Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[S:20]=[C:2]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(F)(F)F
Solvent: ClCCl
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=S)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.21 h
Yield: 95.3 %

Procedure:
To a stirred solution of (R)-tert-butyl 1-oxo-1-(2,2,2-trifluoroethylamino)propan-2-ylcarbamate (100 mg, 0.37 mmol) in CH2Cl2 (10 mL) was added P2S5 (24 mg, 0.11 mmol) and hexamethyldisiloxane (HMDO) (0.13 mL, 0.59 mmol) at room temperature and the mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature and another portion of P2S5 (24 mg, 0.11 mmol) was added and the resulting mixture was refluxed for 18 h. The volatiles were evaporated, pentane (25 mL) was added to the residue and stirred for 10-15 min. The pentane layer was decanted, concentrated in vacuo and the residue was passed through a short silica pad eluting with pentane followed by CH2Cl2 to give the title compound as colorless liquid (30 mg, 30%): 1H NMR (400 MHz, DMSO-d6) δ 10.27 (t, J=5.4 Hz, 1H), 7.00 (d, J=6.8 Hz, 1H), 4.57-4.35 (m, 3H), 1.32 (s, 9H), 1.25 (d, J=7.6 Hz, 3H); ESIMS m/z 286.2 ([M+H]+); IR (thin film) 3233, 1683, 1257 cm−1.
Reaction SMILES: [NH2:1][C:2]1([CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[CH:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:41][CH3:42])[CH2:4][CH2:3]1.[O:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1.CC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:11]1[C:10]2[C:15](=[CH:16][C:7]([O:6][CH2:5][C:2]3([NH:1][CH:46]4[CH2:47][CH2:48][O:43][CH2:44][CH2:45]4)[CH2:3][CH2:4]3)=[C:8]([O:41][CH3:42])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCC1(N)CC1
Reactant: O=C1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCC1(NC2CCOCC2)CC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
The product of Example 2 (200 mg) was mixed with tetrahydro-4H-pyran-4-one (45 mg), NaHB(OAc)3 (96 mg) and HOAc (42 mg) in DCM (5 ml). The reaction mixture was stirred at 30° C. overnight. Saturated NaHCO3 (20 ml) was added to the reaction and the solution was further extracted with EtOAc twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified by preparative TLC plate to give the titled compound. Mass: (M+1), 659
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].[CH:29](Br)([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CC(C)Br
Reactant: O=C(NCCCCCCCCCCCCO)c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1

Procedure:
A solution of 0.7 g of N-(12-hydroxydodecyl)-6-(1-piperazinyl)pyridine-3-carboxamide, 0.24 g of isopropyl bromide and 0.7 g of potassium carbonate in 20 ml of dimethylformamide was stirred at 100° C. for 3 hours. The reaction solution was diluted with chloroform, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford the title compound as a crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[O:7][C:8]2[C:14]([NH:15][C:16](=O)[O:17]CC)=[C:13]([F:21])[CH:12]=[C:11]([Cl:22])[C:9]=2[N:10]=1)([CH3:5])[CH3:4].C[O-].[Na+].[NH2:26]/[C:27](/[C:34]([F:37])([F:36])[F:35])=[CH:28]\[C:29]([O:31]CC)=O.N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:1][O:2][C:3]([C:6]1[O:7][C:8]2[C:14]([N:15]3[C:29](=[O:31])[CH:28]=[C:27]([C:34]([F:35])([F:36])[F:37])[NH:26][C:16]3=[O:17])=[C:13]([F:21])[CH:12]=[C:11]([Cl:22])[C:9]=2[N:10]=1)([CH3:5])[CH3:4]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c2nc(C(C)(C)OC)oc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Yield: 59.3 %

Procedure:
An additional 0.6 gram of 3-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione was prepared in the manner of Step E, Example 1, with 0.8 gram (2.4 mmole) of ethyl N-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl]carbamate, 0.15 gram (2.8 mmole) of sodium methoxide, 0.44 gram (2.4 mmole) of ethyl 3-amino-4,4,4-trifluorocrotonate, 30 mL of N,N-dimethylformamide, arid 0.37 gram (2.4 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene as reagents. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[N:5]/[O:6][CH3:7].CNC(=O)/C(/C1C=CC=CC=1O)=N\OC>>[CH3:1][NH:2][C:3](=[O:15])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[N:5][O:6][CH3:7]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1O
Agent: CNC(=O)/C(=N\OC)c1ccccc1O
Product: CNC(=O)C(=NOC)c1ccccc1O

Procedure:
4.33 g (0.0173 mol) of crude product methyl E/Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate, in particular Example II-1e from process step 8; HPLC: 27.4% methyl E-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=1.48 and 56% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.38) are dissolved in 50 ml of tetrahydrofuran and cooled to 10° C. With cooling, methylamine is introduced. After about 30 minutes, 15 ml of methanol are added, the solution is saturated with methylamine and the mixture is allowed to stand at 10° C. overnight. The solvents are distilled off under reduced pressure and the residue is mixed with a mixture of 15 ml of 2N hydrochloric acid and 15 ml of saturated sodium chloride solution and extracted three times with 25 ml of ethyl acetate each time. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure, giving 4.3 g of crude product which, according to HPLC, contains 38.8% N-methyl-E-2-(2-hydroxyphenyl)-2-methoxyimino-acetamide of log p=0.98 and 51% N-methyl-Z-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide of log p=1.29.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[F:9][C:10]([F:20])([F:19])[CH2:11][I+]C1C=CC=CC=1.[CH2:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22]>C(Cl)Cl>[CH2:21]([N:23]([CH2:11][C:10]([F:20])([F:19])[F:9])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:22]
Reactant: FC(F)(F)C[I+]c1ccccc1
Reactant: CCNc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCN(CC(F)(F)F)c1ccccc1
Yield: 98 %

Procedure:
203 mg (0.465 mmol) of (2,2,2-trifluoroethyl)phenyliodonium trifluoromethanesulfonate, 113 mg (0.931 mmol) of N-ethylaniline and 5 ml of methylene chloride were treated and worked up in the same manner as described in Reference Example 4 to obtain 92.6 mg of N-ethyl-N-(2,2,2-trifluoroethyl)aniline as an oily substance. Yield, 98%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10]([O:17][C:18]1[C:23](=[O:24])[CH:22]=[CH:21]O[C:19]=1[CH3:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.NCCC(O)=O>>[CH2:10]([O:17][C:18]1[C:23](=[O:24])[CH:22]=[CH:21][N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:19]=1[CH3:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCCCCC(=O)O
Agent: NCCC(=O)O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCCCC(=O)O
Yield: 70 %

Procedure:
6-Aminocaproic acid is reacted with 3-benzyloxy-2-methyl-4-pyrone in an exactly analogous procedure to that described in Example 2 for the reaction of the latter compound with β-alanine to give 3-benzyloxy-1-(5'-carboxypentyl)-2-methylpyrid-4-one in 70% yield, this compound being obtained after recrystallisation from ethanol/acetone (1:1 v/v) as white crystals, m.p. 145°-147° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.Cl.C([N:14]([CH2:18][CH3:19])[CH:15]([CH3:17])C)(C)C>O1CCCC1.N1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:14]2[CH2:15][CH2:17][CH2:19][CH2:18]2)[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: Clc1ncc(I)c(N2CCCC2)n1
Reaction time: 3 h

Procedure:
To a solution of 2,4-dichloro-5-iodopyrimidine (5.00 g) synthesized according to the method described in WO2008/155140 A1 in tetrahydrofuran (50 mL), N,N-diisopropylethylamine (3.49 mL) and pyrrolidine (1.65 mL) were added under ice cooling, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, 1.0 mol/L aqueous hydrochloric acid was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-chloro-5-iodo-4-(pyrrolidin-1-yl)pyrimidine (H1, 4.49 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:12]([C:14]1([NH:17][C:18]([C@H:20]2[CH2:24][C@H:23]([S:25]([C:28]3[CH:33]=[CH:32][C:31](Br)=[CH:30][C:29]=3[C:35]([F:38])([F:37])[F:36])(=[O:27])=[O:26])[CH2:22][C@@H:21]2[O:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:19])[CH2:16][CH2:15]1)#[N:13].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:12]([C:14]1([NH:17][C:18]([C@H:20]2[CH2:24][C@H:23]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([N:7]4[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:10])[F:11])[CH2:9][CH2:8]4)=[CH:30][C:29]=3[C:35]([F:37])([F:36])[F:38])(=[O:27])=[O:26])[CH2:22][C@@H:21]2[O:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:19])[CH2:15][CH2:16]1)#[N:13]
Reactant: FC(F)(F)CN1CCNCC1
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCCC2)CC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(N4CCN(CC(F)(F)F)CC4)cc3C(F)(F)F)C[C@@H]2OC2CCCC2)CC1

Procedure:
The title compound was prepared in analogy to example 176 using 1-(2,2,2-trifluoro-ethyl)-piperazine instead of morpholine and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-cyclopentyloxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 195) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 635.2 (M−H)−.
Reaction SMILES: [ClH:1].C([N:15]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1)(C1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[ClH:1].[NH:15]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1
Reactant: COC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1CNC1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
4N hydrochloric acid in ethyl acetate (12.7 ml) and 20% palladium hydroxide (3.57 g) were added to a solution of methyl 1-benzhydrylazetidine-3-carboxylate (3.57 g) in methanol (360 ml), followed by stirring under a pressurized hydrogen atmosphere (0.4 MPa) at room temperature for 11 hours. The catalyst was removed by filtration, and washed with methanol and water. The filtrate was concentrated to give a crude product of the target compound as a pale yellow oil, which was used in the next reaction supposing that the reaction proceeded quantitatively and 1.93 g of the product was obtained.
Reaction SMILES: CC1(C)OO1.[CH3:6][C@@H:7]1[C@H:25]([OH:26])[C@@H:24]([CH3:27])[C:22](=[O:23])[C:21]([CH3:29])([CH3:28])[C@@H:20]([OH:30])[CH2:19][C:17](=[O:18])[O:16][C@H:15](/[C:31](/[CH3:39])=[CH:32]/[C:33]2[N:37]=[C:36]([CH3:38])[S:35][CH:34]=2)[CH2:14][C@@H:12]2[O:13][C@:11]2([CH3:40])[CH2:10][CH2:9][CH2:8]1>>[CH3:6][C@@H:7]1[C@H:25]([OH:26])[C@@H:24]([CH3:27])[C:22](=[O:23])[C:21]([CH3:28])([CH3:29])[C@@H:20]([OH:30])[CH2:19][C:17](=[O:18])[O:16][C@H:15](/[C:31](/[CH3:39])=[CH:32]/[C:33]2[N:37]=[C:36]([CH3:38])[S:35][CH:34]=2)[CH2:14][C@@H:12]2[O:13][C@:11]2([CH3:40])[CH2:10][CH:9]=[CH:8]1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)C/C=C\[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: CC1(C)OO1
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CC=C[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1

Procedure:
We considered whether the incorporation of C9-C10 olefin in epothilone B (51, EpoB) would alter its biological profile in the same direction as was the case with its 12,13 desoxy counterparts. Toward this end, we studied the epoxidation of 28 with 2,2′-dimethydroxirane (DMDO). The reaction indeed proceeded with high chemoselectively at the more substituted C12-C13 olefin. There was obtained an 87% yield of a 1:2.6 ratio of the (E)-9,10-dehydroepothilone B (49) and its diastereomer bearing the α-12,13-oxirane (structure not shown). In vitro studies with 49 (whose configurations at C12 and C13 was established by its reduction to afford Epo B) revealed it to be roughly 2-4 fold more potent than the parent EpoB (51) in various cell lines. While compound 49 proved to be the most potent epothilone we encountered in our program, its narrow therapeutic index in xenografts, as well as its difficult accessibility (vide supra) served to discourage further its pre-clinical development. Interestingly, the unnatural α-oxirane was virtually devoid of activity.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH2:9](O)[CH2:10][CH2:11][CH3:12]>Cl>[ClH:1].[CH2:9]([O:7][C:6](=[O:8])[C@H:3]([CH2:4][SH:5])[NH2:2])[CH2:10][CH2:11][CH3:12]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCCCO
Agent: Cl
Product: CCCCOC(=O)[C@@H](N)CS
Yield: 30 %

Procedure:
L-Cysteine hydrochloride (100 g) is dissolved in 250 ml of butanol saturated with dry HCl. The solution is heated under reflux for 4 hours. Excess solvent is evaporated and ethyl acetate (150 ml) is added to the residue. The crystals which form are recrystallized from ethyl acetate, mp 91° C., yield 30%, IR (KBr)1745 cm-1 ; NMR (CDCl3) δ9.2-3.4 (b, 3, NH3⊕), 4.7 (t, 1, --CH), 4.3 (t, 2, --OCH2 --), 3.3 (b, 2, CH2S), 1.0 (5, 3, --CH3), 1.0-3.0 (m, 4, --CH2CH2).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[S:16])=[CH:10][C:9]=2[O:17][CH3:18])[CH:7]=1>>[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:1])=[S:16])=[CH:10][C:9]=2[O:17][CH3:18])[CH:7]=1
Reactant: COc1cc(N=C=S)ccc1-n1cnc(Cl)c1
Reactant: N
Product: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
Step A (4): Methanolic ammonia (1.0 M, 100 mL, 100 mmol) was added to a flask charged with 4-chloro-1-(4-isothiocyanato-2-methoxy-phenyl)-1H-imidazole (4.27 g, 16.1 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated to dryness in vacuo. The solid was suspended in ethanol (200 mL) and stirred for 2 hours. The solid was collected by vacuum filtration and dried under high vacuum for 24 h to afford 1-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (3.85 g, 83% yield) as a white solid. LC-MS (M+H)+ 283.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:29][CH2:26][CH2:27][CH3:28])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: CCCN
Solvent: COCCOC
Product: CCCNc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile and propylamine in DME. ES-MS m/e (%): 382 (M+K+, 10), 366 (M+Na+, 20), 344 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH2:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH3:18])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCc2ccccc2C)c1
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 29.8 %

Procedure:
To a solution of methyl 3,5-dihydroxybenzoate (50 g, 0.30 mol) in DMF (500 ml) at 0° C. was added sodium hydride (10.8 g, 0.27 mol) portion wise. The reaction was allowed to warm to 15° C., and stirred for 20 minutes. The mixture was re-cooled to 0° C. and a solution of 2-methylbenzyl bromide (36 ml, 0.27 mol) in DMF (50 ml) was added over 30 minutes. The reaction was warmed to ambient temperature and concentrated in vacuo. The residual oil was partitioned between ethyl acetate (500 ml) and water (250 ml), and the ethyl acetate layer was separated, washed with water and evaporated. The residue was purified by column chromatograph on silica gel (gradient, 0-100% ethyl acetate in isohexane) to give the desired compound (21.9 g, 27%).
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:16])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[Br:17][C:8]1[CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](=[O:16])[N:4]([CH:1]([CH3:2])[CH3:3])[C:9]=1[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)c(C)n(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in Example 1(5) (1.12 g, 5.00 mmol) and N-bromosuccinimide (890 mg, 5.00 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h, and then the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=2/1˜1/1) to give 1.34 g (91%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=1>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2csc(C)n2)n1
Reactant: Fc1cncc(Br)c1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-thiazol-4-yl)-amide and 3-Bromo-5-fluoropyridine in accordance with the general method of example 20 to yield the final compound as an off-white solid, MS (ISP): m/e=344.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:9]1)[C:5]([OH:7])=O)[CH3:2].[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:22]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:9]2)=[CH:25][CH:24]=1)#[N:21]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOC(C(=O)O)n1ccc(-c2ccc(OC)cc2)n1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)n1ccc(-c2ccc(OC)cc2)n1

Procedure:
(RS)-Ethoxy-[3-(4-methoxy-phenyl)-pyrazol-1-yl]-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-[3-(4-methoxy-phenyl)-pyrazol-1-yl]-acetamide. White amorphous solid. MS 391.2 ([M+H]+)
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:53])[CH2:10][C:11]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl>[NH:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:45]=[CH:46][C:47]([C:49]([F:50])([F:51])[F:52])=[CH:48][C:11]=4[CH2:10][C:9]([NH2:8])=[O:53])[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][N:18]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(C(F)(F)F)cc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1cc(C(F)(F)F)ccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
TFA (1.0 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-4-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A109) (0.121 g, 0.185 mmol) in DCM (10 mL) and the resulting mixture stirred for 24 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue was dissolved in DCM. Cyclohexane was added and the resultant precipitate was collected by vacuum filtration to give the title compound 25 as a cream solid (0.065 g, 68%); 1H NMR (400 MHz, d4-MeOH) δ 8.55 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.6 Hz, 2H), 4.73-4.49 (m, 2H), 3.74 (s, 2H), 3.28-3.21 (m, 2H), 3.17-3.09 (m, 2H), 2.95 (m, 2H), 2.84-2.71 (m, 1H), 1.96 (d, J=13.6 Hz, 2H), 1.79 (m, 2H). LCMS-A: rt 4.679 min; m/z 552.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:43]1([O:49][C:50]([O:52][CH:53]([O:55][C:56](=[O:77])[C@@:57]([CH2:75][OH:76])([CH3:74])[CH2:58][C@H:59]([NH2:73])[CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)[CH3:54])=[O:51])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C=O)C>[CH:43]1([O:49][C:50]([O:52][C@H:53]([O:55][C:56](=[O:77])[C@@:57]([CH2:75][OH:76])([CH3:74])[CH2:58][C@H:59]([NH:73][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:63][CH:62]=2)[CH3:54])=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CC(OC(=O)OC1CCCCC1)OC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](OC(=O)OC1CCCCC1)OC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,2,3-Triazole-4-carboxylic acid (45.2 mg, 400 μmol), DIPEA (209 μL, 1.2 mmol) and HCTU (165 mg, 400 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester (193 mg, 400 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The products were purified and separated by preparative HPLC, then lyophilized to yield to yield compound ZC (20 mg; purity 95%), MS m/z [M+H]+ calc'd for C31H38N4O2, 579.27. found 579.6, and compound ZD (15 mg; purity 95%), MS m/z [M+H]+ calc'd for C31H38N4O2, 579.27. found 579.6.