Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1.[BH4-].[Na+]>CO.Cl>[N:1]1([CH:6]([CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]([OH:12])[C:8]([CH3:10])([CH3:11])[CH3:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)C(=O)CC(C(=O)C(C)(C)C)n1cncn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(=O)CC(C(O)C(C)(C)C)n1cncn1

Procedure:
4-(1,2,4-triazol-1-yl)-2,2,7,7-tetramethyl-octan-3,6-dione (0.005 mol) was dissolved in methanol (50 ml). Sodium borohydride (0.005 mol) was added portionwise at room temperature for 2 hours, the solution was refluxed for 11/2 hours. Removal of the methanol gave a white solid which was dissolved in dilute hydrochloric acid (50 ml) and the solution extracted into chloroform (50 ml), washed with saturated sodium bicarbonate (50 ml) and with water (2×100 ml) and dried over anhydrous sodium sulphate. Removal of the chloroform gave a colourless oil which was crystallised from petroleum ether/chloroform to give the title compound as a white crystalline solid, m.p. 95°-96°.
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:21]=[CH:20][C:10]([CH:11]=[C:12]2[S:16][C:15](SC)=[N:14][C:13]2=[O:19])=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1>CN(C=O)C>[CH:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:21]=[CH:20][C:10]([CH:11]=[C:12]2[S:16][C:15]([N:26]3[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]3)=[N:14][C:13]2=[O:19])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)C1CNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc(Oc3ccccc3C(C)C)cc2)S1
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1Oc1ccc(C=C2SC(N3CC(C(=O)O)C3)=NC2=O)cc1

Procedure:
was prepared from 5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid and substituting MeCN with DMF as described in Example 5C
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)([O-:3])=[O:2].O1CCCC1.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:14](=[O:16])/[CH:13]=[CH:12]/[CH:11]=[CH:10]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)/C=C/C=C/c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)/C=C/C=C/c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of (2E,4E)-5-(2-nitrophenyl)penta-2,4-dienoic acid (9a) (0.44 g, 2.0 mmol) in dry tetrahydrofuran (10 ml) 1,1′-carbonyldiimidazole (0.36 g, 2.2 mmol) (Sigma-Aldrich) was added and the mixture was stirred for 1 hour at ambient temperature. To the reaction mixture triethylamine (0.30 g 3.0 mmol) and methyl 6-aminohexanoate hydrochloride (10) (0.40 g, 2.2 mmol) successively were added and the resultant suspension was stirred for 6 hour at ambient temperature. The solvent was evaporated, to the obtained residue water (15 ml) was added and the precipitate was filtered off. The precipitate was washed with an additional amount of water and dried to give the title compound (0.62 g, 89%) as a yellow solid, m.p. 115-117° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.10-1.79 (6H, m, CH2); 2.29 (2H, J=7.0 Hz, CH2); 3.17 (2H, q, J=5.6 Hz, CH2N); 3.60 (3H, s); 6.24 (1H, d, J=14.8 Hz, CH); 7.04-8.10 (8H, m, CH—CH═CH, C6H4, NH).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@@H:16]4[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][C@H:17]4[CH3:23])=[N:13][CH:12]=[C:11]([C:24]#[N:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:22][C@@H:19]1[CH2:20][CH2:21][C@@H:16]([NH:15][C:14]2[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([C:30]5[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=5)=[CH:10][C:9]=4[NH:8][C:7]=3[C:11]([C:24]#[N:25])=[CH:12][N:13]=2)[C@H:17]([CH3:23])[CH2:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3cc(Cl)ccc3c12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3cc(-c4cnn(C)c4)ccc3c12
Temperature: 100 °C

Procedure:
A flask containing 7-chloro-1-{[(1R,2R,4R)-4-hydroxy-2-methylcyclohexyl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (37 mg, 0.104 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (65 mg, 0.31 mmol), Pd2(dba)3 (9.6 mg, 0.010 mmol), tricyclohexylphosphine (7.3 mg, 0.026 mmol), and K3PO4 (1.27 M, 0.28 mL, 0.35 mmol) was evacuated and refilled with nitrogen (×3). Dioxane (3 mL) was added to the mixture, and the resultant reaction mixture was heated to 100° C. overnight, and purified by flash chromatography to afford the title compound. LRMS (APCI) calc'd for (C23H24N6O) [M+H]+, 401.2. found 401.1.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.C[O:9][C:10](=[O:36])[CH2:11][O:12][C:13]1[C:18]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[Cl:30])[CH:21]=2)=[C:17]([OH:31])[C:16]([CH:32]=[O:33])=[C:15](C)[C:14]=1Cl.C(=O)([O-])[O-].[K+].[K+].Cl.[OH-].[K+]>CO.O.C1COCC1.CC(C)=O>[Cl:30][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[CH:28]=[CH:29][C:20]([CH2:19][C:18]1[C:17]([O:31][CH3:5])=[C:16]([CH:32]=[O:33])[CH:15]=[CH:14][C:13]=1[O:12][CH2:11][C:10]([OH:9])=[O:36])=[CH:21]2
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)COc1c(Cl)c(C)c(C=O)c(O)c1Cc1ccc2c(Cl)cccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1c(C=O)ccc(OCC(=O)O)c1Cc1ccc2c(Cl)cccc2c1
Reaction time: 4 h
Yield: 43.1 %

Procedure:
Dimethyl sulfate (0.54 g, 4.3 mmol) was added dropwise into a mixture of [2-chloro-6-(5-chloro-naphthalen-2-ylmethyl)-4-formyl-5-hydroxy-3-methyl-phenoxy]-acetic acid methyl ester (0.76 g, 2.05 mmol), potassium carbonate (0.65 g, 4.8 mmol) and acetone (75 mL). The mixture was refluxed for 2 hours, poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation gave a yellow oil, which was dissolved in MeOH (15 mL), THF (15 mL) and treated with KOH (10%, 3.1 mL). After stirring for 4 hours the mixture was poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from hexane/EtOAc, gave an off-white solid (0.34 g, 43% yield, m.p. 191°-192° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:28][C:4]1[CH:3]=[C:2]([S:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Sc2ccc(-c3ccc(CCC4(NC(C)=O)COC(C)(C)OC4)cc3)c(F)c2)cc1
Yield: 114.4 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (170 mg) of Reference Example 10, 4-methoxybenzenethiol (53 mg), diisopropylethylamine (98 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (9.8 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (11.2 mg) in 1,4-dioxane (1.5 mL) was heated under reflux for 9 hr under a nitrogen atmosphere. 4-Methoxybenzenethiol (11 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (3.9 mg) and Xantphos (4.4 mg) were added to the reaction mixture, and the mixture was further heated under reflux for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.22 g) as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Al](C)C.[NH2:12][C:13]1[C:14]2[N:15]([C:19]([C@H:31]3[CH2:36][CH2:35][C@H:34]([C:37](OC)=[O:38])[CH2:33][CH2:32]3)=[N:20][C:21]=2[C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=[CH:17][N:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:12][C:13]1[C:14]2[N:15]([C:19]([C@H:31]3[CH2:32][CH2:33][C@H:34]([C:37]([NH:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:38])[CH2:35][CH2:36]3)=[N:20][C:21]=2[C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=[CH:17][N:18]=1
Reactant: Nc1cccnc1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(=O)Nc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A suspension of 3-aminopyridine (40 mg, 0.43 mmol) in toluene (1.3 mL) was treated with a 2M toluene solution of trimethylaluminum (0.3 mL, 0.60 mmol). After 25 min, the resulting solution was treated with methyl trans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (30 mg, 0.08 mol) and the mixture stirred at rt overnight. The mixture was then stirred with 2M NaOH (20 mL) and ethyl acetate (20 mL) for 10 min., then the organic phase was separated and the aqueous extracted EtOAc (3×5 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo to give crude product which was subjected to mass-directed preparative HPLC to afford pure desired product. 1H NMR (d6-DMSO, 400 MHz): δ 11.45 (br s, 1H), 10.12 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.25 (d, J=4.8 Hz, 1H), 8.14 (s, 1H), 8.08 (dd, J=8.0, 1.6 Hz, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.34 (m, 1H), 7.15-7.00 (m, 3H), 6.65 (s, 1H), 6.42 (br s, 2H), 3.22 (m, 1H), 2.47 (m, 1H), 2.15-1.95 (m, 4H), and 1.85-1.65 (m, 4H). MS (ES+): m/z 452.17 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C:10]([F:13])([F:12])[CH2:9]2)=[CH:4][CH:3]=1.N#N.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:49][N:50](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:49]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C:10]([F:13])([F:12])[CH2:9]2)=[CH:4][CH:3]=1)#[N:50]
Reactant: CN(C)C=O
Reactant: COC(=O)C1(c2ccc(Br)cc2)CC(F)(F)C1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: N#N
Solvent: O
Product: COC(=O)C1(c2ccc(C#N)cc2)CC(F)(F)C1
Temperature: 120 °C
Yield: 85 %

Procedure:
To a solution of Intermediate 314D (500 mg, 1.639 mmol) in DMF (10 mL) was added Zn(CN)2 (289 mg, 2.458 mmol) and the reaction mixture was degassed with N2 gas for 15 min Pd2(dba)3 (75 mg, 0.082 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (67.3 mg, 0.164 mmol) were then added and the reaction mixture was heated at 120° C. for 1 h. The reaction mixture was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (3×40 mL) The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 10% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 314E as a colorless liquid (350 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 3.62 (s, 3H), 3.51-3.37 (m, 2H), 3.28-3.13 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]2.[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:34][CH3:35])=[C:20]([C:22]([CH3:33])([CH3:32])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=O)[CH:21]=1.C(O)(=O)C.O>C1(C)C=CC=CC=1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:34][CH3:35])=[C:20]([C:22]([CH3:32])([CH3:33])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]3)[CH:21]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: NC(=O)c1ccc2c(N)cccc2n1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(N)=O)ccc12)C(F)(F)F

Procedure:
A solution that consists of 290 mg (1.55 mmol) of 5-aminoquinoline-2-carboxylic acid amide, 616 mg (2.0 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 3.80 ml of concentrated acetic acid in 30 ml of toluene is refluxed for 20 hours in a water separator. Then, the solvent is removed in a vacuum. After the residue is purified on silica gel with hexane/ethyl acetate (0-70%), 438 mg (59% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].Cl>CC(C)=O>[Cl:1][C:2]1[C:3]([O:12][CH:20]([CH3:22])[CH3:21])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 60 °C
Yield: 91.3 %

Procedure:
To a stirred solution of 15.8 g (0.083 mole) of 2-chloro-4-fluoro-5-nitrophenol in 90 mL of acetone was added 17.1 g (0.12 mole) of potassium carbonate followed by a solution of 21.0 g (0.12 mole) of 2-iodopropane in 10 mL of acetone. After complete addition, the reaction mixture was heated at 60° C. for approximately 18 hours. The mixture was cooled and poured into a mixture of ice and concentrated hydrochloric acid. The resultant mixture was extracted with ethyl acetate, and the extract was washed with a 1N sodium hydroxide solution. The washed extract was dried over anhydrous magnesium sulfate and was filtered. The solvent was evaporated under reduced pressure to leave 17.7 g of 4-chloro-2-fluoro-5-(1-methylethoxy)nitrobenzene as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:39]=[CH:38][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([C:28]([O:30]CC4C=CC=CC=4)=[O:29])([CH3:27])[CH3:26])[CH:19]=3)[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:26])[CH:19]=3)[CH2:13]2)=[O:11])=[CH:38][CH:39]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(COC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(COC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)O)c3)C2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester (1.07 g, 2.02 mmol), potassium carbonate (0.56 g, 4.04 mmol), methanol (15 mL) and water (3 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (150 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was eluted through a 20 g plug of silica with 300 mL methylene chloride then 300 mL ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to yield 835 mg (94%) of 3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester as a clear glassy solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([O:8][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][N:7]=1
Reactant: Oc1cnc(Cl)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(OCc2ccccc2)cnc1Cl
Temperature: 80 °C

Procedure:
0.5 g (3.38 mM) of 6-chloro-5-fluoro-3-pyridinol, 10 ml of dimethyl-formamide and 0.843 g (6.08 mM) of potassium carbonate are mixed. 0.8 ml (6.76 mM) of benzyl bromide is added and the mixture is heated at 80° C. for one hour. After hydrolysis in 100 ml of water, the mixture is extracted with ethyl acetate and the organic phases are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: pure toluene) to give the expected product in the form of a white solid with a quantitative yield.
Reaction SMILES: [NH:1]([C:35](OC(C)(C)C)=[O:36])[C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.[NH:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@@H:43](C(O)=O)[CH3:44].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@@H:43]([C:35]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)=[O:36])[CH3:44]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)NCC(=O)NCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)NCC(=O)NCC(=O)O)cc1

Procedure:
Using 300 mg Boc-Cys(MBzl)-Phe-Gly-Gly-OH, 104 mg Boc-D-Ala-OH, 110 mg HONB and 120 mg DCC, the desired product was obtained in the same manner as in Example 1-(XXI).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:24]=2[Cl:23])[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cc(Cl)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cc(Cl)ccc2Cl)[nH]1
Reaction time: 2 h

Procedure:
32.8 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid were dissolved in 120 ml of ethanol and 39 g of 2,5-dichlorobenzylhydrazine were added under nitrogen. After stirring for 2 hours the mixture was left to stand overnight and the compound identified above, which precipitated, was filtered off and recrystallised from ethanol. Melting point: 195°-196° C; Yield: 23 g (43%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18].[OH-].[K+].[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24](Cl)=[O:25])[CH3:22]>C1C=CC=CC=1.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.CCOCC>[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([O:18][C:10]1[CH2:11][C:12]([CH3:16])([CH3:17])[CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])=[O:25])[CH3:22]
Reactant: Cc1ccc(C)c(C2C(=O)CC(C)(C)CC2=O)c1
Reactant: CCCCC(CC)C(=O)Cl
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCC(CC)C(=O)OC1=C(c2cc(C)ccc2C)C(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A suspension of 1.50 g (6.14 mmol) of 2-(2',5'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione in 15 ml of dry benzene was prepared and 0.49 g (7.37 mmol) of 85% powered potassium hydroxide was added, followed by 1 drop of dicyclohexyl-18-crown-6-ether. After stirring for 30 minutes, 1.20 (7.37 mmol) of 2-ethylhexanoyl chloride was added, and the reaction mixture refluxed for 12 hrs. The reaction mixture was cooled to room temperature, taken up in 150 ml ether and 50 ml of water, washed three times with 0.25N NaOH, two times with water, two times with 6N HCl, and one more with water. The ether solution was dried and stripped to leave 2.10 g (92% yield) of 3-(2-ethylhexanoyloxy)-5,5-dimethyl-2-(2',5'-dimethylphenyl)-2-cyclohexenone as a clear, colorless oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]>>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)Cc1ccc(F)cc1Br
Reactant: O=[N+]([O-])O
Product: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 5 °C
Yield: 91.6 %

Procedure:
Nitric acid (16.00 mL, 322 mmol) was cooled to −15° C. and treated portion-wise with 2-bromo-4-fluorophenylacetic acid (10.00 g, 42.9 mmol) maintaining an internal temperature of −10° C. to −5° C. Once the addition was complete the mixture was warmed to 5° C. over −15 minutes, poured onto ice (200 mL), stirred vigorously until all of the ice melted, and then filtered and rinsed with water. The resulting solid was dissolved in EtOAc, washed with brine, dried (MgSO4) and concentrated to dryness to afford 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (10.93 g, 92% yield) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.29 (d, 1H), 8.04 (d, 1H), 3.85 (s, 2H).
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[S:8][C:9]=1[CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:33]CC1>>[CH3:10][C:9]1[S:8][C:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[N:6][C:5]=1[CH:4]([OH:33])[CH3:3]
Reactant: COC(=O)Cc1nc(-c2ccc(-c3ccccc3)nc2)sc1C
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1sc(-c2ccc(-c3ccccc3)nc2)nc1C(C)O
Temperature: 25 °C

Procedure:
A solution of [5-methyl-2-(6-phenyl-pyridin-3-yl)-thiazol-4-yl]-acetic acid methyl ester (6.0 g, 18.5 mmol) in THF (500 mL) was added dropwise to a suspension of LAH (0.90 g, 22.2 mmol) in THF (300 mL) at −78° C. After the addition was completed, the reaction mixture was allowed to warm to ambient temperature, cooled to −20° C., and quenched sequentially with H2O (1.1 mL), 15% NaOH (1.1 mL), and H2O (3.3 mL). The mixture was filtered through Celite, and the filtrated was concentrated to give the title compound as an oil that was used directly in the next step.