Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]1)=[O:19])=[N:5]2
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 90 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 3.20-3.30 (m, 4H), 3.74-3.77 (m, 3H), 4.11-4.14 (m, 4H), 6.74-6.77 (m, 3H), 7.16-7.25 (m, 4H), 7.64-7.81 (m, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C=O)C.[NH2:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=[CH:17][C:16]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40])=[O:37].O>C(OCC)(=O)C>[NH2:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:18]([Br:1])=[CH:17][C:16]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:40])[CH3:41])=[O:37]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1ccc(C(=O)NC(C)(C)c2ccccc2)c(N)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(N)c(C(=O)NC(C)(C)c2ccccc2)cc1Br
Reaction time: 1 h
Yield: 100.7 %

Procedure:
N-bromosuccinimide (22 mg) was added to a DMF (5 ml) solution containing tert-butyl cis-2-(6-amino-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (60 mg) at 0° C., followed by stirring for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (silica gel:silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=4:1 to 3:1), and a white solid of tert-butyl cis-2-(6-amino-3-bromo-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (68 mg) was thus obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29]([N:35]3[CH2:41][C:40]4[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:39]=4[O:38][CH2:37][CH2:36]3)=[N:30][CH:31]=[N:32][C:33]=2[CH3:34])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.ClCCl>CN(C)C=O.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29]([N:35]3[CH2:41][C:40]4[CH:42]=[C:43]([C:2]5[N:7]=[C:6]6[S:8][C:9]([NH:11][C:12](=[O:19])[C:13]7[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=7)=[N:10][C:5]6=[CH:4][CH:3]=5)[CH:44]=[CH:45][C:39]=4[O:38][CH2:37][CH2:36]3)=[N:30][CH:31]=[N:32][C:33]=2[CH3:34])=[CH:23][CH:22]=1
Reactant: O=C(Nc1nc2ccc(Br)nc2s1)c1ccccc1
Reactant: Cc1ncnc(N2CCOc3ccc(B(O)O)cc3C2)c1Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc5nc(NC(=O)c6ccccc6)sc5n4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 105 °C
Yield: 40.8 %

Procedure:
A solution of N-(5-bromothiazolo[5,4-b]pyridin-2-yl)benzamide (reagent preparation 13) (0.14 g, 0.42 mmol), (4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (0.14 g, 0.35 mmol) and diisopropyethylamine (0.40 mL, 2.10 mmol) in 10% aqueous dimethylformamide (3 mL) was deoxygenated for five minutes by bubbling nitrogen gas, followed by the addition of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) complex with dichloromethane (20 mg, 0.021 mmol). The reaction mixture was heated to 105° C. for 4 hours. On cooling to room temperature the mixture was diluted with ethyl acetate (50 mL) then it was filtered through a pad of Celite. The organic filtrate was washed with 10% aqueous citric acid (20 mL), brine, aqueous saturated sodium bicarbonate (20 mL) and brine then dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography (chloroform/methanol 95:5 to 9:1) provided N-[5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)[1,3]thiazolo[5,4-b]pyridin-2-yl]benzamide (86 mg. 41%). MS (EI) for C34H27FN6O2S: 603 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:19]3[N:20]=[C:21]([NH2:24])[S:22][CH:23]=3)=[C:14]([CH3:25])[CH:13]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:19]3[N:20]=[C:21]([NH:24][C:36](=[O:43])[C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)[S:22][CH:23]=3)=[C:14]([CH3:25])[CH:13]=2)=[CH:9][CH:8]=1
Reactant: COCCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.3 %

Procedure:
To a solution of 4-{4-(4-(3-methoxypropoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (21-5, 0.28 g, 0.74 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.5 mL, 3.59 mmol) followed by isonicotinoyl chloride hydrochloride (0.22 g, 1.22 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-{4-(4-(4-(3-methoxypropoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (21, 0.99 mg) as light yellow solids in 27% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.00 (s, 1 H), 8.81 (s, 2 H), 7.99 (d, J=5.7 Hz, 2 H), 7.15 (s, 1 H), 6.98 (m, 4 H), 6.68 (s, 2 H), 4.00 (t, J=6.3 Hz, 2 H), 3.47 (t, J=6.3 Hz, 1 H), 2.05 (s, 6 H), 1.94 (t, J=6.3 Hz, 2 H). ESI-MS: m/z 489.7 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH:14]([F:16])[F:15])=[N:4][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:6]=1[CH3:7].[O:17]1CCC[CH2:18]1.C([Li])CCC.CN(C)C=O>CCCCCC>[F:15][CH:14]([F:16])[C:3]1[C:2]([CH:18]=[O:17])=[C:6]([CH3:7])[N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[N:4]=1
Reactant: C1CCOC1
Reactant: Cc1c(Br)c(C(F)F)nn1C1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1c(C=O)c(C(F)F)nn1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 4-bromo-3-(difluoromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0.60 g, 2.0 mmol) in tetrahydrofuran (7.00 mL, 86.3 mmol) was cooled at −78° C. Into the reaction was added 1.6 M of n-butyllithium in hexane (2.00 mL) and was stirred at −78° C. for 5 min. N,N-Dimethylformamide (0.31 mL, 4.1 mmol) was added and stirred at −78° C. for 1 h. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification. 1H NMR (CDCl3): δ 10.12 (s, 1H), 6.81-6.95 (t, 1H), 5.38 (m, 1H), 4.03 (m, 1H), 3.68 (m, 1H), 2.66 (s, 3H), 2.42 (m, 1H), 2.14 (m, 1H), 1.96 (m, 1H), 1.50-1.75 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:53][CH2:54][F:55]>O1CCCC1.O>[F:55][CH2:54][CH2:53][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=1
Reactant: FCCI
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2OCCF)c1
Temperature: 25 °C
Reaction time: 90 h
Yield: 59.8 %

Procedure:
124 mg (0.20 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(2-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 2.2 ml tetrahydrofurane. 130 mg (0.40 mmol) cesium carbonate and 66 mg (0.38 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 90 hours. 66 mg (0.38 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 20 hours. 66 mg (0.38 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 60 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 80 mg (54%) tert-butyl 4-(3-{(3R)-3-[(1-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:25]=4[CH3:32])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Br:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[O:33]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[C:28]([CH2:30][NH:38][C:37]5[CH:39]=[CH:40][CH:41]=[C:35]([Br:34])[CH:36]=5)[CH:27]=[CH:26][C:25]=4[CH3:32])=[CH:22][CH:23]=3)=[O:17])=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Nc1cccc(Br)c1
Reactant: Cc1ccc(C=O)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(CNc2cccc(Br)c2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h
Yield: 59.8 %

Procedure:
5′-Formyl-2′-methyl-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (40 mg) and 3-bromo-aniline (18 mg) were stirred together in dry dichloromethane (10 ml) containing 3 A molecular sieves. The mixture was then heated to 40 C for 4 h. Sodium (triacetoxy)borohydride (50 mg) and glacial acetic acid (1 ml) were then added and stirring continued at 20 C for 18 h. The sieves were then removed by filtration and the mother liquor evaporated. The residue was purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 200:8:1 gave the title compound as a pale yellow solid (32 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)=[CH2:2]>C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:8]=1)[CH3:2]
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1ccc(C(F)(F)F)cc1

Procedure:
A solution of 1-ethenyl-4-(trifluoromethyl)benzene (1.72 mL, 11.6 mmol) in THF (60 mL) was stirred in the presence of Pd/C (10%, 400 mg), under a hydrogen atmosphere (45 psi) for 7 h. The solid was filtered through celite (washed with DCM) and the filtrate was carefully concentrated, keeping the temperature of the bath below 20° C. at 200 mmHg. The concentrated solution thus obtained was used in the next step without further manipulation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N+:15]([O-:18])=[C:14]([CH3:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N+:15]([O-:18])=[C:14]([CH3:19])[CH:13]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)ccc1[C@H](CC(=O)c1cc[n+]([O-])c(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1[C@H](C/C(=N\O)c1cc[n+]([O-])c(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 132, step 6, from (R)-4-(3-(4-bromophenyl)-3-(4-chloro-2-methyl-phenyl)propanoyl)-2-methylpyridine 1-oxide (example 383, step 1) and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=459.1 ([M+H]+).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([O-:20])=[O:19])=[C:14]([CH2:16]O)[CH2:15][C@H:11]12)[CH3:9])=O)C=C.[OH:23][CH2:24][C:25]1[N:32]2[C:28]([S:29][CH:30]=[CH:31]2)=[CH:27][N:26]=1>>[OH:7][C@@H:8]([C@H:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([O-:20])=[O:19])=[C:14]([CH2:16][N:26]3[CH:27]=[C:28]4[S:29][CH:30]=[CH:31][N+:32]4=[C:25]3[CH2:24][OH:23])[CH2:15][C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)[O-])=C(CO)C[C@H]12
Reactant: OCc1ncc2sccn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc[n+]4c3CO)C[C@H]12
Yield: 6.6 %

Procedure:
The same procedure as in Example 1 was repeated except that 43 mg of (5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-carbapen-2-em-3-carboxylate and 96 mg of 5-hydroxymethylimidazo[5,1-b]thiazole were used, thereby obtaining 3.3 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:12]4[N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[N:9]=[N:10][C:11]=4[CH3:27])[N:14]=[CH:15]3)=[N:19][CH:20]=2)[CH2:30][CH2:29]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NC1CC1
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3CC3)cn2)cn1
Yield: 38 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (65 mg, 0.178 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (27 mg, 38%) which was obtained as an off white solid. MS: m/e=404.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:34])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:17]=2)=[C:10]([Cl:35])[CH:9]=1)=[O:6].[OH-].[Na+]>CO.O.[OH-].[K+]>[Cl:14][C:12]1[CH:13]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:36])=[O:2])[CH:9]=[C:10]([Cl:35])[C:11]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:34])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:17]=1
Reactant: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(NC(=O)CC(=O)OC)cc2Cl)ccc1O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCNC(=O)c1cc(Oc2c(Cl)cc(NC(=O)CC(=O)O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[3,5-Dichloro-4-(4-hydroxy-3-nonylcarbamoyl-phenoxy)-phenyl]-malonamic acid methyl ester (78 mg, 0.14 mmol) was dissolved in a mixture of MeOH (2 ml), water (1.5 ml), and 1 M NaOH (0.5 ml, 0.5 mmol). The resulting solution was stirred at RT for 2 h then diluted with 15 ml 0.1 M KOH. The solution was washed with a 1:1 mixture of Et2O and EtOAc (3×10 ml) and the combined organic washings were extracted with 0.1 M KOH (2×10 ml). The combined basic solutions were acidified with concentrated HCl and extracted with EtOAc (3×15 ml) and the combined organic extracts washed with brine. The dried extracts were filtered and concentrated to give the title compound of Step G and Example 3, (64 mg). MS (APCl+) Calc.: 524.1, Found: 525.1 (M+).
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[NH:44][C:45]5[C:50]([CH:51]=4)=[CH:49][C:48]([O:52][CH3:53])=[CH:47][CH:46]=5)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:56][CH:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:55]=[CH:54][C:33]([NH:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([C:43]3[NH:44][C:45]4[C:50]([CH:51]=3)=[CH:49][C:48]([O:52][CH3:53])=[CH:47][CH:46]=4)=[O:42])[CH2:39][CH2:40]2)=[CH:32][CH:31]=1
Reactant: COc1ccc2[nH]c(C(=O)N3CCC(Nc4ccc(CCNC[C@H](O)COc5ccc(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)cc5)cc4)CC3)cc2c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]c(C(=O)N3CCC(Nc4ccc(CCNCC(O)COc5ccc(O)cc5)cc4)CC3)cc2c1
Yield: 28.6 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}(5-methoxy-1H-indol-2-yl)methanone (0.128 g, 0.161 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.026 g, 0.046 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:29][Si](C(C)C)(C(C)C)C(C)C)[C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1.I[CH2:41][CH2:42][CH3:43].[F-].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([S:29][CH2:41][CH2:42][CH3:43])[C:12]2[O:21][CH:20]3[CH:15]([CH2:16][N:17]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:19]3)[C:13]=2[CH:14]=1
Reactant: CCCI
Reactant: CC(C)[Si](Sc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCN(C(=O)OC(C)(C)C)CC21)(C(C)C)C(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CCCSc1cc(-c2ccc(Cl)cc2Cl)cc2c1OC1CCN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 8-(2,4-dichlorophenyl)-6-[(triisopropylsilyl)thio]-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.111 g, 0.182 mmol) was dissolved in DMF (3 mL). 1-Iodopropane (0.2 mL) and cesium fluoride (0.060 g) were added to the reaction mixture. The reaction mixture was stirred at rt under N2 for 2.5 h. The reaction mixture was partitioned between EtOAc (30 mL) and 2:3 water:brine (25 mL). The aqueous layer was back extracted with EtOAc (30 mL). The combined organic layers were washed with water (20 mL), with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. tert-Butyl 8-(2,4-dichlorophenyl)-6-(propylthio)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate was obtained in quantitative yield (0.090 g). MS (ESI+) for C25H29Cl2NO3S m/z 517.0 (M+23)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[C@H:3]1[C:16]([OH:18])=[O:17].[C:20]([C@@H:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=1)#[N:21]>>[CH3:1][C:2]1([CH3:19])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])[C@H:3]1[C:16]([O:18][C@H:22]([C:20]#[N:21])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1)=[O:17]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OC1CCCCC1
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CCCCC1
Yield: 42.4 %

Procedure:
Using the procedure of Step D in Example 7, 2.5 g of the product of Step C and 2.2 g of (S)α-cyano-3-phenoxybenzyl alcohol were reacted and the product was chromatographed over silica gel. Elution with a 9-1 hexane-ether mixture yielded 1.883 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-(cyclohexyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+41°±2.5° (c=0.5% in chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:15][CH:16]([CH3:20])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CC(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(Cl)C(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 92.7 %

Procedure:
47.2 g (0.25 mole) of 6-(p-aminophenyl)-4,5-dihydropyridaz-3-one and 35.6 g (0.28 mole) of 2-chloropropionyl chloride in 250 ml of absolute benzene are refluxed for 2 hours. The product is filtered off at 10° C., washed first with benzene and then with water and dried under reduced pressure at 100° C. 64.8 g (93% of theory) of 6-[p-(2-chloropropionylamino)-phenyl]-4,5-dihydropyridaz-3-one are obtained as a beige solid which, after recrystallization from propanol, melts, with decomposition, at 243°-244° C.
Reaction SMILES: [CH3:1][CH:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([CH3:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:21]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:24]=O)[CH3:22].[Na].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:20][CH:15]([N:14]([CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])[C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH:2]([CH3:1])[CH2:3][CH:4]([CH3:5])[CH3:6])[CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:9][CH:10]=1)[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CCCCC(C=O)CC
Reactant: CC(C)CC(C)Nc1ccc(NC(C)CC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CCCCC(CC)CN(c1ccc(N(CC(CC)CCCC)C(C)CC(C)C)cc1)C(C)CC(C)C
Yield: 92.8 %

Procedure:
N,N′-di-(1,3-dimethylbutyl)-p-phenylenediamine (17 g, 61.5 mmol) and 2-ethylhexanal (18.53 g, 144.5 mmol) were dissolved in dichloromethane (500 mL) and were stirred together in a 1 liter round bottomed flask fitted with a condenser and magnetic stirring at room temperature whilst sodium triacetoxyhydroborate (30.63 g, 144.5 mmol) was added portionwise over 1 hour. The mixture was left standing for a total of 18 hours. The crude product was stirred with 150 ml water for a few minutes followed by addition of aqueous sodium carbonate solution (60 g in 250 ml water) in portions. Most of the effervescence subsided after 50% of this had been added. The mixture was stirred with a further 100 ml water and separated using a separating funnel. The organic phase was washed with water (500 ml+750 ml) and brine (500 ml). It was then dried with magnesium sulphate, filtered through celite 521 and evaporated to leave a dark brown oil. The product was chromatographed (eluent 5% EtOAc in heptane). Relevent fractions were combined and concentrated to afford the product as a dark oil (28.6 g, 93% yield).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([C:17]#[N:18])=[C:8]([CH3:19])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Se](=O)=[O:21]>CCOCC>[CH2:1]([NH:5][C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]([C:17]#[N:18])=[C:8]([CH:19]=[O:21])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[Se]=O
Reactant: CCCCNc1nc(C)c(C#N)cc1C(=O)OCC
Solvent: CCOCC
Product: CCCCNc1nc(C=O)c(C#N)cc1C(=O)OCC

Procedure:
130.5 g of 2-butylamino-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester (0.5 mol) are dissolved in 400 ml of diethyleneglycoldimethyl ether. 61.1 g of selenium dioxide are added and the mistrue is heated at reflux temperature for 1 hour. The mixture is filtered hot and evaporated to dryness. The resulting yellow oil of 2-butylamino-5-cyano-6-formyl-3-pyridine-carboxylic acid, ethyl ester is crystallized with diethyl ether. Yield 95 g (69%); m.p. 81°-83° C. (methanol).