Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:43]1[CH:44]=[N:45][CH:46]=[N:47][CH:48]=1)CCC.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.F[B-](F)(F)F.[H+].[F-].[Cs+]>O1CCOCC1.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]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:44]=[N:45][CH:46]=[N:47][CH:48]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4cncnc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 100 °C
Yield: 41.1 %

Procedure:
A mixed solution of 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 (600 mg) obtained in Example 120-(1), tri-n-butyl(5-pyrimidinyl)tin (600 mg), tri-tert-butylphosphine.tetrafluoroboric acid adduct (116 mg), cesium fluoride (414 mg), and tris(dibenzylideneacetone)dipalladium (0) (91 mg) in 1,4-dioxane (18 ml) was heated under reflux at 100° C. for 3 hours under argon atmosphere. Insoluble materials were filtered off, and the filtrate was diluted with ethyl acetate and washed with brine. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25-40:60) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3-(5(5-pyrimidinyl)-2-thienylmethyl)benzene (266 mg) as colorless crystals. APCI-Mass m/Z 597 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([C@@H:52]([N:54]2[CH2:59][C@@H:58]3[CH2:60][C@H:55]2[CH2:56][NH:57]3)[CH3:53])=[C:48]([CH3:61])[C:47]=1[CH3:62]>CC(N(C)C)=O.CCOC(C)=O>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([C@@H:52]([N:54]2[CH2:59][C@@H:58]3[CH2:60][C@H:55]2[CH2:56][N:57]3[C:7]([C:5]2[CH:4]=[N:3][CH:2]=[N:1][CH:6]=2)=[O:9])[CH3:53])=[C:48]([CH3:61])[C:47]=1[CH3:62]
Reactant: COc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3)c(C)c1C
Reactant: O=C(O)c1cncnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3C(=O)c2cncnc2)c(C)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pyrimidine-5-carboxylic acid (14.9 mg, 0.12 mmol), BOP (66.3 mg, 0.15 mmol), and Et3N (34.8 μL, 0.25 mmol) are added to a solution of (1S,4S)-2-[(S)-1-(4-methoxy-2,3-dimethylphenyl)-ethyl]-2,5-diazabicyclo[2.2.1]heptane (26 mg, 0.1 mmol) in anhydrous DMA (1 mL). The reaction mixture is stirred at room temperature for 16 h, diluted with EtOAc, washed with aqueous NaOH 1N (2×8 mL) and brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by preparative thin layer chromatography eluting with CH2Cl2-MeOH—NH4OH (90-9-1) to afford a yellow oil. LC/MS: 367 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16](O)[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([SH:31])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCn2c(CCc3ccccc3)nc3cccc1c32
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: SC1CCn2c(CCc3ccccc3)nc3cccc1c32
Yield: 30.9 %

Procedure:
A portion (5.55 g) of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-ol obtained in Example 4 was suspended in xylene (700 mL); following the addition of a Lawesson reagent (4.04 g), the suspension was heated under reflux for 30 min under an argon atmosphere. After standing to cool, the supernatant was concentrated under vacuum and the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate) to yield the titled compound as colorless crystals (0.91 g).
Reaction SMILES: Cl.[CH2:2]([C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.[OH2:18]>CS(C)=O>[C:3]1([C:2]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[O:18])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O
Reactant: O=C(Cc1ccccc1)c1cccnc1
Agent: Br
Agent: Cl
Solvent: CS(C)=O
Product: O=C(C(=O)c1cccnc1)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
23.4 g (0.1 mol) of benzyl-(3-pyridyl)-ketone-hydrochloride are taken up in 180 ml of dimethyl sulphoxide and the solution is treated with 20 ml of 48% hydrobromic acid. The reaction mixture is stirred for 18 hours at 80° - 85°C and subsequently poured on a mixture of 800 g of ice and 1000 ml of water. The yellow emulsion is extracted with 2 × 200 ml of ethyl acetate. The two organic phases are combined, washed with water and dried over sodium sulphate. The red solution is concentrated in a rotary evaporator until a residual oil is left which is distilled in a bulb tube at 140° - 150°C/0.1 Torr (m.p. 56° - 57°C).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:42]=[CH:41][C:27]([CH2:28][P:29](=[O:40])([O:35][CH2:36][CH2:37][O:38][CH3:39])[O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:26][CH:25]=1>>[CH3:14][NH:13][C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[NH:8][C:6]1[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][P:29](=[O:40])([O:30][CH2:31][CH2:32][O:33][CH3:34])[O:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:41][CH:42]=2)[N:7]=1)=[O:12]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: COCCOP(=O)(Cc1ccc(N)cc1)OCCOC
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCCOC)OCCOC)cc2)ncc1C(F)(F)F

Procedure:
The title product was prepared according to the procedure for Example 102 using 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 0.050 g, 0.15 mmol) and bis(2-methoxyethyl) (4-aminobenzyl)phosphonate (Compound 185A, 0.0917 g, 0.302 mmol) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=4.80 Hz, 1H), 8.44 (s, 1H), 7.69-7.74 (m, 1H), 7.57 (d, J=7.58 Hz, 2H), 7.50 (t, J=7.96 Hz, 1H), 7.13-7.21 (m, 3H), 3.94-4.05 (m, 4H), 3.46 (t, J=4.55 Hz, 4H), 3.21-3.26 (m, 6H), 3.18 (s, 2H), 2.78 (d, J=4.55 Hz, 3H); MS (ES+): m/z: 598.1695 [MH+]. HPLC: tR=1.32 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH3:24][NH:25][O:26][CH3:27].N1C=CC=CC=1>ClCCl>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:25]([CH3:24])[O:26][CH3:27])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
16.25 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.05 mol) and 5.36 g of N,O-dimethyl hydroxylamine hydrochloride (0.055 mol, 1.1 eq) are dissolved in 100 mL of dichloromethane. The reaction mixture is cooled to 0° C. and 9.25 g of pyridine (0.11 mol, 2.2 eq) is added. The mixture is heated to room temperature and it is stirred for 1 hour. The solvent is evaporated in vacuum and 30 mL of brine and 30 mL of dichloromethane are added to the residue. After 15 min stirring the phases are separated and the organic phase is dried on sodium sulfate, the solvent is evaporated and the residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 11.9 g of the title compound (VIc) (68%) as a brown solid.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[C:18]([OH:20])(=[O:19])[CH3:17].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)COc1ccc(N)cc1
Yield: 126.1 %

Procedure:
To a solution of the product of step (b) (5 g) in ethanol (300 ml) containing glacial acetic acid (0.8 ml) under argon was added 10% Pd on C (250 mg). The argon was replaced by hydrogen and the reaction mixture was stirred under a blanket of hydrogen for 4 hours. The catalyst was filtered off through a pad of diatomaceous earth and washed with ethanol, and the combined filtrate and washings were evaporated to dryness to yield t-butyl 4-aminophenoxyacetate, acetate salt (2.5 g) as brown oil: NMR Spectrum (DMSO-d6) 1.41 (9H, s), 1.86 (3H, s), 4.43 (2H, s), 5.12 (2H, s), 6.49 (2H, d), 6.60 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][O:13][CH3:14])[CH:3]=1.S(=O)(=O)(O)O.[N+:20]([O-])([O-:22])=[O:21].[K+]>>[F:1][C:2]1[C:11]([N+:20]([O-:22])=[O:21])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][O:13][CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COCc1cc(F)ccc1C(=O)OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COCc1cc(F)c([N+](=O)[O-])cc1C(=O)OC
Temperature: -10 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a mixture of 1.75 g of methyl 4-fluoro-2-(methoxymethyl)benzoate and 8.7 mL of concentrated sulfuric acid was added 964 mg of potassium nitrate over 5 minutes under cooling at −10° C. After stirring at the same temperature for 4 hours and a half, the reaction mixture was added to 300 mL of ice water, followed by stirring. The solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 1.87 g of methyl 4-fluoro-2-(methoxymethyl)-5-nitrobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][C:19]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25](B4OC(C)(C)C(C)(C)O4)[CH:26]=3)[C:20]=2[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:40][O:41][C:42](=[O:55])[C:43]1[CH:48]=[CH:47][C:46](Br)=[C:45]([O:50][C:51]([F:54])([F:53])[F:52])[CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:40][O:41][C:42](=[O:55])[C:43]1[CH:48]=[CH:47][C:46]([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[C:20]2[N:21]=[C:17]([C@@H:12]4[CH2:13][C@H:14]([CH3:16])[CH2:15][N:11]4[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:39])[CH:6]([CH3:7])[CH3:8])[NH:18][C:19]=2[CH:29]=[CH:28]3)=[C:45]([O:50][C:51]([F:52])([F:54])[F:53])[CH:44]=1
Reactant: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(-c4ccc(C(=O)OC)cc4OC(F)(F)F)ccc32)[nH]1)C(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
A solution of ((S)-2-methyl-1-{(2S,4S)-4-methyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (250 mg, 0.48 mmol; Preparation 13), 4-bromo-3-trifluoromethoxy-benzoic acid methyl ester (140 mg, 0.47 mmol), and potassium carbonate (323 mg, 2.34 mmol) in toluene (2 mL) and water (0.5 mL) was purged with nitrogen for 5 min, then Pd(dppf)Cl2 (20.5 mg, 0.029 mmol) was added. The reaction mixture was stirred at 100° C. overnight, diluted with ethyl acetate (50 mL), washed with water (2×5 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (EtOAc/hexane 20 to 100%) to give the title intermediate (284 mg, 97% yield). (m/z): [M+H]+ calcd for C32H32F3N4O6 627.24 found 627.3.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[N:16]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][C:19]1[CH:20]=[CH:15][N:16]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[N:18]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: OCCCNc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(NCCCO)n2)c(F)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
358 mg (14.2 mmol) 95% sodium hydride was given to a solution of 2.12 g (13.5 mmol) 2-fluoro-4-nitrophenol in 25 ml DMF. Stirring was continued for 30 min. at room temperature. 2.53 g (13.5 mmol) 3-(4-Chloro-pyrimidin-2-ylamino)-propan-1-ol were added and the mixture heated to 140° C. for 24 h. The reaction mixture was evaporated, taken up with water and extracted with dichloromethane. The organic phase was extracted with sodium carbonate solution, dried (sodium sulphate) and evaporated. The obtained material was purified by chromatography over silica (dichloromethane/ethanol 95:5) to give 2.92 g (70%) 3-[4-(2-fluoro-4-nitro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol as slightly yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([C:22]([NH:24][NH2:25])=[O:23])[N:6]=1)([CH3:4])[CH3:3].[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27].C(N(CC)CC)C>C1COCC1>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:19])([CH3:20])[CH3:21])[N:8]=[C:7]([C:22]2[O:23][C:26](=[O:27])[NH:25][N:24]=2)[N:6]=1)([CH3:4])[CH3:1]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C(=O)NN)nc1C(C)(C)C
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(-c2n[nH]c(=O)o2)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 64 h

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy) methoxy]-2-pyrimidine carboxylic acid hydrazide (1.0 g, 2.8 mmoles), carbonyl diimidazole (0.7 g, 4.2 mmoles), and triethylamine (0.6 g, 5.9 mmoles) are combined in 20 mL of THF and the reaction mixture is stirred at room temperature under argon for 64 hours. The reaction is quenched with 50 mL of 10% HOAc/H2O. The organics are extracted into ether (3×30 mL) and washed with 50 nil of brine. The solvent is evaporated and the residue is taken up in 20 mL of acetic acid. The reaction mixture is warmed to reflux for 18 hours. It is cooled to room temperature and diluted with 150 mL of H2O. The organics are extracted into EtOAc (3×100 mL) and washed with H2O (3×100 mL) followed by brine (3×100 mL). The solvent is evaporated, and the remaining oil is purified by flash chromatography (50% EtOAc|Hexane). Yield of 5-[4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]-1,3,4-oxadiazole-2 (3H)-one=0.11 g (13%), mp 230°-232° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:38]4[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Nc1ncc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.273 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.19 g, 68%). MS (ISP) 560.2 [(M+H)+]; mp 250° C.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2cccnc2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncc(Sc2cccnc2)s1
Yield: 79.1 %

Procedure:
A mixture of 2-acetylamino-5-(3-pyridylthio)thiazole (8.5 g) in a mixture of ethanol (160 ml), tetrahydrofuran (50 ml) and aqueous 6N hydrochloric acid (100 ml) was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and the precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(3-pyridylthio)thiazole (5.6 g yield: 78.9%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCCCC3)nc2c1C#N
Yield: 89.5 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.15 ml, 0.88 mmol) and piperidine (83.0 μl, 0.84 mmol) were added. This was heated under reflux for 3 hours, and diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain a colorless solid (0.21 g, 90%).
Reaction SMILES: [CH2:1]([N:5]([CH2:51][CH2:52][CH2:53][CH3:54])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH2:14][CH2:15][OH:16])[N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:38])[NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)(=[O:27])=[O:26])=[CH:19][C:18]=2[C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)=[O:57].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:13][C:12]1[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:51][CH2:52][CH2:53][CH3:54])=[N:9][N:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:38])[NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)(=[O:27])=[O:26])=[CH:19][C:18]=2[C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[C:11]=1[CH2:14][C:15]([OH:57])=[O:16]
Reactant: CC(C)=O
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CCO)c1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CC(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 21.9 %

Procedure:
To N,N-dibutyl-4-chloro-5-(2-hydroxyethyl)-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamide (Example 170, 27 mg, 0.035 mmol) in acetone (640 μL) was added Jones reagent (39 μL, 0.11 mmol). The resulting reaction mixture was stirred at room temperature for 25 min. Additional Jones reagent (39 μL, 0.11 mmol) was added and stirring was continued for 1.5 h. The reaction mixture was then quenched with i-PrOH followed by water. The aqueous layer was extracted with EtOAc (3×), and the combined organics were washed with sat. aq. NaCl solution and dried over Na2SO4. After filtering through a pipette containing a small plug of CELITE®, concentration in vacuo afforded a yellow oil. The crude oil was purified by preparative HPLC to give the title compound (6 mg, 22%) as a white solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.56 (s, 1H), 8.19 (ddd, J=8.4 Hz, 3.2, 1.9 1H), 8.12 (d, J=1.8 Hz, 1H), 8.04-7.99 (m, 2H), 7.96-7.90 (m, 2H), 7.85 (dd, J=12.8, 8.4 Hz, 1H), 7.63-7.54 (m, 2H), 7.25-7.06 (m, 3.5H), 6.94 (d, J=7.0 Hz, 0.5H), 4.77-4.41 (m, 1.5H), 4.09 (br s, 0.5H), 3.79-3.38 (m, 5H), 3.24-2.67 (m, 5H), 1.60-0.84 (m, 11H), 0.78 (t, J=7.3 Hz, 2H), 0.71-0.65 (m, 1H); MS(ESI+) m/z 784.3 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:45])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([F:29])[CH:23]=3)=[CH:16][C:15]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:9][CH:8]=1.C1CCN2[C:51](=[N:52][CH2:53]CC2)CC1.CNC>O1CCCC1>[CH3:51][N:52]([CH3:53])[C:5](=[O:45])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([F:29])[CH:23]=3)=[O:30])=[CH:16][C:15]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:11][CH:12]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1F
Agent: CNC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)N(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1F
Temperature: 60 °C
Yield: 87.5 %

Procedure:
The product of Example 105B (0.108 g, 0.15 mmol) in tetrahydrofuran (3 mL) was treated with DBU (0.023 g, 0.15 mmol) and Dimethylamine (2.0 M in THF, 0.75 mL, 1.5 mmol) and heated at 60° C. for 20 minutes in a sealed tube, cooled, and concentrated under vacuum. The resulting residue was purified by chromatography on silica eluting with 97:3 dichloromethane/methanol to provide the title compound (0.08 g, 88%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H), 2.19 (s, 3 H), 2.93 (s, 6 H), 3.15-3.29 (m, 1 H), 7.01 (d, J=8.46 Hz, 1 H), 7.23 (t, J=8.64 Hz, 1 H), 7.33 (d, J=8.46 Hz, 2 H), 7.43 (dd, J=8.27, 1.65 Hz, 1 H), 7.57 (d, J=8.82 Hz, 2 H), 7.62-7.71 (m, 2 H), 7.80 (dd, J=8.27, 1.65 Hz, 1 H), 7.99 (s, 1 H), 8.50 (s, 1 H), 8.60 (s, 1 H), 8.87 (d, J=8.46 Hz, 1 H), 10.22 (s, 1 H), 10.30 (s, 1 H); MS (ESI+) m/z 610 (M+H)+.