Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH2:18](I)[CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: CCCI
Reactant: FC(F)(F)c1cc(C2CCNCC2)ccc1Cl
Product: CCCN1CCC(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidine and 1-propyliodide, the title compound was re-covered by the procedure described in Example 2. m.p. 218-220° C. (HCl), MS m/z (rel. intensity, 70 eV) 305 (M+, 4), 278 (35), 277 (13), 276 (bp), 70 (40).
Reaction SMILES: [H][H].[O:3]1[C:9]2([CH3:10])[CH:4]1[C:5]([O:7][C:8]2([CH3:12])[CH3:11])=[O:6]>[Pd].O1CCCC1>[OH:3][C:9]1([CH3:10])[C:8]([CH3:12])([CH3:11])[O:7][C:5](=[O:6])[CH2:4]1
Reactant: [H][H]
Reactant: CC1(C)OC(=O)C2OC21C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC1(C)C
Yield: 82 %

Procedure:
By using ethyl crotonate instead of ethyl acrylate, 2 hydroxy-3,4,4-trimethyl-γ-butyrolactone was prepared in a yield of 15% in the same manner as in Production Example 10. The prepared 2-hydroxy-3,4,4-trimethyl-γ-butyrolactone was subjected to a reaction (dehydration reaction) with equivalent P2O5 at room temperature to yield a corresponding α,β-unsaturated-γ-butyrolactone in a yield of 34%. This compound was then allowed to react with m-chloroperbenzoic acid (MCPBA) in methylene chloride at room temperature to yield 2,3epoxy-3,4,4-trimethyl-γ-butyrolactone in a yield of 75%. Hydrogen was bubbled in a mixture of 10 mmole of the above-prepared 2,3-epoxy-3,4,4-trimethyl-γ-butyrolactone, 1 g of a 5% by weight Pd-C, and 20 ml of tetrahydrofuran at room temperature for 11 hours. The reaction mixture was filtrated and was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield 3-hydroxy-3,4,4-trimethyl-γ-butyrolactone in a yield of 82%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:22]1([CH:27]2[CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][N:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH:27]([N:22]5[CH:26]=[CH:25][N:24]=[N:23]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1cn(C2CNC2)nn1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(n4ccnn4)C3)c(F)cc2c1=O
Yield: 91.8 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.18 mmol) was reacted with 3-(1,2,3-triazol-1-yl) azetidine hydrochloride (72 mg, 0.45 mmol) in 3 ml of dry pyridine in the presence of 68.5 mg (0.45 mmol) of DBU at 80° C. for 16 h. The yellow solution was then evaporated to dryness, water was added to the residue, solid was collected and dried to yield 64 mg (92%) of the desired product. m.p. 315°-316° C. 1H NMR (TFA) δ: 9.26 (s, 1H), 8.75 (d, 1.2Hz, 1H), 8.60 (d, 1.2Hz, 1H), 8.10 (d, 11.8Hz, 1H), 6.35-6.0 (m, 1H), 5.8-5.15 (m, 4H), 4.65-4.3 (m, 1H), 1.9-1.3 (m, 4H). Anal. calcd. for C18H15F2N 5 O3H2O: C, 53.33; H, 4.23; N, 17.28. Found: C, 53.68; H, 4.23; N, 17.28.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[H-].[Na+].[N+]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20])([O-])=O>CS(C)=O>[N+:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]=1[C:19]#[N:20])([O-:27])=[O:26]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Product: N#Cc1c(OCCOc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.7 %

Procedure:
2-Phenoxyethanol (4.15 ml, 0.033 mole) is added to dimethylsulfoxyl sodium prepared from 1.39 g of 57 percent sodium hydride and 40 ml dimethylsulfoxide, giving a mixture of the solid salt of the alcohol after about 20 minutes. This mixture is added to a solution of 5.8 g (0.030 mole) 2,6-dinitrobenzonitrile in 20 ml of dimethylsulfoxide at 30-40° C., and the resulting purple solution is stirred over night at room temperature. The solvent is removed at 70° C. on a rotary evaporator, and the residue is triturated with water. A solid is filtered off and it is dissolved in ethylacetate. The ethylacetate solution is washed twice with H2O, brine, and dried with calcium sulfate. Evaporation of the ethylacetate, gives 8.5 g of 2-nitro-6(2-phenoxyethoxy)benzonitrile, which is crystallized from 200 ml ethyl alcohol, giving 6 g, m.p. 129°-137.5° C.
Reaction SMILES: Cl[C:2]1[CH2:3][S:4][C@@H:5]2[CH:25]([NH:26][C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:24](=[O:36])[N:6]2[C:7]=1[C:8]([O:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].O>C(O)(=O)C.C(Cl)Cl.[Zn]>[C:29]1([CH2:28][C:27]([NH:26][CH:25]2[C:24](=[O:36])[N:6]3[C:7]([C:8]([O:10][CH:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:9])=[CH:2][CH2:3][S:4][C@H:5]23)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cl)CS[C@H]12
Agent: [Zn]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To benzhydryl 3-chloro-7-phenylacetamido-3-cephem-4-carboxylate (1.038 g) in a mixture of acetic acid (30 ml) and methylene chloride (10 ml) one adds activated zinc powder (3.9 g), stirs at room temperature for 1 hour, filters, dilutes with water, extracts with methylene chloride, washes with water, dries, concentrates, and crystallizes from ether to give benzhydryl 7-phenylacetamido-3-cephem-4-carboxylate (865 mg), m.p. 168°-170° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:14]C1C=C(C(O)=O)C(O)=CC=1.O>C(O)(=O)C>[Cl:14][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([OH:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The following procedure demonstrates the preparation of compound 1 with X=5-Cl, with comparable procedures being useful for obtaining related compounds having different X substituents. A solution suspension of 10 g of 5-chlorosalicylic acid in 50 mL glacial acetic acid was cooled in an ice bath until the solvent began to freeze. The bath was exchanged to a room temperature water bath and 4.47 g of 90% fuming nitric acid (1:1 equivalent) in 3 mL glacial acetic acid was added dropwise. After addition was complete, the mixture was stirred for 150 minutes at room temperature (R.T.) in the water bath. It was then poured into 120 mL of ice and water and stirred in an ice bath for 30 minutes. The precipitated solid was collected by filtration and air-dried overnight.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:26]5[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=5)=[C:18]4[O:21][CH2:22]OCC)=[CH:13][C:12]=3[O:35]C)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:37]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH:45]1[C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:1]45[CH2:8][CH:7]6[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]6)[CH2:2]4)[CH2:10]5)=[C:12]([O:35][CH2:17][CH2:18][O:21][CH3:22])[CH:13]=3)[C:18]=2[O:21][CH3:22])=[CH:34][CH:33]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOCOc1c(-c2ccc(C(=O)Cl)cc2)ccc2cc(OC)c(C34CC5CC(CC(C5)C3)C4)cc12
Product: COCCOc1cc2ccc(-c3ccc(C(=O)C4CNCCN4Cc4ccccc4)cc3)c(OC)c2cc1C12CC3CC(CC(C3)C1)C2
Yield: 64.6 %

Procedure:
Following the procedure of Example 27(b), but reacting 7.3 g (14.4 mmol) of 4-[7-(1-adamantyl)-6-methoxy-ethoxymethoxy-2-naphthyl]benzoic acid chloride with 2.5 ml (14.4 mmol) of 4-benzylpiperazine, 3 g (33%) of the expected compound were obtained, which compound had a melting point of 176°-7° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=[O:18].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:18])[CH3:12])=[C:7]([OH:11])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)Oc1ccc2nc(C)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(C)=O)cc1O
Temperature: 25 °C

Procedure:
2-methyl-1,3-benzoxazol-6-yl acetate (8.1 g, 42.3 mmol) was dissolved in tetrahydrofuran (60 mL), and trifluoroacetic acid (4 mL, 53.2 mmol) was added. The light brown solution was stirred over night at room temperature. Sodium hydrogen carbonate (aq, sat) was added, and the solution was extracted twice with ethyl acetate. The combined organic layers were concentrated to the titled compound (8.0 g, 91%) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([S:21][CH3:22])[N:15]=1.O>CN(C=O)C.C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:17]=[C:16]([S:21][CH3:22])[N:15]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2cc(Cl)nc(SC)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 4-methoxybenzyl alcohol (8.9 g, 65 mmol) in dry DMF (100 ml) was added a 60% suspension of sodium hydride (2.2 g, 55 mmol) in portions and the mixture was stirred for two hours at room temperature. The mixture was cooled in an ice bath and 4,6-dichloro-2-methylsulfanyl-pyrimidine (9.8 g, 50 mmol) in dry THF (20 ml) was added. The mixture was then stirred for 72 h at room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The organic phase was washed with water, dried with sodium sulphate and evaporated under reduce pressure. The residue was purified by silica gel chromatography eluted with hexane ethyl acetate which gave the title compound (9.1 g, 61%), (M+H)+296
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>CCN(CC)CC.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.[Cu]I>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc([N+](=O)[O-])c1
Reaction time: 12 h
Yield: 94 %

Procedure:
A mixture of 3-iodonitrobenzene (2.0 g, 8.0 mmol), bis(triphenylphosphine)palladium(II) chloride (0.30 g, 0.40 mmol) and copper(I) iodide (0.080 g, 0.40 mmol) in 25 mL of Et3N was degassed by freeze/pump/thaw technique (three times). Trimethylsilylacetylene (1.0 g, 10 mmol) was added and the mixture was stirred for 12 hours. The reaction mixture was filtered through a celite pad and the pad was rinsed with CH2Cl2. The filtrate was washed with sat. NH4Cl (aq.) and brine and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (Hexane, then EtOAc;Hexanes =1:30) to afford trimethyl((3-nitrophenyl)ethynyl)silane (1.65 g, 94%): 1H-NMR (300 MHz, CDCl3) δ 8.32 (dd, J=1.8, 1.8 Hz, 1H), 8.17 (ddd, J=8.4, 2.1, 0.9 Hz, 1H), 7.76 (ddd, J=7.5, 1.2, 1.2 Hz, 1H), 7.49 (dd, J=8.1, 8.1 Hz, 1H), 0.28 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22]([NH:24][CH2:25][CH2:26][NH2:27])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C.O>CS(C)=O>[NH2:1][C:2]1[N:23]=[C:22]([NH:24][CH2:25][CH2:26][NH:27][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2ccc([N+](=O)[O-])cc2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.1 %

Procedure:
2-Amino-6-(2-amino-ethylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (25 mg, 65 μmol) described in Preparation Example A+-12, 4-fluoronitrobenzene (7.6 μl, 71 μmol) and N,N-diisopropylethylamine (22.7 μl, 130 μmol) were dissolved in dimethylsulfoxide (0.5 mL), the solution was stirred for 3.5 hours at room temperature, and then, the solution was stirred for 15.5 hours at 70° C. The reaction solution was cooled to room temperature, water was added, the solution was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, residue was purified by reverse phase high performance liquid chromatography (mobile phase:acetonitrile-water (containing 0.1% trifluoroacetic acid) was used), and the title compound (23 mg) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(O)=O>[Pd].C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: O=c1c2sccc2nc(C=Cc2ccccn2)n1-c1ccccc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Solvent: O
Product: O=c1c2sccc2nc(CCc2ccccn2)n1-c1ccccc1Cl
Yield: 77.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-2-[2-pyrid-2-yl-vinyl]-3H-thieno[3,2-d]pyrimidin-4-one (0.12 g, 0.33 mmol), ethanol, 10 mL), formic acid (0.55 mL, 14.8 mmol) and 10% palladium on carbon (0.12 g) was refluxed 4 hours, cooled and diluted with ethanol and water. The mixture was filtered through Celite® (trademark) and the pad was rinsed with ethyl acetate and water. The filtrate was treated with saturated aqueous sodium bicarbonate and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with water and brine, dried over sodium sulfate, and concentrated to afford 0.094 g of 3-(2-chloro-phenyl)-2-(2-pyridin-2-yl-ethyl)-3H-thieno[3,2-d]pyrimidin-4-one as a tan film. The material was dissolved in dioxane (3 mL) and treated with ether saturated with hydrogen chloride. The solid was collected and weighed 0.094 g. The solid was taken up in water, concentrated, and azeotropically dried by suspending the product in chloroform and concentrating three times to yield 3-(2-chloro-phenyl)-2-(2-pyridin-2-yl-ethyl)-3H-thieno[3,2-d]pyrimidin-4-one hydrochloride (0.038 g, 31%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H].F[C:17]1[CH:18]=[CH:19][C:20]([N+:31]([O-:33])=[O:32])=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=1>CN(C=O)C.O>[CH2:24]([O:23][C:21]1[CH:22]=[C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=[CH:19][C:20]=1[N+:31]([O-:33])=[O:32])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
In DMF (100 ml) was suspended sodium hydride (4.63 g, 115.7 mmol). Under cooling at 0° C. and stirring, diethyl malonate (18.5 g, 115.7 mmol) was added dropwise. After vigorous evolution of a hydrogen gas stopped, a solution of benzyl 5-fluoro-2-nitrophenyl ether (14.3 g, 57.8 mmol) in DMF (100 ml) was added to the reaction mixture at 0° C. The reaction mixture was stirred for 15 hours at room temperature. Water (500 ml) was poured and the mixture was extracted with ethyl acetate (300 ml). The extract was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (3:1) eluate fractions, the title compound (22.0 g, 100%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=O)[C:5](=[CH:10][C:11]=1[F:12])[C:6]([O:8]C)=O.[H-].[Na+].[CH3:19]CCCCC.CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][C:11]=1[F:12])[C:6](=[O:8])[CH2:19][C:13]2=[O:15]
Reactant: CCCCCC
Reactant: COC(=O)c1cc(C)c(F)cc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1F)C(=O)CC2=O
Temperature: 100 °C
Yield: 62 %

Procedure:
Dimethyl 4-methyl-5-fluorophthalate 9e (1.65 g, 7.29 mmol) was dissolved in anhydrous ethyl acetate (4 mL). Sodium hydride (348 mg, 14.5 mmol) was added and the mixture was heated at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and a mixture containing 10 mL of hexane and 6 mL of ethyl ether/ethanol (1/1) was added. The yellow precepitate was triturated for 5 min, filtered and dried under vacuum. The yellow solid (1.07 g) was then suspended in a solution containing water (22 mL) and concentrated hydrochloric acid (2.2 mL) and the suspension was heated for 17 min at 80° C. The mixture was then lyophilized to give 810 mg (62%) of 5-methyl-6-fluoro-1,3-indandione 9f as a beige solid.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5](S(C)(=O)=O)[N:4]=1.[OH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22].[C:25](=O)([O-])[O-:26].[K+].[K+]>CC(CC)=O.O>[CH3:10][O:9][C:7]1[C:8]([O:26][CH3:25])=[CH:3][N:4]=[C:5]([O:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23][CH3:24])=[O:22])[N:6]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sccc1O
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1sccc1Oc1ncc(OC)c(OC)n1
Yield: 60.7 %

Procedure:
2.2 g (0.01 mol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.6 g (0.01 mol) of methyl 3-hydroxythiophene-2-carboxylate are dissolved in 50 ml of ethyl methyl ketone, and 13.8 g (0.1 mol) of potassium carbonate are added. The mixture is refluxed for 4 hours, cooled down, diluted with water and extracted with methylene chloride. The extract is dried over sodium sulfate and concentrated under reduced pressure. The residue is stirred up with n-hephtane, filtered off and dried under reduced pressure, leaving 1.8 g of methyl 3-(4,5-dimethoxypyrimidin-2-yloxy)thiophene-2-carboxylate of m.p. 107°-109° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:68]=[CH:67][N:66]([CH2:69][C:70]([CH3:73])([OH:72])[CH3:71])[N:65]=1>>[OH:72][C:70]([CH3:73])([CH3:71])[CH2:69][N:66]1[CH:67]=[CH:68][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[N:65]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with 1-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (WO2009127544) (0.11 g, 0.67 mmol) at room temperature and purified by Prep-HPLC to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a trifluoroacetic acid salt: white solid (Yield 62 mg, 20%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:17][CH2:16][CH2:15][C:9]2[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)cc3C)CC2)nn1-c1ccccc1

Procedure:
73 mg (49%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(2,4-dimethylphenyl)piperazine (63 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].C([Li])CCC.[CH:16]([CH:18]=[CH2:19])=[O:17].OS(O)(=O)=O>CCOCC.CCCCCC>[CH:18]([CH:16]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10])[OH:17])=[CH2:19]
Reactant: Fc1cc(F)c(F)c(Br)c1
Reactant: C=CC=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C=CC(O)c1cc(F)cc(F)c1F
Temperature: -73 °C
Reaction time: 0.03 h

Procedure:
A solution of 4.1 g (0.0194 mol) of 1-bromo-2,3,5-trifluorobenzene in 50 ml of anhydrous ether is cooled to -76 ° C. under a nitrogen atmosphere. 12.1 ml (0.0194 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise over 15 minutes at a temperature below -72° C. The mixture is stirred for 2 minutes at -73° C. and then a solution of 1.15 g (0.0205 mol) of acrolein in 5 ml of anhydrous ether is added dropwise. The mixture is stirred for 30 minutes at -70° C. and is then allowed to return to room temperature. The mixture is poured onto a mixture of 100 g of ice and 10 g of concentrated H2SO4. Extraction with ether, washing with water, drying over Na2SO4, filtration and concentration under vacuum are carried out. The residue obtained is used without other purification in the following stage. Weight obtained: 3.1 g (Yd.=86%)