Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[CH3:30][NH:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:30][N:31]([CH2:22][C:20]1[S:19][CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:6]2[CH2:5][CH2:4][S:3](=[O:27])(=[O:28])[C:2]([CH3:29])([CH3:1])[CH2:7]2)[CH:21]=1)[CH3:32]
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)C(C)(C)C4)c3c2)cs1
Yield: 37.3 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid was added, dimethylamine (0.348 mL, 0.697 mmol) was added. The mixture was stirred 2 hours at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring overnight at 23° C. The sodium triacetoxyborohydride polymer bound was removed by filtration (syringe filter 45 um). The product was purified by preparative HPLC (NH4OH buffer). The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[Cl:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[CH:21]=[C:20]([N:6]2[CH2:7][CH2:8][C@:4]([CH2:1][CH3:3])([OH:12])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (204 mg), 2-chloro-4-fluorobenzonitrile (314 mg) and lithium carbonate (205 mg), the title compound was obtained as pale-yellow oil (yield: 262 mg, yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[C:4]([F:32])[CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[C:4]([F:32])[CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3F)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1F)c1c[nH]c2c(CSC)cc(F)cc12

Procedure:
1.9 mg (0.03 mmol) of copper powder were added to 2.20 g of the compound from Example 16A with a purity of 71% (3.26 mmol) in 25 ml of pyridine and 6.7 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) to result in 1.22 g (88% of theory) of the target compound.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:11]([C:14]1[CH:25]=[C:18]2[C:19](OC(=O)[NH:23][C:17]2=[CH:16][CH:15]=1)=[O:20])([O-:13])=[O:12]>>[NH2:23][C:17]1[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:25][C:18]=1[C:19]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:20]
Reactant: NOCc1ccccc1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Agent: Cl
Product: Nc1ccc([N+](=O)[O-])cc1C(=O)NOCc1ccccc1
Yield: 71 %

Procedure:
In the same manner as Example 35(a), O-benzylhydroxylamine hydrochloride (0.52 g, 3.25 mmol) reacted with 5-nitro-isatoic anhydride (0.52 g, 2.5 mmol) to give 2-amino-5-nitro-N-benzyloxylbenzamide as a yellow solid (0.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13].[N+:17](=[CH2:19])=[N-:18]>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH:19]=[N+:17]=[N-:18])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13]
Reactant: C=[N+]=[N-]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl

Procedure:
14.1 g of 4-chloro-3-dimethylsulfamoylbenzoyl-chloride were reacted as prescribed in Example 66b) with diazomethane in diethyl ether and the crystalline product was filtered off. Melting point: 136° - 137° C (decomposition).
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:8])[C:3]([F:7])([F:6])[CH2:4][OH:5].C([O-])([O-])=O.[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([F:16])=[C:9]([C:2]([NH:1][C:25](=[O:26])[CH2:24][Cl:23])([C:3]([F:6])([F:7])[CH2:4][OH:5])[CH3:8])[CH:14]=1
Reactant: CC(N)(c1cc(Br)ccc1F)C(F)(F)CO
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(NC(=O)CCl)(c1cc(Br)ccc1F)C(F)(F)CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice cooled solution of 3-amino-3-(5-bromo-2-fluorophenyl)-2,2-difluorobutan-1-ol (3.1 g, 10.4 mmol), in DCM (60 ml) was added aqueous Na2CO3 (2.74 g, 25.8 mmol in 7.0 mL H2O) and stirred for 10 min. Chloroacetyl chloride (0.986 ml, 11.4 mmol) was then added to the resultant reaction mixture and stirring continued for 30 min at 0° C. Upon formation of the new product by TLC analysis, K2CO3 (1.5 g, 10.4 mmol) in MeOH (17 mL) was added to the reaction mixture and stirred at rt for 30 min. The reaction mixture was diluted with DCM, separated the organic layer and washed successively with water and brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish title compound as a colorless gum. Yield=3.3 g (78.5%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:15])[CH3:2].[H-].[Na+].I[CH:21]([CH3:23])[CH3:22]>CN(C)C=O>[CH2:16]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]([CH:21]([CH3:23])[CH3:22])[C:4]1=[O:15])[CH3:17]
Reactant: CCC1(CC)C(=O)Nc2ccc([N+](=O)[O-])cc21
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(CC)C(=O)N(C(C)C)c2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A solution of 3,3-diethyl-5-nitro-1,3-dihydro-indol-2-one (11.7 g, 49.95 mmol) in anhydrous N,N-dimethylformamide (DMF) (60 ml) was treated with sodium hydride (1.558 g, 64.93 mmol). The resulting suspension was stirred for 1 h at 60° C. A solution of 2-iodo-propane (4.99 ml, 8.49 g, 49.95 mmol) was added. The mixture was kept at 60° C. for further 3 h, allowed to cool to room temperature poured into ice water. The precipitate was filtered off, washed with water and dried to yield 12.6 g 3,3-diethyl-1-isopropyl-5-nitro-1,3-dihydro-indol-2-one (45.60 mmol, 91%)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[C:9]([O:11]C)=[O:10].Cl[C:16]1[N:21]=[CH:20][NH:19][C:18]2=[N:22][CH:23]=[CH:24][C:17]=12.N1C=CC=CC=1.[Li+].[OH-]>CN(C=O)C.[Cl-].[Na+].O.O>[N:19]1[C:18]2[NH:22][CH:23]=[CH:24][C:17]=2[C:16]([N:6]2[CH2:7][CH2:8][C@@H:3]([C:2]([F:14])([F:13])[F:1])[C@H:4]([C:9]([OH:11])=[O:10])[CH2:5]2)=[N:21][CH:20]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: COC(=O)[C@@H]1CNCC[C@H]1C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(O)[C@@H]1CN(c2ncnc3[nH]ccc23)CC[C@H]1C(F)(F)F
Reaction time: 68 h
Yield: 52.5 %

Procedure:
A solution of racemic trans-methyl 4-(trifluoromethyl)piperidine-3-carboxylate E (1.00 g, 4.74 mmol), 4-chloropyrrolo[2,3-d]pyrimidine (0.873 g, 5.68 mmol) and pyridine (0.766 mL, 9.47 mmol) in DMF (5 mL) was heated at 80° C. for 24 hours. The solution was diluted with brine and the reaction mixture was extracted with EtOAc. The organic phase was concentrated in vacuo to afford a residue which was treated with LiOH (0.9 g, 37.8 mmol) in water (40 mL) was stirred for 68 h. The resulting precipitate was filtered to afford a solid G (782 mg, 52.5% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.63 (br. s., 1H), 8.11 (s, 1H), 7.15 (dd, J=2.5, 3.5 Hz, 1H), 6.60 (dd, J=1.9, 3.6 Hz, 1H), 4.48 (m, 2H), 3.46-3.34 (m, 1H), 3.25-3.12 (m, 1H), 2.18 (m, 1H), 1.88 (m, 1H), 1.51 (m, 1H); m/z 315 [M+1].
Reaction SMILES: C(=O)([O-])O.[Na+].C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:40])[N:17]([CH2:19][C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH:33]4[S:37][C:36](=[O:38])[NH:35][C:34]4=[O:39])=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)[CH3:18])=[CH:12][CH:11]=1)(=O)C.Cl>O1CCCC1.O.C(OC(=O)C)C>[O:38]=[C:36]1[NH:35][C:34](=[O:39])[CH:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][N:17]([CH3:18])[C:16](=[O:40])[C:13]4[CH:12]=[CH:11][C:10]([OH:9])=[CH:15][CH:14]=4)[CH:21]=3)=[CH:31][CH:30]=2)[S:37]1
Reactant: CC(=O)Oc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
110 mg (1.3 mmol) of sodium hydrogen carbonate are added to 350 mg (6.7 mmol) of 4-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}phenyl acetate (obtained in Example 56) in 5 ml of tetrahydrofuran and 500 μl of water. The reaction medium is stirred at room temperature for 48 hours and then diluted in ethylacetate and acidified to pH 3-4 with 1N hydrochloric acid solution. The organic phase is separated out after settling of the phases has taken place, dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 99/1 dichloromethane/methanol mixture. After evaporation of the solvents, 250 mg (83%) of N-[4′(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-4-hydroxy-N-methylbenzamide are collected in the form of a white powder with a melting point of 110° C.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[CH:8][C:9]([N+:32]([O-])=O)=[C:10]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][N:31]=3)[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:16])[CH:11]=2)[CH2:4][CH2:3][CH2:2]1>[Pd].CO>[NH2:32][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)=[CH:11][C:10]=1[C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][N:31]=1)[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1)=[O:16]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OC3CCC3)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A mixture of 62 mg of 2-(5-cyclobutoxy-2-nitrophenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide, 10 mg of 10% Pd/C, and 4 mL of methanol was stirred for 2 h under a hydrogen atmosphere. The mixture was filtered and concentrated to give 46 mg of product.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:9]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][C:10]([C:8]2[CH:9]=[C:5]([C:3]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:4])[NH:6][CH:7]=2)=[O:19])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cc1cccc(Cl)c1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Cl)c1)c1c[nH]c(C(=O)N2CCOCC2)c1
Reaction time: 24 h

Procedure:
To a solution of compound 2 (1 equivalent) in DMF, at ambient temperature, was added morpholine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 5 was used without purification. FIA/MS (M+1) 3.33.3, (M−1) 331.2. 1H NMR was consistent with expected structure.
Reaction SMILES: N1C2C(=CC=CC=2)CC1=O.[C:11]1(=[O:18])[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]1.Cl.[NH2:20][CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]([OH:27])=[O:26].C([O-])(=O)C.[Na+]>O>[C:25]([CH2:24][CH2:23][C:22]1[C:12]2[C:11](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=2[NH:20][CH:21]=1)([OH:27])=[O:26]
Reactant: NCC(=O)CCC(=O)O
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C1Cc2ccccc2N1
Solvent: O
Product: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Temperature: 100 °C

Procedure:
The route shown in Scheme 1 below exemplifies synthesis of the indolinone compounds of the present invention. A reaction mixture of 1,3-cyclohexanedione (1), 5-aminolevulinic acid hydrochloride (2), sodium acetate, and H2O is heated at 100° C. for 16 h to give 3-carboxyethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole (3). A solution of 3 in ethanol (100 mL) is added with sulfuric acid. The resulting reaction mixture is refluxed for 12 h to provide 3-(3-ethoxy-3-oxopropyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole (4) as yellow solids. Trimethylorthoformate is then added to a solution (47 mL) containing 4 in trifluoroacetic acid at 0° C. The reaction mixture thus formed is stirred at 0° C. for 30 min, warmed up to room temperature, and stirred for 2.0 h. The mixture is then added with ethyl acetate, water, and NaOH. The organic layer is collected, washed with saturated aqueous NaHCO3, dried over MgSO4 (s), and concentrated under reduced pressure. The oily residue is purified to give 3-(3-ethoxy-3-oxopropyl)-2-formyl-4-oxo-4,5,6,7-tetrahydro-1H-indole (5) as yellow solids. Next, a mixture of 5 and an indolin-2-one (6) is added into EtOH and piperidine. The resulting solution is refluxed for 12 h. The resultant precipitate is filtered and washed with EtOH to provide the corresponding (Z)-3-((3-(3-ethoxy-3-oxopropyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indolin-2-one (7). To obtain the corresponding carboxylic acid (8), 3.0 N aqueous NaOH is added into a solution of 7 in EtOH; the resulting mixture is refluxed for 2 h and cooled to room temperature; the solution is then acidified with 6 N HCl to pH 3.0; and the resultant precipitate is filtered and washed with MeOH. To afford the corresponding sodium salt (9), a mixture of aqueous NaOH, MeOH, and 8 can be stirred and heated to boiling; 2-propanol can then be slowly added to the mixture; and the solution can be stirred for 12 h.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([O:40][CH2:41][CH3:42])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH3:38])[CH2:15][CH2:16][CH:17]2[O:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:9][C:8]=1[CH3:39])C.[Li+].[OH-]>>[O:22]1[CH2:21][CH2:20][CH2:19][O:18][CH:17]1[CH2:16][CH2:15][CH:14]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38])[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:40][CH2:41][CH3:42])[C:4]([OH:43])=[O:3])=[C:8]([CH3:39])[CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(OC(CCC2OCCCO2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OC(CCC2OCCCO2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], 3-(4-{3-[1,3]dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 3-(4-{3-[1,3] dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid as a mixture of two diastereomeric racemates as colorless liquid.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:10]([N:19]([CH3:39])[C:20](=[O:38])[C:21]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)([CH3:23])[CH3:22])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:32][C:30]([F:31])([F:33])[C:28]1[CH:29]=[C:24]([C:21]([CH3:22])([CH3:23])[C:20]([N:19]([CH3:39])[C@H:10]2[C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][NH:8][CH2:9]2)=[O:38])[CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a solution of rac-N-((3S,4R)-1-Benzyl-4-phenyl-pyrrolidin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide (1.0 g, 1.82 mmol) in MeOH (30 ml) was added ammonium formate (0.59 g, 9.3 mmol) and Pd/C 10% (0.25 g). Stirring was continued at RT for 1 h, the reaction mixture was then filtered through celite, concentrated under vacuo. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 8:2) yielded 0.87 g (84%) of rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide as a colorless oil. ES-MS m/e: 459.4 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC#N.O>[CH2:1]([O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([Cl:20])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(CCc1ccc(O)c(Cl)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-hydroxy-phenyl)-propionic acid benzyl ester (13.36 g, 52.1 mmol) in MeCN (100 ml) was cooled to 0° C. Trichloroisocyanuric acid (4.00 g, 17.2 mmol) was added, and the resulting white suspension was gradually allowed to warm to RT and stirred overnight. The reaction mixture was diluted with water (200 ml) and the product was extracted into EtOAc (250 ml) and dried (MgSO4). Purification by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (1H, s), 7.32 (3H, m), 7.29 (2H, d), 7.18 (1H, d), 6.97 (1H, dd), 6.85 (1H, d), 5.07 (2H, s), 2.76 (2H, t), 2.64 (2H, t). LC-MS Rt 1.46 mins; 313.2 [M+H]+, Method 2minLC_v002.
Reaction SMILES: I[C:2]1[C:3]2([CH2:8][CH2:9][CH2:10][CH:11]=1)[O:7][CH2:6][CH2:5][O:4]2.C([Li])CCC.[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20](OC(C)C)[O:19]1.O>C1COCC1>[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:2]2[C:3]3([CH2:8][CH2:9][CH2:10][CH:11]=2)[O:7][CH2:6][CH2:5][O:4]3)[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: IC1=CCCCC12OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(C2=CCCCC23OCCO3)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 6-iodo-1,4-dioxaspiro[4.5]dec-6-ene (Synlett, 2008, 1086-1090; 2.70 g, 10.2 mmol) in THF (30 mL), butyl lithium (1.65 M solution in hexane; 6.7 mL, 11.1 mmol) was added at −78° C. The reaction solution was stirred at −78° C. for 1 hour. Then, 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (4.0 mL, 19.8 mmol) was added thereto, and the mixture was stirred at −78° C. for 2 hours. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=9:1) to yield the title compound (1.52 g, 56%) as a colorless oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([S:83][CH:84]2[CH2:86][CH2:85]2)=[C:33]([CH2:35][N:36]([CH3:82])[C:37]([CH:39]([NH:55][C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][CH:65]=2)[C:62]([N:66]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[N:61][CH:60]=[C:59]3[F:81])[C:40]2[CH:45]=[C:44]([CH3:46])[C:43]([CH2:47][CH:48]([OH:53])[CH2:49][C:50]([OH:52])=O)=[C:42]([CH3:54])[CH:41]=2)=[O:38])[CH:34]=1>CN(C1C=CN=CC=1)C.ClCCl.CN(C=O)C>[C:77]([O:76][C:74]([N:66]([C:62]1[C:63]2[C:58](=[CH:57][C:56]([NH:55][C@H:39]3[C:37](=[O:38])[N:36]([CH3:82])[CH2:35][C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][C:32]=4[S:83][CH:84]4[CH2:85][CH2:86]4)[NH:28][C:50](=[O:52])[CH2:49][CH:48]([OH:53])[CH2:47][C:43]4[C:42]([CH3:54])=[CH:41][C:40]3=[CH:45][C:44]=4[CH3:46])=[CH:65][CH:64]=2)[C:59]([F:81])=[CH:60][N:61]=1)[C:67](=[O:68])[O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:75])([CH3:78])([CH3:79])[CH3:80]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2SC2CC2)cc(C)c1CC(O)CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2cc(C)c1CC(O)CC(=O)Nc1ccc(SC3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1
Reaction time: 4 h
Yield: 32.6 %

Procedure:
To a solution of BOP (234 mg, 0.529 mmol), TEA (0.074 mL, 0.529 mmol) and DMAP (129 mg, 1.058 mmol) in dichloromethane (10 mL) and DMF (10 mL) was added 2E in dichloromethane (10 mL) via a syringe pump over 10.0 h. The reaction was continued at rt for 4 h, quenched by water and extracted by EtOAc (×3). The combined organics were washed by brine, dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 100% ethyl acetate in hexane over 10 min using a 4 g silica gel cartridge) to give a mixture of diastereoisomers (92 mg, 43% yield). The diastereoisomers were separated to give 2F (30 mg, 0.037 mmol, 32.6% yield) using a R,R-Welko-O 1 column (21.1 mm×250 mm, 10 micron, Regis Technologies, Inc.). MS (ESI) m/z: 814.7 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[NH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[C:20](F)=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:24][CH2:23]3)=[CH:13][C:12]=2[F:29])[CH2:7]1>CO>[NH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]([O:2][CH3:1])=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:23][CH2:24]3)=[CH:13][C:12]=2[F:29])[CH2:7]1
Reactant: C[O-]
Reactant: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(N2CCC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 49 h

Procedure:
To a solution of sodium methoxide prepare from sodium (0.2 g) and absolute methanol (10 ml) was added 7-(3-amino 1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid (0.47 g) and the mixture in sealed tube was stirred for 49 hours at 140° to 150° C. and then concentrated. The residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1) and recrystallized from a solution of dichloromethanemethanol (1:1) to give the title compound (6 mg as pale yellow prisms, mp 207.5°-212° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[S:13]([NH:16][C:17]1[C:22](Cl)=[N:21][C:20]([Cl:24])=[CH:19][N:18]=1)(=[O:15])=[O:14]>>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[S:13]([NH:16][C:17]1[C:22]([O:4][CH2:1][C:2]#[CH:3])=[N:21][C:20]([Cl:24])=[CH:19][N:18]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: C#CCO
Product: C#CCOc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using propargyl alcohol (0.3 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.35 g). Yield 0.2 g.