Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][N:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]1=[O:8]
Reactant: Fc1cccc(CBr)c1
Reactant: O=c1ccc(Br)c[nH]1
Product: O=c1ccc(Br)cn1Cc1cccc(F)c1
Yield: 62 %

Procedure:
According to Scheme 1 Step 2: 1-(3-Fluorobenzyl)-5-bromopyridin-2(1H)-one was prepared from 5-bromopyridin-2(1H)-one (Example 1 Step 1) and 3-fluorobenzyl bromide according to the procedure described for Example 2 Step 1. The crude product washed with pentane/Et2O 50/50 to afford 1-(3-fluorobenzyl)-5-bromopyridin-2(1H)-one (10.7 mmol, 3.00 g, 62%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)=[CH:15][C:14]=3[F:31])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>ClCCl>[F:31][C:14]1[CH:15]=[C:16]([CH:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:17]=[CH:18][C:13]=1[C:10]1[NH:9][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]=2[N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 50E (1.5 g) in dichloromethane (50 mL) was treated with TFA (10 mL), stirred for 1 hour and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN, 0-100% gradient). 1H NMR (CD3OD) δ 2.21-2.36 (m, 3H), 2.54-2.63 (m, 1H), 3.47-3.59 (m, 2H), 4.76 (dd, J=9.51, 7.06 Hz, 1H), 7.43 (t, J=7.83 Hz, 1H), 7.50-7.55 (m, 2H), 7.84 (d, J=7.36 Hz, 1H), 7.98 (d, J=7.67 Hz, 1H), 8.42 (t, J=8.13 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=O)OC(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH3:9][NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CNCCCCCCO
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Intermediate 20 (2.14 mmol) was added to a stirring solution at 0° C. containing 95% LAH (0.426 g, 10.68 mmol) in 10 mL of anhydrous THF. This mixture was then heated to 80° C. and allowed to reflux for 3 h. After 3 h the reaction was cooled to 0° C. and water (0.426 mL), 20% (w/v) NaOH (0.426 mL), and water (1.215 mL) were added sequentially. This was stirred for 15 min at rt then MgSO4 was added and stirred for another 30 min. The mixture was filtered through celite, washed with THF, and concentrated to give the title compound. The compound was used with no further purification. ES/MS calcd. for C7H18NO+ 132.1. Found m/z=132 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH3:5])[CH3:3].[P:6](Cl)([Cl:9])([Cl:8])=[S:7]>CCOCC>[CH:2]([NH:1][P:6]([Cl:9])([Cl:8])=[S:7])([CH2:4][CH3:5])[CH3:3]
Reactant: CCC(C)N
Reactant: S=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCC(C)NP(=S)(Cl)Cl
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A solution of 2-aminobutane (45 mL, 0.449 mol) in 45 mL of anhydrous ether was added dropwise to a solution of 93 mL (0.915 mol) of thiophosphoryl chloride in 200 mL of anhydrous ether at 0° C. under an argon atmosphere. The resultant slurry was stirred while slowly warmed to room temperature. After filtering to remove sec-butylamine hydrochloride (40.6 g), the filtrate was concentrated at reduced pressure to provide 32.3 g (69.7%) of a yellow oil.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:35])([CH2:33][CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:32])([CH3:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:35])([CH2:33][CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:32])([CH3:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[CH:20][CH:19]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3cccc(C)n3)cc2)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(C(C)(O)Cc2ccc(-c3cccc(C)n3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 mL, 8 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[4-(6-methylpyridin-2-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (120 mg, 0.25 mmol) in methanol (4 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. (M+H) found: 378.
Reaction SMILES: Cl.[F:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2([C:16]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH:20]3[OH:25])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][CH:4]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[C:36]([F:39])([F:38])[F:37]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2([C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[C:36]([F:37])([F:39])[F:38])[CH2:21][C:20]3=[O:25])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])=[CH:26][CH:27]=1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1ccc(F)cc1
Agent: Cl
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3C(F)(F)F)CC2=O)CCCCC1)c1ccc(F)cc1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(4-fluorobenzoyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-4-fluoro-2-trifluoromethylbenzene was used instead of 1-bromo-4-fluoro-2-thiomethoxybenzene in Step 1 thereof, 137 mg of the titled compound was prepared.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([NH2:9])[N:6]=[CH:5]1)([CH3:3])[CH3:2].[C:10](Cl)([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH:1]([N:4]1[CH:8]=[C:7]([NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnc(N)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)n1cnc(NC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.7 %

Procedure:
To a stirring solution of 1-isopropyl-1H-imidazol-4-amine (0.532 g, 4.25 mmol) in EtOAc (70 ml) was added Troc-Cl (0.614 ml, 4.46 mmol) followed by satd. NaHCO3 (17.23 ml 12.75 mmol). The biphasic mixture was stirred briskly at RT. After 6 h, the layers were separated and the aqueous was extracted with EtOAc (1×). The combined organics were washed with satd. NaHCO3 (1×) and brine (1×), dried, evaporated and triturated (EtOAc/hexanes). The solids were collected by filtration, rinsed with hexanes and dried on the filter to afford 2,2,2-trichloroethyl 1-isopropyl-1H-imidazol-4-ylcarbamate (0.392 g, 31% yield) as a pink-orange solid. 1H NMR (400 MHz, DMSO-d6): δ 10.2 (s, 1H), 7.49 (s, 1H), 7.02 (s, 1H), 4.80 (s, 2H), 4.3-4.25 (m, 1H), 1.35 (d, 6H); MS (ESI) m/z: 300.0 (M+H+), 302.0 (M+2+H+).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:22][CH2:23][C@H:24]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CC#N>[C:28]([O:27][C:25](=[O:26])[C@@H:24]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:23][NH:22][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[CH:20][CH:19]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
To a stirred solution of 1-4 (200 mg, 0.71 mmol), 2-1 (260 mg, 0.85 mmol), NMM (313 μL, 2.8 mmol), and CH3CN (4 mL) at ambient temperature was added BOP reagent (473 mg, 1.1 mmol). After 20 h the reaction mixture was diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10% KHSO4 and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) gave 2-3 as a white solid. Rf 0.19 (silica, 40% EtOAc/hexanes).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([CH2:16][CH2:17][CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:17]([C:16]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[NH:7][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:18]
Reactant: NNc1ccccc1
Reactant: CCCC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccccc2c1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A solution of phenylhydrazine (1.0 g, 6.92 mmol) in absolute ethanol (50 mL) was placed in an oil bath at 60° C. and a reflux condenser attached. Ethyl 2-oxopentanoate (1.0 g, 6.94 mmol) (prepared according to Singh, J; Kissick, T. P.; Mueller, R. H. Organic Preparations and Procedures International (1989), 21(4), 501-4.) was added dropwise. The reaction mixture was heated to reflux and stirred overnight. The solution was cooled to RT and the solvent concentrated. Purification was accomplished by column chromatography (hexanes:EtOAc) to afford ethyl 3-ethyl-1H-indole-2-carboxylate (0.625 g, 41%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.45 (s, 1H) 7.66 (d, 1H) 7.41 (d, 1H) 7.25 (t, 1H) 7.05 (t, 1H) 4.34 (q, 2H) 3.05 (q, 2H) 1.35 (t, 3H) 1.19 (t, 3H). MS: m/z 218.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:12][C:13]([O:15]CC)=[O:14])[OH:11])=[CH:4][CH:3]=1.[OH-].[Li+:19]>C(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:12][C:13]([O-:15])=[O:14])[OH:11])=[CH:4][CH:3]=1.[Li+:19]
Reactant: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CC1(O)CCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
A mixture of ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate (2.0 g. 8.4 mmol), 1N lithium hydroxide (8.4 mL) and absolute ethanol (13.0 mL) was stirred for 18 h at room temperature. The mixture was concentrated in vacuo, diluted with H2O and extracted with diethyl ether. The aqueous phase was concentrated in vacuo, diluted with toluene (100 mL) and concentrated in vacuo to give lithium 2-(6-fluoro-1-hydroxy-1-indanyl)acetate as a white solid (1.4 g, 77%);
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=3[C:18]#[N:19])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[O:30]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=3[C:18]#[N:19])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C#N)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)c(C#N)c1
Yield: 68.8 %

Procedure:
Using 2-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (150 mg) described in Preparation Example 184 and isothiazolidine 1,1-dioxide (71 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (114 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-])=O)=[N:6][CH:7]=1.[NH4+].[Cl-].CCOC(C)=O>O.[Fe]>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[NH:8][C:5]1[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Nc2cnc(Br)cn2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Nc2cnc(Br)cn2)c(N)c1
Temperature: 65 °C
Yield: 74.1 %

Procedure:
Into a 250 mL 3-necked roundbottom flask, was placed a solution of methyl 4-(5-bromopyrazin-2-ylamino)-3-nitrobenzoate (x) (5.0 g, 14.2 mmol) in TI-IF (75 mL). This was followed by the addition of a solution of NH4Cl (3.8 g, 71 mmol) in H2O (25 mL). To the above was added Fe (4.0 g, 71 mmol) in several batches, while warming to a temperature of 65° C. The resulting solution was allowed to react for 3 hours at 65° C. The reaction progress was monitored by TLC (EtOAc/PE=1:2). Undissolved material was removed by filtration. The filtrate was extracted three times with 200 mL of EtOAc and the organic layers were combined and dired (Na2SO4). After removal of the solvent, the residue was separated by silica gel chromatography eluting with a mixture of PE/EtOAc (starting at 10:1 and proceeding through 5:1, 3:1, and 2:1, v/v) to afford the product methyl 3-amino-4-(5-bromopyrazin-2-ylamino)benzoate (xi) (3.4 g, yield 74%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][N:12]([C:10]([C:5]2[CH:4]=[CH:3][C:2]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])=[CH:9][C:6]=2[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C#N)CC2)c(C)c1

Procedure:
Using 5-bromo-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]benzonitrile (398 mg) described in Preparation Example 188 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (377 mg) was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@H:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33](OC)[CH:32]=4)=[CH:27][CH:26]=3)[C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]([NH2:39])[N:14]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[CH3:40][C:41]1[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:45][CH:46]=1.O.C(#N)C.O.C1C[O:59][CH2:58]C1>O.O.O.S(C1C=CC(C)=CC=1)(O)(=O)=O.N[C@@H](CC1C=CC(C2C=C(O[C@H](C3C=CC(C4C=CC=C(OC)C=4)=CC=3)C(F)(F)F)N=C(N)N=2)=CC=1)C(O)=O>[OH2:4].[OH2:48].[S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH3:40])=[CH:42][CH:43]=1)([OH:50])(=[O:49])=[O:48].[NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][C@H:20]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][C:30]=3[O:59][CH3:58])[C:21]([F:22])([F:23])[F:24])[N:16]=[C:15]([NH2:39])[N:14]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: C1CCOC1
Reactant: COc1cccc(-c2ccc([C@@H](Oc3cc(-c4ccc(C[C@H](N)C(=O)[O-])cc4)nc(N)n3)C(F)(F)F)cc2)c1
Agent: COc1cccc(-c2ccc([C@@H](Oc3cc(-c4ccc(C[C@H](N)C(=O)O)cc4)nc(N)n3)C(F)(F)F)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1cc(-c2ccccc2)ccc1[C@@H](Oc1cc(-c2ccc(C[C@H](N)C(=O)O)cc2)nc(N)n1)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
(S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate (120.0 g, 88 w %, 105.6 g active, 196 mmol) was added to a solution of TsOH.H2O (39.8 g, 209 mmol) in a mixture of THF (240 mL) and water (48 mL). The mixture was heated to 50° C. to give a homogeneous solution. Approximately 120 mL of a mixture of ACN/water (1200/60 mL) was added and the mixture was seeded with (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate tosylate dihydrate (0.63 g). After aging for 1 hour at 40° C., a nice slurry was obtained. The remaining ACN/water mixture was added slowly over 3 hours at 40° C. and the slurry was aged at 40° C. for 2 hours then slowly cooled to 20° C. and aged overnight. The solid was collected by filtration and the filter cake was washed with 5/1 ACN/THF with ˜5 vol % water (500 mL). Air drying at room temperature overnight gave 138.5 g of the product as a white solid (99.5 A %, 93.4% yield corrected for purity). Loss in the mother liquor and wash was 6.5%. KF of solid was 4.4%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].ON1C2C=CC=CC=2N=N1.CN(C)CCCCN=C=NCC.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:19])[NH:21][CH2:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)O
Agent: CCN=C=NCCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NCC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
3,4-Dihydro-1H-isoquinoline-2,3-dicarboxylic acid-2-tertbutyl ester (2.77 g, 10 mmol) and 2-amino-1 phenyl-ethanone (1.71 g, 10 mmol), and HOBT (1-hydroxybenzo-triazole) (2.70 g, 20 mmol) were dissolved in dichloromethane (100 ml). The solution was cooled to 0° C. and then (4-dimethylamino-butyl)-ethyl-carbodiimide (2.29 g, 12 mmol) was added followed by NMM (N-methyl-morpholine) (1.31 g, 13 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.Cl.[C:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:8]([NH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: CC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)Nc2ccncc2)CC1
Reaction time: 24 h
Yield: 34.6 %

Procedure:
To a solution of O-phenyl N-(4-pyridyl)carbamate (0.81 g) in chloroform (10 ml) were added 1-acetyl-4-aminopiperidine hydrochloride (0.68 g) and triethylamine (1.06 ml) at ambient temperature. After stirring for 1 day, the mixture changed to a solution. The solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 100 ml, dichloromethane:methanol=10:1 to 5:1, and silica gel 50 ml, dichloromethane:methanol:aqueous ammonia=10:1:0.1). The solvents of desired fractions were removed under reduced pressure. A residue was dissolved with methanol (5 ml) and dichloromethane (5 ml), and 4N hydrogen chloride in dioxane (1.5 ml) was added to the solution. The solvents were removed under reduced pressure, and the residue was evaporated azeotropically with methanol. After crystallization from diisopropyl ether and n-hexane, N-(1-acetylpiperidin-4-yl)-N′-(4-pyridyl)urea (343 mg) was obtained.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([Cl:25])=[CH:17][C:14]=1[CH2:15]Br)(=[O:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([Cl:25])=[CH:17][C:14]=1[CH2:15][N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])(=[O:11])[CH3:10]
Reactant: CNC1CCCCC1
Reactant: CC(=O)Nc1cc(C(C)(C)C)c(Cl)cc1CBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1cc(C(C)(C)C)c(Cl)cc1CN(C)C1CCCCC1

Procedure:
26 gm of N-methyl-cyclohexylamine were added to 29 gm of 2-acetylamino-4-tert.butyl-5-chloro-benzyl bromide in 1.5 liters of carbon tetrachloride, and the mixture was refluxed for 2 hours. After cooling, the precipitated N-methyl-cyclohexylamine hydrobromide was filtered off, and the filtrate was evaporated. The residue was taken up in 2 N acetic acid, the solution was extracted with chloroform, and the acid phase was made alkaline with concentrated ammonia, extracted three times with chloroform, and the organic phase was evaporated. After column-chromatographic purification on silicagel with ethyl acetate/chloroform (1:1), the 2-acetylamino-4-tert.butyl-5-chloro-N-cyclohexyl-N-methyl-benzylamine thus obtained was recrystallized from absolute ethanol and recrystallized from ethanol, whereupon it had a melting point of 174-175.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[N:20]=[CH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([NH:18][C:2]2[CH:7]=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]3)[CH:5]=[CH:4][N:3]=2)[N:20]=1
Reactant: Nc1cc2ccccc2cn1
Reactant: CC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(Cc2ccnc(Nc3cc4ccccc4cn3)c2)CC1

Procedure:
1-(2-Chloropyridin-4-ylmethyl)-4-acetylpiperazine (1.0 equiv) (Preparation B-15) was mixed with 3-aminoisoquinoline (1.0 equiv), Pd2(dba)3(0.1 equiv), xantphos (0.15 equiv), and Cs2CO3 (1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound was obtained as a yellow solid (50 mg, yield 48%). 1H NMR (CDCl3, 300 MHz) δ: 2.10 (s, 3H, Ac), 2.47 (t, J=4.1 Hz, 4H, PyCH2NCH2CH2), 3.58 (dt, J=4.8 Hz, 50.7 Hz, 4H, NCH2CO), 3.60 (s, 2H, pyridylCH2), 6.86-8.99 (m, 9H, isoquinolyl+pyridyl).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.Cl.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)NCC(F)(F)F)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (80 mg, 0.189 mmol) with 2,2,2-trifluoroethanamine hydrochloride (28 mg, 0.208 mmol) in the presence of EDCI hydrochloride (72 mg, 0.378 mmol), DMAP (43 mg, 0.378 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 60 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 3.57 (s, 2H), 4.10-4.18 (m, 2H), 7.17 (t, J=74.7 Hz, 1H), 7.20 (d, J=7.5 Hz, 2H), 7.39-7.48 (m, 2H), 7.60-7.66 (m, 1H), 7.84 (d, J=15.6 Hz, 1H), 8.00 (s, 1H), 8.85 (br s, 1H); ESI-MS (m/z) 504.22 (MH)+.