Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH2:23])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH:23][C:35]([NH:34][C:32]4[N:31]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=4)=[O:36])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1nc2nccc(Oc3ccc(N)c4ccccc34)c2[nH]c1=O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4nc(N)c(=O)[nH]c34)c3ccccc23)n(-c2ccccc2)n1
Yield: 44 %

Procedure:
Method F2 was used with 3-amino-8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a yellow/orange solid (46 mg, 44%).
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][C:7]1[CH:34]=[CH:33][C:10]2[C:11]3[C:20](=[O:21])[O:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:17]=4)[C:12]=3[CH2:30][CH2:31][O:32][C:9]=2[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CC(C[Al]CC(C)C)C.CO>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([Si:5]([CH3:35])([CH3:36])[O:6][C:7]1[CH:34]=[CH:33][C:10]2[C:11]3[CH:20]([OH:21])[O:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[CH:17]=4)[C:12]=3[CH2:30][CH2:31][O:32][C:9]=2[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCc1c-2c(=O)oc2cc(O[Si](C)(C)C(C)(C)C)ccc12
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(O)C1=C2CCOc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: -78 °C
Reaction time: 3 h

Procedure:
2,8-Bis-(tert-butyl-dimethyl-silyloxy)-11,12-dihydro-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-one (35 mg, 0.066 mmol) was dissolved in toluene (5 mL) and the resulting solution was cooled to −78° C. A solution of Dibal-H solution (70 μL, 1.5 M solution in toluene) was then added to above reaction mix at −78° C. The reaction mixture was stirred at −78° C. for 3 h. To the reaction mixture was then added methanol (0.5 mL), and then Rochelle solution (2 ml, 1M solution). The reaction mixture was gradually warmed to room temperature. The reaction mix was diluted with CH2Cl2 (30 mL), the organic layer was separated and dried over Na2SO4. The solution was filtered and evaporated to yield a crude product that was purified on SiO2 to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][C@H:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[O:26][C:7](=[O:11])[CH2:6][C@H:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2c(c1)[C@H](c1ccccc1)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1)[C@H](c1ccccc1)CC(=O)O2
Reaction time: 48 h
Yield: 90.9 %

Procedure:
5-Methyl-3-(S)-phenyl-indan-1-one (400 mg, 1.8 mmol) and mCPBA (98%, 485 mg, 2.8 mmol) were suspended in dry CH2Cl2 (6 ml) at 0° C. followed by TsOH:H2O (20 mg). The reaction was kept at 4° C. for 48 h. The mixture was diluted with 10 ml of CH2Cl2 and washed with 2×10 ml of saturated Na2SO3, saturated NaHCO3 and brine. Flash chromatography eluting with ethyl acetate:pentane 10:90 gave 390 mg (90%) of the title compound. Rf 0.83 (ethyl acetate:pentane 20:80) (ChiralCel OD-H) 0.5 mL/min of hexane/isopropanol 95/5 (S)-isomer 15.18 min, (R)-isomer 17.42 min, 89% ee. IR (neat cm−1): 2900, 2360, 1769, 1495, 1208, 1145. 1H NMR δ: 2.28 (s, 3H), 3.05 (m, 1H), 4.32 (t, J=6.8 Hz, 1H), 6.98 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.11 (dd, J=2.0, 8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 7.33 (m, 3H) 13C NMR δ: 20.7 37.1, 40.7, 116.8, 125.3, 127.5, 127.6, 128.6, 129.1, 129.3, 134.3, 140.5, 149.6, 167.8. MS (EI 70 eV) m/z (rel. intensity): 238 (55) [M+], 220 (57), 195 (100), 181(10), 165 (12), 152 (9).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:34]([CH3:33])(=[O:36])=[O:35])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(C(=O)N2CCOCC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone (example 10), sodium hydride and methanesulfonyl chloride in N,N-dimethylformamide, to give the desired product as a colorless foam (54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:17])([F:19])[F:18])(=[O:15])=[O:14])=[C:7]([C@H:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:27])=[CH:5]2
Reactant: CCOC(=O)C(=O)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](O)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (2 g, 4.26 mmol) and (R)-2-methyl-CBS-oxazaborolidine (0.236 g, 0.85 mmol) in anhydrous toluene at −40° C. was added a solution of catecholborane (0.615 mL, 5.79 mmol) in toluene (10 mL) over 40 minutes. The reaction mixture was stirred for 1 hour and quenched with sodium carbonate solution, diluted with ethyl acetate and stirred vigorously for 20 minutes at −20° C., then at room temperature for 45 minutes. The aqueous layer was removed and the organic layer was washed with sodium carbonate solution (4×), saturated ammonium chloride solution, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give the desired compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10]1([NH:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[F:9][C:2]([F:1])([F:8])[C:3]([NH:19][CH2:18][CH2:17][NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: NCCNc1ccccc1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCCNc1ccccc1)C(F)(F)F
Temperature: 25 °C
Yield: 114.4 %

Procedure:
Ethyl trifluoroacetate [383-63-1] (5.5 mL, 46.1 mmol) was added to a stirred, 0° C., solution of N1-phenylethane-1,2-diamine [1664-40-0] (5.0 mL, 38.4 mmol) in THF (125 mL) and was allowed to stir and warm to ambient temperature under N2 blanket over 17 h then was partitioned between brine and ethyl acetate. The extract was dried (MgSO4) and evaporated to provide 10.2 g of clear dark yellow liquid. LRMS (ESI) m/z 232.9 [(M+H)]+, calc'd for C10H11F3N2O: 232.21.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Br:29]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:29])[N:6]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: Nc1nc(Sc2ccc3ccccc3c2)nc2c1ncn2Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(Sc2ccc3ccccc3c2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 44 %

Procedure:
6-Amino-9-benzyl-2-(2-naphthylthio)purine (221 mg, 0.58 mmol) and bromine (0.4 ml) were dissolved in 160 ml of methylene chloride and the solution was stirred at room temperature for 5.5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (118 mg, yield 44%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].O.[Cl:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([S:22][CH2:23][C@H:24]([CH3:28])[C:25](Cl)=[O:26])=[O:21])=[CH:18][C:17]=1[S:31](=[O:34])(=[O:33])[NH2:32]>CO>[Cl:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([S:22][CH2:23][C@@H:24]([CH3:28])[C:25]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:26])=[O:21])=[CH:18][C:17]=1[S:31](=[O:34])(=[O:33])[NH2:32]
Reactant: C[C@@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
3 g of L-proline and 2 g of sodium hydrogen carbonate are added to 120 ml of water whereupon 3.5 g of 3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionyl chloride is addedslowly under ice-cooling and stirring, and the resulting mixture is stirredat room temperature for 3 hours. The reaction mixture is then treated in ananalogous manner of Example 1 to give 1-[3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionyl]-L-proline as white non-crystalline powder, [α]D25 -102.3 (methanol).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19](S(C)=O)=[N:20]2)=[CH:15][CH:14]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[C:30]2([CH3:38])[CH3:37]>>[O:1]=[S:2]1(=[O:25])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19]([NH:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][C:31](=[O:36])[C:30]4([CH3:38])[CH3:37])=[N:20]2)=[CH:15][CH:14]=1
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3N3CCCS3(=O)=O)n2n1
Reactant: CC1(C)C(=O)Nc2ccc(N)cc21
Product: CC1(C)C(=O)Nc2ccc(Nc3ncc4ccc(-c5ccccc5N5CCCS5(=O)=O)n4n3)cc21
Yield: 23.9 %

Procedure:
Analogous to Example 1491c, 7-[2-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-2-(methylsulfinyl)pyrrolo[2,1-f][1,2,4]triazine (68 mg, 0.18 mmol) and 5-Amino-3,3-dimethyl-1,3-dihydro-indol-2-one (0.0637 g, 0.361 mmol) were reacted to afford 5-({7-[2-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-yl}amino)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a yellow solid (21 mg, 24%). LCMS: 489 (M+H); 1H-NMR (DMSO-d6): 10.12 (s, 1H), 9.24 (s, 1H), 8.94 (s, 1H), 7.86 (m, 1H), 7.63 (m, 1H), 7.53 (m, 1H), 7.28 (dd, 1H, J=8.53 Hz), 6.98 (d, 1H, J=4.93 Hz), 6.91 (d, 1H, J=4.93 Hz), 6.69 (d, 1H, J=8.53 Hz), 3.29 (s, 2H), 3.24 (t, 2H, J=7.69 Hz), 2.14 (quin, 2H, J=7.69 Hz), 1.05 (s, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:12]=3[CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:31]([NH:23][S:20]([C:18]2[CH:17]=[CH:16][C:13]3[CH2:14][CH2:15][N:9]([C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:8])[CH2:10][CH2:11][C:12]=3[CH:19]=2)(=[O:22])=[O:21])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCOCC1)CC2
Reactant: O=C=NC1CCCCC1
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCOCC1)CC2

Procedure:
By the reaction of 2,3,4,5-tetrahydro-3-morpholinocarbonyl-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-[(2,3,4,5-tetrahydro-3-morpholinocarbonyl-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 190°-191° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with 4-morpholinecarbonyl chloride.
Reaction SMILES: O.[OH:2][C:3]([C:6]1[N:7]=[C:8]([CH2:59][CH2:60][CH3:61])[N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[O:16][C:17](=[O:21])[O:18][C:19]=1[CH3:20])=[O:12])([CH3:5])[CH3:4]>C(O)(=O)C>[OH:2][C:3]([C:6]1[N:7]=[C:8]([CH2:59][CH2:60][CH3:61])[N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[O:16][C:17](=[O:21])[O:18][C:19]=1[CH3:20])=[O:12])([CH3:5])[CH3:4]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
75 ml of water were added to a suspension of 29.3 g of (5-methyl -2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 225 ml of acetic acid, and the resulting mixture was stirred at 60° C. for 1.5 hours. At the end of this time, 75 ml of water were added to the mixture, which was then cooled. Precipitated trityl alcohol was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. Toluene was added to the residue, and the mixture was again concentrated by evaporation under reduced pressure, to remove the remaining water and acetic acid. The residue was crystallized in ethyl acetate, to give 16.6 g of the title compound as crystals, melting at 177°-180° C. (with decomposition).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:21][C:22](=[O:25])[CH2:23]Cl)[CH2:18][CH2:19][CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:17]([O:21][C:22]([CH2:23][S:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:25])[CH2:18][CH2:19][CH3:20]
Reactant: Sc1nc2cccnc2s1
Reactant: CCCCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CSc1nc2cccnc2s1
Temperature: 25 °C
Yield: 99 %

Procedure:
Twenty-four (24) g of 2-mercaptothiazolo[5,4-b]pyridine was dissolved in 300 ml of N,N-dimethylformamide, and 43.3 g of potassium carbonate and 23.65 g of chloroacetic acid n-butyl ester were added to the solution, followed by one-hour stirring at room temperature. Seven hundred (700) ml of ethyl acetate was added to the solution, which was then washed with water three times, dehydrated over magnesium sulfate, dried and distilled to remove the solvent to obtain the title compound (39.9 g, 99%).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[CH2:8]([Mg]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+].Cl>O1CCCC1>[CH3:6][C:2]([OH:1])([C:3]([CH3:4])([OH:5])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: CC(=O)C(C)(C)O
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)C(C)(O)Cc1ccccc1

Procedure:
A solution of 41 g. of 3-hydroxy-3-methyl-2-butanone in 300 ml. of dry tetrahydrofuran was treated at -10° under nitrogen with 500 ml. of 2M benzyl magnesium chloride and stirred at 25° C. for 20 hours. An aqueous ammonium chloride solution was added at 0° and the mixture was acidified at 0° with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was evaporated and the residue chromatographed on silica gel. Elution with 20% ethyl acetate in hexane followed by recrystallization from the same solvent afforded 38 g. of the title product, m.p. 72°-74°, λmaxKBr 2.95, 3.35, 6.2, 6.63, 6.82, 7.23, 7.45, 7.65, 8.32, 8.70, 9.13, 10.58, 11.0, 11.40, 12.30, 12.97 and 14.06 μ.
Reaction SMILES: [C:1]([CH:4]([NH:12][C:13]1[C:14]([Cl:24])=[CH:15][C:16]([Cl:23])=[C:17]([CH:22]=1)[C:18]([O:20]C)=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])(=[O:3])N.Cl.C(O)(=[O:28])C>>[C:18]([C:17]1[C:16]([Cl:23])=[CH:15][C:14]([Cl:24])=[C:13]([NH:12][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])[C:1]([OH:28])=[O:3])[CH:22]=1)([OH:20])=[O:19]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(NC(C(N)=O)c2ccccc2Cl)c(Cl)cc1Cl
Agent: Cl
Product: O=C(O)c1cc(NC(C(=O)O)c2ccccc2Cl)c(Cl)cc1Cl

Procedure:
A mixture of 43 parts of methyl 5-(α-carbamoyl-o-chlorobenzylamino)-2,4-dichlorobenzoate, 400 parts of a hydrochloric acid solution and 200 parts of glacial acetic acid is stirred and refluxed for 70 hours. The reaction mixture is cooled and the precipitated product is filtered off. It is washed on the filter with fresh water and then dissolved in ether. The ethereal solution is shaken with water and with alkaline water. The aqueous phase is separated, acidified with a hydrochloric acid solution and the product is extracted with ether. The latter is washed twice with water, dried, filtered and evaporated, yielding 34.1 parts of N-(5-carboxy-2,4-dichlorophenyl)-2-(o-chlorophenyl)glycine as a solid residue; mp. 210° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[O:34])[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[N:42](OCCC(C)C)=[O:43]>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24](=[O:34])[C:23](=[N:42][OH:43])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CCON=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)C(=NO)CC4)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To a solution of tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (1.00 g, 2.134 mmol) in anhydrous THF (30 mL) was added dropwise potassium tert-butoxide (1M in THF, 2.56 ml, 2.56 mmol) over a period of 10 min to give a deep red solution. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. To this was added dropwise isopentyl nitrite (0.286 ml, 2.134 mmol) over a period of 5 min to give a red solution. The reaction mixture was stirred at 50° C. under a nitrogen atmosphere for 1 hour then allowed to cool to room temperature and concentrated to dryness under reduced pressure. The residue was redissolved in water (5 mL), acidified with 1M HCl solution (5 mL) and extracted into ethyl acetate (3×10 mL). The combined organic phases were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified via Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as a brown solid (436 mg, 41% yield)). 1H-NMR (500 MHz, CDCl3) δ 8.40 (1H, s), 7.40 (2H, d), 7.32 (2H, d), 7.25-7.29 (3H, m), 7.18-7.22 (2H, m), 5.04 (1H, br s), 3.38 (2H, t), 3.29 (2H, t), 2.26-2.59 (4H, br m), 2.01-2.12 (1H, m), 1.76-1.86 (1H, m), 1.15-1.45 (9H, br m). LCMS (Method A) RT=6.74 min, M+H+=498.13.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[C:4][CH2:5][Cl:6].[Cl:7][CH:8]([SiH3:10])[Cl:9]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[Cl:1][CH2:2][C:3]([SiH2:10][CH:8]([Cl:9])[Cl:7])=[CH:4][CH2:5][Cl:6]
Reactant: [SiH3]C(Cl)Cl
Reactant: ClCC#CCCl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: ClCC=C(CCl)[SiH2]C(Cl)Cl
Yield: 87.2 %

Procedure:
To a mixture of 10 ml (0.106 mol) of 1,4-dichloro-2-butyne and 11.5 ml (0.11 mol) of dichloromethylsilane (boiling point: 41° C.) was added 0.05 ml (4.8 mmol %) of an isopropanol solution of chloroplatinic acid prepared in the same manner as in Example 1, followed by heating under reflux for 1 hour, thereby obtaining 22 g of 1,4-dichloro-2-(dichloromethyl)silyl-2-butene.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH2:20])=[S:19])=[CH:16][C:3]1=2.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClCCl.CO>CN(C=O)C>[CH2:21]([S:19][C:18](=[NH:20])[NH:17][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[C:3]=2[CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Reactant: BrCc1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N=C(Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 9, 50 mg, 0.18 mmol) in DMF (1 mL) was added benzyl bromide (21 μL, 0.18 mmol). The solution was stirred at room temperature for 2 hr then heated at 60° C. for 1 hr. The solvent was removed under vacuo. The residue was dissolved in a mixture of tetrahydrofuran (5 mL) and diethyl ether (5 mL) and treated with 2 mL of saturated sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated to give an oily residue which was subjected to silica gel column chromatography (98% dichloromethane: 2% methanol). H1 NMR (acetone d6) δ: 8.91 (bs, 1H), 7.42-7.21 (m, 5H), 7.09-6.89 (m, 7H), 5.93 (bs, 1H), 4.31 (s, 2H).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:19])[NH:16][CH2:17][CH3:18])[N:11]=[CH:10][C:9]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=O)=[CH:25][CH:24]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN([C:57](=[N+](C)C)[O:58][N:59]1[C:63]2=NC=CC=C2N=N1)C>CN(C=O)C.CCOC(C)=O>[CH2:17]([NH:16][C:15](=[O:19])[NH:14][C:12]1[CH:13]=[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([N:59]([O:58][CH3:57])[CH3:63])=[O:33])=[CH:27][CH:28]=2)=[O:21])=[CH:10][N:11]=1)[CH3:18]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccc(CCC(=O)O)cc2)cn1
Agent: CN(C)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccc(CCC(=O)N(C)OC)cc2)cn1
Temperature: 25 °C
Yield: 51 %

Procedure:
3-[4-[[4-anilino-6-(ethylcarbamoylamino)pyridine-3-carbonyl]amino]phenyl]propanoic acid (Compound 78) (14.5 mg, 0.032 mmol) and dimethyl hydroxylamine (3.8 mg, 0.039 mmol) were dissolved in DMF (1 mL) and the DIPEA (17 μL, 0.098 mmol) added, followed by [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (15 mg, 0.039 mmol). The mixture was stirred at RT. After 1 h the mixture was diluted with EtOAc and evaporated to dryness. The residue was dissolved in DCM and applied to a silica column, eluting with MeOH/DCM, to afford Compound 123 (8 mg).