Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:29]([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[N:22]=2)[CH2:16][CH2:15]1)=S.[S]>[Hg]=O.O1CCCC1>[CH2:33]([O:32][CH2:31][CH2:30][N:29]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=[C:21]1[CH2:20][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][C:9]2[NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)[CH2:15][CH2:16]1)[CH3:34]
Reactant: CCOCCn1c(CN2CCN(CCNC(=S)Nc3cnccc3N)CC2)nc2cccnc21
Agent: O=[Hg]
Agent: [S]
Solvent: C1CCOC1
Product: CCOCCn1c(CN2CCN(CCNc3nc4cnccc4[nH]3)CC2)nc2cccnc21
Reaction time: 3 h
Yield: 30 %

Procedure:
A mixture of 16.9 parts of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl)-1-piperazinyl]ethyl]thiourea, 11.4 parts of mercury(II)oxide, 0.1 parts of sulfur and 135 parts of tetrahydrofuran was stirred for 3 hours at reflux temperature. The reaction mixture was filtered while hot over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 4.73 parts (30.0%) of N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazinyl]ethyl]-1H-imidazo[4,5-c]pyridin-2-amine; mp. 124.5° C. (compound 123).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH:3]=[CH:4][C:5](=[O:8])[CH2:6][CH3:7].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[CH:2]([C@H:3]1[C@@H:12]2[CH2:13][C@H:14]([CH:10]=[CH:11]2)[C@H:4]1[C:5](=[O:8])[CH2:6][CH3:7])([CH3:9])[CH3:1]
Reactant: C1=CCC=C1
Reactant: CCC(=O)C=CC(C)C
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CCC(=O)[C@H]1[C@@H](C(C)C)[C@H]2C=C[C@H]1C2
Temperature: 0 °C
Reaction time: 84 h
Yield: 78 %

Procedure:
Prepared according to general procedure A from 6-methylhept-4-en-3-one (89 μL, 0.60 mmol), cyclopentadiene (99 μL, 1.2 mmol), 70% aqueous perchloric acid (10.3 μL, 0.12 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (32 mg, 0.12 mmol) in water (120 μL) for 2.5 days at 0° C. Then, an additional 1.2 mmol of cyclopentadiene was added and the mixture was allowed to stir for an additional 3.5 days at 0° C. Purification by silica gel chromatography (18:1 pentane:ether) provided the title compound as a colorless oil in 78% yield (90 mg, 0.47 mmol); 6:1 endo:exo, endo 90% ee. For the purpose of characterization, the more quickly eluting exo diastereomer was removed by silica gel chromatography as above. IR (film) 3057, 2961, 2869, 1709, 1460, 1367, 1334, 1136, 1028, 904.2, 716.6 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.26 (dd, J=5.7, 3.3 Hz, 1H, CH═CH), 5.79 (dd, J=5.7, 2.7 Hz, 1H, CH═CH), 3.14 (m, 1H, CHCH═CH), 2.77 (m, 1H, CHCH═CH), 2.63 (dd, J=3.6, 3.6 Hz, 1H, CHCO), 2.49 (m, 2H, CH2CO), 1.40 (m, 3H, CH(CH3)2 and CHCH2CH), 1.05 (d, J=7.5 Hz, 3H, one of CH(CH3)2), 0.99 (dd, J=4.8, 4.8 Hz, 3H, CH2CH3), 0.84 (d, J=7.5 Hz, 3H, one of CH(CH3)2), 13C NMR (75 MHz, CDCl3) δ 211.6, 139.6, 131.9, 57.8, 49.1, 47.4, 47.2, 45.5, 35.2, 33.1, 22.7, 22.2, 8.5; HRMS (CI) exact mass calc'd for (C13H20O) requires m/z 192.1514, found m/z 192.1513. [α]D=+20.1 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (162° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=4.4 min, and (1S, 2S, 3R, 4S) endo isomer tr=4.2 min, exo isomers tr=3.9, 4.1 min.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.N[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CC[N:21]=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:3]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:21]1[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][N:15]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)c1cccoc1=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2ccccn2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.4 %

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (462 mg, 3 mmol, Aldrich) in DMF (6 mL) at rt was added 3-aminopyridine (282 mg, 3 mmol). The reaction mixture was stirred at rt for 12 h and treated with EDCI.HCl (650 mg, 3.4 mmol) and DMAP (200 mg). The reaction mixture was stirred for 2.5 days at rt, and most of the DMF was removed in vacuo. The residue was purified by preparative HPLC to afford the desired product (500 mg, 72%) as a glassy material. 1H NMR (CDCl3) δ 8.53 (d, 1H, J=5.0 Hz), 8.20 (dd, 1H, J=9.2, 2.2 Hz), 8.06 (dd, 1H, J=6.0, 1.1 Hz), 7.89-7.82 (m, 2H), 7.32 (dd, 1H, J=6.6, 5.0 Hz), 6.36 (t, 1H, J=6.6 Hz), 3.86 (s, 3H); MS(ESI+) m/z 231.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][C:6]([C:7]([O:22][C@@H:23]2[C@@H:27]([CH:28](C=O)[OH:29])[O:26][C@@H:25]([N:32]3[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]3=[O:34])[CH2:24]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11](OC)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:43]=[O:44].[OH-].[Na+].[C:47]([OH:50])(=O)C>O1CCOCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:42]=[CH:41][C:6]([C:7]([O:22][C@@H:23]2[C:27]([CH2:28][OH:29])([CH2:47][OH:50])[O:26][C@@H:25]([N:32]3[CH:40]=[C:38]([CH3:39])[C:36](=[O:37])[NH:35][C:33]3=[O:34])[CH2:24]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:44][CH3:43])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: C=O
Reactant: COc1ccc(C(O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)O[C@@H]2C(O)C=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)OC2(CO)CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.3 %

Procedure:
To a stirred solution of 3′-O-(4,4′dimethoxytrityl)-5′-formylthymidine (16.3 g, 30.07 mmol) in dioxane (120 ml) at 0° C. was added dropwise, in turn, 36% formaldehyde (24 ml) and 2N NaOH (60 ml). The resulting solution was stirred at room temperature for 6 h. The reaction mixture was cooled to 0° C. and 10% acetic acid in water added dropwise until pH reached 7.5. The mixture was diluted with ethyl acetate (1 L), washed with 10% brine (500 ml, then 2×300 ml), dried (Na2SO4), and concentrated. The crude was purified by chromatography on silica (EtOAc-hexane, 3:1) to give 11.45 g (66.3%) of 3′-O-(4,4′-dimethoxytrityl)-4′-C-hydroxymethylthymidine as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH2:14].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(F)cc(N)c1N

Procedure:
A slurry of 2-amino-5-fluoro-3-nitro-benzoic acid methyl ester (1.8 g, 84.0 mmol) and 10% Pd/C (0.5 g) in methanol (50 mL) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered over celite bed, concentrated to dryness. the resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: COc1ccc(C=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(CC2=C(O)CC(CCc3ccc(OC)c(Cl)c3)(C3CCCC3)OC2=O)cc1

Procedure:
The title compound was prepared by coupling 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 of Example B(13), to 4-Methoxy-benzaldehyde using the AlCl3/reduction procedure described for Example B(13). 1H NMR (CDCl3): δ 1.45–1.85 (brm, 8H), 1.98 (m, 2H), 2.29 (t, J=7.6 Hz, 1H) 2.44–3.02 (m, 7H), 3.88 (s, 3H), 3.94 (s, 3H), 6.73–7.85 (m, 7H). ESIMS (MH+): 471.7.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:13])[C:8]=1[C:9](=[O:12])[CH2:10][CH3:11])[NH2:5].[C:14](Cl)(Cl)=[O:15].C(N(CC)CC)C.[CH:25]#[C:26][CH:27]([OH:29])[CH3:28]>C1(C)C=CC=CC=1>[CH3:13][C:7]1[CH:6]=[C:4]([NH:5][C:14](=[O:15])[O:29][CH:27]([CH3:28])[C:26]#[CH:25])[CH:3]=[C:2]([CH3:1])[C:8]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CCC(=O)c1c(C)cc(N)cc1C
Reactant: C#CC(C)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CC(C)OC(=O)Nc1cc(C)c(C(=O)CC)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.8 %

Procedure:
3,5-Dimethyl-4-propionylaniline (1.77 g) in toluene (20 ml) was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation uner reduced pressure to give crude 3,5-dimethyl-4-propionylphenyl isocyanate. The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and 1-butyn-3-ol (0.75 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give 1-methyl-2-propynyl N-(3,5-dimethyl-4-propionylphenyl)carbamate (Compound No. 60) (2.45 g) in a yield of 89.9%. nD23.0 1.5247.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:8]([N+]([O-])=O)=[CH:7][C:5]=1N)([CH3:3])[CH3:2].OS(O)(=O)=O.N([O-])=O.[Na+].N[C:24](N)=O.[OH2:27]>>[CH:1]([C:4]1[CH:10]=[CH:9][C:8]([CH3:24])=[CH:7][C:5]=1[OH:27])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1N
Reactant: NC(N)=O
Reactant: O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc(C(C)C)c(O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
2-Isopropyl-5-nitro-aniline (1.89 g, 10.49 mmol) was added dropwise to a mixture of conc.H2SO4 (9 mL) and H2O (50 mL). This reaction mixture was cooled to 0° C. and a solution of NaNO2 (763 mg, 11.06 mmol) in H2O (2 mL) was added. The reaction mixture was stirred for 10 minutes and then 1 g of urea was added to decompose the excess NaNO2, followed by the addition of 10 mL of 1:2 conc.H2SO4: H2O. The reaction mixture was then refluxed for 10 minutes, cooled to room temperature and extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. The residue was then purified via silica gel column chromatography using 10 to 20% EtOAc in hexanes to obtain 2-isopropyl-5-methyl-phenol (1.41 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J=8.5, 2.3 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.26 (s, 1H), 3.39-3.18 (m, 1H), 1.29-1.26 (m, 6H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:40](O)=[O:41])([N:34](C)[C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:47](N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:47])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:40]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(OC3CC4C(=O)NCCCCC=CC5CC5(C(=O)O)N(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid 46 (560 mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 47 as a white powder: m/z=750 (M+H)+. 1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, 1H), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1H), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J=13 Hz, 1H), 5.04 (t, J=11 Hz, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.21 (s, 1H), 7.02 (s, 1H), 7.22 (d, J=10 Hz, 1H), 7.45 (s, 1H), 7.99 (d, J=10 Hz, 1H), 10.82 (broad s, 1H).
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:29]([Li])[CH2:30][CH2:31]C.C(=O)CC.CCCCCC>C1COCC1>[Br:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:5]([CH:6]=[CH:29][CH2:30][CH3:31])[CH:4]=1
Reactant: [Li]CCCC
Reactant: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCC=O
Product: CCC=Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a suspension of (3-bromo-benzyl)-triphenyl-phosphonium chloride (10 g, 23.2 mmol) in THF (100 mL) at 0° C. was added n-butyl lithium (10.2 mL, 2.5 N in hexane, 25.5 mmol) dropwise. The resulting orange suspension was stirred for 30 minutes. Propanal (1.61 g, 28 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0° C. and cold hexane (500 mL) was added. The white precipitate was filtered, and the filtrate was concentrated. The residue was purified with flash chromatography using hexane to afford 1-bromo-3-but-1-enyl-benzene (4.4 g, 90%) as a mixture of 3:1 (E):(Z) isomers. MS: m/z 211 (M+H+). The mixture was distillled under vacuum to afford the (E) isomer (1 g, >95% E) and the (Z) isomer (200 mg, 75% Z).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:18])[NH:10][CH:11]([C:15]([OH:17])=O)[NH:12]2)=[CH:7][CH:6]=1)=[O:4].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:48][CH:49]1[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]1>O.CN(C=O)C>[C:58]([O:57][C:55]([N:52]1[CH2:53][CH2:54][CH:49]([NH:48][C:15]([CH:11]2[NH:10][C:9](=[O:18])[C:8]3[C:13](=[CH:14][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[NH:12]2)=[O:17])[CH2:50][CH2:51]1)=[O:56])([CH3:61])([CH3:59])[CH3:60]
Reactant: COC(=O)c1ccc2c(c1)NC(C(=O)O)NC2=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc2c(c1)NC(C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)NC2=O
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
A mixture of 7-(methoxycarbonyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxylic acid (0.15 g, 0.6 mmol), DMF (8 mL), N-methylmorpholine (66 μL, 0.6 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.23 g, 1.2 mmol) and 1-hydroxybenzotriazole (81 mg, 0.6 mmol) was stirred for 15 min and 4-amino-1-Boc-piperidine (144 mg, 0.72 mmol) was added. The reaction mixture was stirred at rt for 1 d. Water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 100% EtOAc/DCM) to afford to afford methyl 2-({[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}carbonyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (60 mg, 20%). LC-MS: (FA) ES+ 333.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11](=O)[CH:12]=[CH2:13].[N:15]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:30]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)(=[O:23])=[O:22])=[CH:25][CH:26]=3)[C:11]([CH3:10])=[CH:12][CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C=CC(C)=O
Reactant: Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Product: Cc1ccc(-c2cccc(Br)c2)n1-c1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
3-Bromobenzaldehyde and but-3-en-2-one were treated according to the procedure outlined in General Procedure C followed by subjecting the resulting product to conditions outlined in General Procedure D along with p-piperidinylsulfonyl phenylamine to obtain the titled compound. 1H NMR (CDCl3) δ ppm 1.45-1.60 (6H), 2.18 (3H), 3.05 (4H), 6.18 (1H), 6.40 (1H), 7.05-7.90 (8H); MS (ESI) m/z 459/461 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19].[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29]O)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(OC(C)(C)C)=O>CCCCCC.CCOC(C)=O>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][O:19][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:7][CH2:6][C:5]=2[CH:17]=[CH:18][C:2]=1[Cl:1])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Agent: CC(C)(C)OC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2

Procedure:
Use a method similar to the General Procedure 4-3, using 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (277 mg, 0.94 mmol) and N-(tert-butoxycarbonyl)ethanolamine (244 mg, 1.51 mmol) to give, after chromatography on silica gel eluting with hexane/EtOAc (1:0 and 3:1), the desired intermediate (392 mg, 95%). MS (ES+) m/z: 337 (M+H-Boc)+.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([F:14])[C:5]=1[C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([C:25]#N)=[CH:17][CH:16]=1.[OH2:27]>C(O)CO.CCOCC.O>[F:14][C:6]1[C:7]([O:12][CH3:13])=[CH:8][C:9]([O:10][CH3:11])=[C:4]([F:3])[C:5]=1[C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([C:25]([OH:27])=[O:1])=[CH:17][CH:16]=1
Reactant: O
Reactant: [OH-]
Reactant: COc1cc(OC)c(F)c(-c2ccc(C#N)c3nccnc23)c1F
Agent: [K+]
Solvent: CCOCC
Solvent: OCCO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Temperature: 150 °C
Reaction time: 4 h

Procedure:
A solution of KOH (2.4 g, 42.8 mmol, 10 equiv) in H2O (10 mL) was added to 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carbonitrile (Step 88.2) (1.4 g mg, 4.3 mmol) in ethylene glycol (20 mL). The reaction mixture was stirred at 150° C. for 4 h, allowed to cool to rt, diluted with Et2O/H2O, and extracted with Et2O. The aqueous phase was acidified to pH 5 by addition of 6 N HCl. Vacuum filtration of the resulting suspension afforded 1.47 g of the title compound as a brown solid, which was used without further purification: ESI-MS: 347.1 [M+H]+; tR=4.22 min (System 1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:35][C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([OH:45])[CH2:43][NH2:44])=[CH:38][C:37]=1[NH:46][S:47]([CH3:50])(=[O:49])=[O:48])C1C=CC=CC=1>>[OH:45][C@H:42]([C:39]1[CH:40]=[CH:41][C:36]([OH:35])=[C:37]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:38]=1)[CH2:43][NH:44][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1OCc1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide (which was obtained in Example 8) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.70 (m, 2 H), 1.90–2.10 (m, 2 H), 2.06 (s, 3 H), 2.50–2.65 (m, 2 H), 2.90–3.15 (m, 3 H), 2.94 (s, 3 H), 3.55–3.70 (m, 2 H), 4.65–4.80 (m, 1 H), 6.79 (d, J=9.0 Hz, 2 H), 6.97 (d, J=9.0 Hz, 2 H), 7.00 (d, J=8.0 Hz, 1 H), 7.06 (dd, J=8.0, 1.2 Hz, 1 H), 7.22 (d, J=1.2 Hz, 1 H), 7.40 (d, J=8.7 Hz, 2 H), 7.69 (d, J=8.7 Hz, 2 H), 10.42 (s, 1 H), 10.44 (s, 1 H); MS (ES) m/z: 618.0 (MH+); HRMS Calcd. for C28H36N5O7S2 (MH+): 618.2056. Found: 618.2056.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])OC(C)(C)C)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C@@H:22]1([NH2:32])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]C1.[CH2:33]([N:36]([CH2:50][CH2:51][CH3:52])[C:37]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([CH2:48]C)[CH:47]=1)C(O)=O)=[O:38])[CH2:34][CH3:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[C:41]1[CH:45]=[C:46]([CH3:48])[CH:47]=[C:39]([C:37]([N:36]([CH2:33][CH2:34][CH3:35])[CH2:50][CH2:51][CH3:52])=[O:38])[CH:40]=1)[C@H:11]([OH:12])[CH2:13][NH:32][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN[C@@H]2CCc3ccccc32)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3), (1R)-2,3-dihydro-1H-inden-1-ylamine (VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH+=578.