Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2ccc(N)cc21
Reaction time: 2 h
Yield: 98.6 %

Procedure:
1-Acetyl-6-nitroindoline (3.8 g, 18.3 mmol) is suspended in EtOAc (200 mL). Pd/C (650 mg, 10%) is added, and the mixture is hydrogenated at 40-55 p.s.i. for 2 hours. The mixture is then filtered through celite. The filtrate is concentrated, and the residue is triturated with ether to yield 1-acetyl-6-aminoindoline (3.18 g, 99%) as an orange solid.
Reaction SMILES: Br[C:2]1[C:3]([O:27][CH3:28])=[C:4]([CH:9]([NH:11][C:12]2[N:20]=[CH:19][N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3C2CCCCO2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.O1CCOCC1.CO.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>[Cl:8][C:6]1[CH:7]=[C:2]([C:32]2[CH:33]=[N:34][CH:35]=[C:30]([Cl:29])[CH:31]=2)[C:3]([O:27][CH3:28])=[C:4]([CH:9]([NH:11][C:12]2[N:20]=[CH:19][N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][NH:16]3)[CH3:10])[CH:5]=1
Reactant: COc1c(Br)cc(Cl)cc1C(C)Nc1ncnc2c1ncn2C1CCCCO1
Reactant: OB(O)c1cncc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COc1c(-c2cncc(Cl)c2)cc(Cl)cc1C(C)Nc1ncnc2[nH]cnc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A solution of N-[1-(3-bromo-5-chloro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (45 mg, 0.096 mmol) and (5-chloropyridin-3-yl)boronic acid (23 mg, 0.15 mmol) in water (0.5 mL) and 1,4-dioxane (1 mL) was treated with potassium carbonate (33 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 9.6 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated at 80° C. overnight. The reaction mixture was cooled treated directly with 6 M hydrogen chloride in water (170 μL, 1.0 mmol) and stirred at room temperature for ˜30 minutes. The reaction mixture was diluted slightly with methanol, filtered, and directly purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (6 mg, 15%). LCMS for C19H17Cl2N6O (M+H)+: m/z=415.1. Found: 415.0; 1H NMR (300 MHz, DMSO-d6): δ 8.72 (d, J=1.8 Hz, 1H), 8.66 (d, J=2.3 Hz, 1H), 8.20-8.09 (m, 4H), 7.65 (d, J=2.1 Hz, 1H), 7.40 (d, J=2.6 Hz, 1H), 5.91-5.71 (m, 1H), 3.52 (s, 3H), 1.51 (d, J=7.0 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C=O>[CH2:24]([N:26]([CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCNCC
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)o1
Yield: 84.6 %

Procedure:
0.33 g (1 mmol) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature overnight with 2 ml (2 mmol) of diethylamine and 5 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/ethanol 9/1 there was obtained 0.31 g (84%) of 3-(5-diethylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 235°-238°.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[NH:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[NH:28]1[C:36]2[C:31](=[CH:32][C:33]([C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH3:27])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCc1nc(C)c(-c2ccc3[nH]ccc3c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 61.9 %

Procedure:
A mixture of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.61 g), 1H-indol-5-ylboronic acid (0.33 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution (5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.41 g, 62%).
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][NH:11][C:12](=[O:32])[C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25](=[O:27])[CH3:26])=[C:20]([O:28][C:29](=[O:31])[CH3:30])[CH:19]=1)[NH:14]C=O)C1C=CC=CC=1.[ClH:34].CO.C(O)(=O)C>CCOCC>[ClH:34].[C:29]([O:28][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][C:25](=[O:27])[CH3:26])[CH2:17][C@@H:13]([C:12]([NH:11][CH2:10][C:9]([OH:33])=[O:8])=[O:32])[NH2:14])(=[O:31])[CH3:30]
Reactant: CC(=O)Oc1ccc(C[C@H](NC=O)C(=O)NCC(=O)OCc2ccccc2)cc1OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C[C@H](N)C(=O)NCC(=O)O)cc1OC(C)=O
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Next, the step of deprotecting the N-formyl-3,4-diacetyloxy-L-phenylalanyl-glycine-benzyl ester was performed. 0.90 g (2.0 millimole) of the aforementioned compound was allowed to react with a 2.2 ml of a 1N methanolic-hydrochloric acid solution (prepared by diluting 2 ml of concentrated hydrochloric acid to 24 ml with methanol) overnight. Initially, a suspension formed and an additional 5 ml of methanol was added to the suspension. After about 0.5 hours, all of the solid had gone into solution. The solution was concentrated in vacuo at room temperature and the nmr spectrum of the residue showed the absence of CH3CO2 and O=CH-N absorptions. The residue was dissolved in 60 ml of anhydrous methanol to which 0.5 ml of glacial acetic acid had been added. The solution was shaken in a Parr shaker under hydrogen atmosphere over 0.1 g of a 10% Pd/C catalyst overnight. The suspension was then filtered to remove the catalyst and concentrated in vacuo at room temperature. The residue was twice diluted with acetone (100 ml) and concentrated. Then, it was dissolved in glacial acetic acid saturated with hydrogen chloride (10 ml) and allowed to react with acetyl chloride (10 ml). A solid formed, but soon went back into solution. After eight hours at room temperature, the acetic acid solution was then diluted to 125 ml with ether. The ether was then decanted and the gummy dark residue left behind was suspended in ether (100 ml). The suspension was stirred overnight to yield a fine white solid in suspension, which was filtered quickly and dried in vacuum desiccator to yield 0.59 g (shrinking at 100° C, wet at 114° C, and foaming from 120°-127° C, 78% yield) of 3,4-diacetyloxy-L-phenylalanyl-glycine hydrochloride. The nmr was consistent with the proposed structure of the compound obtained and upon analysis of a sample of this compound, by recrystallization from methanol-ether, the following data was obtained. Analysis Calculated for: C15H19N2O7Cl: C, 48.06; H, 5.11; and N, 7.48. Found: C, 48.22; H, 5.34; and N, 7.72.
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29]Br>CN(C=O)C>[N:18]1[CH:19]=[CH:20][C:15]([C:3]2[C:4]([C:7]3[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=3)[C:10]#[N:11])=[N:5][N:6]3[CH2:29][CH2:28][S:1][C:2]=23)=[CH:16][CH:17]=1
Reactant: BrCCBr
Reactant: N#Cc1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
3-(5-Mercapto-4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile (4.59 g, 16.1 mmol) was dissolved in dry DMF (200 mL) under nitrogen atmosphere. Solid potassium carbonate (11.1 g, 80.5 mmol, 5 eq) was added followed by 1,2-dibromoethane (1.53 mL, 17.71 mmol, 1.1 eq) and the suspension was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure and diluted with ethyl acetate. It was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was treated with methanol and the solid was filtered and discarded. The mother liquor was evaporated to dryness and purified by chromatography on silica gel (eluant DCM/MeOH 97:3) to give 1.27 g of 3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-benzonitrile as a white solid (26% over 2 steps).
Reaction SMILES: C[O:2][C:3](=O)[NH:4]S(C1C=CC=CC=1)(=O)=O.C1(S(N)(=O)=O)C=CC=CC=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCOCC1>[CH:25]1([NH:31][C:3](=[O:2])[NH2:4])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: COC(=O)NS(=O)(=O)c1ccccc1
Agent: NS(=O)(=O)c1ccccc1
Solvent: C1COCCO1
Product: NC(=O)NC1CCCCC1

Procedure:
2.0 g of 4-(β<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonyl carbamic acid methyl ester (melting point 160 - 161° C, prepared from 4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido]-ethyl)-benzenesulfonamide and chlorofomic acid methyl ester) in 30 ml of dioxane were gently boiled for 2 hours together with 0.5 g of cyclohexyl amine in a vessel with descending condenser. The solvent was then concentrated under reduced pressure, the residue was dissolved in dilute ammonia and precipitated with dilute hydrochloric acid, the reaction mixture was filtered with suction and the precipitate recrystallized from methanol. The N-[4-(β-<1-ethyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonyl]-N'-cyclohexyl urea obtained melted at 189 - 190° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[F:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=2)[NH:24][C:23]1=[O:27])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2ccc(F)cc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(F)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-fluoro-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:21]([CH3:38])[C:22](=[O:37])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:24]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:21]([CH3:38])[C:22](=[O:37])[C:23]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[C:25]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:24]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1O
Reaction time: 5 h

Procedure:
To a solution of N-[4-(2-benzyloxy-phenyl)-pyridin-3-yl]-3-methanesulfonyl-N-methyl-5-trifluoromethyl-benzamide (200 mg, 370 μmol, example 258) in MeOH (2 mL) and EtOAc (2.00 mL) was added 10% palladium on charcoal (30 mg, 370 μmol) under argon atmosphere. The reaction was evacuated and purged with hydrogen gas. The reaction was stirred for 5 hours at 1.7 bar under H2 atmosphere. The reaction mixture was filtered over dicalite and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (150 mg, 90%). MS (ESI): m/z=451.094 [M+H]+.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](O)=[O:15])[CH2:9][CH2:8]1)([CH3:3])[CH3:2].C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.[Cl-].[Li+].[C:39]1([CH2:45][CH:46]2[CH2:50][O:49][C:48](=[O:51])[NH:47]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([CH2:45][CH:46]2[CH2:50][O:49][C:48](=[O:51])[N:47]2[C:14](=[O:15])[CH2:13][CH:10]2[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:21])[CH3:22])[CH2:8][CH2:9]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: CC(C)[Si](OCC1CCC(CC(=O)O)CC1)(C(C)C)C(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCC1CCC(CC(=O)N2C(=O)OCC2Cc2ccccc2)CC1)(C(C)C)C(C)C

Procedure:
The acid (8.5 g, 25.9 mmol) from step F was treated with 3.14 g (3.2 mL, 26 mmol) of pivaloyl chloride and 10.5 g (14.5 mL, 26 mmol) of triethylamine followed by 1.32 g (28 mmol) of lithium chloride and 4.60 g (26 mmol) of 4-phenylmethyl-2-oxazolidinone according to the procedure of G.-J. Ho and D. J. Mathre, J. Org. Chem. 1995, 60, 2271–2273 to provide, after purification by flash chromatography on silica gel (10% ethyl acetate/hexane), 11.5 g (91%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.32 (m, 2H), 7.27 (m, 1H), 7.23 (d, 2H, J=6.9 Hz), 5.31 (m, 1H),
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[O:8]2)=[CH:4][C:3]=1[N+:19]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[F:1])[CH:6]=[C:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[O:8]1
Reactant: O=C1OC(=Cc2ccc(F)c([N+](=O)[O-])c2)C2=C1CCCC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(C=C2OC(=O)C3=C2CCCC3)ccc1F
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 2A (2.25 g) and ammonium chloride (0.83 g) in ethanol (35 mL) and water (25 mL) at 70° C. was treated with iron powder (4.35 g), stirred for 3 hours and filtered through diatomaceous earth (CELITE®, World Minerals, Santa Barbara, Calif.) with hot ethanol. The filtrate was concentrated, and the concentrate was stirred with water for 30 minutes and filtered. The solid was washed with water and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[CH:3]=1.[CH3:35][O-:36].[Na+]>CO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:4]3[CH:3]=[C:2]([O:36][CH3:35])[N:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4cc(Cl)ncn4)CC3)nc3ccccc32)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ncn1

Procedure:
A mixture of 6 parts of N-[1-[2-[(6-chloro-4-pyrimidinyl)amino]ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 2.5 parts of a sodium methoxide solution 30% and 40 parts of methanol was stirred and refluxed overnight. The reaction mixture was evaporated and water was added to the residue. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.4 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(6-methoxy-4-pyrimidinyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 145.8° C. (compound 98).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:5])[CH3:2].[CH:17]1([OH:24])[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1>>[OH:23][CH:20]1[CH2:21][CH2:22][CH:17]([O:24][C:7]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])=[O:16])[CH2:18][CH2:19]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: OC1CCC(O)CC1
Product: CCOC(=O)NC(=O)c1ccccc1C(=O)OC1CCC(O)CC1

Procedure:
According to the same manner as described in Example 1 except for reacting N-ethoxycarbonylphthalimide with 1,4-cyclohexanediol under conditions shown in Table 19, ethyl N-{2-(4-hydroxycyclohexyloxycarbonyl)benzoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 10.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]([CH:11]=O)=[N:2]1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH2:27])=[C:22]([NH2:28])[CH:21]=1>CCO>[CH3:26][C:24]1[C:23]2[NH:27][C:11]([C:3]3[CH2:4][C:5]4([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)[O:1][N:2]=3)=[N:28][C:22]=2[CH:21]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])[CH:25]=1
Reactant: O=CC1=NOC2(CCCCC2)C1
Reactant: Cc1cc(-c2ccccc2F)cc(N)c1N
Solvent: CCO
Product: Cc1cc(-c2ccccc2F)cc2nc(C3=NOC4(CCCCC4)C3)[nH]c12
Temperature: 80 °C
Yield: 44 %

Procedure:
1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (167 mg, 1.00 mmol, as prepared in Example 19, step B) was placed in a 25 mL round-bottom flask equipped with a magnetic stir bar. 2′-Fluoro-5-methyl-biphenyl-3,4-diamine (218 mg, 1.01 mmol, as prepared in the previous step) was added as a solution in EtOH (10 mL). The flask was fitted with a reflux condenser (top open to air), and the mixture was heated to 80° C. for 6 h. The cooled mixture was concentrated under reduced pressure. The residue was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min, yielding 159 mg (44%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 7.57 (br. s., 1H), 7.50 (td, J=7.8, 1.9 Hz, 1H), 7.31-7.37 (m, 1H), 7.08-7.28 (m, 4H), 2.64 (s, 3H), 2.31 (s, 2H), 1.69-1.89 (m, 6H), 1.47-1.64 (m, 4H).
Reaction SMILES: [I-].C[S+](C)C.[CH3:6]C(C)([O-])C.[K+].[C:12]([O:16][C:17]([CH:19]=[C:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(OCC)(=O)C>CS(C)=O>[CH2:33]([O:32][C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:23]2[CH2:24][CH2:25][C:20]3([CH:19]([C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])[CH2:6]3)[CH2:21][CH2:22]2)=[CH:36][CH:35]=1)=[O:31])[CH3:34]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1ccc(C2CCC(=CC(=O)OC(C)(C)C)CC2)cc1
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C2CCC3(CC2)CC3C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 7.6 %

Procedure:
5.11 g of trimethylsulfonium iodide (23.23 mmol, 4 eq.) are dissolved with stirring in 20 mL of DMSO in a 250 mL three-necked flask under a nitrogen atmosphere. 2.61 g of potassium tert-butoxide (23.23 mmol, 4 eq.) are added and the reaction medium is stirred for 3 hours. 2 g of ethyl 4-(4-tert-butoxycarbonylmethylenecyclohexyl)benzoate dissolved in 5 mL of DMSO are added and stirring is continued for 2 days. 2.56 g of trimethylsulfonium iodide (11.61 mmol, 2 eq.) are dissolved in 20 mL of DMSO in a 25 mL three-necked flask under a nitrogen atmosphere, and 1.0 g of potassium tert-butoxide (11.61 mmol, 2 eq.) is added with stirring. After 3 hours, this reaction medium is added to the 250 mL three-necked flask and stirring is continued for 18 hours. Ethyl acetate is added. The organic phase is washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate and filtered. The residue is chromatographed on silica gel with a gradient of ethyl acetate in heptane ranging from 10% to 50%. 0.159 g of tert-butyl 6-(4-ethoxycarbonylphenyl)spiro[2.5]octane-1-carboxylate is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[H-].[Na+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[OH-].[Na+]>CN1CCCN(C)C1=O.C(OCC)(=O)C>[CH3:21][C:15]([O:11][C:5]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
A solution of 2-nitro-4-methylphenol (11.48 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (50 ml) was cooled at 5° C. and treated with portions of sodium hydride (55% w/w dispersion in mineral oil, 3.27 g). The mixture was stirred at room temperature for 2 hours, then cooled to 5° C. and treated with ethyl 2-bromo-2-methylpropionate (13.15 g). The mixture was heated at about 100° C. for 18 hours, then cooled to room temperature and poured into a mixture of aqueous sodium hydroxide solution (1M) and ethyl acetate. The organic solution was separated and washed twice with 1M sodium hydroxide solution, then dried (MgSO4) and concentrated. The resulting oil was purified by flash column chromatography, eluting with a mixture of ethyl acetate and hexane, (increasing from 5:95 v/v to 10:90 v/v), to give ethyl 2-methyl-2-(2-nitro-4-methylphenoxy)propionate (4.48 g) as an oil; NMR: 1.25 (3H, t), 1.60(6H, s), 2.35(3H, s), 4.25(2H, q) and 6.8-7.6(3H, m).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[F:28])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Br[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:15][C:14]=2[F:28])[O:11][CH3:12])=[CH:30][CH:31]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Brc1cccnc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2cccnc2)cc1F

Procedure:
In analogy to example 57.1 (RS)-N-(4-cyano-benzyl)-2-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methoxy-acetamide was reacted with 3-bromopyridine to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-pyridin-3-yl-phenyl)-2-methoxy-acetamide. Light brown amorphous solid. MS 376.3 ([M+H]+)