Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[N+:26]([C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH:38]=O)=[CH:34][NH:35]2)=[CH:31][CH:30]=1)([O-:28])=[O:27]>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:38]/[C:33]3[C:32]4[C:36](=[CH:37][C:29]([N+:26]([O-:28])=[O:27])=[CH:30][CH:31]=4)[NH:35][CH:34]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc([N+](=O)[O-])ccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.050 g, 0.14 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-nitro-1H-indole-3-carboxaldehyde (0.026 g, 0.14 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was washed with a mixed solvent of chloroform and methanol to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(6-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.049 g, 67%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27](O)(=O)[CH:28]=[CH2:29]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:29]([CH:28]=[CH2:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: C=CC(=O)O
Product: C=Cc1nc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)no1
Yield: 20 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and acrylic acid, this compound was obtained in 20% yield (89.4% purity by HPLC).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[N:11]([CH2:12][CH2:13][N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=3[N:8]=2)[CH2:2]1.[C:29]([O:33][C:34]([NH:36][C@H:37]([CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)[CH2:38][C:39](O)=[O:40])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][N:11]1[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[N:8]=[C:7]1[C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:39](=[O:40])[CH2:38][C@H:37]([NH:36][C:34](=[O:35])[O:33][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:42][C:43]2[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=2)[CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1c(C2CCCNC2)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3n2CCN2C(=O)c3ccccc3C2=O)C1)Cc1ccc2ccccc2c1
Yield: 4 %

Procedure:
(R)-2-(2-(2-(piperidin-3-yl)-1H-benzo[d]imidazol-1-yflethypisoindoline-1,3-dione (129B) (500 mg of mixture) from previous step, was weighed into a 25 mL round-bottomed flask equipped for stirring under nitrogen. DMF (3 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (2.48 mmoles, 0.817 g) and N-methylmorpholine (7.44 mmoles, 0.818 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (2.73 mmoles, 1.04 g) was added and the resultant solution was stirred at room temperature for 3 hrs. The reaction solution was then directly purified by preparative LC/MS (35-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (129C) as a clear oil. (0.105 mmoles, 0.072 g, 4% yield over 2-steps). ESI-MS: m/z 686.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][N:37]([CH2:39][C:40]1[O:44][C:43]([C:45]2[CH:51]=[CH:50][C:48]([NH2:49])=[C:47]([O:52][CH3:53])[CH:46]=2)=[N:42][N:41]=1)[CH3:38].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:48]3[CH:50]=[CH:51][C:45]([C:43]4[O:44][C:40]([CH2:39][N:37]([CH3:36])[CH3:38])=[N:41][N:42]=4)=[CH:46][C:47]=3[O:52][CH3:53])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(-c2nnc(CN(C)C)o2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Solvent: OCC(F)(F)F
Product: COc1cc(-c2nnc(CN(C)C)o2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 85 °C
Yield: 48 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.12 g, 0.25 mmol) and 4-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-(methyloxy)aniline (0.069 g, 0.28 mmol) in trifluoroethanol (5 mL) was added HCl (0.050 mL, 4 M in dioxane, 0.20 mmol). The reaction was heated at 85° C. for 48 hours. Purification by flash chromatography followed by trituration with diethyl ether provided the title compound (0.089 g, 0.12 mmol, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6H), 3.76 (s, 2H), 3.96 (d, J=4.6 Hz, 6H), 6.76 (d, J=4.9 Hz, 1H), 7.03 (t, J=6.9 Hz, 1H), 7.15 (t, J=8.1 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.30-7.40 (m, 1H), 7.42-7.50 (m, 1H), 7.51-7.59 (m, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 8.10 (br. s., 1H), 8.35 (d, J=8.6 Hz, 1H), 8.39 (d, J=5.5 Hz, 1H), 8.69 (br. s., 1H), 9.44 (d, J=6.8 Hz, 1H), 9.74 (s, 1H). MS (M+H, ES+) 704.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[C:42]([C:59]([NH2:61])=[O:60])[C:43]3[NH:44][C:45]4[CH:46]=[C:47]([N:53]5[CH2:58][CH2:57][O:56][CH2:55][CH2:54]5)[CH:48]=[CH:49][C:50]=4[C:51]=3[N:52]=2)[CH:36]=[CH:37][C:38]=1[OH:39].[O:62]1[CH2:67][CH2:66][N:65]([CH2:68][CH2:69]O)[CH2:64][CH2:63]1>C1COCC1>[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[C:42]([C:59]([NH2:61])=[O:60])[C:43]3[NH:44][C:45]4[CH:46]=[C:47]([N:53]5[CH2:54][CH2:55][O:56][CH2:57][CH2:58]5)[CH:48]=[CH:49][C:50]=4[C:51]=3[N:52]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH2:69][CH2:68][N:65]1[CH2:66][CH2:67][O:62][CH2:63][CH2:64]1
Reactant: OCCN1CCOCC1
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(OCCN3CCOCC3)c(Cl)c2)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Reaction time: 8 h
Yield: 0 %

Procedure:
Diethyl azodicarboxylate (0.012 mL, 0.074 mmol) was added to a solution of triphenylphosphine (19 mg, 0.074 mmol), 2-(3-chloro-4-hydroxyphenyl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (16 mg, 0.037 mmol) and 2-morpholinoethanol (9.0 μL, 0.074 mmol) in dry THF (0.5 mL) at RT under nitrogen. After stirring overnight, the solvent was removed and preparative HPLC (PHENOMENEX® Luna C18 30×100 10u Column, Solvent A=10 mM NH4OAc in 95% water:5% acetonitrile; B=10 mM NH4OAc in 5% water:95% acetonitrile, gradient of 10 to 100% B over 25 min at 30 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 2-(3-chloro-4-(2-morpholinoethoxy)phenyl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (4.9 mg, 8.2 nmol, 22% yield) as a solid. MS (ESI) m/z 536.38 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.26 (1H, s), 8.54 (1H, s), 8.34 (1H, d, J=2.01 Hz), 8.27 (1H, s), 8.21 (1H, dd, J=8.69, 2.14 Hz), 8.07 (1H, d, J=8.56 Hz), 7.84 (1H, s), 7.32 (1H, d, J=8.81 Hz), 7.20 (1H, d, J=2.01 Hz), 7.00 (1H, dd, J=8.81, 2.01 Hz), 4.26 (2H, t, J=5.79 Hz), 3.74-3.85 (4H, m), 3.53-3.66 (4H, m), 3.18-3.28 (4H, m), 2.78 (2H, t, J=5.67 Hz), 2.52-2.59 (4H, m).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:13])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(CO)cc1
Solvent: c1ccccc1
Product: CSc1ccc(CCl)cc1

Procedure:
To a stirred solution of 154 g (1 mol) of 4-methylmercaptobenzyl alcohol in 1 liter of dry benzene was added dropwise 80 mL 1.1 mol) of thionyl chloride. The mixture immediately turned blue. After the addition of the thionyl chloride was completed, the mixture was heated at reflux for 2 hours. After cooling the benzene and excess thionyl chloride were distilled at ambient pressure. The product was distilled in vacuo at 105° C. (0.5 mm), to yield 160 g (93%) of water clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc([N+](=O)[O-])cc1N1CCC(N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-methoxy-5-nitrophenyl)piperidin-4-one (Preparation Example 502) (296 mg), 1-methylpiperazine (0.20 mL) and 1,2-dichloroethane (11 mL), sodium triacetoxyborohydride (385 mg) was added and stirred overnight at room temperature. After addition of water and saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=100:0 to 10:1) to give 1-[1-(2-methoxy-5-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.40 g) as a brown oil.
Reaction SMILES: [O:1]=[C:2]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[OH:19][CH:20]([CH3:40])[CH2:21]N1CCN(C(=O)COC2C=C(C=CC=2)C=O)CC1>>[OH:19][CH:20]([CH3:40])[CH2:21][N:16]1[CH2:17][CH2:18][N:13]([C:2](=[O:1])[CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][CH:12]=2)[CH2:14][CH2:15]1
Reactant: O=Cc1ccc(OCC(=O)N2CCNCC2)cc1
Reactant: CC(O)CN1CCN(C(=O)COc2cccc(C=O)c2)CC1
Product: CC(O)CN1CCN(C(=O)COc2ccc(C=O)cc2)CC1
Yield: 66 %

Procedure:
4-(2-oxo-2-(piperazin-1-yl)ethoxy)benzaldehyde (55) was treated in an analogous manner to compound 51 to yield the desired product (66%) as a colorless oil. LCMS: 96% (M++1).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:17][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]([OH:16])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=1
Reactant: COc1ccc2c(O)c(C(C)C)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(O)c(C(C)C)cc(Br)c2c1
Yield: 91.3 %

Procedure:
In 100 ml of DMF was dissolved 5 g of 2-isopropyl-6-methoxy-1-naphthol, and a solution of 4.03 g of N-bromosuccinimide in DMF (50 ml) was added under ice-cooling. The mixture was stirred under ice-cooling for 3 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent:diethyl ether:n-hexane:chloroform=10:50:1) to provide 6.1 g of 4-bromo-2-isopropyl-6-methoxy-1-naphthol. m.p. 81.5°-83.5° C.
Reaction SMILES: [CH:1](=[N:8][C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]([NH2:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH:1](=[N:8][C:9]1[N:10]=[CH:11][N:12]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]=1[C:14]([NH2:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(N=Cc2ccccc2)ncn1Cc1ccccc1
Reaction time: 1 h
Yield: 79 %

Procedure:
12.8 g (60 mmol) of 4-benzylideneamino-5-imidazole carboxamide which is an intermediate material obtained in the Reference Example 1 was suspended in a mixed solvent of 240 ml dimethylformamide and 30 ml distilled water, and 16.6 g (120 mmol) of potassium carbonate was added to the suspension. 13.8 ml of benzyl chloride was added dropwise to the solution over 45 minutes at 80° C. After the addition, the mixture was stirred for one hour. The solvent was evaporated under vacuum, the residue was dissolved in chloroform, and the chloroform layer was washed with distilled water. Crude crystals obtained after evaporation of solvent was recrystallized from ethanol to obtain 14.4 g of 4-benzylideneamino-1-benzyl-5-imidazole carboxamide (yield 79%).
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:27]=3)[CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[CH3:40][CH2:41][OH:42].CCOCC>CCOCC>[ClH:1].[C:41]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C@@H:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:27]=3)[CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:42])[CH3:40]
Reactant: COc1ccc([C@@H](Cc2ccncc2)c2ccc(Oc3ccc(N)cc3)cc2)cc1OC1CCCC1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: COc1ccc([C@@H](Cc2ccncc2)c2ccc(Oc3ccc(NC(C)=O)cc3)cc2)cc1OC1CCCC1

Procedure:
Treatment of the free base (303.6 mg) in EtOH-Et2O (30 ml; 1:2) with 1.0M HCl in Et2O (0.62 ml) as described for the compound of Example 7 followed by the recrystallisation (THF-Et2O) afforded the title compound as an off-white amorphous solid (highly hygroscopic). δH (CD3OD) 1.50-1.90 (8H, br m), 2.11 (3H, s), 3.67 (2H, d, J 8.3 Hz), 3.76 (3H, s), 4.40 (1H, t, J 8.3 Hz), 4.73 (1H, br m), 6.79 (1H, s), 6.83 (1H, s), 6.84 (1H, s), 6.85-6.95 (4H, m), 7.28 (2H, d, (fine split), J 8.5 Hz), 7.50 (2H, dd, J 6.9, 2.3 Hz), 7.80 (2H, d, J 6.4 Hz), and 8.60 (2H, d, J 5.9 Hz).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)C(N)=O.C[N:14](C)[CH:15]=[O:16].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>O>[C:2]12[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH:14][C:15](=[O:16])[O:12][C:1]2=[O:11]
Reactant: CN(C)C=O
Reactant: NC(=O)c1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)o1
Reaction time: 0.67 h

Procedure:
A 100 ml. flask was charged with 2.0 g. phthalamic acid suspended in 20 ml. dimethylformamide at room temperature. A 5.4 g. portion of lead tetra-acetate was added to the suspension, and the reaction mixture was held at room temperature for 40 minutes. The reaction mixture was poured into 30 ml. water. Isatoic anhydride was filtered from the water, recrystallized from dioxane, and dried in vacuo for 2 hours. The final yield of isatoic anhydride amounted to 1.07 g. tan solids, melting point 243°, and represented 54 percent of theory based on the phthalamic acid.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[NH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].O>COCCOC>[NH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([NH:12][CH2:2][CH2:1][OH:3])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: C1CO1
Reactant: Nc1cc([N+](=O)[O-])c(N)cc1F
Solvent: COCCOC
Solvent: O
Product: Nc1cc(F)c(NCCO)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Ethylene oxide is passed in portions into a mixture of 34 g (0.2 mol) of 1,4-diamino-5-fluoro-2-nitrobenzene, 200 ml of water and 17 g of monoethylene glycol dimethyl ether at 60° C. in the course of 90 minutes and the reaction is monitored by thin layer chromatography. When the monohydroxyethylation is complete, the mixture is cooled slowly to room temperature and the solid precipitate is filtered off and washed twice with 25 ml of a water/ethanol mixture (1/1) each time.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([C@H:21]1[C@@H:25]([CH2:26][OH:27])[O:24][C:23](=[O:28])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C1COCC1.CN1CCOCC1>[CH2:14]([C@H:21]1[C@@H:25]([CH2:26][O:27][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[O:24][C:23](=[O:28])[NH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Reaction time: 4.5 h
Yield: 94.2 %

Procedure:
15.4 g of p-nitrobenzenesulphonyl chloride are added in portions at 20°-25° C. to a stirred suspension of 12.0 g of the alcohol from Example 8 in 35 ml of THF and 7.66 ml of N-methylmorpholine and stirred for 4.5 hours. The suspension is again treated with 0.77 ml of N-methylmorpholine and stirred at 22° C. for 4.5 hours. The mixture is treated with 70 ml of a 2% sodium bicarbonate solution, stirred for 1.5 hours, filtered, the residue is washed with water and ethanol and dried to give 21.4 g (94%) of 98.5 % p-nitrobenzenesulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester, m.p. 148°-149.5° C., α!D20 : +10.0° (1% in acetone).
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([OH:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[C:30](O)(=[O:52])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:7]([O:52][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCCCCCC

Procedure:
300 parts by mol of benzene, 200 parts by mol of docosanol (behenyl alcohol), 200 parts by mol of docosanoic acid (behenic acid), and further 10 parts by mol of p-toluenesulfonic acid were added to a reactor equipped with a Dimroth condenser, a Dean-Stark water separator and a thermometer, and sufficiently stirred and dissolved, and thereafter refluxed for 6 hours; and thereafter, a valve of the water separator was opened and azeotropic distillation was carried out. After the azeotropic distillation, the resultant was sufficiently cleaned with sodium hydrogencarbonate, and thereafter dried to thereby distil away benzene. An obtained product was recrystallized, and thereafter cleaned and refined to thereby obtain an ester wax 17 (behenyl behenate). The physical properties of the obtained ester wax 17 are shown in Table 2.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:44]=[CH:43][C:42]([S:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)(=[O:47])=[O:46])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)(=[O:47])=[O:46])=[CH:41][CH:40]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Yield: 80.5 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 250 mg) in acetonitrile (8 mL) with 4-(4-bromophenylsulfonyl)morpholine (148 mg) was treated with aqueous sodium carbonate (2M, 0.5 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h under nitrogen. The reaction mixture was evaporated onto silica and purified by chromatography on silica eluting with ethyl acetate/isohexane (50:50 to 100:0) to afford the sub-titled compound (240 mg).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([N:19](CC)[CH2:20][C:21]4C=CC(OC)=CC=4)[C:16]4=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:15]4[N:14]=3)[CH:10]=2)[N:5]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)[CH:4]=1)#[N:2].[C:49]1([O:55]C)[CH:54]=CC=C[CH:50]=1.C(O)(C(F)(F)F)=O>ClCCCl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH2:20][CH3:21])[C:16]4=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:15]4[N:14]=3)[CH:10]=2)[N:5]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:50][C@@H:49]([OH:55])[CH3:54])[CH2:38][CH2:37]2)[CH:4]=1)#[N:2]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2ccc3c(c2)c(C#N)cn3C2CCN(C(=O)OC(C)(C)C)CC2)nn2c(C#N)cnc12
Reactant: COc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1nc(Nc2ccc3c(c2)c(C#N)cn3C2CCN(C[C@H](C)O)CC2)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 4-(3-cyano-5-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-1H-indol-1-yl)piperidine-1-carboxylate (500 mg, 0.503 mmol) was mixed with anisole (0.5 mL, 4.58 mmol) and DCE (5 mL). TFA (1 mL, 12.98 mmol) was added. The mixture was stirred at 25° C. for 24 hrs. LC/MS showed product formation. The mixture was concentrated to dryness, diluted with MeOH and applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents left 2-((3-cyano-1-(piperidin-4-yl)-1H-indol-5-yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg) as solid.