Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42](O)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:45][CH2:46][CH3:47])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:48][CH:49]([CH2:52][OH:53])[CH2:50][NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]([NH:51][CH2:50][CH:49]([OH:48])[CH2:52][OH:53])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:45][CH2:46][CH3:47])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NCC(=O)O)CC1
Reactant: NCC(O)CO
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NCC(=O)NCC(O)CO)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-ylamino}-acetic acid (example 229) was reacted with N-(2,3-dihydroxy-propyl)-amine (Aldrich) to give the title compound as a mixture of diasteromers. HR-MS (ES, m/z) calculated for C39H51Cl2N6O5 [(M+H)+] 753.3293, observed 753.3293.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CN(C)C(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc(N)cc2o1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Cc1nc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-1,3-benzoxazol-6-amine (1.00 g, 6.74 mmol) and pyridine (1.64 ml, 20.2 mmol) in N,N-dimethylacetamide (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.39 ml, 10.1 mmol) under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling. The reaction mixture was poured into ice-water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate, and 1.45 g (66.5%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:34])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:34])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(CO)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 86.3 %

Procedure:
To a suspension of 6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (2.89 g, 7 mmol) in toluene (30 mL) was added thionyl chloride (1.0 mL, 14 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (2.61 g, 86.4%) as crystals.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][CH:10]([CH3:40])[C:11]([O:13][C@@H:14]1[C@@H:18]([CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[O:17][C@@H:16]([N:26]2[C:30]3[N:31]=[C:32]([NH:37][CH:38]=[O:39])[N:33]=[C:34]([O:35][CH3:36])[C:29]=3[CH:28]=[CH:27]2)[CH2:15]1)=[O:12]>C(Cl)Cl>[Cl:1][C:28]1[C:29]2[C:34]([O:35][CH3:36])=[N:33][C:32]([NH:37][CH:38]=[O:39])=[N:31][C:30]=2[N:26]([C@@H:16]2[O:17][C@H:18]([CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[C@@H:14]([O:13][C:11](=[O:12])[CH:10]([CH3:40])[CH3:9])[CH2:15]2)[CH:27]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(NC=O)nc2c1ccn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Solvent: ClCCl
Product: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
N-Chlorosuccinimide (87 mg, 0.67 mmol) is added to a solution of compound (18) (300 mg, 0.67 mmol in 5 ml of DMF). After it has been stirred (at room temperature for 20 h), the solution is added to a mixture of CH2Cl2/5% aq. NaHCO3 (50 ml, 9:1). The organic layer is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2/acetone, 95:5). The main zone is concentrated, and n-hexane is added to the residue. The precipitated colorless crystals (230 mg, 71%) are isolated. Melting point: 119-120° C. 1H-NMR ([D6] DMSO): δ=1.09 (d, J=7.0, CH3), 1.15 (d, J=6.9, CH3), 2.45, 2.60, 2.63, 2.89 (4m, CH and Hα,β-C(2′)), 4.06 (s, OCH3), 4.18 (m, H—C(5′)), 4.28 (m, H—C(4′)), 5.35 (m, H—C(3′)), 6.47 (m, H—C(1′)), 7.58 (s, H—C(6)), 9.45 (d, J=8.9, NH), 10.84 (d, J=9.6, HCO). Anal. calculated for C21H27CIN4O7 (482.9): C 52.23, H 5.64, N 11.60; found: C 52.51, H 5.69, N 11.65.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][CH2:22]Br.CS(C)=O.[OH-].[Na+]>O>[C:15]([C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: BrCBr
Reactant: CCCCC(C#N)c1ccccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(C#N)(CBr)c1ccccc1Oc1ccccc1
Yield: 82.3 %

Procedure:
Into a three-necked 300 ml round bottom flask are charged 10 g (0.038 mole) of 2-(2-phenoxyphenyl)hexanenitrile, 6.6 g (0.038 mole) of dibromomethane and 50 ml of dimethyl sulfoxide. To this mixture with stirring is added 3.2 g (0.04 mole) of 50% sodium hydroxide solution dropwise. Reaction mixture is heated to give 60° for two hours and then poured into water and extracted with hexane. Combined hexane extracts are washed with water and dried over MgSO4. Solvent is evaporated under vacuum to give 11.2 g of product.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.C([Li])CCC.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].O>O1CCCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([N:6]([Si:17]([CH3:19])([CH3:18])[CH3:16])[Si:17]([CH3:19])([CH3:18])[CH3:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)cc(C)c1N([Si](C)(C)C)[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-2,6-dimethylaniline (commercially available) (40 g, 0.2 mol) in tetrahydrofuran (500 ml) under a nitrogen atmosphere was added a solution of n-butyl lithium in hexanes (1.6 M) (125 ml, 0.2 mol). During this operation, the internal temperature was kept between −70° C. and −78° C. After five minutes, trimethylsilyl chloride (25 ml, 0.2 mol) was added whilst the internal temperature was kept below −68° C. After five minutes, the cooling bath was replaced with a water bath and the internal temperature rose to 0° C. Then the cooling bath was put back and the reaction mixture was cooled to −78° C. To this solution, a solution of n-butyl lithium in hexanes (1.6 M) (125 ml, 0.2 mol) was added whilst keeping the internal temperature below −70° C., followed by addition of trimethylsilyl chloride (30 ml, 0.237 mol) whilst keeping the internal temperature below −68° C. The reaction mixture was gradually allowed to warm to 20° C. Hexanes (200 ml) and water (40 ml) were added and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was distilled under a high vacuum leading to the title compound as a colorless oil which crystallized on standing. M.p. 47-52° C. 1H-NMR (CDCl3, 400 MHz): 0.08 (s, 18H), 2.21 (s, 6H), 7.15 (s, 2H) ppm.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9]CC)=[O:8])[CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.C[O+](C)C.[C:21]([NH:24][NH2:25])(=O)[CH3:22]>ClCCl>[CH3:22][C:21]1[N:3]2[CH2:4][CH2:5][CH:6]([C:7]([OH:9])=[O:8])[C:2]2=[N:25][N:24]=1
Reactant: CCOC(=O)C1CCNC1=O
Reactant: CC(=O)NN
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nnc2n1CCC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane:methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:45][N:46]1[CH:50]=[CH:49][C:48](B(O)O)=[N:47]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[N:47]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Reactant: Cn1ccc(B(O)O)n1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cn1ccc(-c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)n1
Temperature: 120 °C

Procedure:
To a solution of (1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (20 mg, 0.00005 mol, example 238) in tetrahydrofuran (0.2 mL, 0.002 mol) were added tris(dibenzylideneacetone)dipalladium(0) (0.2 mg, 0.0000002 mol), tri-tert-butylphosphine (0.12 mg, 5.8×10−7 mol), (1-methyl-1H-pyrazol-3-yl)boronic acid (6.8 mg, 0.0000534 mol). The mixture was heated at 120° C. under microwave for 30 minutes. The reaction mixture then was filtered and the filtrate was diluted with methanol and purified with prep-HPLC to afford the desired product. LC/MS: 414.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[C:8](=[O:16])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][CH:4]2[CH2:3]1.[C:17]1([Li])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([OH:16])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][CH:4]2[CH2:3]1
Reactant: CN1CCC2C(=O)c3ccccc3SC2C1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CN1CCC2C(C1)Sc1ccccc1C2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
40 g of 1,2,3,4,4a,10a-hexahydro-2-methyl-5H-[1]-benzothiopyrano[2,3-c]pyridin-5-one were dissolved in 2 liters of dry ether and the solution obtaining was cooled to 5° C. in an ice bath while 220 ml (2 moles) of phenyl lithium were added dropwise thereto over 30 minutes with the temperature held below 0° C. When the addition was complete, the ice bath was removed and the solution thus obtained was stirred at room temperature for 30 minutes. 3 liters of water were added dropwise thereto and the resultant suspension was stirred vigorously for 2 hours and then was filtered. The product was washed with water and ether and was dried to obtain 20.5 g of 2-methyl-5-phenyl-1,3,4,4a,5,10a-hexahydro-2H[1]benzothiopyrano[2,3-c]pyridin-5-ol (37% yield) melting at 176°-181° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[C:4]1=[O:14])[CH3:2].[CH3:15][O:16][C:17]1[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=1.FC(F)(F)C(O)=O>O1CCOCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([OH:13])([CH2:23][C:18]2[C:17]([O:16][CH3:15])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4]1=[O:14])[CH3:2]
Reactant: COc1cccnc1C
Reactant: CCN1C(=O)C(=O)c2cc(C)ccc21
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(O)(Cc2ncccc2OC)c2cc(C)ccc21
Temperature: 110 °C

Procedure:
To a flame dried sealed tube cooled under argon was added the 1-ethyl-5-methylindoline-2,3-dione (0.03 grams, 0.15 mmol) and 3-methoxy-2-methyl-pyridine (0.072 grams, 0.59 mmol, purchased from Fisher Scientific) and 0.5 mL of 1,4 dioxane. After the addition of trifluoro acetic acid (2 μL) the vessel was sealed and heated to 110° C. for 48 hours. The reaction was then concentrated. 1H-NMR δ 8.21 (s, 1H), 7.35 (bs, OH), 7.26 (m, 1H), 7.20 (d, 1H), 7.09 (d, 1H), 6.90 (s, 1H), 6.75 (d, 1H), 3.78 (s, 3H), 3.77 (m, 2H), 3.34 (d, 1H), 3.18 (d, 1H), 2.27 (s, 3H), 1.28 (t, 3H). Calculated mass for C18H20N2O3, 312.15. Observed 313.1 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:33])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[NH:15][C:14]([CH:16]3[CH2:18][CH2:17]3)=[N:13][C:12]=2[C:19]2[C:20]([Cl:32])=[C:21]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:8]=[CH:7][N:6]=1.C([O-])(O)=O.[Na+].Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1.O.O>[Cl:32][C:20]1[C:21]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][C:19]=1[C:12]1[N:13]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[NH:15][C:11]=1[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][CH2:3][C@@H:2]([NH:1][C:40](=[O:41])[O:42][CH3:43])[CH3:33])[N:10]=1
Reactant: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)[nH]c2-c2ccnc(NC[C@H](C)N)n2)c1Cl
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)[nH]c2-c2ccnc(NC[C@H](C)NC(=O)OC)n2)c1Cl
Reaction time: 0.08 h

Procedure:
To a mixture of (S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide in THF-water (1:1, 2 mL) at 0° C. was added solid NaHCO3 (137 mg, 1.6 mmol) and the resulting mixture was stirred for 5 minutes. Methyl chloroformate (14 μL, 0.18 mmol) was added and the reaction mixture was stirred at 0° C. for 15 minutes. The reaction was diluted with water and extracted with EtOAc (2×). The combined organic portions were washed with water, brine, dried (Na2SO4), and concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC. Product fractions were combined and lyophilized to give (S)-methyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (19.9 mg) as the TFA salt (4A-3): LCMS (m/z) 548.0 (MH+), tR=0.61 minute, 1H NMR (400 MHz, CD3OD) δ 1.04 (t, J=7.4 Hz, 3H) 1.14 (d, J=6.6 Hz, 3H) 1.27 (t, J=4.5 Hz, 2H) 1.34-1.44 (m, 2H) 1.80-1.95 (m, 2H) 3.14-3.21 (m, 2H) 3.67 (br s, 3H) 3.97 (br s, 1H) 6.40 (br s, 1H) 7.45 (d, 7.0 Hz, 1H) 7.54 (m, 1H) 7.84 (d, J=7.4 Hz, 1H) 8.13 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([N:4]([CH3:5])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(Cc1cccc(I)c1)C1CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CN(Cc1cccc(C#C[Si](C)(C)C)c1)C1CC1
Yield: 79.4 %

Procedure:
Following General Procedure D and using cyclopropyl-(3-iodo-benzyl)-methyl-amine (Intermediate 89, 0.97 g, 3.4 mmol), triethyl amine (10 mL), copper(I)iodide (0.051 g, 0.27 mmol), trimethylsilyl acetylene (2 mL, 14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.19 g, 0.27 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane-5% ethyl acetate in hexane as the eluent, the title compound (0.695 g, 80%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.O.[OH-].[Na+]>CS(C)=O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Nc2cncc(C(=O)Nc3nnn[nH]3)n2)cc1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 15 ml of dimethylsulfoxide, 5.36 g of p-toluidine was added, and the mixture was heated for 18 hours at 80°-90 ° C., and heated for 6 hours at 100°-110 ° C. Water and 10%-sodium hydroxide aqueous solution was added to the reaction mixture, and the aqueous alkaline solution was washed with chloroform. Aqueous layer was filtered, and the filtrate was adjusted with 10%-hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.93 g of the desired compound as yellow needles, m.p. 289.5°-294 ° C. (decomp.).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCOc1ccc(-n2ccnc2)cc1
Yield: 49.9 %

Procedure:
A stirred mixture of 8.0 g (0.050 mole) of 4(1H-imidazol-1-yl)phenol, 13.5 ml (0.20 mole) of 2-chloroethanol and 28 g (0.2 mole) of potassium carbonate in 200 ml of methyl ethyl ketone was heated at reflux, filtered, and concentrated to obtain 5.1 g of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanol (50%). This alcohol (0.25 mole) and 5.2 g (0.030 mole) of sulfamic acid phenyl ester (Example 33) in 100 ml of dioxane was heated at reflux for 20 minutes, concentrated and the residual solid triturated in acetone. The triturant was acidified with an anhydrous solution of hydrogen chloride in isopropyl alcohol and the solid hydrochloride collected by filtration. The product was recrystallized from isopropyl alcohol-isopropyl ether to yield 4.26 g of solid, monohydrochloride, mp 156°-157° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[S:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([OH:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1ccc(Sc2ccc(Cl)cc2)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(F)(F)F)ccc2Sc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of n-butyl lithium (2.5 M in hexane, 6.5 mL, 16.2 mmol) was slowly added to a stirred solution of 1-bromo-2-(4-chlorophenylsulfanyl)-5-(trifluoromethyl)benzene (5.96 g, 16.2 mmol) in dry THF (40 mL) under argon at −78° C. The solution was stirred for 10 min before 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.23 g, 16.2 mmol) was added in one portion. The solution was allowed to warm to rt and then stirred overnight. Saturated aqueous ammonium chloride (80 mL) was added and the solution was extracted with ethyl acetate (80 mL). The organic phase was washed with saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate and the solvent was evaporated off. The crude product was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane 2:8) to produce the target compound as a white foam, yield: 4.53 g (57%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20]CC2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=Cc1ccccc1OCc1ccccc1)CCCCCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1CCCCCCCc1ccccc1
Yield: 69 %

Procedure:
The whole of this benzyl 2-(7-phenyl-1-heptenyl)phenyl ether was then treated with hydrogen in the presence of 200 mg of 5% w/w palladium-on-carbon in 250 ml of ethanol at 50° C. for 5 hours at atmospheric pressure. At the end of this time, insoluble materials were removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.03 g (yield 69%) of the title compound as a colorless oil.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[CH:46]1(N)[CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH:46]1([NH:8][C:9](=[O:38])[C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:13]=[CH:12][C:11]=2[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: NC1CCCC1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)NC3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (187 mg) described in Example 769 and cyclopentylamine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (87 mg) was obtained.