Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([N:42]2[CH2:47][CH2:46][CH:45]([C:48]([O:50]C)=[O:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].C(O)C(F)(F)F.O.[OH-].[Li+]>O.CO>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:42]4[CH2:43][CH2:44][CH:45]([C:48]([OH:50])=[O:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21].[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]
Reactant: COC(=O)C1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: OCC(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCC(C(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (30.0 mg, 0.0661 mmol), methyl 1-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)piperidine-4-carboxylate (Compound 256A, 20.0 mg, 0.0659 mmol), trifluoroacetic acid (15.2 uL, 0.198 mmol) and trifluoroethanol (1.0 mL, 14 mmol) was irradiated in microwave reactor at 105° C. for 30 minutes. The crude mixture was concentrated to dryness, taken up in THF (0.1 mL), methanol (0.1 mL) and treated with a solution of lithium hydroxide monohydrate (27.7 mg, 0.659 mmol) in water (0.1 mL). The mixture was stirred at room temperature overnight. The crude was purified by MDP to obtain the title compound as a trifluoroacetic acid salt (7.2 mg, 15.5% yield). 1H NMR (400 MHz, DMSO-d6) δ=1.29 (t, J=7.1 Hz, 6 H), 1.83-1.97 (m, 2 H), 2.03-2.14 (m, 2 H), 2.46-2.57 (m, 1 H), 2.93 (t, J=10.5 Hz, 2 H), 3.18 (s, 3 H), 3.34 (d, J+ 18.7 Hz, 2 H), 3.40 (d, J=12.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:35]5[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-4), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (312 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (373 mg, 73%) as a colorless foamy substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.ClC(Cl)(Cl)C(=N)O[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1CCCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([C:14]([O:16][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-2-methylalanine (1 g, 4.21 mmol) in DCM (10 ml anhydrous), cyclohexane (10 ml) at 0° C. under nitrogen was added boron trifluoride diethyl etherate (7.7 μl, catalytic). tert-Butyl 2,2,2-trichloroacetimidate (1.51 ml, 8.43 mmol) in cyclohexane (10 ml) was then added slowly over 30 minutes before allowing to warm to RT. Reaction was allowed to stir at RT for 16 hours. To the crude reaction mixture was added 190 mg of NaHCO3 and the reaction filtered. The mother liquors were concentrated in vacuo. The crude extract was purified by column chromatography (10% EtOAc in heptane) to yield the desired product (0.863 g, 70% yield).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[OH:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][OH:18])[CH:25]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: OCc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Yield: 82.3 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (1.0 g), 3-hydroxymethylphenylboronic acid (0.497 g, 1.05 eq), triphenylphosphine (65.3 mg, 0.08 eq) and tetrabutylammonium bromide (50.2 mg, 0.05 eq) were dissolved in tetrahydrofuran (12 mL). Tripotassium phosphate (1.98 g, 3 eq) dissolved in water (5 mL) was added, and palladium acetate (14.0 mg) was added under a nitrogen atmosphere. The mixture was stirred under heated reflux for 8 hr. To the reaction mixture was added ethyl acetate (12 mL), and the insoluble material was removed. The filtrate was partitioned, and the organic layer was washed with 10% brine. After treatment with activated carbon, ethanol was added, and the mixture was concentrated is under reduced pressure. To the obtained oil was added ethyl acetate (3 mL), and the oil was dissolved. n-Heptane (10 mL) was added to allow crystallization. The obtained crystals were collected by filtration, and dried to give the title compound (0.893 g).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[CH:22][C:21]3[C:20](=[O:24])[CH2:19][CH2:18][C:17]([CH3:26])([CH3:25])[C:16]=3[CH:15]=2)=[CH:8][C:7]=1[F:27])C.ClCCl.C1(N)CC1.C([BH3-])#N.[Na+]>CCCCCC.C(OCC)(=O)C.C(O)(=O)C.C(#N)C>[F:27][C:7]1[CH:8]=[C:9]([C:12]#[C:13][C:14]2[CH:23]=[CH:22][C:21]3[C:20](=[O:24])[CH2:19][CH2:18][C:17]([CH3:26])([CH3:25])[C:16]=3[CH:15]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F
Agent: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(CC(=O)O)c(F)c3)cc21

Procedure:
Following general procedure G and using [2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)phenyl]acetic acid ethyl ester (Compound 14, 0.258 g, 0.68 mmol), dichloromethane (4 mL), acetonitrile(2 mL), cyclopropyl amine(1 mL, 14.45 mmol), acetic acid (1 mL)and sodium cyanoborohydride (0.266 g, 4.23 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 16-20-25% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow oil (0.21 g, 73%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][N:5]2[CH:8]=[N:9][CH:10]=[C:4]2[CH:3]1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1.[CH3:26][N:27](C)C=O>[C-]#N.[Zn+2].[C-]#N.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]>[CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][N:5]2[CH:8]=[N:9][CH:10]=[C:4]2[CH:3]1[C:11]1[CH:16]=[CH:15][C:14]([C:26]#[N:27])=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC1(C)CCn2cncc2C1c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: CC1(C)CCn2cncc2C1c1ccc(C#N)cc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
1.03 mmol of trifluoromethanesulphonic acid 4-(7,7-dimethyl-5,6,7,8-tetrahydroimidazo-[1,5-a]pyridin-8-yl)phenyl ester and 2.06 mmol of zinc(II) cyanide are introduced under argon in 10 ml of absolute N,N-dimethylformamide. The reaction mixture is admixed with 0.05 mmol of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and stirred at 120° C. for 20 hours. The reaction mixture is poured into ice-water and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried with magnesium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60 F) as a pale pink solid. Rf=0.17 (dichloromethane/ammonia (2M in EtOH) 97:3), Rf=5.40 (Gradient I).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: [H][H]
Reactant: FC(F)(F)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccccc1CC1c2ccccc2CCc2ccccc21
Reaction time: 17 h

Procedure:
Add 5-(2-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.16 g, 0.45 mmol) to a mixture of 10% Pd/C (0.075 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (2.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrated the filtrate to give the title product. MS (m/e): 352 (M+). Analysis for C23H19F3: Calcd: C, 78.39 H, 5.43. Found: C, 78.84 H, 5.11.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].Br[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([N:19]=[CH:20][N:21]=2)[CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.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]>[N:21]1[CH:20]=[N:19][N:17]2[CH:18]=[C:13]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH:1]=[O:2])[CH:14]=[CH:15][C:16]=12
Reactant: Brc1ccc2ncnn2c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccc(-c2ccc3ncnn3c2)c1
Yield: 86 %

Procedure:
To a mixture of 3-formylphenylboronic acid (21.41 g, 143 mmol), 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (28.27 g, 143 mmol) in DMSO (600 mL) and water (50 mL) was added Pd(dppf)Cl2 (5.83 g, 7.14 mmol) and Cs2CO3 (116 g, 357 mmol). The reaction temperature reached 45° C. after the addition. HPLC showed that starting materials were consumed after 15 min. The reaction was diluted with water (400 mL). The black precipitate was collected by filtration and dissolved in DCM (300 mL), and washed with brine (200 mL). The aqueous layer was back extracted with DCM (100 mL). The combined organic layers were filtered through a Celite pad and the filtrate was concentrated to give a black solid mixture. The product was recrystallized in methanol to give 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)benzaldehyde (27.4 g, 123 mmol, 86% yield) as a pale grey solid: m/z=224.0 [M+1]; 1H NMR (400 MHz, DMSO-D6) δ ppm 7.74 (t, J=7.68 Hz, 1H), 7.91-8.02 (m, 2H), 8.11 (dd, J=9.19, 1.89 Hz, 1H), 8.17 (d, J=7.81 Hz, 1H), 8.36 (s, 1H), 8.57 (s, 1H), 9.45 (s, 1H), 10.11 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH2:14])[CH:3]=1.NC1C(C#N)=C(OC(C)C)N=C(N[C:29](=[O:41])[CH2:30][C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=2[O:39][CH3:40])C=1.O.[OH-].[Na+]>N1C=CC=CC=1.C(Cl)Cl.C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][C:29](=[O:41])[CH2:30][C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=2[O:39][CH3:40])[CH:3]=1
Reactant: COc1ccc(OC)c(CC(=O)Nc2cc(N)c(C#N)c(OC(C)C)n2)c1
Reactant: N#Cc1c(N)cc(N)nc1OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CC(=O)Nc2cc(N)c(C#N)c(OCCO)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.4 %

Procedure:
To a solution of 39 mg (0.20 mmol) of 4,6-diamino-2-(2-hydroxy-ethoxy)-nicotinonitrile in 0.2 mL of pyridine and 1 mL of CH2Cl2 was added 75 mg (0.39 mmol) of 2,5-dimethoxyphenylacetyl chloride (Example 60B). The mixture was stirred at ambient temperature for 1 hours then 1 mL of water was added, and the solvents were removed under reduced pressure. The residue was taken up in 10 mL of ethyl acetate, then extracted with 1M HCl(aq.) (2×5 mL), saturated NaHCO3(aq.) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was dissolved in 1:1 DMSO:methanol and purified by reversed phase HPLC, eluting with a 5-100% CH3CN gradient in 0.01M NH4OAc(aq.) to provide a white solid. This was dissolved in 1 mL of THF, and 1 mL of 2M NaOH(aq.) was added. The solution was stirred at ambient temperature for 18 hours then concentrated under reduced pressure. The residue was taken up in 10 mL of ethyl acetate, then extracted with water (1×3 mL), 2M NaOH(aq.) (1×3 mL), and brine (1×3 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to a white solid. This was recrystallized from 1 mL of methanol to provide 4 mg (5%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.10 (s, 11H), 7.13 (s, 1H), 6.90 (m, 3H), 6.79 (m, 2H), 4.81 (t, 1H, J=5.4 Hz), 4.31 (m, 2H), 3.69 (m, 8H), 3.66 (s, 2H); MS (ESI) m/e=329 (M−EtOH+H)+, 373 (M+H)+, 371 (M−H)−.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:45]1[C:49]([C:50]2[CH:51]=[C:52]([Cl:59])[C:53]([F:58])=[C:54]([CH:57]=2)[CH2:55][NH2:56])=[N:48][N:47]=[N:46]1)(C)(C)C.ClC1C(F)=C(C=C(C2N=NNN=2)C=1)CN.CCN(C(C)C)C(C)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:56][CH2:55][C:54]1[CH:57]=[C:50]([C:49]2[N:48]=[N:47][NH:46][N:45]=2)[CH:51]=[C:52]([Cl:59])[C:53]=1[F:58])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: CC(C)(C)n1nnnc1-c1cc(Cl)c(F)c(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1cc(-c2nn[nH]n2)cc(Cl)c1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cc(-c2nn[nH]n2)cc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-boc-trans-4-fluoro-L-proline (107 mg, 0.46 mmol) and HATU (260 mg, 0.69 mmol) in DMF (2 mL) was added a 1:2 mixture of 5-(1-tert-butyl-1H-tetrazol-5-yl)-3-chloro-2-fluoro-benzylamine and 3-chloro-2-fluoro-5-(2H-tetrazol-5-yl)-benzylamine (preparation described in Part C, 220 mg, 0.46 mmol) and DIPEA (319 μl, 1.8 mmol) and the resulting solution was stirred overnight at ambient temperature. The reaction mixture was purified without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 ml/min) to give the title compounds (2S,4R)-2-[3-chloro-2-fluoro-5-(2H-tetrazol-5-yl)-benzylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester: MS (LC-MS): 343.0 [M−100]+; tR (HPLC conditions c): 3.27 min and (2S,4R)-2-[5-(1-tert-butyl-1H-tetrazol-5-yl)-3-chloro-2-fluoro-benzylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester: MS (LC-MS): 499.0 [M]+; tR (HPLC conditions c): 4.02 min.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH:35]1[CH2:49][CH2:48][CH2:47][C@H:36]1[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].Cl.C(N(CC)CC)C>C1COCC1.C(Cl)(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:35]1[CH2:49][CH2:48][CH2:47][C@H:36]1[C:37]([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
Boc-(D)Phe-Pro-OH was produced by first preparing the dipeptide benzyl ester and then removing the ester by catalytic hydrogenation. Boc-(D)Phe-OH (10.0 g, 37.7 mmoles) was dissolved in 50 mL of THF and N-methylmorpholine (4.14 mL, 37.7 mmoles) was added. The solution was cooled to -20° and isobutyl chloroformate (4.90 mL, 37.7 mmoles) was added. After 5 min, H-Pro-OBzl.HCl (9.11 g, 37.7 mmoles), dissolved in 50 mL of chloroform and cooled to -20°, was added. Triethylamine (5.25 mL, 37.7 mmoles) was added and the mixture was stirred for 1 h at -20° and 2 h at room temperature. The reaction mixture was filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate and was washed with 0.2N hydrochloric acid, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to yield 15.2 g of Boc-(D)Phe-Pro-OBzl as an oil. The benzyl ester (15.2 g) was dissolved in 100 mL of methanol and it was hydrogenated at an initial pressure of 40 psi on a Parr apparatus in the presence of 0.5 g of 10% Pd/C. The reaction solution was filtered through Celite™ and evaporated to yield a solid. This solid material was isolated and was washed with ethyl acetate and then by ether to yield 10.0 g of the desired product (mp 176.5°-177°).
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[Br:9][C:10]1[CH:11]=[C:12](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[N:14][CH:15]=1.[CH3:22]COC(C)=O>CS(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:22][CH:17]2[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[N:14][CH:15]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)/C=C/c1cncc(Br)c1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COC(=O)C1CC1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
DMSO (20 ml) was added slowly to a mixture of sodium hydride (0.215 g, 5.37 mmol) and trimethylsulfoxonium iodide (1.227 g, 5.58 mmol). The mixture was stirred at room temperature for 15 min, and then (E)-methyl 3-(5-bromopyridin-3-yl)acrylate (1 g, 4.13 mmol) in DMSO (8 ml) was added. The reaction mixture was stirred at room temperature for 3 min. Ice water and EtOAc were added. The organic layer was washed with water and brine. The aqueous layer was extracted with EtOAc twice. The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified via flash column (EtOAc/Heptane=0-30%, v/v) to give methyl 2-(5-bromopyridin-3-yl)cyclopropanecarboxylate (257 mg, 1.004 mmol, 24% yield). ESI-MS m/z: 358[M+1]+; 1H NMR (CDCl3, 400 MHz); 1.33-1.38 (m, 1H), 1.66-1.71 (m, 1H), 1.94-1.98 (m, 1H), 2.49-2.54 (m, 1H), 3.75 (s, 3H), 7.51 (t, J=2.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.53 (t, J=2.0 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)=[O:4].[CH2:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:24]1([CH2:23][N:30]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)=[O:4])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(CBr)c1cccc(OCCCOCc2ccccc2)c1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CN(Cc1ccccc1)Cc1ccccc1)c1cccc(OCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-bromo-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone (13.17 g), dibenzylamine (6.4 g) and dichloromethane (25 mL) was added a solution of sodium carbonate (7.6 g) in water (50 mL). The reaction mixture was stirred at ambient temperature overnight. The organic layer was separated and concentrated to a minimum and tert-butyl methyl ether was added. The organic layer was washed with dilute acetic acid (4 times) and 0.1N sodium hydroxide once and brine once. The organic solution was concentrated to dryness. The oil was washed with methanol and purified by chromatography to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:12])(=O)[CH2:9][CH3:10].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:35][C:36]1[C:44]([O:45][C@@H:46]2[CH2:51][CH2:50][C@H:49]([NH2:52])[CH2:48][CH2:47]2)=[CH:43][C:42]([CH3:53])=[C:41]2[C:37]=1[CH:38]=[N:39][NH:40]2>CN(C)C=O>[CH3:35][C:36]1[C:44]([O:45][C@@H:46]2[CH2:51][CH2:50][C@H:49]([NH:52][C:8](=[O:12])[CH2:9][CH3:10])[CH2:48][CH2:47]2)=[CH:43][C:42]([CH3:53])=[C:41]2[C:37]=1[CH:38]=[N:39][NH:40]2
Reactant: CCC(=O)O
Reactant: Cc1c(O[C@H]2CC[C@@H](N)CC2)cc(C)c2[nH]ncc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N[C@H]1CC[C@@H](Oc2cc(C)c3[nH]ncc3c2C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 110.1 %

Procedure:
Triethylamine (108 μl, 0.775 mmol), propionic acid (32 μl, 0.429 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (83 mg, 0.433 mmol) and 1-hydroxybenzotriazole (58 mg, 0.429 mmol) were added in that order to a dimethylformamide solution (2 ml) of the cis-4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.386 mmol) obtained in Example 658, and the resulting mixture was stirred at room temperature for 20 hours. The reaction was terminated by the addition of water, followed by extraction with ethyl acetate-toluene (1:1). The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was purified by a silica gel chromatography (eluent: chloroform/methanol=100:2) to obtain cis-N-{4-[(4,7-dimethyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide (134 mg, 100%).