Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]1([N:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[C:19]([C:21]2[C:22]([CH:28]([F:30])[F:29])=[N:23][N:24]([CH3:27])[C:25]=2[F:26])=O)[CH2:17][CH2:16]1.O>O1CCOCC1>[CH:15]1([N:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[C:19]([C:21]2[C:22]([CH:28]([F:30])[F:29])=[N:23][N:24]([CH3:27])[C:25]=2[F:26])=[S:2])[CH2:17][CH2:16]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cn1nc(C(F)F)c(C(=O)N(Cc2ccccc2[Si](C)(C)C)C2CC2)c1F
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(C(F)F)c(C(=S)N(Cc2ccccc2[Si](C)(C)C)C2CC2)c1F
Temperature: 100 °C

Procedure:
A solution of 140 mg (0.31 mmol) of phosphorus pentasulfide and 500 mg (1.26 mmol) of N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-N-[2-(trimethylsilyl)benzyl]-1H-pyrazole-4-carboxamide in 20 ml of dioxane was heated at 100° C. for 2.5 hours. 2 ml of water were then added and the reaction mixture was heated at 100° C. for another 1 hour.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:22][CH3:23])=[C:8]([CH:10]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]2=[O:21])[CH:9]=1.[N:29]([O-:31])=[O:30].[Na+].[N+]([O-])(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:22][CH3:23])=[C:8]([C:10]2([N+:29]([O-:31])=[O:30])[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[O:13][C:12]([CH3:19])([CH3:20])[C:11]2=[O:21])[CH:9]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1([N+](=O)[O-])C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 1202.4 %

Procedure:
To a solution of 4-(2′,4′-dichloro-4-ethylbiphen-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.200 g, 0.478 mmol) in glacial acetic acid (5 ml) is added sodium nitrite (0.0025 g, 0.036 mmol) then fuming nitric acid (0.12 ml). The mixture is stirred at room temperature for 2 hours, then the resulting slurry is poured into ice-water (50 ml). After swirling for 5 minutes the precipitate is filtered, dried, then washed with hexanes to afford 4-(2′,4′-dichloro-4-ethyl-biphen-3-yl)-2,2,6,6-tetramethyl-4-nitropyran-3,5-dione (0.201 g, 91%) as a yellow solid, m.p.=138-140° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8]C(C)C.ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: CCCc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1
Yield: 82 %

Procedure:
When the product of Step A was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 82% yield, as colourless Solid. 1H-NMR (CDCl3) 8.48 (d, 1H, J=1.98 Hz); 8.08 (d, 2H, J=8.25 Hz); 8.03 (dd, 1H, J=8.49, 2.01 Hz); 7.33 (d, 2H, J=8.25 Hz); 7.07 (d, 1H, J=8.49 Hz); 2.66 (t, 2H, J=7.5 Hz); 1.71-1.61 (m, 2H); 0.95 (t, 3H, J=7.29 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.CS(C)=O.[CH:14]([Si:17]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:18][CH:19]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23][CH:22]([OH:30])[CH2:21][CH2:20]1)([CH3:16])[CH3:15]>O>[CH:34]([Si:17]([CH:14]([CH3:16])[CH3:15])([CH:31]([CH3:33])[CH3:32])[O:18][CH:19]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH2:23][C:22](=[O:30])[CH2:21][CH2:20]1)([CH3:36])[CH3:35]
Reactant: CC(C)[Si](OC1CCC(O)Cc2cccnc21)(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](OC1CCC(=O)Cc2cccnc21)(C(C)C)C(C)C
Temperature: -60 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
In an oven dried 500 mL round bottom flask was charged with OXALYL CHLORIDE (6.49 mL, 72.9 mmol), CH2Cl2 (150 mL) under N2. The flask was cooled to −60° C. and DMSO (6.90 mL, 97 mmol) was added to the reaction mixture dropwise. After finish addition, the reaction was stirred at −60° C. for 30 min before cannula the 9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-6-ol (8.1557 g, 24.31 mmol) (dissolved in 20 mL CH2Cl2 and rinsed with 20 mL CH2Cl2) to the reaction mixture at −60° C. The reaction was stirred at −55° C. for 40 min before addition of TEA (16.94 mL, 122 mmol). The reaction seems formed a thick suspension. The reaction was stirred for 1 hour and water was added to the reaction mixture. The organic layer was separated and the aqueous layer was extract by CH2Cl2 twice. The CH2Cl2 layer was combined, dried (Na2SO4), filtered and concentrated. Flash column by ethyl acetate in hexane from 25% to 50% gave the product as yellow oil (1.49 g, 18.4%). MS (ESI)[M+H+]=334.30; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.36 (d, J=5.04 Hz, 1H) 7.46 (d, J=7.55 Hz, 1H) 7.16 (dd, J=7.55, 4.78 Hz, 1H) 5.22 (dd, J=4.78, 2.27 Hz, 1H) 4.66 (d, J=14.35 Hz, 1H) 3.26 (d, J=14.60 Hz, 1H) 2.94-3.05 (m, 1H) 2.42-2.55 (m, 1H) 2.36 (dd, J=14.10, 5.04 Hz, 1H) 2.03-2.17 (m, 1H) 1.03-1.16 (m, 3H) 0.96-1.00 (m, 9H) 0.89-0.92 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][C:26]=1[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][C:26]=1[C:27]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][C:2]([F:1])=[C:3]([C:20]([F:23])([F:21])[F:22])[CH:4]=1)=[O:28]
Reactant: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)nccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(F)c(C(F)(F)F)c4)nccc23)c1
Yield: 18.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(4-fluoro-3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-42, 80 mg, 0.24 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 134 mg, 0.49 mmol), oxalyl chloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (93 mg, 0.72 mmol) in CH2Cl2 (5 mL) to afford 26 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.30 (d, 1H), 8.21 (t, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.98 (d, J=6.3 Hz, 1H), 7.82-7.55 (m, 7H), 7.37 (d, J=8.4 Hz, 1H), 4.32 (J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 574.22 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[S:48][C:47]([CH2:49][NH2:50])=[CH:46][CH:45]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:50][CH2:49][C:47]2[S:48][C:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=3)=[CH:45][CH:46]=2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCc1ccc(-c2ccccn2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C(=O)NCc2ccc(-c3ccccn3)s2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, commercially available [5-(2-pyridinyl)-2-thienyl]methylamine (36.2 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.08-1.28 (m, 3H) 1.29-1.37 (m, 2H) 4.25-4.53 (m, 2H) 4.54-4.69 (m, 2H) 6.95-7.06 (m, 1H) 7.09-7.12 (m, 1H) 7.16-7.32 (m, 1H) 7.49-7.64 (m, 1H) 7.68-7.91 (m, 2H) 8.31-8.52 (m, 1H); MS (ESI) positive ion 380 (M+H).
Reaction SMILES: CO.Br[C:4]1[C:9]([Cl:10])=[C:8]([F:11])[N:7]=[C:6]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[F:17]>[Pd].C(N(CC)CC)C>[C:13]([NH:12][C:6]1[C:5]([F:17])=[CH:4][C:9]([Cl:10])=[C:8]([F:11])[N:7]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)Nc1nc(F)c(Cl)c(Br)c1F
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1nc(F)c(Cl)cc1F
Reaction time: 120 h
Yield: 98.6 %

Procedure:
To 30 ml of methanol were added 12.8 g of 4-bromo-2-(t-butylamino)-5-chloro-3,6-difluoropyridine and 2.5 g of triethylamine together with 0.57 g of 10% palladium on carbon, and the mixture was hydrogenated at 50° C. for 5 days. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 80 ml of chloroform, and the mixture was washed with 70 ml of distilled water, and the chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.3 g of the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26](O)([CH3:29])([CH3:28])[CH3:27].N12CCCN=C1CCCCC2>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([O:12][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: Cc1ccc2sc(C(=O)O)cc2c1
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2sc(C(=O)OC(C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-methyl-1-benzothiophene-2-carboxylic acid (1.50 g) in N,N-dimethylformamide (10.5 mL) was added 1,1′-carbonyldiimidazole (1.27 g), followed by stirring at room temperature for 2.5 hours. Subsequently, tert-butyl alcohol (1.44 mL) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (1.17 mL) were added thereto, followed by heating at 50° C. for 24 hours. To the reaction mixture was added ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid and a saturated aqueous sodium chloride solution in this order, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 5-methyl-1-benzothiophene-2-carboxylate (1.78 g).
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C(N1C=CN=C1)([N:14]1C=CN=C1)=O.[OH-].[NH4+]>C(OCC)(=O)C>[CH:1]1([C:9]([NH2:14])=[O:11])[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CC12CCCCC2
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)C1CC12CCCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.8 %

Procedure:
A 100 mL flask was charged with the product from Example 1B (2.8 g, 18 mmol), 1,1′-carbonyldiimidazole (2.9 g, 18 mmol) and ethyl acetate (20 mL). The mixture was stirred under nitrogen at ambient temperature for 4 hours, then 20 mL of concentrated ammonium hydroxide was added and the mixture stirred for 18 hours. The mixture was diluted with ethyl acetate (50 mL) and the layers were separated. The organic extract was washed with water (3×15 mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude product was treated with carbon and recrystallized from aqueous methanol to provide the title compound as white crystals (3 g, 78% yield). 1H NMR (CDCl3, 300 MHz) δ 5.55 (s, 2H), 1.3-1.7 (m, 10H), 1.28 (dd, 1H), 1.11 (t, 1H), 0.75 (dd, 1H); 13C NMR (CDCl3, 100 MHz) δ 174.1, 37.6, 28.9, 28.6, 27.5, 26.2, 25.8, 25.6, 19.4; MS m/z 154 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[N:9]=[CH:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:3]1=2.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[C:19]([Cl:25])[CH:18]=1>[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:13]([C:11]2[CH:10]=[N:9][C:4]3[O:5][CH2:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]=3[CH:12]=2)=[O:15])=[C:19]([Cl:25])[CH:18]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: CN1C(=O)COc2ncc(C(=O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Product: CN1C(=O)COc2ncc(C(=O)Cc3ccc(Br)cc3Cl)cc21

Procedure:
In analogy to Example 49, step 1, 1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene in the presence of zinc and tetrakis(triphenylphosphine)palladium(0) to give the title compound as a light yellow solid. MS (m/e, ISP neg. ion)=392.9 [M−H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:4]([F:16])[CH:3]=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]3[CH:29]=[CH:30][N:31]=[C:25]3[CH:24]=2)=[CH:19][CH:18]=1>>[C:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[N:26]3[CH:27]=[CH:28][C:23]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[CH:24][C:25]3=[N:31][CH:30]=2)=[CH:3][C:4]=1[F:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: c1cc(-c2ccn3ccnc3c2)ccn1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Br)cc1F
Product: CC(C)(C)OC(=O)Cc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1F

Procedure:
Couple 4-bromo-2-fluoro-phenylacetic acid, tert-butyl ester (3.65 g, 18.68 mmol) with 7-pyridin-4-yl-imidazo[1,2-a]pyridine (5.40 g, 18.68 mmol) as described in Preparation 153. MS(ES), m/z 404 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].C(O)C>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: O=Cc1c(F)cccc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1c(F)cccc1F
Temperature: 0 °C
Yield: 110.3 %

Procedure:
In a fashion similar to that for preparation 13, 2,6-difluorobenzaldehyde (5.00 g, 35.2 mmol), hydroxylamine hydrochloride (2.93 g, 29.6 mmol), NaOH (7.04 g in 7.0 ml of water), ethanol (15 ml), water (15 ml), and ice (30 g) afforded 2,6-difluorobenzaldehyde oxime (5.13 g, 93%).
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=C(C(N)=O)C=1.[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH:38]4[CH2:43][CH2:42][N:41]([CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH2:40][CH2:39]4)=[O:36])=[CH:31][CH:30]=3)=[C:20]([C:25]([OH:27])=O)[CH:21]=[N:22]2)=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:81][CH:82]1[CH2:87][CH2:86][N:85](CC2C=CC=CC=2)[CH2:84][CH2:83]1>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18]([C:19]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH:38]4[CH2:43][CH2:42][N:41]([CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH2:40][CH2:39]4)=[O:36])=[CH:33][CH:34]=3)=[C:20]([C:25]([NH:81][CH:82]3[CH2:87][CH2:86][N:85]([CH2:4][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:84][CH2:83]3)=[O:27])[CH:21]=[N:22]2)=[CH:23][CH:24]=1
Reactant: NC(=O)c1cnc2ccccc2c1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2c(C(=O)O)cnc3cc(Cl)ccc23)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2c(C(=O)NC3CCN(Cc4ccccc4)CC3)cnc3cc(Cl)ccc23)cc1
Temperature: 90 °C
Yield: 76 %

Procedure:
Step 5, 7-Chloro-N-[1-(phenylmethyl)-4-piperidinyl]-4-[[4-[[[1-(phenylmethyl) -4-piperidinyl]]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide: 7-Chloro -4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]-carbonyl]phenyl]amino]-3-quinolinecarboxylic acid (2.00 g, 3.88 mmol), 1-hydroxybenzotriazole hydrate (0.640 g, 4.74 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.968 g, 5.05 mmol) were stirred in 22 ml of DMF and treated with triethylamine (1.57 g, 2.2 ml, 15.5 mmol) followed by 4-amino-1-benzylpiperidine (0.813 g, 0.87 ml, 4.27 mmol). The reaction mixture was then heated at 90° C. under nitrogen for 4 h, cooled to room temperature and poured into 250 ml of CH2CH2. The solution was then washed with 3×200 ml of water and concentrated under reduced pressure to a pale beige powder that was dried in vacuo overnight affording 2.037 g (2.96 mmol, 76% yield) of 7-Chloro-N-[1-(phenylmethyl)-4-piperidinyl]-4-[[4-[[[1-(phenylmethyl) -4-piperidinyl]amino]-carbonyl]phenyl]amino]-3-quinolinecarboxamide: mp 230.5°-232° C.; IR (KBr) 3440, 3330, 30 30, 2950, 2800, 1630 cm-1 ; 1H NMR (Me2SO-d6, 400 MHz) δ 9.7 (s, 1 H ), 8.8 (s, 1 H ), 8.39 (d, J=7.5 Hz, 1 H ), 8.11 (d, J=9.1 Hz, 1 H), 8.0 (m, 2 H ), 7.7 (d, J=8.7 Hz, 2 H ), 7.6 (d of d, J=2.2, 9.1 Hz, 1 H ), 7.1-7.35 (m, 10 H ), 6.9 (d, J=8.7 Hz, 2 H ), 3.7 (m, 1 H ), 3.4 (m, 5 H ), 2.74°-2.82 (m, 2 H), 2.64-2.7 (m, 2 H), 1.84-2.04 (m, 4 H ), 1.64°-1.72 (m, 2 H ), 1.46-1.58 (m, 4 H), 1.3-1.4 (m, 2 H ); MS (+DCI, isobutane) m/z (rel intensity)=687 (M+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([CH2:17][O:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][C@H:12]1[OH:13].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1.[S:43](Cl)(Cl)(=[O:45])=[O:44].O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([CH2:17][O:18][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:14][C@H:12]1[O:13][C:39]1[N:38]=[CH:42][C:41](=[S:43](=[O:45])=[O:44])[N:40]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O[C@@H]1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)=C1C=NC(O[C@@H]2C[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2n2cnc3c(Cl)ncnc32)=N1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
604 mg (1.18 mmols) of 6-chloro-9-[3-deoxy-5-O-(triphenylmethyl)-β-D-erythro-pentofuranosyl]-9H-purine was dissolved in 11.8 ml of methylene chloride, to which was added 486 mg (7.07 mmols) of imidazole. This reaction mixture was cooled to −35° C., to which was added 0.15 ml (1.77 mmols) of sulfuryl chloride, and stirred for 30 minutes. Then, after having been restored to be at room temperature, this was stirred overnight. To the reaction mixture, water was added to stop the reaction. Then, the mixture was separated into layers, and the aqueous layer was washed with dichloromethane. The organic layers were combined together, dried with anhydrous sodium sulfate, and filtered. The solvent was evaporated from the resulting filtrate. The residue was purified through silica gel column (silica 40 g), using 33 to 50% hexane/ethyl acetate, to obtain 570 mg (yield 75.0%) of the intended product, which was colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6]1=[O:16].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:15][O:14][C:12]([CH2:11][C@H:7]1[C:6](=[O:16])[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:17])[CH2:10][CH2:9][N:8]1[C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:13]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC)C1=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC)CCN1C(=O)CCC(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a mixture of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid methyl ester (3.67 g) and succinic anhydride (1.5 g) in dimethylformamide (25 ml) was added 4-dimethylaminopyridine (0.2 g) and the solution was stirred for 3 hours at 60° C. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by means of CHP-20 column chromatography (H2O→50% acetonitrile aqueous solution) to give the titled compound (3.44 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)[C:26]([C:28]([OH:30])=O)=[CH:27][C:20]=2[N:19]=1.ClC(N(C)C)=C(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][C:56]=1[F:57])[NH2:53].CCN(C(C)C)C(C)C>CC#N>[Cl:49][C:50]1[CH:51]=[C:52]([NH:53][C:28]([C:26]2[C:25]([N:31]3[CH2:32][CH2:33][CH:34]([C:37]([F:39])([F:38])[F:40])[CH2:35][CH2:36]3)=[CH:24][C:21]3[N:22]([CH3:23])[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:27]=2)=[O:30])[CH:54]=[CH:55][C:56]=1[F:57]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(N3CCC(C(F)(F)F)CC3)cc21
Reaction time: 0.33 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (72 mg, 0.120 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (33 mg, 0.25 mmol) and MeCN (2 mL) is stirred for 20 min. This mixture is added to 3-chloro-4-fluoro-aniline (36 mg, 0.25 mmol) and DIPEA (129 μL, 0.75 mmol) in MeCN (3 mL) and it is stirred overnight. The mixture is concentrated and the residue is taken up in DMF (2 mL) and purified by reverse phase HPLC.
Reaction SMILES: [CH:1]1([C:4]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[CH3:8])[CH2:3][CH2:2]1.[Mg]>CO.C(O)C>[CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:5]=[CH:6][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]=2)[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(=CC=C(c1ccc(Cl)cc1)C1CC1)c1ccc(F)c(Oc2ccccc2)c1
Agent: [Mg]
Solvent: CO
Solvent: CCO
Product: CC(C=CC(c1ccc(Cl)cc1)C1CC1)c1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.7 %

Procedure:
A mixture of 0.40 gram (0.01 mole) of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)-1,3-pentadiene and 2.43 grams (0.1 mole) of magnesium in 25 ml of methanol and 5 ml of ethanol was vigorously stirred for about 18 hours at ambient temperature. After this time the reaction was quenched with aqueous 3N hydrochloric acid, and the reaction mixture was extracted with two 25 ml portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.23 gram of 1-cyclopropyl-1-(4-chlorophenyl)-4-(4-fluoro-3-phenoxyphenyl)-2-pentene. The nmr spectrum was consistent with the proposed structure.