Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)CCCCC1.[CH2:26]([S:32](Cl)(=[O:34])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:26]([S:32]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=1)(=[O:34])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Product: CCCCCCS(=O)(=O)Nc1cccc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
Sulfonation of aniline 17 by hexane-1-sulfonyl chloride following the method used in Example 6 gives tert-butyl 3-(3-(hexylsulfonamido)phenyl)propylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[NH:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[NH:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH2:13][CH3:17])=[O:10]
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Product: CCCOC(=O)C(=O)Nc1cc(Cl)ccc1O
Temperature: 100 °C
Reaction time: 48 h
Yield: 300.7 %

Procedure:
A mixture of 2.5 g of ethyl 5-chloro-2-hydroxyoxanilate, 200 mg of p-toluenesulfonic acid, and 100 ml of n-propanol was stirred for 2 days at 100° C. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether and recrystallized from n-propanol to provide 0.9 g of n-propyl 5-chloro-2-hydroxyoxanilate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([I:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:25]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:14]([CH3:25])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[C:11]([I:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cncc(F)c2)nc1I
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1I
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
To a solution of tert-butyl 2-(5-fluoropyridin-3-yl)-4-iodothiazol-5-ylcarbamate (1.20 g, 2.85 mmol) in DMF (5.7 mL) at 0° C. was added sodium hydride (125 mg, 3.13 mmol, 60% oil suspension) and the mixture was stirred at 0° C. for 10 min. To the yellow mixture was added iodomethane (0.49 g, 3.42 mmol) and the reaction mixture was stirred at 0° C. for 30 min. The ice-water bath was removed and the mixture was stirred for an additional 1 hour. The mixture was acidified with 0.1 N aq. HCl to neutral pH and diluted with ethyl acetate (100 mL) and aqueous sodium bicarbonate (5 mL). The organic phase was separated and rinsed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow residue. This residue was purified on silica gel chromatography (6:4 hexane/ethyl acetate) to give tert-butyl 2-(5-fluoropyridin-3-yl)-4-iodothiazol-5-yl(methyl)carbamate as a pale yellow solid (1.13 g, 91%): mp 70-71° C.; 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.53 (bs, 1H), 7.99 (d, J=0.9 Hz, 1H), 3.23 (s, 3H), 1.45 (s, 9H); ESIMS m/z 436.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.[N:22]1([CH2:27][CH2:28][CH2:29]Cl)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:29][CH2:28][CH2:27][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: ClCCCN1CCCC1
Reactant: Oc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(OCCCN4CCCC4)cc23)cc1Cl
Temperature: 100 °C
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to 100° C. for 16 hours, 4-(3'-chloro-4'-fluoroanilino)-6-hydroxyquinazoline was reacted with 3-(pyrrolidin-1-yl)propyl chloride hydrochloride (Chem. Abs., 82, 57736) to give 4-(3'-chloro-4'-fluoroanilino)-6-(3-pyrrolidin-1-ylpropoxy)quinazoline in 45% yield; NMR Spectrum: 1.73 (m, 4H), 2.03 (m, 2H), 2.58 (m, 4H), 2.69 (t, 2H), 4.22 (t, 2H), 7.44 (t, 1H), 7.51 (m, 1H), 7.73 (d, 1H), 7.85 (m, 1H), 7.9 (d, 1H), 8.17 (m, 1H), 8.52 (s, 1H), 9.72 (broad s, 1H); Elemental Analysis: Found C, 62.3; H, 5.9; N. 13.7; C21H22ClFN4O 0.25H2O requires C, 62.2; H, 5.6; N, 13.8%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[C:18]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19].Cl>N1C=CC=CC=1>[C:18]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([S:26]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:16])([F:17])[F:1])=[CH:10][CH:11]=2)(=[O:28])=[O:27])=[CH:30][CH:31]=1)(=[O:20])[CH3:19]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
To 8.5 g (36 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)aniline in 30 ml pyridine, add 7.8 g (30 mmole) N-acetylsulfanilyl chloride. Stir 2 hours, pour onto ice and acidify with concentrated HCl. Extract with Et2O, and wash this with 1N NaOH. Acidify the aqueous layer, extract with Et2O and dry and concentrate. Recrystallize from Et2O-hexane to give the product; m.p. 198°-200° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:37]=[CH:36][C:16]2[N:17]([CH3:35])[C:18]([NH:20][C:21]3[S:22][C:23]4[CH:29]=[C:28]([O:30][C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[N:19][C:15]=2[CH:14]=1)=[O:12])(C)(C)C.[ClH:39]>>[ClH:39].[NH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:37]=[CH:36][C:16]2[N:17]([CH3:35])[C:18]([NH:20][C:21]3[S:22][C:23]4[CH:29]=[C:28]([O:30][C:31]([F:32])([F:33])[F:34])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[N:19][C:15]=2[CH:14]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-amino-ethyl)-amide hydrochloride (27 mg) was prepared by following General Procedure L using (2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester (55 mg), and hydrochloric acid (0.1 ml, 4.0 N solution dioxane). LC/MS: m/z 452. 1H NMR (DMSO-d6, 400 MHz): δ 8.63 (br, 1H), 8.42 (br, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.71 (m, 2H), 7.44 (d, 1H), 7.35 (d, 1H), 4.19 (t, 2H), 3.64 (s, 3H), and 3.08 (m, 2H), 2 —NH proton signals were not observed.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(I)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
2-Chloro-4-iodobenzoic acid (5.0 g, 18 mmol) was dissolved in tetrahydrofuran (7 mL), and a solution of a borane-tetrahydrofuran complex in tetrahydrofuran (1 M, 21 mL, 23 mmol) was added at 0° C., followed by stirring at room temperature for 3 days. Water and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure to afford (2-chloro-4-iodophenyl)methanol (4.8 g, 18 mmol) as a white solid (quantitative yield).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[C:4]([Cl:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[Cl:25][C:4]1[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[CH:6][C:7]([F:8])=[C:2]([N:28]2[CH2:29][CH2:30][O:26][C:27]2=[O:31])[CH:3]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3cc(F)c(Br)cc3Cl)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3cc(F)c(N4CCOC4=O)cc3Cl)CC2)c(C)c1
Yield: 58.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-chloro-5-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (851 mg) described in Preparation Example 7 and oxazolidin-2-one (174 mg), the title compound (506 mg) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]=[C:10]([CH2:12][N:13]2[C:18]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:21][C:17]=3[C:16](=[O:28])[N:15]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:14]2=[O:35])[O:9][N:8]=1.[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[CH:53][C:54]([C:55]([N:32]4[CH2:31][CH2:30][CH:29]([N:15]5[C:16](=[O:28])[C:17]6[S:21][C:20]([C:22]7[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=7)=[CH:19][C:18]=6[N:13]([CH2:12][C:10]6[O:9][N:8]=[C:7]([CH2:6][CH2:5][CH2:4][O:3][CH3:2])[N:11]=6)[C:14]5=[O:35])[CH2:34][CH2:33]4)=[O:56])=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: COCCCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CCCOC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-{[3-(3-methoxypropyl)-1,2,4-oxadiazol-5-yl]methyl}-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (210 mg; compound B90) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10) and HBTU (167 mg) in DCM (3.5 ml) in the presence of DIPEA (207 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluent: EtOAc] as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[CH2:17][CH2:16]1)=[O:12]
Reactant: BrCCBr
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C1(c2cccc(Br)c2)CC1
Reaction time: 0.5 h

Procedure:
A solution of (3-Bromo-phenyl)-acetic acid methyl ester (4.54 g, 20 mmol) dissolved in dry THF (10 mL) was added dropwise to suspension of NaH (95% dry, 1.05 g, 44 mmol) in DMF (40 mL) and THF (10 mL), under a nitrogen atmosphere, at 0° C. After 30 min, gas evolution ceased, and 1,2-dibromoethane (3.79 mL, 44 mmol) was added dropwise over 20 min. The resulting mixture was stirred for 1 h, then quenched with 1N HCl, extracted with ether, washed with brine, dried over MgSO4, and stripped of solvent. The resulting oil was distilled under high vacuum. The product was collected between 95° C. and 105° C. Yield 2 g, 39%.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:17]([C@@H:18]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH3:19])=[CH:16][C:15]2[C:10](=[C:11]([Cl:31])[CH:12]=[CH:13][CH:14]=2)[N:9]=1)=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1COCC1.C1(C)C=CC=CC=1>[Cl:31][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[S:41][C:1]([CH3:2])=[N:4][N:5]=1)[C:17]([C@@H:18]([N:20]1[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]1=[O:30])[CH3:19])=[CH:16]2
Reactant: CC(=O)NNC(=O)c1nc2c(Cl)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N2C(=O)c3ccccc3C2=O)s1
Temperature: 120 °C

Procedure:
To a stirred solution of (S)—N′-acetyl-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)-ethyl)quinoline-2-carbohydrazide (85 mg, 0.19 mmol) in THF (1.5 mL) and toluene (3.0 mL) was added Lawesson's reagent (118 mg, 0.29 mmol). The reaction was heated in the microwave at 120° C. for 20 minutes and then cooled to room temperature and purified by column chromatography (SiO2, 12 g, hexanes:ethyl acetate, 1:0 to 1:1) to give 2-((S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (1H, s), 7.77-7.84 (4H, m), 7.70 (2H, dd, J=5.3, 2.9 Hz), 7.46-7.51 (1H, m), 7.06 (1H, q, J=7.0 Hz), 2.85 (3H, s), 2.11 (3H, d, J=7.0 Hz).
Reaction SMILES: O.[OH-].[Li+].[C:4]([N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH2:19][C:20]([NH:22][C@@H:23]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24](=[O:31])[C:25]([O:27]C(C)C)=[O:26])=[O:21])[C:9](=[O:39])[C@H:8]1[CH:40]([CH3:42])[CH3:41])(=[O:6])[CH3:5]>CO>[C:4]([N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH2:19][C:20]([NH:22][C@@H:23]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:24](=[O:31])[C:25]([OH:27])=[O:26])=[O:21])[C:9](=[O:39])[C@H:8]1[CH:40]([CH3:42])[CH3:41])(=[O:6])[CH3:5]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)C(=O)OC(C)C)C(=O)[C@H]1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)C(=O)O)C(=O)[C@H]1C(C)C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Water (0.45 ml) and a 1 N aqueous lithium hydroxide solution (55 μl) are added to a solution of isopropyl (3S)-3-{(3R)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate (24.5 mg, Compound No. 2-2) in methanol (0.5 ml), and the mixture is stirred for one hour. The reaction mixture is concentrated under reduced pressure, and 1 N hydrochloric acid is added to the concentrate to acidify the system. The whole is extracted with ethyl acetate, and the extract is washed with water and a saturated aqueous sodium hydrogencarbonate solution successively and dried over magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (21.8 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:45][C:46]([NH:48][CH:49]1[C:59]2[CH:60]=[C:61](O)[CH:62]=[CH:63][C:58]=2[C:57]2[C:52](=[CH:53][C:54]([O:69][CH3:70])=[C:55]([O:67][CH3:68])[C:56]=2[O:65][CH3:66])[CH2:51][CH2:50]1)=[O:47]>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:61]1[CH:62]=[CH:63][C:58]2[C:57]3[C:56]([O:65][CH3:66])=[C:55]([O:67][CH3:68])[C:54]([O:69][CH3:70])=[CH:53][C:52]=3[CH2:51][CH2:50][C@H:49]([NH:48][C:46](=[O:47])[CH3:45])[C:59]=2[CH:60]=1)=[O:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
A mixture of 3-{[(2R)-2,6-di(tertbutoxycarbonylamino)hexanoyl]amino}propanoic acid (2) (0.178 g; 0.5 mmol), DCCI (0.124 g; 0.6 mmol), DMAP (0.013 g; 0.1 mmol) and N-acetyl-colchicinol (0.25 g; 1.2 mmol) in dichloromethane was stirred under argon atmosphere at ambient temperature for 5 hours. After filtration of the insoluble material the residue was purified by flash chromatography eluting with dichloromethane/ethanol (95/5) to give (1).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:29]([NH:21][S:18]([C:16]2[CH:15]=[CH:14][C:11]3[CH2:12][CH2:13][N:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:9][C:10]=3[CH:17]=2)(=[O:20])=[O:19])=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)NC(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Reactant: O=C=NC1CCCCC1
Product: CC(C)NC(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
By the reaction of 3-isopropylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(3-isopropylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with isopropylisocyanate in a manner analogous to that described in Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]3[CH2:39][C:40](O)=[O:41])=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.CN(C)C=O.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:40](=[O:41])[CH2:39][CH:27]1[CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31][N:26]1[C:24]([O:23][CH2:22][CH:20]1[C:21]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)O)C1
Reactant: Nc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)Nc2ccccc2Br)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromoaniline (3.69 g, 21.44 mmol), and 2-(1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (10 g, 21.44 mmol) in a 1:1 solution of N,N-dimethylformamide:pyridine (100 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.27 g, 53.6 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and was subsequently washed with brine (3×) and 1 M HCl (3×). The organic solution was then concentrated onto silica gel and purified via flash chromatography (10-70% ethyl acetate/hexanes) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (s, 1 H), 7.81-7.95 (m, J=7.67 Hz, 2 H), 7.53-7.75 (m, 4 H), 7.22-7.48 (m, 5 H), 7.10 (dd, J=7.21 Hz, 1 H), 4.56 (s, 1 H), 4.17-4.42 (m, 3 H), 3.61-3.98 (m, 3 H), 2.89-3.18 (m, 2 H), 2.62-2.88 (m, 2 H), 2.49-2.58 (m, 1 H), 1.32-1.50 (m, 9 H); MS (APCI+) m/z 522.2 (M-Boc+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[CH3:45][N:46]1[CH:50]=[CH:49][N:48]=[C:47]1[Sn](CCCC)(CCCC)CCCC>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.C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9]([C:47]2[N:46]([CH3:45])[CH:50]=[CH:49][N:48]=2)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccccc3)c(Cl)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(-c3nccn3C)c(Cc3ccccc3)c(Cl)c2c1
Temperature: 110 °C

Procedure:
A mixture of (3-benzyl-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (1.01 g, 1.86 mmol, Example 109), 1-methyl-2-(tributylstannyl)-1H-imidazole (1.42 g, 3.68 mmol), Pd(PPh3)4 (206 mg, 0.180 mmol), and toluene (10 mL) was sparged with N2 for about 10 minutes, then heated at 83° C. for 16 hours and 110° C. for 3 hours. After cooling down to room temperature, the mixture was concentrated in vacuo and DCM was added. The precipitated solid was filtered and dissolved in DMSO and MeOH. A few drops of TFA were added to improve solubility. The mixture was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a TFA salt. 1H NMR (400 MHz, MeOH-d4) δ 9.06 (s, 1H), 8.94 (s, 1H), 8.86 (d, J=2.02 Hz, 1H), 8.54 (d, J=2.02 Hz, 1H), 8.22 (d, J=9.09 Hz, 1H), 8.16 (dd, J=2.02, 8.08 Hz, 1H), 7.90-7.94 (m, 2H), 7.64 (d, J=1.52 Hz, 1H), 7.19-7.26 (m, 3H), 7.18 (d, J=1.52 Hz, 1H), 6.86-6.90 (m, 2H), 4.54 (s, 2H), 3.74 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=1[C:25](O)=[O:26]>>[CH3:33][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[C:24]=1[C:25]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:26]
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: COc1cccc(OC)c1C(=O)O
Product: COc1cccc(OC)c1C(=O)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. for C25H26N4O3, 430.51; m/z found, 431.2 [M+H]+.