Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[C:17]([F:32])=[C:18]([C:23]2[C:24]([C:30]#[N:31])=[CH:25][CH:26]=[CH:27][C:28]=2[F:29])[C:19]([F:22])=[CH:20][CH:21]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:20]3[C:19]([F:22])=[C:18]([C:23]4[C:24]([C:30]#[N:31])=[CH:25][CH:26]=[CH:27][C:28]=4[F:29])[C:17]([F:32])=[CH:16][CH:21]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: N#Cc1cccc(F)c1-c1c(F)ccc(Br)c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4c(F)cccc4C#N)c3F)cnc2c1F
Yield: 10 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 3′-bromo-6,2′,6′-trifluorobiphenyl-2-carbonitrile as described in Example 6 to give 3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]-6,2′,6′-trifluorobiphenyl-2-carbonitrile as an off-white solid (17 mg, 10%): δH (400 MHz, d6-DMSO) 1.58 (6H, s), 5.56 (1H, s), 7.23 (1H, t, J 7), 7.61 (1H, t, J 8), 7.84-7.87 (3H, m), 7.95-8.01 (2H, m), 8.08 (1H, dd, J 7 and 3); m/z (ES+) 426 [MH+]
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:11]=1[O:12][C:13]1[N:18]=[C:17]2[NH:19][N:20]=[CH:21][C:16]2=[C:15]([NH:22][CH2:23][C@H:24]([OH:26])[CH3:25])[N:14]=1>CN(C=O)C>[F:9][C:10]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:11]=1[O:12][C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([I:1])[C:16]2=[C:15]([NH:22][CH2:23][CH:24]([OH:26])[CH3:25])[N:14]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]ncc12
Solvent: CN(C)C=O
Product: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(I)c12
Temperature: 80 °C
Yield: 109.3 %

Procedure:
N-iodo succinimide (35 mg. 0.157 mmol) was dissolved in 3 mL of DMF, and (R)-1-[6-(2,4-Difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (42 mg, 0.131 mmol) was added. The reaction mixture was heated to 80° C. for two hours, after which an additional 35 mg of N-iodo succinimide was added. After heating for two more hours at 80° C., an additional 35 mg of N-iodo succinimide was added. The reaction mixture was heated at 80° C. for 5 more hours, then was cooled to room temperature. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure to give 64 mg of 1-[6-(2,4-Difluoro-phenoxy)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=448.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([OH:21])=O.Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>>[F:13][C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([NH:41][O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:21]
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccccc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccccc1F
Yield: 98.3 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.76 g, 16.8 mmol), 2-(2-fluoro-anilino)-4,5-difluorobenzoic acid (Example R, 4.08 g, 15.3 mmol), O-benzylhydroxylamine hydrochloride (2.44 g, 15.3 mmol), and triethylamine (2.3 mL, 16.8 mmol) provided 5.6 g of the crude title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=[O:8])[CH2:3][CH2:2]1.Cl>[OH-].[Na+].CO.O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCOCC1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
Methyl tetrahydro-2-H-pyran-4-carboxylate (400 μL, 3.00 mmol) was dissolved in a 5:1 mixture of 10M NaOH and MeOH (4.0 ml: 0.8 ml). The mixture was heated to 60° C. for 3 hours. After the reaction was complete, all volatiles were removed under high vacuum to leave a residual solid. The residue was dissolved in H2O and subsequently acidified to pH˜1 using aqueous HCl. The acidic aqueous phase was extracted with DCM and dried over Na2SO4. The solvent was removed to give tetrahydro-pyran-4-carboxylic acid (339 mg, 87%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27](F)(F)F)[CH:22]=3)[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[CH3:32]C1C(C)=CC=CC=1N1CCNCC1>>[CH3:32][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:12]2[C:11](=[O:31])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]2[CH2:1][CH3:2])[CH2:16][CH2:17]1
Reactant: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: Cc1cccc(N2CCNCC2)c1C
Product: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C)c2C)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 7d, using 1-(2,3-dimethylphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([CH3:25])=[C:10]2[C:26](=[O:39])[NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8].IC.[C:42]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([CH3:25])=[C:10]2[C:26](=[O:39])[N:27]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)(=[O:29])=[O:30])[CH3:42])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(S(=O)(=O)NC(=O)C2=C(C)N(C(=O)OC(C)(C)C)c3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(C)C(=O)C2=C(C)N(C(=O)OC(C)(C)C)c3ccnn3C2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of the product obtained from Step B (59.3 mg, 0.1 mmol) and iodomethane (excess) in DMF was added solid K2CO3 (excess). The mixture was stirred at room temperature under N2 for 4 h. LC-MS indicated the completion of reaction. Most of the solvent was evaporated, and mixture was diluted with ethyl acetate, washed with water, brine and dried. After reverse phase HPLC (acetonitrile/water) purification, the desired tert-butyl 7-(3,4-dichlorophenyl)-6-((4-methoxyphenylsulfonyl)(methyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidine-4(7H)-carboxylate was obtained as white solid. LC-MS found: (M+1)+=607.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[N:7]=1.[C:13](O)(=[O:16])[CH:14]=[CH2:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:12][C:8]1[N:7]=[C:6]([NH:5][CH2:4][CH2:3][NH:2][C:13](=[O:16])[CH:14]=[CH2:15])[CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)O
Reactant: NCCNc1cccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NCCNc1cccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
A mixture of 105c (1.88 g, 10 mmol), acrylic acid (720 mg, 10 mmol), HATU (3.80 g, 10 mmol) and DIPEA (6.97 mL, 40 mmol) in DCM (50 mL) was stirred at rt for 16 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (EA/MeOH=4/1) to give N-(2-(6-aminopyridin-2-ylamino)ethyl)acrylamide 105d (1.07 g, 52%) as pale-yellow oil.
Reaction SMILES: C([NH:8][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:43].CCOC(C)=O>CCOC(C)=O>[ClH:43].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:31][CH:30]=1)[CH3:28])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 75 %

Procedure:
Prepared according to the method described in Example 1(b) above from crude (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-[1-(4-benzyloxyphenyl)ethyl]-ornithine amide (6.37 mmol; from step (a) above), EtOAc (200 mL) and HCl/EtOAc (75 mL), 3 hours reaction time. The resultant heterogeneous solution was concentrated to 100 mL, slurried with Et2O and the solids collected and dried to afford the sub-title compound as a white solid (2.5 g; 75%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[S:23][C:24]([NH:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[N:25][N:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[S:23][C:24]([NH:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(NCC4CC4)s3)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2c(c1CSc1nnc(NCC3CC3)s1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-[5-(cyclopropylmethyl-amino)-[1,3,4]thiadiazol-2-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.082 g, 0.171 mmol) in anhydrous DCM (3.5 mL) at room temperature add trifluoroacetic acid (3.5 mL) and stir the solution at room temperature overnight. Concentrate in. vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, load the solution on to a RediSep® column (12 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 90:10 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 7-chloro-6-[5-(cyclopropylmethyl-amino)-[1,3,4]thiadiazol-2-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.051 g, 78%). MS (ES+) m/z: 381.1 (M+H)+. To a solution of 7-chloro-6-[5-(cyclopropylmethyl-amino)-[1,3,4]thiadiazol-2-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.044 g, 0.116 mmol) in absolute ethanol (5 mL), add succinic acid (0.014 g, 0.116 mmol). After acid dissolves, concentrate the reaction mixture in vacuo. Combine the residue with MTBE, concentrate in vacuo several times and dry under high vacuum at room temperature overnight to obtain the title compound (0.058 g, 100%) as a white foam. MS (ES+) m/z: 381.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=[N:17][OH:18]
Reactant: CC(C)C(C)n1ccc(Cl)c(C=O)c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)C(C)n1ccc(Cl)c(C=NO)c1=O
Temperature: 75 °C
Yield: 76.9 %

Procedure:
A mixture of 4-chloro-1-(3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step C (400 mg), hydroxylamine hydrochloride (244 mg) and sodium acetate (288 mg) in methanol/water (4:1, 6.0 mL) was heated at 75° C. for 1 hr, and cooled to room temperature. The reaction mixture was poured into ice water, and the resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (328 mg).
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:55][O:56][C:57]1[CH:69]=[CH:68][C:60]([CH2:61][C:62]2N=C(N)[S:64][N:63]=2)=[CH:59][CH:58]=1>ClCCl>[CH3:55][O:56][C:57]1[CH:69]=[CH:68][C:60]([CH2:61][C:62]2[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]3[CH2:20][C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])=[CH:18][C:17]3=[O:29])[CH2:12][CH:13]([CH3:14])[CH3:15])[S:64][N:63]=2)=[CH:59][CH:58]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: COc1ccc(Cc2nsc(N)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(Cc2nsc(NC(=O)[C@H](CC(C)C)N3CC(Oc4ccccc4Cl)=CC3=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 60 mg, 0.19 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mmol). The resulting solution was stirred for 5 min before 3-(4-methoxy-benzyl)-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.23 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(4-methoxy-benzyl)-[1,2,4]thiadiazol-5-yl]-amide (48 mg, 49%) as a light yellow solid: HR-ES-MS m/z calculated for C26H27ClN4O4S [M+H]+ 527.1515, observed 527.1514; 1H NMR MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.44 (br. s., 1H), 1.54-1.71 (m, 1H), 1.71-1.90 (m, 1H), 2.76 (q, J=7.5 Hz, 2H), 4.25 (d, J=18.4 Hz, 1H), 4.48 (d, J=18.4 Hz, 1H), 4.79 (s, 1H), 4.97 (dd, J=10.9, 4.8 Hz, 1H), 7.33 (td, J=7.8, 1.5 Hz, 1H), 7.43 (td, J=7.8, 1.4 Hz, 1H), 7.50 (dd, J=7.8, 1.5 Hz, 1H), 7.62 (dd, J=7.8, 1.4 Hz, 1H), 13.24 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([CH3:11])[N:7]=1.[Cl-].[C:16]([O:20][C:21](=[O:24])[CH2:22][Zn+])([CH3:19])([CH3:18])[CH3:17]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:11][C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([CH2:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])[CH:14]=[CH:13][CH:12]=2)[O:10][N:9]=1
Reactant: Cc1noc(Cc2cccc(Br)c2)n1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1noc(Cc2cccc(CC(=O)OC(C)(C)C)c2)n1
Reaction time: 20 h
Yield: 52.8 %

Procedure:
To a solution of 5-(3-bromobenzyl)-3-methyl-1,2,4-oxadiazole 1098 (0.50 g, 1.97 mmol) in dioxane (1 mL), under an atmosphere of Argon, was added Bis(tri-t-butylphosphine)palladium(0) (0.15 g, 0.295 mmol) followed by the addition of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in diethyl ether, 4.92 mmol, 9.84 mL). The mixture was allowed to stir under argon for 20 hours and the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (10 mL) and washed with water (2×5 mL), brine (2×5 mL) and dried over Na2SO4. The Na2SO4 was removed by filtration and the volatiles removed under reduced pressure. The crude material was purified by normal phase chromatography 0-50% EtOAc/Hexanes to give 0.300 g tert-butyl 2-(3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)phenyl)acetate 1099. 1H NMR 300 MHz CDCl3: δ 7.40-7.18 (m, 4H), 4.17 (s, 2H), 3.51 (s, 2H), 2.36 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[C:27]([CH3:37])[C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[C:27]([CH3:37])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Br)cnc1OC1CCOC1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)cnc1OC1CCOC1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-5-bromo-3-methyl-2-(tetrahydro-furan-3-yloxy)-pyridine (Intermediate 29) in analogy to Example 1a): MS (ISP): 481.3 and 483.2 (M+H)+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH3:13])=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: Cc1ccc(CCl)cc1
Product: Cc1ccc(CN(CCO)CCO)cc1

Procedure:
2-[(2-Hydroxy-ethyl)-(4-methyl-benzyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (4.8 g, 46 mmol) and 4-methylbenzyl chloride (8.5 g, 46 mmol). Yield 9.8 g (99%); MS: 209.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]=1[CH3:20]>C(O)(C(F)(F)F)=O.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]=1[CH3:20]
Reactant: COc1nc(CC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: COc1nc(CC(=O)O)c([N+](=O)[O-])cc1C
Yield: 94.4 %

Procedure:
A solution of tert-butyl 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetate (83.0 g, 294 mmol) in TFA (200 mL) was heated in a hot water bath for 1 h. The solution was concentrated in vacuo to give a brown oil. The oil was diluted with hexane and stirred. The resulting solid was collected by filtration and air dried to give 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetic acid (62.8 g, 94% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.70 (s br, 1H), 8.20 (s, 1H), 4.25 (s, 2H), 4.03 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.59, 163.80, 146.52, 139.16, 135.30, 121.53, 54.86, 42.88, 15.32. An analytical sample was recrystallized from hexane: mp 135-137° C. Anal. calcd. for C9H10N2O5: C, 47.79; H, 4.46; N, 12.39. Found: C, 47.65; H, 4.14; N, 12.30.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]1([F:31])[CH2:21][CH2:20][C:19]([CH2:29][NH2:30])([C:22]2[CH:23]=[N:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:19]1([C:22]2[CH:23]=[N:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:20][CH2:21][C:16]([F:15])([F:31])[CH2:17][CH2:18]1)=[O:6]
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cc(C(F)(F)F)ccc1Cl

Procedure:
From 2-chloro-5-trifluoromethylbenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=451.1, tR (minutes, Method C)=1.15
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18](OC)=[O:19])[C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH3:24]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH2:24])=[O:19])[C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc2[nH]c(-c3cccc(C(F)(F)F)c3)nc12
Reactant: N
Product: NC(=O)c1cccc2[nH]c(-c3cccc(C(F)(F)F)c3)nc12

Procedure:
Following standard procedure C, the acetate salt of methyl 2-(3'-trifluoromethylphenyl)-1-H-benzimidazole-4-carboxylate (134.8 mg, 0.358 mmol) was treated with excess liquid ammonia in a sealed vessel. The product was purified by recrystallisation from methanol, to yield off-white needles. (78 mg, 72%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC

Procedure:
As described in Example 50 the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.105 g, 0.36 mmol) was reacted with 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline from Example 7A (0.134 g, 0.5 mmol), and Cs2CO3 (0.325 g, 1 mmol) in isopropanol (8 mL) at 70° C. for 4 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.69 (s, 1H), 7.84 (m, 1H), 7.51 (m, 1H), 7.44 (t, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.28 (m 1H), 6.49 (s, 1H), 4.33 (t, 2H), 4.00 (s, 3H), 3.76 (t, 2H), 3.34 (s, 3H), 1.28 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.Cl.[NH2:34][CH2:35][C:36]1[C:37]([NH2:43])=[N:38][C:39]([CH3:42])=[N:40][CH:41]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:43][C:37]1[C:36]([CH2:35][NH:34][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[CH:41][N:40]=[C:39]([CH3:42])[N:38]=1
Reactant: Cc1ncc(CN)c(N)n1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ncc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)c(N)n1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 5-(aminomethyl)-2-methylpyrimidin-4-amine-2HCl (22.02 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-N-((4-amino-2-methylpyrimidin-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (17.5 mg, 0.032 mmol, 45.6% yield): LCMS=552.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14 (2 H, d, J=8.53 Hz), 7.93 (1 H, s), 7.50-7.70 (7 H, m), 5.15 (1 H, s), 4.25 (2 H, d, J=4.02 Hz), 2.40 (3 H, s); HPLC peak RT=2.4 min (Method E).