Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.O.[NH2:14]N.C[N:17]([CH:19](OC)OC)C>C(O)C>[NH:14]1[C:2]2[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]=2[CH:19]=[N:17]1
Reactant: NN
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: COC(OC)N(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CCc2[nH]ncc2C1

Procedure:
A solution of ethyl 4-oxocyclohexanecarboxylate (50 g, 0.29 mol) in DMF-DMA (275 mL) was heated at 110° C. for 12 h. The mixture was concentrated and hydrazine hydrate (73.5 g, 1.47 mol) in ethanol (1000 mL) was heated under reflux overnight. Most of ethanol was removed and the remaining mixture was treated with water (400 mL). The resulting mixture was extracted with EtOAc (400 ml×2). The combined organic layers were washed with brine (400 mL) and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford crude ethyl 4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (18 g) as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:9][C:10](=[O:41])[C@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[NH:12][S:13]([C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22](C(=O)C(F)(F)F)[CH2:23]2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:8]>O.C(O)C>[CH2:7]([O:9][C:10](=[O:41])[C@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[NH:12][S:13]([C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH2:23]2)=[CH:18][CH:17]=1)(=[O:14])=[O:15])[CH3:8]
Reactant: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A solution of sodium carbonate (11.5 g, 108.5 mmol) in water (115 ml) was added to a stirred solution of N-(2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-cyano-(S)-phenylalanine ethyl ester (Preparation 21; 11.5 g, 22.6 mmol) in ethanol (115 ml) and the resulting mixture stirred for 3 hours at room temperature. The bulk of the ethanol was then removed under reduced pressure, water added and the resulting suspension extracted with dichloromethane. The organic extract was washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure, then the residue dissolved in the minimum volume of dichloromethane. Dilution of this solution with ethanol, followed by concentration and overnight standing of the mixture, provided the title compound as a white solid (6.4 g), after filtration and washing with ether. Rf 0.26 (SS 6). m/e 414 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8].[CH:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.O>CS(C)=O>[CH3:20][C:19]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:21]=[C:2]([N:31]2[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]2)[CH:3]=[CH:4][C:5]=1[N+:22]([O-:24])=[O:23]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CC(C)N1CCNCC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCN(C(C)C)CC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.9 %

Procedure:
To a solution of methyl 3-[(5-fluoro-2-nitrobenzoyl)amino]-4-methylbenzoate (8 g) in DMSO (24 ml) was added N-isopropylpiperazine (3.4 g) and N,N-diisopropylethylamine (4.7 ml) and the reaction stirred at room temperature for 6 hours. Water (200 ml) was added and the resultant solid collected by filtration, washed with water (×3) and dried in vacuo at 50° C. for 16 hours to yield methyl 4-methyl-3-{[5-(4-isopropylpiperazin-1-yl)-2-nitrobenzoyl]amino}benzoate as a yellow solid (10.7 g); NMR Spectrum: (DMSOd6) 0.99 (d, 6H), 2.34 (s, 3H), 2.55 (m, 4H), 2.71 (m, 1H), 3.50 (m, 4H), 3.85 (s, 3H), 7.07 (m, 2H), 7.39 (d, 1H), 7.71 (m, 1H), 8.06 (d, 1H), 8.20 (m, 1H), 9.96 (s, 1H); Mass Spectrum: M+H+ 441.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[SH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=1.CCN(CC)CC>CN(C=O)C>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([S:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)Cc1ccc(S)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(Sc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 110 °C
Yield: 100 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.120 g, 0.40 mmol), methyl 2-(4-mercaptophenyl)acetate (0.100 g, 0.55 mmol), and Et3N (0.145 g, 1.3 mmol) in DMF was heated at 110° C. for 24 h. After this time, the mixture was concentrated, diluted with EtOAc (100 mL), washed with 10% aqueous LiCl (2×100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 100% hexanes to 1:1 ethyl acetate/hexanes to afford the title compound (0.164 g, 100%) as a white solid. MW=409.93. 1H NMR (CDCl3, 300 MHz) δ 7.78-7.77 (m, 1H), 7.61-7.46 (m, 3H), 7.37 (d, J=8.2 Hz, 2H), 7.30-7.28 (m, 3H), 6.89 (s, 1H), 3.73 (s, 3H), 3.70 (s, 2H), 3.09 (t, J=7.7 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.24-2.05 (m, 4H); APCI MS m/z 410 [M+H]+.
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)=[CH:4][CH:3]=1.[I:14](O)(=O)=O.II>C(O)(=O)C.S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: [O-][I+2]([O-])O
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(-c2ccc(I)cc2)cc1
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 325.1 %

Procedure:
A 4-neck one liter round bottom flask equipped with mechanical stirrer, thermometer and reflux condenser topped with nitrogen bubbler inlet was charged with 4-bromobiphenyl (23.31 g, 100 mmol) in acetic acid (400 mL), sulfuric acid (10 mL) and water (20 mL). To this stirring mixture was added iodic acid (4.84 g, 27.5 mmol) followed immediately by addition of iodine chips (11.17 g, 44.0 mmol). The reaction flask was immersed in a preheated tri(ethylene glycol) heating bath and heated at 65° C. internal temperature. After 30 min the bath temperature was increased such that the internal temperature raised to 85° C. after 20 min. Heating at this temperature was continued for 4.5 hours at which point HPLC analysis showed the reaction to be complete. After stirring overnight at room temperature the reaction mixture was vacuum filtered through a coarse fritted funnel and the solids were rinsed with water. The resulting white solid (32.1 g, 89% yield) had mp 177-179° C. and was used without further purification in the next step. NMR analysis confirmed the structure of Intermediate Compound 3,4-bromo-4′-iodobiphenyl. Purity (HPLC): >99%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: Fc1ccccc1Br
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccccc1-c1cccc2[nH]ccc12
Temperature: 75 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.431 g, 10.0 mmol), and 2-bromofluorobenzene (1.75 g, 10.1 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (0.347 g, 0.30 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30.0 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.35 g (64%) of the product 4-(2-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C(C)(C)C)[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.Cl>ClC1C=CC=CC=1Cl.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:15]=[C:9]([C:9]([CH3:15])([CH3:10])[CH3:8])[C:8]2[O:12][C:11](=[O:13])[C:10](=[C:10]3[C:7]4[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:15]=[C:9]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:8]=4[O:12][C:11]3=[O:13])[C:7]=2[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2=C1C(=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Reaction time: 0.5 h

Procedure:
10 g of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (prepared as described in Ex.1 a of U.S. Pat. No. 5,614,572) are placed in 25 ml of 1,2-dichlorobenzene, and 0.5 g of 4-dimethylaminopyridine and 3 ml of thionyl chloride are added thereto. The solution is then slowly heated to 373 K at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. It is then stirred at that temperature for a further ½ hour. The temperature is then increased to reflux temperature. After 75 min, the 1,2-dichlorobenzene is distilled off, under reduced pressure at the end. The isoxindigo is crystallised out by adding 30 ml of acetonitrile to the residue, is filtered off, washed with acetonitrile and dried, yielding 6.8 g (73% of the theoretical yield) of 5,7,5′,7′-tetra-tert-butyl-[3,3′]bibenzofuranylidene-2,2′-dione of formula (LIa).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(#N)C>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: N#Cc1ccccc1F
Solvent: CC#N
Product: N#Cc1ccccc1N1CCOCC1
Temperature: 110 °C
Yield: 956.3 %

Procedure:
2-Fluorobenzonitrile (1.21 g, 1.00 mmol) was dissolved in acetonitrile (50 ml), and morpholine (33 ml, 377 mmol) was added thereto followed by stirring at 110° C. for 2 nights. After the reaction was completed, the reaction mixture was concentrated to give oily substances which were then purified by silica gel chromatography (eluent: chloroform) to give the title compound (1.80 g, 95%) as oily substances.
Reaction SMILES: [CH:1]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.FC1C=C(OC)C=CC=1>>[CH:1]1([C:8]([C:17]2[CH:16]=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[F:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCCC1
Reactant: Oc1cccc(F)c1
Agent: COc1cccc(F)c1
Product: O=C(c1ccc(O)cc1F)C1CCCCCC1

Procedure:
Using the same procedure but replacing 1-adamantyl carbonyl chloride by cycloheptane carbonyl chloride and 3-fluorophenol by 3-fluoroanisole, the following compound was obtained:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[F:20][CH2:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:25][CH2:24][NH:23][CH:22]([CH2:21][F:20])[CH2:27]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: FCC1CNCCN1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(CF)C3)c(F)cc2c1=O
Temperature: 115 °C
Yield: 93.9 %

Procedure:
A suspension of 530.4 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 90.7 mg of 2-(fluoromethyl)piperazine and 2 ml of pyridine was heated at 115° C. for 30 minutes, then filtered and the filtrate refrigerated overnight. The resulting crystals were collected, washed with water, ether and dried, giving 262 mg of the desired compound as light yellow crystals, mp 202°-203° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH2:35]([C:42]1([OH:48])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:35]([C:42]1([OH:48])[CH2:47][CH2:46][N:45]([C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[O:13])[CH2:44][CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: Cc1[nH]c2ccccc2c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1[nH]c2ccccc2c1C(=O)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a stirred solution of 0.1 g (0.57 mmol) 2-methyl-1H-indole-3-carboxylic acid in 10 ml CH2Cl2 were added 0.14 g (0.73 mmol) EDC, 0.10 g (0.73 mmol) HOBt, 90 μl (0.63 mmol) Et3N and 0.11 g (0.57 mmol) 4-benzyl-piperidin-4-ol. The mixture was stirred overnight at RT and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 0.15 g (75%) of (4-benzyl-4-hydroxy-piperidin-1-yl)-(2-methyl-1H-indol-3-yl)-methanone as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][N:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:18])C=CC=CC=1.C([N:30]([CH2:33]C)CC)C>C1(C)C=CC=CC=1>[N:30]([C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=1)=[C:33]=[O:18]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C(=O)O)cn1
Solvent: Cc1ccccc1
Product: Cc1ccc(N=C=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-methyl-nicotinic acid (0.41 g, 3 mmol) (Aldrich) in toluene (15 mL) was added diphenylphosphoryl azide (0.958 g, 3.5 mmol) (Aldrich), followed by the addition of triethylamine (0.35 g, 3.6 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes and the mixture became clear. Then the mixture was heated at 80° C. for 2 hours. The mixture was cooling down to room temperature to give crude 5-isocyanato2-methyl-pyridine as 0.2 M solution of toluene and used for the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[CH:7][N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:16].BrC1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[CH3:25]C(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:21]1([CH3:24])[CH:22]=[CH:23][C:1]([C:2]2([CH3:25])[CH2:6][CH2:5][C:4](=[CH:7][N:8]([CH3:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3]2=[O:16])=[CH:19][CH:20]=1
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(C2(C)CCC(=CN(C)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 88.4 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with palladium acetate (5.6 mg, 0.025 mmol, 5 mol % Pd), (−)-1 (18.5 mg, 0.038 mmol, 7.5 mol %) and 2-methyl-5-(N-methyl-anilinomethylene)cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 4-Bromotoluene (171 mg, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 135 mg (88%) of the title compound. The ee was determined to be 75% by chiral HPLC analysis.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:45][CH:44]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[CH:45][CH:44]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc(OCc4ccccc4)cc3)cc12

Procedure:
25.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.1 g of N-[6-chloro-5-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 50 cm3 of tetrahydrofuran. The medium is then refluxed for 18 hours and the resulting mixture is allowed to return to room temperature and 100 cm3 of ethyl acetate are added; the organic phase is washed with 2×100 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 30 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed with 2×20 cm3 of diisopropyl ether. After drying under reduced pressure (90 Pa; 50° C.), 1.3 g of N-[6-chloro-5-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide are obtained in the form of white crystals melting at 230° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:25]4[N:29](COCC[Si](C)(C)C)[C:28]5[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=5[N:26]=4)[C:13](=[O:24])[N:14](COCC[Si](C)(C)C)[N:15]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.C(O)C>Cl.O1CCOCC1>[NH:29]1[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[N:26]=[C:25]1[C:12]1[C:13](=[O:24])[NH:14][N:15]=[C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)[CH:11]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccnc(C3CC3)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1[nH]nc(-c2ccnc(C3CC3)n2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
27 mg of 6-(2-cyclopropylpyrimidin-4-yl)-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one are dissolved in 2.5 ml of 4M hydrochloric acid solution in dioxane and 1 ml of ethanol and stirred at room temperature for 2 days. The solvent is then distilled off, and the residue is dissolved in 2 ml of dichloromethane and 1 ml of trifluoroacetic acid and again stirred at room temperature for 3 h. Distillation off is then repeated, and the residue is dissolved in 1 ml of 2M sodium hydroxide solution and 2 ml of water, and the mixture is stirred at room temperature for 10 h. For workup, it is neutralized with 2M hydrochloric acid, the volatile components are distilled off, and the crude product is purified by RP HPLC (acetonitrile (+0.05% HCOOH)/water (+0.05% HCOOH)).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[N:17]=[CH:16][CH:15]=2)=[C:10]([CH3:27])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:8]1=[O:38])C.[OH-].[Na+].O>CO.C(OCC)C>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([N:18]2[C:14]([C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][C:4]([OH:39])=[O:3])[C:8](=[O:38])[N:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=4)[C:10]=3[CH3:27])=[CH:15][CH:16]=[N:17]2)=[CH:24][CH:23]=1)#[N:26]
Reactant: CCOC(=O)CCn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCC(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid ethyl ester (prepared in Example 4) (351.0 mg) in methanol (1.0 ml) was cooled under ice-cooling and thereto was added 2N aqueous sodium hydroxide solution (340 μl) and the resulting mixture was stirred at room temperature for twelve hours. The reaction mixture was diluted with diethylether (30 ml) and thereto was added water (30 ml). The organic layer and the aqueous layer were separated and the aqueous layer was then acidified with sodium hydrogen sulfate (500 mg) and extracted with ethyl acetate (50 ml×3). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained amorphous was washed with hexane (30 ml) to afford 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid (239.5 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C@H:7]([CH2:16][OH:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(O[C:22](=O)[CH:23]([C:25]#[N:26])[CH3:24])C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[C@H:7]([CH2:16][OH:17])[N:8]([CH2:22][CH:23]([C:25]#[N:26])[CH3:24])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(C)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C#N)CN(C(=O)OC(C)(C)C)[C@@H](CO)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a 100 mL flask with a Dean-Stark condenser and an argon inlet was added N-Boc-L-serine tert-butyl ester 2 (5.00 g, 19.1 mmol), ethyl-2-cyanopropionate (3.65 g, 28.7 mmol), p-toluenesulfonic acid monohydrate (0.200 g, 1.05 mmol) and anhydrous toluene (60 mL). The reaction mixture was heated to reflux while stirring. Solvent was removed through the Dean-Stark trap and replaced with an equal amount of fresh toluene. After refluxing for 6 h, the reaction mixture was cooled to room temperature. The solution was washed once with saturated aqueous NaHCO3, twice with H2O, and twice with saturated aqueous NaCl. The organic layer was separated, dried over anhydrous MgSO4, and concentrated to a viscous yellow oil. 1H NMR (CDCl3): δ 1.43 (m, 21H, CH3—CH—NH—, 2 (CH3)3), 3.25 (s, 1H, CH3-CH—CN), 3.85 (t, 2H, CO2, —CH2—CH—), 3.85 (t, 2H, CO2—CH2—CO2Bu), 4.25 (s, 1H, NH—CH—CH2—), 5.55 (d, 1H, NH). This material can be converted to the cyanoacrylic monomer by following the general procedure set forth above for the alanine-derived monomer.