Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([C:16]#[N:17])=[C:14]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]([C:24]#[N:25])=[C:12]([S:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[S:31][CH:32]=2)[N:11]=1.[ClH:40]>C(#N)C.[Cu](Cl)Cl>[Cl:40][C:10]1[C:15]([C:16]#[N:17])=[C:14]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]([C:24]#[N:25])=[C:12]([S:26][CH2:27][C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[S:31][CH:32]=2)[N:11]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3.85 g (29.55 mmol) of isopentyl nitrite and 3.97 g (29.55 mmol) of copper(II) chloride were initially charged in 40 ml of acetonitrile, and 2.30 g (4.93 mmol) of the compound from Example 45A were added. The reaction mixture was stirred at 60° C. for 3 h. 20 ml of 1N hydrochloric acid were added to the reaction solution. The aqueous phase was extracted twice with in each case 40 ml of ethyl acetate. The combined organic phases were washed in each case once with 20 ml of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed on a rotary evaporator. The residue was purified by column chromatography on silica gel 60 (mobile phase gradient cyclohexane:ethyl acetate=10:1→1:4).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[Br:15][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2ccncc2[nH]1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]c2cnccc2c1Br
Temperature: 20 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 2.24 g of ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate in 150 mL of pyridine is added dropwise a solution of 3.53 g of pyridinium tribromide in 30 mL of pyridine, at 5° C. The reaction mixture is then stirred for 16 hours at a temperature in the region of 20° C., and then washed with 500 mL of ice-cold water. The suspension is filtered. The resulting solid is washed with water and then dried in a vacuum oven at 40° C. 1.97 g of ethyl 3-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate are obtained, the characteristics of which are as follows:
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([NH:35][NH2:36])([CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2C3C(=CC=CC=3)C(=O)O2)=[C:8]([O:23][CH:24]2C3C(=CC=CC=3)C(=O)O2)[CH:7]=1.[Li+].[OH-]>O.CO.C1COCC1>[CH3:24][O:23][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([NH:35][NH2:36])([CH3:34])[C:3]([OH:37])=[O:2])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COC(=O)C(C)(Cc1ccc(OC2OC(=O)c3ccccc32)c(OC2OC(=O)c3ccccc32)c1)NN
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(C)(NN)C(=O)O)cc1OC

Procedure:
Following the procedure for preparation of compound 119, and treatment of the resulting 120 with 0.33M of LiOH in H2O/MeOH/THF before Boc removal by TFA, provided the title compound 121. 1H NMR (CD3OD, 400 MHz): 1.49 (s, 3H), 3.05 (dd, 2H), 3.80 (2 s, 6H), 6.77–6.92 (m, 3H). MS (ESI) m/z 255.25 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH2:13][C:12]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH:13]=[C:12]2[NH:44][C:43]2[CH:45]=[CH:46][C:40]([F:39])=[CH:41][CH:42]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C(Nc2ccc(F)cc2)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1

Procedure:
To a solution of 55 mg (0.156 mmol) 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione in 2 mL dry toluene was added 36 mg (0.187 mmol)p-toluenesulfonic acid monohydrate and 0.030 mL (0.312 mmol) 4-fluoroaniline. The reaction mixture was refluxed for 24 hrs. The solvent was then removed by concentration in vacuum. The residue was purified by preparative HPLC (5→95% CH3CN/H2O over 30 min, 0.05% added TFA, C18 PRO YMC 20×150 mm) to afford 8-benzyl-1-(3-fluorophenyl)-4-[(4-fluorophenyl)amino]-1,8-diazaspiro[4.5]dec-3-en-2-one as a white solid. 1H NMR (CD3OD, 400 MHz): δ 7.50-7.20 (m, 7H), 7.20-6.98 (m 6H), 5.24 (s, 1H), 3.60 (s, 2H), 2.99-2.80 (m, 2H), 2.36-2.43 (m, 2H), 2.24-1.98 (m, 2H), 2.10 (m, 1H), 1.00 (m, 2H). High resolution mass spec (FT/ICR): calc M+H=446.2039 found 446.2035.
Reaction SMILES: [CH2:1]1[O:36][C:18]2([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][CH:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19]2)[O:17][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CC1(C)O[O:39]1>C(O)C>[CH2:1]1[O:36][C:18]2([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]([OH:39])[CH:20]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:19]2)[O:17][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC1(C)OO1
Reactant: CCCCCCCCCCCCCCC1COC2(CC(c3ccccc3)NC(c3ccccc3)C2)O1
Solvent: CCO
Product: CCCCCCCCCCCCCCC1COC2(CC(c3ccccc3)N(O)C(c3ccccc3)C2)O1
Yield: 64.8 %

Procedure:
The general procedure of Example 2 is repeated using 10.9 g (22.2 mmol) of 2,6-diphenyl-4-piperidone 1,2-hexadecylene ketal and 376 mL (22.2 mmol) of dimethyldioxirane (0.059M in acetone). 7.3 g (65% yield) of the title compound is isolated as a white solid by recrystallization from ethanol: mp 98°-100° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:23]([O:25]C(C)(C)C)=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a cold suspension of tert-butyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (syn isomer) (1.0 g) in methylene chloride (20 ml) were added trifluoroacetic acid (4.4 g) and anisole (0.2 ml), and the mixture was gradually warmed at 40° C., followed by stirring at 10° C. for 3 hours. After evaporation of the reaction mixture, to the residue was added ethyl acetate (20 ml), followed by extracting with an aqueous solution of sodium bicarbonate. The resultant aqueous solution was adjusted to pH 2.0 with diluted hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride in turn, dried and then evaporated to dryness under reduced pressure. The residue was stirred for 30 minutes in diethyl ether, and the remained substance was collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.56 g).
Reaction SMILES: [C@H:1]1([C:12]2[S:16][C:15]([NH2:17])=[N:14][N:13]=2)[CH2:5][CH2:4][C@H:3]([C:6]2[S:10][C:9]([NH2:11])=[N:8][N:7]=2)[CH2:2]1.[C:18]([OH:21])(=O)[CH3:19].[CH3:22]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[NH2:11][C:9]1[S:10][C:6]([C@H:3]2[CH2:22][CH2:4][CH2:5][C@H:1]([C:12]3[S:16][C:15]([NH:17][C:18](=[O:21])[CH3:19])=[N:14][N:13]=3)[CH2:2]2)=[N:7][N:8]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nnc([C@H]2CC[C@H](c3nnc(N)s3)C2)s1
Reactant: CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1nnc([C@H]2CCC[C@H](c3nnc(N)s3)C2)s1

Procedure:
A solution of 5,5′-((1S,3S)-cyclopentane-1,3-diyl)bis(1,3,4-thiadiazol-2-amine) (200 mg, 0.71 mmol), acetic acid (42.5 mg, 0.71 mmol), HATU (260.0 mg, 0.71 mmol), and N-ethyl-N-isopropylpropan-2-amine (110.0 mg, 0.85 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The mixture evaporated in vacuum to dryness. The residue was purified by a standard method to afford desired compound. LC-MS: m/z (M+H)=325.4
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc(Cl)cc1C(=O)OC
Yield: 61 %

Procedure:
To a solution of methyl 2-amino-5-chlorobenzoate (15 g) and triethylamine (12 ml) in methylene chloride (150 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (10 ml). The mixture was stirred at room temperature for further two hours. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and water, followed by drying. The solvent was distilled off to afford a pale yellow crystals (13.4 g, 61%), m.p. 48-49° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17]OS(C)(=O)=O)[CH2:11]2)=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:17][C@H:12]1[C@H:13]([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11]1)=[N+:24]=[N-:25]
Reactant: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN=[N+]=[N-]
Temperature: 50 °C
Reaction time: 28 h

Procedure:
A mixture of methanesulfonic acid trans-{l-[2-(4-fluorophenyl)ethyl]-4-methylpiperidin-3-ylmethyl} ester (the crude material from Part D, about 1.0 mmol) and sodium azide (195 mg, 3 mmol) in N,N-dimethylformamide (4 mL) was stirred at 50° C. for 28 hours. The mixture was cooled to room temperature, filtered, and the solid was rinsed with ethyl acetate. The combined filtrates were diluted with ethyl acetate, and the resulting solution was washed twice with water, dried over sodium sulfate, and concentrated under vacuum. The residue was an orange oil (252 mg, 91%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.17 (m, 2H), 6.98 (t, J=9 Hz, 2H), 3.50 (dd, J=12, 3 Hz, 1H), 3.25 (dd, J=12, 8 Hz, 1H), 3.08 (dm, J=10 Hz, 1H), 3.00 (dm, J=11 Hz, 1H), 2.83 (m, 2H), 2.60 (m, 2H), 2.04 (m, 1H), 1.88 (t, J=11 Hz, 1H), 1.71 (m, 1H), 1.60 (m, 1H), 1.5-1.3 (m, 2H), 1.00 (d, J=7 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH:11]([CH2:14]O)CO)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]=[CH:28]/[CH:29]=[O:30])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:44](=O)([O-])[OH:45].[Na+]>C(Cl)Cl>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([S:7]([O:10][C@H:11]2[CH2:14][CH2:44][O:45][C@@H:29](/[CH:28]=[CH:27]/[CH:26]=[CH:25]/[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:31])([F:32])[F:17])=[CH:24][CH:23]=3)[O:30]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(CO)CO)cc1
Reactant: O=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCO[C@@H](/C=C/C=C/c3ccc(C(F)(F)F)cc3)O2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
In 4.5 ml of methylene chloride were dissolved 200 mg (0.81 mmol) of 2-(p-toluenesulfonyloxy)-1,3-propanediol and 206 mg (0.91 mmol) of (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal, and 15 mg of p-toluenesulfonic acid and 0.8 g of molecular sieves 4A were added to the solution, followed by stirring of the resulting mixture at 0° C. for 1 hour. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes. Then, the molecular sieves were removed by filtration and the filtrate was extracted with methylene chloride. The oil obtained by evaporation of the solvent was separated by preparative thin layer chromatography of silica gel (developing solvent: 20% ethyl acetate-hexane) to obtain 107 mg (yield: 29%) of a trans isomer having less polarity and 153 mg (yield: 42%) of a cis isomer having higher polarity as an oil, respectively.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: C1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1 g, 2.53 mmol) and pyrrolidine (0.544 g, 5.06 mmol) were suspended in iPrOH (2.53 mL), and DIPEA (1.325 mL, 7.58 mmol) was added. The RM was subjected to MW irradiation at 140° C. for 1 hr. The RM was treated with 0.5 M HCl (40 mL) and extracted with EtOAc. The combined extracts were sequentially washed with 0.5 M HCl (40 mL) and brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. Crystallization from a cyclohexane/EtOAc mixture yielded the title compound as an off-white solid. UPLC-MS (Condition 3) tR=1.34 min, m/z=430.1/432.1 [M+H]+, m/z=428.3/430.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.76-2.01 (m, 4H) 3.60-3.80 (m, 4H) 7.33 (d, J=8.20 Hz, 2H) 7.72-7.91 (m, 2H) 8.32 (d, J=1.95 Hz, 1H) 8.66 (d, J=1.95 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[C:1]([O:4][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Agent: [K+]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCOC(C)=O

Procedure:
The title compound can be prepared from potassium acetate and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.83 (s, 2H), 7.95 (d, 1H), 7.22 (s, 1H), 4.65 (s, 1H), 4.00 (m, 4H), 3.93 (s, 3H), 2.00 (s, 3H), 1.73-1.52 (m, 6H); MS (ESI): 480.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[NH:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1>C(Cl)Cl>[N:19]1([C:2]2[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N+:5]([O-:13])=[C:4]([NH:14][C:15]([O:17][CH3:18])=[O:16])[CH:3]=2)[CH2:23][CH:22]=[CH:21][CH2:20]1
Reactant: C1=CCNC1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A suspension of 12.5 g. of dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 100 ml. of methylene chloride is treated with 15 g. of 3-pyrroline and the mixture is stirred at room temperature under an argon atmosphere for 26 hours. The white precipitate formed is filtered off and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure dimethyl 6-(3-pyrrolin-1-yl)-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 206° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([S:11](=[O:18])(=[O:17])[NH:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:19][NH:20][CH2:21][CH:22]([CH:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[OH:23]>>[OH:23][CH:22]([CH:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[CH2:21][N:20]([CH3:19])[C:5](=[O:7])[C:4]1[C:8]([S:11](=[O:18])(=[O:17])[NH:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1cc(F)ccc1S(=O)(=O)NC(F)(F)F
Reactant: CNCC(O)C1COC(C)(C)O1
Product: CN(CC(O)C1COC(C)(C)O1)C(=O)c1cc(F)ccc1S(=O)(=O)NC(F)(F)F

Procedure:
Analogously to Example 22(a), 4.31 g (15 mmol) of 3-fluoro-6-(trifluoromethylsulfamoyl)-benzoic acid is reacted with 3.22 g (20 mmol) of 2-methylamino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethanol and the crude product is purified by chromatography on silica gel with ethyl acetate/hexane. 4.93 g=76.3% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH2:18].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])[CH:10]([OH:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: CCNCC
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCN(CC)C1CN(Cc2ccccc2)CC1O
Yield: 74.1 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). 21.9 g (0.3 mol) of diethylamine (produced by Katayama Chemical Industry Co., Ltd.) was continuously added to the reaction mixture and stirred for 5 hours under reflux. After completion, acetone and excess diethylamine were evaporated under reduced pressure, and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 18.4 g of 1-benzyl-4-diethylamino-3-pyrrolidinol (yield 73.9%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[CH3:25]>>[CH3:23][N:24]([CH3:25])[C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[CH:28][CH:27]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CN(C)c1ccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)cc1
Yield: 10 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-(N,N-dimethylamino)benzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(4′-dimethylamino-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (19 mg, 10%): m/z (ES+) 408 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([NH:15][C:16](=[O:29])[CH:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:4]=1)#[N:2].I[CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH:33][CH2:32][CH2:31][O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[NH:15][C:16](=[O:29])[CH:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: OCCI
Reactant: CC(C(=O)Nc1cc(C#N)ccc1CCCC(=O)O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1cc(C#N)ccc1CCCC(=O)OCCO)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of the compound prepared in Example 2(6) (150 mg) and 2-iodoethanol (100 mg) in DMF (2 ml), potassium carbonate (65 mg) was added under an atmosphere of argon. The mixture was stirred for overnight at room temperature. Water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over and concentrated to give the crude crystal. The crude crystal was recrystallized with ethyl acetate/hexane to give the title compound (95 mg) having the following physical data.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Br.Br.[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C)C=O>[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:37][CH2:36]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Oc1ccccc1N1CCNCC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2O)CC1
Temperature: 20 °C
Yield: 55 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7.02 g), triethylamine (10.5 cc) and 4-(2-hydroxyphenyl)piperazine dihydrobromide (8.5 g) in dimethylformamide (150 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (50-50 vol) as eluant, and recrystallization from acetonitrile (25 cc), 2-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (5.8 g) is obtained, m.p. 128° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[NH:18]1[CH2:25]CC[C@H:19]1[C:20](O)=[O:21]>CS(C)=O.CC(=O)OCC.O.[Cu]I>[OH:21][CH:20]1[CH2:19][N:18]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:25]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COC(=O)c1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N2CC(O)C2)c1
Temperature: 90 °C
Yield: 164.3 %

Procedure:
To a solution of methyl 3-iodobenzoate (4.5 g, 17.2 mmol) in DMSO (30 mL) was added 3-azetidin-3-ol hydrogen chloride salt (1.3 g, 11.8 mmol), Cs2CO3 (9.5 g, 29.2 mmol), CuI (446 mg, 2.3 mmol) and L-proline (540 mg, 4.7 mmol) and then the mixture was heated at 90° C. for 18 h under argon atmosphere. The solution was diluted with EA and water and the organic layer was washed with brine three times, concentrated under reduced pressure and purified by CC (PE/EA=2:1) to give compound 3a (1.6 g, 66%) as a yellow solid.