Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH:13]1[CH:18]2[CH:14]1[CH2:15][N:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17]2)[CH2:8][CH2:9][CH2:10][CH2:11]Br)(C)(C)[CH3:2].BrCCCCl.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH:41]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:42][C:43]([OH:45])=[O:44].N12CCCN=C1CCCCC2>C1(C)C(C)=CC=CC=1>[CH2:19]([N:16]1[CH2:15][CH:14]2[CH:18]([CH:13]2[N:7]([C:6]([O:5][CH2:1][CH3:2])=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][O:44][C:43](=[O:45])[CH2:42][CH:41]([C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[O:33][CH3:32])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:17]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(C)cc1C(CC(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(CCCCBr)C1C2CN(Cc3ccccc3)CC21
Agent: ClCCCBr
Solvent: Cc1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)N(CCCCOC(=O)CC(c1ccccc1)c1cc(C)ccc1OC)C1C2CN(Cc3ccccc3)CC21

Procedure:
The compound, 3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-(4-bromobutyl)-carbamic acid t-butyl ester, 211.5 mg, 0.5 mmole, 1 eq (prepared by reacting boc-protected 3-benzyl-3-azabicylo[3.1.0]hex-6-yl amine, which in turn, was prepared following the procedure of T. F. Braish et al., Synlett, 1996, 1100, with 1-bromo-3-chloropropane) was dissolved in xylene (15 ml). To the reaction mixture, 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid (203 mg, 0.75 mmole, 1.5 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.75 mmole, 1.5 eq) were added. The resulting reaction mixture was refluxed for 2 hrs. Xylene was removed under reduced pressure and the residue was purified by column chromatography by using ethyl acetate in hexane solvent system to yield the compound, 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid 4-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-ethoxy carbonylamino]butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=5[Cl:29])[CH:20]=4)[OH:15])=[CH:4][CH:3]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2c(F)cccc2Cl)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5c(F)cccc5Cl)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-6-fluoro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:12]([O:14]C)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[NH2:2].[CH:16](=O)[CH3:17].C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[CH3:16][C:17]1[N:8]2[CH:7]=[C:6]([C:9]3([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]3)[CH:5]=[CH:4][C:3]2=[N:1][N:2]=1
Reactant: CC=O
Reactant: COC(=O)C1(c2ccc(NN)nc2)CC1
Solvent: Ic1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nnc2ccc(C3(C(=O)O)CC3)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
To a solution of methyl 1-(6-hydrazinopyridin-3-yl)cyclopropanecarboxylate (150 mg, 0.72 mol) in ethanol (3 mL) was added acetaldehyde (33.5 mg, 0.760 mmol) and acetic acid (41 μL, 0.72 mmol). The mixture was stirred at RT for 2 h, and then concentrated to dryness. The residue was dissolved in methylene chloride (3 mL), and iodobenzene diacetate (256 mg, 0.796 mmol) was added dropwise. The reaction mixture was stirred at RT overnight. The reaction solution was concentrated to dryness. The residue was purified through silica gel chromatograph using 10% MeOH in CH2Cl2 to afford the desired compound (50 mg, 30%). Analytical LCMS: (M+H)+=218.0.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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>[F:9][C:10]([F:24])([F:25])[C:11]1[CH:12]=[C:13]([C:2]2[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1ccc(Br)o1
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: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)o1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of 5-bromofuran-2-carbaldehyde (2.54 g, 14.5 mmol), [3,5-bis(trifluoromethyl)phenyl]boronic acid (3.93 g, 15.2 mmol), tetrakis(triphenylphosphine)palladium (0.59 g, 0.51 mmol) and 2M sodium carbonate solution (36 mL, 72 mmol) in THF (150 ml) was stirred under an argon atmosphere for 16 hr. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate filtration, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate), and the obtained solid was disrupted in hexane to give the title compound (4.46 g, yield>99%) as a pale-yellow solid. LC/MS (ESI+) m/z: 309 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(CC)CC)C.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23]>ClCCl.O>[C:22]([O:25][CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[C:5]([C:6]#[N:7])=[CH:8][C:9]=1[CH3:10])=[O:28])(=[O:24])[CH3:23]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(C#N)c(C(F)(F)F)cc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1cc(C(F)(F)F)c(C#N)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 4-amino-5-methyl-2-(trifluoromethyl)benzonitrile (Intermediate 60, 300 mg, 1.50 mmol) and triethylamine (0.230 mL, 1.65 mmol) in dichloromethane (8 mL) was added 2-chloro-2-oxoethyl acetate (0.161 mL, 1.50 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. Reaction mixture was diluted with DCM (100 ml) and water (50 ml) and aqueous was extracted with DCM (100 ml). Organics were combined, passed through a phase separator and concentrated to afford 452 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>O>[CH2:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:2]=[CH2:3]
Reactant: CCCCCBr
Reactant: C=CCNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCN(CCCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
N-Allylphenylamine (1.95 g, 14.7 mmol) and bromopentane (2.22 g, 14.7 mmol) were stirred at 80° C. for 16 hours. After cooled to room temperature, the mixture was treated with a solution of sodium hydroxide(714 mg, 17.9 mmol) in water (1.5 ml), stirred for 30 minutes and extracted with ether (80 ml). The extract was dried over potassium carbonate, filterd and concentrated in vacuum. The residue was chromatographed on silica gel to give N-allyl-N-pentylphenylamine (1.68 g) in 56% yield as a colorless oil.
Reaction SMILES: C([NH:3][C@@H:4]1[C:20](=[O:21])[N:6]2[CH:7]([C:17]([OH:19])=[O:18])[C:8]([CH2:11][C:12]3[S:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][S:10][C@H:5]12)=O.[ClH:22].O>O1CCOCC1>[ClH:22].[NH2:3][C@@H:4]1[C:20](=[O:21])[N:6]2[CH:7]([C:17]([OH:19])=[O:18])[C:8]([CH2:11][C:12]3[S:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][S:10][C@H:5]12
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: N[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cccs3)=CS[C@H]12
Reaction time: 72 h

Procedure:
A solution of 0.975 g of 7β-formylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid in 10 ml of dioxane is treated with 1.2 ml of a 1:1-mixture of concentrated hydrochloric acid and water and left to stand for 3 days at room temperature. The faintly yellow reaction solution is lyophilised to yield the 7β-amino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid hydrochloride, which according to thin-layer chromatogram which contains only traces of the starting material; thin-layer chromatogram (silica gel; detection with iodine vapour); Rf = 0.40 (system: n-butanol/acetic acid/water 67:10:23; starting material Rf = 0.56), Rf = 0.51 (system: n-butanol/pyridine/acetic acid/water 40:24:6:30; starting material Rf = 0.60), and Rf = 0.43 (system: ethyl acetate/n-butanol/pyridine/acetic acid/water 42:21:21:6:10; starting material Rf = 0.64).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH:3]=[CH:4][CH3:5].[C:9](OC)(=[O:14])/C=C/CC.C(OC)(=O)/C=C\CC.C(OC)(=O)CCC=C>>[CH3:9][O:14][CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: CC=CCC(=O)OC
Reactant: CC/C=C/C(=O)OC
Agent: C=CCCC(=O)OC
Agent: CC/C=C\C(=O)OC
Product: CCC(CC(=O)OC)OC
Yield: 22 %

Procedure:
10 g/hour of methyl 3-methoxyvalerate were pumped into an evaporator and passed from there, in gaseous form together with 3 l of nitrogen, at 300° C., over 5 g of an Al2O3 catalyst. The gaseous reaction products were condensed, weighed and analysed by gas chromatography. In the course of a reaction time of 6 hours, 49 g of reacted mixture consisting of 37% of methyl 3-pentenoate, 33% of methyl 2-trans-pentenoate, 5% of methyl 2-cis-pentenoate, 1% of methyl 4-pentenoate and 22% of unconverted methyl 3-methoxyvalerate were obtained. The ratio of 3-pentenoates to 2-pentenoates was accordingly 1:1.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([O-:16])=[O:15])[CH3:12].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([O:16][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][Cl:10])=[O:15])[CH3:12]
Reactant: CCCCC(CC)C(=O)[O-]
Agent: ClCc1ccccc1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CC)C(=O)OCc1ccccc1CCl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a glass-made three-necked flask (volume: 100 ml) with a condenser, 8.8 g (50 mmol) of α,α′-dichloro-o-xylene, 4.0 g of N,N-dimethylformamide and 2.1 g (12.5 mmol) of sodium 2-ethylhexanoate were added. After the mixture was heated and stirred at 120° C. for one hour, the reaction mixture was analyzed by the gas chromatography. The conversion of α,α′-dichloro-o-xylene, the yield of [2-(chloromethyl)phenyl]methyl 2-ethylhexanoate (based on sodium 2-ethylhexanoate), and the molar ratio of the [2-(chloromethyl)phenyl]methyl 2-ethylhexanoate produced to the diester compound as a by-product are shown in Table 1 below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[C:12]([C:17]1[CH2:18][S:19][CH2:20][CH2:21][N:22]=1)(OCC)=[O:13].CCCCCC>CCOCC.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:17]3=[CH:18][S:19][CH2:20][CH2:21][N:22]3[C:9]2=[O:10])=[C:4]([F:11])[CH:3]=1
Reactant: CCOC(=O)C1=NCCSC1
Reactant: O=C=Nc1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C1C2=CSCCN2C(=O)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
A solution of 8.6 g of 4-chloro-2-fluorophenylisocyanate in 20 ml of anhydrous ether was added dropwise to a mixture of 9.8 g of crude 3-carbethoxy-5,6-dihydro-1,4-thiazine and 10 drops of triethylamine in 20 ml of ether. After the addition, 30 ml of hexane was added dropwise in 20 min. The solution was stirred at room temperature for 3 hrs. The solution was concentrated in vacuo to remove solvent. The resulting oil was crystallized from ether to give 10 g of 2-(4-chloro-2-fluorophenyl)-5,6-dihydro-1H-imidazo[5,1-c][1,4]thiazine-1,3(2H)-dione, m.p. 117.5°-120.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH3:23])[CH2:10][C:11]3[N:12]([C:13](=O)[NH:14][C:15]=3[C:16]#[C:17]C(O)(C)C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-:24].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(Cl)cccc2-n2c(c(C#CC(C)(C)O)[nH]c2=O)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
660 mg (2 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-one was heated to boiling under reflux overnight with 80 mg of sodium hydroxide in 10 ml of toluene. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution was washed twice with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 200°-201°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:7]=[CH:6][N:5]2[C:16]=1[CH2:17][C:18]1[CH:37]=[CH:36][C:21]2/[C:22](=[C:32](/[CH3:35])\[C:33]#[N:34])/[C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[O:25][CH2:26][C:20]=2[CH:19]=1.O>C1COCC1>[C:10]([C:8]1[CH:7]=[CH:6][N:5]2[C:16]([CH2:17][C:18]3[CH:37]=[CH:36][C:21]4/[C:22](=[C:32](/[CH3:35])\[C:33]#[N:34])/[C:23]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=5[O:25][CH2:26][C:20]=4[CH:19]=3)=[C:2]([CH3:1])[N:3]=[C:4]2[CH:9]=1)#[CH:11]
Reactant: C/C(C#N)=C1/c2ccc(Cc3c(C)nc4cc(C#C[Si](C)(C)C)ccn34)cc2COc2cc(F)ccc21
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccn2c(Cc3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
[step 2] (E)-2-{8-[(2-methyl-7-trimethylsilylethynylimidazo[1,2-a]pyridin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (340 mg, 0.62 mmol) obtained in step 1 was dissolved in THF (3 ml), 1 mmol/L tetrabutylammonium fluoride THF solution (0.81 ml, 0.81 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane/ethyl acetate=1/2 v/v) to give the title compound (152 mg, 53%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[CH:3]=[N:2]1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][C:12]=1[CH2:24][S:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[C:26]([S:25][CH2:24][C:12]1[CH:13]=[C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=[CH:16][C:11]=1[CH2:10][N:1]1[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[CH:3]=[N:2]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1CBr
Reactant: N#CCc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cn1cc(CC#N)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(1H-Pyrazol-4-yl)-acetonitrile (0.19 g, 1.77 mmol) and N-(4-bromomethyl-3-tert-butylsulfanylmethyl-phenyl)-2,2-dimethyl-propionamide (0.20 g, 0.55 mmol) were combined in MeCN. Cesium carbonate (0.95 g, 2.90 mmol) was added, and the reaction was stirred for 45 minutes at room temperature. The mixture was worked-up and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([C:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)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: [Na+]
Solvent: COCCOC
Product: COc1ccc(Cn2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (250.0 mg, 0.5099 mmol, prepared in Example 7, step B), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (315.3 mg, 1.020 mmol), tetrakis(triphenylphosphine)palladium (117.8 mg, 0.1020 mmol), 1M Na2CO3 (1.275 ml, 2.550 mmol) and DME (25 mL). The reaction mixture was stirred at 100° C. overnight. The reaction was cooled to room temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (273.3 mg, 98%). LRMS (APCI pos): >99% purity, 254 nm, m/e 546 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:19]1(C2CCC(=COC)CC2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[CH3:34][C:35]([CH3:37])=O.Cl.[OH2:39]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:20][CH2:21][CH:22]([CH:2]2[CH2:7][CH2:37][CH:35]([CH:34]=[O:39])[CH2:4][CH2:3]2)[CH2:23][CH2:24]1
Reactant: O
Reactant: CC(C)=O
Reactant: CCCCCC1CCC(c2ccc(C3(C4CCC(=COC)CC4)CCCCC3)c(F)c2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(C=O)CC4)CC3)c(F)c2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The compound (8) (23.28 g) and acetone (350 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 50° C. 6N-Hydrochloric acid (150 ml) was added dropwise thereto in the temperature range of 40° C. to 50° C., and the mixture was stirred for 3 hours, and then cooled slowly to room temperature. Water (700 ml) and toluene (700 ml) were added and mixed thereto. Then, the mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by means of recrystallization from a mixed solvent of toluene and heptane (toluene: heptane=1:1 by volume), and dried, giving 18.33 g of 4′-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-bicyclohexyl-4-carbaldehyde (9). The yield based on the compound (8) was 81.3%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[CH2:36]([O:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][C:44]([O:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:45])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
To a solution of 288 mg (0.74 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 4 ml of dichloromethane, 0.21 ml (1.48 mmol) of triethylamine and 0.1 ml (0.89 mmol) of benzyloxycarbonyl chloride were added, and the resulting mixture was stirred at room temperature for one day. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic phases were combined, washed with 10% aqueous citric acid solution and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=60:1) to obtain 284 mg of 2-benzyloxycarbonylamino-3-((3-methyl-4-oxo-1-phenyl-1,3,8,-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 73%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[NH:10][N:9]=2)=[C:4]2[NH:18][CH:19]=[C:20]([C:21](=[O:41])[C:22](=[O:40])[N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:32]=[N:31][N:30]=4)[CH2:25][CH2:24]3)[C:3]=12.O.[OH-].[Li+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[NH:10][N:9]=2)=[C:4]2[NH:18][CH:19]=[C:20]([C:21](=[O:41])[C:22](=[O:40])[N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:33]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:32]=[N:31][N:30]=4)[CH2:25][CH2:24]3)[C:3]=12
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
To a rb flask containing ethyl 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate (0.058 g, 0.10 mmol) in DMF (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.044 g, 1.05 mmol). The mixture was heated to 100° C. for 21.5 h. The mixture was cooled to rt, and HCl was added to PH=1. Solids precipitated out of solution, and were collected by filtration to give the title compound as a yellow solid (0.03 g). LCMS: m/e 531.15 (M+H)+, ret time 2.10 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 14.37 (s, 1H) 13.58 (s, 1H) 12.23 (s, 1H) 8.21-8.42 (m, 2H) 7.52-7.77 (m, 5H) 7.35 (s, 1H) 3.08-3.76 (m, 8H).