Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:9][C:10]([N:12]3[CH2:17][CH2:16][C:15](=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>CN(C=O)C.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>[N:27]1[CH:32]=[C:31]([C:2]2[CH:26]=[CH:25][C:5]3[N:6]=[C:7]([NH:9][C:10]([N:12]4[CH2:17][CH2:16][C:15](=[CH:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)[CH2:14][CH2:13]4)=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:30]=[N:29][CH:28]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1nc2ccc(Br)cc2s1)N1CCC(=Cc2ccccn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(-c3cncnc3)cc2s1)N1CCC(=Cc2ccccn2)CC1
Yield: 40.1 %

Procedure:
The compound (400 mg, 932 μmol) obtained in Example 1 and pyrimidine-5-boronic acid (289 mg, 2.33 mmol) were dissolved in DMF (10 mL), and a 2N sodium carbonate aqueous solution (1.62 mL, 3.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (107 mg, 93.2 μmol) were added thereto. The resulting mixture was subjected to reaction at 120° C. for 40 minutes in a microwave reactor. A saturated ammonium chloride aqueous solution was added to the resulting mixture to stop the reaction, and after extraction with ethyl acetate, the extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the residue obtained by evaporation under reduced pressure was purified using medium pressure flash column chromatography (silica gel; methanol:chloroform=1:40), thereby giving the title compound (160 mg, 40%) as a pale brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:25][OH:26])([CH3:24])([CH3:23])[CH3:22]>C1C=CC=CC=1>[CH3:16][O:15][CH2:14][O:13][C:12]1[C:11]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:10][C:7]([CH:8]=[N+:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[O-:26])=[CH:6][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: COCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Reactant: CC(C)(C)NO
Solvent: c1ccccc1
Product: COCOc1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 69 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde (11 42 g, 40 mmol) in benzene (200 mL) was added tert-butylhydroxylamine (4 0 g, 50 mmol). The resulting solution was refluxed for 72 h until no more aldehyde was detected by TLC (Rf=0.56 for product and 0.78 for starting material in 1 1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was suspended in hexane/EtOAc. The suspension was filtered, washed with hexanes and defined to afford the title compound (69% yield) as a white solid, m.p 202.2-205.9° C.
Reaction SMILES: [Li]N1C(C)(C)CCCC1(C)C.[Li]CCCC.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[Te:27][CH:28]=[CH:29][CH:30]=2)=[C:22]([F:31])[C:21]=1[F:32])[CH3:18].[CH:33](N1CCOCC1)=[O:34].Cl>C1COCC1.O>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[Te:27][C:28]([CH:33]=[O:34])=[CH:29][CH:30]=2)=[C:22]([F:31])[C:21]=1[F:32])[CH3:18]
Reactant: O=CN1CCOCC1
Reactant: CCOc1ccc(-c2ccc[te]2)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(-c2ccc(C=O)[te]2)c(F)c1F
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of LiTMP (comprising 3.9 ml (22.9 mmol) of TMP and 14.0 ml (22.3 mmol, 15% soln. in hexane) of n-BuLi) is added to 6.8 g (20.3 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)tellurophene in 70 ml of THF at 0° C. The mixture is stirred at this temperature for 1 h. The solution is cooled to −60° C., and N-formylmorpholine is added. The reaction mixture is warmed to 0° C. and stirred for 1 h. Water and 2 N hydrochloric acid are added, and the mixture is extracted with MTBE. The organic phase is washed with sodium chloride and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is recrystallised from toluene. Drying in vacuo gives 5-(4-ethoxy-2,3-difluorophenyl)tellurophene-2-carbaldehyde as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][N:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]2)=[CH:5][N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.Cl>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[N:17]2[CH2:22][CH2:21][N:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]2)=[CH:5][NH:4][N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(N)=O)CC3)c2c1
Agent: Cl
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(C(N)=O)CC3)c2c1
Yield: 42.1 %

Procedure:
94 mg 4-[6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]-1-piperazine carboxamide obtained in Example 179 and 1.3 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 162, to give 23 mg of the title compound as a pale yellow solid.
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:20])[NH:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N+:2]=[N-:3].[H-].[Na+].[CH3:23]N(C)C=O>>[N:1]([C:4]1[C:5](=[O:20])[N:6]([CH3:23])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N+:2]=[N-:3]
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=Nc1c(-c2ccccc2)c2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Product: Cn1c(=O)c(N=[N+]=[N-])c(-c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 10.0 g of 3-azido-4-phenylcarbostyril in 125 ml. of dry dimethylformamide was added 2.2 g. of a 57 percent dispersion of sodium hydride in oil. After stirring at room temperature for about 45 minutes, the mixture was filtered to remove a small amount of insoluble material. To the clear solution was added 5 ml. of methyl iodide. The solution soon turned from an orange color to light yellow, accompanied by the formation of a precipitate. After 1 hour, the mixture was diluted with water and 10 g. (95 percent) of 3-azido-1-methyl-4-phenylcarbostyril, mp indefinite in the range of 140°-150° with decomposition, was collected. This material was pure by tlc. After recrystallizations from dimethylformamide-methanol, yellow needles were obtained, having a melting point of 140°-150° dec.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H].O.N>[Pd].O1CCOCC1>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:2]=1)[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(C(=O)c2cccc(N)c2)cc1
Temperature: 30 °C
Reaction time: 7 h

Procedure:
In a closed vessel equipped with a thermometer and a stirrer there are charged 105 g (0.3 moles) of 4-bromo-3,4'-dinitro benzophenone, 5 g of 5% palladium/active carbon catalyst (from Nihon-Engelhardt Co.) and 300 ml of dioxane. At 70°-80° C., with the mixture being stirred, there is introduced 41 l (1.83 moles) of hydrogen so as to be absorbed in the mixture in about 11 hours. Following cooling the mixture to 30° C., there is added 38.5 g (0.33 moles) of 30% ammonia water. Then, again with the mixture being stirred, at 30°-40° C., there is introduced an additional amount of hydrogen, 7.2 l (0.32 moles), during seven hours. The reaction liquid is filtered at 30°-40° C. to remove the catalyst and then allowed to cool giving yellow crystals of 3,4'-diamino benzophenone. The crystals are filtered, washed with 30 ml of 50% aqueous dioxane solution and dried. Yield 58 g (91%). M.P. 121°-123° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:17])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:18](Cl)(Cl)=[O:19]>C(Cl)Cl.C1C=CC=CC=1>[C:1]([N:5]1[CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[O:17][C:18]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)NCC(O)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)N1CC(c2ccc([N+](=O)[O-])cc2)OC1=O
Temperature: -5 °C
Reaction time: 3.5 h

Procedure:
In 270 ml of CH2Cl2, 12.97 g of α-[(tert-butylamino)methyl]-p-nitrobenzyl alcohol is dissolved. The solution is cooled to -5° C. and 54 ml of 12.5% phosgene in benzene is added slowly. After the addition is completed, the mixture is stirred for 3.5 hours and poured on ice. The organic phase is separated, and the aqueous layer is extracted with CH2Cl2 (2×100 ml). The combined organic layers are washed with saturated NaHCO3 solution (2×250 ml), 100 ml of H2O and dried over MgSO4. The solution is evaporated to dryness to give 16.3 g, which is recrystallized from MeOH twice to afford 12.58 g of 3-tert-butyl-5-(p-nitrophenyl)-2-oxazolidinone, mp 123°-125° C. This product (10 g) is dissolved in 200 ml of MeOH and hydrogenated over 6 g of Raney nickel at 51 p.s.i.g. at 40° C. to give, after filtration and evaporation, 8.21 g of 5-(p-aminophenyl)-3-tert-butyl-2-oxazolidinone, mp 125°-129° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][NH:18][C@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:31][C:32]1C=CC(S(O)(=O)=O)=C[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C#C.CNC>CN(C=O)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:37][C:32]#[CH:31])[C@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1OCCN[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C#CCBr
Agent: CNC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C#CCN1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine TsOH salt (1.83 assay Kg, 3.00 mol) was suspended in 10 L of DMF and potassium carbonate (1.04 Kg, 7.5 mol) was added in one portion to give a white slurry. Propargyl bromide (80 wt % in toluene, 535 g, 3.6 mol) was added dropwise over 30 minutes, the reaction was sligtly exothermic <30° C. (without cooling). The reaction mixture was stirred at room temperature for ~3 hours (~99.9% conversion) and then 40% aqueous dimethylamine was added, and aged for 30 minutes (to destroy excess propargyl bromide), then the reaction solution was partitioned between 20 L of toluene and 20 L of water. The organic layer was washed with water twice (2×18 L). The resulting organic layer was concentrated to 6 L with KF<250 μg/mL (additional toluene may need to be used to achieve this KF specifcation).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH:12]([CH3:13])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:14]([O-])=O)=[CH:8][CH:9]=2)[CH2:4]1>CO>[ClH:1].[CH3:2][N:3]1[CH:12]([CH3:13])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:14])=[CH:8][CH:9]=2)[CH2:4]1
Reactant: CC1Cc2ccc([N+](=O)[O-])cc2CN1C
Agent: Cl
Solvent: CO
Product: CC1Cc2ccc(N)cc2CN1C
Reaction time: 1 h

Procedure:
To 2,3-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g, 8.24 mmol) in methanol (100 ml) was added a catalytic amount of 10% Pd--C. The mixture was hydrogenated at 50 psi for 1 h, filtered, and concentrated to a solid which was used immediately in the next reaction (1.6 g, 92%), m.p. 215-217° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20]Br>C(#N)C>[Br:18][CH2:19][CH2:20][O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1OCCBr
Temperature: 70 °C
Yield: 99.1 %

Procedure:
A solution of 5-fluoro-2-nitrophenol (1.5 g, 9.55 mmole) in acetonitrile (100 mL) under a nitrogen atmosphere was treated with potassium carbonate (4.5 g, 32.6 mmole) and 1,2-dibromoethane (16.0 mL, 186 mmole), The reaction mixture was heated to 70° C. for 40 hours. The reaction was then filtered and concentrated. The crude material was purified by flash chromatography (SiO2, 20% ethyl acetate/hexane) to give 2-(2-bromoethoxy)-4-fluoro-1-nitrobenzene (2.5 g, 98%). 1HNMR (CDCl3) δ 7.97 (m, 1H), 6.79 (m, 2H), 4.40 (t, 2H, J=8.0 Hz), 3.69 (t, 2H, J =8.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][N:43]1[C:48]2[CH:49]=[CH:50][C:51]([S:53](Cl)(=[O:55])=[O:54])=[CH:52][C:47]=2[O:46][CH2:45][CH2:44]1>C(#N)C>[CH3:42][N:43]1[C:48]2[CH:49]=[CH:50][C:51]([S:53]([O:1][C:2]3[CH:10]=[CH:9][C:8]([C:11]4[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]5[C:18]([CH:19]=4)=[CH:17][C:16]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:15][CH:14]=5)=[C:7]4[C:3]=3[CH2:4][NH:5][C:6]4=[O:34])(=[O:55])=[O:54])=[CH:52][C:47]=2[O:46][CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CN1CCOc2cc(S(=O)(=O)Cl)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCOc2cc(S(=O)(=O)Oc3ccc(-c4cc5cc(CN6CCCCC6)ccc5n4C(=O)OC(C)(C)C)c4c3CNC4=O)ccc21
Yield: 58 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0324 g, 0.0702 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0590 mL, 0.421 mmol) and 3,4-dihydro-4-methyl-1,4-benzoxazine-7-sulfonyl chloride (0.0520 g, 0.211 mmol) to obtain 4-(3,4-dihydro-4-methyl-1,4-benzoxazin-7-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0274 g, yield 58%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([C:22]3([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:24][O:23]3)([F:21])[F:20])=[CH:17][CH:18]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:33]1[CH:37]=[N:36][N:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])([OH:23])[CH2:24][N:33]3[CH:37]=[N:36][N:35]=[N:34]3)=[N:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Fc1ccc(C2(C(F)(F)c3ccc(Oc4ncc(C(F)(F)F)cc4Cl)cn3)CO2)c(F)c1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of 3-chloro-2-((6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)oxy)-5-(trifluoromethyl)pyridine (U) (356 mg, 0.744 mmol) and 1H-tetrazole (62.5 mg, 0.892 mmol) in dry DMSO (3.718 mL) was added potassium carbonate (206 mg, 1.487 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at 60° C. overnight, cooled to RT and diluted with ice-cold water/2N HCl and DCM and the layers were separated on a Phase Separator. The aq. layer was extracted again with DCM and the combined organic extracts were evaporated. The crude residue was purified on silica (ISCO, 40 gram column, gradient to 40% EtOAc/Hexanes over 20 minutes) to afford the title compound. Yield=119 mg (27.7%) of a brown glass. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.27 (dd, J=2.1, 0.9 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.74-7.63 (m, 2H), 7.34 (td, J=8.9, 6.4 Hz, 1H), 7.21 (s, 1H), 6.83-6.72 (m, 1H), 6.72-6.64 (m, 1H), 5.64 (d, J=14.3 Hz, 1H), 5.13 (d, J=14.1 Hz, 1H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ −61.74 (s), −103.20 (d, J=15.0 Hz), −103.72-−104.09 (m), −107.86 (d, J=10.9 Hz), −110.78 (d, J=45.0 Hz), −111.48 (d, J=45.0 Hz). MS(ESI): m/z 549.1 (M+H)+.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:12](=[O:25])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[I:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH:53]=O>ClCCCl>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:15][CH2:16][N:17]([CH2:53][C:52]4[CH:55]=[CH:56][CH:57]=[C:50]([I:49])[CH:51]=4)[CH2:18][CH2:19]3)[N:13]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:12](=[O:25])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCNCC2
Reactant: O=Cc1cccc(I)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1cccc(I)c1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(cyclohexylamino)-1-pent-4-en-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one dihydrochloride (1 g, 2.56 mmol, intermediate I.1.c.1) in DCE (16 mL), was added Hunig's base (0.67 mL, 1.42 mmol), sodium triacetoxyborohydride (0.25 g, 1.18 mmol) and 3-iodo-benzaldehyde (329 mg, 3.83 mmol) in DCE (0.5 mL) dropwise. The reaction mixture was stirred at rt for 18 h, quenched with aq NaHCO3, extracted twice with EtOAc, washed with brine, concentrated in vacuo and purified flash chromatography (silica gel, EtOAc) to provide the desired product LRMS (M+1)=535.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>CO>[CH3:17][O:16][C:12]([CH2:13][CH2:14][N:1]([CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])[CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15])=[O:15]
Reactant: C=CC(=O)OC
Reactant: CO[Si](CCCN)(OC)OC
Solvent: CO
Product: COC(=O)CCN(CCC[Si](OC)(OC)OC)CCC(=O)OC
Temperature: 30 °C
Yield: 99.1 %

Procedure:
3-Aminopropyltrimethoxysilane (11.05 g, 61.7 mmol) and methanol (20 ml) are stirred together for 30 minutes at room temperature. To the mixture is added 41.46 g (482 mmol) of methyl acrylate. The reaction mixture is heated overnight in a 30° C. oil bath. The reaction mixture is concentrated at reduced pressure to give 21.50 g of crude methyl 3-[(2-methoxycarbonylethyl)-(3-trimethoxysilylpropyl)amino]propionate, a yellow viscous oil. A mixture of the crude product, 1-[4-(2-hydroxyethyoxy)phenyl]-2-hydroxy-2-methylpropan-1-one (26.85 g, 119.7 mmol) and 1,2-dimethoxyethane (80 ml) is heated in an oil bath at 85° (bath temperature). Zirconium(IV) acetylacetonate (1.16 g, 2.38 mmol) is added, and the mixture is stirred at 85° C. overnight and then at room temperature for 24 hours. Solvent is evaporated, and approximately one-half of the crude product is passed through a silica gel column with 5:1 chloroform:methanol as eluent to obtain 15.74 g of the title compound, a yellow semisolid product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:11][N:12](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:11]#[N:12])=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C#N)cnc1N
Temperature: 100 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
To a solution of 5-bromo-3-methoxy-pyridin-2-amine (3.00 g, 14.8 mmol) in N,N-dimethylformamide (55 mL) under a nitrogen atmosphere was added zinc (II) cyanide (2.78 g, 23.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.06 g, 1.77 mmol). The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was diluted with ethyl acetate and washed successively with a saturated solution of ammonium hydroxide and brine. The phases were separated. The organic phases was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:5) to give 6-amino-5-methoxy-pyridine-3-carbonitrile (1.2 g, 54% yield). 1H NMR (400 MHz, CDCl3): 7.99 (s, 1H), 6.99 (s, 1H), 3.88 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): 152.83, 144.58, 141.27, 118.32, 115.52, 97.66, 55.65. LC-MS (Method B): RT 0.69, 150 (M+H+)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][C:13]([F:16])=[C:14]([F:15])[C:9]=2[O:8][CH2:7][C:6]1=[O:17].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:26]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29]>CCCCCCC.CCOC(C)=O>[CH2:26]([CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][C:13]([F:16])=[C:14]([F:15])[C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCC1CCNCC1
Reactant: O=C1COc2c(ccc(F)c2F)N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCC1CCN(CCCN2C(=O)COc3c2ccc(F)c3F)CC1
Yield: 63.7 %

Procedure:
4-(3-Chloropropyl)-7,8-difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082b) (0.16 g, 0.60 mmol), K2CO3 (0.17 g, 11.9 mmol), NaI (0.18 g, 11.9 mmol) and 4-butylpiperidine (0.09 g, 0.63 mmol) were mixed according to GP12. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF2082x) (0.14 g, 65%). 1H NMR (CDCl3) δ 6.88-6.76 (m, 2H) 4.66 (s, 2H), 3.96 (t, J=7.2 Hz, 2H), 2.84 (d, J=11.2, 2H), 2.34 (t, J=6.8 Hz, 2H), 1.91-1.78 (m, 4H), 1.67 (d J=9.6 Hz, 2H), 1.30-1.15 (m, 9H); 13C NMR (CDCl3) δ 163.1, 147.4 (q, J=245.0 Hz, J=10.6 Hz), 140.1 (q, J=248.7 Hz, J=15.7 Hz), 135.4 (d, J=12.0 Hz), 126.5, 109.5 (d, J=18.4 Hz), 109.0 (q, J=7.6 Hz, J=3.8 Hz), 67.8, 55.8, 52.3, 40.1, 36.4, 35.9, 32.7, 29.1, 24.8, 23.0, 14.2.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:18]#[N:19])=[CH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.O>[Ni].C1COCC1>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]2[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3](=[O:2])[NH:19][CH:18]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccccc1C(C#N)=Cc1ccncc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]cc(Cc2ccncc2)c2ccccc12

Procedure:
In the presence of 5×40 g of Raney nickel (added at intervals), 163 g (617 mmol) of 2-[(1-cyano-2-(pyridin-4-yl)-vinyl]-benzoic acid methyl ester are hydrogenated in 3 liters of THF at 40° C. for 90 hours. The reaction mixture is filtered, and the filtrate is concentrated by evaporation and crystallised from acetonitrile/ethyl acetate (→title compound). Further product can be obtained from the mother liquor by chromatography (SiO2; ethyl acetate→acetone): m.p. 189-190° C.; FAB-MS: (M+H)+=237; 1H NMR (DMSO-d6) 11.27 (sb, HN), 8.45 (d, 2H), 8.23 (d, 1H), 7.65 (t, 1H), 7.48 (m, 2H), 7.27 (d, 2H), 7.18 (s, 1H), 4.05 (s, 2H); Anal. calc. (Cl5H12N2O.0.05 H2O) C 75.96%, H 5.14%, N 11.81%; found C 75.8%, H 5.2%, N 11.9%.