Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[N:19](COCC[Si](C)(C)C)[C:20]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1.Cl>C(O)C.Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:19][C:20]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)(=[O:30])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)nc(C(=O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)n2COCC[Si](C)(C)C)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)c2[nH]c(C(=O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)nc2-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone (15 mg, 21.5 mmol) in Ethanol (1 mL) was added 5 drops of 2N HCl. The solution was stirred at room temperature for 18 hours. A solution of 1 M HCl in ether (0.5 mL) was then added and the reaction mixture was heated to 70° C. for 2 hours. The volatile components were then removed under reduced pressure. Flash silica gel chromatography (2:1 hexane/ethyl acetate to 1:1 hexane/ethyl acetate to ethyl acetate to 4:1 ethyl acetate/methanol) afforded the product [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1H-imidazol-2-yl]-methanone as a yellow powder (12 mg, 98%). 1H NMR (CDCl3) δ2.3 (s, 3H), 5.3 (s, 2H), 7.0 (d, 2H, J=7), 7.1-7.3 (m, 9H), 7.8 (t, 1H, J=7), 7.9 (d, 2H, J=7), 8.4 (d, 1H, J=7), 8.6 (s, 1H), 8.7 (d, 1H, J=7), 8.85 (s, 1H). ESMS calcd for (C31H23ClN4O3S): 566.2; found: 567.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH:10]=[CH:11]2)[CH3:2].C(O)C[OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:9]12[CH2:14][CH:12]([CH:11]=[CH:10]1)[CH2:13][CH:8]2[CH2:7][CH2:6][CH2:5][CH:4]1[O:17][CH2:2][CH2:1][O:3]1
Reactant: CCOC=CCCC1CC2C=CC1C2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C1=CC2CC1CC2CCCC1OCCO1
Yield: 85 %

Procedure:
Next, the thus obtained 5-(4-ethoxy-3-buten-1-yl)-2-norbornene was mixed with 90 g of ethylene glycol, 1.0 g of p-toluenesulfonic acid and 300 ml of toluene and heated under reflux for one hour. The reaction mixture was allowed to cool down and poured into 100 ml of saturated sodium bicarbonate water. The resulting mixture separated into two layers. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 177 g of 2-{3-(5-norbornen-2-yl)-1-propyl}-1,3-dioxolane (boiling point 92° C./27 Pa, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
The product from Example 126b (4.0 g, 13.6 mmol) in 40 mL of CH2Cl2 was treated with oxalyl chloride (3.5 g, 27.2 mmol) and DMF (catalytic amount). Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound as a yellow oil (4.2 g, 100%).
Reaction SMILES: [CH2:1](/[C:3](/[CH:11]([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4]\[C:5](=[N:9][OH:10])[C:6]([NH2:8])=[O:7])[CH3:2].[N+](=[CH2:18])=[N-].C(O)(=O)C>CO>[CH2:1](/[C:3](/[CH:11]([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4]\[C:5](=[N:9][O:10][CH3:18])[C:6]([NH2:8])=[O:7])[CH3:2]
Reactant: CC/C(=C\C(=NO)C(N)=O)C(C)[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: CC/C(=C\C(=NOC)C(N)=O)C(C)[N+](=O)[O-]

Procedure:
To (E)-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide (37 mg) in methanol (5 ml) was added excess etheral diazomethane at -20° C. The resulting mixture was allowed to stand at 0° C. for an hour and then acetic acid was added thereto until the yellow color of the solution was discharged. The resulting reaction mixture was evaporated under reduced pressure to give an oil which was purified by preparative thin layer chromatography, developing with chloroform containing 5% methanol to give (E)-4-ethyl-2-methoxyimino-5-nitro-3-hexenamide (21.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12]1[C:21]([F:22])=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([F:23])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:23][C:14]1[CH:13]=[C:12]([CH2:11][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:21]([F:22])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COc1cccc(O)c1
Reactant: COC(=O)c1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)c(COc2cccc(OC)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-methoxyphenol (221 mg, 1.8 mmol) in DMSO (5 mL) was added methyl 4-(bromomethyl)-2,5-difluorobenzoate (Preparation 27, 491 mg, 1.8 mmol) followed by potassium carbonate (491 mg, 3.5 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 18 hours. The mixture was poured into water and extracted with EtOAc (3×20 mL), washed with 1 M aqueous NaOH and water, dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound as a solid, which was taken to the next step without further purification (441 mg, 81%).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:20]([OH:24])(=[O:23])[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:7]([O:6][C:4]([C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[CH:22]=[CH:21][C:20]([OH:24])=[O:23])=[O:5])[CH3:8]
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1C=CC(=O)O
Temperature: 110 °C
Yield: 103 %

Procedure:
To a solution of ethyl o-bromobenzoate (20.0 g), P(o-tol)3 (2.66 g), triethylamine (17.6 g) and acrylic acid (12.6 g) in toluene (70 mL) was added palladium acetate (980 mg) under nitrogen atmosphere, and the mixture was heated at 110° C. for one hour. The reaction solution was filtered, and extracted with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, dried, filtered, and concentrated to give 3-(2-ethoxycarbonylphenyl)acrylic acid (19.8 g, 103%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34](=O)([O-])[O-:35].[K+].[K+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([O:35][CH3:34])=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(C(=O)c2ccc(F)cc2)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)c2cc(CCNS(=O)(=O)c3ccc(Cl)cc3)cc(CCC(=O)O)c2)cc1
Yield: 85.9 %

Procedure:
A mixture of 3-[2-[(4-chlorophenyl)sulphonylamino]ethyl]-5-(4-fluorobenzoyl)benzenepropanoic acid (0.25 g) and potassium carbonate (0.212 g) in anhydrous methanol (5.0 ml) was heated under reflux for 18 hours. Additional potassium carbonate (0.212 g) was added and the mixture was heated under reflux for a further 20 hours and then cooled. Water (15 ml) was added and the solution was evaporated to about 10 ml and then acidified with 2N hydrochloric acid. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (MgSO4). Evaporation of the solvent gave the title compound as a glass (0.22 g). Found: C,60.25; H,4.92; N,2.51. C25H24ClNO6S requires C,59.81; H,4.82; N,2.79%.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[I:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][N:16]2[CH:17]=[C:12]([I:11])[CH:13]=[N:14][C:15]2=[O:18])=[CH:5][CH:6]=1
Reactant: O=c1ncc(I)c[nH]1
Reactant: ClCOc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(I)cn1COc1ccc(Cl)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 6, by adding a solution of 1-chloromethoxy-4-chlorobenzene (see Preparation 3) (10 mmol) in dichloromethane (10 ml) to a solution of 5-iodopyrimidin-2-one (10 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml), and heating the resultant mixture under reflux for 3 h. The product, 2.05 g (56%), consisted of the N- and O-isomers in the ratio 4:1. The O-isomer was removed from the product by extraction with acetone and the remaining N-isomer was recrystallized from EtOAc; m.p. 216° C. (Found C36.64; H2.24 Calc. for C11H8ClIN2O2 : C36.44; H2.23) 1H NMR (DMSO-d6 /CDCl3); δ 5.85 (CH2), 6.9-7.5 (Ph), 8.68 and 8.82 (H-4 and H-6, respectively, J 3 Hz). IR (KBr) 1650 cm-1 (CO). MS (70 eV, m/z (% rel. int.)): 362 (37,M) 235 (100), 222 (6), 108 (22).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[C:19]=2[OH:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[CH3:28][O:29]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:19]([OH:27])=[C:20]([CH3:26])[C:21]([CH3:25])=[C:22]([CH:28]=[O:29])[C:23]=2[CH3:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)cc(C)c(C)c1O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl (R)-7-(4-fluorophenyl)-7-(2-hydroxy-3,4,6-trimethylphenyl)heptanoate (0.8 g, 2.1 mmol) and dichloromethyl methyl ether (0.62 ml) in dichloromethane (10 ml) was added dropwise a solution of titanium tetrachloride (0.76 ml) in dichloromethane (3 ml) under argon atmosphere while maintaining the temperatures of the reaction mixture at a range from -10 ° C. to -12° C. The reaction mixture was then stirred for 30 minutes at the same temperature range. The reaction mixture was then added to ice-water, which was subjected to extraction with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous saline solution, successively, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform/hexane to afford 0.63 g of methyl (R)-7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoate. Physico-chemical properties and spectral data of the product were shown in [Table 4].
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[CH2:18][CH2:17]3)[C:7]=2[CH:8]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: N#Cc1ccccc1N1CCNCC1
Product: N#Cc1ccccc1N1CCN(Cc2csc3ccc(Cl)cc23)CC1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 2-(1-piperazinyl)benzonitrile were processed as described in Example 2 to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 3.2–3.65 (m, 10H), 7.21 (m, 1H), 7.28 (d, 1H, J=7.8 Hz), 7.51 (dd, 1H, J=7.8,1.5 Hz), 7.66 (m, 1H), 7.79 (dd, 1H, J=7.5,1.5 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.25 (s, 1H), 8.40 (s, 1H). MS (DCI/NH3) m/z 368.1 (M+H)+.
Reaction SMILES: I[CH2:2]CI.ICI.[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][CH:14]2[C:18](=[O:19])[CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[C:18]3([O:19][CH2:2]3)[CH:17]([C:20]([F:21])([F:22])[F:23])[CH2:16][CH2:15]2)=[CH:24][CH:25]=1
Reactant: O=C1C(Cc2ccc(Cl)cc2)CCC1C(F)(F)F
Reactant: ICCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ICI
Solvent: C1CCOC1
Product: FC(F)(F)C1CCC(Cc2ccc(Cl)cc2)C12CO2
Reaction time: 2 h

Procedure:
Under nitrogen flow, anhydrous THF (1 ml) was combined with Sm (705 mg, 4.7 mmol), and a solution of 1,2-diiodoethane (662 mg, 2.3 mmol) dissolved in anhydrous THF (2 ml) was added dropwise with stirring. The reaction solution was stirred for 30 minutes at room temperature. Thereafter, while cooling with ice, a solution of diiodomethane (723 mg, 2.7 mmol) and 5-(4-chlorobenzyl)-2-trifluoromethylcyclopentanone (Compound (V), (Ra)Xana=H, (Rb) Xbnb=CF3, Ym=4-Cl) (432 mg, 1.6 mmol) dissolved in anhydrous THF (2 ml) was added dropwise, and stirring was continued for 2 hours at room temperature. The reaction solution was poured into a solution mixture of an aqueous solution of NaOH (NaOH (1.1 g) dissolved in 10 ml of water) and THF (10 ml), and stirring was continued for 30 minutes at room temperature. This reaction solution was combined with ice, neutralized with a 1N aqueous solution of hydrochloric acid, and then extracted with hexane. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Silica gel chromatography (eluent; hexane:ethyl acetate=70:1) was conducted for purification to obtain the desired substance.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CS(C)=O>O>[C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13]([N:35]3[CH2:36][CH2:37][N:32]([C:30]4[S:29][N:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:31]=4)[CH2:33][CH2:34]3)=[O:20])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1cc(-c2ccccc2)no1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cc(-c2ccccc2)no1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 71.7 %

Procedure:
A solution of 2,2,2-trichloroethyl (3-phenylisoxazol-5-yl)carbamate (336 mg, 1.00 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (246 mg, 1.00 mmol) diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and a solid was collected by filtration. This was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (310 mg, 71.8%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:15]1([N:14]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)c1cccn1C
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=Nc1ccccc1)c1cccn1C
Yield: 43 %

Procedure:
To a solution of 4.0 ethyl 1-methylpyrrole-2-glyoxylate and 2.23 g aniline in 20 ml toluene is added 30 mg p-toluenesulfonic acid. Heating at reflux for 2 days with water being removed with a Dean-Stark trap is followed by dilution with ether. The precipitate is removed by filtration and the filtrate washed successively with aqueous hydrochloric acid, aqueous sodium bicarbonate and brine. After drying, the solvent is evaporated to afford a residue which is recrystallized twice from isopropanol to give a 43% yield of ethyl α-phenylimino-1-methylpyrrole-2-acetate, m.p. 69°-71° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH2:14])=[N:12][C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:10]1.[Cu][C:29]#[N:30].O>CN(P(N(C)C)(N(C)C)=O)C>[NH2:14][C:13]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([C:29]#[N:30])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=1
Reactant: N#C[Cu]
Reactant: Nc1nc(Nc2ccc(N3CCOCC3)cc2)nn1-c1ccc(I)cc1F
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(-n2nc(Nc3ccc(N4CCOCC4)cc3)nc2N)c(F)c1
Temperature: 55 °C
Yield: 10.6 %

Procedure:
A mixture of 1-(2-fluoro-4-iodo-phenyl)-N3-(4-morpholino-phenyl)-1H-[1,2,4]triazole-3,5-diamine (0.48 g, 0.99 mmol) and copper (I) cyanide (0.09 g, 0.99 mmol) in HMPA (3 mL) was heated at 55° C. for 2 h, then poured into water (75 mL) and filtered, washing with water. The filter cake was suspended in chloroform (100 mL) and methanol (5 mL), was refluxed for 2 h, cooled, filtered and evaporated. Purification by semi-preparative HPLC provided the title compound (0.04 g, 9% yield) as a pale tan lyophilate.
Reaction SMILES: C(#N)C.F[C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9](=[O:24])[C:10]([C:21]([OH:23])=[O:22])=[CH:11][N:12]2[C@@H:17]2[CH2:19][C@@H:18]2[F:20])=[CH:7][CH:6]=1.Cl.C(N(CC)CC)C.C(O)(=O)C(O)=O.[NH:39]1[CH2:43][CH2:42][C@@H:41]([C:44]2([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:46][CH2:45]2)[CH2:40]1>C(N(CC)CC)C>[C:50]([O:49][C:48]([NH:47][C:44]1([C@@H:41]2[CH2:42][CH2:43][N:39]([C:5]3[C:14]([O:15][CH3:16])=[C:13]4[C:8]([C:9](=[O:24])[C:10]([C:21]([OH:23])=[O:22])=[CH:11][N:12]4[C@@H:17]4[CH2:19][C@@H:18]4[F:20])=[CH:7][CH:6]=3)[CH2:40]2)[CH2:45][CH2:46]1)=[O:54])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1c(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
An acetonitrile solution (45 mL) containing 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3 g), triethylamine hydrochloride (2.8 g), and boron trifluoride-tetrahydrofuran complex (2.84 g) was stirred at room temperature for 30 minutes. tert-Butyl {1-[(3R)-pyrrolidin-3-yl]cyclopropyl}carbamate oxalic acid salt (3.54 g) and triethylamine (5.71 mL) were further added to reaction mixture, followed by stirring for 10 hours at the same temperature. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 12 hours, and the solvent was evaporated under reduced pressure. 80% Hydrated methanol (20 mL) was added to the residue, and the pH of the product was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, followed by stirring at 60° C. for 30 minutes and at room temperature for 16 hours. The thus-produced crystals were recovered through filtration and dried, to thereby yield 4.79 g of the title compound (yield: 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH3:10][C@@H:11](O)[CH2:12][CH:13]=[CH2:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C@H:13]([CH2:12][CH:11]=[CH2:10])[CH3:14]
Reactant: C=CC[C@@H](C)O
Reactant: Oc1cc(F)ccc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 2-bromo-5-fluorophenol (1.46 g, 7.64 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.94 mL, 9.17 mmol, 1.2 equiv), and PPh3 (2.40 g, 9.17 mmol, 1.2 equiv) in THF (26 mL) was added DIAD (1.78 mL, 9.17 mmol, 1.2 equiv). After stirring 2 h, the yellow solution was diluted with ether, washed with 1 N NaOH, dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (hexane) to provide the product (1.18 g, 60%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.49 (dd, J=8.7, 6.3 Hz, 1H), 6.67 (dd, J=10.6, 2.8 Hz, 1H), 6.62-6.56 (m, 1H), 5.91 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.22-5.12 (m, 2H), 4.49-4.38 (m, 1H), 2.62-2.52 (m, 1H), 2.49-2.40 (m, 1H), 1.39 (d, J=6.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)[N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34](B(O)O)=[CH:33][N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CN=3)N(C3C(=O)N(C)C=C(Cl)C=3)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:21][C:16]1[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:34]4[C:35]([O:37][CH3:38])=[N:36][C:31]([O:30][CH3:29])=[N:32][CH:33]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cn1)N(c1ccc(F)c(Cl)c1)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cn1)N(c1cc(Cl)cn(C)c1=O)C2=O
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cn2)N(c2ccc(F)c(Cl)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(3-chloro-4-fluoro-phenyl)-6-(5-chloro-pyridin-2-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate BL) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(5-chloro-pyridin-2-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a white solid. ESI-MS: tR=1.23 min, [M+H]+ 542/544 (LC-MS 1).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of dimethyl malonate (6.24 g, 46.7 mmol) and potassium carbonate (6.51 g, 47.2 mmol) in DMF (20 ml) is added 2,4-difluoronitrobenzene (5.00 g, 30.8 mmol). The reaction is stirred at room temperature for 1 hour and then is brought to 60° C. After stirring for 1 hour, it is cooled to room temperature and 1 N HCl (100 ml) is added. The mixture is extracted with ethyl acetate (80 ml×2). The organic layers are combined, dried and concentrated. The desired compound is obtained after flash column chromatography purification (silica gel, eluted with hexanes-ethyl acetate): 1H NMR (CDCl3) δ 3.82 (s, 6H), 5.40 (s, 1H), 7.18-7.26 (m, 21), 8.16 (dd, 1H, J1=4.8 Hz, J2=8.8 Hz); LC-MS: 272.1 (MH+).