Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.BrC1C=CC(I)=C(S(C)(=O)=O)C=1.[Cl:30]C1C=CC=CC=1B(O)O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:30])=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Agent: CS(=O)(=O)c1cc(Br)ccc1I
Product: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1Cl

Procedure:
Following the general method as outlined in Intermediate 203, starting from 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202) and 2-chlorophenylboronic acid, the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[SH:34][CH2:35][CH2:36][OH:37]>C(Cl)Cl>[OH:37][CH2:36][CH2:35][S:34][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: OCCS
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)C(SCCO)c1ccccc1CO2
Temperature: 25 °C

Procedure:
In 400 ml of methylene chloride was suspended 40.0 g of Compound b obtained in Reference Example 2. Trifluoroacetic anhydride, 21.0 ml, was added to the suspension followed by stirring at room temperature for an hour. Them, 10.7 ml of 2-mercaptoethanol was added to the mixture followed by stirring for further 4 hours. After 100 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from toluene to give 37.6 g of methyl 11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate as white crystals.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30](O)=[O:31])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1>>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:31])[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: COc1cc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc(OC)c1

Procedure:
The product of Example 1B and 2-(3,5-dimethoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=1.3 Hz, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 6.58 (d, J=2.3 Hz, 2H), 6.41 (t, J=2.3 Hz, 1H), 3.80-3.84 (m, 4H), 3.76 (s, 6H), 3.59 (s, 2H), 3.08-3.11 (m, 4H); MS (ESI−) M/Z 423 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10][CH3:11])[CH:5]=[O:6].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].CCN(CC)CC>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:13][CH2:12][C:14](=[O:15])[CH3:16])[CH:7]=[CH:8][C:9]=1[S:10][CH3:11]
Reactant: CSc1ccc(C=O)cc1F
Reactant: C=CC(C)=O
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSc1ccc(C(=O)CCC(C)=O)cc1F
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a stirred solution of 3-fluoro-4-(methylthio)benzaldehyde (3.04 g, 17.9 mmol) in ethanol (12 mL) was added methyl vinyl ketone (1.3 mL, 15.5 mmol), 3-benzyl-5-(2-hydroxyethyl)4-methylthiazolium chloride (0.84 g, 3.1 mmol), and Et3N (4.32 mL, 31 mmol) at room temperature. After stirring for 2 hours, volatiles were removed by evaporation. The residue was taken up with ethyl acetate (200 mL), and washed with water (120 mL), dil. aqueous HCl (120 mL), water (120 mL), brine (120 mL), dried over MgSO4, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to provide 1-[3-fluoro-4-(methylthio)phenyl]pentane-1,4-dione (2.7 g, 73% yield). To a stirred suspension of 1-[3-fluoro-4-(methylthio)phenyl]pentane-1,4-dione (2.7 g, 11.25 mmol) in methanol (50 mL) was added Oxone (14.14 g, 23 mmol) in water (50 mL) at room temperature. After stirring for 5 hours, the mixture was diluted with water. The whole was extracted with CH2Cl2 (50 mL×4), the combined organic layer washed with brine, dried over MgSO4, and evaporated in vacuo to give the subtitle compound (2.8 g, 66% yield).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:36])[CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:20])=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:26]([C@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:36])([OH:28])=[O:27]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 108.9 %

Procedure:
A solution of 256 mg (0.5 mmol) (R)-1-[4-[(R)-2-benzyloxycarbonyl-pyrrolidin -1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylic acid benzyl ester in 5 ml ethanol as stirred with 13 mg 10% Palladium on carbon under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, concentration in vacuo afforded 170 mg (100%) of the title compound (R)-1- [4-[(R)-2-carboxy-pyrrolidin-1-yl]-4-oxo-butyryl]-pyrrolidine-2-carboxylic acid as a colorless viscous oil. MS m/e (%): 313 (M+H)+, 100).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:37])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[F:37][C:24]([F:23])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 3 h
Yield: 69.8 %

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5 g, 19.19 mmol, supplier Aldrich), in DCM (80 mL), DIPEA (5.03 mL, 28.8 mmol) was added under argon atmosphere at room temperature then 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (2.326 mL, 19.19 mmol) was added at 0° C. then ice bath was removed and the reaction mixture was stirred for 3 hrs. The reaction mixture was partitioned between DCM (30 ml) and sodium bicarbonate (2×20 ml). The organic phase was washed with HCl (2×20 ml) and water (2×20 ml), then it was dried using phase separator and DCM was removed under vacuum to give the title compound (5.5 g) as a yellow viscous liquid.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[O:2].[Cl-].[Na+].C(O)(=[O:17])C>>[CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:17])[CH2:6][CH2:5]1)=[O:2]
Reactant: CC(=O)O
Reactant: O=CNC1CCCc2sccc21
Agent: [Cl-]
Agent: [Na+]
Product: O=CNC1CCC(=O)c2sccc21

Procedure:
A solution of N-formyl-4,5,6,7tetrahydrobenzo[b]thiophen-4-amine (60 g) in 50% aqueous acetic acid (1,112 ml) is stirred and ceric ammonium nitrate (727 g) is added over 20-25 minutes at 25° to 30° C. The mixture is stirred at room temperature for 15 minutes, saturated with sodium chloride and extracted with methylene chloride (2 × 770 and 1 × 400 ml). The combined methylene chloride extracts are washed with brine (380 ml) and then with water (155 ml). The water wash is extracted with methylene chloride (155 ml) and this extract is combined with the main methylene chloride extract. The methylene chloride is evaporated and the residue is triturated with ether (250 ml), collected and washed with ether to afford the title formamide, m.p. 104° to 110° C.
Reaction SMILES: O=[C:2]1[CH2:7][S:6](=[O:9])(=[O:8])[C:5]2[S:10][C:11]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:12][C:4]=2[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C(COC)OC>[O:8]=[S:6]1(=[O:9])[CH2:7][C:2](=[S:26])[NH:3][C:4]2[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[S:10][C:5]1=2
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CC(=S)N2

Procedure:
A mixture of 2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine (5 g) and Lawesson's reagent (3.8 g) in dimethoxyethane (25 ml) was heated under reflux for seven hours. The solvent was removed under reduced pressure and the residue was chromatographed over silica gel with chloroform/methanol/acetic acid (90:8:2, v/v/v) as the eluent. The fractions containing the desired product were combined and evaporated to dryness to yield 1.4 g. Two recrystallizations from ethyl acetate/hexane gave pure 2,3-dihydro-4,4-dioxo-6-sulfamoyl-2-thiono-1H-thieno[2,3-b][1,4]thiazine, mp 219°-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:21](O)(=[O:23])[CH3:22]>>[C:21]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)(=[O:23])[CH3:22]
Reactant: OCc1cccc(Cl)c1
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OCc1cccc(Cl)c1
Yield: 93 %

Procedure:
71 g. of 3-chlorobenzyl alcohol, 60 cm3. of acetic acid and 1 g of p-toluene sulfonic acid are refluxed for 5 hours then the excess of acetic acid distilled off in vacuo. The residue is dissolved in 100 cm3. of 1,2-dichloro ethane and the solution washed with 10% sodium hydrogen carbonate solutin then with water and evaporated. The residue is distilled in vacuo. 85.5 g. of 3-chlorobenzyl acetate are obtained. Boiling point 105°-110° C./933.4 Pa, nD25 : 1.5185, yield 93%.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([NH:24][NH2:25])=[S:23])[CH2:18][CH2:17]1>C(O)C.C(Cl)Cl>[CH3:15][N:16]1[CH2:17][CH2:18][N:19]([C:22](=[S:23])[NH:24][N:25]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)[CH2:20][CH2:21]1
Reactant: O=C(c1ccccc1)c1ccnnc1
Reactant: CN1CCN(C(=S)NN)CC1
Solvent: CCO
Solvent: ClCCl
Product: CN1CCN(C(=S)NN=C(c2ccccc2)c2ccnnc2)CC1
Temperature: 65 °C
Yield: 42.6 %

Procedure:
A mixture of phenyl-pyridazin-4-yl-methanone (12; Synthon A, 2.3 g, 12.4 mmol) and 4-Methylpiperazine-1-carbothioic acid hydrazide (6; Synthon B, 2.82 g, 16.18 mmol) in ethanol (7.5 mL) was heated to 65° C. for 5 h under N2 in a 50 mL pyrex tube equipped with a screw cap. The mixture remained heterogeneous during the heating and a brown suspension resulted at the end of the reaction. The mixture was diluted with CH2Cl2 (7.5 mL) and was chromatographed on silica gel that was eluted with MeOH/CH2Cl2 (2.5-5%) to give 1.8 g of a yellow foamy solid 1A (99.3% pure by HPLC); m.p. 141-143° C. (m.p. of a crystalline sample 143-145). TLC (CH2Cl2/MeOH/NH4OH: 95/5/0.5): Rf=0.6, product is visibly yellow, UV and Dragendorff stain active. MS (ESI+): [M+H]+=340.93. HRMS: m/z calcd. for C17H21N6S ([M+H]+): 341.15429. found: 341.15501. 1H NMR (300 MHz, CDCl3), δ ppm: 2.38 (s, 3H), 2.61 (t, 4H, J=5.0 Hz), 4.12 (t, 4H, J=5.0 Hz), 7.29 (m, 3H), 7.63 (m, 3H), 8.64 (s, 1H), 9.14 (dd, 1H, J=5.7 Hz, J′=1.5 Hz), 9.44 (dd, 1H, J=2.4 Hz, J′=1.5 Hz). 13C NMR (75.4 MHz, CDCl3), δ ppm: 45.75, 51.64, 54.75, 123.30, 128.29, 128.39, 130.40, 131.10, 134.86, 143.94, 148.31, 151.31, 181.49.
Reaction SMILES: [SH:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH2:11]([O:15][C:16](=[O:35])[C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:18][C:19]([C:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][CH2:13][CH3:14].ON1C2N=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH2:11]([O:15][C:16](=[O:35])[C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:18][C:19]([C:21]1([NH:26][C:7]([C:2]2([SH:1])[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(N)CCCC1
Reactant: O=C(O)C1(S)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)C2(S)CCCC2)CCCC1
Reaction time: 14 h

Procedure:
To a stirred solution of 1-mercapto-1-cyclopentanecarboxylic acid (1.74 g, 4.54 mmol) in dichloromethane (50 mL) and triethylamine (0.63 mL) is added [(1-amino-(1-cyclopentyl)carbonyl]-L-tyrosine butyl ester hydrochloride (0.66 g). To this solution is added 1-hydroxy-7-azabenzotriazole (0.68 g, 4.55 mmol) and 1,3-dicyclohexylcarbodiimide (1.03 g, 4.99 mmol). The mixture is stirred for 14 hours and then the solid precipitate is removed by filtration. The organic phase is washed with a saturated solution of sodium bicarbonate (10 mL), brine (10 mL), dried over magnesium sulfate and the solvent is removed to give a clear oil. The oil is purified by flash chromatography (SiO2, hexane/ethyl acetate, 6:4) to give a clear foam. The foam is crystallized from ethyl ether to yield N-[[1-[[(1-mercapto- 1-cyclopentyl)carbonyl]amino]- 1-cyclopentyl]carbonyl]-L-tyrosine butyl ester, m.p. 106°-107° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([N:43]([CH3:45])[CH3:44])=[CH:39][CH:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([N:43]([CH3:44])[CH3:45])=[CH:39][CH:38]=2)=[O:36])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: CN(C)c1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(C(=O)CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.3 g), 2-bromo-4'-dimethylaminoacetophenone (0.2 g) and potassium carbonate (0.16 g) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel using toluene-ethyl acetate (2:1) as an eluent. Fractions containing objective compound were collected and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-dimethylaminophenylcarbonylmethyl)-2-(1H-indol-3-ylmethyl)piperazine (0.26 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](\[Cl:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](\[Cl:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: CCOC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxybenzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+21.5°±2.5° (c=0.3% in chloroform).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[C:11]1([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:31]4[CH2:32][CH2:33][CH:28]([N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[CH2:29][CH2:30]4)=[N:7][N:6]3[C:8]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Clc1ccc2nc(-c3ccccc3)c(-c3ccncc3)n2n1
Solvent: CCO
Product: c1ccc(-c2nc3ccc(N4CCC(N5CCCC5)CC4)nn3c2-c2ccncc2)cc1
Temperature: 155 °C
Yield: 27 %

Procedure:
A mixture of 4.03 g (13.1 mmol) of 6-chloro-2-phenyl-3-pyrid-4-ylimidazo[1,2-b]pyridazine and 4.4 g (29 mmol) of 4-pyrrolidin-1-ylpiperidine in 50 mL of ethanol is heated at 155° C. for 4 hours. After cooling, the solvent is evaporated off under reduced pressure and the residue is chromatographed on silica gel, eluting with a mixture of dichloromethane and methanol (93:7). The product is then recrystallized from 40 mL of methanol to give 1.5 g of yellow crystals after drying under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](I)=[N:11][CH:10]=1.[CH2:34]([O:36][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH2:38])[CH3:35].[F-].[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:34]([O:36][CH2:37][CH3:38])=[CH2:35])=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
A solution of 1.00 g (1.73 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) and 0.61 ml (1.8 mmol) 1-ethoxyvinyltri-n-butyltin in 5 ml toluene was deoxygenated by three freeze-thaw cycles. After addition of 61 mg (0.087 mmol) bis(triphenylphosphine)palladium(II) chloride the reaction mixture was heated at reflux for 16 h. The mixture was cooled to room temperature, treated with 500 mg (2.25 mmol) potassium fluoride on aluminum oxide (5.5 mmol fluoride/g) and stirred for 15 min. After filtration and washing with toluene the filtrate was concentrated. Column chromatography afforded 592 mg (66%) of the title compound as a light yellow foam.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1.O.[NH2:33][NH2:34].O>CN(C=O)C>[N+:28]([C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)[CH:27]=[CH:26][CH:25]=1)([O-:30])=[O:29]
Reactant: O=C(CCc1cccc([N+](=O)[O-])c1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(CCc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 7 h
Yield: 23.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(3-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (415 mg, 11.0 mmol, prepared in Synthetic Example 9) in DMF (10 ml) was added hydrazine monohydrate (80%, 160 μl, 3.99 mmol, 4.0 eq.), and the mixture was then stirred at 100 to 110° C. for 7 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-[2-(3-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (389 mg, 94%).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(Oc3cccc(Cl)c3)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), 3-chlorophenol (0.23 mL), potassium carbonate (0.76 g) and DMF (10 mL) was stirred at 100° C. for 16 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(3-chlorophenoxy)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.58 g, 83%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C=O)C>O>[CH2:9]([N:5]1[C:4](=[O:12])[C:3]2[NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)=[N:1][C:2]=2[NH:7][C:6]1=[O:8])[CH2:10][CH3:11]
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)c2cnn(Cc3cccc(C(F)(F)F)c3)c2)c1=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)[nH]c2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 100 °C
Yield: 87.9 %

Procedure:
A mixture of 1-(3-Trifluoromethyl-benzyl)-1H-pyrazole-4-carboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (30 g, 0.068 mol), P2O5 (34.0 g, 0.240.8 mol) and DMF (300 ml) were heated at 100° C. for 30 minutes. The reaction mixture was cooled to 20-25° C. The reaction mixture was slowly poured into water (1.5 L) with vigorous stirring. Solid material separated was filtered off, and washed with water (200 ml) to obtain 1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (25 g, 88%) as a pale yellow solid.