Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[C:37]([CH2:39][CH2:40][CH2:41][OH:42])[N:36]=[C:35]([C:43]#[N:44])[N:34]=2)[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.CCOC(C)=O>[C:23]([C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[C:37]([CH2:39][CH2:40][CH:41]=[O:42])[N:36]=[C:35]([C:43]#[N:44])[N:34]=2)[CH:30]=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cccc(-c2cc(CCCO)nc(C#N)n2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(-c2cc(CCC=O)nc(C#N)n2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dess-Martin periodinane (679 mg) was added to a solution of 4-(3-tert-butyl-phenyl)-6-(3-hydroxy-propyl)-pyrimidine carbonitrile (394 mg) in DCM (5 ml) and the resulting suspension was stirred at room temperature for 45 mins. Reaction mixture was diluted with EtOAc (100 ml) then washed with water (2×100 ml). Organic layer was dried over MgSO4 and concentrated in vacuo. The residue was columned on silica gel using petrol and ethyl acetate (1:1) as eluent to generate 4-(3-tert-butyl-phenyl)-6-(3-oxo-propyl)-pyrimidine-2-carbonitrile as a pale yellow solid (266 mg).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C=O)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21]([C:24]1[CH:25]=[C:26]([CH2:33]O)[C:27]2[O:31][CH:30]=[CH:29][C:28]=2[CH:32]=1)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:4][CH2:33][C:26]1[C:27]2[O:31][CH:30]=[CH:29][C:28]=2[CH:32]=[C:24]([S:21]([C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[O:13][CH3:12])(=[O:23])=[O:22])[CH:25]=1
Reactant: COc1ccc(C)cc1S(=O)(=O)c1cc(CO)c2occc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1S(=O)(=O)c1cc(CCl)c2occc2c1

Procedure:
Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dry DCM (2 mL) and DMF (0.9 mL, 1.1 mmol) was added (very exothermic reaction). {5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-yl}methanol (370 mg, 1.1 mmol; Intermediate 68)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(O)=[O:11]>>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccccc1C(=O)O
Reactant: NCCc1ccccc1
Product: COC(=O)CCc1ccccc1C(=O)NCCc1ccccc1

Procedure:
The sub-title compound was prepared from benzeneethanamine and the product of step (a) using the method of Example 6(a) as a white solid mp 68°-70°.
Reaction SMILES: [C:1]1([C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17]>O1CCCC1>[C:1]1([C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([N:14]2[CH2:21][CH2:20][CH2:19][C@H:15]2[C:16]([OH:18])=[O:17])=[O:13])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C/CC(=O)c1cccs1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: O=C(C/C=C/C(=O)N1CCC[C@H]1C(=O)O)c1cccs1
Reaction time: 2 h

Procedure:
To a mixture of 0.01 mole of 4-(2-thenoyl)crotonic acid in 50 ml. of tetrahydrofuran is added 0.011 mole of N,N'-carbonyldiimidazole. After stirring for 2 hours, L-proline (0.01 mole) is added and the mixture is stirred for 24 hours at room temperature and refluxed for one hour to give 1-[4-(2-thenoyl)crotonyl]-L-proline.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:16]=[CH:15][C:9](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:8][C:7]=1[O:17][CH3:18])[CH2:2][CH2:3][CH3:4].Cl[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:9]1[CH:15]=[CH:16][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([O:17][CH3:18])[CH:8]=1
Reactant: OCCCCCCCl
Reactant: CCCCOc1ccc(/C=C/C(=O)O)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: CCCCOc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC
Yield: 79.3 %

Procedure:
1.38 g (5.50 mmol) (E)-4-butyloxy-3-methoxycinnamic acid was suspended in 3 ml acetonitrile. A mixture of 0.84 g (5.50 mmol) 1,8-diazabicyclo[5 4.0]undec-7-ene(1,5-5) (DBU) and 3 ml acetonitrile was added dropwise over a period of 5 minutes. 0.46 g (1.25 mmol) tetrabutylammonium iodide and 0.68 g (5.00 mmol) 6-chlorohexanol was added and the resulting mixture was then refluxed for 6 hours. The reaction mixture was cooled and then extracted using ethyl acetate and water. The ethyl acetate phase was washed with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography using a silica gel column (120 g) and toluene:ethyl acetate (1:1) as eluant to give 1.39 g (79%) (E)-4-butyloxy-3-methoxycinnamic acid 6-hydroxyhexyl ester as colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[I:12]N1C(=O)CCC1=O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([I:12])=[CH:7]2
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1cccc2cccnc12
Solvent: CC(=O)O
Product: Brc1cccc2cc(I)cnc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 8-bromoquinoline (commercially available, 1.0 g) in glacial acetic acid (6 mL) was added portionwise, N-iodosuccinimide (1.08 g). The resulting mixture was stirred at 70° C. for 18 hours. The reaction was cooled to room temperature and concentrated on a rotary evaporator. The residue was taken up in CH2Cl2 and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica using hexane/ethyl acetate to give 0.74 g of the desired product as a white solid; MS (ES) m/z (relative intensity): 334 (M+H)+ (100).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])CCC.Cl>CN(C=O)C.[Cu]Cl>[CH2:1]([O:3][P:4]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccsc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1sccc1P(=O)(OCC)OCC
Agent: Cl[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1ccsc1-c1sccc1P(=O)(OCC)OCC
Temperature: 80 °C
Reaction time: 10 h
Yield: 71 %

Procedure:
At room temperature, 0.6790 g (1.96 mmols) of the 3-(diethoxyphosphoryl)-2-iodothiophene obtained in Example 12(1) and 0.9982 g (1.96 mmols) of the 2-(tributylstannyl)-3-(diethoxyphosphoryl)thiophene obtained in Example 12(2) were dissolved in DMF, to which 0.2326 g (2.35 mmols) of commercially available copper(I) chloride was added at room temperature. Thereafter, the reaction mixture was heated to 80° C. and stirred for 10 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 10% hydrochloric acid aqueous solution, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (gradiated from ethyl acetate:hexane=1:1 with acetone) to obtain the specified substance in the form of white crystals at a yield of 0.6101 g (yield: 71%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[S:12][C:13]2[CH2:19][C@@H:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:17][CH2:16][C:14]=2[N:15]=1)C1C=CC=CC=1.CCOCC.[BrH:32].CC(O)=O>>[BrH:32].[BrH:32].[N:20]1([C@H:18]2[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([NH2:10])[S:12][C:13]=3[CH2:19]2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: O=C(Nc1nc2c(s1)C[C@@H](N1CCOCC1)CC2)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1nc2c(s1)C[C@@H](N1CCOCC1)CC2
Reaction time: 48 h

Procedure:
Dissolved ((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester (7.46 g, 20.00 mmol) in 25 mL of 33% HBr/AcOH. Stirred mixture for 48 h. LC-MS indicated complete deprotection. Added 200 mL of Et2O resulting in a pale orange ppt. Filtered to give 7.46 mg of (S)-6-Morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-ylaminedihydrobromide a light brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[C:7]1([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26]([CH:28]4[CH2:29][CH2:30]4)=[O:27])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCCSc1ccccc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(Nc1cccc(C2CCN(CCCCSc3ccccc3)CC2)c1)C1CC1

Procedure:
Prepared by Procedure G and Scheme B1 using [(4-chlorobutyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 409.5 (M+H)+.
Reaction SMILES: C[O-].[Na+].[CH:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22]([CH3:24])=[O:23].S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.C(OCC)(=O)C>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](/[CH:24]=[CH:4]/[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:23]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: O=Cc1cccnc1
Agent: C[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(/C=C/c1cccnc1)c1ccc2ccccc2c1
Reaction time: 30 h
Yield: 45.9 %

Procedure:
A 28% solution of sodium methoxide in MeOH (0.90 g) was added to a stirred mixture of nicotinaldehyde (9.70 g) and methyl 2-naphthyl ketone (15.26 g) in MeOH (150 ml). Sodium sulfate (10 g) was added to the mixture and the mixture was stirred for 30 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was recrystallized from cold MeOH to give the titled compound (10.68 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:19]=3)[CH:11]=2)=[O:8])=[CH:5][C:4]=1[C:32]([F:35])([F:34])[F:33].Cl.Cl.[CH3:38][N:39]([CH2:41][C@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1)[CH3:40].C(=O)([O-])[O-].[K+].[K+]>>[CH3:38][N:39]([CH2:41][C@H:42]1[CH2:46][CH2:45][N:44]([CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]4[N:23]=[C:22]([C:24]5[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=5)[CH:21]=[CH:20][N:19]=4)[CH:11]=3)=[O:8])=[CH:5][C:4]=2[C:32]([F:35])([F:34])[F:33])[CH2:43]1)[CH3:40]
Reactant: CN(C)C[C@H]1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccc(CBr)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2ccc(CN3CC[C@H](CN(C)C)C3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
This compound was prepared in the same manner as in Example 47, except that 4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]phenyl}benzamide (Reference Example 82) and (S)-3-(dimethylaminomethyl)pyrrolidine dihydrochloride (Reference Example 35) were used, and that potassium carbonate was used in an amount of 5 equivalents based on a raw material.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:7][N:6]=[C:5]([CH2:8]O)[CH2:4]1.C(N(S(F)(F)[F:16])CC)C>C(Cl)Cl>[Cl:1][CH2:2][CH:3]1[O:7][N:6]=[C:5]([CH2:8][F:16])[CH2:4]1
Reactant: OCC1=NOC(CCl)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCC1=NOC(CCl)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
To a solution of (5-(chloromethyl)-4,5-dihydroisoxazol-3-yl)methanol (1.58 g, 10.56 mmol, 6a rac, Tetrahedron 1986, 42, 5267) in DCM (30 mL) at −78° C. was added (diethylamino)sulfur trifluoride (1.60 ml, 12.11 mmol). The reaction mixture was stirred at −78° C. for 10 min, warmed from −78° C. to room temperature over 15 min, stirred at room temperature for 1 h and quenched with saturated aq. saturated NaHCO3 solution. The reaction mixture was diluted with diethyl ether and water. The aqueous phase was extracted with diethyl ether (4×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to give a dark red oil. Purification by flash column chromatography on silica gel (20% diethyl ether in pentane) gave the title compound (0.79 g, 49% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:8][C:6]1[CH:5]=[C:4]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-Amino-4,6-dichloropyrimidine (1.0 g, 6.1 mmol, Alfa Aesar, Cat. No. A11330), 1-methyl piperazine (0.74 mL, 6.7 mmol, Aldrich, Cat. No. 130001), and N,N-diisopropylethylamine (1.3 mL, 7.3 mmol) in isopropyl alcohol (5 mL) was heated at 110° C. for 2 hours. The reaction mixture was cooled to room temperature (r.t.). The precipitate formed was filtered and then washed by a small amount of isopropanol. The precipitate collected was dried under vacuum to afford this compound and used in the next step without further purification. LCMS(M+H)+: m/z=228.1.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([O:7][C:8]([C:10]1N=C(Br)N2[C:22]3[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)[N:16]([CH3:27])[C:15](=[O:28])[C:14]=12)=[O:9])[CH3:6]>>[CH2:5]([O:7][C:8]([C:10]1[N:1]=[C:2]([SH:3])[N:4]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=3)[N:16]([CH3:27])[C:15](=[O:28])[C:14]=12)=[O:9])[CH3:6]
Reactant: NC(N)=S
Reactant: CCOC(=O)c1nc(Br)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Product: CCOC(=O)c1nc(S)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 43.8 %

Procedure:
To an ethanolic solution (200 ml) of 1-bromo-5-methyl-4-oxo-7-trifluoromethyl-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (1.8 g) was added thiourea (0.4 g). The mixture was refluxed on a steam bath for two hours. After cooling to room temperature, the precipitate was collected, taken up in chloroform and put through a short silica gel dry column (5% methanol in chloroform as eluant). From column, the product was isolated as a white solid (0.7 g, 44% yield). Recrystallized from acetonitrile, m.p. 282° C.
Reaction SMILES: [C:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17])[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[Cl-].[CH2:19]=[N+:20]1[CH2:24][CH2:23][S:22][CH2:21]1>C(#N)C>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH:9]=[C:4]([C:1](=[O:3])[CH2:2][CH2:19][N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=[N+]1CCSC1
Reactant: COC(=O)C(=Cc1ccc(F)cc1Cl)C(C)=O
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)C(=Cc1ccc(F)cc1Cl)C(=O)CCN1CCSC1

Procedure:
3.24 g (12.6 mmol) of methyl 2-acetyl-3-(2-chloro-4-fluorophenyl)acrylate from Example VII are stirred with 1.74 g (12.6 mmol) of 3-methylene-1,3-thiazolidin-3-ium chloride [prepared in analogy to H. Mohrle et al., Z. Naturforsch. 42, 1035–1046 (1987)] in 50 ml of acetonitrile at 40° C. for 48 hours. After concentration, the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulfate and concentrated, and the residue is chromatographed on silica gel with cyclohexane/ethyl acetate (5:1→2:1) as mobile phase.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7](=[O:11])[N:8]([CH2:9][CH3:10])[C:4]=2[CH:3]=1.[O:20]=[S:21]1(=[O:37])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35]Br>>[O:37]=[S:21]1(=[O:20])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35][N:15]1[CH2:14][CH2:13][CH:12]([N:6]2[C:5]3[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]=3[N:8]([CH2:9][CH3:10])[C:7]2=[O:11])[CH2:17][CH2:16]1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Reactant: CCn1c(=O)n(C2CCNCC2)c2ccc(C)cc21
Product: CCn1c(=O)n(C2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccc(C)cc21

Procedure:
From 4-(5-methyl-3-ethyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 22) using the procedures described in Example 1 there was obtained a white solid upon formation of the HCl salt (from methanol), melting point 229-231° C. Analysis calculated for C26H31N4O4S.HCl.0.75 H2O: C, 53.82; H, 5.80; N, 9.66; found: C, 53.79; H, 5.52; N, 9.53. The NMR was consistent with the structure.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O.C(O)(=O)C.S(=O)(=O)(O)O>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[N:5]=[N:1][C:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[C:13]2[OH:21]
Reactant: Cc1cccc(C(=O)Cc2ccccc2)c1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c(O)c(-c3ccccc3)nnc12
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 22.3 %

Procedure:
A solution of sodium nitrite (0.20 g, 2.8 mmol) in water (0.5 mL) was added dropwise, to a solution of 1-(2-amino-3-methylphenyl)-2-phenylethanone (0.42 g, 1.9 mmol) in acetic acid (9 mL) and sulfuric acid (1.5 mL). After the solution was stirred for 20 min at 80° C., the solution was poured into iced water. After the pH was adjusted to 6 with 2 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organics was dried over MgSO4 and concentrated. The material was purified via column chromatography using 5-50% ethyl actetate in hexane as the eluent to yield 0.10 g of 8-methyl-3-phenylcinnolin-4-ol as a gum. MS (ESI) m/z 237; HRMS (ESI, [M+H]+) 237.102;
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C1(C)C=CC=CC=1>[CH3:8][S:9]([O:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](C)O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A stirred solution of (R)-methyl 2-hydroxypropanoate (1.0 g, 9.61 mmol) in toluene (15 mL) was cooled to 0° C. Methanesulfonyl chloride (0.82 mL, 10.6 mmol) was added drop wise. After 2 h, the solution was warmed to room temperature and further stirred for 45 min. The resulting heavy white precipitate was removed by vacuum filtration and the clear solution was concentrated to provide 1.75 g (99%) of (R)-methyl 2-((methylsulfonyl)oxy)propanoate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.14 (q, J=7.0 Hz, 1H), 3.81 (d, J=4.5 Hz, 3H), 3.16 (d, J=4.5 Hz, 3H), 1.62 (d, J=7.0 Hz, 3H). (S)-methyl 2-((methylsulfonyl)oxy)propanoate was prepared in an analogous fashion using (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:9][C:10]([NH:12][NH2:13])=O)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[O:34][CH2:33][CH2:32][N:31]=[C:30](OC)[C:29]=2[CH:37]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:9][C:10]1[N:31]2[CH2:32][CH2:33][O:34][C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:37][C:29]=3[C:30]2=[N:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1=NCCOc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)ccc1F
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)Cc1nnc2n1CCOc1ccc(Cl)cc1-2

Procedure:
By the procedure of Example 5, Step A, the title compound was prepared from tert-butyl[(1R)-1-(2,5-difluorobenzyl)-3-hydrazino-3-oxopropyl]carbamate (Intermediate 2) and 7-chloro-5-methoxy2,3-dihydro-1,4-benzoxazepine (Intermediate 15). LC-MS 491 (M+1).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N+:7]([O-:11])=[CH:6][C:5]=1[Cl:12].[N+](C1C=CC([O:22][C:23]([C:25]2[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]3[O:33][C:32]([CH:34]([O:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH3:35])=[CH:31][C:30]=23)=O)=CC=1)([O-])=O>CN(C)C=O>[Cl:12][C:5]1[CH2:6][N:7]([OH:11])[CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:23]([C:25]1[CH:26]=[CH:27][C:28]([O:43][CH3:44])=[C:29]2[O:33][C:32]([CH:34]([O:36][CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[CH3:35])=[CH:31][C:30]=12)=[O:22]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(C)OC3CCNCC3)oc12
Reactant: Nc1c(Cl)c[n+]([O-])cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC2=C(Cl)CN(O)C=C2Cl)c2cc(C(C)OC3CCNCC3)oc12
Yield: 24.9 %

Procedure:
Prepared from sodium hydride (115 mg of a 60% dispersion in oil), 4-amino-3,5-dichloropyridine-N-oxide (474 mg), 7-methoxy-2-(1-methyl-piperidin-4-yloxymethyl)-benzofuran-4-carboxylic acid 4-nitrophenyl ester (389 mg) in N,N-dimethylformamide. Purification by column chromatography eluting with 20% methanol in dichloromethane afforded the desired product as a light brown solid (106 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[C:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: NCCCc1ccccc1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CCO
Product: N#Cc1c(NCCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and phenylpropylamine in ethanol. ES-MS m/e (%): 320 (M+H+, 100).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([O:15][Si](C)(C)C)[NH:13][C:12]1=[O:20])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21](O)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:21]([O:15][C@H:14]1[NH:13][C:12](=[O:20])[C@@H:11]1[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1O[Si](C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -35 °C
Reaction time: 21 h
Yield: 59 %

Procedure:
After 156 mg of (3R,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one was dissolved in 1.6 ml of ethyl acetate, the mixture was cooled to -35° C. and thereto 0.03 ml (concentration: 1.84% by volume) of acetic acid, 0.5 ml of acetic anhydride and then 30 mg (concentration: 1.36% by weight) of 4-dimethylaminopyridine were added. The mixture was stirred for 21 hours at -35° C. After completion of the reaction and the same treatment as in Example 16, it was analyzed by means of high performance liquid chromatography used in Example 16 to find 83 mg of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (yield: 59%).