Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OC1CCCCC1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OC2CCCCC2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. EI-MS m/e (%): 294 (M+, 12), 213 ([M—C6H9]+, 100), 212 ([M—C6H10]+, 48), 170 (60).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:7][CH2:6][CH2:5]2.[C:20](OCC)(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C1CCN2C(=NCCC2)CC1>C(O)C>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:2](=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)[NH:1][C:20](=[O:27])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1ccccc1C(=O)c1cc2c(cc1N)CCC2
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2[nH]c1=O)CCC3
Yield: 98.1 %

Procedure:
A mixture of 5-amino-6-(2-methylbenzoyl)indan (5.02 g), diethyl malonate (6.4 g) and DBU (0.3 ml) was heated at 170°-180° C. for 1 hour. To this reaction mixture was added ethanol to give crystals of ethyl 4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (6.81 g, 98.1%). Recrystallization from ethanol-chloroform gave colorless crystals, m.p. 296°-298° C.
Reaction SMILES: [CH3:1][C:2]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]2[C:5](=[CH:6][C:7]([NH:14][C:15]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=O)=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][C:3]1=[O:23]>[Pd].C(O)C>[CH3:1][C:2]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]2[C:5](=[CH:6][C:7]3[NH:14][C:15]([C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]=4)=[N:11][C:8]=3[CH:9]=2)[NH:4][C:3]1=[O:23]
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3cnccn3)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C)C(=O)Nc2cc3[nH]c(-c4cnccn4)nc3cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3.2 g. (8.3 mmol) 3-methyl-3-ethoxycarbonyl-5-nitro-6-(2-pyrazinoylamino)-indolin-2-one in 100 ml. ethanol are hydrogenated in 100 ml. ethanol in the presence of 0.5 g. 10% palladium on charcoal. After completion of the take up of hydrogen, the solution is filtered off from the catalyst, the ethanol is evaporated off and the residue is stirred for 1 hour in glacial acetic acid at 60° C.
Reaction SMILES: C([Mg]Cl)(C)C.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[C:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[CH:15][C:14]([CH2:17][C:18](N(OC)C)=[O:19])=[CH:13][CH:12]=1>O1CCCC1>[C:11]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:12]=[CH:13][C:14]([CH2:17][C:18]([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)=[O:19])=[CH:15][CH:16]=1
Reactant: c1cscn1
Reactant: CON(C)C(=O)Cc1ccc(-c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Cc1ccc(-c2ccccc2)cc1)c1nccs1
Temperature: -10 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
2.0 M of Isopropylmagnesium chloride in tetrahydrofuran (0.24 mL) was added to a solution of 1,3-thiazole (40 mg, 0.47 mmol) in tetrahydrofuran (6 mL) at −78° C. The reaction was stirred for 1 h. as it was warmed to −10° C. 2-Biphenyl-4-yl-N-methoxy-N-methylacetamide (100 mg, 0.4 mmol) in Tetrahydrofuran (2 mL) was added dropwise at −10° C. The reaction was stirred for 2 h. while the reaction was warmed to r.t. gradually. The reaction was quenched with saturated NH4Cl, and was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by Flash chromatography on a silica gel column (EtOAc:Hexane, 1:3 to 1:1) gave the 2-biphenyl-4-yl-1-(1,3-thiazol-2-yl)ethanone (70 mg, 60%) as a white solid. Analytical LCMS (M+H)+: m/z=279.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:17][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: O=[N+]([O-])c1cnccc1OCc1ccc(Cl)cc1
Yield: 78 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 4-chlorobenzyl alcohol, the titled compound was obtained as a white solid. (Yield: 78.0%)
Reaction SMILES: [NH:1]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH:11][C@H:12]([C:36](N(C)OC)=[O:37])[CH2:13][C:14](=[O:35])[NH:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:10])[CH3:8])=[O:5])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[NH:1]([C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH:11][C@H:12]([CH:36]=[O:37])[CH2:13][C:14](=[O:35])[NH:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:10])[CH3:8])=[O:5])[CH3:3]
Reactant: CON(C)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@H](C=O)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 91.2 %

Procedure:
The aldehyde Z-Ala-Ala-Asn(Trt)-H (4) was prepared according to the method of Fehrentz and Castro, 2000: To a stirred solution of Z-Ala-Ala-Asn(Trt)-N(OCH3)CH3 (1.50 g, 2.16 mmol) in absolute THF (20 ml) was added dropwise lithium aluminium hydride (1.0 M, 2.7 ml, 2.7 mmol) at 0° C. After 15 minutes the mixture was hydrolyzed with aqueous citric acid (10 ml) and after brought to room temperature the solvent was evaporated in vacuo. The mixture was diluted with pH-7 buffer solution (15 ml). The organic material was extracted (5×30 ml) with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the aldehyde as a white solid (1.25 g, 91%), which was used without further purification.—TLC (MeOH/CHCl3, 1:9): Rf=0.64.—1H NMR (400 MHz, CDCl3): δ=1.33 (d, 3 H, J=7.0 Hz, CH3), 1.37 (d, 3 H, J=7.2 Hz, CH3), 2.56-2.72 (m, 2 H, CHCH2), 4.08-4.13 (m, 1 H, CH), 4.28-4.34 (m, 1 H, CH), 4.54-4.63 (m, 1 H, CH), 5.04-5.09 (m, 2 H, CH2O), 7.24-7.32 (m, 20 H, aryl-H), 9.49 (s, 1 H, aldehyde).—MS (EI) m/z (%): 635 [M+H+], 657 [M+Na+], 732 [M+K+].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([CH:9]=1)[NH2:8].[H+].[B-:14]([F:18])([F:17])([F:16])[F:15].[N:19]([O-])=O.[Na+]>O>[F:15][B-:14]([F:18])([F:17])[F:16].[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([N+:8]#[N:19])[CH:9]=1
Reactant: Cc1ccc(C(F)(F)F)cc1N
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(F)(F)F)cc1[N+]#N
Reaction time: 0.25 h

Procedure:
Seventeen and one-half grams of 5-trifluoromethyl-2-methylaniline was melted and the melted material added to 100 ml. of a cold 48 percent HBF4 solution. 7.9 g. of sodium nitrite in 10 ml. of water were added thereto in dropwise fashion. The temperature of the diazotization reaction was maintained below 15° C. during the addition. The diazotization mixture was stirred in the cold for about 15 minutes and then poured onto a sintered glass funnel. 5-Trifluoromethyl-2-methylphenyldiazonium fluorborate formed in the above reaction was collected thereon as a solid precipitate. The filter cake was washed once with cold HBF4 solution, twice with cold ethanol and several times with cold ether; weight = 20.2 g.; m.p. above 250° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:26]([O:63][CH3:64])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:61][CH3:62])[C@@H:36]([CH3:60])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]/[C:50]1[CH:55]=[CH:54][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:52][CH:51]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:70][CH2:71][CH2:72][C:73]([OH:75])=[O:74].C([BH3-])#N.[Na+]>>[C:73]([CH2:72][CH2:71][CH2:70][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:26]([O:63][CH3:64])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:61][CH3:62])[C@@H:36]([CH3:60])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]/[C:50]1[CH:51]=[CH:52][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:55]=1)[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:75])=[O:74]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
The title compound was synthesized by analogy with the synthesis process of Example 1 by reacting 45 mg (47 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S,3E)-4-[4-(methoxycarbonyl)phenyl]-1-phenylbut-3-en-2-yl}amino)-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 23) with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:13]#[CH:14])=[N:4]1)[CH3:2].Br[C:16]1[N:26]=[C:19]2[C:20]([CH3:25])=[N:21][CH:22]=[C:23]([CH3:24])[N:18]2[N:17]=1.C(N(CC)CC)C>O1CCOCC1.[Cu]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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:3]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:13]#[C:14][C:16]2[N:26]=[C:19]3[C:20]([CH3:25])=[N:21][CH:22]=[C:23]([CH3:24])[N:18]3[N:17]=2)=[N:4]1)[CH3:2]
Reactant: C#Cc1nc(N2CCCC2)n(CC)n1
Reactant: Cc1ncc(C)n2nc(Br)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCn1nc(C#Cc2nc3c(C)ncc(C)n3n2)nc1N1CCCC1
Yield: 37.2 %

Procedure:
A mixture of 1-ethyl-3-ethynyl-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (79 mg, 415 μmol, Eq: 1.00), 2-bromo-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (104 mg, 457 μmol, Eq: 1.1) and triethylamine (63.0 mg, 86.8 μl, 623 μmol, Eq: 1.5) in dioxane (2.11 ml) was purged with argon, then copper (I) iodide (1.58 mg, 8.31 μmol, Eq: 0.02), bis(triphenylphosphine)palladium(II) chloride (5.83 mg, 8.31 μmol, Eq: 0.02) and triphenylphosphine (2.18 mg, 8.31 μmol, Eq: 0.02) were added, the vessel was capped and heated for 18 hours to 110° C. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate 100% as eluent affording 2-((1-ethyl-5-(pyrrolidin-1-yl)-1H-1,2,4-triazol-3-yl)ethynyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (52 mg, 37.2%) as an orange oil. MS: m/z=337.4 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:1][C:16]2[C:17](=[O:22])[C:18](=[O:19])[C:15]=2[O:14][CH2:12][CH3:13])[CH:3]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cnc2ccccc2c1
Solvent: CCO
Product: CCOc1c(Nc2cnc3ccccc3c2)c(=O)c1=O
Yield: 79.7 %

Procedure:
To a solution of 3-aminoquinoline (2.12 g, 14.69 mmol) in ethanol (60 mL) was added 3,4-diethoxy-3-cyclobutene-1,2-dione (2.50 g, 14.69 mmol) and the resulting mixture was heated to reflux for 24 hours. The mixture was cooled, filtered, and the product was washed with diethylether and dried in vacuo to give 3.14 g (80%) of yellow solid which was used without purification: 1H NMR (DMSO-d6) δ11.14 (s, 1H), 8.92 (dd, 1H), 8.20 (dd, 1H), 7.90 (m, 2H), 7.63 (m, 2H).
Reaction SMILES: S([N:11]1[C:23]2[C:22]([C:29]([F:32])([F:31])[F:30])([O:24][Si](C)(C)C)[CH2:21][CH2:20][CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([C:33]#[N:34])[CH:16]=2)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>C1COCC1.O>[OH:24][C:22]1([C:29]([F:32])([F:30])[F:31])[C:23]2[NH:11][C:12]3[C:17](=[CH:16][C:15]([C:33]#[N:34])=[CH:14][CH:13]=3)[C:18]=2[CH2:19][CH2:20][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(C#N)ccc42)CCCC3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c3c(c2c1)CCCC3(O)C(F)(F)F
Temperature: 55 °C
Yield: 89.2 %

Procedure:
9-Tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile (0.03 g, 0.06 mmol) was dissolved in THF (2 mL) and KOH (11 mg, 0.2 mmol), in H2O (2 mL) was added. The reaction mixture was heated to 55° C. for 24 h, then cooled to room temperature, diluted with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to afford the title compound as a white solid (15 mg, 79%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.4 (bs, 1H), 7.9 (s, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 2.89-2.85 (m, 1H), 2.76-2.74 (m, 1H), 2.45 (s, 1H), 2.32-2.28 (m, 1H), 2.14-2.12 (m, 2H), 2.05-2.03 (m, 1H).
Reaction SMILES: [C:1](Cl)(=O)C.[NH2:5][C:6]1[N:7]([C:25]2[CH:30]=[C:29]([OH:31])[C:28]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][C:26]=2[CH3:39])[N:8]=[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:14][C:13]=3[NH:12][C:11](=[O:24])[C:10]=12.C(=O)([O-])O.[Na+]>CO>[CH3:1][O:22][C:21](=[O:23])[CH2:20][O:19][C:15]1[CH:16]=[CH:17][C:18]2[C:9]3[C:10](=[C:6]([NH2:5])[N:7]([C:25]4[CH:30]=[C:29]([OH:31])[C:28]([O:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:27][C:26]=4[CH3:39])[N:8]=3)[C:11](=[O:24])[NH:12][C:13]=2[CH:14]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(Oc2ccccc2)c(O)cc1-n1nc2c(c1N)c(=O)[nH]c1cc(OCC(=O)O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc2c(c1)[nH]c(=O)c1c(N)n(-c3cc(O)c(Oc4ccccc4)cc3C)nc12

Procedure:
To a mixture of acetyl chloride (2 ml) and methanol (20 ml) was added {[3-amino-2-(5-hydroxy-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-7-yl]oxy}acetic acid (145 mg). The mixture was heated under reflux with stiring for one night. The reaction mixture was cooled, a 5% aqueous sodium hydrogen carbonate solution was added thereto, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the residue was added ethyl acetate-hexane, the precipitated solid was collected by filtration, washed with ethyl acetate-hexane to obtain the target compound (130 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC1(C)C(=O)N(CCCC#N)c2cc([N+](=O)[O-])c(N)cc21
Yield: 125.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.24 g) is alkylated using 4-bromobutyronitrile (0.1 ml; 1 mmol) and K2CO3 (0.28 g; 2 mmol) at 50° C. for 3 days. After aqueous work-up the crude material (0.4 g) is de-acetylated in MeOH (10 ml) using DBU (0.1 ml) at RT in 3 h. After aqueous work-up 4-(5-amino-3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-indol-1-yl)-butyronitrile (0.33 g) is obtained and used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[OH:19][C:20]1([C:25]2[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:26]=[C:25]([C:20]4([OH:19])[CH2:24][CH2:23][CH2:22][CH2:21]4)[O:29][N:28]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(C2(O)CCCC2)on1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C2(O)CCCC2)on1
Yield: 23.2 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxycyclopentyl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.69 mmol) and 5-(1-hydroxycyclopentyl)isoxazole-3-carboxylic acid (173 mg, 0.878 mmol). The product purified twice by Flash-chromatography (normal phase and reverse phase). Yield 23.2%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 1.75-2.12 (m, 8H), 4.28-4.44 (m, 2H), 4.52-4.64 (m, 1H), 6.51 (s, 1H), 6.77 (d, 1H), 7.70 (d, 1H), 7.77 (dd, 1H), 7.88 (dd, 1H), 8.09 (dd, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:35])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)[CH2:23][C:22](=[O:35])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc([N+](=O)[O-])c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K62) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (62 mg).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35](O)=[O:36]>>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35]([NH:29][CH2:28][CH2:27][CH:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:31])=[CH:9][CH:8]=2)[CH2:25][CH2:24]1)[CH3:30])=[O:36]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Product: Cc1cccc(Cl)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1

Procedure:
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 164) (73 mg, 0.17 mmol) and 2-chloro-6-methylbenzoic acid (43 mg, 0.25 mmol) followed by general procedure K with the resulting ester gave 4-[{1-[3-(2-chloro-6-methyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-(3-cyano-benzyl)-amino]-benzoic acid as a beige solid (44.5 mg, 46% over 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][O:19]CC2C=CC=CC=2)[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CCCOCc2ccccc2)C(=O)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(CCCO)C(=O)CCN1C(=O)OC(C)(C)C
Yield: 97.9 %

Procedure:
A solution of 0.650 g (1.73 mmol) of (R)-4-(3-benzyloxy-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (example 1A) in 30 ml methanol was treated with 0.065 g of Pd/C (10%) and was stirred over H2-atmosphere over night. After filtration, the solution was evaporated, reevaporated (3 times) with toluene and the solvent was removed under vacuum to give 0.485 g (98%) of the title compound as colorless oil. MS: 287.1 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[C:14]([CH2:16][CH:17]([CH2:18][C:19]([OH:21])=[O:20])[C:10]=2[CH:9]=1)=[O:15].[CH3:22]O>>[CH3:22][O:20][C:19](=[O:21])[CH2:18][CH:17]1[C:10]2[C:11](=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)[C:14](=[O:15])[CH2:16]1
Reactant: COc1ccc2c(c1)C(CC(=O)O)CC2=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1CC(=O)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (3.0 mL) is added to 5-methoxy-1-indanone-3-acetic acid (13.0 g) dissolved in methanol (100 mL). The solution is stirred at reflux temperature for 4 h and then cooled to room temperature. About two third of the methanol is removed under reduced pressure and water (100 mL) and ethyl acetate (200 mL) are added to the remainder. The organic phase is separated and washed with water, 1 M NaOH solution, and brine. The organic phase is dried (MgSO4) and the solvent is evaporated to give the product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:17][OH:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H-].[Na+].[CH3:21]I>C(COC)OC>[CH3:21][O:18]/[N:17]=[C:9](/[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])\[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CI
Reactant: ON=C(Cc1cccnc1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CO/N=C(\Cc1cccnc1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2',4'-difluoro-2-(3-pyridyl)acetophenone oxime in 25 ml of dimethoxyethane is treated in portions with 0.50 g of sodium hydride dispersion (55% in oil) and the mixture is stirred at room temperature for 30 minutes. 1.8 g of methyl iodide is then added and the mixture is heated to reflux temperature. After 4 hours, it is cooled to room temperature, poured onto ice and extracted with ethyl acetate, and the organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After separation by column chromatography on silica gel, (E)-2',4'-difluoro-2-(3-pyridyl)acetophenone O-methyloxime [1H-NMR (CDCl3, 200 MHz): 4.05 ppm (s, CH3O--N=)] is obtained first and then (Z)-2',4'-difluoro-2-(3-pyridyl)acetophenone O-methyloxime [1H-NMR (CDCl3, 200 MHz): 3.91 ppm (s, CH3O--N=)].