of 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acid methyl ester and 2-methylpropionyl chloride instead of propionyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([OH:24])[CH3:23])=[CH:18][CH:17]=3)[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH2:3][CH2:2]1.O=[C:26]([CH3:40])[CH2:27][CH2:28][N:29]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:29][CH2:28][CH2:27][CH:26]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2([C:16]3[CH:17]=[CH:18][C:19]([CH:22]([OH:24])[CH3:23])=[CH:20][CH:21]=3)[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11]2)[CH2:5][CH2:6]1)[CH3:40]
Reactant: CC(O)c1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(O)c1ccc(C2(C3CCN(C(C)CCN)CC3)Oc3ccccc3O2)cc1

Procedure:
Using general procedure B with the above amine (166 mg, 0.510 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (222 mg, 1.03 mmol) and then using general procedure D afforded 1-(4-{2-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-2-yl}-phenyl)-ethanol as a colourless oil (139 mg, 69% over 2 steps).