Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][C:11](=O)[C:10]2=O)[CH3:3].[NH2:22][N:23]1[C:27]([NH2:28])=[N:26][N:25]=[C:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>C(O)CO.O>[ClH:1].[CH2:2]([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][C:11]1[C:10]2=[N:22][N:23]2[C:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[N:25][N:26]=[C:27]2[N:28]=1)[CH3:3]
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: CCN(CC)CCc1cc(C)c2c(c1C)C(=O)C(=O)N2
Agent: Cl
Solvent: OCCO
Solvent: O
Product: CCN(CC)CCc1cc(C)c2[nH]c3nc4nnc(Cc5ccc(O)cc5)n4nc3c2c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.60 mmol of 5-(2-Diethylamino-ethyl)-4,7-dimethyl-1H-indole-2,3-dione hydrochloride (186.5 mg) and 0.70 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (144 mg) in 1.5 mL of ethylene glycol was stirred at 125° C. for 1 day. The mixture was cooled to room temperature, diluted with water (5 mL), stirred for 10 min. Allowed to crystallize in a refrigerator (+5° C.) overnight. The precipitated product was collected by filtration, washed with water (3×1 mL) and dried on high vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[OH:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].N1C=CC=CC=1>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: OB(O)c1cccc(Br)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.6 %

Procedure:
To a mixture of 3-bromophenylboronic acid (246 mg, 1.23 mmol), 2-hydroxyisoindoline-1,3-dione (100 mg, 0.61 mmol), cupric acetate (223 mg, 1.23 mmol) and activated 4 Å molecular sieves (155 mg) in 1,2-dichloroethane (3 mL) under a nitrogen atmosphere was added pyridine (0.11 mL, 1.35 mmol). The reaction was stirred at ambient temperature for 24 h, concentrated in vacuo and purified by flash column chromatography (82:18 hexanes/ethyl acetate) to provide 2-(3-bromophenoxy)isoindoline-1,3-dione (102 mg, 52%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.93 (dd, J=5.4, 3.0 Hz, 2H), 7.83 (dd, J=5.6, 3.0 Hz, 2H), 7.33 (t, J=2.1 Hz, 1H), 7.29 (dt, J=7.8, 2.0 Hz, 1H), 7.22 (t, J=8.1, 1H), 7.16-7.10 (m, 1H).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[NH3:25]>CO>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][NH2:25])[S:7]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccc(F)cc1F
Reactant: N
Solvent: CO
Product: NC/C=C/CN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.14 g, 0.33 mmol) was treated with 7N ammonia in methanol to give (2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-en-1-amine which was treated with 1N hydrochloric acid in ether to give hydrochloride salt as a white solid (0.052 g, 40%). MS (ES) m/z 351.9 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1>>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Nc1ccc(-n2cccn2)cc1

Procedure:
The title compound is obtained as described in Example 18a/b using 1-fluoro-4-nitrobenzene (Fluka, Buchs, Switzerland) and 1H-pyrazole (Fluka, Buchs, Switzerland). Title compound: ES-MS: 160.2 (M+H)+; analytical HPLC: tret=3.61 minutes (Grad 2).
Reaction SMILES: Cl.[NH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][CH:4]=[CH:3]1.C(Cl)Cl.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>Cl>[CH2:20]([O:19][C:17]([N:2]1[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8]1)=[O:18])[CH3:21]
Reactant: C1=CNc2ccccc2C=C1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccccc2CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a stirred solution of benzazepine hydrochloride (5.0 g, 27.2 mmol) in DCM (˜50 ml) diisopropyl ethylamine (10.4 ml, 59.8 mmol) was added at 0° C., followed by dropwise addition of ethyl chloroformate (2.86 ml, 29.9 mmol). The reaction was stirred at 0° C. for 1 hour and then allowed to warm to room temperature over 2 hours. LCMS indicated reaction was complete, and 1N HCl (˜100 ml) was added to the reaction. The layers were separated and the aqueous layer was extracted with additional DCM (2×). The combined DCM extracts were washed with brine and dried over Na2SO4. The solvent was evaporated in vacuo and the residue purified by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexanes) to provide the sub-title product as an oil (5.5 g). 1HNMR (CDCl3) δ 7.14 (s, 4H), 4.18 (q, J=7.2 Hz, 2H), 3.61 (bs, 4H), 2.92 (bs, 4H), 1.29 (t, J=7.2 Hz, 3H); MS: ESI (positive): 220 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccc(F)cc3)o2)c1

Procedure:
5-(4-Fluoro-phenyl)-furan-2-carboxylic acid (54 mg, 0.26 mmol) was coupled to ethyl ester (60) (50 mg, 0.26 mmol) using Method C. The crude residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:17]2[C:12](=[N:13][C:14](Br)=[CH:15][N:16]=2)[C:11]([C:19](=[O:33])[NH:20][C:21]([CH3:32])([CH3:31])[CH2:22][O:23][Si](C(C)(C)C)(C)C)=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:34][N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]#[N:45])[CH:42]=2)[C:37]([Sn](CCCC)(CCCC)CCCC)=[N:36]1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([O:7][CH2:8][N:9]1[C:17]2=[N:16][CH:15]=[C:14]([C:37]3[C:38]4[C:43](=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=4)[N:35]([CH3:34])[N:36]=3)[N:13]=[C:12]2[C:11]([C:19](=[O:33])[NH:20][C:21]([CH3:31])([CH3:32])[CH2:22][OH:23])=[CH:10]1)(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C#N)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COC(=O)C(C)(C)C)c2ccc(C#N)cc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
In a round-bottomed flask, (2-bromo-7-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-ylcarbamoyl)-5H-pyrrolo[3,2-b]pyrazin-5-yl)methyl pivalate (305 mg, 0.565 mmol) and a crude mixture of 1-methyl-3-(tributylstannyl)-1H-indazole-6-carbonitrile and 1-methyl-3-(tributylstannyl)-1H-indazole-6-carbonitrile were dissolved in DMF (5 mL) under nitrogen. Pd (PPh3)4 (32 mg, 0.028 mmol) and CuI (21 mg, 0.113 mmol) were added and mixture was sonicated for 5 minutes while bubbling nitrogen. The reaction mixture was stirred at 80° C. for 16 hours. The concentrated mixture was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (1:1, v/v) to give (2-(6-cyano-1-methyl-1H-indazol-3-yl)-7-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (45 mg, 16%). MS: (M+H)+=504.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[Cl:25][CH2:26][C:27](Cl)=[O:28].CCN(CC)CC>C1COCC1>[Cl:25][CH2:26][C:27]([NH:24][C:8]1[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[N:10][C:11]([CH3:13])=[CH:12][C:7]=1[O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:28]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1NC(=O)CCl

Procedure:
The title compound was prepared by acylation of 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with chloroacetyl chloride, NEt3 in THF at room temperature. A tan solid was isolated, mp. 79–82° C. Anal. For C22H30CIN3O2 calc. C, 65.41; H, 7.49; N, 10.40; found: C, 65.56; H, 7.62; N, 10.98.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]([F:23])([F:22])[C:14]1[N:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1>C1COCC1>[F:23][C:13]([F:22])([F:12])[C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:8][O:21]2)=[CH:18][N:19]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C2CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 6-(trifluoromethyl)pyridine-3-carbaldehyde (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[C:6]2[C:7]([N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[N-:26]=[N+:27]=[N-].[Na+].O>CS(C)=O>[N:1]([C:4]1[CH:25]=[CH:24][CH:23]=[C:6]2[C:7]([N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=12)=[O:8])=[N+:26]=[N-:27]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1c1cccc2ccc(O)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(c1cccc3ccc(O)cc13)C2=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
A mixture of 2.4 g (0.007 mol) of 1-(3-nitrophthalimidyl)-7-hydroxynaphthalene and 0.52 g (0.008 mol) of sodium azide in 14 ml of dimethylsulphoxide is stirred for 24 hours at 80° C. 100 ml of water are added to the solution. The crystals which have precipitated are filtered off with suction, washed with water and dried at 80° C./100 mm Hg. 1.7 g (73.6% of theory) of 1-(3-azidophthalimidyl)-7-hydroxynaphthalene are obtained; melting point 154° C. (with decomposition). IR spectrum (KBr): 1775 and 1720 cm-1 (CO--N--CO); 2130 cm-1 (N3).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25]Br)[CH3:21]>C1COCC1>[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25][CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[CH3:21]
Reactant: Cc1cnccn1
Reactant: CCOC(=O)CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCCc1cnccn1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
Butyllithium (1.6 M in hexane solution, 10 ml, 16 mmol) was added dropwise to a solution of diisopropylamine (2.25 ml, 16 mmol) in anhydrous THF (50 ml) at −20° C. under a nitrogen atmosphere. The mixture was stirred at −20° C. for 30 minutes and after cooling at −70° C. a solution of 2-methyl-pyrazine (1.47 ml, 16 mmol) in THF (10 ml) was added dropwise. After 15 minutes, a solution of 3-bromo-propionic acid ethyl ester (2.54 ml, 19.2 mmol) in THF (10 ml) was added and the mixture maintained at −70° C. for 2 hours and then stirred at room temperature overnight. The reaction was then quenched with a saturated solution of NH4Cl and extracted with ethyl acetate, the organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (hexane/ethyl acetate from 9/1 to 1/1 respectively) to give the title compound (1 g, 33% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:24][CH:23]([O:25][S:35]([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36])[CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3][C:2]([CH3:1])([CH3:28])[CH2:7]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: CC(O)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)CCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1

Procedure:
The title compound was prepared from 4-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-butan-2-ol and p-toluenesulfonyl chloride in pyridine. Yield: 182 mg (93%).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7].[C:34](Cl)(=[O:36])[CH3:35].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:34]([NH:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]2[N:15]([C:16](=[O:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:13][O:12][C:11]2([CH3:28])[CH3:27])=[O:7])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N)c(OCc1ccccc1)c2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 23 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To a solution of intermediate 169, N-(2-amino-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.033 g, 0.073 mmol) in dry tetrahydrofuran (10 mL) was added acetyl chloride (5.7 μL, 0.08 mmol) and diisopropylethylamine (38 μL, 0.22 mmol). The reaction mixture was stirred at 23° C. for 3 h. NaHCO3 (0.25 M, 20 mL) was then added and the organic material extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate:Hex (1:2 to 2:1) as eluent to afford the title compound (0.025 g, 69% yield). 1HNMR 400 MHz (MeOD) δ (ppm): 7.66 (1H, dd, J=10.5, 2.8 Hz), 7.43-7.25 (6H, m), 6.87 (1H, ddd, (dt), J=8.8, 2.6 Hz), 5.19 (2H, s), 4.47 (2H, m), 4.08 (2H, t, J=4.9 Hz), 3.99 (2H, t, J=4.9 Hz), 2.19 (3H, s), 1.62 (6H, s). LCMS (M+H)+ m/z 495.
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[NH:4][CH2:3]1.[N:11]([O-])=[O:12].[Na+]>CC(O)=O.O>[N:11]([N:4]1[CH:5]([C:8]([OH:10])=[O:9])[CH2:6][CH2:7][S:2][CH2:3]1)=[O:12]
Reactant: O=C(O)C1CCSCN1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CSCCC1C(=O)O
Reaction time: 3 h

Procedure:
To a suspension of DL-tetrahydro-1,3-thiazine-4-carboxylic acid hydrochloride (48.6 g, 0.26 mol) in 666 mL of AcOH was added to the solution of 27.4 g (0.40 mol) of NaNO2 in 333 mL of water over 16 min at room temperature and stirred for 3 h. The solution was concentrated under reduced pressure. Acetone (300 mL) was added to the residue and the precipitate was filtered off. The filtrate was concentrated under reduced pressure to dryness and crude 3-nitroso[1,3]thiazinane-4-carboxylic acid was obtained as brown amorphous solid.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C([NH:27][OH:28])=O)(=O)=O)CC3)=NC=2)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56](O)=[O:57])(=[O:53])=[O:52])[CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:46][CH2:47][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56]([NH:27][OH:28])=[O:57])(=[O:53])=[O:52])[CH2:49][CH2:50]3)=[N:43][CH:44]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)NO
Yield: 76 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methyl-butyramide, from 2-(R)-{4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine-1-sulfonyl-methyl}-3-methylbutyric acid (0.068 g), to provide the title compound as a cream solid (0.053 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH3:37][CH:38](O)[CH3:39]>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH:38]([CH3:39])[CH3:37])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCC(OC(C)C)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (151.3 mg, 0.368 mmol) in 2-propanol (10.0 mL) was added sulfuric acid (0.45 mL) at 0° C. The reaction mixture was stirred at 100° C. for 16 hrs. The mixture was poured into aqueous saturated sodium hydrogen carbonate and concentrated. The residue was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (84.7 mg, 0.187 mmol, 51%).
Reaction SMILES: OO.[CH:3]([OH:5])=O.[C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C[CH2:9][CH2:8][CH:7]=1>>[C:11]1([CH:6]2[CH2:7][CH2:8][CH2:9][C:3]2=[O:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CO
Reactant: C1=C(c2ccccc2)CCC1
Agent: OO
Product: O=C1CCCC1c1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A mixture of 30% hydrogen peroxide (23 mL, 149 mmol) and 85% formic acid (100 mL, 2619 mmol) was heated at 40° C. for 15 minutes. The mixture was carefully added to cyclopentenylbenzene (21.49 g, 149 mmol) and the resulting two-phase system was vigorously stirred at room temperature for 4 h. An exothermic reaction was observed in the beginning. In the end of the stirring the solution became homogeneous. The reaction mixture was carefully quenched with saturated aqueous solution of sodium bicarbonate. The product was extracted with ether. The combined etherial layers were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the product was purified by column chromatography on silica gel to give 2-phenylcyclopentanone (19.995 g, 125 mmol, 84% yield) as brown oil. LC-MS (M+H)+=161.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.38 (1H, t, J=7.3 Hz), 7.30-7.35 (2H, m), 7.19 (2H, d, J=7.3 Hz), 3.28-3.37 (1H, m), 2.71 (1H, td, J=4.6, 2.7 Hz), 2.58-2.63 (1H, m), 2.43-2.55 (1H, m), 2.29 (1H, ddd, J=19.0, 10.5, 9.0 Hz), 2.07-2.21 (1H, m), 1.88-1.99 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:43][CH2:44][C:45]([O:47]C(C)(C)C)=[O:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:43][CH2:44][C:45]([OH:47])=[O:46])=[O:31])=[CH:33][CH:34]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 0.17 h

Procedure:
[4-((2R,3R)-1-(4-Chlorophenyl)-3-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid, 302.1 mg, 0.585 mmol) was dissolved in DCM (6 ml). N-Methylmorpholine (190 μl, 1.728 mmol) and tert-butyl glycinate hydrochloride (133.4 mg, 0.80 mmol) were added. After 10 minutes, TBTU (224.3 mg, 0.67 mmol) was added and the reaction mixture was stirred for 60 h. The intermediate tert-butylester of the title compound was confirmed. M/z: 626.88 (M−H). DCM (10 ml) and water (15 ml) were added and the mixture was acidified to pH of 3 using KHSO4 (2M). The organic phase was washed with water (2×15 ml). The combined aqueous phases were extracted with DCM (10 ml), dried over Na2SO4, filtered and concentrated. A solution of the residue (500 mg) in DCM (10 ml) and TFA (4 ml) was stirred overnight. The solvent was removed under reduced pressure. Toluene was added and evaporated to assist the removal of TFA. The residue was purified with preparative HPLC on a C8 column. A gradient from 20 to 50% MeCN in 0.1M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (166.9 mg, 50%). H-NMR (400 MHz, DMS-d6): 3.51 (d, 2H), 4.33 (d, 1H), 4.34 (s, 1H), 4.36 (s, 1H), 4.47 (s, 2H), 5.17 (d, 1H), 6.96 (d, 2H), 7.16-7.21 (m, 2H), 7.35 (d, 4H), 7.54-7.59 (m, 2H), 7.83-7.90 (brs, 1H), 7.91-7.95 (m, 2H). M/z: 571.04 (M−H) and 572.88 (M+H).