Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C1C=CN=CC=1)C.COC(C)(C)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([CH3:17])[C:18]2[CH:19]=[N:20][C:21]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[CH:22][C:23]=2[C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Product: Cc1ncccc1-c1cc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 92 %

Procedure:
A mixture of 0.16 g (0.30 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramide, 0.67 ml (6.0 mmol) 1-methylpiperazine and 2 mg (0.02 mmol) 4-(N,N-dimethylamino)pyridine was heated at 140° C. over night. After cooling to room temperature the mixture was diluted with tert-butyl methyl ether and washed with water. The aqueous layer was extracted with two portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash chromatography gave 0.16 g (93%) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[N:12])[CH:2]=1.C[Si]([N-:17][Si](C)(C)C)(C)C.[Li+]>C(OCC)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH2:17])=[NH:12])[CH:2]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1cnc2ccccc2c1
Agent: [Li+]
Solvent: CCOCC
Product: N=C(N)c1cnc2ccccc2c1
Reaction time: 3 h

Procedure:
Quinoline-3-nitrile (1.0 g) was dissolved in diethyl ether (30 mL) and treated with lithium bis(trimethylsilyl)amide (1.0 M in THF, 13 mL). The reaction was stirred for 3 hours, then washed 3 times with 1 N HCl (50 mL). The combined aqueous washes were neutralized with 6 N NaOH and extracted 6 times with ethyl acetate (50 mL). The ethyl acetate extractions were dried over sodium sulfate and the solvent was evaporated to provide 0.63 g of quinoline-3-carboxamidine.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([Br:21])[C:19]=1[OH:20])[CH:15]=[O:16]>>[Br:21][C:18]1[C:19]([O:20][CH:2]([CH3:3])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[C:12]([O:11][CH3:10])[CH:13]=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: CC(C)CCCC(C)Br
Reactant: COc1cc(C=O)cc(Br)c1O
Product: COc1cc(C=O)cc(Br)c1OC(C)CCCC(C)C

Procedure:
2-bromo-6-methyl-heptane was reacted with 3-methoxy-4-hydroxy-5-bromo-benzaldehyde to obtain 5-bromo-4-[(1,5-dimethyl-hexyl)-oxy]-m-anisaldehyde (boiling point = 190°-193°C/0.1 mmHg); 2-bromo-6-methyl-heptane was reacted with p-hydroxy-benzonitrile to obtain p-[(1,5-dimethyl-hexyl)-oxy]-benzonitrile (boiling point = 165°-168°C/1.0 mmHg);
Reaction SMILES: [N:1]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(#N)C>[CH3:32][O:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([C:2]1[N:1]([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:4][N:3]=1)=[O:37]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Clc1ccc(C(CCOC2CCCCO2)Cn2ccnc2)cc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)c1nccn1CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(Imidazol-1-yl)-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (0.86 g) (see Preparation 30) and triethylamine (1.3 ml) were dissolved in acetonitrile (15 ml), under a nitrogen atmosphere, the solution cooled in an ice-bath and 2-methoxybenzoyl chloride (1.4 ml) added, dropwise. The mixture was allowed to warm to room temperature slowly and then stirred for 2 days. The acetonitrile was removed under reduced pressure and the residue dissolved in dichloromethane (20 ml) and washed sequentially with water and brine. The organic phase was then dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with 97:3, by volume, dichloromethane:methanol to give 1-[2-(2-methoxybenzoyl)imidazol- 1-yl]-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (1.1 g) as an oil and as a mixture of diastereomers.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[NH:7][C:8]3[C:9]([N:16]=2)=[N:10][C:11]([CH3:15])=[CH:12][C:13]=3[CH3:14])[CH2:5][CH2:4]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][N:19]=1>CS(C)=O.O>[CH:3]1([C:6]2[N:16]([CH2:24][C:21]3[CH:20]=[N:19][C:18]([Br:17])=[CH:23][CH:22]=3)[C:9]3=[N:10][C:11]([CH3:15])=[CH:12][C:13]([CH3:14])=[C:8]3[N:7]=2)[CH2:5][CH2:4]1
Reactant: Cc1cc(C)c2[nH]c(C3CC3)nc2n1
Reactant: BrCc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(Br)nc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
255 mg (6.4 mmol) of sodium hydride and 994 mg (5.3 mmol) of 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine are stirred at 0° C. for 2 h in 15 ml of dimethyl sulphoxide. After adding 2 g (7.97 mmol) of 2-bromo-5-bromomethylpyridine, the mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and washed twice with ethyl acetate; the combined organic phases are washed with water and sodium chloride solution, dried over sodium sulphate and then chromatographed on 150 g of silica gel using ethyl acetate/petroleum ether mixtures 1:2→1:0 to yield 1.32 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1.CO.[H][H]>[Ni].O1CCCC1>[NH2:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:12]=[C:13]2[NH:17][CH2:16][CH2:15][NH:14]2)[CH:4]=1
Reactant: [H][H]
Reactant: Cc1cc(Cl)c(N=C2NCCN2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)c(N=C2NCCN2)cc1N
Yield: 30.5 %

Procedure:
25.4 gm (0.10 mol) of 2-(2-chloro-4-methyl-5-nitro-phenylimino)-imidazolidine were hydrogenated in a shaker autoclave at 25° to 30° C. and atmospheric pressure in the presence of Raney nickel and in a 1:1 mixture of methanol and tetrahydrofuran until the theoretical amount of hydrogen had been absorbed. Thereafter, the catalyst was separated by suction filtration, and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in 2 N hydrochloric acid, and the solution was extracted with ether; the ether extracts were discarded. The aqueous phase was fractionally extracted with ether at stepwisely increasing pH-values (alkalization with 2 N NaOH), and the uniform fractions were combined, dried over magnesium sulfate and filtered. The ether was removed from the filtrate in vacuo until the weight of the residue remained constant, leaving 6.85 gm (30.5% of theory) of 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine, m.p. 155°-157° C., Rf -value 0.70 in the mobile phase 70 parts ethyl acetate, 50 parts isopropanol, 20 parts concentrated ammonium hydroxide; carrier: silicagel G; detector: ultraviolet light and potassium iodoplatinate.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1(O)[NH:7][N:6]=[C:5]([CH3:8])[CH2:4]1.[Br:11]Br>C(Cl)Cl>[Br:11][C:4]1[C:3]([CH:2]([F:10])[F:1])=[N:7][NH:6][C:5]=1[CH3:8]
Reactant: CC1=NNC(O)(C(F)F)C1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1[nH]nc(C(F)F)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(difluoromethyl)-3-methyl-4,5-dihydro-1H-pyrazol-5-ol (1.00 g, 6.66 mmol) in methylene chloride (20 mL) was added bromine (0.43 mL, 8.3 mmol) dropwise. The reaction was stirred at 25° C. for 3 h. and then quenched with a Na2S2O4 solution and neutralized with NaHCO3. The reaction was extracted with dichloromethane and the organic extracts were washed with water, brine, dried (MgSO4), and concentrated in vacuo. 1H NMR (CDCl3): δ 6.56-6.82 (t, 1H), 2.33 (s, 3H). Mass spec(EI) m/z=211&213 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:2].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:3]1[C:8]([B:9]2[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:15])[O:13]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19]1)[CH3:2]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN1CCC(c2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Temperature: 60 °C
Yield: 48.9 %

Procedure:
To a solution of 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (300 mg, 0.952 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added ethyl 4-bromobutanoate (0.272 mL, 1.903 mmol) and potassium carbonate (526 mg, 3.81 mmol). The reaction solution was heated to 60° C. overnight. Ethyl acetate was added and the resulting solution was washed with water, brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to afford ethyl 4-{4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperidinyl}butanoate (D121) (200 mg). MS (ES): C25H40BNO4 requires 429.3. found 430.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[C:26]([CH2:31][O:32][CH3:33])[N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].C(=O)([O-])[O-:35].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[C:26]([CH2:31][O:32][CH3:33])[N:25]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH2:19])=[O:35])[CH:8]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COCc1ccc(F)c(-c2ccc(Cl)c(C(=O)Nc3cc(C#N)nn3-c3ccccc3)c2)n1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COCc1ccc(F)c(-c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
To a solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-5-(3-fluoro-6-(methoxymethyl)pyridin-2-yl)benzamide (Example 89, 200 mg, 0.43 mmol) in DMSO (4 mL) was added potassium carbonate (120 mg, 0.87 mmol) followed by H2O2 (1.79 mL, 17 mmol, 30% w/w in water) slowly, maintaining the internal temperature below 30° C. The reaction was stirred at room temperature for 3 hours before quenching with the addition of water (15 mL). The solution was extracted into ethyl acetate (3×15 mL), the organic extracts were collected, dried over sodium sulphate, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate 0-10% MeOH in EtOAc followed by preparative HPLC. The residue was dissolved in DCM (5 mL) and washed with water (4 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo to afford the title compound (29 mg, 14%).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:3][CH2:4]OS(C)(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:14][C:13](=[CH:12][CH2:11][CH2:10][C@H:2]([CH3:1])[CH2:3][CH3:4])[CH3:15]
Reactant: CC(C)=CCC[C@H](C)CCOS(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To methanesulfonic acid (S)-3,7-dimethyl-oct-6-enyl ester (60 g, 0.256 mol) in THF (1 L) at 0° C. was added lithium aluminum hydride (3.8 g, 0.128 mol). After 7 hours, a further 3.8 g of lithium aluminum hydride was added and the solution warmed to room temperature. After 18 hours, a further 3.8 g of lithium aluminum hydride was added. After a further 21 hours, the reaction was carefully quenched with 1N citric acid and the solution diluted further with brine. The resultant two phases were separated and the organic phase was dried (MgSO4) and concentrated to afford the titled compound as an oil which was used without further purification. MS, m/z (relative intensity): 139 [M+H, 100%].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]1[N:15]([CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH2:14][CH2:13][N:12]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:11]12>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:15]2[CH2:14][CH2:13][N:12]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:11]3[CH2:10]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(CCCN1CCN2CCCCC2C1)Nc1ccc(Cl)c(Cl)c1

Procedure:
The procedure is as for Example 2 using as substrate 3,4-dichloroaniline and the compound obtained in Step B of Example 2.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[C:5]([C:9]1[CH:10]=[C:11]([C:20]2[C:21]([OH:34])=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)[C:12]([OH:19])=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]1([Cl:4])[O:34][C:21]2[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:25][C:20]=2[C:11]2[CH:10]=[C:9]([C:5]([CH3:6])([CH3:7])[CH3:8])[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]=2[O:19]1
Reactant: ClP(Cl)Cl
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c2op(Cl)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
45.21 grams of phosphorous trichloride in 50 ml of toluene was added dropwise over 85 minutes to a solution of 123.0 grams of 4,4',6,6'-tetra-tert.-butyl-2,2'-biphenol and 60.6 grams of triethylamine in about 600 ml of toluene and stirred at room temperature overnight (about 20 hours). The reaction product was filtered free of triethylamine hydrochloride, the desired product being isolated by removal of the solvent at reduced pressure to yield a solid m.p. 168°-174°.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]1([S:19][C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Sc2ccccc2)nc1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A suspension of ethyl 2-bromo-4-methyl-5-thiazolecarboxylate (22 g), thiophenol (10.75 g) and potassium carbonate powder (24.3 g) in dimethylformamide (100 ml) is stirred for 4 hours at 80° C. The reaction mixture is treated in the same manner as in Example 1 to give ethyl 2-phenylthio-4-methyl-5-thiazolecarboxylate (24.2 g) boiling at 160°-161° C at 1 mmHg.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:45]([NH:52][CH2:53][CH:54]([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:45]([N:52]([CH2:53][CH:54]([O:55][CH2:56][CH3:57])[O:58][CH2:59][CH3:60])[C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:23])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(CNCc1ccccc1)OCC
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid 1.98 g (6.0 mmol), a solution of 1-hydroxybenzotriazol 1.01 g (7.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 1.44 g (7.5 mmol) in dichloromethane 20 ml, and a solution of N-benzyl-2,2-diethoxyethanamine (Compound IV-1) 1.12 g (5.0 mmol) and 4-dimethylaminopyridine 61 mg (0.5 mmol) in dichloromethane 5 ml were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 20 ml and washed with saturated aqueous sodium bicarbonate 20 ml, water 20 ml and brine 20 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 70:30) to obtain the title compound 1.1 g (yield 42%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11](N2C=CN=C2)=[O:12])=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[C@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:22][C:21](=[O:30])[NH:20]1.C1CCN2C(=NCCC2)CC1>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([N:20]2[C@@H:19]([CH3:18])[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][C:21]2=[O:30])=[O:12])=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1C[C@@H]1c1ccc(Br)cc1)n1ccnc1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1C(=O)C1CC1c1ccc(Br)cc1

Procedure:
A mixture of (cis)-1-{[2-(4-bromophenyl)cyclopropyl]carbonyl}-1H-imidazole (1 eq) from Step 1, (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (1.2 eq) or (−)-isomer and DBU (added at 0° C., 1.2 eq) in CH3CN (0.2M) was stirred at 0° C. for 4 h. The solvent evaporated and residue purified by flash chromatography (Hexane:EtOAc; 100:0 to 80:20) to afford each diastereoisomer.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)[C:5](O)=[O:6].B.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH:4]([CH:5]=[O:6])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(CC(CCBr)C(=O)O)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: B
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(C=O)CCBr)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
At 0° C., 10.7 g (33.95 mmol) of 4-bromo-2-[4-(methoxycarbonyl)benzyl]butanoic acid from Ex. VII in 200 ml of THF are treated with 40.74 ml (40.74 mmol) of a 1M solution of borane in THF, and the mixture is stirred with warming to room temperature for 2 hours. Excess borane is destroyed by addition of water. The mixture is extracted with ether and the organic phase is then dried over magnesium sulfate and the solvent is distilled off under reduced pressure. 10.23 g (33.92 mmol) of the highly unstable methyl 4-[4-bromo-2-(hydroxymethyl)butyl]benzoate remain, and this residue is immediately dissolved in 100 ml of methylene chloride and added dropwise to a suspension of 10.98 g (50.92 mmol) of pyridinium chlorochromate in 200 ml of methylene chloride. After 3.5 hours, the solution is filtered through silica gel which is washed thoroughly with ether, and the solvent is distilled off. The crude product is purified by flash chromatography on silica gel (0.04-0.063 nm) using methylene chloride/methanol 3/1 as mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][C:6]#[N:7].Br[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[Cl:23].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([C:13]2[C:14]([Cl:23])=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][C:18]=2[Cl:19])[C:6]#[N:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Reaction time: 1 h
Yield: 67 %

Procedure:
To 150 ml of 20% hydrous DMSO were added 6.15 g of 3,4-dichlorobenzyl cyanide, 8.13 g of 4-bromo-3,5-dichloronitrobenzene and 1.50 g of sodium hydroxide. The reaction was allowed to proceed for one hour at temperatures ranging from 60 to 70° C. After completion of the reaction, DMSO was removed, and the residue was dissolved in 50 ml of toluene. The solution was washed with water, dried and concentrated. To the concentrate was added ethyl alcohol to cause crystallization to afford the titled compound in a yield of 67%, m.p.171-172° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1O>O1CCCC1>[CH:43]1[C:44]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[CH:41][C:42]=1[O:33][C:32](=[O:34])[C@H:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Oc1ccc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc2ccccc2c1
Reaction time: 12 h

Procedure:
6.2 g of dicyclohexylcarbodiimide are added to a solution of 7.8 g of tert.-butyoxycarbonyl-L-phenylalanine and 5.3 g of β-naphthol in 50 ml of absolute tetrahydrofurane at 0° C. and the reaction mixture was kept at 4° C. for 12 hours. The dicyclohexylurea which had precipitated was then separated off by filtration and the filtrate was evaporated to dryness in vacuo. The crystalline residue was recrystallised twice from ethyl acetate/cyclohexane and finally from acetonitrile. 8.5 g (73% of theory) of melting point 118°-119° C. were obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:32]=[CH:31][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=5)[N:17]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56](O)=[O:57]>CN(C=O)C>[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56]([NH:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:16]=[C:15]2[C:13]1[NH:12][C:11]2[CH:31]=[CH:32][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][C:10]=2[N:14]=1)=[O:57]
Reactant: O=C(O)C1CC1(F)F
Reactant: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(N)cc45)nc3c2)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.4 %

Procedure:
3-(5-(4-Methylpiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (50 mg, 0.116 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (HOBt) (23.54 mg, 0.174 mmol), EDC (33.4 mg, 0.174 mmol) and sodium bicarbonate (9.76 mg, 0.116 mmol) was added to a solution of 2,2-difluorocyclopropanecarboxylic acid (14.18 mg, 0.116 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (35 mg). 1H NMR: (400 MHz, CD3OD): δ 8.49 (s, 1H), 7.75 (m, 1H), 7.66 (d, 1H, J=8.8 Hz), 7.54 (bs, 1H), 7.06 (m, 2H), 5.84 (dd, 1H, J=2.8 and 9.2 Hz), 3.96 (m, 1H), 3.80 (m, 1H), 3.58 (m, 2H), 2.69 (m, 4H), 2.11 (m, 3H), 1.82 (m, 4H), 1.70 (m, 2H), 1.49 (m, 1H), 1.41 (m, 2H), 0.99 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 535.2.