Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:34])(=[O:35])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)Nc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
Lithium hydroxide monohydrate (0.026 g, 0.62 mmol) was added to a stirred solution of {6-chloro-4-[4-(3-chloro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.080 g, 0.15 mmol) in a 3:1 mixture of THF—H2O mixture (10 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-4-[4-(3-chloro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.064 g, 85%) as a solid. The final product contained a large amount of water as an impurity. 1H NMR (DMSO-d6) δ: 7.76-8.08 (m, 4H), 7.40-7.54 (m, 3H), 7.25-7.38 (m, 1H), 7.01-7.23 (m, 3H), 6.81 (s, 1H), 3.83 (s, 2H), 1.98 (s, 3H). MS calcd. for C25H18Cl2NO4S [(M−H)−] 498, obsd. 498.3.
Reaction SMILES: O[CH:2](O)[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:45]=[CH:44][C:31]2[N:32]([CH2:42][CH3:43])[C:33](=[O:41])[C:34]([CH3:40])([CH3:39])[C:35](=[O:38])[N:36]([CH3:37])[C:30]=2[CH:29]=1.S([O-])(O)=O.[Na+].C(OC(=O)C)C.[ClH:57]>C(OCC)(=O)C.CN(C=O)C>[ClH:57].[ClH:57].[CH2:42]([N:32]1[C:33](=[O:41])[C:34]([CH3:40])([CH3:39])[C:35](=[O:38])[N:36]([CH3:37])[C:30]2[CH:29]=[C:28]([O:27][CH2:26][CH2:25][CH2:24][N:23]3[C:22]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:16]=[C:2]3[CH2:3][N:4]3[CH:9]=[CH:8][C:7]4[O:10][C:11]([CH3:13])=[CH:12][C:6]=4[C:5]3=[O:14])[CH:45]=[CH:44][C:31]1=2)[CH3:43]
Reactant: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNc3ccncc3N)ccc21
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(Cn4ccc5oc(C)cc5c4=O)nc4cnccc43)ccc21
Temperature: 25 °C

Procedure:
A DMF solution(4 ml) of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one(0.20 g), 7-[3-(3-aminopyridin-4-ylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.37 g), and sodium hydrogensulfite(0.47 g) were heated at 180° C. for 10 minutes (microwave reactor). After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol=95:5→60:40). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue, which was stirred at room temperature. The generated insoluble matter was separated by filtration, and dried to give the title compound(0.47 g) as a white amorphous solid.
Reaction SMILES: N1CCC[C@H:2]1[CH2:3][OH:4].[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH:20]=O)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][CH2:2][CH:3]=[O:4])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: OC[C@@H]1CCCN1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCC=O

Procedure:
Prepared from L-prolinol using the procedure described for Intermediate 2.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:1]([CH:2]=[CH:3][C:4]([OH:6])=[O:5])=[O:7])=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Clc1ccccc1
Product: O=C(O)C=CC(=O)c1ccc(Cl)cc1

Procedure:
3-(4-chlorobenzoyl)acrylic acid (1A) was prepared, as a yellow crystalline solid, m.p.: 157°-158° C., by the Friedel-Crafts acylation of chlorobenzene with maleic anhydride by the method of Papa et al., J. Am. Chem. Soc., 70, 3356 (1948).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=5)[C:19]([CH3:30])=[C:18]([CH3:31])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Si](I)(C)(C)C.CO.C(OCC)(=O)C>CC#N>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([CH3:31])[C:19]([CH3:30])=[C:20]([C:22]5[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)cn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(-c2ccc(=O)[nH]c2)c1C
Temperature: 55 °C
Reaction time: 1.08 h
Yield: 62.3 %

Procedure:
To a suspension of 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (100 mg, 0.24 mmol) in CH3CN (4.75 mL) was added TMSI (68.4 μL, 0.48 mmol) drop wise. The reaction was stirred at 55° C. After 65 minutes, mainly starting material and some product observed. Two more equivalents of TMSI were added and the heating at 55° C. was continued for 3 hours 20 minutes. The reaction was allowed to cool down to room temperature. Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). The organic layer was washed with NaHSO3 (2×: until the yellow colour disappeared), and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (60 mg, 62%). ESI-MS m/z calc. 401.5. found 402.3 (M+1)+. Retention time 1.33 minutes.
Reaction SMILES: [C:1]1([N:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.[Ni](Cl)Cl>[C:1]1([N:7]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13][CH2:12]2)[C:8](=[O:10])[CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N(c1ccccc1)c1ccnc2ccccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N(c1ccccc1)C1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a solution of N-phenyl-N-quinolin-4-ylacetamide (2 g) and Nickel dichloride (7.6 mmol) in methanol, cooled at 0° C., was added sodium borohydride (20 eq). The solution was then stirred overnight, at room temperature. The solvent was removed to give an amorphous materiel, which is crystallized in diethyl ether. After fitration, dichloromethane was added and the solution was washed with water. The organic layer was separated and dried over sodium sulfate. The solvent was removed to obtain an amorphous material. The product was purified by chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (95:5) as eluent to give a N-phenyl-N-1,2,3,4-tetrahydroquinolin-4-ylacetamide (380 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[C:9](=[N:18]\[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])/[N:10]([CH3:17])[CH2:11][C:12]([O:14]CC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C(Cl)Cl>[C:22]([O:21][C:19]([NH:18]/[C:9](=[N:8]\[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])/[N:10]([CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[O:20])([CH3:24])([CH3:25])[CH3:23]
Reactant: CCOC(=O)CN(C)/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(CC(=O)O)/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl N—{(E)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}-N-methylglycinate (630 mg, 1.75 mmol) was dissolved in tetrahydrofuran (6.3 mL) at room temperature. To this was added 1.0 M aqueous sodium hydroxide (0.75 mL, 1.75 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated under vacuum to remove the tetrahydrofuran. The mixture was cooled in an ice bath and acidified with 1 M aqueous sulfuric acid (1.72 mL, 1.75 mmol). The mixture was diluted with methylene chloride, and then the water was removed using anhydrous magnesium sulfate. After filtering, the methylene chloride was removed under vacuum to give the title compound in a quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=O)[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:5]2[N:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:3]=[C:2]([CH3:1])[C:6]=12
Reactant: Cc1cc(Nc2ccccc2C(=O)O)n(-c2ccccn2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (50.2 g, 0.17 mol) in phosphorous oxychloride (120 mL, 1.27 mol) was heated under reflux for 1 hour. After the solution was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was poured into iced water. The solution was made basic by the addition of a sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue thus obtained by silica gel column chromatography (chloroform:methanol=98:2) gave the title compound (21.5 g, 43% yield).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:28]=[CH:27][C:26]([Sn](C)(C)C)=[CH:25][CH:24]=1)=[O:19].[F-].[Cs+]>C1(C)C=CC=CC=1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@@H:22]([C:23]1[CH:24]=[CH:25][C:26]([C:2]2[S:6][C:5]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)=[CH:27][CH:28]=1)[OH:33])=[O:19]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 90 °C
Yield: 63.1 %

Procedure:
To a solution of tert-butyl ((5-bromothiophen-2-yl)methyl)carbamate (0.508 g, 1.74 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethyl-stannyl)phenyl)propan-2-yl)acetamide (0.7 g, 1.58 mmol) in toluene (10 mL) is added cesium fluoride (0.478 g, 3.16 mmol) and copper iodide (30 mg, 0.158 mmol) and degassed with nitrogen for 30 minutes. To this mixture is added Pd(PPh3)2Cl2 (0.11 g, 0.16 mmol) and the mixture is heated to 90° C. for 26 hours. The solvent is evaporated in vacuo to get the crude which is purified by column chromatography on silica gel using methanol in CH2Cl2 to afford the title compound (490 mg): 1HNMR (400 MHz, DMSO-d6) δ:1.39 (s, 9H), 4.17-4.29 (m, 3.5H), 4.37-4.41 (m, 0.5H), 4.54-4.57 (m, 0.5H), 4.65-4.69 (m, 0.5H), 4.84 (t, J=3.56 Hz, 1H), 5.95 (d, J=4.12 Hz, 1H), 6.50 (s, 1H), 6.88 (d, J=3.48 Hz, 1H), 7.29-7.37 (dd, J=8.2 Hz, J=3.6 Hz, 3H), 7.51-7.56 (d, J=8.04 Hz, 3H). m/z (CI) 489[M−H].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(OCCO)C>[NH:10]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Cc1ccnc(F)c1
Solvent: CCOCCO
Solvent: O
Product: Cc1ccnc(NN)c1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
3.33 g (30.0 mmol) 2-fluoro-4-methylpyridine are initially introduced into 40 ml 2-ethoxyethanol, 14.6 ml (15.0 g, 300 mmol) hydrazine hydrate are added to the solution and the mixture is stirred at the boil (150° C. bath temperature) for 16 h. The reaction solution is concentrated on a rotary evaporator, the residue is introduced on to 100 ml water and the mixture is extracted with ethyl acetate (three times with 100 ml each time). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is dried in vacuo.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH3:10])[CH2:3][CH2:2]1.C1(S(O)(=O)=O)C=CC=CC=1>C1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:10])[CH2:3][CH2:2]1
Reactant: CC(O)(CCN1CCOCC1)c1ccccc1-c1ccccc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: c1ccccc1
Product: CC(=CCN1CCOCC1)c1ccccc1-c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 3.1 g of 1-morpholino-3-p-biphenylylbutan-3-ol, 0.1 g of benzenesulfonic acid and 80 ml of benzene is boiled for 24 hours under a water separator. After working up in the customary manner, 1-morpholino-3-p-biphenylyl-2-butene is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:10]=2[CH2:11][N:12]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:13]2[N:14]=[N:15][N:16]([CH3:18])[N:17]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:52]([O:54][CH2:55][CH3:56])=[O:53]>C(Cl)Cl>[F:29][C:26]([F:28])([F:27])[C:24]1[CH:25]=[C:20]([CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=1)[CH2:19][N:12]([CH2:11][C:10]1[CH:34]=[C:35]([C:38]([F:41])([F:39])[F:40])[CH:36]=[CH:37][C:9]=1[C:3]1([O:2][CH3:1])[CH2:4][CH2:5][N:6]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:7][CH2:8]1)[C:13]1[N:14]=[N:15][N:16]([CH3:18])[N:17]=1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCNCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCC(OC)(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a suspension of N-(2-(4-methoxypiperidin-4-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (31 mg; 0.049 mmol) in methylene chloride (0.5 mL) was added diisopropylethylamine (0.05 mL; 0.287 mmol). Ethyl chloroformate (10uL; 0.104 mmol) was then added. The resulting reaction was stirred at room temperature for 16 hours. The reaction was filtered over a column of silica/sodium sulfate and concentrated under reduced pressure. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (30-85% ethyl acetate in heptane) to give 32 mg (98%) of a gum. MS (ES+): Calc: 668.5, Found: 669.6 (M+H), 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (s, 1H), 7.73 (s, 2H), 7.51 (d, J=6.64 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J=8.71 Hz, 1H), 5.10 (s, 2H), 4.82 (s, 2H), 4.2 (s, 3H), 4.14 (q, J=7.05, 2H), 4.02 (bm, 2H), 3.16 (t, J=12.45 Hz, 2H), 2.95 (s, 3H), 2.14 (m, 2H), 1.9-1.63 (m, 2H), 1.27 (t, J=7.05 Hz, 3H).
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Pd].CCO>[OH:9][C:4]1[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:2][NH:7][C:6](=[O:8])[CH:5]=1
Reactant: O=c1cc(O)c(-c2ccccc2)c(Cl)[nH]1
Agent: [Pd]
Solvent: CCO
Product: O=c1cc(O)c(-c2ccccc2)c[nH]1
Temperature: 60 °C
Yield: 58 %

Procedure:
A suspension of palladium on carbon (480 mg, 50 wt % wet, 0.451 mmol) and 6-chloro-4-hydroxy-5-phenylpyridin-2(1H)-one (1000 mg, 4.51 mmol) in EtOH (40 mL) was placed under a hydrogen balloon and stirred at 60° C. After stirring under hydrogen for 30 h, the mixture was filtered while hot through a pad of CELITE® 545 filter aid and rinsed with hot ethanol. The filtrate was concentrated to give 490 mg crude product as a yellow solid. MS (ESI) 188 (M+H).
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:23][CH3:24])=[N:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]=1.[C:25](O)(=O)[CH2:26][OH:27]>C1C=CC=CC=1>[CH3:24][N:23]1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH:11]=2)=[N:3][N:2]=[C:25]1[CH2:26][OH:27]
Reactant: O=C(O)CO
Reactant: CNC(=NCCCOc1cccc(CN2CCCCC2)c1)NN
Agent: I
Solvent: c1ccccc1
Product: Cn1c(CO)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 0.7 %

Procedure:
N-Amino-N'-methyl-N"-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]guanidine hydroiodide (2.24 g) and glycolic acid (1.52 g) were heated together for 3 h in dry benzene (25 ml) at reflux. The benzene was decanted from the residual oil, which was partitioned between ethyl acetate and aqueous 1N sodium hydroxide solution. The organic phase was chromatographed on silica using methanol to give a white solid. This solid was washed with boiling ethyl acetate to leave the title compound as a white solid (0.013 g) m.p. 151°-2°.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:17]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]([CH3:32])[CH:20]=3)=[CH:18][C:11]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>>[CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][C:17]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]([CH3:32])[CH:20]=3)=[CH:18][C:11]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(-c3cc4c(CNCc5ccccc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNCc5ccccc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 73.9 %

Procedure:
Benzyl[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is prepared as described in Example 179a starting with 0.070 g of benzyl[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]-pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.54 cm3 of 5N potassium hydroxide. 0.038 g of benzyl[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is obtained, the characteristics of which are as follows:
Reaction SMILES: [N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.N1C=CN=N1.C([O-])([O-])=O.[K+].[K+].[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=1.NC1C=CC=CC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>S1(CCCC1)(=O)=O.C1COCC1.O>[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncco2)cc1
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(-c2ncco2)cc1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 4-(2-oxazolyl)aniline to generate the title compound. The 4-(2-oxazolyl)aniline was prepared by treating 4-nitrobenzoyl chloride sequentially with 1,2,3-triazole at 140° C. in sulfolane containing K2CO3 to generate 4-(2-oxazolyl)nitrobenzene which was reduced to the desired aniline with Na2S2O4 in THF/H2O at 90° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](F)=[CH:24][CH:25]=2)[C:20]([C:28](=[N:30][OH:31])[CH3:29])=[CH:19][N:18]=1.[NH4+].[Cl-]>CC(N(C)C)=O>[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:24][CH:25]=2)[C:20]([C:28](=[N:30][OH:31])[CH3:29])=[CH:19][N:18]=1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: CC(=NO)c1cnc(N)c2ccc(F)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: CC(=NO)c1cnc(N)c2ccc(-n3cc(C)c4c3CC(C)(C)CC4=O)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
To 3,6,6,-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.104 g, 1.4 eq) in dimethylacetamide (3 mL), sodium hydride (14.4 mg, 1.4 eq) is added slowly and stirred at RT for 0.5 h. Then 1-(1-amino-6-fluoro-isoquinolin-4-yl)-ethanone oxime (90 mg, 1 eq) is added and the mixture is stirred at 150° C. overnight. The reaction is poured into Sat'd NH4Cl aq. (200 mL), extracted by EtOAc (3×100 mL), dried over Na2SO4, filtered, concentrated to give a crude product. That is purified by Biotage chromatography, eluted by 20% MeOH in DCM to give 1-(1-amino-4-(1-(hydroxyimino)ethyl)isoquinolin-6-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one (20 mg, 13%). LC/MS m/z=377 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[C:6]([OH:8])[CH:7]=1.O(C)[C:11]([S-])=[S:12].[Na+].ClC1C(N)=C(O)C=CC=1.S.P(=O)(O)(O)O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:11]([SH:12])[O:8][C:6]=2[CH:7]=1
Reactant: COC(=S)[S-]
Reactant: Nc1ccc(Cl)cc1O
Agent: Nc1c(O)cccc1Cl
Agent: O=P(O)(O)O
Agent: S
Solvent: O
Product: Sc1nc2ccc(Cl)cc2o1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
143.6 g (1 mol) of 5-chloro-2-aminophenol, 164 g (1.02 mols) of sodium methyl xanthate (90% strength) and 500 ml of water were introduced into a 1 liter flask equipped with stirrer, thermometer and reflux condenser. The reaction mixture (the chloro-aminophenol remained undissolved) was warmed with stirring, from 80° C. on vigorous hydrogen sulfide development occured. After about 1 hour the reaction was essentially complete, but stirring with reflux was continued for a further 2 hours. The resulting black reaction solution was cooled, and acidified with 70 g of 85% phosphoric acid. The precipitate was suction-filtered, washed thoroughly with water and subsequently dried at about 80° C. under reduced pressure. After drying, 180.5 g (97.3% of th.) of 6-chloro-2-mercaptobenzoxazole having a melting point of 221°-223° C. were obtained. (The literature gives a m.p. of 224°-225° C. after recrystallization from water/isopropanol, J. org. Chem. 19, 758). According to gas chromatography, the purity degree of the product was higher than 98%.