Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH:24]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])[CH3:25]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:31][C:30]4[CH:32]=[CH:33][C:27]([CH:24]([CH3:26])[CH3:25])=[CH:28][CH:29]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CC(C)c1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CC(C)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 53.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-isopropylaniline (46.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(1-methylethyl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (36.3 mg).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([CH3:34])=[C:9]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH3:37].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:6][C:7]2[C:8]([CH3:34])=[C:9]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][N:36]([CH3:37])[CH3:35])=[CH:17][CH:18]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (0.11 g, 0.24 mmol) and N,N-dimethylamine (0.044 g, 1.2 mmol) in methanol (3 mL) was added acetic acid (0.014 g, 0.24 mmol) and the solution stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.030 g, 0.48 mmol) was added and the solution stirred overnight. The solvent was removed under reduced pressure and the residue purified by column chromatography over silica gel to afford desired 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4′-((dimethylamino)methyl)-4-methyl-[1,1′-biphenyl]-3-carboxamide
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C1COCC1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@H:19]([CH:22]=[O:23])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@H:19]([CH:22]([OH:23])[C:1]#[CH:2])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Solvent: C1CCOC1
Product: C#CC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.5 M Ethynylmagnesium bromide in THF (6.3 mL, 3140 μmol) was added dropwise over 5 minutes to a stirred solution of (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (0.5 g, 2 mmol) in THF (5 mL, 60 mmol) at 0° C. The mixture was allowed to warm to room temperature. After 4 hours, the reaction was quenched with the addition of saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2×10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[Br:12]N1C(C)(C)C(=O)N(Br)C1=O>CCCCCCC.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2ccccc2s1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Product: CC(Br)c1cc2ccccc2s1
Temperature: 20 °C
Reaction time: 1 h
Yield: 113.7 %

Procedure:
A solution of 9.78 g (60 mmol) of 2-ethylbenzo[b]thiophene in 10 ml of heptane is added, over 10 minutes, to a mixture of 9.43 g (33 mmol) of 1,3-dibromo-5,5-dimethylhydantoin and 0.49 g (3 mmol) of azobisisobutyronitrile in 117.5 ml of heptane preheated to 60° C. The mixture is maintained for 1 additional hour at this temperature. After cooling to 20° C., stirring is continued for 1 hour and then the 5,5-dimethylhydantoin which has precipitated is filtered off and washed with 10 ml of heptane. The filtrate is washed with an aqueous sodium thiosulphate solution (3 g/100 ml) and then with 3 times 100 ml of water. After drying over sodium sulphate, the heptane phase is concentrated to approximately 40 ml and then cooled to -10° C. for one hour and a half. The precipitate formed is filtered off and dried under partial vacuum at 20° C. to provide 9.05 g of the desired compound in the form of a beige powder, which represents a yield of 57% (M.p.: 53° C., purity by liquid phase chromatography: 92%). A second, less pure sample is obtained by concentrating the mother liquors (16%).
Reaction SMILES: C([N:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH2:31])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)(=O)C.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.O>O1CCCC1>[NH2:31][C:25]1[C:21]2[C:22](=[O:24])[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[C:13]([F:32])[CH:14]=3)[O:19][C:20]=2[C:28]([F:29])=[CH:27][C:26]=1[F:30]
Reactant: C1CCNC1
Reactant: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCCCN4CCCC4)c(F)c3)cc(=O)c12

Procedure:
500 mg (1.07 mmol) of 5-amino-2-[4-(6-bromohexylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 52 was dissolved in 15 ml of tetrahydrofuran, 0.891 ml of pyrrolidine was added and the mixture was heated at reflux for 1.5 hours. Water was added to the reaction solution and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:triethylamine=90:10:1) and recrystallized from chloroform/n-hexane to give Compound 54 which was converted into hydrochloride according to the same manner as that in Example 16 to give 88 mg (17%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]([CH3:16])=[C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:25])[CH:12]=2)[N:7]=1)(=O)C.[OH-].[Na+]>C1COCC1.CO>[CH2:18]([O:17][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:25])[CH:12]=2)[N:7]=[C:6]([CH2:5][OH:4])[C:15]=1[CH3:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OCc1nc2ccc(C)cc2c(OCc2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2nc(CO)c(C)c(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of [4-(benzyloxy)-3,6-dimethylquinolin-2-yl]methyl acetate (1.20 g) in THF-methanol (1:3, 24 mL) was added a 1M aqueous sodium hydroxide solution (5.5 mL), followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and water was then added to the residue. The precipitated solid was collected by filtration, washed with water, and dried to obtain [4-(benzyloxy)-3,6-dimethylquinolin-2-yl]methanol (900 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][C:24]#[N:25].[NH2:26][OH:27]>CS(C)=O>[OH:27][N:26]=[C:24]([NH2:25])[CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: N#CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: NO
Solvent: CS(C)=O
Product: NC(CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
To a stirred solution of 3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanenitrile (2.00 g, 6.0 mmol) in dimethyl sulfoxide (15.0 mL) was added hydroxylamine (50% wt solution in water, 1.6 mL, 24 mmol). The reaction was stirred at ambient temperature for 16 h, then the product was precipitated upon addition of water/ethanol (3:1, 100 mL). The solvent was decanted and the remaining solid was triturated in distilled water (75 mL). The solid was filtered and air-dried to afford N′-hydroxy-3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanimidamide as a colorless solid (2.00 g, 91%): MS (ES+) m/z 368.2 (M+1).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:13][CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]([CH3:34])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C(F)(F)F.[OH-].[OH-].[Pd+2]>[CH3:34][CH:11]1[CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:13][CH:9]([NH2:8])[CH2:10]1
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: OCC(F)(F)F
Product: CC1CC(N)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Yield: 97.9 %

Procedure:
To a solution of N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (3.0 g, 5.30 mmol) in trifluoroethanol (200 mL) was added 20% wet palladium hydroxide on carbon (0.6 g, 4.27 mmol). The mixture was stirred under 40 psi of hydrogen at about 50° C. for about 90 min. The catalyst was removed by filtration through a pad of Celite® and the filtrate was concd under reduced pressure to yield 3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (2.0 g, 98% yield) as a brown amorphous solid. LC/MS (Table 1, Method a) Rt=1.86 min; MS m/z 386 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.Br>C(O)(=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(F)cc1
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
A solution of ethyl 3-(4-benzyloxyphenyl)-2-(4-fluorophenoxy)propionate (7.00 g), which is the product of Reference example 37(a) in a solution of hydrogen bromide in acetic acid (25%, 70 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Potassium carbonate (6.90 g) was added to a solution of the residue in ethanol (70 ml). This mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=9/1-4/1 as the eluant to afford the desired compound (2.75 g) as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([O:25][CH3:26])[NH:22]3)=[C:18]([NH2:27])[N:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[CH:8]1([CH2:14][O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([O:25][CH3:26])[N:22]3[CH2:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:18]([NH2:27])[N:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: BrCC1CCOCC1
Reactant: COc1nc2c(N)nc(OCC3CCCCC3)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCC3CCCCC3)nc2n1CC1CCOCC1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
2-[(Cyclohexylmethyl)oxy]-8-(methoxy)-9H-purin-6-amine trifluoroacetate salt (0.28 g) was heated with anhydrous potassium carbonate (0.3957 g) in anhydrous DMF (5 mL) under nitrogen for 1 hour at 60° C. (external). The reaction mixture was cooled to room temperature before adding 4-(bromomethyl) tetrahydro-2H-pyran (0.14 g) in anhydrous DMF (1 mL). The reaction mixture was heated to 50° C., overnight. The reaction mixture was quenched into water (20 mL) and extracted into ethyl acetate (20 mL, 3 times). The organic layers was separated, combined and then washed with brine (20 mL). The organic layer was separated and then dried by passing through a hydrophobic frit. Evaporation under reduced pressure gave pale yellow oil that solidified on standing. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (30-80%) to give the title compound as a white solid (0.1677 g).
Reaction SMILES: [C:1]([NH:11][C:12](=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])SC)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40]>>[C:16]([N:15]=[C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: NCCCCCC(=O)O
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
A methanolic (350 mL) solution of N, N'-dicarbobenzyloxy-S-methyl-isothiourea(60 g, 0.18 mol), triethylamine(18.2 g, 0.18 mol), and 6-aminocaproic acid (23.3 g, 0.18 mol) was refluxed for 30 min and subsequently stirred at room temperature for 4 h. The solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4), and concentrated. The residual solid was recrystallized from ethyl acetate/hexane to afford 52.3 g (66%) of the title product, mp 93° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[CH3:25])[C:18]([CH3:27])([CH3:26])[CH2:17]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:21]2[CH:20]=[C:19]3[C:24](=[C:23]([CH3:25])[CH:22]=2)[N:16]([CH3:15])[CH2:17][C:18]3([CH3:27])[CH3:26])=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1cccc2c1N(C)CC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1N(C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Under an argon atmosphere 0.473 g (2.67 mmol) 6-chloropyrimidine-4-carboxylic acid chloride and 0.427 g (3.20 mmol) aluminium trichloride were stirred in 20 mL DCM for 30 min. Then 0.520 g (2.67 mmol) 1,3,3,7-tetramethyl-2,3-dihydro-1H-indole in DCM were added dropwise to the reaction mixture and it was stirred for 45 min at RT, then for 45 min at 40° C. Next, the reaction mixture was decomposed with ice water/sodium hydroxide solution, extracted with DCM and the organic phase was evaporated down i. vac. The residue was taken up in MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: CN(C=O)C.CS(O[CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:16]([Cl:28])=[C:15]([Cl:29])[CH:14]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CCOCC>[N:30]([CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([Cl:29])[C:16]([Cl:28])=[C:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:18]=1)=[N+:31]=[N-:32]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCOS(C)(=O)=O)cc(Cl)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCN=[N+]=[N-])cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a DMF (0.4 M) solution of 2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]ethyl methanesulfonate (1 eq.) from Step 5, Amine 26 was added at RT sodium azide (5 eq.). The resulting solution was stirred at RT for 12 h and then at 80° C. for 3 h. The reaction mixture was then diluted with ether and washed with water. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a pink oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].CCN(CC)CC.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[CH2:3]([O:4][C:5](=[O:7])[CH2:6][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)OCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of bromoethylacetate, 3.3 g (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.2 mL (30.0 mmol) of Et3N and 9 mL (90.0 mmol) of piperidine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between chloroform and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 4.6 g (89%) of the desired product as a tan oil.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:19][CH2:18]1.[Br:32]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Br:32])[C:26]=2[F:31])[CH2:19][CH2:18]1
Reactant: CN1CCC(NCc2ccccc2F)CC1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(NCc2cccc(Br)c2F)CC1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
Add n-butyl lithium (1.6 M in hexanes, 4.3 mL) into a solution of 2,2,6,6-tetramethyl-piperidine (0.97 g) in THF (10 mL) at −78° C. and stir for 30 minutes. Add a solution of 1-methyl-4-(N-(2-fluorophenyl)methylamino)piperidine (Preparation 23, 1.02 g) in THF (10 mL) portion wise and stir for 10 minutes. Add 1,2-dibromo-1,1,2,2-tetrachloroethane (1.50 g) in THF (10 mL) dropwise and stir for 1 hr. Remove the cooling bath and stir for 30 minutes. Partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (110 g), using a gradient of dichloromethane-2M NH3 in methanol to give 0.49 g of the title intermediate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([F:32])[C:18]=1[CH:33]([F:35])[CH3:34].[F-].[K+].CC#N>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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([CH:33]([F:35])[CH3:34])[C:19]=2[F:32])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Reactant: CC(F)c1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(C(C)F)c2F)c(F)c(N)c1OC
Yield: 81 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705 mmol), 2-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared as described in WO2009029735 A1 20090305; 0.671 g, 2.216 mmol), PdCl2(PPh3)2 (0.120 g, 0.170 mmol), and KF (0.258 g, 4.43 mmol) were combined in a 1:1 mixture of CH3CN (2.84 mL) and H2O (2.84 mL). The reaction mixture was irradiated in a Biotage microwave at 115° C. in a sealed vial for 20 min. The cooled reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried and concentrated. The product was purified by flash chromatography (SiO2, 5-40% EtOAc in hexane gradient) to provide the title compound as a sticky brown-orange solid (0.545 g, 81%): 1H NMR (400 MHz, CDCl3) δ 7.53-7.46 (m, 1H), 7.29 (dt, J=8.4, 1.1 Hz, 1H), 6.39-6.03 (m, 1H), 4.61 (s, 2H), 3.97 (d, J=2.1 Hz, 6H), 1.85-1.68 (m, 3H); 19F NMR (376 MHz, CDCl3) δ −113.81, −113.87, −113.90, −113.95, −137.05, −137.14, −175.47, −175.52; ESIMS m/z 375 ([M+H]+), 373 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:12])([C:9]([O-])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:15])=O>>[Cl:15][C:9]([C:3]([O:2][CH3:1])([CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(C)(OC)C(=O)[O-]
Product: CCOC(=O)C(C)(OC)C(=O)Cl
Yield: 100 %

Procedure:
Mon-ethyl methoxy(methyl)malonate (14.52 grams, 0.08 mole) was reacted with thionyl chloride (19.61 grams, 0.16 mole) at 50° C. for a 13-hour reaction period with an additional holding period of approximately 32 hours at room temperature. Vacuum evaporation of the excess thionyl chloride gave 15.2 grams (0.08 mole) of ethyl 2-(chlorocarbonyl)-2-methoxypropionate. NMR analysis of the product indicated the following:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:4]([CH3:18])[C:3]=1[CH3:19].CC([O-])=[O:22].[Na+]>C(O)(=O)C>[CH3:18][C:4]1[C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[N:6][NH:7][C:2](=[O:22])[C:3]=1[CH3:19]
Reactant: CC(=O)[O-]
Reactant: Cc1c(Cl)nnc(Cc2ccc(F)c(C#N)c2)c1C
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(F)c(C#N)c2)n[nH]c(=O)c1C
Temperature: 25 °C

Procedure:
To a solution of intermediate N2 in acetic acid (0.16 M) was added NaOAc (2 eq.) and the mixture was stirred and heated to reflux for 1 h. The solution was cooled to RT and the solvent was removed under reduced pressure. The residue was suspended in water and triturated until a fine suspension was obtained. The solid material was filtered off, washed with water, dried by air stream and then under high vacuum. MS (ES) C14H12FN3O required: 257. found: 258 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=O)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:22][C:21](=[O:23])[CH3:24])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(CCC=O)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(CCC=CC(C)=O)ccc1OCc1ccccc1
Yield: 56.4 %

Procedure:
A solution of 2.3 g of 3-(p-benzyloxy-m-methoxyphenyl)propionaldehyde and 2.97 g of acetylmethylenetriphenylphosphorane in 22 ml of toluene was heated under reflux for 2 hours, toluene was then evaporated and the residue was purified by a chromatography using 30 g of silica gel and recrystallization from a mixture of ethyl ether and n-hexane (1:5) afforded 1.49 g of the desired compound melting at 59.5°-60.5° C.