Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[C:30](OCC)(=[O:32])C>CO>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([O:32][CH3:30])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(OC)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate (500 mg, 1.16 mmol; example A-10, step 1) in MeOH (10 ml) was added sodium methoxide (30%; 280 μl, 1.5 mmol) at room temperature and stirring was continued at r.t. for 2 h. The reaction mixture was poured into ethyl acetate (75 ml) and extracted with potassium hydrogen sulfate (10%). The organic phase was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The organic layers were dried and evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless solid (320 mg, 71%).
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])(=[O:3])[CH3:2].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O.[OH-].[Na+].Cl>C(O)C.O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:7]([O:6][C:5]1[CH:22]=[C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[CH:24]=[CH:25][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:39]/[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)=O)c1ccccc1C
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C(=O)/C=C/c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
A solution of ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)-butanoate (0.5 g) in ethanol (5 mL) is treated with pyridine-2-carboxaldehyde (0.12 g) and aqueous sodium hydroxide solution (0.95 g; 33% w/w) and stirred at 25° C. for 90 minutes. The solution is diluted with water and then brought to pH 7 by treatment with hydrochloric acid (2 M), forming a yellow gum. This gum is extracted with ethyl acetate, and the extract is washed with water, dried and evaporated. The resulting residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (65:35 v/v), followed by trituration with pentane, to give (E)-(RS)-4-(2-methylphenyl)-4-[2-{3-(2-pyridyl) prop-2-enoyl}-5-(3-thienylmethoxy)phenoxy]butanoic acid (0.22 g) in the form of a yellow solid, m.p. 65-70° C. [NMR(CDCl3):- 2.1-2.9 (4H,m),2.4(3H,s),4.9(2H,q),5.6(1H,q), 6.2-7.6(12H),7.7(1H,d,J=16 Hz),7.8(1H,t), 8.0(1H,d,J=16 Hz),8.6(1H,d)].
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O[C@H](CCI)c1ccccc1
Yield: 97.8 %

Procedure:
To a solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (5 g, 29.3 mmol) in acetone (50 mL) was added sodium iodide (4.83 g, 32.2 mmol). The resulting solution was heated at reflux for 16 h. The solution was cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane: ethyl acetate [100:0 to 3:1] to yield the title compound as a white solid (7.51 g, 98%); δH (300 MHz, CDCl3) 7.36 (5H, m, Ar), 4.83 (1H, m, O—CH), 3.34-3.15 (2H, m, CH2), 2.28-2.15 (2H, m, CH2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](O)=[C:13]([C:15]2([CH2:32][OH:33])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:33][CH2:32][C:15]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:24][C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[C:16]3=[O:31])[C:13]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(CO)c1cc(OCc2ccccc2)ccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C12COc1ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.2 %

Procedure:
To a stirred solution of 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chloro-2-thienyl)methyl]-3-hydroxymethyl-1,3-dihydro-2H-indol-2-one (2.71 g, 5.52 mmol) in anhydrous tetrahydrofuran (60 mL) was added dropwise tributylphosphine (1.39 g, 6.90 mmol). The solution was cooled to 0° C. and di-tert-butyl azodicarboxylate (1.59 g, 6.90 mmol) was added. The solution was stirred at 0° C. for 20 min then quenched with aqueous 10% hydrochloric acid (50 mL). The aqueous solution was extracted with ethyl acetate (3×100 mL), brine (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash column chromatography with ethyl acetate in hexanes (20%) to give 5-(benzyloxy)-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.36 g, 90%) as a colorless solid: mp 132-135° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.21 (m, 7H), 7.16-7.12 (m, 2H), 7.02 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.97 (d, J=3.8 Hz, 1H), 6.90-6.32 (m, 2H), 6.21 (d, J=2.3 Hz, 1H), 5.05 (ABq, 2H), 4.82 (s, 2H), 4.72 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.6, 155.0, 153.6, 141.9, 138.6, 137.4, 132.0 130.3, 129.4, 128.8, 128.2, 128.1, 127.9, 127.1, 124.3, 123.8, 116.6, 110.8, 110.0, 109.9, 79.4, 70.4, 58.1, 38.9; MS (ES+) m/z 476.3 (M+1), 474.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=O)[NH:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:11]1[NH:10][C:9]2[CH:14]=[CH:15][C:6]([S:3]([C:2]([F:17])([F:16])[F:1])(=[O:5])=[O:4])=[CH:7][C:8]=2[N:12]=1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)C(F)(F)F)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: O=S(=O)(c1ccc2[nH]c(Cl)nc2c1)C(F)(F)F

Procedure:
Reflux 5-trifluoromethylsulfonyl-1,3-dihydro-benzimidazol-2-one (380 mg) for 8 hours in POCl3 (10 mL). Evaporate the solvent in vacuo, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1:1 hexanes/EtOAc) to obtain 2-chloro-5-trifluoromethylsulfonyl-1H-benzimidazole. G. 1′-(5-trifluoromethylsulfonyl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1cccnc1
Yield: 28.3 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (200 mg, 0.86 mmol) was coupled to 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine (349 mg, 1.2 mmol) as described in Example 3 part g), affording 5-(4-fluoro-3-pyridin-3-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (90 mg, 28%). δH (360 MHz, CDCl3) 7.41-7.46 (2H, m), 7.50-7.55 (1H, m), 7.57-7.61 (2H, m), 7.85 (1H, d, J 8.4), 7.91-7.96 (1H, m), 8.55 (1H, d, J 8.8), 8.68 (1H, dd, J 1.4 and 4.9), 8.86 (1H, s), 9.30 (1H, d, J 4.6). m/z (ES+) 370 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:49])([CH3:48])[C:10]([NH:12][C@H:13]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)[C:14]([NH:16][C:17]1[N:18]=[C:19]([CH:22]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[C:23]([O:25]CC)=[O:24])[NH:20][CH:21]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O1CCOCC1>O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:49])([CH3:48])[C:10]([NH:12][C@H:13]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)[C:14]([NH:16][C:17]1[N:18]=[C:19]([CH:22]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[C:23]([OH:25])=[O:24])[NH:20][CH:21]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(c1ccc2ccccc2c1)c1nc(NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)c[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)Nc1c[nH]c(C(C(=O)O)c2ccc3ccccc3c2)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution consisting of ethyl 2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetate (1.52 grams, 2.28 mmol), lithium hydroxide (0.11 grams, 4.56 mmol), dioxane (10 mL), and water (10 mL) was stirred at ambient temperature until complete as determined by hplc (30 minutes). The reaction mixture was concentrated to dryness and the residue was dissolved in water (20 mL). The aqueous solution was adjusted to a pH of 3 using a 10% sodium bisulfate solution and extracted with ethyl acetate (3×25 mL). The organic layers were combined, dried using sodium, sulfate, filtered, and concentrated to give 1.34 grams (92%) of 2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methyl propanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[C:12](O)(=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]
Reactant: C=CCCCCCCCCC(=O)O
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)OCc1ccccc1[N+](=O)[O-]

Procedure:
One equivalent of 2-nitrobenzyl alcohol (2.39 g, 15.65 mmol) was combined with one equivalent of undecylenic acid (2.88 g, 15.65 mmol) and 0.1 equivalents of DMAP and dissolved in 50 mL CH2Cl2. DCC (3.23 g, 15.65 mmol) was dissolved in 30 mL CH2Cl2 and slowly added to the mixture while stirring. A white precipitate slowly formed after about 5 minutes. The reaction mixture was stirred at room temperature overnight. The precipitate was filtered off by vacuum filtration and the filtrate was concentrated by rotovap. Silica gel column chromatography with CH2Cl2/MeOH (v/v 50:1) as eluent was used for purification. The product was dried over Na2SO4, solvent removed by rotovap, and dried under vacuum producing a yellow oil. Yield: 3.91 g (78.2%). 1H-NMR (CDCl3) δ (ppm): 8.1 (d, 1H, Ar), 7.7 (t, 1H, Ar), 7.6 (d, 1H, Ar), 7.5 (t, 1H, Ar), 5.8 (m, 1H, CH═CH2), 5.5 (s, 2H, CH2—O) 4.9 (dd, 2H, CH2═CH), 2.4 (t, 2H, CH2—C═O), 2.0 (q, 2H, CH2), 1.6 (m, 2H, CH2), 1.2 (m, 10H, CH2). 13C NMR (CDCl3) δ (ppm): 173.5, 147.9, 139.5, 134.1, 132.7, 129.4, 129.1, 125.4, 114.6, 63.2, 34.5, 34.2, 29.7, 29.6, 29.5, 29.4, 29.3, 25.3. MS (ESI): (M+H)+=320.30 (calc. 320.40).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([OH:18])([CH2:11]3)[CH2:9]1)[CH2:15]2)([O-:7])=[O:6]>CN(C=O)C>[C:1]([O:18][C:10]12[CH2:16][CH:14]3[CH2:13][CH:12]([CH2:17][C:8]([N+:5]([O-:7])=[O:6])([CH2:15]3)[CH2:9]1)[CH2:11]2)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])C12CC3CC(CC(O)(C3)C1)C2
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)OC12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-nitro-3-adamantanol obtained by the method of Example 4 and 12 mmole of triethylamine were dissolved in 10 ml of DMF. To the mixture, 11 mmole of acetyl chloride was added dropwise over 30 minutes at 40° C. The mixture was stirred for another 3 hours at 40° C. As a result, the conversion of 1-nitro-3-adamantanol was 99%, and 1-acetyloxy-3-nitroadamantane (yield 95%) was formed.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=2)[CH:15]=[C:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:31]=[CH:30][CH:29]=[C:14]([CH:15]=[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH:13]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl 4-(3-(5-isopropoxypyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.5 g, 1.17 mmol) in CH2Cl2 (3 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.46 mL, 5.97 mmol). The resulting mixture was stirred for 2 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.38 g, 99%). 1H NMR (500 MHz, CDCl3): δ 8.94 (m, 2H), 7.35 (m, 2H), 7.0 (m, 2H), 6.90 (s, 1H), 6.47 (s, 1H), 4.53 (m, 1H), 3.50 (m, 2H), 3.32 (m, 2H), 2.76 (m, 2H), 2.65 (m, 2H), 1.35 (d, J=6 Hz, 6H).
Reaction SMILES: OCCCCCCC[CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].CN[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][OH:53]>>[OH:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][N:10]([CH3:9])[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=1)=[O:12]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: CNCCCCCCO
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)CCCCCCO)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 21 in place of 8-aminooctanol. ES/MS calcd. for C32H37N4O6S+ 605.2. Found m/z=605 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].[NH4+].[OH-]>OS(O)(=O)=O>[NH2:12][C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(C(F)(F)F)cc(N)n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])c(N)n1
Temperature: 25 °C

Procedure:
To a mixture of 2,6-diamino-4-trifluoromethylpyridine (173 mg) in H2SO4 (3 mL) at 0° C. was added HNO3 (0.048 mL, d=1.40). The stirred mixture was sequentially warmed to RT, aged 1.5 hours, poured onto 50 g ice, neutralized with NH4OH, extracted with EtOAc, filtered through 20 g SiO2 (washed with EtOAc until yellow color eluted), and concentrated to give 70 mg of 2,6-diamino-3-nitro-4-trifluoromethylpyridine as a yellow solid. A 1:1THF/MeOH solution of the nitro compound (65 mg) was hydrogenated (1 atm H2, Ra-Ni, 16 hours at RT), filtered, concentrated, and converted to the title compound by the method outlined in Example 21. FAB MS (M+ +1)=465; 1H NMR (300 MHz, CD3OD) δ 7.61 (t, 2H, J=7.5 Hz), 7.54-7.48 (m, 2H), 7.13-7.04 (AB q, 4H), 6.74 (s, 1H), 5.41 (s, 2H), 2.79 (q, 2H, J=7.5 Hz), 1.16 (t, 3H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[C:6]([CH2:8][NH:9][C:10]([C@@H:12]2[CH2:16][CH:15]=[N:14][N:13]2[C:17](=[O:27])[C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[OH:19])=[O:11])[CH:7]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:39]([O:19][C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:17]([N:13]1[C@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:28]2[CH:32]=[N:31][N:30]=[N:29]2)[CH2:16][CH:15]=[N:14]1)=[O:27])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O[C@@H](C(=O)N1N=CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1)c1ccc(F)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 13 %

Procedure:
To a mixture of (3S)—N—[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxy-acetyl]-3,4-dihydropyrazole-3-carboxamide (0.48 g, 1.05 mmol), pyridine (6 mL, 74 mmol), and DMAP (0.023 g, 0.188 mmol) in CH2Cl2 (8 mL) at −10° C. was added benzoyl chloride (135 μL, 1.15 mmol). The reaction mixture was allowed to attain rt and was stirred for 5 h. Another portion of benzoyl chloride (400 μL, 3.4 mmol) was added. The mixture was stirred for 60 h. LCMS analysis indicated only a trace amount of product. The solvents were removed by evaporation and pyridine (5 mL, 62 mmol) was added followed by another portion of benzoyl chloride (400 μL, 3.4 mmol). The reaction mixture was heated to 70° C. overnight. LCMS analysis indicated approximately 20% conversion of starting material. The solvent was evaporated of and the residue was purified by HPLC (MeCN gradient 0 to 100% in 0.1 M NH4OAc buffer containing 5% MeCN). The relevant fractions were combined and lyophilized to give the title compound (77 mg, 13%) together with 289 mg of unreacted starting material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[C:28]([F:34])=[CH:27][C:26]=4[O:35][CH3:36])=[CH:23][N:22]=[C:21]([N:37]4[CH2:40][CH:39]([F:41])[CH2:38]4)[N:20]=3)[C@H:13]2[CH3:42])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:51]1(B(O)O)[CH2:53][CH2:52]1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:51]1([C:2]2[CH:3]=[C:4]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]4[C:24]([C:25]5[CH:30]=[C:29]([CH:31]([CH3:32])[CH3:33])[C:28]([F:34])=[CH:27][C:26]=5[O:35][CH3:36])=[CH:23][N:22]=[C:21]([N:37]5[CH2:38][CH:39]([F:41])[CH2:40]5)[N:20]=4)[C@H:13]3[CH3:42])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)[CH2:53][CH2:52]1
Reactant: OB(O)C1CC1
Reactant: COc1cc(F)c(C(C)C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(Br)cc(C(F)(F)F)c2)[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C3CC3)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 140 °C
Yield: 46.8 %

Procedure:
To (4S,5R)-5-[3-bromo-5-(trifluoromethyl)phenyl]-3-({2-(3-fluoroazetidin-1-yl)-5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (0.031 g, 0.047 mmol) in dioxane (0.5 mL) was added tripotassium phosphate (0.071 mL, 0.142 mmol), cyclopropylboronic acid (6.10 mg, 0.071 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.47 mg, 4.74 μmol). The system was flushed with nitrogen and was sealed before heating at 140° C. by microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc, washed with sat. aqueous sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate, filtered, concentrated and the crude was purified by column chromatography to yield (4S,5R)-5-[3-cyclopropyl-5-(trifluoromethyl)phenyl]-3-({2-(3-fluoroazetidin-1-yl)-5-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (13.3 mg, 0.022 mmol) as white solid. LCMS calc.=617.3. found=617.5.1H NMR (CDCl3, 500 MHz) δ 8.15 (s, 1H), 7.29 (d, J=7.5 Hz, 2H), 7.19 (s, 1H), 7.01 (d, J=8.5 Hz, 1H), 6.69 (d, J=12 Hz, 1H), 5.54˜5.33 (br m, 2H), 4.74 (d, J=17 Hz, 1H), 4.50 (m, 2H), 4.33 (m, 3H), 4.16˜4.15 (br m, 1H), 3.97˜3.94 (br m, 1H), 3.79 (s, 3H), 3.25˜3.19 (m, 1H), 1.31˜1.26 (m, 6H), 1.07 (m, 2H), 0.76 (m, 2H), 0.69 (m, 3H). RTA=98 nM.
Reaction SMILES: C([O:4][C:5](=[O:44])[C:6]([CH3:43])([CH3:42])[CH2:7][C:8]1[N:9]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:10]2[C:15]([C:16]=1[S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]([O:22][CH2:23][C:24]1[N:25]=[CH:26][C:27]3[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:12][CH:11]=2)C=C.CO.[Li+].[OH-].Cl>C1COCC1>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:9]2[C:10]3[C:15](=[CH:14][C:13]([O:22][CH2:23][C:24]4[N:25]=[CH:26][C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:12][CH:11]=3)[C:16]([S:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[C:8]2[CH2:7][C:6]([CH3:43])([CH3:42])[C:5]([OH:44])=[O:4])=[CH:40][CH:39]=1
Reactant: C=CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3cc4ccccc4cn3)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3cc4ccccc4cn3)cc12
Temperature: 25 °C
Yield: 77.4 %

Procedure:
The compound from Step 1 (174 mg) was dissolved in THF (5 mL), MeOH (3 mL), 1N LiOH (1.3 mL) and heated at 65° C. for 1 hr. After cooling to r.t., the mixture was acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography eluting first with 1:1 EtOAc/hexane and followed by the addition of 5% HOAc to this solvent. The title compound (126 mg), was obtained as a white solid; mp 227.5°-228.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:28]>>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[N:14]=[C:15]([O:16][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([C:27]#[N:28])=[CH:30][CH:31]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Oc1nc(-c2cc(Cl)cc(Cl)c2)nc2c1CN(Cc1ccccc1)CC2
Product: N#Cc1ccc(COc2nc(-c3cc(Cl)cc(Cl)c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3,5-dichloro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin4-ol (which was obtained in Intermediate 7) and 4-cyanobenzyl bromide according to Method A; LC retention time 3.01 min; MS: m/z (ESI) 501 (M+H).