Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:10])[C:7]=1OC.Br[C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:6]1[CH:5]=[C:4]([C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22])[CH:3]=[C:2]([Cl:1])[C:7]=1[C:23]([F:26])([F:25])[F:24]
Reactant: C=C(Br)C(F)(F)F
Reactant: COc1c(Cl)cc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(C(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 81.4 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4 g, 1.33 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.28 g, 1.59 mmol), Cs2CO3 (1.33 mL, 2M, 2.66 mmol) and Pd(PPh3)2Cl2 (28 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to give 1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoro-prop-1-en-2-yl)benzene (0.2 g, yield 56%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 2 H), 6.00 (s, 1 H), 5.78 (s, 1 H), 3.93 (s, 3 H) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:14](=[O:21])[C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17]Cl>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:13]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:14]2[C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][O:21]2)=[CH:24][CH:25]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)CCOC1=C(Oc1ccc(Cl)cc1)n1ccnc1
Temperature: 90 °C
Reaction time: 10 h
Yield: 15.9 %

Procedure:
35 g (0.5 mol) of imidazole and 70 g (0.5 mol) of potassium carbonate are dissolved in 700 ml of toluene. 93 g (0.26 mol) of 1-bromo-1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-pentan-2-one in 200 ml of toluene are added to this mixture at 80° C. The reaction mixture is stirred for a further 10 hours at 90° C., cooled and filtered off under suction from the inorganic residue. The filtrate is washed with water, dried over sodium sulphate and evaporated down. The residue is purified by column chromatography (silica gel: ethyl acetate/cyclohexane=3/1). 12.6 g (14.2% of theory) of (4-chlorophenoxy)-(imidazol-1-yl)-3,3-dimethyltetrahydrofuran-2-ylidene-methane of melting point 85°-88° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH3:11])[C:4]=1[CH3:12].ClC1C=C(C=CC=1)C(OO)=[O:18].[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N+:6]([O-:18])=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cnc(C)c(C)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1c[n+]([O-])c(C)c(C)c1OC
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
6.3 g of 4,5-dimethoxy-2,3-dimethylpyridine are dissolved in 120 ml of methylene chloride, 20 g of m-chloroperoxybenzoic acid are added successively and the mixture is stirred first at 20° C. for 2 hours and then at 40° C. for 4 hours. After addition of 20 ml of 5N sodium hydroxide solution, the mixture is washed three times with a mixture of 5% strength sodium thiosulphate solution and 5% strength sodium carbonate solution, the aqueous phases are back-extracted twice with methylene chloride and the combined organic phases are dried over magnesium sulphate and concentrated. 4.6 g (66% of theory) of 4,5-dimethoxy-2,3-dimethylpyridine 1-oxide are obtained. The Rf value in methylene chloride/methanol 19:1 is 0.25.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[N:11][C:3]=12.C(N(CC)CC)C.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1>O1CCOCC1>[Cl:8][C:5]1[N:6]=[N:7][C:2]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[C:3]2[N:11]=[CH:10][NH:9][C:4]=12
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: Clc1nnc(Cl)c2[nH]cnc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(N2CCN(c3nnc(Cl)c4[nH]cnc34)CC2)nc1
Temperature: 80 °C
Yield: 36.4 %

Procedure:
4,7-Dichloro-1H-imidazo[4,5-d]pyridazine (250 mg, 1.32 mmol) is combined with triethylamine (270 μL), dioxane (2 mL), and 1-(5-Trifluoromethyl-pyridin-2-yl)-piperazine (290 mg, 1.26 mmol). The reaction mixture is heated to 80° C. for 70 h. Concentrate in vacuo to remove dioxane. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (176 mg, 57%).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=4)[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: FC(F)(F)c1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]methyl]-1,4-diazepan-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1cccc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1ccc(F)cc1

Procedure:
Following, the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 4-fluoro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=215 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:4][CH2:3]1.[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:37])[C:19]2[CH:24]=[N:23][C:22](S(C)(=O)=O)=[N:21][C:20]=2[N:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[C:18](=[O:37])[C:19]2[CH:24]=[N:23][C:22]([NH:11][CH2:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[N:21][C:20]=2[N:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN1CCN(CCCN)CC1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCN3CCN(C)CC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 3-(4-methyl-piperazin-1-yl)-propylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.04 mmol). 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (17 mg, 80%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H36N6O3: 457.28 (M+H). Found: 457.3.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25](=O)[CH2:26][CH3:27]>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][CH2:26][CH3:27])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CCC=O
Solvent: CC(=O)N(C)C
Product: CCC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 67.2 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with propionaldehyde (0.5 g, 8.6 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 120° C. for 90 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.073 g, 67%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N1CCN(C2C=C(N[C:54]([C:56]3[C:57]4[N:58]=[CH:59][CH:60]=[N:61][C:62]=4[C:63]([C:66]4[C:75]5[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=5)[CH:69]=[N:68][CH:67]=4)=[CH:64][CH:65]=3)=[O:55])C=CC=2)CC1)C>C(Cl)Cl.CO>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:54]([C:56]3[C:57]4[N:58]=[CH:59][CH:60]=[N:61][C:62]=4[C:63]([C:66]4[C:75]5[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=5)[CH:69]=[N:68][CH:67]=4)=[CH:64][CH:65]=3)=[O:55])=[N:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 17 h at rt, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Title compound: ESI-MS: 490.0 [M+H]+; tR=2.21 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:25]([N:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][CH2:34]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][CH2:34][O:16][C:15]([C:5]1[C:6](=[O:14])[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH2:34][CH2:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:8]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1)=[O:17])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(O)ccc21
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)OCCN(Cc2ccccc2)Cc2ccccc2)c(=O)c2cc(OCCN(Cc3ccccc3)Cc3ccccc3)ccc21
Temperature: 65 °C
Reaction time: 72 h
Yield: 120.1 %

Procedure:
1-Ethyl-6-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (GB 1433774) (1.4 g, 6 mmol) was dissolved in dry DMF (80 mL). To this was added potassium carbonate (5 g, 36 mmol) and dibenzyl-(2-chloroethyl)amine hydrochloride (4.37 g, 14.8 mmol). The mixture was heated at 65° C. with stirring for 72 h, then allowed to cool overnight. The mixture was evaporated to a small volume, diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried and evaporated under reduced pressure to give a dark viscous oil (4.9 g). This residue was purified by chromatography on silica gel (100 g), eluting with 0.2-3.8% methanol in dichloromethane, to give the title compound as a brown solid (2.46 g, 60%); ESMS m/z 680 [M+H]+ (100%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH:10]=O)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:14]=1[NH2:15].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:15]/[C:14]1[C:13]([Cl:12])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])=[N+:2]=[N-:3]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Titanium tetrachloride (1M, 4.3 mL, 4.3 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (1.06 g, 7.2 mmol), 2,6-dichloroaniline (1.17 g, 7.2 mmol) and triethylamine (3.0 mL, 21.6 mmol) in DCM (24 mL) under nitrogen. The resultant mixture was stirred for 3 hours at 0° C. before warming to room temperature and stirring for a further 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:25])=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:10](=[O:21])[CH:9]=1)[CH3:2].[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1.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(CC)C(C)C)(C)C>CN(C)C=O>[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:14](=[O:16])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[CH:22]=[CH:23][CH:24]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:25])=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:34]2)[CH2:29][O:28]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 87.3 %

Procedure:
To a solution of (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 114, 570 mg, 1.62 mmol) in N,N-dimethylformamide (10 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 382 mg, 1.94 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.43 g, 3.23 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.417 g, 3.23 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 10% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.750 g, 87%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cccc(C(C)=O)c1
Agent: N
Product: CC(=O)c1cccc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-(3-ethynylphenyl)ethanone (GFS Chemicals, 72 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.69 (s, 3H), 7.54 (s, 1H), 7.71 (t, J=7.5 Hz, 1H), 8.08-8.24 (m, 3H), 8.51 (t, J=1.8 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.99 (t, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 283 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH:11]([CH2:17][CH2:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:11]([CH2:17][CH2:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:6]
Reactant: CCCC(Br)C(=O)OCC
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCC(Oc1cccc(C#N)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5.0 g (42 mmol) of 3-hydroxybenzonitrile and 8.78 g (42.0 mmol) of ethyl 2-bromovalerate in 80 ml of acetonitrile is treated with 13.7 g (42.0 mmol) of caesium carbonate and stirred at room temperature for 18 hours. The reaction mixture is filtered off and the filtrate evaporated. A colourless oil is obtained; FAB 248
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1.N1C=CC=CC=1.[C:59](OC(=O)C)(=[O:61])[CH3:60]>ClCCl>[C:59]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:26][CH:27]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1)(=[O:61])[CH3:60]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCNC(C)=O)c3c2Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 0.185 g of benzyl 3-[1-(2-aminoethyl)-7-bromo-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.1 ml of dichloromethane is admixed successively with 0.50 ml of pyridine and 0.21 ml of acetic anhydride and stirred at room temperature for 2 hours. The reaction mixture is poured onto water (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed successively with 1M sodium hydrogencarbonate solution (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.17 (EtOAc-heptane=4:1); Rt=5.89.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)C=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P([O-])([O-])([O-])=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH:10]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7]
Reactant: OCC=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)C(OC)OC
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(OC)C(=O)CC(=O)OCC=Cc1ccccc1

Procedure:
2.68 g (14.1 mmol) of ethyl 4,4-dimethoxy-3-oxobutyrate, 5.14 ml (40.0 mmol) of cinnamyl alcohol and 244 mg (2.0 mmol) of 4-dimethylaminopyridine were heated under reflux in 40 ml of toluene for two nights. A phosphate buffer solution was added to the reaction liquid. After the extraction with ethyl acetate, the organic layer was washed with a saturated aqueous salt solution and then dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:31]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=4)=[O:32])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N)c2cc(C(=O)Nc3ccc(CNC(=O)c4ccnc(Cl)c4)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a solution of 27 mg (0.05 mmol) 4-Amino-N-[4-(aminomethyl)phenyl]-2-methyl-6-quinolinecarboxamide, 9 mg (0.1 mmol) 2-chloropyridine-4-carboxylic acid, and 0.07 ml (0.5 mmol) triethylamine in 2 ml dichloromethane was added 90 mg (2.0 mmol) PyBrop and stirred at room temperature for 1 d. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 17 mg (74%) of the title compound. MS 446.3 (M+1)+, 1H-NMR (DMSO-d6) δ: 2.60 (s, 3H), 4.47 (d, 2H), 6.64 (s, 1H), 7.34 (d, 2H), 7.73 (d, 2H), 7.81 (dd, 1H), 7.87 (d, 1H), 7.91 (s, 1H), 8.35 (dd, 1H), 8.57 (d, 1H), 8.95 (s, 1H), 9.00 (br. 2H), 9.41 (t, 1H), 10.47 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:19][C:20]([F:50])([F:49])[C:21]([N:23]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:22]>ClCCl>[F:19][C:20]([F:49])([F:50])[C:21]([N:23]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[O:45])=[CH:42][CH:41]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:22]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Nc2ccc(C(=O)OCC)cc2)cc1

Procedure:
To a stirred solution of 1.65 g. of ethyl p-amino-benzoate and 1.6 ml. of pyridine in 5 ml. of dichloromethane at 0° C. is added a solution of 4.75 g. of p-(2,2,2-trifluoro-N-hexadecylacetamido)benzoyl chloride in 10 ml. of dichloromethane. After 20 hours at ambient temperature the solution is diluted with dichloromethane and washed with water and sodium bicarbonate solution. The residue obtained on evaporation of solvent is recrystallized from hexane-ether to give a white, crystalline solid, m.p. 91°-93° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H].C>C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH2:10]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Br
Reactant: [H][H]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Nc1ccc(Cl)c(Cl)c1Br
Yield: 86.1 %

Procedure:
A solution of 2-bromo-3,4-dichloronitrobenzene (23.5 g) in toluene was treated at 25°-35° C. for 1.25 hours with hydrogen in the presence of charcoal containing 5% platinum. The solution was then filtered and the filtrate was evaporated to dryness. The brown solid thus obtained was dissolved in diethyl ether and the solution was treated with decolourising charcoal and filtered. Evaporation to dryness of the filtrate gave 2-bromo-3,4-dichloroaniline (18.0 g), m.p. 78°-80° C. in the form of a brown powder.