Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].[CH3:10][O:11][C:12]([C:14]1[C:15]([CH2:20]Cl)=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13]>CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[C:15]([CH2:20][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:8]=[O:9])=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: O=Cc1ccc[nH]1
Reactant: COC(=O)c1cccnc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1Cn1cccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (5.8 g, 0.12 mol), was in dry N,N-dimethyl formamide (25 mL) was added slowly under nitrogen a solution of pyrrole 2-carboxaldehyde (10.5 g, 0.11 mol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was then cooled to 5° C. and 2-chloromethyl-pyridine-3-carboxylic acid methyl ester of Step A was added slowly, the temperature being maintained at or below 20° C. After the addition was complete, the reaction was stirred at room temperature for 30 minutes. The mixture was evaporated to dryness, and the residue was dissolved in ethyl acetate (250 mL). This solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed in vacuo leaving a dark crystalline solid (23.4 g), which was purified by chromatography on silica gel eluting with a gradient of ethyl acetate/petroleum ether to provide the title compound as a tan crystalline solid (13.75 g), m.p. 91–93° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11]>C(OCC)C.O1CCCC1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(I)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2.5 g 4-Iodobenzaldehyde are dissolved in 25 ml diethylether, cooled to 0° C. and treated dropwise with 6.0 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane. The temperature is slowly raised to room temperature and the mixture is stirred for further 12 hours. Then the reaction is quenched by addition of half saturated aqueous ammonium chloride. The aqueous phase is twice extracted with ethylacetate and the combined organic phases are washed twice with saturated aqueous ammonium chloride and brine. After drying with magnesium sulphate the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 100:0 to 40:60).
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:24]([O:22][C:7]1[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:23])[NH2:2])[C:17]1([OH:19])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:4](=[O:3])[CH2:5][CH3:6])(=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)Cl
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(O)ON2CC2C1N2C(=O)CC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) and 4-dimethylaminopyridine (150 mg) in dimethylformamide (2 ml) was added propionyl chloride (0.1 ml) in an ice-water bath. The mixture was stirred for 20 hours at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and mthanol (10:1, v/v) to afford 8-carbamoyloxymethyl-4-formyl-9-hydroxy-11-propionyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6-yl propionate (30 mg).
Reaction SMILES: C1([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[C:16](=[O:17])[C:15](OC)=[CH:14][N:13](C=C)[CH:12]=3)=[CH:7][CH:6]=2)CCC=1.[C:22]1(C)[C:23](S([O-])(=O)=O)=[CH:24][CH:25]=[CH:26][CH:27]=1>>[CH:9]1([C:15]2[C:16](=[O:17])[C:11]([C:8]3[CH:7]=[CH:6][CH:5]=[C:10]([CH:27]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[CH:9]=3)=[CH:12][N:13]([N:13]([CH3:14])[CH3:12])[CH:14]=2)[CH2:8][CH2:7][CH:6]=[CH:5][CH2:10]1
Reactant: Cc1ccccc1S(=O)(=O)[O-]
Reactant: C=Cn1cc(OC)c(=O)c(-c2ccc(C3=CCC3)cc2)c1
Product: CN(C)n1cc(-c2cccc(C3CCCCC3)c2)c(=O)c(C2CC=CCC2)c1

Procedure:
3-[4-(1-cyclobutenyl)phenyl]-5-methoxy-1-vinyl-4(1H)-pyridone, toluenesulfonate
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1)(O)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.N1C=CN=C1.S(Cl)([Cl:39])=O>C(#N)C>[F:1][C:2]([F:31])([F:30])[C:3]([Cl:39])([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(O)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CCOc1ccc(C(Cl)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A solution of 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propan-2-ol (0.65 g) and imidazole (0.612 g) were dissolved in dry acetonitrile 30 cm3), and the solution cooled to ca. 0° C. Thionyl chloride (1.21 g) was added dropwise, with stirring. The reaction mixture was allowed to warm to the ambient temperature (ca. 22° C.) and was stirred for a further three hours. Analysis of the reaction mixture by thin layer chromatography and gas liquid chromatography at that time showed no starting tertiary alcohol to be present. The reaction mixture was quenched with water, and a small volume of saturated sodium chloride solution was added. The aqueous mixture was extracted four times with diethyl ether and, finally, once with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate and concentrated by evaporation of the solvent under reduced pressure to give an oil. The product was purified by column chromatography on a silica gel support, using n-hexane containing 6% by volume ethyl acetate as eluent, to give 1,1,1-trifluoro-2-chloro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.48 g) as a colourless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:15]=1[NH2:16]>CO.C(O)(=O)C>[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:15]=1[N:16]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[CH3:13])[CH3:11])[N:5]=1)[CH3:2]
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=Nc1ccc(C)cc1C)c1cccc(C(C)=Nc2ccc(C)cc2C)n1
Reaction time: 72 h

Procedure:
Chemicals 2,6-Diacetylpyridine (2.0 g, 12.3 mmol) and 2,4-dimethylaniline (8.9 g, 73.7 mmol) were dissolved in a round-bottom flask with a stirring bar, to which 50 ml of anhydrous methanol were added. Three drops of glacial acetic acid were added, and the flask was sealed. After stirring the solution for three days, 3.79 g (84%) of a yellow solid were collected and identified as the desired ligand for catalyst 5. H NMR (CDCl3) δ8.39 (d,2), 7.85 (t, 1), 7.05 (s, 2), 7.00 (d, 2), 6.60 (d, 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(N)c(F)c1

Procedure:
Into a 2000-mL round-bottom flask maintained with a nitrogen atmosphere, was placed a solution of methyl 3-fluoro-4-nitrobenzoate (98 g, 492.46 mmol, 1.00 equiv) in ethyl acetate:methanol=1:1 (1000 mL). Then Pd/C (10 g, 10 wt %, Degussa type) was added. The flask was fitted with a balloon of hydrogen, and the heterogeneous reaction mixture was stirred fo(16 h under a hydrogen atmosphere at 30°C. The catalyst solids were filtered off and the filtrate was concentrated under vacuum to give the deisred product methyl 4-amino-3-fluorobenzoate.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:21]=[CH:22][C:23]=1[C:24](O)=[O:25]>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:24]([C:23]4[CH:22]=[CH:21][C:20]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=5)=[CH:19][C:18]=4[F:17])=[O:25])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3F)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 3-fluoro-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11]>O>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:11][CH2:10][C:9]([OH:13])=[O:12]
Reactant: Cc1ccccc1N
Reactant: C=CC(=O)O
Solvent: O
Product: Cc1ccccc1NCCC(=O)O

Procedure:
3-(2-Methylanilino)propionic acid is prepared in a manner similar to that described in Example 1, but starting from o-toluidine (64.3 g; 0.60 mol), acrylic acid (11.6 g; 0.16 mol) and water (36.6 cc). A white powder (23.85 g) is thus obtained which, after recrystallisation in a toluene/hexane mixture (70:30 by volume), gives a pure product (21.7 g; 0.12 mol), m.p. 87° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1>C(OCC)(=O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:10]=[N:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cccc(C=O)c1
Solvent: CCOC(C)=O
Product: COc1cccc(C=NNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.4 %

Procedure:
To a solution of t-butyl carbazate (5.59 g, 42.3 mmol) in ethyl acetate (15 mL) was added with stirring m-anisaldehyde (5.17 mL, 5.76 g, 42.3 mmol). Hexanes (70 mL) was added slowly and crystallization occurred. The resulting slurry was stirred at rt for 45 min and then cooled to 0° C. The slurry was stirred at 0° C. for 60 min, then filtered and rinsed with cold hexanes (20 mL), and dried in vacuo at 40° C. to afford the title compound as a solid (9.68 g, 91.4%): mp 135.6-137.4° C.; 1H NMR (DMSO-d6) δ 10.93 (s, 1H), 7.29 (t, 1H, J=8 Hz), 7.14 (d, 2H, J=7 Hz), 6.92 (q, 1H, J=7 Hz), 3.75 (s, 3H), 1.45 (s, 9H); 13C NMR (DMSO-d6) δ 160.2, 153.1, 143.7, 136.8, 130.5, 120.0, 116.2, 111.3, 80.1, 55.7, 28.7; IR (KBr mull): 3360, 3010, 2982, 2838, 1510, 1487 cm−1; A portion was recrystallized from ethyl acetate and submitted for elemental analysis. Anal. Calcd. for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19. Found: C, 62.34.; H, 7.46; N, 11.19.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:14])=[C:4]([C:11]([OH:13])=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28]1[S:29][CH:30]=[C:31]([CH3:33])[N:32]=1>C(#N)C>[F:1][C:2]1[C:3]([OH:14])=[C:4]([C:11]([NH:27][C:28]2[S:29][CH:30]=[C:31]([CH3:33])[N:32]=2)=[O:13])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1csc(N)n1
Reactant: Cc1c(F)c(O)c(C(=O)O)c(=O)n1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1csc(NC(=O)c2c(O)c(F)c(C)n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
200 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid was dissolved in 3 ml of acetonitrile, and 162 mg of carbonyldiimidazole was added to this. The mixture was stirred for 1 hour under heat refluxing condition, then, 114 mg of 2-amino-4-methylthiazole was added, and the resulting mixture was further stirred for 1 hour under heat refluxing condition. Thereafter, the reaction mixture was cooled to room temperature. As a result, a crystal was produced. The produced crystal was collected by filtration, to obtain 90 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-N-(4-methyl-2-thiazolyl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 31) represented by the formula:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2].Br[C:34]1[N:35]=[CH:36][N:37]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:38]=1>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:34]5[N:35]=[CH:36][N:37]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:38]=5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)(O)Cn1cnc(Br)c1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(B4OC(C)(C)C(C)(C)O4)cc2OCC3)n(C(C)C)n1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cn(CC(C)(C)O)cn4)cc2OCC3)n(C(C)C)n1

Procedure:
2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 1-(4-Bromo-imidazol-1-yl)-2-methyl-propan-2-ol to give 252. MS(ESI+) 448.3
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:6]=1)C.[NH3:17]>CO>[CH2:12]([C:8]1[C:9]([CH3:11])=[CH:10][C:5]([C:4]([NH2:17])=[O:3])=[CH:6][N:7]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1cnc(CC(C)C)c(C)c1
Reactant: N
Solvent: CO
Product: Cc1cc(C(N)=O)cnc1CC(C)C

Procedure:
A solution of 6-isobutyl-5-methyl-nicotinic acid ethyl ester (2.86 g, 12.9 mmol) in 7 N NH3 in MeOH (80 mL) is stirred at 60° C. for 20 h before the solvent is removed in vacuo. The residue is dried to give 6-isobutyl-5-methyl-nicotinamide (1.89 g) as a yellow oil; LC-MS: tR=0.66 min, [M+1]+=193.29; 1H NMR (D6-DMSO): δ 0.91 (d, J=6.5 Hz, 6H), 2.08-2.20 (m, 1H), 2.32 (s, 3H), 2.65 (d, J=7.3 Hz, 2H), 7.43 (s, 1H), 7.95 (s, 1H), 8.01 (m, 1H), 8.78 (s, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCOCC4)c23)ccc1OCc1ccccc1
Yield: 58 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and morpholine to give the title compound in 58% yield; NMR Spectrum: 2.22 (s, 3H), 2.50-2.52 (m, 4H), 2.79 (t, 2H), 3.54-3.56 (m, 4H), 4.42 (t, 2H), 5.14 (s, 2H), 7.02 (d, 1H), 7.32-7.48 (m, 7H), 8.20 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 461 (MH+).
Reaction SMILES: OC[C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](CNC)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[C:20]([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:20][C:11]1[C:16]2[C:15](=[CH:10][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:14]=[CH:13][CH:12]=1
Reactant: CNCc1c2ccccc2c(CO)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc2cc3ccccc3cc12
Yield: 103.4 %

Procedure:
10-(hydroxymethyl)-9-((methylamino)methyl)anthracene (0.800 g, 3.18 mmol) and K2CO3 (0.56 g, 4.05 mmol) were taken up in 15 mL acetonitrile. A solution of 2,2-dimethylpropane-1,3-diyl(o-(bromomethyl)phenyl)boronate 3 (1.00 g, 3.44 mmol) in 5 mL acetonitrile was added and the mixture was refluxed under nitrogen for 24 h. The mixture was filtered hot on a sintered-glass frit and upon cooling, a yellow solid precipitated. The resulting solid was triturated with acetonitrile/water (4:1, v/v), filtered on a sintered-glass frit and vacuum dried to yield 11 as a bright yellow solid (0.632 g, 51.6% yield): 1H NMR (300.13 MHz, CD3OD) δ2.58 (s, 3H), 4.58 (s, 2H), 5.22 (s, 2H), 5.61 (s, 2H), 7.62 (m, 6H), 7.80 (m, 2H), 8.18 (m, 2H), 8.58 (m, 2H); 13C-{1H} NMR (75.4 MHz, CD3OD) δ136.9, 136.2, 135.9, 132.9, 132.7, 131.4, 129.9, 128.3, 127.1, 126.8, 126.5, 124.9, 124.1, 63.8, 57.1, 50.9, 40.7.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A suspension of (S)-tert-Butyl 2-(4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (54.1 g), ammonium formate (116 g) and 5% palladium on charcoal (6.5 g) in methanol (930 ml) was stirred at 60° C. for 2 h. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate and water. The organic phase was extracted twice with 0.5 M aq. HCl. The combined aqueous phases were basified with 2 M aq. NaOH and extracted twice with dichloromethane. The organic phases were dried over magnesium sulfate, filtered and dried in vacuo to yield (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (31.95 g, 94%) as an off-white solid. MS (ISP): 279.1 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH2:41][C:42]([NH:44][C:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C:19]([N:21]([CH2:31][C:32]1[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[S:35][CH:36]=1)[C@@H:22]([CH3:30])[CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[O:20]>>[S:35]1[CH:36]=[C:32]([CH2:31][N:21]([C@@H:22]([CH3:30])[CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[CH2:41][C:42](=[O:43])[NH:44][C:45]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]1=2
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 52 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26]>>[F:26][C:25]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=2)[C:2]([Cl:1])=[N:3]1
Reactant: O=Cc1ccc2[nH]nc(Cl)c2c1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Product: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazole-5-carbaldehyde was prepared from 3-Chloro-1H-indazole-5-carbaldehyde and 1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following general procedure A.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH2:19][C@H:18]2[NH2:24])=[O:14].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:24][C@H:18]2[C:17]3[C:21](=[CH:22][CH:23]=[C:15]([C:13]([O:12][CH3:11])=[O:14])[CH:16]=3)[CH2:20][CH2:19]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
DIPEA (447 μl, 2.634 mmol, 3 eq) was added at 0° C. to a solution of (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (0.878 mmol, 1 eq) in dichloromethane (10 ml). A solution of 4-fluorobenzene-1-sulfonyl chloride (170 mg, 0.878 mmol, 1 eq) dissolved in dichloromethane (6 ml) was added dropwise and the mixture was stirred for 16 h at RT. After monitoring by thin-layer chromatography. the reaction solution was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with 10% ammonium chloride solution, sodium hydrogen carbonate solution and sat. NaCl solution (in each case 1x), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 1:5). Yield: 88%
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].[Cl:29][C:30]([Cl:34])([Cl:33])[CH2:31]O.N1C=CC=CC=1>ClCCl>[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:31][C:30]([Cl:34])([Cl:33])[Cl:29])=[O:27]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)CCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCCCCCO)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution of N,N′-dicyclohexylcarbodiimide (DCC, 2.41 g; 14.1 mmol) in dry dichloromethane (15 mL) was added drop-wise to a stirred solution of 10-hydroxydecanoic acid (1.88 g; 10.0 mmol), 2,2,2-trichloroethanol (6.13 g; 41.0 mmol), and pyridine (4.1 mL) in dry dichloromethane (35 mL) cooled to 0° C. (bath temperature) under argon. After stirring one hour at 0° C., the mixture was stirred at ambient temperature overnight. The reaction mixture was vacuum filtered and acetic acid (3 mL) was added to the filtrate. After standing 30 min, the mixture was refiltered and the filtrate was diluted with diethyl ether (150 mL). The solution was washed with 1 M HCl (3×25 mL), water (3×25 mL), saturated NaHCO3 solution (2×25 mL), and saturated NaCl solution (1×25 mL). After drying (MgSO4), filtration, and evaporation, the residue was purified by flash chromatography on a 170×25 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1), collecting 12×25 mL fractions. Fractions 3-5 were evaporated and the residue was vacuum dried at 50° C. and 0.05 mm Hg on a Kugelrohr apparatus to remove excess 2,2,2-trichloroethanol. 2.1 g (66%) product was obtained (colorless oil).