Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH:18]([CH3:20])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[C:32]([OH:36])(=[O:35])[CH:33]=[CH2:34]>O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH:18]([CH3:20])[CH3:19])[C:2]=2/[CH:34]=[CH:33]/[C:32]([OH:36])=[O:35])=[CH:12][CH:13]=1
Reactant: CC(C)n1c(Br)c(-c2ccc(F)cc2)c2ccccc21
Reactant: C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(/C=C/C(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
2 g (6.02 mmol) of 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole, 10 ml of DMF and 0.5 ml of water are introduced into a 50 ml three-necked, round-bottomed flask, which has been purged with nitrogen and is equipped with a magnetic stirrer, thermometer, reflux condenser, gas inlet tube and nitrogen delivery line, and degassing is carried out for 30 min. by introducing nitrogen. 24 mg (1.0 mol %) of the catalyst K4 from WO-A-99/47474 and 2.15 g (6.6 mmol) of caesium carbonate are then added and degassing is carried out for a further 1 hour. 1.0 g (13.8 mmol) of acrylic acid are subsequently added and the suspension is heated at reflux for 2 hours. The DMF is then distilled off, the residue is cooled, 10 ml of 1N hydrochloric acid are added and the aqueous phase is extracted three times with 50 ml of ethyl acetate. The combined organic phases are washed three times with 30 ml of saturated sodium carbonate solution, slightly acidified again using 1N hydrochloric acid, and washed three times with 50 ml of saturated sodium chloride solution in order to render neutral. Drying over magnesium sulfate, filtration and concentration by evaporation are then carried out. The residue (1.83 g) is dissolved in THF, 5 g of silica gel are added and the solution is concentrated by evaporation using a rotary evaporator. The charged silica gel is transferred into a glass frit, and non-polar secondary products are eluted using hexane/ethyl acetate=10:1 and then the product is eluted using ethyl acetate. Concentration by evaporation yields a yellow solid which, according to NMR, is the desired product in pure form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(N)cc2)c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (55 mg, 0.17 mmol) and benzenesulfonyl chloride (61 mg, 0.34 mmol) in THF (3 mL) was added diisopropylethylamine (62 mg, 0.49 mmol) at 0° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (12 g) column, eluting with 2-25% ethyl acetate in hexanes, to afford [4-(4-benzenesulfonylamino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (38 mg, 48%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.84 (d, J=7.5 Hz, 2 H), 7.77 (dd, J=9.1, 6.0 Hz, 1 H), 7.70 (s, 1 H), 7.59 (t, J=7.5 Hz, 1 H), 7.49 (t, J=7.5 Hz, 2 H), 7.15-7.22 (m, 3 H), 7.10 (d, J=8.2 Hz, 2 H), 6.80 (s, 1 H), 6.71 (dd, J=11.3, 2.3 Hz, 1 H), 3.78-3.90 (m, 2 H), 3.73 (s, 3 H), 2.09 (s, 3 H). HRMS calcd. for C26H21FNO4S [(M−H)−] 462.1181, obsd. 462.1179.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:12]=3[Cl:19])[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=3[Cl:19])[C:3]=12
Reactant: COc1ccc(Cl)c(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cc(O)ccc2Cl)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of Example 96 (0.030 g, 0.055 mmoles) in dichloromethane (3 ml), BBr3 (1M in dichloromethane, 0.27 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as pale green solid (0.018 g, 62% yield). MP: 192-195° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.95 (s, 1H), 8.15 (s, 1H), 8.05 (dd, J=7.9, 1.2 Hz, 1H), 7.86 (m, 1H), 7.65-7.49 (m, 4H), 7.39 (d, J=8.7 Hz, 1H), 7.35 (br s, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.97 (dd, J=7.6, 3.2 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.07 (q, J=6.9 Hz, 1H), 1.88 (d, J=7.0 Hz, 3H). Mass: 527.90 (M+).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[F:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([C:41]2[CH:45]=[CH:44][S:43][C:42]=2[CH:46]=O)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:46][C:42]2[S:43][CH:44]=[CH:45][C:41]=2[S:38]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)(=[O:39])=[O:40])=[C:20]1[CH3:29]
Reactant: O=Cc1sccc1S(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
A mixture of triethylsilane (0.79 g), trifluoroacetic acid (0.47 g) and 1,2-dichloroethane (2.0 mL) at −10° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.1 g), 3-(4-fluorobenzenesulfonyl)thiophene-2-carbaldehyde (0.15 g) and 1,2-dichloroethane (3.0 mL), and the resulting mixture was stirred at −10° C. for 15 minutes and then at room temperature overnight. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:1 to 0:1 by volume) to afford the title compound as a colourless gum (0.17 g).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O.NN>C1COCC1.C(O)C.[Ni]>[F:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)c(F)c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(CN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrobenzyl)morpholine (240 mg, 1.0 mmol) in THF/ethanol mixture (1:1) (25 mL) was added a catalytical amount of Raney-Ni and hydrazine hydrate (9.0 mmol) and the mixture was stirred at ambient temperature for 15 minutes, filtered through a Celite pad. The filtrate was evaporated to provide the title compound, (197 mg, 94%), which was used in further reactions without purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=[O:5].C(NC(C)C)(C)C.[Li].C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Cl:33][CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[CH:39][CH:40]=2)[C:35]1=[O:46].[NH4+].[Cl-]>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])[CH2:6][C:35]1([OH:46])[C:36]2[C:41](=[CH:40][CH:39]=[C:38]([O:44][CH3:45])[CH:37]=2)[CH2:42][CH2:43][CH:34]1[Cl:33])[CH3:1]
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)C(=O)C(Cl)CC2
Agent: [Cl-]
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)c2cc(OC)ccc2CCC1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of EtOAc (16.1 ml, 164.48 mmol) in THF (250 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropylamine (prepared from 23.3 ml of diisopropylamine (164.48 mmol) and 102.8 ml of 1.6 M n-BuLi in hexane (164.48 mmol) in THF (250 ml). After stirring at −78° C. for 30 minutes, a solution of 2-chloro-7-methoxy-3,4-dihydro-2H-naphthalen-1-one (31.5 g, 149.53 mmol) in THF (250 ml) is slowly added during 30 minutes. The reaction mixture is stirred at −78° C. for 1 h. TLC analysis indicates complete conversion of starting material. A sat. aqueous solution of NH4Cl (250 ml) is carefully added to the reaction mixture at −78° C. The mixture is warmed to RT. The organic layer is separated, diluted with EtOAc and washed with brine. After drying over Na2SO4, the solvent is removed. Purification by FCC (hexane/EtOAc 4:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.27 (t, J=9.4 Hz, 3H), 2.32-2.48 (m, 2H), 2.78-2.88 (m, 1H), 2.86-3.02 (m, 2H), 3.05-3.14 (m, 1H), 3.82 (s, 3H), 4.18 (q, J=9.4 Hz, 2H), 5.02-5.08 (m, 1H), 6.81-6.84 (m, 1H), 7.03 (d, J=10.5 Hz, 1H), 7.18-7.19 (m, 1H). ES+−MS: 281.3, 283.3 [M+H—H2O]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[CH:13]=[C:14]([Cl:18])[C:15](N)=[CH:16][C:4]=2[S:3]1.Cl.N([O-])=O.[Na+].[C:24]([O-])(=O)[CH3:25].[Na+]>O.C1C=CC=CC=1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[CH:13]=[C:14]([Cl:18])[C:15]([C:25]3[CH:24]=[CH:13][CH:5]=[CH:4][CH:16]=3)=[CH:16][C:4]=2[S:3]1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)Cn1c(=O)sc2cc(N)c(Cl)cc21
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)Cn1c(=O)sc2cc(-c3ccccc3)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 2-oxo-5-chloro-6-amino-3-benzothiazolineacetate (347.8 g) and conc.hydrochloric acid (1040 ml) was stirred for 30 minutes at ambient temperature. After the resultant mixture was cooled to 2° C., a solution of sodium nitrite (88.3 g) in water (120 ml) was added dropwise thereto below 5° C. in the course of 40 minutes. The mixture was stirred for 20 minutes at 0° C. To the resultant mixture was added benzene (5.2 l) in the course of 30 minutes. After the reaction mixture was stirred for an hour and 40 minutes under ice-cooling, a solution of sodium acetate.3H2O (1.56 kg) in water (3.6 l) was added dropwise thereto under ice-cooling in the course of an hour. The mixture was stirred overnight at ambient temperature. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give a residue, which was recrystallized from ethanol to give ethyl 2-oxo-5-chloro-6-phenyl-3-benzothiazolineacetate (311.5 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[S:23]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:22])(=[O:25])=[O:24]
Reactant: Nc1ccc([N+](=O)[O-])cc1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1cc([N+](=O)[O-])ccc1N
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a stirred suspension of 2 (42 g) and triethylamine (30.4 g) in dichloromethane (400 ml) in an ice bath was added dropwise a solution of methanesulfonyl chloride (25.2 g) in dichloromethane (100 ml). The mixture was stirred for 30 min. and the precipitate was collected by filtration and recrystallized from ethyl acetate to give 33.77 g (58%) of 3: mp 132°-135° C.; MS m/e 276 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]2=[O:19])[C:3]=1[CH2:20]OC1CCCCO1.O=S(Cl)[Cl:30].O>C(Cl)Cl>[Cl:30][CH2:20][C:3]1[C:4]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]2=[O:19])=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1COC1CCCCO1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-3-trifluoromethyl-1H-pyridin-2-one (100 mg. 0.26 mmol) was dissolved in DCM (5 mL). SOCl2 (97 μL. 1.31 mmol) and water (25 μL) were added and the reaction mixture was stirred for 1 h at RT. After removal of the solvents in vacuo the resulting title compound was used for the next reaction without purification. MS (m/z): 317.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:18])[C:5]2[CH:11]=[C:10]([C:12]#[CH:13])[C:9](=[O:14])[N:8]([CH:15]([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[CH2:19]([N:21]([CH2:29][CH3:30])[C:22](=[O:28])[O:23][CH2:24][N:25]=[N+:26]=[N-:27])[CH3:20]>S([O-])([O-])(=O)=O.[Cu+2].CC(O)(C)C.O>[CH2:29]([N:21]([CH2:19][CH3:20])[C:22](=[O:28])[O:23][CH2:24][N:25]1[CH:13]=[C:12]([C:10]2[C:9](=[O:14])[N:8]([CH:15]([CH3:16])[CH3:17])[C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:18])[C:5]=3[CH:11]=2)[N:27]=[N:26]1)[CH3:30]
Reactant: C#Cc1cc2c(C)nc(N)nc2n(C(C)C)c1=O
Reactant: CCN(CC)C(=O)OCN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCN(CC)C(=O)OCn1cc(-c2cc3c(C)nc(N)nc3n(C(C)C)c2=O)nn1
Reaction time: 24 h
Yield: 68.5 %

Procedure:
2-amino-6-ethynyl-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (75 mg, 0.31 mmol) and azidomethyl diethylcarbamate (80 mg, 0.46 mmol) was suspended in 1:1 t-BuOH/H2O (4 mL). To this was added saturated copper sulfate solution (0.05 mL) and stirring was continued for 24 h. The mixture was concentrated and diluted with 5 mL water. The mixture was separated and the organic phase was washed with water and evaporated. Flash chromatography of the residue over silica gel, using 0-5% MeOH/CHCl3, gave the title compound (88 mg, 69%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>C(O)CCC>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH:34][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([N:8]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:27][CH2:26]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Clc1ccc2nc(-c3ccccc3)nn2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(-c2nc3ccc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)nn3n2)cc1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
365 mg of 6-chloro-2-phenyl[1,2,4]triazolo[1,5-b]pyridazine and 0.513 g of 4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 8 ml of 1-butanol; 0.54 ml of N-ethyldiisopropylamine was added, followed by heating and refluxing for 19 hours. Ice water and sodium hydrogen carbonate were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated; the resulting crystal was recrystallized from ethyl acetate to yield 308 mg of the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:6]([NH:8][O:9][CH3:10])=[O:7])[NH2:2].[I:15][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=1)[C:19]([C:21](=[CH:24]NC1C=CC=CC=1)[C:22]#[N:23])=[O:20].CCOC(C)=O>CCO>[NH2:23][C:22]1[N:1]([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=2[CH3:14])[C:6]([NH:8][O:9][CH3:10])=[O:7])[N:2]=[CH:24][C:21]=1[C:19](=[O:20])[C:18]1[CH:32]=[CH:33][CH:34]=[C:16]([I:15])[CH:17]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Reactant: CONC(=O)c1ccc(C)c(NN)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CONC(=O)c1ccc(C)c(-n2ncc(C(=O)c3cccc(I)c3)c2N)c1
Temperature: 67.5 °C
Yield: 55 %

Procedure:
To a stirred solution 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (116 mg, estimated 0.14 mmol) in EtOH (10 ml) was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 3 (59 mg, 0.14 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84) and mixture was heated (bath T=65-70° C.) for 4 hr, when additional 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (80 mg, 0.11 mmol) was added and the mixture was heated at the same temperature for 27 hr. It was cooled to room temperature, concentrated and redissolved in EtOAc before it was washed with water and brine, dried over Na2SO4, concentrated to give a crude semisolid. The mixture was then purified by flash chromatography, eluting with 1:1 EtOAc/hexanes to remove impurities then 100% EtOAc give 3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-methoxy-4-methyl-benzamide 4 as an off-white solid (38 mg, 0.08 mmol, 55%). HPLC (6 minute gradient) tR 3.49 min; MS m/z 476.96 [M+H]+; 1H NMR (CD3OD, 300 MHz) δ 8.10 (s, 1 H), 7.95 (d, J=8.0, 1 H), 7.88 (d, J=8.0, 1 H), 7.82 (m, 2 H), 7.78 (s, 1 H), 7.58 (d, J=8.0, 1 H), 7.33 (t, J=7.8, 1 H), 5.02 (s. 3 H), 2.33 (s, 3 H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 189.3, 154.3, 143.5, 143.3, 142.0, 138.3, 137.4, 133.5, 132.9, 132.0, 130.4, 128.8, 128.4, 104.8, 95.4, 64.8, 18.2 ppm.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][NH:7]2.Cl.CN(C)CCCN=C=NCC.[N:26]1([C:32]2[N:33]=[C:34]([CH2:39][C:40]([O-])=[O:41])[NH:35][C:36](=[O:38])[CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[Na+].O>CN(C)C=O.N1C=CC=CC=1>[N:26]1([C:32]2[N:33]=[C:34]([CH2:39][C:40](=[O:41])[N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=[CH:10][CH:9]=4)[CH2:5][CH2:6]3)[NH:35][C:36](=[O:38])[CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: FC(F)(F)c1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c1cccc2C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.4 %

Procedure:
700 mg of 4-trifluoromethyl-2,3-dihydro-1H-indole and 1.15 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 977 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2d of example 1d) in 25 ml of N,N-dimethylformamide and 25 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours, and then water is added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05: v/v), so as to give 220 mg of 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH2:6].[N:18]([CH2:21][CH2:22][C:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1)=[N+:19]=[N-:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C.O.C(OCC)(=O)C.CCCCCC>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH:6][C:28]([C:23]1([CH2:22][CH2:21][N:18]=[N+:19]=[N-:20])[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NCCC1(C(=O)O)CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCN=[N+]=[N-])CCCC1
Yield: 95.1 %

Procedure:
A solution of 4-nitro-L-phenylalanine methyl ester hydrochloride (3.0 g, 11.5 mmol), 1-(2-azidoethyl)cyclopentane carboxylic acid (2.3g, 12.7 mmol) and BOP (5.34 g, 12.1 mmol) in dichloromethane (6 mL) and DMF (4 mL) was treated with diisopropylethylamine (4.2 mL, 24.2 mmol). The mixture was stirred overnight at which time TLC (1:1 hexane:ethyl acetate) indicated no more starting material. The mixture was diluted with water, extracted with ethyl acetate. The extracts were washed with water and brine, then were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography over silica gel (3:1 hexane:ethyl acetate) to afford 4.26 g of N-[[1-(2-azidoethyl)cyclopentyl]carbonyl]-4-nitro-L-phenylalanine Methyl Ester.
Reaction SMILES: Br[C:2]1[O:6][CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[CH3:12][C:13]1[C:14](B2OC(C)(C)C(C)(C)O2)=[CH:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[N:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]([NH:19][C:16]1[CH:15]=[C:14]([C:2]2[O:6][CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=2)[C:13]([CH3:12])=[CH:18][N:17]=1)(=[O:22])[CH3:21]
Reactant: CCOC(=O)c1coc(Br)c1
Reactant: CC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1coc(-c2cc(NC(C)=O)ncc2C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of ethyl 5-bromo-3-furoate (23.7 g, 108.9 mmol), N-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]acetamide (20.0 g, 72.5 mmol), Pd(dppf)Cl2 (5.92 g, 9.09 mmol) and K2CO3 (20.0 g, 72.5 mmol) in water (72.5 mL) and toluene (1240 mL) was allowed to stir at 100° C. under an atmosphere of nitrogen overnight. The mixture was filtered while hot and then concentrated. The residue was washed with EtOH and water and then dried to give ethyl 5-(2-acetamido-5-methylpyridin-4-yl)-3-furoate (20.0 g, 67%).