Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[CH:11]([OH:14])[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)([Br:30])[CH:20]([C@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28])[Br:21].N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:12]([CH:11]([O:14][C:25]([C@H:24]1[C@H:22]([CH:20]([Br:21])[C:19]([Cl:18])([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[Br:30])[C:23]1([CH3:29])[CH3:28])=[O:26])[C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)#[N:13]
Reactant: CC1(C)[C@@H](C(=O)Cl)[C@@H]1C(Br)C(Cl)(Br)c1ccc(Cl)cc1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C(Br)C(Cl)(Br)c1ccc(Cl)cc1
Yield: 92 %

Procedure:
2.25 g (0.01 mol) of 3-phenoxy-α-cyanobenzyl alcohol and 4.63 g (0.01 mol) of trans-3-(2-chloro-2-(4-chloro-phenyl)-1,2-dibromoethyl)-2,2-dimethyl-cyclo-propane-1-(R,S)-carboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 0.8 g (0.01 mol) of pyridine, dissolved in 200 ml of toluene, was added dropwise at 25°-30° C., while stirring. The reaction mixture was then stirred for a further 3 hours at 25° C. It was poured into 150 ml of water and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 6 g (92% of theory) of trans-3-(2-chloro-2-(4-chloro-phenyl)-1,2-dibromoethyl)-2,2-dimethylcyclopropane-1-(R,S)-carboxylic acid α-(R,S)-cyano-3-phenoxy-benzyl ester were obtained as a viscous oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: NN[C:3](NN)=O.ClC1C=[C:15]2[C:11]([C:12](=[O:18])[C:13](=O)[NH:14]2)=[CH:10][C:9]=1I>>[CH3:3][N:14]1[CH2:15][CH2:11][CH2:10][CH2:9][C@H:13]1[CH2:12][OH:18]
Reactant: O=C1Nc2cc(Cl)c(I)cc2C1=O
Reactant: NNC(=O)NN
Product: CN1CCCC[C@H]1CO

Procedure:
Compound (S)-(−)-6 was prepared from carbazide (S)-d and aldehyde C (prepared from 6-chloro-5-iodo-isatin by Method I and Method A) by the procedure described in Example 5. 1H NMR (DMSO-d6) δ 1.10-1.30 (m, 2H), 1.49 (m, 3H), 1.64 (m, 1H), 2.09 (t, 1H), 2.38 (s, 1H), 2.41 (s, 3H), 2.83 (d, 1H), 3.00 (dd, 2H), 3.23 (dd, 2H), 4.13 (s, 3H), 4.18 (q, 1H), 4.31 (q, 1H), 6.90 (s, 1H), 7.30 (s, 1H), 7.85 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H), 8.41 (s, 1H), 8.45 (s, 1H). ESI-MS m/z 493.2 (100, M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]#[N:26])=[CH:23][C:22]([CH3:27])=[N:21]2)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:26][CH2:25][C:24]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:21]=[C:22]([CH3:27])[CH:23]=1)=[S:11]
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: COc1ccc(-n2nc(C)cc2C#N)cc1
Product: COc1ccc(-n2nc(C)cc2CNC(=S)Nc2cccc(Cl)c2Cl)cc1
Yield: 76 %

Procedure:
Prepared in 76% yield from 2,3-dichlorophenylisothiocyanate and the product of Example 204A according to the procedure described for Example 153B. MS (ESI+) m/z 421.1 (M+H)+; 1H NMR (DMSO-d6) δ 2.26 (s, 3H), 3.81 (s, 3H), 4.65 (s, 2H), 6.25 (s, 1H), 7.05 (d, J=9.0 Hz, 2H), 7.34 (dd, J=8.1, 8.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.46-7.50 (m, 1H), 7.71 (d, J=7.5 Hz, 1H), 8.43 (br s, 1H), 9.41 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH:17](Cl)[O:18]C>C(Cl)Cl.[N+](C)([O-])=O>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH:17]=[O:18])[CH:9]=1)=[O:4]
Reactant: COC(Cl)Cl
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: O=Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the compound obtained in Step A (87 mmoles) and AlCl3 in a DCM/nitromethane mixture (80 ml/80 ml) there is added, dropwise, at −30° C., dichloro-methoxy-methane (130.5 mmoles). After stirring for two hours, the reaction mixture is poured into 800 ml of ice-cold water. The aqueous phase is extracted with AcOEt, and then the organic phases are combined. The organic phase is washed with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness to yield the title product (brown crystals), which is used directly in the next Step.
Reaction SMILES: [C:1]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31]Br)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Na+].[I-].[F:36][C:37]1[C:43]([F:44])=[CH:42][C:41]([F:45])=[C:40]([F:46])[C:38]=1[O-:39].[K+]>CC(C)=O.CCOC(C)=O>[C:1]([C:11]([NH:13][C@H:14]([C:18]([NH:20][CH:21]([C:30](=[O:33])[CH2:31][O:39][C:38]1[C:40]([F:46])=[C:41]([F:45])[CH:42]=[C:43]([F:44])[C:37]=1[F:36])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)C(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr
Reactant: [O-]c1c(F)c(F)cc(F)c1F
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)C(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of N-[(carbobenzyloxycarbonyl)valinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (3.36 g, 6.73 mmol) in acetone (20 ml) was added dry NaI (0.20 g, 1.35 mmol) and potassium (2,3,5,6-tetrafluoro)-phenoxide (1.37 g, 6.73 mmol) at room temperature and stirred for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The resultant solid was triturated with ether to provide the titled product as a white solid (3.53 g, 6.04 mmol, 89%). MS C28H32N2O7, [M+Na]+=607, [M−H]−=583.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:13][OH:14]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(C=NO)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
52.9 g (0.35 mol) of p-nitrobenzaldehyde was dissolved in 100 ml of methanol and a solution of 27.8 g (0.38 mol) of hydroxylamine hydrochloride in 35 ml of water was added dropwise over 30 minutes while maintaining the temperature at 30° C. and then, stirred at the same temperature for two hours followed by dilution with 300 ml of water. White crystals deposited were filtered and dried to obtain 55 g of p-nitrobenzaldoxime. Yield 94.7%; M.P. 128°-131° C.
Reaction SMILES: [H-].[Na+].[Br-].[N+:4]([C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)([O-:6])=[O:5].[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>CS(C)=O>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([CH:11]=[C:36]2[CH2:37][CH2:38][O:33][CH2:34][CH2:35]2)=[CH:31][CH:32]=1)([O-:6])=[O:5]
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCOCC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(C=C2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a 500 mL 3-necked flask is added NaH (2.0 g of a 60% suspension in mineral oil) and 35 mL of DMSO. The resulting solution is heated at 80° C. for 1 h then cooled in an ice-water bath. To this is then added a solution of the (4-nitrobenzyl)(triphenyl)phosphonium bromide (23.92 g) in 200 mL warm DMSO. The mixture is stirred at room temperature for 1 h. Tetrahydro-4H-pyran-4-one (4.62 mL) is then added. The mixture is allowed to stir overnight at room temperature and then at 80° C. for 2 days. The mixture is poured over ice and extracted with Et2O. The combined organic extracts are dried and condensed. Chromatography (Biotage flash 40S, gradient from hexanes to 80% CH2Cl2/hexanes) yields 4.83 g (44%) of 4-(4-nitrobenzylidene)tetrahydro-2H-pyran as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:17]1([CH2:16][CH2:15][CH2:14][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCc2ccccc2)cc1

Procedure:
A mixture of 33 g. of ethyl p-aminobenzoate, 19.9 g. of (3-bromopropyl)benzene and 80 ml. of hexamethylphosphoramide is heated at 110° C. for 20 hours. The mixture is chilled, diluted with 25 ml. of water, chilled, diluted with 50 ml. of ethanol and filtered. The solid is washed with cold ethanol-water (1:1) to give tan crystals, m.p. 80°-83° C. Two recrystallizations from ethanol give tan crystals, m.p. 87°-89° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:30])[CH2:17][CH2:16][C:15]([CH2:28][NH2:29])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[F:30][C:12]1([F:11])[CH2:13][CH2:14][C:15]([CH2:28][NH:29][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=2)[CH2:16][CH2:17]1
Reactant: Cc1ccccc1C(=O)O
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: Cc1ccccc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=413.2, tR (minutes, Method D)=0.74
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[C:18]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([CH3:21])([CH3:20])[CH3:19].C(OCC)C>CO.C(OCC)(=O)C>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:23]=1
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)c1cccc(C(=O)Nc2ccccc2C(=O)NCCc2ncc[nH]2)c1

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 46 using 2.50 g (0.0107 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)ethyl]benzamide and 4.20 g (0.0213 mol) of meta-t-butylbenzoyl chloride with the exception that, after reducing the organic layer to dryness the resulting residue was dissolved in a 1:7 methanol/ethyl acetate solution. The resulting solution was concentrated until crystals began to form and then diethyl ether was added. The resulting solution was cooled and 2.90 g of the desired titled compound were recovered by filtration (m.p. 205°-210° C.).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:4])=[O:3].[CH3:18][NH:19][CH3:20]>C(Cl)Cl>[CH3:18][N:19]([CH3:20])[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CNC
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C(=O)OC
Solvent: ClCCl
Product: CCOc1cc(S(=O)(=O)N(C)C)ccc1C(=O)OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
Methyl 4-chlorosulfonyl-2-ethoxy-benzoate (1.3 g, 4.55 mmol) was taken up in anhydrous methylene chloride (30 mL) and cooled to 0° C. Dimethylamine (9.1 mL, 18.2 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature and stirred at room temperature for 16 h. The reaction mixture was washed with water, dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20-50% ethyl acetate in hexanes) gave methyl 4-dimethylsulfamoyl-2-ethoxy-benzoate as a yellow solid (0.528 g, 41%). LC-MS: 288.1 [(M+H)+].
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([S:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)(=[O:15])=[O:14])[CH:9]=[C:8]([C:22]([OH:24])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:25][CH2:26][C:27]1[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>O.CS(C)=O>[CH3:33][C:32]1[CH:31]=[C:30]([CH3:34])[NH:29][C:28](=[O:35])[C:27]=1[CH2:26][NH:25][C:22]([C:8]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:12]=2[CH:11]=[C:10]([S:13]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:15])=[O:14])[CH:9]=1)=[O:24]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(S(=O)(=O)N3CCOCC3)cc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(S(=O)(=O)N3CCOCC3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(1-methylethyl)-6-(4-morpholinylsulfonyl)-1H-indazole-4-carboxylic acid (90 mg, 0.255 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (62.5 mg, 0.331 mmol), 1-hydroxy-7-azabenzotriazole (69.3 mg, 0.509 mmol), EDC (98 mg, 0.509 mmol) and N-methylmorpholine (0.112 mL, 1.019 mmol) were added to Dimethyl Sulfoxide (DMSO) (10 mL) and stirred at room temperature for 16 hours. Next added 40 mL of water and stirred for 10 minutes. The contents were extracted with DCM (5×30 mL), washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified via chromatography (eluent: 0% to 100% gradient Hex:EtOAc then 0 to 10% MeOH:EtOAc). The product was collected as 110 mg (88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, 6H), 2.13 (s, 3H), 2.23 (s, 3H), 2.89-3.05 (m, 4H), 3.54-3.71 (m, 4H), 4.38 (d, J=4.80 Hz, 2H), 5.27 (dt, J=13.07, 6.47 Hz, 1H), 5.90 (s, 1H), 7.80 (d, J=1.01 Hz, 1H), 8.29 (s, 1H), 8.52 (s, 1H), 8.88 (t, J=5.05 Hz, 1H), 11.56 (br. s., 1H); LCMS (ES) [M+H]+ 488.3
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][C@@H:14]2[O:19][C:18]3[C:20]([OH:25])=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][CH:14]2[CH2:15][O:16][C:17]3[CH:23]=[CH:22][C:21]4[N:24]=[CH:26][O:25][C:20]=4[C:18]=3[O:19]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(O)c3O2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: COC(OC)OC
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4ncoc4c3O2)cc1

Procedure:
[(2R)-7-Amino-8-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate hydrochloride (1.05 g, 2.99 mmole) in trimethyl orthoformate (7 mL) was heated to reflux in the presence of 0.20 g of p-toluenesulfonic acid for 3 hours. The solvent was removed under high vacuum to yield a beige solid. The crude product was recrystallized from ethanol to give 0.81 g (75%) of the (R)-enantiomer of the title compound, MS (ESI) m/z 361 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:19]1[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]1=2
Reactant: Brc1cc2ccccc2s1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cc3ccccc3s2)C1=O
Yield: 39.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 109.25 mg, 0.6171 mmol) was reacted with 2-bromo-benzo[b]thiophene (150 mg, 0.6171 mmol), 1,4-dioxane (5 mL), copper iodide (11.75 mg, 0.06171 mmol), trans-1,2-diamino cyclohexane (21.19 mg, 0.1851 mmol) and potassium carbonate (170.62 mg, 1.2342 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 75 mg of the product (62.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:17]=[N:18][C:19]([N:26]2[CH2:29][CH:28](OS(C)(=O)=O)[CH2:27]2)=[C:20]([CH:25]=1)[C:21]([O:23]C)=[O:22].[OH-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:28]1[CH2:29][N:26]([C:19]2[N:18]=[CH:17][C:16]([F:15])=[CH:25][C:20]=2[C:21]([OH:23])=[O:22])[CH2:27]1
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)c1cc(F)cnc1N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)cnc1N1CC(Oc2cccc(Cl)c2)C1
Temperature: 160 °C

Procedure:
To a solution of 3-chlorophenol (0.035 ml, 0.328 mmol) in dimethylformamide (1 ml), potassium carbonate (45.42 mg, 0.328 mmol) and the reaction mixture was stirred 2 h at 80° C. Methyl 5-fluoro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D71) (100 mg, 0.328 mmol) was added and the resulting reaction mixture was heated 12 h at 160° C. After cooling at room temperature 1N NaOH (0.656 ml, 0.656 mmol) was added and the reaction mixture heated 2 h at 120° C. Solvents were evaporated in vacuo and the residue was loaded on SPE-SCX cartridge (5 g). Ammonia fractions after solvent evaporation afforded a residue that was further purified by Biotage column SNAP-C18 (30 g) eluting with water/acetic acid (0.1%)/acetonitrile-acetic acid (0.1%) from 70/30 to 0/100.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:21]([OH:30])[CH:20]=1)=[O:18])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:21]([CH:20]=1)[O:30][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(O)c2)c(OCC(C)C)c1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In 9 ml of N,N-dimethylformamide is dissolved 0.86 g of (2,4-diisobutoxyphenyl)(3-hydroxy-4-isobutoxyphenyl)methanone, to which is added 0.12 g of 60% sodium hydride. After elevating the temperature to 80° C., 0.52 ml of ethyl 2-bromoacetate is added, and the mixture thus obtained is stirred at 80-90° C. for 30 minutes. The reaction mixture is cooled to ambient temperature and added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 1.00 g of ethyl 2-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenoxy]acetate as a light yellow oily product.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][C:4]([CH2:1][CH2:2][CH3:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCC)C(=O)OCC
Yield: 99.5 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using diethyl 2-propylmalonate (5.00 g), 4-benzyloxybenzyl chloride (6.32 g) and sodium hydride (55% suspension in oil, 1.13 g) and the reaction mixture was treated to afford the desired compound (9.80 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19]OS(C)(=O)=O)[CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][N:25]=[N+:26]=[N-:27])[CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCN(C(=N)NC(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CCN(C(=N)NC(=O)OCc2ccccc2)C1
Temperature: 60 °C
Yield: 68.2 %

Procedure:
0.450 g (1.27 mmole) (3RS)-1-(N-benzyloxycarbonylamidino)-3-mesyloxymethyl pyrrolidine and 0.124 g (1.9 mmole) of sodium azide were dissolved in 10 ml dimethylformamide and heated to 60° C. for four hours followed by stirring at room temperature over night. Water was added and the mixture was extracted twice with toluene/ethyl-acetate 2/1. The combined organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography using CH2Cl2 /MeOH 95/5 as eluent to yield 0.262 g (68%) of the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[CH:43]=[CH:42][C:12]([C:13]([NH:15][C:16]2[C:17]3[CH:30]=[C:29]([C:31]([NH:33][N:34]([CH3:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])[S:28][C:18]=3[N:19](C(OC(C)(C)C)=O)[N:20]=2)=[O:14])=[CH:11][CH:10]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:41][N:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:31]([C:29]1[S:28][C:18]2[NH:19][N:20]=[C:16]([NH:15][C:13](=[O:14])[C:12]3[CH:42]=[CH:43][C:9]([CH2:8][N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)[C:17]=2[CH:30]=1)=[O:32]
Reactant: C1CNCCN1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCNCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide, followed by 96 mg (1.11 mmol) of piperazine, are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then treated with ice. It is then extracted with ethyl acetate and then twice with dichloromethane. The organic extracts are combined and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 3 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for twice 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 83 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-piperazin-1-ylmethylbenzamide are thus obtained in the form of a yellow powder melting at 176° C. LC-MS-DAD-ELSD: 490(+)=M(+H)(+).