Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([Cl:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([Cl:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:45])=[CH:28][C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Cl)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1Cl)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 19.1 %

Procedure:
Prepared in 19.1% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-chloro-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.33 (s, 1H), 7.27-7.21 (m, 1H), 7.17 (d, J=8.8 Hz, 2H), 5.75 (br. s., 1H), 4.60 (d, J=4.4 Hz, 1H), 4.01-3.86 (m, 2H), 3.50 (br. s., 1H), 3.37 (br. s., 4H), 2.42 (s, 3H), 2.33 (br. s., 1H), 1.96 (d, J=13.2 Hz, 1H), 1.88-1.73 (m, 3H), 1.70-1.47 (m, 6H), 1.18 (s, 3H), 1.16 (s, 9H), 1.02 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 678.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:30][CH:29]=2)[C@H:10]([O:47][CH2:48][C@H:49]2[CH2:53][O:52]C(C)(C)[O:50]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[OH:50][C@H:49]([CH2:53][OH:52])[CH2:48][O:47][C@H:10]1[C@H:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:32][CH:33]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13][NH:8][CH2:9]1
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3C#N)cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: COc1cc(CO[C@H]2CNC[C@@H](OC[C@H](O)CO)[C@@H]2c2ccc(OCCCOc3ccccc3C#N)cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (g) the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the 2-[3-[4-[(3S,4R,5R)-3-[(2R)-2,3-dihydroxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile as white foam; MS: 613 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:6]=[CH:7][CH:8]=1)=O.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:1]=[C:20]1[S:16][C:17](=[O:22])[NH:18][C:19]1=[O:21]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cccc(-c2ccccc2Cl)c1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cccc(-c3ccccc3Cl)c2)S1

Procedure:
To a solution of 3-formyl-(2′-chloro-1,1′-biphenyl) (0.12 g, 0.55 mmol) and 2,4-thiazolidinedione (0.08 g, 0.65 mmol) in toluene (10 mL) were added piperidine (0.008 mL, 0.073 mMol) and benzoic acid (0.011 mg, 0.08 mmol), and the reaction was refluxed for 4 h with continuous removal of water. The solvent was then distilled off and the oily residue obtained was purified by chromatography on silica-gel using hexane: ethyl acetate (3:1) as the eluent to yield titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1.[CH3:15][CH:16]([CH3:22])[CH2:17][CH:18]([NH2:21])[CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:21][CH:18]([CH2:17][CH:16]([CH3:22])[CH3:15])[CH2:19][CH3:20])=[O:13])=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Reactant: CCC(N)CC(C)C
Product: CCC(CC(C)C)NC(=O)c1cc2cc(OC)ccc2o1
Yield: 67 %

Procedure:
Prepared in a similar manner to example 4 using 5-methoxybenzofuran-2-carboxylic acid and 5-methylhexan-3-amine (example 5a). Yield: 67%. 1H NMR (500 MHz, CDCl3): δ 0.96 (m, 9H); 1.39-1.52 (m, 3H); 1.66 (m, 2H); 3.85 (s, 3H); 4.17 (m, 1H); 6.24 (d, 1H); 7.01 (dd, 1H); 7.08 (d, 1H); 7.38 (m, 2H). MS (290, M+H).
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([CH:8](O)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH:5]1[CH2:24][CH2:25][O:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])[CH3:2].N1C(C)=CC=CC=1C.S(Cl)([Cl:50])=O>O1CCCC1>[CH2:1]([S:3][CH:4]1[N:7]([CH:8]([Cl:50])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH:5]1[CH2:24][CH2:25][O:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])[CH3:2]
Reactant: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 11.3 g p-nitrobenzyl 2(4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl)-2-hyroxyacetate and 3.02 ml 2,6-lutidine in 175 ml anhydrous tetrahydrofuran was cooled to 0° C. under a nitrogen atmosphere. Thionyl chloride (1.75 ml) was added dropwise and the resulting mixture was stirred at 0° C. for 20 min. The mixture was filtered through Supercel and the filtrate was concentrated in vacuo. The concentrate was dissolved in methylene chloride and the resulting solution was washed successively with 200 ml 1N aqueous hydrochloric acid, 200 ml saturated aqueous sodium bicarbonate solution and 200 ml saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil (11.6 g) of the title compound. The NMR spectrum of the title compound in deuterochloroform showed peaks at 1.04-1.6 (c, 6H); 2.6 (m, 2H); 3.4 (m, 1H); 4.8-5.4 (c, 6H); 5.85, 5.9, 5.98, 6.1 (s, 1H); 7.5 (m, 4H); 8.2 (m, 4H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=3)[N:13]=[C:12]([NH:28][NH2:29])[N:11]=2)=[CH:4][CH:3]=1.[F:30][C:31]([F:42])([F:41])[O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:25])([F:27])[F:26])[CH:18]=3)[N:13]=[C:12]([NH:28][N:29]=[CH:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][C:31]([F:30])([F:41])[F:42])=[CH:34][CH:35]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: NNc1nc(NCc2ccc(Cl)nc2)nc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Solvent: CCO
Product: Fc1ccc(Nc2nc(NCc3ccc(Cl)nc3)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
A 20 mL flask was charged with N-(6-chloropyridin-3-yl-methyl)-N′-(4-fluoro-3-trifluoromethylphenyl)-6-hydrazino-1,3,5-triazine-2,4-diamine (XIX) (285 mg, 0.66 mmol), 4-(trifluoromethoxy)benzaldehyde (251 mg, 1.32 mmol), and ethanol (10 mL), and the resulting mixture stirred at ambient temperature for 24 h. The mixture was concentrated under vacuum, the residue washed with hexanes and recrystallized from hexanes-ethyl ether to afford the titled compound (2) as a white solid (182 mg, 45% yield): m.p. 117-125° C.; 1H NMR (CDCl3): δ 8.65 (bs, 1H); 8.54 (d, J=4.5 Hz, 1H); 8.35 (bs, 1H); 7.84 (s, 1H); 7.73 (d, J=7.2 Hz, 2H); 7.49-7.7 (m, 4H); 7.26 (m, 3H); 7.2 (t, J=6.0 Hz, 1H); 4.66 (d, J=6.0 Hz, 2H); Anal. Calcd for C24H17F7N8O: C, 50.89, H, 3.03, N, 19.78. Found C, 50.49; H, 3.17; N, 19.31
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([C:22]1[CH:28]=[C:27]([C:29]([F:41])([C:37]([F:40])([F:39])[F:38])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[CH:26]=[C:25]([CH3:42])[C:23]=1[NH2:24])[CH3:21].N1C=CC=CC=1>ClCCl.O1CCCC1.CN(C)C=O>[CH2:20]([C:22]1[CH:28]=[C:27]([C:29]([F:41])([C:37]([F:38])([F:39])[F:40])[C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[CH:26]=[C:25]([CH3:42])[C:23]=1[NH:24][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[F:1])[CH3:21]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a suspension of 2-fluoro-3-nitrobenzoic acid (6.3 g, 34 mmol) in dichloromethane (20 ml) was added oxalyl chloride (4.3 ml) at ambient temperature, followed by N,N-dimethylformamide (0.2 ml). The reaction mixture was stirred for 1 hour at ambient temperature and then heated to reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature and then concentrated. The residue was suspended in tetrahydrofuran (50 ml). 2-Ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylaniline (preparation as described in WO 08/074427) (10 g, 28.3 mmol) was dissolved in tetrahydrofuran (50 ml) and pyridine (6.8 ml, 84.9 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 hours, then at reflux for 3 hours. The reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (100 ml) and the mixture extracted twice with ethyl acetate (2×200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1 to 0:1) to give N-[2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylphenyl]-2-fluoro-3-nitrobenzamide (6.32 g, 43% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([C:16](=[O:29])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]CC)=[O:25])[CH:19]=1)[CH2:7][CH2:6]2.[OH-].[Na+].Cl>C(O)C>[CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:13])([F:14])[F:15])[N:8]([C:16](=[O:29])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=1)[CH2:7][CH2:6]2
Reactant: CCOC(=O)c1cccc(NC(=O)N2CCc3cc(SC)c(C(F)(F)F)cc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)O)c1)CC2
Yield: 82.6 %

Procedure:
To a suspension of 5-methylthio-6-trifluoromethyl-1-(3-ethoxy carbonyl phenyl carbamoyl) indoline (3 g, 7.1 mmol) in ethanol (30 ml) was added aqueous sodium hydroxide solution (5M) (7.1 ml, 35.5 mmol) and heated gently for 2 hours. It was then allowed to cool and acidified with aqueous hydrochloric acid (5M) forming a white precipitate which was filtered and dried to yield the product as a white solid (2.324 g, 83%), mp>200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:30][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=O>C(#N)C>[S:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:31]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])[CH:5]=[CH:4][N:3]2[CH:30]=1
Reactant: O=C(CBr)c1cccs1
Reactant: Nc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)ccn1
Solvent: CC#N
Product: O=C(Nc1ccn2cc(-c3cccs3)nc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 20.6 %

Procedure:
Compound 11 was prepared according to a process similar to that described in step 10.2, by reacting 0.1 g (0.26 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.11 g (0.53 mmol) of 2-bromo-1-(thien-2-yl)ethanone in 4 mL of acetonitrile. 0.026 g of the expected product is thus obtained in the form of a beige-coloured solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:33]=[CH:32][C:31](C3C4C(=CC(C=O)=CC=4)NN=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([C:28]2[N:33]=[CH:32][C:31]([C:3]3[C:4]4[C:9](=[CH:8][C:7]([CH:10]=[C:11]5[C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[NH:13][C:12]5=[O:20])=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1
Reactant: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=C5C(=O)Nc6ccccc65)ccc34)cn2)CC1

Procedure:
According to the procedure for the synthesis of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one, except substituting 3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-6-carbaldehyde (40 mg, 0.12 mol), the title compound was prepared as a yellow solid (4.9 mg, 9%). A mixture of (E)- and (Z)-isomers (79:21 by NMR) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (br. s, 1H), 10.64 (br. s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.14 (dd, J=8.8, 2.5 Hz, 2H), 7.91 (s, 1H), 7.79 (s, 1H), 7.62 (d, J=7.8, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.85 (t, J=7.3 Hz, 1H), 3.57 (t, J=4.5 Hz, 4H), 2.42 (t, J=5.0 Hz, 4H), 2.23 (s, 3H); MS ESI 437.2 [M+H]+, calcd for [C26H24N60+H]+ 437.20.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:22]=1)([O-:4])=[O:3]>O1CCCC1>[NH2:1][C:13]1[CH2:12][N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:22]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=[CH:7][C:8]=2[N:14]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCC(=S)N2
Reactant: N
Solvent: C1CCOC1
Product: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
300 ml of 25% aqueous ammonia solution were added to a solution of 16 g of 7-nitro-5-phenyl-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester, A. D. Rudzik & B. V. Kamdar, J.Med.Chem., 1971, 14, 1078-1081) in 850 ml of tetrahydrofuran. The solution was stirred at room temperature for 20 h. and then concentrated to about 50 ml in a vacuum. The crystalline precipitate was filtered off and recrystallized from dioxan. There were obtained 8.0 g of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine which was used in this form for the next step.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:20]2[CH:21]=[C:22]([F:24])[CH:23]=[CH:18][C:19]=2[C:25]([F:26])([F:27])[F:28])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: Fc1ccc(C(F)(F)F)c(Br)c1
Product: CCSc1ncc(C(=O)c2cc(F)ccc2C(F)(F)F)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-4-fluoro-1-trifluoromethyl-benzene (Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][N:16]3C(=O)C4C=CC(=O)C(=O)C=4C3=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>C(O)C>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1ccc2c(=O)n(CC3CCN(CCc4ccccc4)CC3)c(=O)c=2c1=O
Agent: NN
Solvent: CCO
Product: NCC1CCN(CCc2ccccc2)CC1
Yield: 108.5 %

Procedure:
A mixture of 1.31 g (3.8 mmoles) of 2-[1-(2-phenylethyl)-4-piperidylmethyl]-1H-isoindole-1,3(2H)-dione dione (Example 2) and 0.25 mL (7.8 mmoles) of hydrazine in 20 mL of ethanol was heated under reflux for 4 hours. The solvent was removed and the residue was made basic with aqueous potassium hydroxide and extracted with chloroform to give 0.90 g of 1-(2- phenylethyl)-4-piperidinemethylamine as an oil. NMR (CDCl3): δ7.14-7.35 (m, 5H); 2.93-3.10 (d, 2H); 2.72-2.85 (m, 2H); 2.52-2.65(m, 4H); 1.92-2.05 (t, 2H); 1.61-1.87 (m, 2H); 1.08-1.48 (m, 5H) .
Reaction SMILES: [OH:1][C:2]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([O:35]C)=[O:34])=[N:31][CH:32]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH-].[Na+].Cl>CO.O>[OH:1][C:2]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[N:31][CH:32]=1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(O)c3ccc(C(=O)O)nc3)s2)c1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
The product of Step 2 (95 mg, 0.184 mmol) was taken up in MeOH (2.0 ml) in a microwave vial, and sodium hydroxide (1.0 M in H2O, 0.369 ml, 0.369 mmol) was added. The reaction was heated to 100° C. for 10 min in the microwave. The colorless solution was adjusted to a pH of 3-4 with 1 N HCl, diluted with water, and extracted with 15% IPA/CHCl3 (2×). The combined organic layers were dried (MgSO4), filtered and evaporated to afford the title compound (85 mg, 0.169 mmol, 92% yield) as an off-white foam. MS ESI: [M+H]+ m/z 502.1. 1H NMR (600 MHz, DMSO-d6) δ 13.12 (s, 1H), 10.23 (s, 1H), 8.89 (d, J=1.9, 1H), 8.80 (d, J=4.9, 1H), 8.09 (dd, J=2.3, 8.2, 1H), 7.99 (d, J=8.2, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 7.25 (d, J=4.9, 1H), 7.13 (d, J=4.5, 2H), 2.28 (s, 3H), 1.95 (s, 3H). rhSYK activity=+++
Reaction SMILES: Cl.[OH:2][C:3]([CH3:8])([CH3:7])[CH2:4][C:5]#[N:6].[CH2:9]([O:11]CC)[CH3:10]>>[CH2:9]([O:11][C:5](=[NH:6])[CH2:4][C:3]([OH:2])([CH3:8])[CH3:7])[CH3:10]
Reactant: CCOCC
Reactant: CC(C)(O)CC#N
Agent: Cl
Product: CCOC(=N)CC(C)(C)O
Yield: 72 %

Procedure:
HCl (g) was bubbled through a solution of 3-hydroxy-3-methylbutyronitrile (5.0 g, 50.4 mmol) in diethyl ether (20 mL) and IMS (3.48 g, 75.6 mmol) at 0° C. for 30 minutes before leaving to stand at −5° C. over night. The solution was concentrated under vacuum affording 6.48 g (72%) of 3-hydroxy-3-methyl-butyrimidic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ: 11.36 (m br, 1H), 4.66 (q, 2H), 2.89 (s, 2H), 1.51 (t, 3H), 1.36 (s, 6H).
Reaction SMILES: [OH:1][CH:2]([C@@H:13]([NH:18][C:19]([C:21]1([NH:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([O:5]CC1C=CC=CC=1)=[O:4]>[C].[Pd].CO>[OH:1][CH:2]([C@@H:13]([NH:18][C:19]([C:21]1([NH:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([OH:5])=[O:4]
Reactant: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)C(O)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Further, to methanol 100 ml solution of 16.8 g (34 mmol) of the above phenylmethyl (2RS,3S)-2-hydroxy-3-[N-[1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarbonyl]amino]heptanoate, 1.5 g of 10% palladium carbon was added under haydrogen atmosphere and was stirred at the room temperature for two hours. After insoluble components of the reaction solution were removed by filtration, the filtrate was concentrated under reduced pressure, whereby 13.6 g of the captioned (2RS,3S)-2-hydroxy-3-[N-[1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarbonyl]amino]heptanoic acid was obtained in a yield of 68%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Cl)c(F)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Then, in a 100 ml-reaction vessel, 9.5 g (4.80×10-2M) of 2-fluoro-4-acetoxybenzoic acid and 50 ml of dry benzene were placed. To the mixture, 10.3 g (4.94×10-2M) of phosphorus pentachloride was added in 30 minutes at room temperature, followed by stirring for 4 hours at 50° C. After cooling, the solvent of the reaction mixture was distilled off to provide oily 2-fluoro-4-acetoxy-benzoyl chloride.
Reaction SMILES: NCCC([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:20]([Cl:33])[CH:19]=1)=O.C(OC(=O)NCCC(=O)NC1C=C2C(=CC=1)N=CN=C2NC1C=CC(OC2C=NC(C)=CC=2)=C(C)C=1)(C)(C)C>>[Cl:33][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([NH2:6])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc34)cc2C)cn1
Product: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
The procedure of (20-1) of Example 20 was repeated except for using 1 g of the compound obtained in Example 49 instead of the compound obtained in (1-4) of Example 1 to obtain the title compound (0.79 g, 98%).
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:15].[Cl:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:16][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSC1C(=O)Nc2ccc([N+](=O)[O-])cc21
Solvent: ClC(Cl)Cl
Product: CSC1(Cl)C(=O)Nc2ccc([N+](=O)[O-])cc21

Procedure:
A solution of 3-methylthio-5-nitrooxindole (900 mg, 4 mmol) and N-chlorosuccinimide (600 mg, 4.5 mmol) in 50 ml of chloroform was stirred at room temperature for 1 hour and then evaporated to dryness in vacuo, yielding 3-chloro-3-methylthio-5-nitrooxindole. The residue was dissolved in 15 ml of tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide powder (900 mg, 4.3 mmol) and boron trifluoride etherate (600 mg, 4.3 mmol) in 100 ml of 20 percent aqueous tetrahydrofuran. After stirring at room temperature for two hours, the reaction mixture was extracted with three 100-ml portions of chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was recrystallized from 95 percent ethanol to give 5-nitroisatin (600 mg, 78%), mp 252°-254°