Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[OH:2].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])[C:9]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:10][S:11]2)=[CH:6][CH:5]=1>O>[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31]([CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:37])([F:38])[F:39])=[O:2])[C:9]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:10][S:11]2)=[CH:6][CH:5]=1
Reactant: CO
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Solvent: O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 45 %

Procedure:
Methanol (16 ml) and water (4 ml) were added to the mixture of (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]thiochroman (85 mg, 0.14 mmol) obtained in Example 33 and NaIO4 (34 mg, 0.16 mmol), and the reaction mixture was stirred for 3.5 hours at room temperature. Water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then purified with preparative TLC (n-hexane:ethyl acetate=1:1) to obtain 39 mg (yield: 45%) of the title compound as a white solid. In this reaction, 13 mg (15%) of the unreacted starting 3RS,4RS-compound was recovered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH:30]C(OCC2C=CC=CC=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Pd+2].[OH-].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH2:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@@H](N)C1
Reaction time: 65 h
Yield: 112.1 %

Procedure:
In a Paar flask charged with palladium hydroxide (20 wt % on carbon, 0.423 g) was added (3R,4S)-3-benzyloxycarbonylamino-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (1.41 g, 2.53 mmol) and methanol (30 mL). The reaction was hydrogenated at 60 psi with vigorous shaking for 65 hours. The reaction mixture was filtered through a bed of celite and then concentrated in vacuo to give a thick oil (1.19 g) which was used without further purification. 1H NMR (300 MHz, CDCl3), δ: 7.06 (m, 4H), 4.45 (m, 2H), 4.21 (m, 2H), 3.81 (m, 2H), 3.62 (m, 2H), 3.23 (m, 2H), 3.08 (m, 1H), 2.67 (m, 2H), 2.45 (m, 2H), 2.21 (m, 1H), 1.45 (s, 9H). MS (APCI), m+/z: (M+H)+=420.3.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]5[CH3:44])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]5[CH3:44])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:11][O:12][S:55]([CH3:54])(=[O:57])=[O:56])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCOS(C)(=O)=O)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Example 118 (43 mg, 0.07 mmol) in DCM (1.5 mL) was added DIPEA (49 μL, 0.18 mmol) followed by methanesulfonyl chloride (11 μL, 0.11 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.38 min, m/z 679 [MH+].
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:24][C:21]([F:22])([F:23])[O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[C:9]([C:10]([F:13])([F:11])[F:12])[CH:8]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1cnc(-c2ccc(OC(F)(F)F)cc2)cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described in example 43D], 6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid methyl ester was treated with lithium aluminium hydride in tetrahydrofuran under reflux conditions for 12 h to give the title compound as yellow oil.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:21]([NH:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:22])[CH2:3][CH2:4][CH3:5]
Reactant: O=C=NC1CCCCC1
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: [I-]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 1A (123 mg, 0.4 mmol) and cyclohexyl isocyanate (63 mg, 0.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a solution of DBU (0.076 mL, 0.5 mmol) in CH2Cl2 (5 mL). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was washed sequentially with water, brine and dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (CH2Cl2-MeOH 9:1) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.10 (m, 3H), 1.29 (m, 4H), 1.51 (m, 3H), 1.70 (m, 4H), 1.95 (s, 3H), 2.02 (s, 3H), 3.33 (m, 3H), 5.02 (s, 1H), 6.74 (br d, J=7 Hz, 1H); MS (ESI) m/z 309 (M+H)+. Anal calcd for C17H28N2OS.0.25H2O: C, 65.24; H, 9.18; N, 8.95. Found: C, 65.49; H, 9.30; N, 8.93.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22]2)=[CH:17][CH:16]=1>CC(N(C)C)=O.N.[Cu-]=O>[O:27]=[C:23]1[NH:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:25](=[O:26])[N:24]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: C=CCOCC1(c2ccc(F)cc2)NC(=O)NC1=O
Agent: O=[Cu-]
Agent: N
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(c2ccc(F)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 160 °C

Procedure:
0.33 g of copper (I) oxide and 0.95 g of 4-bromo-2-trifluoromethylbenzonitrile are added to a solution of 1 g 4-(4-fluorophenyl)-4-[(2-propenyloxy)methyl]imidazolidine-2,5-dione obtained in step 3 in 3 mL of DMAC. The mixture is heated at 160° C. for 3 hours. After cooling, the mixture is diluted with a 50% aqueous ammonia solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 2/1 heptane/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=O)=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:6]2[CH2:5][CH2:4][C:3]3[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: Nc1cccc2c1CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
1,2,3,4-tetrahydro-5-aminoisoquinoline (500 mg, 3.37 mmol) was dissolved in tetrahydrofuran (15 mL) then added 4-quinolinecarboxaldehyde (556 mg, 3.54 mmol) and sodium triacetoxyborohydride (786 mg, 3.71 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate then concentrated under vacuum. The remaining residue was dissolved in ethyl acetate then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude material was purified by silica gel chromatography (50% to 80% ethyl acetate/hexane) to afford 2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine (805 mg) as a yellow solid. MS (ESI, pos. ion) m/z: 290.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Br.[NH2:25][C@@:26]1([CH3:34])[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[C:21](=[O:23])[N:25]([C@@:26]1([CH3:34])[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])[C:15]2=[O:17]
Reactant: C[C@]1(N)CCC(=O)NC1=O
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)c(OC)c1
Agent: Br
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N([C@@]2(C)CCC(=O)NC2=O)C3=O)c(OC)c1
Yield: 41 %

Procedure:
A mixture of 3-(2,4-dimethoxyphenylamino)phthalic acid (0.37 g, 1.2 mmol) and (3S)-3-amino-3-methyl-piperidine-2,6-dione hydrobromide (0.28 g, 1.2 mmol) in pyridine (10 mL) was heated to reflux for 24 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was purified by ISCO silica gel flash chromatography using a hexanes-ethyl acetate gradient, eluting 0.20 g of the product, an orange solid, at 50:50 hexanes-ethyl acetate, in 41% yield: mp 255-257° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 65/35 (CH3CN/0.1% H3PO4): tR=2.72 (97.30%); 1H NMR (DMSO-d6) δ 1.91 (s, 3H), 2.05-2.08 (m, 1H), 2.59-2.73 (m, 3H), 3.79 (s, 6H), 6.57 (d, J=7.5 Hz, 1H), 6.71 (s, 1H), 6.97-7.08 (m, 2H), 7.27 (d, J=8.1 Hz, 1H), 7.52 (m, 1H), 7.94 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 21.0, 28.6, 29.2, 55.4, 55.7, 58.5, 99.5, 104.7, 110.2, 111.8, 118.1, 120.1, 125.0, 131.9, 136.0, 144.0, 153.6, 157.9, 167.8, 169.8, 172.1, 172.4; Anal. calcd for C22H21N3O6.0.2H2O: C, 61.88; H, 5.05; N, 9.84. Found: C, 61.91; H, 5.01; N, 8.52.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]#[N:20])[N:18]=2)=[O:13])=[C:7]([C:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=2)[CH:6]=1)C.[OH-].[K+].C(O)(C(F)(F)F)=O>CCO>[C:19]([C:17]1[N:18]=[C:14]([C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[CH:6][C:7]=2[C:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=2)=[O:13])[NH:15][CH:16]=1)#[N:20]
Reactant: CCOC(=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC1(C)CC=C(c2cc(C(=O)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 60 °C
Yield: 84.4 %

Procedure:
To a solution of 4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-benzoic acid ethyl ester (50 mg, 0.13 mmol) in 1 mL of EtOH was added a 2 N aqueous solution of KOH (0.20 mL, 0.10 mmol) and the mixture heated to 60° C. for 6 h. The pH was adjusted to 2 with 2 N aq TFA and the title compound was purified by RP-HPLC eluting with a linear gradient of 30% to 50% acetonitrile in 0.1% TFA/H2O over 10 min on a C18 column giving 40 mg (87%) of a white solid. 1H-NMR (CD3OD, 400 MHz): δ 8.48 (d, J=8.6 Hz, 1H), 8.04 (s, 1H), 7.96 (dd, J=8.6, 2.0 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 5.85 (m, 1H), 2.40-2.32 (m, 2H), 2.17-2.13 (m, 2H), 1.66 (t, J=6.3 Hz, 2H), 1.15 (s, 6H). Mass spectrum (APCI, m/z): Calcd. for C20H20N4O3, 363.2 (M-H), found 363.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[O-:14].[K+].Br[CH2:17][CH2:18][OH:19].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[O:14][CH2:17][CH2:18][OH:19]
Reactant: COc1cc([N+](=O)[O-])cc(OC)c1[O-]
Reactant: OCCBr
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCCO

Procedure:
A slurry of potassium 2,6-dimethoxy-4-nitrophenolate [Collins, R. P. and Davis, M. J. Chem. Soc. (1961), 1986] (38 g, 160 mmol) in DMF (600 ml) was treated with 2-bromoethanol (25 ml, 353 mmol) and hexamethyl-phosphorus triamide (31 ml, 176 mmol) and the reaction heated at 115° for 6 h. After cooling, the reaction was poured onto 1M hydrochloric acid (1.5 l) and extracted with ethyl acetate (5×500 ml). The organics were washed with 1M sodium hydroxide (4×700 ml), brine (200 ml) and defined (MgSO4). Concentration in vacuo gave 3,5-dimethoxy-4-(2-hydroxyethoxy)nitro-benzene as an off white solid (31 g) δH (CDCl3) 7.52 (2H, s), 4.21 (2H, t, J 2.9 Hz), 3.94 (3H, s), 3.76 (2H, m) and 2.94 (1H, br s). MS (ES+) 266 (MNa+, 50%), 244 (MH+, 100%). A mixture of this nitrobenzene (750 mg, 3.16 mmol) and 10% palladium on carbon (75 mg) in ethanol (50 ml) was degassed and then subjected to an atmosphere of hydrogen (balloon) for 16 h. at 20°. Dichloromethane was added and the solution filtered and solvent removed in vacuo to give 3,5-dimethoxy-4-(2-hydroxyethoxy)-aniline as a grey solid (620 mg) after trituration with diethyl ether. δH (CDCl3 +DMSO) 5.84 (2H, s), 3.87-3.84 (2H, m), 3.64 (6H, s) and 3.52-3.49 (2H, m). MS (ES+) 214 (MH+, 100%.
Reaction SMILES: [C:1]1(CO)[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.ClCCl.[C:20](Cl)(=[O:24])C(C)C>CN(C1C=CN=CC=1)C.[Cl-].[Na+].O>[C:3]1([CH2:20][OH:24])[C:4]([CH2:7][OH:8])=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: CC(C)C(=O)Cl
Reactant: OCc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: OCc1ccccc1CO
Reaction time: 8 h
Yield: 212.9 %

Procedure:
1,4-xylylene glycol (5 g, 0.0306 mol), pyridine (5.7 g, 0.072 mol), and catalyst DMAP (ca. 100 mg) in a solution of dichloromethane (ca. 25 ml) were added to a flask. Isobutyryl chloride (7.71 g, 0.072 mol) was then added to the solution drop wise. The mixture was stirred overnight. 1M HCL brine was used to wash the mixture. The organic layer was dried over MgSO4 and concentrated in vacuo to afford a clear oil as the product (9 g). Its purity was ascertained using 1H NMR (300 MHz in CDCL3): δ 7.34 (s, 4H), 5.11 (s, 4H), 2.60 (sept, 2H), 1.19 (d, 12H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccc(-c3ccc(F)cc3)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 56.7 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 40 mg, 0.09 mmol), 4-fluorobenzeneboronic acid (15.2 mg, 0.11 mmol), potassium carbonate (38 mg, 0.272 mmol), tetrakis(triphenylphosphine)palladium (0) (3 mg, 2.7 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 25-95% acetonitrile/water (0.1% TFA)) to afford the title compound (23.5 mg, 0.051 mmol, 57% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.91 (s, 1H), 12.96 (s, 1H), 10.15 (t, J=5.31 Hz, 1H), 7.69-7.80 (m, 2H), 7.55 (dd, J=11.62, 1.77 Hz, 1H), 7.48 (dd, J=8.08, 1.77 Hz, 1H), 7.23-7.38 (m, 3H), 5.34 (s, 2H), 4.10 (d, J=5.56 Hz, 2H), 3.19 (m, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 458 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][O:7][CH:8]([CH3:10])[CH3:9].NC(N)=[S:13].[OH-].[Na+]>O>[CH:8]([O:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2][SH:13])([CH3:10])[CH3:9]
Reactant: CC(C)OCCC=CCCl
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)OCCC=CCS
Reaction time: 0.5 h

Procedure:
A mixture of 8.1 g (0.05 mol) of 1-chloro-5-isopropoxy-2-pentene, 3.8 g (0.05 mol) of thiourea, and 5 cc of water are heated to 98° during the course of 35 minutes and stirred at this temperature for 30 minutes. The homogeneous reaction mixture is cooled to 60° and 10 cc (0.05 mol) of 5N caustic soda solution are added dropwise at this temperature. The mixture which again has rendered heterogeneous is heated to 100° with stirring, is cooled after 5 minutes and poured on water The reaction mixture is extracted with ether, the ether extract is washed with saturated salt solution, is dried with sodium sulphate and the ether is evaporated. The residue is fractionated at 16 mm, whereby the 5-isopropoxy-2-penten-1-thiol is obtained as malodorous oil which is uniform according to gas-chromatography; it has a B.P. of 87°-89°/16 mm. nD20 = 1.4696.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1>O>[CH3:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CN1CCNCC1
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 120 °C
Yield: 165.4 %

Procedure:
A mixture of 1-methyl-piperazine (1.3 g, 1.2 mmol) and 4-fluoro benzoic acid methyl ester (500 mg, 0.32 mmol) was stirred with heating at 120° C. for 20 hrs. Cold water then added, filtered the solid precipitated to afford 124 mg (16.4% yield) of 4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester. 1H NMR (CDCl3): δ 8.0 (d, 2H), 6.9 (d, 2H), 3.9 (s, 3H), 3.4 (t, 4H), 2.6 (t, 4H), 2.4 (s, 3H).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:44])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@@H:30]2[C:34]([O:36]CC2C=CC=CC=2)=[O:35])=[O:28])[N:20]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:44])[CH2:17][CH2:18][C:19]1[N:20]=[C:21]([CH2:25][CH2:26][C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@@H:30]2[C:34]([OH:36])=[O:35])=[O:28])[CH:22]=[CH:23][CH:24]=1)([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCc1cccc(CCC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCc1cccc(CCC(=O)N2CCC[C@@H]2C(=O)O)n1
Yield: 90.9 %

Procedure:
0.17 g (0.29 mmol) (R)-1-[3-[6-[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]-propionyl]-pyrrolidine-2-carboxylic acid benzyl ester in 100 ml ethanol were hydrogenated in the presence of 35 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 0.11 g (92%) (R)-1-[3-[6-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]propionyl]-pyrrolidine-2-carboxylic acid as colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[N:10][OH:11])[C:2]1=[N:12][OH:13].[H-].[Na+].S(OC)(O[CH3:20])(=O)=O.O>CN(C)C=O>[CH3:20][O:11][N:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]1=[N:12][OH:13]
Reactant: ON=C1Oc2ccccc2C1=NO
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C1C(=NO)Oc2ccccc21
Reaction time: 1 h
Yield: 6.1 %

Procedure:
A solution of 11 g (0.0617 mol) of benzofuran-2,3-dione dioxime in 50 ml of dimethylformamide is added dropwise to a suspension of 2.4 g (0.06 mol) of 60% strength sodium hydride in 25 ml of dimethylformamide, and stirring is effected at 20° C. for one hour. 7.55 g (0.06 mol) of dimethyl sulphate are then added dropwise and stirring is continued at 20° C. for a further 16 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed over silica gel using hexane/acetone (7:3). Stirring the residue with diethyl ether affords 0.7 g of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime (VIII-1) as a mixture of stereoisomers consisting of 90.6% of isomer A and 9% of isomer B (HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:23](=O)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[N:1]=[C:23]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:24]([C:25]#[N:26])=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCC(=O)C1CCCC1
Reactant: Nc1cc(F)c(Cl)cc1C(=O)c1ccccc1
Product: N#Cc1c(C2CCCC2)nc2cc(F)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-4-fluoro-phenyl)-phenyl-methanone and 3-cyclopentyl-3-oxo-propionitrile. Off-white solid. MS (ESI): 351.4 (M+H)+.