Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32](O)=[O:33]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([CH:28]3[CH2:29][CH2:30][CH2:31][O:27]3)=[O:33])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C1CCCO1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCCO1

Procedure:
The title compound, off-white solid (74 mg, 70%), MS (ISP) m/z=425.3 [(M+H)+], mp 132° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-tetrahydro-furan-2-carboxylic acid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=4)[C:32]([NH:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37])=[O:33])=[CH:25][C:19]=3[C:20]=2[C:21](=[O:24])[NH:22][CH3:23])=[CH:12][CH:11]=1.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>CN(C=O)C>[CH3:1][N:2]([CH3:3])[C:36](=[O:37])[C:35]([NH:34][C:32]([C:31]1[CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][C:18]3[O:17][C:16]([C:13]4[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=4)=[C:20]([C:21]([NH:22][CH3:23])=[O:24])[C:19]=3[CH:25]=2)[CH:43]=[CH:42][CH:41]=1)=[O:33])([CH3:39])[CH3:40]
Reactant: CNC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
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: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)N(C)C)c3)cc12
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of dimethylamine in THF (2 molar, 0.10 mL, 0.20 mmol) was added to 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (17 mg, 0.036 mmol) and HATU (15 mg, 0.039 mmol) in a 1 dram vial. DMF (0.3 mL) was added, the vial was capped, and the homogeneous solution was stirred at r.t. for 1 h, at which point DIPEA (50 μL, 0.29 mmol) was added. Stirring was continued for 3 h, at which point the reaction was filtered and purified directly by prep HPLC. Concentration of the collected fractions afforded the title compound as a white solid (13 mg, 71% yield). 1H NMR (500 MHz, CD3OD) δ ppm 8.09-8.17 (m, 1 H) 7.90-7.98 (m, 3 H) 7.86 (d, J=7.94 Hz, 1 H) 7.79-7.84 (m, 1 H) 7.63-7.72 (m, 2 H) 7.57 (t, J=7.63 Hz, 1 H) 7.20-7.32 (m, 2 H) 3.14 (br. s., 3 H) 2.98 (s, 6 H) 1.61 (s, 6 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.29 min, (ES+) m/z (MH+)=502. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=14.80 min, purity=100%; column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=10.37 min, purity=100%.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:20])[NH:11][O:12][CH:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:14].O.[OH-].[Li+]>C1COCC1>[CH2:16]([O:15][CH:13]([O:12][NH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[O:20])[CH3:14])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)CCCCCCC(=O)NOC(C)OCC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COC(C)ONC(=O)CCCCCCC(=O)O
Yield: 828.3 %

Procedure:
7-(1-Isobutoxy-ethoxycarbamoyl)-heptanoic acid methyl ester (36.6 g, 12.1 mmol, 1.0 eq) was stirred in THF (200 mL) and water (200 mL) in the presence of lithium hydroxide (8.68 g, 36.2 mmol, 3.0 eq) for 3 h at 50° C. THF was evaporated under vacuum and to the mixture water (100 mL) and ethyl acetate (200 mL) were added. The mixture was acidified cautiously to pH 3 by addition of 1N HCl. The organic phase was isolated and the aqueous layer re-extracted with ethyl acetate (150 mL). The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo. The product was obtained as a white solid (29.0 g, 83% yield), m/z 288 [M++H]+ and used in stage 4 without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C@H:11]2[CH2:16][NH:15][CH2:14][CH2:13][NH:12]2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[S:27][C:26]2[NH:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[N:22]=[C:21](N)[C:20]=2[N:19]=1.CN1CCCC1=O>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C@@H:11]2[NH:12][CH2:13][CH2:14][N:15]([C:21]3[C:20]4[N:19]=[C:18]([CH3:17])[S:27][C:26]=4[NH:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[N:22]=3)[CH2:16]2)=[CH:7][CH:8]=1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Reactant: COc1ccc(CC[C@H]2CNCCN2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C)nc43)CCN2)cc1
Temperature: 195 °C
Reaction time: 3.75 h
Yield: 109.1 %

Procedure:
Combine (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (180 mg, 0.82 mmol), 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine (188 mg, 0.82 mmol), 1-methyl-2-pyrrolidinone (5 mL). Heat at 195° C. After 3.75 h, cool to ambient temperature and stir 18 h. Combine with another 2.30 mmol reaction executed under same conditions. Dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%–4%) as the eluent to give 388 mg (29%) of the title compound: mass spectrum (ion spray): m/z=434 (M+1), 432 (M−1). HR-MS calculated for C24H28N5OS: 434.2015. Found 434.201 HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.4 min; 100% pure.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH:12]([CH2:13][CH:14]([CH:18]([CH3:20])[CH3:19])[CH2:15][CH2:16][OH:17])[O:11]C(C)(C)[N:9]2C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[K+]>Cl.O1CCOCC1>[NH2:9][C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C@@H:12]([OH:11])[CH2:13][C@@H:14]([CH:18]([CH3:19])[CH3:20])[CH2:15][CH2:16][OH:17]
Reactant: CC(C)C(CCO)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)[C@@H](CCO)C[C@H](O)[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
1.1 g (2.67 mmol) of t-butyl 4-(cyclohexylmethyl)-5-(4-hydroxy-2-isopropylbutyl)-2,2-dimethyl-3-oxazolidinecarboxylate are dissolved in 1.85N hydrochloric acid in dioxan and stirred at room temperature for 2 hours. Thereafter, the reaction mixture is poured into 2N potassium bicarbonate solution and extracted with ethyl acetate. The crude product obtained after drying and evaporating the organic extracts is chromatographed on silica gel with a 4:1 mixture of methylene chloride and methanol as the eluting agent, whereby there are obtained 268 mg (37%) of (3S,5S,6S)-6-amino-7-cyclohexyl-5-hydroxy-3-isopropyl-1-heptanol as a resin, MS: 272 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]=O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([CH2:32][S:33][CH3:34])=[O:31]>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]=[C:32]([S:30]([CH3:29])=[O:31])[S:33][CH3:34])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4C=O)ccc3o2)n1
Reactant: CSCS(C)=O
Solvent: C1CCOC1
Product: CSC(=Cc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)S(C)=O
Temperature: 0 °C
Yield: 32.2 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-formylphenylmethoxy)benzofuran-2-yl]thiazole (0.61 g), methyl methylsulfinylmethyl sulfide (0.46 g) and triton B (phase transfer) (0.7 g) in tetrahydrofuran (3 ml) was stirred under reflux for 5 hours. After being cooled, the resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with diluted aqueous hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and chloroform (1:5). The fractions containing object compound were combined and concentrated in reduced pressure to give a syrup of 4-tert-butyl-2-[5-{2-[2-methylsulfinyl-2-methylthioethenyl)phenylmethoxy}benzofuran-2-yl]thiazole (0.25 g).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ICC>C1COCC1.CN1CCCN(C)C1=O>[C:9]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([CH2:1][CH3:2])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (6.5 mL, 2.0 M in heptane/THF/ethylbenzene) in THF (25.0 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5.0 mL) was added methyl 3-(4-(benzyloxy)phenyl)propanoate 23.1 (3.00 g, 11 mmol) in THF (10 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes and then iodoethane (1.0 mL, 13 mmol) in THF (5.0 mL) was added. The reaction mixture was stirred at the same temperature for 20 minutes. The reaction was then stirred at room temperature for 16 hours. The reaction was quenched with water (30.0 mL), and the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with brine (2×25 mL), and dried with Na2SO4. The residue was purified by silica gel column (eluent with hexane/EtOAc; 85/15) to give the title compound 32.1. MS ESI (pos.) m/e: 299.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH2:26])=[CH:23][C:24]=3[CH2:25][C@H:14]12)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][C:24]=3[CH2:25][C@H:14]12)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(N)cc3C[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(NS(C)(=O)=O)cc3C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylsulfonyl chloride (42 μL) is added to a solution of cis-7-amino-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridine-1-carboxylic acid tert-butyl ester (160 mg) and triethylamine (76 μL) in dichloromethane (3 mL) at room temperature. The solution is stirred for 1 h at room temperature and then aqueous NaHCO3 solution is added. The mixture is stirred vigorously for 20 min and then extracted with dichloromethane. The combined extract is concentrated and the residue is chromatographed (cyclohexane/ethyl acetate 7:3→1:9) to give the title compound. Yield: 120 mg (59% of theory); LC (method 1): tR=3.80 min; Mass spectrum (ESI−): m/z=365 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[CH2:14]=O.[ClH:16]>>[ClH:16].[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[CH2:14][NH:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]2
Reactant: N[C@@H](Cc1cccc(O)c1)C(=O)O
Reactant: C=O
Agent: Cl
Product: O=C(O)C1Cc2cc(O)ccc2CN1

Procedure:
To a mixture of 100.0 g of 3-hydroxyphenylalanine in 820 ml of 5% hydrochloric acid were added 78 ml of formaldehyde (37% in water). The reaction mixture was heated at 90°-95° C. (external bath temperature) for 45 minutes. The mixture was cooled and concentrated in vacuo. Five hundred milliliters of ethanol were added and the mixture was again concentrated in vacuo, affording 115 g of the title intermediate as a pale white solid, used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([OH:17])=O.FC(F)(F)C(O)=O.[CH2:29]([O:36][C:37](=[O:49])[N:38]=[C:39]([NH2:48])[N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][NH2:47])[CH2:42][CH2:41]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:29]([O:36][C:37](=[O:49])[N:38]=[C:39]([NH2:48])[N:40]1[CH2:41][CH2:42][CH:43]([CH2:46][NH:47][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:12]([O:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH2:44][CH2:45]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCC1CCN(C(N)=NC(=O)OCc2ccccc2)CC1
Reactant: Cc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NCC2CCN(C(N)=NC(=O)OCc3ccccc3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
97 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid and 124.3 mg of [Amino-(4-aminomethyl-piperidin-1-yl)-methylene]-carbamic acid benzyl ester trifluoroacetic acid salt were dissolved in 5 ml of DMF. After cooling to 0° C. 136 mg of HATU and 106 mg of NEM were added. The mixture was stirred at 0° C. for 2 hours and at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column) (gradient acetonitrile water (containing 0.1% trifluoro-acetic acid) 90:10 to 0:100). The fractions containing the product were evaporated and lyophilized.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Br)[CH:6]=[C:7]([F:14])[C:8]=2[O:12][CH3:13])[N:3]=1>C(O)C.[Pd]>[F:14][C:7]1[C:8]([O:12][CH3:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: COc1c(F)cc(Br)c2nc(C)ccc12
Agent: [Pd]
Solvent: CCO
Product: COc1c(F)ccc2nc(C)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of 2-methyl-5-methoxy-6-fluoro-8-bromoquinoline (2.95 g, 10.9 mmol) in ethanol (100 ml) was charged with 10% palladium on charcoal (250 g) and stirred at room temperature and pressure under an atmosphere of hydrogen for 2 h. The mixture was then filtered through a pad of kieselguhr and the filtrate evaporated in vacuo to give the title compound as a brown solid (2.09 g, 100%).
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1>>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][NH:15][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Product: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure A was used to convert benzophenone hydrazone (6.31 g, 32.3 mmol; Aldrich) and 1-bromo-4-methylbenzene 5.0 g, 29.2 mmol; Aldrich) into the title compound: MS (DCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH2:9][CH2:8][CH2:7]2)([O-])=O>C(O)C.O1CCCC1.[Pd]>[O:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][N:10]2[C:11]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:13][CH:12]=3)[CH2:7][CH2:8][CH2:9]2)[CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCN2CCCN1CCOCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc2c(c1)CCCN2CCCN1CCOCC1
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a stirred solution of 4-(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)morpholine (250 mg, 0.819 mmol) in Ethanol (4 ml) and Tetrahydrofuran (4.00 ml) was added Palladium on activated carbon, 10 wt. % (87 mg, 0.082 mmol). The reaction was then stirred under a hydrogen atmosphere (balloon pressure) for 2 h. When TLC analysis showed that the starting material was consumed, the mixture was filtered through a pad of celite which was then washed with methanol. The filtrate was concentrated, giving the desired 1-(3-morpholinopropyl)-1,2,3,4-tetrahydroquinolin-6-amine (190 mg, 0.690 mmol, 84% yield) as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]([O:8][CH3:9])[C:5](O)=[O:6].[F:11][C:12]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:13][NH2:14]>>[CH3:1][O:2][C:3](=[O:10])[CH:4]([O:8][CH3:9])[C:5]([NH:14][CH2:13][C:12]([F:19])([F:11])[C:15]([F:18])([F:17])[F:16])=[O:6]
Reactant: COC(=O)C(OC)C(=O)O
Reactant: NCC(F)(F)C(F)(F)F
Product: COC(=O)C(OC)C(=O)NCC(F)(F)C(F)(F)F

Procedure:
2-Methoxy-malonic acid monomethyl ester was coupled with 2,2,3,3,3-pentafluoro-propylamine in analogy to the description in Example 73 to yield 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid methyl ester as colourless oil,
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH:2]([CH3:4])[CH3:3].[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53]([C:58]([OH:60])=O)[CH2:54][C:55]([OH:57])=[O:56])(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[CH3:42][C:43]1[CH:44]=[CH:45][C:46]([S:49]([NH:52][C@H:53]([C:58]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:1][CH:2]([CH3:4])[CH3:3])[C:29]([OH:31])=[O:30])=[O:60])[CH2:54][C:55]([OH:57])=[O:56])(=[O:50])=[O:51])=[CH:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CC(=O)O)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC(=O)O)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(4-methylbenzenesulfonyl)-L-aspartic acid (340 mg, 1.2 mmol) prepared in step A of this example. The final product was purified by preparative HPLC to yield 20 mg (26%) of the desired material.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:35][C:36]1[C:44]2[C:43]([N:45]3[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]3)=[N:42][CH:41]=[N:40][C:39]=2[NH:38][CH:37]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([NH:51][CH:48]2[CH2:47][CH2:46][N:45]([C:43]3[C:44]4[C:36]([CH3:35])=[CH:37][NH:38][C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:50][CH2:49]2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCN(c3ncnc4[nH]cc(C)c34)CC2)ccn1
Reaction time: 0.17 h

Procedure:
To a mixture of 2-methyl-4-pyridinecarboxylic acid (41 mg, 0.299 mmol), EDC (86 mg, 0.448 mmol), HOBt (68.6 mg, 0.448 mmol) and DIPEA (0.130 mL, 0.747 mmol) in DCM (1 mL), prestirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (80 mg) and the mixture stirred at room temperature for 18 hours. The solvent was removed in vacuo and the mixture purified by MDAP to give the title compound E25 (37 mg), 1H NMR (d6-DMSO) δ 11.52 (1H, s), 8.59 (1H, d), 8.57 (1H, d), 8.22 (1H, s), 7.65 (1H, d), 7.56 (1H, d), 7.07 (1H, s), 4.11-3.99 (3H, m), 3.06 (2H, t), 2.53 (3H, s), 2.37 (3H, s), 1.94 (2H, d), 1.73 (2H, ddd), MS(ES+) 351 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][OH:27])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC[C@H]1CO

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-1-pyrrolidin-2-yl-methanol (CAN 23356-96-9) as starting materials, MS (EI): m/e=368.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])=[CH2:10].C(O)(=O)C>C(O)C>[O:12]=[S:11]1(=[O:13])[CH2:14][CH2:15][N:1]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:10][CH2:9]1
Reactant: C=CS(=O)(=O)C=C
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Temperature: 0 °C

Procedure:
The preparation of stabilizer compounds of formula S of the invention is illustrated by the following synthesis of Stabilizer S-3. ##STR16## A mixture of para-aminophenol (25 g, 229 mmol) and divinylsulfone (32.5 g, 275 mmol) was heated at reflux in ethanol (100 ml) for two days. The reaction mixture was cooled and poured into ice water (1 l). The mixture was made acidic with the addition of acetic acid and the resulting tan solid was isolated by filtration and washed with water. Recrystallization from methanol afforded the desired 4-(1',1'-dioxothiomorpholino)phenol as a light tan crystalline solid (35 g, 67%). Mp. 149-151° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[C:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1>O>[N+:1]([C:7]1[CH:6]=[CH:5][C:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C:9]=2[CH:8]=1)([O-:4])=[O:2]
Reactant: O=C1CCc2ccccc2CC1
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: -35 °C

Procedure:
A flask containing 90% nitric acid was cooled to at −35° C. using an acetonitrile-dry ice bath. 5,6,8,9-Tetrahydro-benzocyclohepten-7-one (0.5 g, 0.003 mol) was added in portions over 30 minutes. The mixture was warmed slightly to at −20° C. for 1.5 h until all of the material was dissolved. The mixture was poured over ice and water and the resulting precipitate was collected by filtration and washed with water. The solid was dried at under vacuum overnight to give a tan solid (0.58, 78%), 2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.09 (d, 1H, J=8.4 Hz), 7.40 (d, 1H, J=8.4 Hz), 3.03 (m, 4H), 2.65 (m, 4H),