Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:8]1[CH2:9][C@@H:6]([N:18]=[N+:19]=[N-:20])[CH2:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 85 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (29 g, 109 mmol) in DMF (100 mL) was added sodium azide (5.68 mL, 162 mmol, Sigma-Aldrich Chemical Company, Inc.) portionwise and the mixture stirred at 85° C. for 18 h. The reaction was diluted with water (200 mL) after cooling and extracted with EtOAc (3×100 mL). The combined organic was washed with water (2×100 mL) and brine, dried over Na2SO4 and evaporated in vacuo to give product tert-butyl(cis-3-azidocyclobutyl)carbamate (22 g, 104 mmol, 95% yield) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: Cc1ccc(C)c(N=C=S)c1
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cc(C)ccc2C)C1=S
Yield: 42.7 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 16.3 g of 2,5-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (10.6 g) as an off-white solid, m.p. 176°-178° C. Anal. Calcd. for. C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.70; H, 6.46; N, 11.27. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([S:17][CH2:18][CH3:19])[N:14]3[CH:20]=[CH:21][N:22]=[C:13]3[CH:12]=2)=[CH:7][C:6]=1[O:23][CH3:24].[OH-:25].[Na+]>N1CCOCC1>[CH2:18]([S:17][C:15]1[N:14]2[CH:20]=[CH:21][N:22]=[C:13]2[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:14]3[CH2:20][CH2:21][O:25][CH2:12][CH2:13]3)=[C:6]([O:23][CH3:24])[CH:7]=2)[N:16]=1)[CH3:19]
Reactant: CCSc1nc(-c2ccc(OCCCl)c(OC)c2)cc2nccn12
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCN1
Product: CCSc1nc(-c2ccc(OCCN3CCOCC3)c(OC)c2)cc2nccn12
Temperature: 25 °C
Yield: 71 %

Procedure:
Then a solution of 7-[4-(2-Chloro-ethoxy)-3-methoxy-phenyl]-5-ethylsulfanyl-imidazo[1,2-c]pyrimidine (800 mg, 2.2 mmol) in morpholine (10 ml) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was poured into a dilute NaOH solution and extracted with CH2Cl2. The combined organic extract was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography to give 5-Ethylsulfanyl-7-[3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenyl]-imidazo[1,2-c]pyrimidine (650 mg, 71%).
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([C:16]2[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.[Cl:24][C:25]1[C:30](C=O)=[C:29](Cl)[N:28]=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]2[N:9]([C@H:10]3[CH2:11][CH2:12][C@H:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:22])[CH3:23])[N:17]=4)[CH2:14][CH2:15]3)[N:8]=[CH:6][C:30]=12
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CC(C)c1noc([C@H]2CC[C@@H](NNC(=O)OC(C)(C)C)CC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1noc([C@H]2CC[C@H](n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-hydrazinecarboxylic acid tert-butyl ester (Intermediate 13; 691 mg, 2.03 mmol) in tetrahydrofuran (3 mL) was added to a cooled (0° C.) solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 361 mg, 2.03 mmol) and diisopropylethylamine (718 μL, 4.06 mmol) in anhydrous tetrahydrofuran (6 mL), and the mixture was stirred at 0° C. for 30 min and then at room temperature for 5 h. The mixture was filtered, and the filtrate was washed with brine. The aqueous layer was extracted with methyl tert-butyl ether and the organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, evaporated, and held under high vacuum. Toluene (15 mL) was added and the mixture was held at 110° C. overnight. The solvent was evaporated and the residue was purified on a Supelco 50 g column, eluting with 0-3% methanol/dichloromethane to give 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclo-hexyl]-1H-pyrazolo[3,4-d]pyrimidine (489 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 1.24 (d, 6H, J=6.9 Hz), 1.74-1.88 (m, 2H), 2.04-2.28 (m, 6H), 2.98-3.08 (m, 1H), 3.11-3.22 (m, 1H), 4.91-4.97 (m, 1H), 8.49 (s, 1H), 8.86 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[CH3:20][C:21]1[C:26]([CH:27]=O)=[CH:25][N:24]=[C:23]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[C:3]2[N:10]=[C:27]([C:26]3[C:21]([CH3:20])=[N:22][C:23]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[N:24][CH:25]=3)[NH:9][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1cc(C)c(N)c(N)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c2nc(-c3cnc(NCCCC4CCN(C)CC4)nc3C)[nH]c2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a 2 L Erlenmeyer flask were added 3,5-dimethyl-benzene-1,2-diamine.2HCl (54.85 g, 262.3 mmol) and Na2S2O5 (64.82 g, 341.0 mmol), as well as 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde (prepared as in Example 3 above) (72.5 g, 262.3 mmol) in DMF (725 mL). After addition of triethylamine (73.1 mL, 524.6 mmol), the resultant mixture was warmed on a hot plate with stirring to 90° C. and held at this temperature for 2 hours. The resultant mixture was then concentrated to near dryness and partitioned between dichloromethane (0.7 L) and 1 N NaOH (1 L). The resultant mixture was stirred for 1 hour and then filtered to isolate the voluminous solid which had formed. The solids were dried and then partitioned between chloroform (700 mL) and saturated aqueous NaHCO3 (700 mL). The layers were separated, the organic layer was dried over sodium sulfate and concentrated to a residue. The residue was recrystallized in hot heptane/ethyl acetate (1.8:1, 840 total volume) with initial hot filtration (˜1 g of oily residues removed) and final filter cake washing with heptane/ethyl acetate (3:1, 250 mL total volume) to yield the title compound as a crystalline solid.
Reaction SMILES: [C:1]([CH2:6][CH:7]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCOC(C)=O>C1COCC1>[CH2:27]([O:34][C:35]1[CH:36]=[C:37](/[CH:38]=[C:6](\[CH3:7])/[C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:40]=[CH:41][CH:42]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(C)=C/c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (carbethoxyethylidene)triphenylphosphorane (available from Aldrich) (5.50 g, 15.2 mmol) in THF (25 mL) was added 3-(benzyloxy)benzaldehyde (available from Aldrich) (2.93 g, 13.8 mmol) in THF (10 mL) under nitrogen at −78° C. The reaction was allowed to slowly warm to room temperature and stirred for 2 hours. EtOAc (100 mL) was added, and the mixture was washed with brine (30×2 mL). The organic layer was dried over MgSO4. The solvent was removed by evaporation. The crude product was purified by passing through a short silica gel column, eluting with hexane/EtOAc (85/15) to give (E)-ethyl 3-(3-(benzyloxy)phenyl)-2-methylacrylate 62.B.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([O:22][CH3:23])=[CH:20]C=[CH:18][N:17]=3)[CH2:12][CH:11]2[CH3:24])[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.COC1C(N2CCNC(C)C2)=[N:44]C=NC=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([O:22][CH3:23])=[CH:20][N:44]=[CH:18][N:17]=3)[CH2:12][CH:11]2[CH3:24])[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cncnc1N1CCNC(C)C1
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cncnc1N1CCN(CCCc2csc3ccccc23)C(C)C1

Procedure:
The title compound was prepared (0.80 g, 85%, mp 200°-205° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thienepropanol tosylate with 1-(5-methoxy-4-pyrimidinyl)-3-methylpiperazine.
Reaction SMILES: Cl.[CH2:2]([O:6][NH2:7])[CH:3]([CH3:5])[CH3:4].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25](O)=[O:26])[C:10]=1[Cl:28].Cl.C(N=C=NCCCN(C)C)C.C(O)(=O)C>CN(C)C1C=CN=CC=1.ClCCCl>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25]([NH:7][O:6][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:26])[C:10]=1[Cl:28]
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Reactant: CC(C)CON
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)NOCC(C)C)n2)c1F
Temperature: 23 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
O-iso-Butylhydroxylamine hydrochloride (380 mg, 3.0 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (740 mg, 6.0 mmol, 4.0 equiv) were sequentially added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared as in Balko et al., U.S. Pat. No. 7,314,849 B2; 500 mg, 1.5 mmol, 1.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.2 g, 6.0 mmol, 4.0 equiv) in 1,2-dichloroethane (5.0 mL) at 23° C. The resulting tan suspension was stirred at 23° C. for 18 h. The reaction mixture was quenched with glacial acetic acid (430 μL, 7.5 mmol, 5.0 equiv) and concentrated by a nitrogen stream. The residue was directly subjected to silica gel column chromatography (50% EtOAc in hexane) to afford a white powder (370 mg, 61%): mp 145-148° C.; 1H NMR (300 MHz, CDCl3) δ 9.87 (br s, 1H), 7.53 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=2 Hz, 1H), 4.95 (br s, 2H), 3.99 (d, J=1 Hz, 3H), 3.83 (d, J=7 Hz, 2H), 2.07 (m, 1H), 1.01 (d, J=6 Hz, 6H); IR (neat film) 3221 (m), 2941 (w), 2878 (w), 1653 (s) cm−1; ESIMS m/z 402.2 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:22])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: COc1ccc2cc(Br)cnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2cc(Br)c[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-7-methoxyquinoline (2.0 g, 8.40 mmol) in DCM (42 mL) at RT, mCPBA (2.9 g, 16.8 mmol) was added, and the reaction mixture was stirred at RT for 1 hour. A second portion of mCPBA (2.9 g, 16.8 mmol) was then added, and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was poured onto 10% aqueous Na2SO3 and DCM, and the layers were separated. The organic layer was washed with NaHCO3, dried over MgSO4, filtered and concentrated. The resulting product was used with no further purification. LRMS (M+H)+=254.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:39])([F:38])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35](O)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:35]([C:30]3[C:29]([C:26]4[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:38])[F:39])=[CH:24][CH:25]=4)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:36])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a stirred solution of 4-(4-aminophenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g), 4′-trifluoromethyl-biphenyl-2-carboxylic acid (0.17 g), HOBt (0.1 g), and Et3N (80 mg) in CH2Cl2 (10 mL) was added at room temperature EDCl (0.15 g) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with petroleum ether/AcOEt (70/30) to give the title compound (0.25 g) as an orange oil.
Reaction SMILES: ClC1C=CC(OC2C=CC(CCO[C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=CC=2)=CC=1C(F)(F)F.[CH3:36]CN(C(C)C)C(C)C.CI>ClCCl>[CH3:36][N:19]1[CH:20]=[C:21]([CH2:25][C:26]2[CH:31]=[N:30][CH:29]=[N:28][CH:27]=2)[C:22](=[O:24])[N:23]=[CH:18]1
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: Cn1cnc(=O)c(Cc2cncnc2)c1
Yield: 43.8 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (45 mg, 0.089 mmol) in dichloromethane (DCM) (2 mL) was added DIPEA (0.031 mL, 0.179 mmol) and MeI (8.39 μL, 0.134 mmol). The mixture was purified by reverse phase biotage affording 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy})phenyl)ethyl]oxy}-1-methyl-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (20 mg, 0.039 mmol, 43.2% yield) LCMS: rt=3.37 min, [M+H+]=517
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2)CC1.[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59][CH2:60]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOCC>[CH:4]1([N:7]([CH2:40][C:41]2[CH:42]=[C:43]([O:52][CH2:60][CH2:59][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][N:53]=3)[CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=2)[C:8](=[O:39])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[Cl:38])=[CH:22][CH:21]=2)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:5][CH2:6]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Reactant: OCCc1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCc2ccccn2)c1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in toluene (0.1 M) was added 2-pyridin-2-ylethanol (1.2 eq.) and 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.). The resulting orange solution was deoxygenated before tributylphosphine (1.2 eq.) was added. The now yellow-orange solution was heated at 100° C. for 14 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a red oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=1[CH3:20].O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:20][C:12]1[C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: COc1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1CBr
Temperature: 25 °C
Yield: 86.7 %

Procedure:
N-bromosuccinimide (590 mg, 3.30 mmol) was added to a solution of 1-methoxy-2-methyl-3-nitro-benzene (500 mg, 3.0 mmol) in carbon tetrachloride (5 mL) followed by a catalytic amount of dibenzoyl peroxide (25 mg). The reaction mixture was heated at reflux for 3 h then cooled to room temperature and poured into water. The organic phase was separated, washed with water (2×20 mL), dried over the anhydrous sodium sulfate and concentrated in vacuo to afford 2-bromomethyl-1-methoxy-3-nitro-benzene (640 mg, 86%) as a solid.
Reaction SMILES: [CH3:1][Mg]Cl.CON(C)[C:7]([C:9]1[N:10]=[C:11]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[S:12][CH:13]=1)=[O:8].[NH4+].[Cl-]>C1COCC1>[N:14]1([C:11]2[S:12][CH:13]=[C:9]([C:7](=[O:8])[CH3:1])[N:10]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1csc(-n2ccnc2)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1csc(-n2ccnc2)n1
Temperature: 25 °C
Yield: 98 %

Procedure:
Methyl magnesium(II)chloride (1.12 mL of a 3.0 M solution in THF, 3.36 mmol) was added dropwise to a 0° C. solution of 2-imidazol-1-yl-thiazole-4-carboxylic acid methoxy-methyl-amide obtained from Step 1 (400 mg, 1.68 mmol) in THF (5 mL) under a nitrogen atmosphere. The reaction was then warmed to r.t. over a period of 2 hours, sat. NH4Cl (50 mL) was added and the solution was extracted with methylene chloride (2×70 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent gave 319 mg (98%) of 1-(2-imidazol-1-yl-thiazol-4-yl)-ethanone as a white solid which was which was used without further purification in the subsequent step. [M+H]+ 194.06.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:31]([OH:34])[C:32]#[CH:33].C(NCC)C>[Cu]I.CCOC(C)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:33]#[C:32][CH2:31][OH:34])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(I)cc34)CC2)cc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(C#CCO)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A mixture of 4-(6-iodo-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide (1.056 g, 2.05 mmol), as prepared in Example 11d, CuI (3.9 mg, 20.5 μmol), trans-PdCl2[P(C6H5)3]2 (26.8 mg, 38.2 μmol), propargyl alcohol (139 μL, 2.36 mmol), and diethylamine (3.4 mL) was flushed with a stream of argon for 30 s, and then quickly sealed and vigorously stirred at rt under argon for 5 h. The resulting dark brown bilayer was concentrated under reduced pressure at rt, dissolved in DCM (10 mL), and vigorously shaken with 0.75 M EDTA (tetrasodium salt) (1×2 mL). The light green aqueous layer was extracted with DCM (1×10 mL), the organic layers were combined, dried (Na2SO4), and concentrated to give a beige foam soluble in 9:1 EtOAc/DCM (˜5 mL). Flash chromatography (1:9 hex/EtOAc→EtOAc) provided the title compound as a yellow foam (825 mg, 91%). 1H-NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 8.26 (d, 1H), 8.01 (d, 1H), 7.87 (dd, 1H), 7.25 (m, 2H), 6.85 (m, 2H), 6.33 (br s, 1H), 4.59 (d, 2H), 4.48 (heptet, 1H), 4.32-4.23 (m, 2H), 3.71 (m, 1H), 3.22-3.10 (m, 2H), 2.21-1.94 (m, 5H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 444.2, found 445.2 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].CN(C)CCCN=C=NCC.Cl.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:15])=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.44 g (26.39 mmol) of 5-nitro-1H-indole-2-carboxylic acid from Example XLVII, 7.59 g (39.58 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 1.61 g (13.19 mmol) of 4-dimethylaminopyridine are initially charged in 400 ml of a 10:1 dichloromethane:DMF mixture. 2.95 g (2.89 ml, 31.67 mmol) of aniline are added, and the mixture is stirred at RT overnight. For work-up, the mixture is diluted and extracted with aqueous hydrochloric acid and dichloromethane. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:6](=[O:22])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:38](OCC)(=[O:44])[C:39](OCC)=[O:40]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:4]3[C:1](=[O:3])[CH:2]=[C:38]([OH:44])[C:39]([OH:40])=[C:5]3[C:6]2=[O:22])=[CH:20][CH:19]=1
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)c2ccccc21
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1c2c(O)c(O)cc(=O)n2c2ccccc2n1Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-1-(4-fluorobenzyl)-3,4-dihydro-quinoxalin-2(1H)-one (0.15 g, 0.52 mmol) in DMF (5 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (0.57 mL, 0.57 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with diethyl oxalate (0.078 mL, 0.57 mmol), and stirred at room temperature overnight. The resultant mixture was then treated with additional lithium bis(trimethylsilyl)amide in THF (1.6 mL, 1.6 mmol) and stirred at room temperature for 6 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and dichloromethane. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.