Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[O:26][C:27]=1[CH3:28]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:25]1[O:26][C:27]([CH3:28])=[C:23]([CH2:22][N:12]2[C:13]3[C:9](=[C:8]([CH3:16])[C:7]([CH2:6][CH:5]([O:17][CH2:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)[N:24]=1
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1C)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3Cl)oc2C)c1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(4-methyl-1H-indol-5-yl)-propionic acid ethyl ester [preparation 10h)] was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxy-propionic acid as yellow solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29]([CH2:28][CH2:27][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:13])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:30]
Reactant: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CCBr
Product: COC(=O)CCN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21

Procedure:
Using the procedure outlined in Example 29, the title compound was prepared from N-(1,2,3,4-tetrahydroquinolin-7-yl)-1,1′-biphenyl-4-carboxamide (Example 24) (66 mg, 0.2 mmol) and methyl 3-bromopropionate (264 ul, 2.4 mmol) as a yellow gum. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.94 (d, 2H), 7.76 (br, 1H), 7.70 (d, 2H), 7.63 (d, 2H), 7.48 (t, 2H), 7.40 (t, 1H), 7.04 (d, 1H), 6.93 (d, 1H), 6.79 (dd, 1H), 3.69 (s, 3H), 3.65 (t, 2H), 3.31 (m, 2H), 2.72 (t, 2H), 2.67 (t, 2H), 1.93 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Cl)ccc1NC1CCCCC1
Temperature: 70 °C

Procedure:
Methyl 5-chloro-2-(cyclohexylamino)benzoate was dissolved in ethanol, a 1 M sodium hydroxide aqueous solution was added, followed by stirring at 70° C. By post-treating the reaction liquid, 5-chloro-2-(cyclohexylamino)benzoic acid was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:20]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])(=[O:22])=[O:21])[CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][Si](C(C)C)(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:19][C:6]1[CH:5]=[C:4]([S:20]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])(=[O:22])=[O:21])[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:8]
Reactant: CCOP(=O)(CS(=O)(=O)c1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)c1cc(C)c(O)c(C)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 1000 %

Procedure:
To a stirring solution diethyl (3,5-dimethyl-4-triisopropylsilanyloxy-benzenesulfonyl)methylphosphonate in THF (3 mL) at room temperature was added TBAF (0.3 mL, 1 M in THF). It was stirred at room temperature for 2 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (5:1) to afford diethyl (3,5-dimethyl-4-hydroxybenzenesulfonyl)methylphosphonate as a light yellow oil (70 mg, 1000%): 1H NMR (300 MHz, CDCl3-d6): δ 7.54 (s, 2 H), 4.12 (m, 4 H), 3.65 (d, J=16.8 Hz, 2 H), 2.22 (s, 6 H), 1.22 (d, J=7.2 Hz, 6 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (5:1); Rf=0.44.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[Br:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: COC(=O)c1ccc([C@@H](C)O)cc1
Reactant: Oc1cccc(Br)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)Oc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of (R)-methyl 4-(1-hydroxyethyl)benzoate (1.8 g, 10 mmol), 3-bromophenol (1.9 g, 11 mmol) in 30 mL of anhydrous tetrahydrofuran was added Triphenyl phosphine (2.9 g, 11 mmol). The reaction mixture was stirred at room temperature for 0.5 hour under nitrogen atmosphere. Then diisopropylazodicarboxylate (2.4 g, 12 mmol) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, it was quenched with water, and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give (S)-methyl 4-(1-(3-bromophenoxy)ethyl)benzoate (2.2 g, 66%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([CH:32]([OH:35])[CH2:33][OH:34])=[CH:30][CH:31]=[C:26]4[C:25]([C:36]#[N:37])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:42])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([CH:32]([OH:35])[CH2:33][OH:34])=[CH:30][CH:31]=[C:26]4[C:25]([C:36]([NH2:37])=[O:42])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(C(O)CO)nc54)c3CO)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(C(O)CO)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(1,2-dihydroxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (14 mg, 26.5 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (373 μg, 0.870 μmol, Eq: 0.0328) were combined with Ethanol (200 μl) and Water (200 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate is lyophilized to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(1,2-dihydroxy-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (11.2 mg, 77%, [M+H]+ 546).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=2[CH2:4][CH2:3]1>CO.[Pd]>[O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cnc2c(c1)CCC(=O)N2
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
To a stirred solution of 49a (7.7 g, 34.3 mmol) in methanol (150 ml) was added 10% Pd/C (3 g) under nitrogen. The reaction mixture was stirred in presence of H2 gas at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through celite and concentrated to get the desired compound as a white solid (7 g, 90.2%); 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.95 (s, 1H), 7.48 (s, 1H), 4.05 (q, J=7.1 Hz, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.79-2.60 (m, 4H), 2.58-2.55 (m, 2H), 1.16 (m, 3H); MS (ES) m/e 249.1 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[N:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[CH2:17][C:16]([F:30])([F:29])[CH2:15]2)[N:6]=1.CC1(C)C(C)(C)OB([C:49]2[N:54]=[C:53]([C:55]#[N:56])[CH:52]=[CH:51][CH:50]=2)O1>>[NH2:33][C:4]1[S:3][C:2]([C:49]2[CH:50]=[CH:51][CH:52]=[C:53]([C:55]#[N:56])[N:54]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[N:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[CH2:17][C:16]([F:30])([F:29])[CH2:15]1)=[O:32]
Reactant: CC1(C)OB(c2cccc(C#N)n2)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CC[C@@H](NC(=O)OC(C)(C)C)CC(F)(F)C1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(C#N)n3)sc2N)c1N1CC[C@@H](N)CC(F)(F)C1

Procedure:
Following the procedures in Example 428, tert-butyl N-[2-bromo-4-[[5-[(5R)-5-(tert-butoxycarbonylamino)-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate was reacted with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile to give 461. LCMS (ES+) m/z 474 (M+1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22].[CH3:25][S:26]([O-:28])=[O:27].[Na+].N1CCC[C@H]1C(O)=O>CS(C)=O.O.[Cu](I)I>[CH3:25][S:26]([C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])(=[O:28])=[O:27]
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Reactant: CS(=O)[O-]
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCN1C(=O)C2(COc3cc(S(C)(=O)=O)ccc32)c2ccccc21
Temperature: 100 °C
Yield: 5 %

Procedure:
A mixture of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.60 g, 1.55 mmol), sodium methanesulfinate (0.19 g, 1.86 mmol), copper iodide (0.03 g, 0.16 mmol), and L-proline (0.04 g, 0.31 mmol) in dimethyl sulfoxide (3.00 mL) was heated at 100° C. for 2 days under N2. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (4×15.0 mL). The combined organics was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/3) to give the title compound (0.03 g, 46%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.46-7.48 (m, 1H), 7.38 (dt, 1H), 7.34 (dt, 1H), 7.13-7.02 (m, 2H), 6.94 (d, 1H), 6.86 (d, 1H), 5.03 (d, 1H), 4.78 (d, 1H), 3.87-3.64 (m, 2H), 3.02 (s, 3H), 1.79-1.68 (m, 2H), 1.41-1.32 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.1, 161.2, 142.6, 142.1, 135.4, 131.5, 129.5, 124.3, 124.0, 123.5, 120.7, 109.5, 109.0, 80.5, 57.7, 44.5, 40.6, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 386.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:19][C:15]1[CH:14]=[C:13]([Cl:12])[CH:18]=[N:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1cncc(Cl)c1
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)c(F)c1

Procedure:
3,4-Difluoronitrobenzene (5.0 g, 32 mmol) and 5-chloro-3-pyridinol were combined using the procedure described in Example 1, to produce 8.2 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[F:24][CH:25]([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:24][CH:25]([F:34])[O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC(F)F)cc4)CC3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (46.9 mg, 0.14 mmol), as prepared in Example 3a, in DMSO (1 mL) was added 4-(difluoromethoxy)aniline (26.6 mg, 0.17 mmol), followed by DIEA (35.9 mg, 0.28 mmol). The mixture was heated at 100° C. with stirring. After 2 h, it was cooled to room temperature and partitioned between EtOAc and water. The combined EtOAc extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc→5% MeOH/EtOAc as eluent) to afford the title compound as a white solid (20.4 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.40 (s, 1H), 7.38 (d, J=8.99 Hz, 2H), 7.27 (s, 1H), 7.07 (d, J=8.93 Hz, 2H), 6.48 (s, 1H), 6.45 (t, J=74.22 Hz, 1H), 4.28 (m, 2H), 4.08 (s, 3H), 4.07 (s, 3H), 3.62 (m, 1H), 3.20 (td, J=13.02 and 2.64 Hz, 2H), 2.14 (m, 2H), 2.01 (m, 2H). LC-MS (ESI) calcd mass 458.2, found 459.3 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1COCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOCC3)c(F)c21
Yield: 52.2 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.43 g), morpholine (1.4 g), and pyridine (3 ml) was refluxed for 6 hours. After the mixture evaporated to dryness, the residue was acidified with aqueous acetic acid and extracted with dichloromethane. The organic layer was washed with water, dried, and evaporated. The solid was recrystallized from a mixture of DMF and ethanol and gave 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-morpholinyl)-4-oxoquinoline-3-carboxylic acid (0.28 g), mp 268°-271° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH:11]([CH2:16][OH:17])[C:12]([O:14][CH3:15])=[O:13])=O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][CH2:16][CH:11]([C:12]([O:14][CH3:15])=[O:13])[N:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(CO)NC(=O)c1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1COC(c2ccc(F)cc2)=N1
Temperature: 25 °C
Yield: 149.3 %

Procedure:
To 25 ml tetrahydrofuran was added methyl 2-[(4-fluorophenyl)carbonylamino]-3-hydroxypropanoate (0.750 g, 3 mmol), triphenylphosphine (1.0 g, 4.5 mmol) and diisopropylazodicarboxylate (0.800 g, 4.5 mmol). The reaction was stirred at room temperature under nitrogen until SM was shown to be consumed (TLC, 1:1 Ethyl Acetate:Hexane). The reaction mixture was concentrated under reduced pressure and purified using a Flash 40 Column (1:1 EtOAc:Hexane, 20 psi) to yield 1 g of methyl 2-(4-fluorophenyl)-1,3-oxazoline-4-carboxylate (M+1=224.2).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:8]=[C:7]([C:18](=[O:22])[NH:19][CH2:20][CH3:21])[CH:6]=1)C.[OH-].[Li+].C1COCC1>O>[CH2:20]([NH:19][C:18]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:8]=1)[C:4]([OH:23])=[O:3])=[O:22])[CH3:21]
Reactant: CCCN(C)C(=O)c1cc(C(=O)NCC)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)NCC)c1
Yield: 72.5 %

Procedure:
Stir a solution of 3-ethylcarbamoyl-5-(methyl-propylcarbamoyl)-benzoic acid ethyl ester (157 mg, 0.5 mmol), 1 N aqueous lithium hydroxide (2.45 mL, 2.45 mmol) and THF (2.45 mL) at room temperature overnight. Dilute the reaction with water and extract with dichloromethane. Acidify the aqueous with 5 N HCl , extract the aqueous with dichloromethane and dry (magnesium sulfate) and concentrate to give the title compound (106 mg, 74%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7]Cl.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7][N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][OH:11])[CH2:14][CH2:15]1
Reactant: OCC1CCNCC1
Reactant: COC(CCCCCl)OC
Product: COC(CCCCN1CCC(CO)CC1)OC

Procedure:
To a cooled (0° C.) and stirred suspension of isonipecotic acid (25.83 g, 200 mmol), in anhydrous THF (100 ml) was added lithium aluminium hydride (1M in THF; 200 ml), under a nitrogen atmosphere. The reaction was allowed to attain room temperature and it was stirred for 18 h, then refluxed for a further 4 h. The reaction was quenched by sequential addition of water (7.5 ml), 15% sodium hydroxide solution (7.5 ml) and water (15 ml). The reaction was filtered to remove a granular precipitate and the filtrate was concentrated under vacuum to give 11.24 g of 4-(hydroxymethyl)piperidine as a colourless oil. The title compound was prepared from 5-chloropentanal dimethyl acetal (20.4 g, 122 mmol) and 4-(hydroxymethyl)piperidine (15.7 g) using a similar method to that described for Example 8 (step 2). δ (360 MHz, DMSO-d6) 1.10 (2H, m), 1.28 (2H, m), 1.39 (2H, m), 1.48 (2H, m), 1.60 (2H, br d), 1.77 (2H, t), 2.20 (2H, t), 2.80 (2H, br d), 3.21 (8H, m), 4.31 (1H, t), 4.37 (1H, t).
Reaction SMILES: [NH:1]1[C:46](=[O:47])[C@H:41]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:40][C:38](=[O:39])[C@@H:34]([CH:35]([CH3:37])[CH3:36])[NH:33][C:31](=[O:32])[C@H:26]([CH2:27][CH2:28][S:29][CH3:30])[NH:25][C:23](=[O:24])[C@@H:18]([CH2:19][C:20](=[O:22])[OH:21])[NH:17][C:15](=[O:16])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1.[OH:48]O>C(O)(=O)C>[NH:1]1[C:46](=[O:47])[C@H:41]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:40][C:38](=[O:39])[C@@H:34]([CH:35]([CH3:37])[CH3:36])[NH:33][C:31](=[O:32])[C@H:26]([CH2:27][CH2:28][S:29]([CH3:30])=[O:48])[NH:25][C:23](=[O:24])[C@@H:18]([CH2:19][C:20](=[O:21])[OH:22])[NH:17][C:15](=[O:16])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH:13]=[O:14])[CH:5]=1
Reactant: OO
Reactant: CSCC[C@@H]1NC(=O)[C@@H](CC(=O)O)NC(=O)[C@@H](Cc2cn(C=O)c3ccccc23)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C(C)C)NC1=O
Solvent: CC(=O)O
Product: CC(C)C[C@@H]1NC(=O)[C@@H](C(C)C)NC(=O)[C@H](CCS(C)=O)NC(=O)[C@@H](CC(=O)O)NC(=O)[C@@H](Cc2cn(C=O)c3ccccc23)NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cyclo(-DTrp(CHO)-DAsp-Met-DVal-Leu-) (12.9 mg) which was prepared in Example 55 in acetic acid(2.0 ml) was added 35% H2O2 (5 μl). The reaction mixture was stirred at room temperature for 3 h and concentrated under reduced pressure till the volume of the mixture was reduced to ca. 1 ml. The residue was triturated with water(3 ml) to give the title compound (7.6 mg) as a pale yellow powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:18]([CH2:19][N:20]([CH3:22])[CH3:21])=[N:17][C:16]([C:23]([OH:25])=[O:24])=[N:15]1)=[O:6].[CH3:30]O>>[CH3:30][O:24][C:23]([C:16]1[N:17]=[C:18]([CH2:19][N:20]([CH3:22])[CH3:21])[N:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[C:5](=[O:6])[C:4]2[CH:26]=[CH:27][CH:28]=[CH:29][C:3]=2[Cl:2])[N:15]=1)=[O:25]
Reactant: CO
Reactant: CN(C)Cc1nc(C(=O)O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: Cl
Product: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1

Procedure:
For conversion into the methyl ester already mentioned, 10 ml of a 6 N solution of hydrogen chloride in methanol is added to a solution of 2.08 g (0.005 mole) of crude 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(dimethylamino-methyl)-1H-1,2,4-triazole-3-carboxylic acid in 30 ml of methanol, and the whole is refluxed for 16 hours. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed twice with ice-cold 1 N sodium bicarbonate solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue crystallises out on trituration with ether. After filtration with suction and drying in vacuo, there is obtained pure 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(dimethylamino-methyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 133°-135°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[N:20]=1.[CH:22](=O)[CH3:23]>CCO.[Pd]>[CH2:22]([NH:21][C:4]1[C:3]([O:2][CH3:1])=[N:20][C:7]2[CH2:8][CH2:9][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:11][CH:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:23]
Reactant: CC=O
Reactant: COc1nc2c(cc1N)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Pd]
Solvent: CCO
Product: CCNc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -pyrido[2,3-d]azepin-3-amine (455 mg, 1.5 mmol), acetaldehyde (253 μl, 4.50 mmol) and 5% Pd/C (23.0 mg) in EtOH (18 ml) was subjected to H2 (50 psi) for 16 h at room temperature. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography to provide 280 mg (56%) of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H NMR (CDCl3) δ 6.47 (1H), 4.03 (0.5H), 3.88 (5H), 3.71 (0.5H), 3.43 (1H), 3.64 (3H), 2.98 (2H), 1.20 (6H) ppm. A mixture of of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (331 mg, 1.00 mmol), K2CO3 (415 mg, 3.00 mmol), MeOH (13 ml) and H20 (2.7 ml) was stirred for 16h at room temperature. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 204 mg (87%) of N-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 6.48 (s, 1H), 3.87 (s, 3H), 3.80 (br s, 1H), 3.10-2.70 (m, 9H), 2.48 (br s, 1H), 1.26 (d, 3H), 1.24 (t, 3H) ppm.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15](Cl)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[C-:30]#[N:31].[K+]>CN1CCCC1=O>[F:29][C:2]([F:28])([F:1])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=4)=[C:15]([C:30]#[N:31])[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1c(-c2ccc(Cl)cc2)cnn2c(=O)n(Cc3ccc(C(F)(F)F)cc3)nc12
Temperature: 120 °C
Yield: 72.1 %

Procedure:
A suspension of 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (43.8 mg, 0.10 mmol), prepared as described in example 361G, and KCN (33 mg, 0.5 mmol) in dry 1-methyl-2-pyrrolidinone (1 mL) was heated at 120° C. for 2 h under argon. HPLC/MS analysis indicated complete reaction. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (5 mL×2) to obtain a yellow solid. The crude product was purified by reversed phase preparative HPLC (C-18, MeOH/H2O gradient, 0.1% TFA) to obtain title compound (31 mg, 72%), 2-(4-(trifluoromethyl)benzyl)-7-(4-chlorophenyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazine-8-carbonitrile as a yellow solid. MS [M+H]+ 430; HPLC retention time=3.76 min.