Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:40][O:41][C@@H:42]1[CH2:46][NH:45][CH2:44][C@H:43]1[NH2:47].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCCCCC.CC(O)C>[NH2:47][C@H:43]1[C@H:42]([O:41][CH3:40])[CH2:46][N:45]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=3)=[O:16])=[CH:4][N:3]=2)[CH2:44]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Reactant: CO[C@@H]1CNC[C@H]1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncc(F)c2)C[C@H]1N
Temperature: 110 °C
Reaction time: 40 h

Procedure:
2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide (Stage 266.1, 70 mg, 0.160 mmol) and DIPEA (0.196 mL, 1.121 mmol) were added to a vial containing iPrOH (1 mL) and trans-4-methoxypyrrolidin-3-amine dihydrochloride (Stage 284.1, 32.5 mg, 0.168 mmol) was added under argon atmosphere. The RM was stirred at 110° C. for 40 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 14). Fractions containing product were treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The aq. phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a residue which was suspended in DCM/n-hexane. The obtained solid was filtered off, washed with n-hexane and dried to afford the title product as a white solid. HPLC (Condition 10) tR=6.11 min, UPLC-MS (Condition 3) tR=0.86 min, m/z=508.2/510.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63 (br. s, 2H) 2.83-2.90 (m, 1H) 3.03-3.11 (m, 1H) 3.20-3.22 (m, 3H) 3.27-3.35 (m, 2H) 3.48-3.56 (m, 2H) 7.34 (d, J=8.21 Hz, 2H) 7.80-7.90 (m, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.75-8.80 (m, 1H) 10.18 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-])=O>CO.[Ni]>[CH:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7][N:8]=1
Reactant: O=[N+]([O-])c1cccc2cnccc12
Agent: [Ni]
Solvent: CO
Product: Nc1cccc2cnccc12
Yield: 97.8 %

Procedure:
5-Nitroisoquinoline (100.3 g, 0.576 mol) was dissolved in MeOH and shaken with Raney nickel (10 g) on a Parr apparatus under a H2 atmosphere (50 psi) for 21 hours. The MeOH was removed in vacuo, the residue dissolved in chloroform (150 mL), and filtered into 600 mL petroleum ether. The solid was collected by filtration. This trituration procedure was repeated several times to give 81.24 g (98%) of the desired product.
Reaction SMILES: O[C:2]1[C:3]2[S:10][C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:2]1[C:3]2[S:10][C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(-c2cc3ncnc(O)c3s2)c1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(-c2cc3ncnc(Cl)c3s2)c1
Temperature: 100 °C

Procedure:
The hydroxy compound prepared in Step 1 was treated with phosphorous oxychloride (150 mL) and diisopropylethylamine (2 mL). The mixture was then heated at 100° C. for 4 hours. The solvents were evaporated under reduced pressure and the residue was carefully treated with ice water. The resulting solid was filtered off and crystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C@H:24]2[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]2)[CH2:20][CH2:19]1>N1C=CC=CC=1>[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][C@H:18]1[CH2:19][CH2:20][C@H:21]([C@H:24]2[CH2:29][CH2:28][C@H:27]([O:30][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:26][CH2:25]2)[CH2:22][CH2:23]1
Reactant: O[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: O=C(O[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1.7 g of 4-fluorobenzoyl chloride in 5 ml of pyridine is treated with 2.8 g of trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]-cyclohexanol (prepared according to Example 3) and stirred at room temperature for 12 hours. Thereafter, the reaction mixture is poured on to ice-water and extracted three times with diethyl ether. The organic phases are washed in succession with saturated sodium hydrogen carbonate solution, with 10 percent hydrochloric acid, with saturated sodium hydrogen carbonate solution and with water, then dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the resulting crude product-on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gives 4-fluorobenzoic acid trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]-cyclohexyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:24]1[CH:28]=[C:27]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[CH:26]=[N:25]1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:30]([CH2:29][C:27]1[CH:26]=[N:25][N:24]([CH2:22][CH3:23])[CH:28]=1)[C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:38])[CH3:39])=[CH:33][CH:32]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 71.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as starting materials, 5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) was obtained.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][C:22]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[CH:14][C:13]=1[O:42][CH3:43])(=[O:10])=[O:9])[CH2:5][CH2:6][CH3:7].O.C(O)(=O)C>O1CCCC1.CO.O>[CH2:4]([S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][C:22]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[CH:14][C:13]=1[O:42][CH3:43])(=[O:9])=[O:10])[CH2:5][CH2:6][CH3:7]
Reactant: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)cc2OCc2cccc(F)c2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)O)cc2OCc2cccc(F)c2)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.3 %

Procedure:
0.4 g (1 mmol) of lithium hydroxide monohydrate is added to a solution of 0.3 g (0.5 mmol) of corresponding methyl 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-3-(3-fluorobenzyloxy)phenyl]propanoate in 10 ml of a tetrahydrofuran/methanol/water mixture (5/1/1). The reaction medium is stirred at room temperature for 15 hours, treated with water, acidified to pH 4 with acetic acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on a column of silica eluted with a 97/3 dichloromethane/methanol mixture. 0.23 g (77%) of 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-3-(3-fluorobenzyloxy)phenyl]propanoic acid is obtained in the form of a colorless oil.
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:25]=1[O:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:38])[NH2:37])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[C:36]([O:35][CH2:34][C@H:31]1[NH:30][CH2:29][C@@H:28]([CH2:27][O:26][C:25]2[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:24]=2[NH:23][C:5](=[O:7])[C@H:4]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[NH:1][C:36]([O:35][CH3:34])=[O:38])[O:33][CH2:32]1)(=[O:38])[NH2:37]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2c(N)cccc2F)OC[C@H]1COC(N)=O
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)c1cccc(F)c1
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN[C@H](COC(N)=O)CO1)[C@@H](c1ccc(F)cc1)c1cccc(F)c1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 5 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=617 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([O-])=[O:23].[Na+]>CCOCC.O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COc1cccc(C(=O)[O-])c1
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1cccc(C(=O)c2ccc(C(F)(F)F)cc2)c1
Reaction time: 64 h
Yield: 55 %

Procedure:
This is carried out under nitrogen at -60° C. 0.29 mol (65 g) of para-bromo-trifluoromethylbenzene dissolved in 100 ml of anhydrous ether is added dropwise to 0.29 mol of butyl-lithium in solution in ether (1.48 mol/liter). The reaction is followed by gas phase chromatography; when there is no longer any remaining para-bromo-trifluoromethylbenzene, 0.29 mol (50.5 g) of sodium 3-methoxybenzoate is added. The mixture is allowed to return to ambient temperature. After stirring for 64 hours, it is hydrolysed in iced water. The batch is extracted with ether. The ether phase is dried, decolorised and concentrated. 45 g of a product which has been recrystallised from a mixture of isopropyl ether and hexane are obtained. Melting point 69° C. Yield: 55%.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2([OH:16])[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.Cl>C(O)CCC>[CH2:8]([O:16][C:2]1[C:3]([C:8]2([OH:16])[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1)[CH2:13][CH2:12][CH3:11]
Reactant: OC1(c2nccnc2Cl)CN2CCC1CC2
Agent: Cl
Solvent: CCCCO
Product: CCCCOc1nccnc1C1(O)CN2CCC1CC2
Temperature: 60 °C
Yield: 12 %

Procedure:
To a solution of 40 ml of butanol that had reacted with 0.5 g of Na (0.022 mol) was added 0.78 g of (7) (0.033 mol). The reaction was heated to 60° C. for 1.5 h and the cooled reaction treated with 6 ml of 5 N HCl. The butanol was azeotroped off with water, the residue made basic with saturated aqueous K2CO3, and the mixture extracted 3× with 25 ml of CH2Cl2. The extracts were washed with brine, dried, and the solvent evaporated to give a yellow solid that was purified by radial chromatography eluting with 5% ethanol-0.5% NH4OH-CHCl3 to give 0.55 g of (18) as a yellowish solid. Recrystallization from ether gave a white solid, mp 107°-108° C. NMR ppm (CDCl3) 1.0 (3H, t), 1.15 (1H, m), 1.35-1.6 (4H, m), 1.85 (2H, m), 2.25 (1H, m), 2.37 (1H, bs), 2.75 (1H, m), 2.82-3.0 (3H, m), 3.05 (1H, m), 3.95 (1H, s), 4.2 (1H, d), 4.45 (2H, q), 8.0 (1H, d), 8.12 (1H, d). Anal. C15H23N3O2 requires C: 64.96; H: 8.36; N: 15.15%. Found C: 65.21; H: 8.11; N: 15.25%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])(O)=O.[Na+]>CN(C)C=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:17][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)[CH3:26]
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(N3CCCC3)cc(C)nc2c1
Reaction time: 0.5 h
Yield: 60154.1 %

Procedure:
To a cooled (0° C.) solution of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol (797 mg, 3.49 mmol) in dimethylformamide (13 mL) was added sodium hydride (ca. 60% in oil, 168 mg, 4.19 mmol). After 30 min at 0° C., ethyl bromoacetate (0.5 mL, 4.50 mmol) was injected. After 2 h30, an aqueous solution of NaHCO3 was added and the aqueous layer was extracted with dichloromethane. The combined organic phases were washed with brine and water and then dried over sodium sulfate. After filtration, solvents were removed in a high vacuum. The brown oil was triturated with diethylether. After filtration, the solid was dried in a high vacuum to give 660 g (60.2%) of (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-acetic acid ethyl ester as a light brown solid. ISP mass spectrum, m/e: 315.4 (M+1 calculated for C18H22N2O3: 315.4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.O.[CH:12](O)=[O:13]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:12]=[O:13])=[C:4]([Cl:10])[N:3]=1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 52.5 °C
Reaction time: 3 h

Procedure:
2,5-Diamino-4,6-dichloropyrimidine (0.01 mol; 2.0 g) and water (0.25 mol; 4.55 ml) were stirred at room temperature. 98% strength formic acid (0.4 mol; 18.27 g; 14.97 ml) was then added to the reaction. The reaction was subsequently heated to 50-55° C. and kept at this temperature for 3 h. Toluene (0.38 mol; 34.6 g; 40 ml) was then added for the azeotropic distillation under high vacuum at 50° C. (toluene was added twice to guarantee a good distillation, i.e. a total of 80 ml).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:37]I>C(Cl)Cl>[I:37][CH2:2][CH2:3][O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: II
Reactant: COC(=O)C(C)(C)COCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)COCCI
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of methyl 3-(2-hydroxyethoxy)-2,2-dimethylpropanoate (2.30 g, 1 eq.), 1H-imidazole (1.07 g, 1.2 eq.) and DCM (100 ml) was slowly added resin-bound triphenylphosphine (1.2 eq.) and iodine (3.98 g, 1.2 eq.). The reaction mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated and subject to silica gel chromatography using 0-25% ether-heptane to yield the title compound as a colorless oil (3.73 g, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[CH3:11][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:11])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 3-bromo-5-fluorobenzaldehyde (6.0 g, 29.6 mmol, prepared according to patent WO 0066556) in THF (100 ml) was added dropwise at 0° C. methylmagnesiumchloride (3N in THF, 12 ml). The reaction mixture was stirred for 3 hours at room temperature and then sat. NH4Cl solution was added. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography over silica gel to yield 1-(3-bromo-5-fluoro-phenyl)-ethanol (2.9 g, 45%), 1H-NMR (300 MHz, CDCl3): δ=7.31 (s, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 4.82-4.94 (m, 1H), 1.51 (d, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][CH2:20][CH2:21][C:22](O)=[O:23].Br.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][NH:32][CH2:31]2.C(N=C=NCCCN(C)C)C>ClCCl>[O:23]=[C:22]([N:32]1[CH2:31][C:30]2[C:34](=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=2)[CH2:33]1)[CH2:21][CH2:20][CH2:19][N:3]1[CH2:4][CH2:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]1=[O:1]
Reactant: O=C(O)CCCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(CCCN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Reaction time: 18 h

Procedure:
To 4-(2-oxo-3,3-diphenylpyrrolidin-1-yl)butanoic acid (Example 155A, 0.039 g, 0.121 mmol) and 5-(trifluoromethyl)isoindoline hydrobromide (0.036 g, 0.133 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.032 mL, 0.181 mmol) and the reaction stirred for 18 hours. The reaction was loaded onto a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.0, 1H), 7.45 (d, J=14.3, 1H), 7.36-7.13 (m, 11H), 4.67 (d, J=9.6, 2H), 4.57 (d, J=5.5, 2H), 3.50 (t, J=6.5, 2H), 3.41 (t, J=6.5, 2H), 2.74 (t, J=6.5, 2H), 2.26 (t, J=6.9, 2H), 2.01 (p, J=6.6, 2H); MS (ESI+) m/z 493.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]=[N+:31]=[N-:32])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(OC(=O)NCCC1C=CC(OS(C2C=CC(F)=CC=2)(=O)=O)=CC=1)(C)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]=[N+:31]=[N-:32])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: CC(C)(C)OC(=O)NCCc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(S(=O)(=O)N=[N+]=[N-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (0.594 g, 2.50 mmol) in DMF (12.5 mL). Add NaH (80% in mineral oil) (0.083 g, 2.75 mmol). Stir at room temperature for 30 minutes. Add 4-fluorobenzenesulfonyl azide (0.504 g, 2.50 mmol) and heat to 60° C. Remove DMF as an azeotrope with xylenes after 3.75 hours. Purify by flash 40 chromatography, eluting with 30% ethyl acetate in hexanes to give a mixture of (2-(4-(4-fluorobenzenesulfonyl)oxyphenyl)ethyl)carbamic acid tert-butyl ester and the title compound: HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 50-99% over 19 min], tR=16.1 min, 35% purity; TLC [silica gel 60 F254, 5% ethyl acetate in hexanes] Rf=0.49.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:4]5[CH2:5][CH2:6][CH2:7][O:1][CH2:2][CH2:3]5)=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCOCC4)n3c2)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCOCC5)n4c3)c3ccccc32)cc1
Temperature: 105 °C
Reaction time: 3.5 h
Yield: 21 %

Procedure:
A solution of Intermediate 49b (90.0 mg, 0.237 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 97 mg, 0.24 mmol) in 1,4-dioxane (3 mL) and DIPEA (63 μL, 0.36 mmol) was stirred at 90° C. for 4 h, then more DIPEA (63 μL, 0.36 mmol) was added and mixture stirred at 100-110° C. for 3.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give the product (31 mg, 21%). This was further purified by HPLC (C18 X-select column, 35-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as a white powder after freeze-drying (20 mg, 13%). LCMS (Method 5): Rt 4.40 min, m/z 635.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.80-2.18 (6H, m), 2.36 (3H, s), 3.44-3.51 (4H, m), 3.78-3.85 (4H, m), 4.77-4.85 (1H, m), 5.51 (1H, t, J 4.4), 6.32 (1H, s), 7.10-7.16 (2H, m), 7.25-7.40 (8H, m), 7.60 (1H, d, J 9.6), 7.65 (1H, d, J 1.5), 8.10 (1H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[N:26]([CH2:34][CH3:35])[N:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36].O1CCOCC1>ClCCl>[ClH:36].[ClH:36].[C:30]([C:28]1[CH:29]=[C:25]([NH:24][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)=[O:23])[N:26]([CH2:34][CH3:35])[N:27]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: CCn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
4-{4-[3-(5-tert-Butyl 2-ethyl-2H-pyrazol-3-yl)-ureido]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (105 mg, 0.216 mmol) is dissolved in dichloromethane (3 mL) and a 4M solution of HCl in 1,4-dioxane (0.86 mL, 3.5 mmol) is added and the mixture stirred at room temperature for 2 hours. After removal of solvent, the residue is triturated with diethyl ether and air-dried to obtain the title compound (99 mg, 99% yield, ES+(m/z) 385 [M+H]).