Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)=O.CC(C)=O.C([N-]C(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([CH:3]([C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1])[C:4]([OH:6])=[O:5])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(c1ccccc1)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
In accordance with a modified literature procedure (Pfeffer, P. E.; Silbert, L. S.; Chirinko, J. M. J. Org. Chem. 37(3), 1972, 451-458), a solution of 3,3-dimethyl-3-phenyl propionic acid (0.22 g, 1.2 mmol, from Reference Example 22) in tetrahydrofuran (2 mL) is cooled to −40° C. (dry ice/acetone) while stirring under a nitrogen atmosphere. Lithium diisopropylamide (Aldrich, 2.0 M solution in tetrahydrofuran/ethylbenzene/heptane, 1.4 mL, 2.8 mmol) is added dropwise via syringe, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU, 0.16 mL, 1.3 mmol). The reaction mixture is then allowed to warm to room temperature and to stir for 30 minutes before being re-cooled to 0° C. (ice water bath). Benzyl bromide (0.15 mL, 1.3 mmol) is then added neat via syringe and the reaction mixture is allowed to stir overnight while warming to room temperature. The reaction is quenched by the addition of 10% aqueous hydrochloric acid solution and extracted thrice with ethyl acetate. The combined extracts are washed twice with 10% aqueous hydrochloric acid solution and once with saturated sodium chloride solution, dried over anhydrous sodium sulfite, and concentrated under reduced pressure. Flash chromatography (silica gel, ether/hexanes) is performed to give a straw colored gum (0.91 g, 70% for two combined reactions). MS (ES−): (M−H)=266.9
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[O:3].[CH2:6]([NH:13][C:14]([NH2:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C(O)(=O)C>[CH2:6]([N:13]1[CH:1]([OH:5])[C:2](=[O:3])[NH:16][C:14]1=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: O=CC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)N(Cc2ccccc2)C1O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3000 parts by weight of 50% strength aqueous glyoxylic acid solution and 500 parts by weight of acetic acid (100% strength) are placed in a heatable, stirred apparatus and heated to 100° C. A mixture of 3000 parts by weight of benzylurea, 1300 parts by weight of water and 1500 parts by weight of acetic acid having a temperature of 80° C. is added to this solution over a period of one hour. The total reaction mixture is subsequently stirred at an internal temperature of 100° C. for another hour. 4500 parts by weight of an acetic acid/water mixture are then distilled off to a pressure of 200 mbar and a temperature at the bottom of 100° C. The remaining liquid residue is admixed at 90° C. with 900 parts by weight of water and 12.5 parts by weight of acetic acid, cooled to 35° C., admixed with 3000 parts by weight of methylene chloride and stirred at 25° C. for 12 hours. The temperature is then held at 3° C. for 1 hour by cooling.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].ClC(Cl)(Cl)C[O:14][C:15](=[O:36])[CH:16]([S:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=1>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH2:27][S:26][CH:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:9][C:8](=[O:10])[CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:22][CH:23]=2)[C:15]([OH:36])=[O:14])=[CH:30][CH:31]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Product: O=C(Cc1ccccn1)OCc1ccc(CC(SCCc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared starting from 2-pyridineacetic acid (HCl salt) and 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2-trichloro-ethyl ester in the same manner as described for example 7 (yield: 8.6 mg, 29%). 1H-NMR (300 MHz, CDCl3): δ 2.83-3.16 (m, 6H), 3.54-3.71 (m, 1H), 3.64 (s, 2H), 5.06-5.20 (m, 2H), 6.91-7.00 (m, 2H), 7.09-7.35 (m, 7H), 7.66 (brd, 1H), 8.06 (brs, 1H), 8.45 (brd, 1H); Mass Spectrum: M+H+ 455.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:14][CH2:13][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:28])[NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:5][N:6]=3)=[O:11])[CH2:17][CH2:16]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Reactant: COCCN
Product: COCCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Yield: 73 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 2-methoxyethylamine. And then, the product was recrystallized with methylene chloride and hexane to give a desired compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:16]C)=[C:10]([O:14]C)[C:11]=2[F:13])[C:6](=[O:18])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:4]1)[CH3:2].B(Br)(Br)Br>ClCCl.CCO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:16])=[C:10]([OH:14])[C:11]=2[F:13])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(OC)c(OC)cc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(O)c(O)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 1-ethyl-8-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (24 g, 74.2 mmol) in Dichloromethane (DCM) (300 mL) was added boron tribromide (35.1 mL, 371 mmol) at −78° C. The mixture was warmed up to rt and stirred at 25° C. overnight. LCMS indicated completion of the reaction. The mixture was diluted with EtOH and concentrated in vacuo. The same procedure was repeated several times to afford 1-ethyl-8-fluoro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (18 g, 67.4 mmol, 91% yield) as a yellow solid. This product was used in next step reaction without further purification. LCMS (M+H)+: 268.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCCCn1ccc2cc(Br)ccc21
Product: CCCCn1ccc2cc(-c3ccc(Cl)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole and 4-chlorophenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 284. 1HNMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.67 (d, 2H, J=8.56 Hz), 7.54 (d, 1H, J=8.55 Hz), 7.46 (d, 2H, J=8.55 Hz), 7.42-7.40 (m, 2H), 6.47 (d, 1H, J=3.0 Hz), 4.18 (t, 2H, J=7.02 Hz), 1.73 (p, 2H, J=7.18, Hz), 1.24 (h, 2H, J=7.47 Hz), and 0.88 ppm (t, 3H, J=7.33 Hz). Elemental Analysis for C18H18ClN: Calculated: C, 76.18; H, 6.39; N, 4.94. Found: C, 75.71; H, 6.16; N, 4.74.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:12](F)=[C:11]([F:14])[C:10]([F:15])=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:16]([OH:18])=[O:17].[OH:19][ClH](O)(=O)=O>O>[F:3][C:4]1[C:12]([OH:19])=[C:11]([F:14])[C:10]([F:15])=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c(F)c(O)c(F)c(F)c1C(=O)O
Temperature: 90 °C
Reaction time: 9 h

Procedure:
An amount of 2 g (30.7 mmole) of 86% potassium hydroxide was dissolved in 10 ml of water and heated to 90° C. To this solution, under stirring, was added gradually 1.0 g (4.20 mmole) of 3,4,5,6-tetrafluorophthalic acid, and the reaction was carried out at 90° C. for 9 hours. After left to cool, to the aqueous reaction solution was added concentrated hydroxychloric acid to adjust pH to 2 to give 3,5,6-trifluoro-4-hydroxyphthalic acid. To this was added 15 ml of diethyl ether, and 3,5,6-trifluoro-4-hydroxyphthalic acid was extracted in the organic layer. This extraction operation was repeated for 5 times, and the diethyl ether layers obtained were dried over anhydrous sodium sulfate, then evaporated to dryness and washed with chloroform to give 1.05 g of 3,5,6-trifluoro-4-hydroxyphthalic acid monohydrate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)(=[O:25])=[O:24])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(OC(F)(F)F)cc2cccnc12)c1cccnc1
Yield: 84.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-(trifluoromethoxy)quinolin-8-ylamine (Intermediate 46) (110 mg, 0.48 mmol), pyridine-3-sulfonyl chloride (Intermediate 17) (102 mg, 0.57 mmol), pyridine (0.08 ml, 0.96 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (150 mg, 85%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[I-].C([N+]1(C)[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)C>C(O)C.O>[O:31]=[C:28]1[CH2:29][CH2:30][N:1]([CH2:2][C:3]2([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)C1(CN)CCOCC1
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C1(CN2CCC(=O)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a refluxing mixture of tert-butyl 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate (8.00 g, 0.0372 mol, step 2 of Example 1) and K2CO3 (0.51 g, 0.0372 mol) in ethanol-H2O (2:1, 240 mL) was added dropwise 1-ethyl-1-methyl-4-oxopiperidinium iodide (12.0 g, 0.0445 mol, J. Org. Chem. 1995, 60, 4324) in ethanol-H2O (2:1, 150 mL), and the resulting mixture was stirred at the same temperature for 1 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was poured into sat. NaHCO3 aq. (200 mL), and the mixture was extracted with CH2Cl2 (200 mL×3). The extracts were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (3:1 to 2:1) to give 10.77 g (98%) of the title compound as colorless syrup.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20](O)[CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([O:13][C:20]1[CH:19]=[CH:18][C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1)=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
N-[2-[(Acetylthio)methyl]-4-methyl-1-oxopentyl]glycine (0.5 g) is dissolved in 30 ml of ethyl acetate along with p-nitrophenol (0.2 g). This solution is cooled to 5° C., N,N'-dicyclohexylcarbodiimide (0.4 g) is added portionwise and the reaction mixture is stirred at 5° for about 16 hours. The dicyclohexyl urea is filtered off and the filtrate is concentrated thoroughly in vacuo. Isopropyl ether is added to the residue and allowed to sit for about 16 hours. The crystalline solid is filtered to yield 0.4 g of product, melting point 95°-100° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[NH2:60][CH:61]([C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[CH2:62][NH:63][C:64](=[O:66])[CH3:65]>CN1C(=O)CCC1>[C:64]([NH:63][CH2:62][CH:61]([NH:60][C:48]([C:33]1([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1)=[O:50])[C:67]1[CH:68]=[CH:69][C:70]([Cl:73])=[CH:71][CH:72]=1)(=[O:66])[CH3:65]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CC(=O)NCC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)NCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 81.7 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (80 mg, 0.22 mmol) and N-ethyldiisopropylamine (0.046 mL, 0.27 mmol) in NMP (3 mL). The mixture was treated with N-(2-amino-2-(4-chlorophenyl)ethyl)acetamide (Intermediate 83) (52 mg, 0.24 mmol). The solution was stirred for 65 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water. The organic solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM). Product containing fractions were combined to give tert-butyl 4-(2-acetamido-1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (100 mg, 81%) as colourless solid.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](/[CH:9]=[C:10](\[CH3:27])/[CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[N:5]1)([CH3:3])[CH3:2].C(C/C(/C)=C/CC/C(/C)=C/CC(Cl)=O)/C=C(/CCC=C(C)C)\C>>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](/[CH:9]=[C:10](\[CH3:27])/[CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/C1=N[C@@H](C(C)C)CO1
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC(=O)Cl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/C1=N[C@H](C(C)C)CO1
Yield: 7 %

Procedure:
Similar to the preparation of 27a, the reaction of 25 with 26e afforded the desired compound 27e (8.0 mg, 7%) as oil. TLC Rf: 0.35 (20% EtOAc/petroleum ether); 1H NMR (400 MHz, CDCl3): δ 5.14-5.09 (m, 3H), 4.25-4.20 (m, 1H), 3.95-3.90 (m, 3H), 2.20-1.60 (m, 28H), 0.99-0.97 (m, 3H), 0.89-0.87 (m, 3H). LCMS: MS (m/z): 372.30 (M+H); ret. time: 6.31 min.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:19]([O-])=O)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C(O)C.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[OH-].[Na+]>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH2:19])[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Reaction time: 8 h
Yield: 73 %

Procedure:
Add 1,8-dinitroanthraquinone (1.49 g, 5 mmol) into 56 ml ethanol and stir the mixture. Then add a reductive solution containing sodium sulfide nonahydrate (5.4 g, 22.5 mmol), sodium hydroxide (2.14 g, 53.5 mmol) dissolved in 95 ml water. The mixed solution is reflux heated for 6 hours, standing overnight, and filter the precipitate. The precipitate is recrystallized from ethanol to get red compound 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)=[N:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:21])#[N:25]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: COc1ccc(CN(CCN(C)CCN)c2ccccn2)cc1
Product: COc1ccc(CN(CCN(C)CCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.53 g (1.7 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil which crystallises from absolute ether at -20° C. and is recrystallised from ethanol/ether; MS (+FAB method): m/z (rel. int. [%])=596 ([M+H]+, 1), 121 (100); IR (KBr): 2163 cm-1 (C≡N); m.p.: 56°-58° C. (ethanol/ether).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:22]([CH2:25][OH:26])[CH2:23][NH2:24]>>[O:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:24][CH2:23][CH2:22][CH2:25][OH:26])[CH:3]=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCCO
Reactant: Clc1cccc(Nc2ccc(Oc3ccccc3)cc2)n1
Product: OCCCNc1cccc(Nc2ccc(Oc3ccccc3)cc2)n1
Yield: 73 %

Procedure:
A mixture of 150 mg of 6-chloro-N-(4-phenoxyphenyl)pyridin-2-amine in 304 mg of n-propanolamine in a screw cap vial under argon was treated analogously to the method as set out in Example 16b. 3-(6-(4-Phenoxyphenylamino)pyridin-2-ylamino)propan-1-ol was obtained in the form of a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N

Procedure:
The title compound was prepared from [4-cyano-5-(isopropyl-methyl-amino)-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C28) (1.73 g, 5.17 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an off-white solid (1.56 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][CH2:13][C@@H:14]([OH:19])[C:15]([O:17]C)=[O:16])[CH:6]=[CH:5]2.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][CH2:13][C@@H:14]([OH:19])[C:15]([OH:17])=[O:16])[CH:6]=[CH:5]2
Reactant: COC(=O)[C@H](O)CSc1ccc2cc(Cl)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@H](O)CSc1ccc2cc(Cl)ccc2c1
Yield: 97.2 %

Procedure:
To a suspension of methyl (2S)-3-[(6-chloronaphthalen-2-yl)thio]-2-hydroxypropionate (5.4 g) obtained in Example 112a) in ethanol (150 mL), a 8 N aqueous sodium hydroxide solution (6.8 mL) was added, and the mixture was mixed at room temperature for 3 hours. Ethanol was distilled off under reduced pressure, and then the precipitates were collected by filtration. The solid was suspended in water (100 mL), pH was adjusted to about 3 with 1 N hydrochloric acid, and the precipitates were then collected by filtration to give the title compound (5.0 g, 97%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=O.[OH-].[K+]>>[F:12][C:13]1[CH:14]=[C:15](/[CH:16]=[CH:2]/[C:1]([C:4]2[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)=[O:3])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: COc1ccc(C(C)=O)cn1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(=O)/C=C/c2cc(F)cc(F)c2)cn1

Procedure:
In analogy to example 170, step 1, 5-acetyl-2-methoxypyridine was reacted with 3,5-difluorobenzaldehyde in the presence of potassium hydroxide to give the title compound as a colourless solid. MS (ESI+): m/z=276.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16][CH:17]([NH2:18])[CH:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][S:29](Cl)(=[O:31])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][S:29]([NH:18][C@H:17]2[C@@H:11]3[CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:8]=4)[CH2:14][CH2:13][N:12]3[CH2:15][CH2:16]2)(=[O:31])=[O:30])=[CH:26][CH:27]=1
Reactant: NC1CCN2CCN(c3cccc(C(F)(F)F)n3)CC12
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1ccc(Cl)cc1)N[C@@H]1CCN2CCN(c3cccc(C(F)(F)F)n3)C[C@@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 96B (100 mg, 0.349 mmol) in dry dichloromethane (2 mL) was added (4-chlorophenyl)methanesulfonyl chloride (118 mg, 0.524 mmol) and triethylamine (212 mg, 2.096 mmol). The mixture was stirred at room temperature for 16 hours and then concentrated. The residue was purified via HPLC (Gilson®, XBridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=254 nm) to give the title compound as the first eluting diastereomer. 1H NMR (500 MHz, methanol-d4) δ 1.57-1.66 (m, 1 H), 1.91-1.99 (m, 1 H), 2.21-2.29 (m, 2 H), 2.34 (q, 1H, J=8 Hz), 2.62 (dd, 1H, J=12, 10 Hz), 2.92 (td, 1H, J=12, 3 Hz), 3.00-3.06 (m, 2 H), 3.41 (td, 1H, J=9, 6 Hz), 4.33-4.40 (m, 3 H), 4.52 (dd, 1H, J=12, 1 Hz), 6.98 (t, 2H, J=7 Hz), 7.38-7.41 (m, 2 H), 7.44-7.48 (m, 2 H), 7.66-7.72 (m, 1 H); MS (DCI) m/z 475 (M+H)+.