Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21]O)=[N:19][N:18]=[C:17]2[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:32]3[C:28](=[O:38])[C:29]4=[CH:37][CH:36]=[CH:35][CH:34]=[C:30]4[C:31]3=[O:33])=[N:19][N:18]=[C:17]2[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc(F)cc1C(=O)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 1B, 5-fluoro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in 1,2-dimethoxyethane is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 5-fluoro-2-[3-[2-(dimethylamino)-ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[N:5][CH:6]=[C:7](Br)[CH:8]=1.[CH3:12][C:13]1[N:14]=[C:15]([NH:18][C:19]([C:21]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[C:23]([CH3:36])[N:22]=2)=[O:20])[S:16][CH:17]=1>>[CH3:12][C:13]1[N:14]=[C:15]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([C:7]3[CH:6]=[N:5][CH:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:8]=3)[CH:24]=[C:23]([CH3:36])[N:22]=2)=[O:20])[S:16][CH:17]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Product: Cc1cc(-c2cncc(C(F)(F)F)c2)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 3-Trifluoromethyl-5-bromopyridine and 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 1, step 6 to yield the final compound as a white solid, MS (ISP): m/e=379.2 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[C:5]([O:18][CH2:19][C:20]#[CH:21])[CH:4]=1.C([O-])(=O)/C=C/[C:25]([O-])=[O:26]>>[CH3:25][O:26][C:8]1[CH:7]=[C:6]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([O:18][CH2:19][C:20]#[CH:21])=[CH:4][CH:3]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: C#CCOc1cc(OC)ccc1-c1nc2cnccc2[nH]1
Product: C#CCOc1ccc(OC)cc1-c1nc2cnccc2[nH]1

Procedure:
2-(4-Methoxy-2-propargyloxyphenyl)imidazo(4,5-c)-pyridine, fumarate, m.p. 210°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][C:7]1([CH3:13])[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[O:19]=[C:20]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][N:21]1[CH2:37][C:38](O)=[O:39].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][C:7]1([CH3:13])[NH:8][CH2:9][CH2:10][N:11]([C:38](=[O:39])[CH2:37][N:21]2[CH2:22][CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:20]2=[O:19])[CH2:12]1
Reactant: COc1ccc(CC2(C)CNCCN2)cc1OC
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CC2(C)CN(C(=O)CN3CCC(c4ccccc4)(c4ccccc4)C3=O)CCN2)cc1OC
Reaction time: 8 h

Procedure:
To 2-(3,4-dimethoxybenzyl)-2-methylpiperazine (0.052 g, 0.208 mmol; German Patent No. DE2438725), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.061 g, 0.208 mmol; Example 1C) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.079 g, 0.208 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.054 mL, 0.312 mmol) and the reaction stirred overnight. The reaction was loaded onto silica gel and the product eluted using a gradient of 0.5% methanol/dichloromethane to 5% methanol/dichloromethane containing 7 N NH3 over 30 minutes to provide the title compound. MS (ESI+) m/z 528.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].O.[OH-].[Li+].O>O1CCCC1.CO>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Yield: 95.9 %

Procedure:
A solution of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (8.30 g, 16.1 mmol) and lithium hydroxide monohydrate (2.05 g, 48.9 mmol) in tetrahydrofuran (60 mL), methanol (20 mL), and water (40 mL) was stirred at room temperature overnight. The solution was concentrated to remove tetrahydrofuran and methanol, and ethyl acetate (200 mL) and 1 M HCl (100 mL) were added. The aqueous layer was extracted with ethyl acetate (100 mL) and the combined organic layers were washed with brine (200 mL), dried (MgSO4), filtered, and evaporated to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (7.75 g, 96%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N+](C1C=CC(S(O[C@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)(=O)=O)=CC=1)([O-])=O.[F-].[Cs+].CN(C)C=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@@H:40]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (prepared as described in the starting materials used in Example 22; 4.0 g, 12.5 mmol) was mixed with tert-butyl (3S)-3-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate (4.7 g, 12.6 mmol) and cesium fluoride (5.7 g, 7.5 mmol). Dry N,N-dimethylformamide (60 ml) was then added and the mixture stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, 50% aqueous brine then brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (98/2). The fractions containing the expected product were combined and evaporated to give 4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline as a dry foam (2.35 g, 38%); 1H NMR Spectrum: (DMSO d6) 1.39 (s, 9H); 2.10-2.30 (m, 2H); 3.35-3.50 (m, 3H); 3.64-3.71 (m, 1H); 3.92 (s, 3H); 5.12 (m, 1H); 7.21 (s, 1H); 7.23-7.27 (m, 1H); 7.44-7.55 (m, 2H); 7.80 (s, 1H); 8.37 (s, 1H); 9.61 (s, 1H); Mass Spectrum: (M+H)+ 489.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:16]([F:17])=[C:15]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:14]=[CH:13][N:12]=1)=O.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[C:11]1[C:16]([F:17])=[C:15]([C:18]2[CH:19]=[N:20][CH:21]=[N:22][CH:23]=2)[CH:14]=[CH:13][N:12]=1)=[N:25]/[OH:26]
Reactant: O=C(c1ccc(F)cc1Cl)c1nccc(-c2cncnc2)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O/N=C(/c1ccc(F)cc1Cl)c1nccc(-c2cncnc2)c1F
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of (2-chloro-4-fluorophenyl)(3-fluoro-4-(pyrimidin-5-yl)pyridin-2-yl)methanone (0.030 g, 0.090 mmol) and hydroxylamine hydrochloride (0.043 g, 0.615 mmol) in pyridine (Volume: 0.452 ml) was refluxed for 3 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 0-100% EtOAc in hexanes over 11 min, tr=0.4, 2 min) gave the title compound (29 mg, 0.079 mmol, 88% yield) as a yellow residue. ESI MS (M+H)+=347.0.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46]OS(C)(=O)=O)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:52][NH:53][CH3:54]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][N:53]([CH3:54])[CH3:52])[CH:44]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCn1cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 15 %

Procedure:
To a solution of Intermediate 108e (0.20 mmol) in THF (2 mL) was added dimethylamine (2M in MeOH, 0.8 mL, 1.6 mmol) and stirring at RT was continued for 48 h. The crude reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by MDAP (Method 7) purification, to give the title compound (20 mg, 15%). LCMS (Method 5): Rt 3.34 min, m/z 666 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.24 (9H, s), 1.54-1.65 (2H, m), 1.67-1.77 (4H, m), 1.81-2.13 (4H, m), 2.16 (6H, s), 2.67 (2H, t, J=6.5 Hz), 3.13 (4H, t, J=5.3 Hz), 4.20 (2H, t, J=6.5 Hz), 4.79-4.87 (1H, m), 5.55 (1H, t, J=4.5 Hz), 6.26 (1H, s), 7.11-7.19 (2H, m), 7.26-7.41 (4H, m), 7.58-7.64 (3H, m), 7.99-8.05 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.Br[CH2:17][C:18]([C:20]([F:23])([F:22])[F:21])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:21][C:20]([F:23])([F:22])[C:18]1[C:11]2[C:12](=[O:14])[CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:9][C:10]=2[O:15][CH:17]=1
Reactant: Cc1ccccc1C1CC(=O)CC(=O)C1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CC(=O)c2c(C(F)(F)F)coc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
A mixture of 5-(2-methylphenyl)cyclohexane-1,3-dione (2.0 g), 1-bromo-3,3,3-trifluoroacetone (1.9 g), potassium carbonate (2.7 g) and dimethylformamide (30 ml) was stirred at room temperature for 2 hours, and then at 150° C. for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from isopropylether and hexane to give colorless crystals of 3-trifluoromethyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.26 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:17]1[O:18][CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=1.CCN(C(C)C)C(C)C>CCO>[CH2:25]([O:24][C:22]([C:20]1[N:21]=[C:17]([N:8]2[CH2:7][CH2:6][CH:5]([O:4][C:3]3[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:2]=3[Br:1])[CH2:10][CH2:9]2)[O:18][CH:19]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1coc(Cl)n1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1coc(N2CCC(Oc3cc(F)ccc3Br)CC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (3.281 g, 11.97 mmol) in EtOH (28.5 mL) was added ethyl 2-chlorooxazole-4-carboxylate (1 g, 5.70 mmol) and DIPEA (1.990 mL, 11.39 mmol). The reaction mixture was stirred at rt for 5 h. The solvent was evaporated under reduced pressure. The residue was diluted with 1N HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>O1CCCC1.[Zn]>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:16]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A 0.1 g/mL suspension of highly activated zinc powder in tetrahydrofuran (33 mL, 50 mmol) was transferred via cannula to a solution of 2-bromo-4-fluorobenzonitrile (5.0 g, 25 mmol) in anhydrous tetrahydrofuran (100 mL) at room temperature under an atmosphere of argon. The mixture was stirred at room temperature for 5 h and then sonicated with ultrasound for 30 min. The excess zinc was allowed to settle over night at −20° C. The solution on top was transferred via cannula to another flask under argon atmosphere and cooled to −20° C. To this was added 1 M CuCNx2LiBr complex solution in tetrahydrofuran (26.3 mL). The resulting solution was stirred at −20° C. for 10 min and at 0° C. for 25 min, then it was cooled to −25° C. and 3-bromobenzoyl chloride was added. The mixture was stirred for 1 h while the temperature was kept between −25° C. and −15° C., and then it was stored in a refrigerator at 0° C. for two and a half days. The reaction was quenched by the addition of saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, the phases were separated and the organic phase was washed with 1 M hydrochloric acid and 1 M sodium carbonate solution, dried over magnesium sulfate and evaporated. Purification by column chromatography using a gradient of gradually increasing concentration of ethyl acetate in heptane (0-40%) gave 5.58 g of the title product (73% yield): 1H NMR (CDCl3) δ 7.96 (t, J=1.64 Hz, 1 H), 7.88 (dd, J=8.46, 4.93 Hz, 1 H), 7.80 (m, 1 H), 7.72 (m, 1 H), 7.44-7.37 (m, 2 H), 7.35 (dd, J=8.08, 2.53 Hz, 1 H); MS (EI) m/z 304, 306 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[C:15]([Br:22])[N:14]=2)=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[C:15]([Br:22])[N:14]=2)=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)c2nc(Br)c3ccccn23)cc1C(=O)O
Product: CC(=O)Nc1ccc(C(=O)c2nc(Br)c3ccccn23)cc1C(=O)O

Procedure:
0.92 g (2.56 mmol) of 2-amino-5-(1-bromoimidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid in 30 ml of acetic anhydride are refluxed for 5.5 hours. The reaction medium is concentrated under reduced pressure. The residue is taken up in water and then filtered and dried under reduced pressure overnight at 40° C. 1.1 g of a yellow solid are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:25]2)=[O:23])[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31][C:30]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:24]([C:22](=[O:23])[NH:21][C@H:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([OH:8])[CH:10]=3)[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:25]2)=[O:46])[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-({(1S)-1-[5-(benzyloxy)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (650 mg, 1.02 mmol) was dissolved in ethyl acetate (45 mL) and methanol (7.4 mL) and palladium on charcoal (65 mg, 10%) was added. The mixture was shaken under a hydrogen atmosphere for 16 hours filtrated through celite which were washed with methanol. The filtrate was concentrated and purified by chromatography on silica gel (methanol in ethyl acetate 0% to 25%) to yield 422 mg of tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.[H-].[Na+].[C:12](=O)([O:15]C)[O:13][CH3:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([C:12]([O:13][CH3:14])=[O:15])[C:4](=[O:8])[CH2:3]1
Reactant: COC(=O)OC
Reactant: CC1(C)CCCC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(C)(C)CC1=O
Temperature: 25 °C

Procedure:
A solution of 3,3-dimethylcyclohexanone (0.5 g, 3.97 mmol, 1 equiv) and sodium hydride in toluene was stirred at rt for half an hour. To the mixture was added dimethyl carbonate and heated at reflux for 5 h. After the reaction was cooled to rt, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give the crude product, which was directly used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[OH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH:19][C:24](=[O:25])[CH:23]([OH:22])[CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:6])[CH3:7]
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was coupled with (S)-2-hydroxy-3-methyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 16.0, 19.1, 19.4, 28.1, 32.2, 35.5, 47.1, 51.9, 52.7, 56.4, 105.1, 131.1, 137.6, 169.6, 170.0, 174.0.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(Oc2ccc(F)cc2)c(-c2ccccc2)n1
Yield: 7.8 %

Procedure:
6-(4-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 8%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 4-fluorophenol (0.36 g, 3.18 mmol) according to the general procedure of Example 3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1)([O-])=O>[Pd].CO>[CH:10]1([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccccc1C1=CCCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1C1CCCCCC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 61.8 %

Procedure:
A mixture of the 1-(2-nitrophenyl)cycloheptene (1.00 g, 4.61 mmol) produced in Example (44a), 10% palladium on carbon (300 mg, wet) and methanol (130 mL) was stirred for 21 hours at atmospheric pressure and room temperature under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 539 mg of the title compound as a light orange oil.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[K+:12].[C:13](=[S:15])=[S:14]>C(O)C>[C:1]([NH:9][NH:10][C:13]([S-:15])=[S:14])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[K+:12]
Reactant: NNC(=O)c1ccncc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NNC(=S)[S-])c1ccncc1
Reaction time: 1 h

Procedure:
Isonicotinohydrazide (10.96 g, 79.9 mmol) was dissolved in ethanol (80 ml) containing potassium hydroxide (5.3 g, 94.4 mmol). Carbon disulfide was then added with stirring, which was continued for 1 hr. Filtration gave crude potassium 3-isonicotinoyldithiocarbazate which was washed with ether and then dried in vacuum. This was then added slowly with stirring to concentrated sulfuric acid (25 ml) maintained at −5° C. Stirring was continued for an additional 5 min and then the reaction mixture was poured into crushed ice. After 10 min, the solid was filtered off to give 5-(pyridine-4′yl)-1,3,4-thiadiazole-2(3H)-thione.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26](S(C)(=O)=O)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:33]([O:35][C:36](N1CCNCC1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([N:26]1[CH2:25][CH2:24][N:23]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:28][CH2:27]1)=[O:37])[CH3:34]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and 1-ethoxycarbonylpiperazine to afford the desired product as a light-brown solid (72%). MS (ISP): 456.3 (M+H)+.