Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:60])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]3[CH2:33][CH:32]([OH:34])[CH2:31][CH:30]3[CH:35]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:36][CH:37]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)=[O:28])[CH2:15][C:14]1=[CH:13][CH2:12][CH:11]1[CH:3]2[CH2:4][CH2:5][C:6]2([CH3:69])[CH:10]1[CH2:9][CH2:8][CH:7]2[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68].[C:70]1(=[O:76])[O:75][C:73](=[O:74])[CH2:72][CH2:71]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([CH:37]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[O:36][CH:35]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:30]2[N:29]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]([O:19][CH:16]3[CH2:15][C:14]4[C:2]([CH3:1])([CH:3]5[CH:11]([CH2:12][CH:13]=4)[CH:10]4[C:6]([CH3:69])([CH:7]([CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:8][CH2:9]4)[CH2:5][CH2:4]5)[CH2:18][CH2:17]3)=[O:60])[CH2:33][CH:32]([O:34][C:70](=[O:76])[CH2:71][CH2:72][C:73]([OH:75])=[O:74])[CH2:31]2)=[CH:47][CH:48]=1
Reactant: CCCCCCCCC1CCC2C3CC=C4CC(OC(=O)NCCCCCC(=O)N5CC(O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC1CCC2C3CC=C4CC(OC(=O)NCCCCCC(=O)N5CC(OC(=O)CCC(=O)O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
Referring to scheme 3, Compound 6 (22 g, 23.2 mmol) was mixed with succinic anhydride (3.48 g, 34.8 mmol) and DMAP (0.283 g, 2.32 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (50 mL), triethylamine (7 g, 9.6 mL, 70 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 8 as white solid (21.7 g, 89% yield; Rf=0.5 in 10% MeOH/CHCl3).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:54][C@@H:55]([CH3:71])[CH2:56][N:57]1[CH:61]=[CH:60][C:59]([C:62]2[CH:69]=[CH:68][C:65]([C:66]#[N:67])=[C:64]([Cl:70])[CH:63]=2)=[N:58]1>O.C(Cl)Cl.CN(C=O)C>[Cl:70][C:64]1[CH:63]=[C:62]([C:59]2[CH:60]=[CH:61][N:57]([CH2:56][C@@H:55]([NH:54][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])[CH3:71])[N:58]=2)[CH:69]=[CH:68][C:65]=1[C:66]#[N:67]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
2-Methyl-1H-imidazole-4-carboxylic acid (29.0 g, 230 mmol), 335 ml of DMF and 165 ml of DCM were placed in to the reaction vessel under nitrogen. HBTU (7.27 g, 19.18 mmol), EDCI (44.1 g, 230 mmol) and 66.8 ml of DIPEA were added. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (50 g, 192 mmol) was added and the reaction stirred overnight at RT. 600 ml of water was slowly added and water phase was washed with 335 ml and 500 ml of DCM. DCM phases were combined, washed with 3×600 ml of water and distilled to dryness. Acetonitrile (300 ml) was added and the mixture was heated up to 75° C. Water (300 ml) was added at >60° C., solution was allowed to cool to RT for precipitation and the mixture was stirred overnight at RT. Stirring was continued for additional 2 h at <10° C. The precipitate was filtered, washed with cold ACN:water and dried under vacuum to obtain 47 g of crude product. The title compound was recrystallized from EtOH with 75% yield. 1H-NMR (400 MHz, DMSO-d6): δ 1.08 (d, 3H), 2.30 (s, 3H), 4.23-4.48 (m, 3H), 6.95 (d, 1H), 7.41 (s, 1H), 7.82 (d, 1H), 7.95-8.07 (m, 3H), 8.09-8.12 (m, 1H), 12.12 (bs, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:36][CH2:37]O.COC(=O)CC(=O)C(Br)C.FC(F)(F)OC1C=CC(C(N)=S)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:37][CH2:36][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=3)[S:24][C:20]=2[CH3:19])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: Cc1sc(-c2ccc(OC(F)(F)F)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Agent: NC(=S)c1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(OC(F)(F)F)cc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[5-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-trifluoromethoxy-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[5-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[5-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as colorless solid.
Reaction SMILES: C(O[C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][C:6]=1[CH:18]=[CH:19][O:20]C(=O)C)(=O)C.P(=O)(O)(O)O>>[CH3:16][O:15][C:14]1[C:13]2[O:12][C:11](=[O:17])[CH:10]=[CH:9][C:8]=2[CH:7]=[C:6]2[CH:18]=[CH:19][O:20][C:5]=12
Reactant: COc1c(OC(C)=O)c(C=COC(C)=O)cc2ccc(=O)oc12
Agent: O=P(O)(O)O
Product: COc1c2occc2cc2ccc(=O)oc12

Procedure:
A solution of 40 mg. (.13 mmole) of 7-acetoxy-6-[2-acetoxyvinyl]-8-methoxycoumarin in 5 ml. of 85% phosphoric acid was heated at 90° for 30 minutes. The solution was cooled and partitioned between water/methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic phases were combined, dried over sodium sulfate, and evaporated to afford pure 9-methoxy-7H-furo[3,2-g][1]benzopyran-7-one, mp 145°-146°, as a crystalline white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH2:55]>ClCCl>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:55][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[F:48])=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: Nc1ccccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccccc4F)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D (53 mg, 0.1 mmol), N,N-diisopropylethylamine (0.052 mL, 0.3 mmol), 2-Fluoro-phenylamine (0.014 mL, 0.15 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour, then concentrated under vacuum to provide the title product.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](C(O)=O)=[CH:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[F:1][C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2sc(C(=O)O)cc12
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: COc1ccc(F)c2sccc12
Temperature: 190 °C

Procedure:
A mixture of 7-fluoro4-methoxy-1-benzothiophene-2-carboxylic acid (61.4 g, 271 mmol) and copper powder (22.4 g, 352 mmol) in quinoline (500 mL) was heated at 190° C. for 1 h. Cooled to ambient and poured onto aqueous hydrochloric acid (2 N, 750 mL). Stirred with ethyl acetate (500 mL) for 15 minutes. Filtered through Celite, washing with ethyl acetate. The aqueous layer was extracted into ethyl acetate and the combined organic layers were washed with aqueous hydrochloric acid (2 N, 500 mL), water (500 mL), brine (500 mL), dried over MgSO4 and evaporated in vacuo. Purified by column chromatography, eluting silica gel with iso-hexane/diethyl ether 0-5% to give the product as a brown oil which crystallised to give the title compound (41.3g, 84%); δH (300 MHz, CDCl3) 7.51 (1H, m, ArH), 7.38 (1H, d, ArH), 6.98 (1H, t, ArH), 6.65 (1H, dd, ArH) and 3.92 (3H, s, OCH3).
Reaction SMILES: [N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:7])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:48]1[C:60]2[CH:59]([CH2:61][O:62][C:63](=[O:93])[NH:64][C@H:65]3[CH2:69][C@@H:68]([C:70](=[O:82])[NH:71][C@H:72]4[C:81]5[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=5)[CH2:75][CH2:74][CH2:73]4)[N:67]([C:83](=[O:92])[C@@H:84]([NH2:91])[CH:85]4[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]4)[CH2:66]3)[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]=2[CH:51]=[CH:50][CH:49]=1>CN(C=O)C.C(OCC)(=O)C>[CH:48]1[C:60]2[CH:59]([CH2:61][O:62][C:63](=[O:93])[NH:64][C@H:65]3[CH2:69][C@@H:68]([C:70](=[O:82])[NH:71][C@H:72]4[C:81]5[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=5)[CH2:75][CH2:74][CH2:73]4)[N:67]([C:83](=[O:92])[C@@H:84]([NH:91][C:4](=[O:6])[C@@H:2]([N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7])[CH3:3])[CH:85]4[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]4)[CH2:66]3)[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]=2[CH:51]=[CH:50][CH:49]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Boc-N-Me-Ala-OH (2.55 g, 12.57 mmol) in DMF (30 mL) were added HATU (4.78 g, 12.57 mmol) and DIPEA (9.9 mL, 57.16 mmol). After 30 min, the mixture was cooled to 0° C. and {(3S,5S)-1-((S)-2-amino-2-cyclohexyl-acetyl)-5-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-pyrrolidin-3-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester (Intermediate 24) (7.5 g, 11.43 mmol) in DMF (50 mL) and the cooling bath removed. After 4 h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography to afford the title compound as an off white solid (5.32 g) LC-MS: 806 (M+H).
Reaction SMILES: [CH:1]12[CH2:29][CH:4]([CH:5]([CH2:7][NH:8][C:9]([C:11]3[C:12]([S:17][CH2:18][CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[O:21])=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])[CH2:6]1)[CH2:3][CH2:2]2.[BH4-].[Na+].C(Cl)Cl.CCCCCC.CC(=O)OCC>CO>[CH:1]12[CH2:29][CH:4]([CH:5]([CH2:7][NH:8][C:9]([C:11]3[C:12]([S:17][CH2:18][CH2:19][CH:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[OH:21])=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])[CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=C(CCSc1ncccc1C(=O)NCC1CC2CCC1C2)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NCC1CC2CCC1C2)c1cccnc1SCCC(O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
A solution of 400 mg (0.97 mmol) of N-(5-bicyclo[2.2.1]heptanyl-methyl)-2-[[3-(4-fluorophenyl)-3-oxo-propyl]sulfanyl]-pyridine-3-carboxylic acid amide (exemplary compound 43) in MeOH (10 ml) was cooled to 0° C., and 18 mg (0.49 mmol) of NaBH4 were added in portions. Stirring was then carried out for 2 h at 0° C. and for 1 h at RT. The reaction solution was then poured onto ice-water and extraction with DCM was carried out. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC (hexane/EA 2:1→1:1) of the residue yielded 180 mg (0.43 mmol, 45%) of N-(5-bicyclo[2.2.1]heptanyl-methyl)-2-[[3-(4-fluorophenyl)-3-hydroxy-propyl]sulfanyl]-pyridine-3-carboxylic acid amide. MS: m/z 415.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:23]>C(#N)C>[Cl:23][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:8][N:9]=1
Reactant: COc1ccc2c(Cc3ccncc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A suspension of 7-methoxy-4-pyridin-4-ylmethyl-2H-phthalazin-1-one (11.4 g, 42.65 mmoles), prepared as described in example 130, and POCl3 (7.95 ml, 85.30 mmoles) in acetonitrile (110 ml) was refluxed for 1.5 hours. Further POCl3 (40 ml) was added and the reflux was kept on overnight. The mixture was dried, dissolved in water, neutralised with NaHCO3, extracted with CH2Cl2 and dried. The residue was chromatographed (eluent: CH2Cl2/CH3OH 97:3) to give 2.9 g of the title compound (yield: 23.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:34]=[CH:35][N:36]=4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=4)[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:44]([C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:34]=[CH:35][N:36]=4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:52](=[O:53])[C:51]5[CH:55]=[CH:56][C:48]([C:44]([CH3:46])([CH3:45])[CH3:47])=[CH:49][CH:50]=5)[CH:28]=4)[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(-c4cccc(N)c4)cn4ccnc34)cc2)CC1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(-c4cccc(NC(=O)c5ccc(C(C)(C)C)cc5)c4)cn4ccnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An ice-cold solution of 4-{4-[6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (14) (2.35 mmol), triethylamine (3.53 mmol), and tetrahydrofuran (20 mL) is treated dropwise with a solution of 4-t-butylbenzoyl chloride (2.35 mmol) in tetrahydrofuran (10 mL). The mixture is stirred at room temperature for 1 hr. Water (50 mL) is added and the mixture extracted with ethyl acetate (3×70 mL). The extracts are washed with water (2×50 mL) and brine (1×50 mL), dried over magnesium sulfate, and evaporated in vacuo. The residue is triturated with diethyl ether to give 4-(4-{6-[3-(4-tert-butyl-benzoylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (15) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:5][CH2:6][C:7]1[S:8][C:9]([C:19]2[CH:24]=[CH:23][C:22]([S:25](C)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:11]=1.C([Mg]Cl)CCC.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:51]OS(O)(=O)=O>C1COCC1.C(OCC)(=O)C.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:11]=[C:7]([CH2:6][O:5][C:4]3[CH:3]=[C:2]([Cl:1])[CH:31]=[C:30]([Cl:32])[CH:29]=3)[S:8][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:51])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(-c2sc(COc3cc(Cl)cc(Cl)c3)nc2-c2ccc(F)cc2)cc1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2sc(COc3cc(Cl)cc(Cl)c3)nc2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a solution of 2-((3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole (Example 33) (0.508 g, 1.0 mmol) in THF (5 mL) at 0° C. under nitrogen was added 2.0M n-butyl magnesium chloride in THF (1.6 mL, 3.2 mmol) slowly, via syringe, and the mixture stirred at 0° C. for 30 minutes and then at room temperature (25° C.) for 2 hours. After cooling to 0° C., a 1.0M solution of triethyl borane in THF (5 mL, 5 mmol) was added and the mixture was warmed to room temperature and stirred for 2 hours, and then heated to reflux for 36 hours. After cooling to room temperature and stirring for 3 hours, water (3 mL) was added followed by sodium acetate (1.2 g) and hydroxylamine-O-sulfonic acid (0.82 g). After stirring at room temperature overnight, the mixture was poured into 3 volumes of ethyl acetate, and the organic layer washed with water and brine and dried over MgSO4. After solvent removal, the white solids (a mixture of product and starting material) were purified by flash chromatography on silica gel using 30% ethyl acetate/70% hexane to provide 4-[4-(4-fluorophenyl)-2-((3,5-dichlorophenoxy)methyl)-5-thiazolyl]benzenesulfonamide as a white solid (0.147 g): Anal. Calc'd for C22H15N2O3S2FCl2 : C, 51.87; H, 2.97; N, 5.50. Found: C, 52.19; H, 2.84; N, 5.40
Reaction SMILES: CN1CCOCC1.[NH2:8][C@H:9]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].Cl.C1C=CC2N(O)N=NC=2C=1.[NH:56]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:57]([C:62]([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60].CC(C)N=C=NC(C)C>CN(C=O)C.O>[NH:56]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:57]([C:62]([NH:64][C@H:65]([C:70]([NH:8][C@H:9]([C:25]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[CH2:29][CH:30]([CH3:31])[CH3:32])=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[O:71])[CH2:66][CH:67]([CH3:68])[CH3:69])=[O:63])[CH2:58][CH:59]([CH3:61])[CH3:60]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 19 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
4-Methylmorpholine (2.53 g, 25 mmol) was added to a solution of H-Lys(Z)-Leu-Leu-OMe·HCl (13.93 g, 25 mmol) in DMF (85.0 g) at 10° C. HOBt (3.38 g, 25 mmol), Boc-Leu-Leu-OH (8.61 g, 25 mmol) and DIC (3.47 g, 27.5 mmol) were added over 30 min at 8-10° C. An additional portion of DMF (5.0 g) was added and the reaction was kept at 8-10° C. for 16 h. The reaction was stirred at 18-20° C. for 3 h, cooled to 5-10° C. and treated with H2O (130.0 g). A solid precipitated at 25° C. which was filtered, washed with H2O and recrystallized from MeOH and H2O to give Boc-Leu-Leu-Lys(Z)-Leu-Leu-OMe (SEQ. ID No. 2) (18.3 g, 86.4%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[C:7]1([CH2:13]C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>OS(O)(=O)=O.[N+]([O-])([O-])=O.[Ag+]>[CH2:13]([C:5]1[CH:4]=[CH:3][N:2]=[N:1][CH:6]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: c1ccnnc1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Product: c1ccc(Cc2ccnnc2)cc1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a 70° C. solution of pyridazine (9; 10 g, 0.125 mole) in aqueous H2SO4 (2N,125 mL) was added AgNO3 (6.37 g, 0.0375 mole). Phenylacetic acid (10; 85.06 g 0.625 mole) was added to the mixture. The reaction mixture was stirred vigorously at 70° C. for 20 minutes and was degassed with a flow of nitrogen for 2 minutes, followed by a slow portionwise addition of ammonium persulfate (85.62, 0.375 mole) with rapid gas evolution. The reaction mixture was then heated at 90° C. for 30 minutes. The reaction mixture was then cooled at room temperature and the solution was extracted with CH2Cl2. A 50% NaOH solution was added to the aqueous phase, which was re-extracted with CH2Cl2 twice. The combined extracts were dried over MgSO4. The solvent was evaporated to dryness and the residue was purified by silica gel chromatography using CH2Cl2/5% methanol as the eluent. The yield of 4-benzylpyridazine (11) obtained was 8.2 g or 39%. MS (ESI+): [M+H]+=171.47; 1H NMR (300 MHz, CDCl3), δ ppm: 4.0 (s,2H), 7.18-7.4 (m, 6H), 9.02-9.18 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].N1C=CC=CC=1.C([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=O)C>CCOCC>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([OH:26])=[CH:28][CH:29]=1)#[N:12]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccccc1Sc1ccccc1N
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#Cc1ccccc1Sc1ccccc1NC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
In 60 ml of ether were dissolved 2.6 g of 2-(2-aminophenylthio)benzonitrile (prepared in accordance with Reference Example 5, Step 4) and 2.8 g of pyridine, followed by dropwise addition of a solution of 2.7 g of 4-acetoxybenzoyl chloride in ether with ice-cooling and stirring. After completion of dropwise addition, the mixture was stirred at room temperature for 10 hours. The ether was then distilled off and ethanol was added to the residue. The resulting crystals were collected by filtration and washed with ethanol. The crystals were then suspended in 70 ml of ethanol, and after 7 ml of 10% aqueous sodium hydroxide solution was added, the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with concentrated hydrochloric acid and diluted with water. The crystals separated out therefrom were collected by filtration and dried to give 3.3 g of the title compound as white crystals.