Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][C:36](=[O:39])[N:35]5COCC[Si](C)(C)C)=[CH:30][CH:29]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.CCOCC.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54].C(Cl)Cl>>[F:56][C:55]([F:58])([F:57])[C:53]([OH:59])=[O:54].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([N:34]5[CH:38]=[N:37][C:36](=[O:39])[NH:35]5)=[CH:32][CH:33]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1c(=O)ncn1-c1ccc(-c2c(CCc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1ncn(-c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)[nH]1

Procedure:
A solution of compound 52e (45 mg, 0.070 mmol) in TFA:DCM (1:3 v/v, 5 mL) was stirred overnight at rt. The resulting mixture was concentrated under reduced pressure and the residue obtained was treated with Et2O (10 mL). The solids formed were collected by filtration and washed with Et2O (2×20 mL). The title compound 59 was obtained as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.92 (d, J=8.4 Hz, 1H), 8.87 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.06-8.03 (m, 3H), 7.94-7.85 (m, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 6.30 (d, J=5.7 Hz, 1H), 3.56-3.43 (m, 12H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C29H26N8O2: 519.2 (M+H). Found: 519.1.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15].COC(=O)CCCCCCCCCCCCCC(O)=O>>[CH2:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)CCCCCCCCCCC(=O)O
Agent: COC(=O)CCCCCCCCCCCCCC(=O)O
Product: O=C(O)CCCCCCCCCCCO
Yield: 37 %

Procedure:
The same procedure as in Example 12 was repeated except that a barium salt of dodecanedioic acid monomethyl ester (20 mmol) was used instead of the barium salt of pentadecanedioic acid monomethyl ester, and the amount of the catalyst was 0.31 g to obtain ω-hydroxy dodecanoic acid. The yield was 37%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>CN(C)C(=O)C>[C:22]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[CH:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[CH:14]=1)=[O:19])(=[O:24])[CH3:23]
Reactant: CSc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CSc1ccc(-n2cnc3ccc(C(=O)NNC(C)=O)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carbohydrazide (1.0 g, 3.35 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (262 μL, 3.69 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hr. Ethyl acetate was added to the reaction mixture, the precipitate was collected by filtration and washed with ethyl acetate to give the title compound (1.14 g, yield 100%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13]([CH3:21])([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:22](=[O:24])[CH3:23])[N:3]=1.FC(F)(F)S(O[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])(=O)=O>C(Cl)Cl>[Si:31]([O:24][C:22]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([NH:12][C:13]([CH3:21])([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH3:14])[C:2]([CH3:1])=[N:3]2)=[CH2:23])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cccc2nc(C)c(NC(C)(C)CCS(C)(=O)=O)nc12
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(NC(C)(C)CCS(C)(=O)=O)nc12

Procedure:
A solution of 1-(2-methyl-3-((2-methyl-4-(methylsulfonyl)butan-2-yl)amino)quinoxalin-5-yl)ethanone (338c, 0.51 g, 1.46 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (0.50 mL, 2.20 mmol), and TEA (0.61 mL, 4.40 mmol) in DCM (14.68 mL) was stirred at 0° C. for 30 min when silyl enol ether was observed via lcms. The reaction mixture was diluted with DCM (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-N-(2-methyl-4-(methylsulfonyl)butan-2-yl)quinoxalin-2-amine (338d) as a yellow oil. MS (ESI, pos. ion) m/z: 464.2 (M+1).
Reaction SMILES: C1([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][C:13]=2[CH:14]=[O:15])[N:10]([CH3:16])[C:9](=[O:17])[CH2:8][CH2:7]3)CC1.[C:18]([O-])(=[O:20])[CH3:19].[NH4+].CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[CH2:18]([O:20][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH:14]=[O:15])[N:10]([CH3:16])[C:9](=[O:17])[CH2:8][CH2:7]2)[CH3:19]
Reactant: CN1C(=O)CCc2cc(C3CC3)c(C=O)cc21
Reactant: CC(=O)[O-]
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: [NH4+]
Solvent: CC#N
Product: CCOc1cc2c(cc1C=O)N(C)C(=O)CC2

Procedure:
The title compound was prepared according to the procedure used for the preparation of 6-cyclopropyl-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.47 (3H, t, J=7.0 Hz), 2.65 (2H, m), 2.93 (2H, m), 3.36 (3H, s), 4.14 (2H, q, 7.1 Hz), 6.81 (1H, s), 7.42 (1H, s), 10.45 (1H, s). m/z (APCI+) 233.9 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 4.167 min.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:18])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)[N:7]=2)[CH2:3][CH2:2]1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:25]=[C:24]([CH:26]=O)[O:23][N:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:48]>O1CCCC1.C(OCC)(=O)C>[ClH:48].[CH:1]1([NH:4][C:5](=[O:18])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH2:13][CH2:14][N:15]([CH2:26][C:24]4[O:23][N:22]=[C:21]([C:20]([F:29])([F:28])[F:19])[CH:25]=4)[CH2:16][CH:17]=3)[N:7]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cc(C(F)(F)F)no1
Reactant: O=C(NC1CC1)c1cccc(C2=CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1cccc(C2=CCN(Cc3cc(C(F)(F)F)no3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
A mixture of N-cyclopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide free base (5b) (133 mg, 0.545 mmol), 3-(trifluoromethyl)isoxazole-5-carbaldehyde (75) (270 mg, 0.818 mmol) and acetic acid (0.037 ml, 0.654 mmol) in tetrahydrofuran (5 ml) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (347 mg, 1.636 mmol) was added to the reaction mixture and stirred at room temperature for 15 hours. The reaction was quenched with saturated NaHCO3 solution (10 ml), extracted with ethyl acetate (50 ml×3), washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 75/25 to 85/15) to give the desired free base. This was diluted with ethyl acetate and HCl solution (4 N in 1,4-dioxane) was added to the solution. The resulted solid was triturated with hexane to give N-cyclopropyl-6-(1-((3-(trifluoromethyl)isoxazol-5-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinamide hydrochloride (76) (33 mg, yield 14%) as a pale yellow solid. 1H NMR (DMSO-d6): δ 8.52 (brs, 1H), 8.00 (m, 1H), 7.92 (m, 1H), 7.77 (m, 1H), 7.47 (m, 1H), 6.93 (s, 1H), 4.77 (m, 2H), 3.93 (m, 2H), 2.83-3.20 (m, 5H), 0.72 (m, 2H), 0.64 (m, 2H); MS: 393 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][C:6]([C:13]([O:15]CC)=O)=[C:5]2[OH:18].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][C:6]([C:13]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:15])=[C:5]2[OH:18]
Reactant: CCOC(=O)c1cnc2nc(C)c(Br)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1Br

Procedure:
A solution of ethyl 6-bromo-4-hydroxy-7-methyl[1,8]naphthyridine-3-carboxylate (Prep 1 0.57 g) and 4-chlorobenzylamine (2.59 g) is heated to 180° C. for 1 h. The mixture is cooled and diluted with EtOAc. The resulting precipitate is collected and dried. Physical characteristics are as follows: m.p. 269-270° C.; 1H NMR (DMSO-d6) δ 13.21, 10.09, 8.67, 8.62, 7.38, 4.54, 2.71; IR (drift) 3028, 2974, 2907, 1653, 1598, 1555, 1526, 1493, 1410, 1354, 1326, 1242, 1096, 806, 639 cm−1; Anal. Calcd for C17H13BrClN3O2: C, 50.21; H, 3.22; N, 10.33; Found: C, 50.31; H, 3.23; N, 10.17.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19](=S)[CH2:20][C:21](=O)[CH3:22])=[O:4].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19]1[N:33]([C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:32][CH:31]=2)[N:34]=[C:21]([CH3:22])[CH:20]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=S)CC(C)=O
Reactant: NNc1ccc(C(F)(F)F)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-benzenesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound as yellow solid. MS (ESI): m/z=394.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:28]=[N:29][C:30]([NH:33][C:13]([NH:12][C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[F:1])=[O:14])=[CH:31][CH:32]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)nc2)c1C(N)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)nc2)c1C(N)=O
Reaction time: 18 h
Yield: 6.6 %

Procedure:
0.068 cm3 (0.466 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate is added at a temperature in the region of 23° C. and under an argon atmosphere to 0.11 g (0.424 mmol) of 2-acetylamino-4-(6-aminopyridin-3-yl)-1H-pyrrole-3-carboxamide in solution in 20 cm3 of tetrahydrofuran. After stirring for 1 hour at a temperature in the region of 20° C., 0.059 cm3 (0.424 mmol) of triethylamine is added to the medium. The reaction mixture is then stirred for 18 hours at this temperature and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography [eluent: dichloromethane/methanol (95/5 by volume) and pure ethyl acetate gradient]. After concentrating the fractions under reduced pressure, 0.013 g of 2-acetylamino-4-{6-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]pyridin-3-yl}-1H-pyrrole-3-carboxamide is obtained in the form of a white solid. ES+: m/z=466 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27][CH2:28][C:29]([CH2:31][C:32](OC)=[O:33])=[O:30]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:32](=[O:33])[CH2:31][C:29](=[O:30])[CH2:28][CH3:27])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)CC(=O)OC
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: Cc1ccccc1C
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)CC(=O)CC
Temperature: 135 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 303-2 and 3-keto-n-valeric acid methyl ester (1.46 g) were dissolved in xylene (10 mL), and the mixture was stirred at 135° C. for 8 hr. After cooling to room temperature, the solution was directly packed and purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give 2-[(4-{2-[heptyl(3-oxopentanoyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.6 g) as a colorless oil. The present compound was used in the next step without particular purification. The title compound was obtained by an operation similar to that of Example 446 for the steps after cyclization reaction using hydrazine monohydrate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[C:10]=1[CH:17]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[C:21](=[O:35])[CH:20]=[CH:19][CH2:18]1)C1C=CC=CC=1>CCO>[OH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:1])[C:10]=1[CH:17]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:26][CH:25]=2)[C:21](=[O:35])[CH2:20][CH2:19][CH2:18]1
Reactant: COc1cccc(OCc2ccccc2)c1C1CC=CC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: COc1cccc(O)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 6-(2-(benzyloxy)-6-methoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)-5,6-dihydropyridin-2(1H)-one (313 mg; 0.64 mmol), and 10% Pd(C) (300 mg) in anh. EtOH (20 ml) was stirred at rt, under hydrogen atmosphere (1 atm), for 17 h. Filtration over a pad of celite, concentration to dryness under reduced pressure, and additional drying under HV afforded 6-(2-hydroxy-6-methoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one as a grey solid. LC-MS (conditions E): tR=0.73 min.; [M+H]+: 396.24 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].O.[C:17](OCC)(=[O:19])[CH3:18]>C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>[C:17]([O:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])(=[O:19])[CH3:18]
Reactant: O=C(O)C=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of 4-hydroxy-3-nitrocinnamic acid (prepared as described in Preparation 1) were dissolved in 30 ml of acetic anhydride. One drop of sulfuric acid was added to the solution, which was then stirred for 2 hours at room temperature. 50 ml of water were added the solution, and it was then stirred for a further 2 hours. At the end of this time, ethyl acetate was added, and the mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was mixed with toluene; the remaining acetic acid was removed by azeotropic distillation to obtain 10.2 g of the title compound as crystals.
Reaction SMILES: [H-].[Na+].[CH:3]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:31]=[CH:30][C:29]([C:32]4[CH:33]=[CH:34][C:35](=[O:38])[NH:36][CH:37]=4)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:27]=[CH:28][C:29]([C:32]4[CH:33]=[CH:34][C:35]([O:38][CH:3]5[CH2:7][CH2:6][CH2:5][CH2:4]5)=[N:36][CH:37]=4)=[CH:30][N:31]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=c1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)c[nH]1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(OC2CCCC2)ncc1-c1cnc(OC2CCN(C3CCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
60% sodium hydride (21 mg) and cyclopentyl bromide were added to a DMF solution (4 ml) of 2-(1-cyclopentylpiperidin-4-yloxy)-5-(1H-pyridin-2-on-5-yl)pyrimidine (120 mg), and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=9:1) to obtain the entitled compound.
Reaction SMILES: B(O)(O)O.[N+:5]([C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[N+:23]([O-:25])=[O:24])[C:13](=[O:26])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-])=O.[S].S(=O)(=O)(O)[OH:29]>OS(O)(=O)=O.O=S(=O)=O.O>[OH:29][C:11]1[C:12]2[C:13](=[O:26])[C:14]3[C:19](=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=[CH:16][CH:15]=3)[C:20](=[O:22])[C:21]=2[C:8]([NH2:5])=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=S(=O)=O
Agent: OB(O)O
Agent: [S]
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1c(cccc1[N+](=O)[O-])C2=O
Temperature: 25 °C

Procedure:
50 parts of crystalline boric acid are dissolved in 1,000 parts of 30% strength oleum. 100 parts of 1,8-dinitroanthraquinone (analysis: 97.6% of 1,8-DNA; 0.8% of 1,5-DNA) are then added at room temperature with stirring. 15 parts of pulverulent sulphur are then added in portions at a temperature of 50° C. in the course of 45 minutes. The reaction mixture is further stirred for 1 hour at 50° C., cooled down to room temperature and then diluted with cooling by means of 211 parts of 78% strength sulphuric acid and then with 525 parts of water. The precipitated reaction product is filtered off with suction and washed with 133 parts of 60% strength sulphuric acid and thereafter with warm water until neutral. 64.5 parts of 1-hydroxy-4-amino-5-nitroanthraquinone are obtained which after recrystallisation from N-methylpyrrolidone melts at 270° C.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[C:12]#[N:13])[NH:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].[OH2:26]>S(=O)(=O)(O)O>[C:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=3)[C:12]([NH2:13])=[O:26])[NH:10][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O
Reactant: N#CC(=C1Nc2ccc(C(=O)O)cc2N1)c1nccc(C(F)(F)F)n1
Agent: O=S(=O)(O)O
Product: NC(=O)C(=C1Nc2ccc(C(=O)O)cc2N1)c1nccc(C(F)(F)F)n1
Temperature: 50 °C
Yield: 68 %

Procedure:
The 2-[5-carboxy-1H-benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)-acetonitrile (450 mg, 1.29 mmol) from the previous step, dissolved in concentrated sulfuric acid (2 mL), was heated to 50° C. for 6 hr. The mixture was cooled to room temperature and added dropwise to rapidly stirred room-temperature water (500 mL). The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to give 2-[5-carboxy-1H-benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (322 mg, 0.88 mmol, 68% yield) as a dark brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Li]CCCC.[B:18](OC)([O:21]C)[O:19]C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH2:6][OH:7])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[B:18]([OH:21])[OH:19]
Reactant: COc1cc(CO)cc(OC)c1
Reactant: COB(OC)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)cc(OC)c1B(O)O
Temperature: 25 °C

Procedure:
To a solution of 3,5-dimethoxybenzyl alcohol (80 g) in THF (1900 ml) was added n-BuLi (1.6 M in n-hexane, 750 ml) portionwise at −50° C. for 0.5 hour under argon. The mixture was warmed up to room temperature for 2 hours and cooled again to −60° C. To the mixture was added (MeO)3B (200 ml). The resulting mixture was warmed to room temperature and stirred over night. To the reaction mixture was added a solution of citric acid (300 g) in H2O (1200 ml) portionwise at 0° C. The aqueous layer was separated, saturated with NaCl and extracted with AcOEt. The combined AcOEt extract was dried (Na2SO4) and evaporated. The crystalline residue was triturated with AcOEt and collected by filtration to yield the title compound (75.1 g). mp. 92-98° C.; IR (Nujol) 3460, 3408, 3218, 1613, 1578, 1288, 1231, 1123, 1055, 960, 779 cm−1; MS (APCI) m/z 230 (M+NH4).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:32][C:33]1[C:34](=[O:48])[N:35]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:36]([CH3:40])=[CH:37][C:38]=1[OH:39].[F:49][C:50]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:51]=1[CH2:52]O>CN(C=O)C>[Cl:32][C:33]1[C:34](=[O:48])[N:35]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:36]([CH3:40])=[CH:37][C:38]=1[O:39][CH2:52][C:51]1[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:50]=1[F:49]
Reactant: Cc1cc(O)c(Cl)c(=O)n1Cc1cccnc1
Reactant: OCc1ccc(F)cc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cccnc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a degassed cold solution of DMF (10 mL) and PPh3 (resin, 2.2 g, 6.6 mmol) was added DEAD (1.038 mL, 6.6 mmol). The reaction mixture stirred at −10° C. for 20 minutes under nitrogen. A solution of 3-chloro-4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one (1.00 g, 4.0 mmol) and 2,4-difluorobenzylalcohol (0.66 mL, 6.0 mmol) in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at −10° C. for 30 minutes and then allowed to stir at room temperature for 1 hour. The resin was filtered and rinsed with fresh MeOH and the filtrate concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (5% methanol in ethyl acetate). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (ddd, 2H, J=1.6 Hz, 1.6 Hz, 1.6 Hz), 7.61 (m, 2H), 7.41 (dd, 1H, J=4.4 Hz, 4.8 Hz), 7.02 (m, 2H), 6.55 (s, 1H), 5.43 (s, 2H), 5.29 (s, 2H), 2.41 (s, 3H); ES-HRMS m/z 377.0882/379.0840 (M+H calculated for C19H16N2O2F2Cl requires 377.0863/379.0840).
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH2:20]O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:67]=[N+:68]=[N-:69])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[C:1]([O:7][CH2:8][CH:9]([CH2:20][N:67]=[N+:68]=[N-:69])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(CCC(CO)COC(=O)C(C)(C)C)cc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CCC(CN=[N+]=[N-])COC(=O)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A mixture of alcohol (17) (10 mmol), triphenylphospine (20 mmol, 5.25 g), diethyl azodicarboxylate (20 mmol, 3.15 ml) in THF (70 ml) was treated with diphenylphosphorylazide (20 mmol, 4.32 ml) and stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with EtOAc/hexanes (1:10) as an eluant to give compound 19.