Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:14][C@H:15]2[CH2:19][CH2:18][C@H:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:16]2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.[O-2].[O-2].[Mn+4]>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][C@H:17]1[CH2:18][CH2:19][C@H:15]([NH:14][C:7]2[C:6]([CH:4]=[O:3])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=2)[CH2:16]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1cnc(SC)nc1N[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [Mn+4]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ncc(C=O)c(N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (−)-(1S,3S)-4-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (910 mg, 2.21 mmol) (from Example 29d supra) in tetrahydrofuran (55 mL) at 0° C. was added in portions lithium aluminum hydride (250 mg, 6.63 mmol) (Aldrich). The reaction mixture was allowed to slowly warm up to room temperature. After stirring overnight the reaction mixture was poured in portions into a vigorously stirred mixture of ethyl acetate and saturated aqueous potassium sodium tartrate solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a solid that was then dissolved in dichloromethane (55 mL). To this solution was added manganese dioxide (1.92 g, 22.11 mmol) (Aldrich) and the mixture was stirred overnight. The slurry was filtered, the solids were washed with tetrahydrofuran (approximately 25 mL) and the combined organic layer was evaporated to a residue that was purified by chromatography on a silica gel column with a 0–50% diethyl ether in hexanes gradient to give (−)-(1S,3S)-4-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carbaldehyde as a viscous colorless oil. (Yield 615 mg, 76%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.C([O:35][C:36](=[O:40])[CH2:37][CH2:38][NH2:39])(C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH2:38][CH2:37][C:36]([OH:35])=[O:40])=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)NCCC(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 1 Step D (0.1 mmol, 41 mg), the hydrochloride salt of β-alanine tert-butyl ester (0.15 mmol, 27 mg), HOBt (0.25 mmol, 38 mg) and EDC (0.4 mmol, 77 mg) in 1 mL of DMF was added DIEA (0.5 mmol, 90 μL). The reaction mixture was allowed to stand at ambient temperature overnight, then partitioned into EtOAc/H2O. The aqueous phase was washed with EtOAc, and the combined organic phase was dried with MgSO4 and the solvent was removed under reduced pressure. The residue was treated with 3 mL of 2:30:68H2O/TFA/DCM for 1 hr and the solution was concentrated under reduced pressure. Purification by reverse-phase chromatography (Condition A), followed by lyophilization, afforded the product as a white solid. MS (ESI): m/z 477 (M+H). HPLC A: 1.70 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[S:11][CH:12]=1.[NH:25]1[CH:29]=[C:28]([CH2:30][CH2:31]O)[CH:27]=[N:26]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:31][CH2:30][C:28]3[CH:29]=[N:25][NH:26][CH:27]=3)=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: OCCc1cn[nH]c1
Reactant: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1c(-c2ccccc2Cl)csc1-c1ccc(OCCc2cn[nH]c2)cc1
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of methyl [4-(2-chlorophenyl)-2-(4-hydroxyphenyl)thien-3-yl]acetate (0.485 g, 1.35 mmol), 2-(1H-pyrazol-4-yl)-ethanol (0.166 g, 1.48 mmol), and PPh3 (0.388 g, 1.4 mmol) in THF (3 mL) was added at 0° C. diethyl azo-dicarboxylate (DEAD) (0.265 g, 0.24 mL, 1.52 mmol). The solution was stirred overnight and the solvent removed. The product was purified directly by flash chromatography (20:1 CHCl3:MeOH) to yield methyl (4-(2-chlorophenyl)-2-{4-[2-(1H-pyrazol-4-yl)ethoxy]phenyl}thien-3-yl)acetate (0.565 g). This material was reacted as in Example 1, Steps 7 and 8 to yield 2-(4-(2-chlorophenyl)-2-{4-[2-(1H-pyrazol-4-yl)ethoxy]phenyl}thien-3-yl)-N-(diaminomethylene)acetamide (0.151 g) as a white solid. mp 71-72° C.; 1H NMR (500 MHz, DMSO-d6) δ: 2.90 (t, 2H, J=6.7 Hz), 3.50 (s, 2H), 4.15 (t, 2H, J=6.9 Hz), 7.05 (m, 2H), 7.44 (m, 6H), 7.55 (m, 2H), 7.70 (s, 1H). MS (ES) m/z 478.1 ([M−H]−). MS (ES) m/z 538.1 ([M+CH3COO]−). MS (ES) m/z 957.3 ([2M−H]−). Anal. Calcd for C24H22ClN5O2S.H2O: C, 57.88; H, 4.86; N, 14.06. Found: C, 55.49; H, 5.37; N, 14.80. A description of 2-(1H-pyrazol-4-yl)-ethanol can be found in Jones and Mann, J. Am. Chem. Soc., 75, 4048-52; 1953.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]2=[O:31])=[N:22][CH:23]=1>CN(C=O)C>[Cl:30][C:28]1[CH:27]=[CH:26][C:25](=[O:31])[N:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][O:1][C:2]3[CH:9]=[C:8]([CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)[CH:7]=[CH:6][C:3]=3[C:4]#[N:5])=[CH:23][N:22]=2)[CH:29]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(CBr)cn1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1OCc1ccc(-n2cc(Cl)ccc2=O)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Hydroxy 4-imidazol-1-ylmethyl-benzonitrile (0.050 g, 0.25 mmol) and 5'-bromomethyl-5-chloro-[1,2']bipyridinyl-2-one (Example 10 Step 2) (0.079 g, 0.262 mmol) were dissolved in dry DMF (5 mL), treated with CsCO3 (0.123 g, 0.376 mmol) and stirred at ambient temperature for 18 hr. The reaction mixture was partitioned between EtOAc and aqueous satd NaHCO3 solution, the organic layer washed with H2O, brine, and dried (MgSO4). Chromatography (SiO2, 1-4% CH3OH in CH2Cl2) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[CH2:19]([CH:29](CCCCCCCCCCCC)[C:30](Cl)=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN1CCCC1=O>[C:30]([NH:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1)(=[O:31])[CH2:29][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCC(=O)Nc1ccc2c(c1)=NC(=O)N=2
Reaction time: 8 h

Procedure:
5-Aminobenzimidazolone (0.95 g, 6.36 mmol), triethylamine (1.1 mL, 7.89 mmol), N-methylpyrrolidinone (NMP, 5 mL), and dry THE (8 mL) are mixed in a 100 mL round bottom flask under an inert atmosphere. To this solution, a second solution of 2-decyltetradecanoyl chloride from Step I dissolved in dry THE (30 mL) is slowly added. After stirring overnight, deionized water (50 mL) is added and the THF removed by rotary evaporation to give an aqueous slurry. The solid was collected by vacuum filtration and washed with deionized water before suspending in methanol (60 mL) and heating to reflux. The suspension was then cooled and the solid was filtered and washed with fresh methanol to give 5-dodecanamido-2-benzimdazolone as a white powder (1.63 g). The product is identified by 1H and 13C NMR spectroscopy and ESI-MS and is of satisfactory purity.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)=[CH:16][C:17]=3[C@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[C:9]([F:32])[CH:8]=1)(=O)=O.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[CH3:56][C@H:57]1[O:62][C@@H:61]([CH3:63])[CH2:60][NH:59][CH2:58]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>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].O>[CH3:56][C@@H:57]1[CH2:58][N:59]([C:7]2[CH:8]=[C:9]([F:32])[C:10]3[O:11][C:12]4[C:17](=[CH:16][C:15]([C:26]5[CH:31]=[N:30][CH:29]=[CH:28][N:27]=5)=[CH:14][CH:13]=4)[C@@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]=3[CH:20]=2)[CH2:60][C@H:61]([CH3:63])[O:62]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cnccn3)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Product: C[C@@H]1CN(c2cc(F)c3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cnccn4)ccc2O3)C[C@H](C)O1
Temperature: 110 °C

Procedure:
A microwave vial was charged with (S)-2-amino-5′-fluoro-2′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (150 mg, 0.302 mmol), Pd2(dba)3 (13.84 mg, 0.015 mmol), biphenyl-2-yldi-tert-butylphosphine (10.82 mg, 0.036 mmol) and (2R,6S)-2,6-dimethylmorpholine (104 mg, 0.907 mmol) and capped under argon. LiHMDS (1 M in THF) (1.511 mL, 1.511 mmol) was added and the mixture was heated in the microwave at 110° C. for 1 hr. To the reaction was added 1 ml of water and the mixture was concentrated in vacuo. The product was purified via Gilson HPLC (gradient elution 20-70% MeCN/H2O, 0.1% TFA) and freebased with sodium bicarbonte to afford (S)-2′-((2R,6S)-2,6-dimethylmorpholino)-4′-fluoro-7′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off white solid. MS m/z=462.0 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([N:31]3[CH:35]=[N:34][C:33]([CH3:36])=[N:32]3)=[C:26]([F:37])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(C)=O>[F:37][C:26]1[CH:25]=[C:24]([NH:23][C:20]2[N:19]=[C:18]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:22]3[N:21]=2)[CH:29]=[C:28]([F:30])[C:27]=1[N:31]1[CH:35]=[N:34][C:33]([CH3:36])=[N:32]1
Reactant: Cc1ncn(-c2c(F)cc(Nc3n[nH]c(C(CCCCCl)c4ccc(OC(F)(F)F)cc4)n3)cc2F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: Cc1ncn(-c2c(F)cc(Nc3nc4n(n3)CCCCC4c3ccc(OC(F)(F)F)cc3)cc2F)n1
Yield: 34.4 %

Procedure:
A solution of 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (1.24 g, 2.30 mmol), sodium iodide (1.72 g, 11.5 mmol), and diisopropylethylamine (2.00 mL, 11.5 mmol) in acetone (50 mL) was heated in a sealed vessel at 100° C. for 6 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (70% EtOAc/chloroform) to afford 400 mg of the titled compound. The solid was recrystallized from EtOAc/Hex to afford 230 mg (19% yield) of the titled compound as a crystalline white solid. LC-MS (M+H)+ 506.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.11 (1H, s), 7.13-7.23 (6H, m), 6.92 (1 H, s), 4.22-4.33 (3 H, m), 2.49 (3 H, s), 2.15-2.27 (1 H, m), 2.05-2.13 (1H, m), 1.92-2.01 (2 H, m, J=14.8, 9.8, 7.2, 7.2 Hz), 1.82-1.90 (2 H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.S(Cl)([Cl:16])(=O)=O.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:16])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Oc1ccc2cc(Br)ccc2c1Cl
Reaction time: 2 h

Procedure:
The solution of 6-bromo-2-naphthol (10.0 g, 0.045 mol) in chloroform (100 mL) was added sulfuryl chloride (6.4 mL, 0.09 mol). The mixture was stirred at reflux for 0.5 hour then at room temperature for 2 hours. Water (50 mL) was added and the organic phase was washed with water then solvent evaporated. The solid was crystallized from hexane and air dried to give the title compound as a solid, mp 103-105° C. Mass spectrum (−ES, [M−H]−) m/z 255, 257, 259. 1HNMR (500 MHz, DMSO-d6): δ10.63 (s, 1H), 8.15 (d, 1H, J=1.8 Hz), 7.95 (d, 1H, J=9.0 Hz), 7.7 (d, 1H, J=9 Hz), 7.68 (dd, 1H, J=9.0, 1.8 Hz), and 7.32 ppm (d, 1H, J=8.85 Hz). Elemental Analysis for C10H6BrClO: Calculated: C, 46.64; H, 2.35; N, 0.00. Found: C, 46.69; H, 2.35; N, 0.00.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([OH:26])[C:22]([N+:23]([O-:25])=[O:24])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:26][CH3:28])[C:22]([N+:23]([O-:25])=[O:24])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(O)cc(c23)C(=O)N1OCc1ccccc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc2c3c(cccc3c1[N+](=O)[O-])C(=O)N(OCc1ccccc1)C2=O
Yield: 75.5 %

Procedure:
Methylation of 2-benzyloxy-5-hydroxy-6-nitro-benzo[de]isoquinoline-1,3-dione (0.24 g, 0.7 mmol, from Example V) was accomplished following the procedure of Example J using potassium carbonate (0.3 g, 2.2 mmol), and dimethyl sulfate (0.3 g, 2.1 mmol) in acetone (40 mL) to give 0.2 g of the title compound.
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([C:19]1([CH2:28][CH3:29])[CH2:24][CH2:23][CH:22]([N:25]=[C:26]=[O:27])[CH2:21][CH2:20]1)[CH3:18].O>O1CCOCC1>[CH2:28]([C:19]1([CH2:17][CH3:18])[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:27])[NH2:10])[CH2:23][CH2:24]1)[CH3:29]
Reactant: CCC1(CC)CCC(N=C=O)CC1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCC1(CC)CCC(NC(N)=O)CC1
Reaction time: 2 h

Procedure:
9.6 g of 4-(β-<2-methoxy-5-chlorobenzamido>α-methylethyl)-benzenesulfonamide are dissolved in 250 ml of dioxane. 6.9 g of finely ground potassium carbonate are added and the whole is heated to boil for 2 hours while stirring. 4.5 g of 4.4-diethylcyclohexyl-isocyanate are added dropwise while continuing to stir. Stirring and heating is continued for 8 hours, the whole is poured into water and acidified. The crystalline precipitate obtained is filtered off with suction and dried. The whole is dissolved in dimethylformamide, methanol is added and thus a crystalline mass is obtained of N-[4-(β-<2-methoxy-5-chlorobenzamido>α-methyl)-ethyl-benzenesulfonyl]-N'-(4.4-diethyl-cyclohexyl)-urea melting at 161°-163°C.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:33](O)=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:51][C@H:52]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[CH2:53][CH2:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56]>>[C:1]([O:18][CH:19]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:33]([NH:51][C@H:52]([C:65]([O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:66])[CH2:53][CH2:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@H](C(=O)O)[C@@H](C)O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)[C@@H](C)O
Yield: 38.7 %

Procedure:
Starting from N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-threonine (450 mg) prepared by the method of Preparation B-4 and dibenzyl L-glutamate (210 mg), dibenzyl N-[N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-threonyl]-L-glutamate (250 mg) was obtained as crystals according to a similar manner to that of Example 2.
Reaction SMILES: Cl.[CH3:2][NH2:3].C[O:5][C:6]([CH:8]1[CH2:12][C:11]2[CH:13]=[C:14]([NH:17][C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=4)[C:21]([F:36])=[CH:20][N:19]=3)[CH:15]=[CH:16][C:10]=2[O:9]1)=O>>[CH3:2][NH:3][C:6]([CH:8]1[CH2:12][C:11]2[CH:13]=[C:14]([NH:17][C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:35])[F:33])[CH:26]=4)[C:21]([F:36])=[CH:20][N:19]=3)[CH:15]=[CH:16][C:10]=2[O:9]1)=[O:5]
Reactant: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4cccc(OC(F)(F)F)c4)n3)ccc2O1
Reactant: CN
Agent: Cl
Product: CNC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4cccc(OC(F)(F)F)c4)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine, the reaction of methyl amine Hydrogen Chloride with (±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine gave (±)-N2-[2,3-dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine. LCMS: purity: 94%; MS (m/e): 464 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][CH:35]=1)[CH2:18][CH2:19][NH:20][C:21]1[C:22](=[O:32])[N:23]([CH2:28][C:29](O)=[O:30])[C:24]([CH3:27])=[CH:25][N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([CH2:46][NH2:47])[CH:44]=2)[NH:39][CH:38]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O>[CH3:27][C:24]1[N:23]([CH2:28][C:29]([NH:47][CH2:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[C:37]3[CH3:36])=[O:30])[C:22](=[O:32])[C:21]([NH:20][CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([CH:35]=[CH:34][CH:33]=2)[O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:26][CH:25]=1
Reactant: Cc1cnc(NCCc2cccc(OC[C@H]3CCCN3C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(OC[C@H]5CCCN5C(=O)OC(C)(C)C)c4)c3=O)cc12
Yield: 102.8 %

Procedure:
A mixture of 2-[3-[(3-{[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]methoxy}phenethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 136) (65 mg, 0.13 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (25 mg, 0.16 mmol), HOBT (20 mg, 0.15 mmol), WSCDl.HCl (31 mg, 0.16 mmol) and N-methylmorpholine (40 mg, 0.40 mmol) in N,N-dimethylformamide (2.5 ml), was stirred at room temperature for 20 hrs. The reaction mixture was partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with water, brine, then dried over MgSO4 and evaporated under reduced pressure to give the title compound, (84 mg, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][S:28][CH2:29][CH2:30][O:31][C:32]([NH:34][C:35]1[NH:36][C:37](=[O:48])[C:38]2[N:39]=[CH:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=2[N:43]=1)=[O:33]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:45](=[O:46])[CH2:44][N:41]2[CH:40]=[N:39][C:38]3[C:37](=[O:48])[NH:36][C:35]([NH:34][C:32]([O:31][CH2:30][CH2:29][S:28][CH3:27])=[O:33])=[N:43][C:42]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: CSCCOC(=O)Nc1nc2c(ncn2CC(=O)O)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CSCCOC(=O)Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(2-methylthioethoxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.41 (brs, 1H), 11.35 (brs, 1H), 8.35 (m, 1H), 8.25 (m, 1H), 7.82 (d, 0.6H), 7.78 (d, 0.4H), 7.72 (m, 2H), 5.14 (s, 1.2H), 5.03 (s, 0.8H), 4.51 (s, 0.8H), 4.32 (t, 2H), 4.27 (s, 1.2H), 4.24 (t, 1.2H), 4.08 (t, 0.8H), 4.04 (t, 1.2H), 3.85 (t, 0.8H), 2.75 (t, 2H), 2.12 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[CH:16][C:10]=2[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.O>[NH:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[CH:16]=[N:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1n[nH]c2c1CNCC2
Reaction time: 1 h

Procedure:
1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.70 g, 3.1 mmol) was dissolved in trifluoroacetic acid (10 mL) at 0° C., stirred for 1 h, and was concentrated. The residue was dissolved in ethanol and treated with concentrated hydrochloric acid (1 mL). The bis-hydrochloride salt precipitated out as a white solid which was filtered to give 510 mg (83%). The free base was prepared as needed by dissolving the salt in water, loading it onto an SCX column, flushing with methanol, and then eluting with 2 M ammonia in methanol.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26]Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:24][O:25][CH3:26])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1
Reactant: Cc1cnc(Br)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
A mixture of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide (1.4 g, 3.27 mmol), chloromethyl methyl ether (0.4 mL, 5.23 mmol) and K2CO3 (1.35 g, 9.81 mmol) in THF (20 mL) was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was concentrated and purified by flash chromatography (SiO2, 20% EtOAc-hexanes) to afford N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (1.3 g) as a white solid in 84% yield. ESMS m/z (relative intensity): 473 (M+H)+ (100).