Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]1C=CC=CC=1)=[O:21])[CH2:13][C:14]1[CH:19]=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:37]1C=CC(OC(=O)[C@H](CC2C=CC=CC=2)NC(OCC2C=CC=CC=2)=O)=CC=1)([O-])=O.N[C@H](C(O)=O)CC1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:14][CH2:13][C@H:12]1[C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH:24]([CH3:25])[CH3:37])=[O:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O

Procedure:
N-benzyloxycarbonyl-L-phenylalanyl-L-phenyl-alanine (m.p. 148°-151° C.) from N-benzyloxycarbonyl-L-phenylalanine 4-nitrophenyl ester and L-phenylalanine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:3]=1.S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)Cl>[Cl:15][CH:9]([CH3:10])[C:8]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC(=O)c1cc(C)ccn1
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(C(=O)C(C)Cl)c1

Procedure:
To a stirred solution of 1-(4-methylpyridin-2-yl)propan-1-one (0.9 g) in chloroform (5 ml) was added a solution of sulfuryl chloride (0.533 ml) in chloroform (5 ml) dropwise. The resultant mixture was refluxed for 2 hours and evaporated under reduced pressure. The pH was adjusted to 8.5 with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:dichloromethane=1:1) to give 2-chloro-1-(4-methylpyridin-2-yl)propan-1-one (0.71 g).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[OH:10])=[CH:4][CH:3]=1.CC(N(C)C)=O.[CH2:24]([S:32](Cl)(=[O:34])=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>N1C=CC=CC=1>[CH2:24]([S:32]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[OH:10])=[CH:4][CH:3]=1)(=[O:34])=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: Nc1ccc(CCc2cc(O)ccc2O)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCCCCCCCS(=O)(=O)Nc1ccc(CCc2cc(O)ccc2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 1 l-volume three-necked flask were charged 100 g of (4-aminophenethyl)hydroquinone, 500 ml of dimethylacetamide, and 36 ml of pyridine, and 85 ml of octanesulfonyl chloride were slowly added dropwise thereto at room temperature while stirring. After the dropwise addition, the stirring was continued for 4 hours. The reaction mixture was poured into a hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated to obtain 129 g of the entitled compound as an oily substance.
Reaction SMILES: [C:1]([NH:11][C:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([NH:11][C:12]1([CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:13][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1(CO)CC1)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-CBZ-amino-1-(hydroxymethyl)cyclopropane (similarly prepared according to JMC 31, 2004, 1998) (250 mg) was dissolved into DCM (25 ml) with DIPEA (250 l) and stirred at 0° C. for 15 minutes. To the reaction was added MsCl (1.1 eq) and stirred for 30 minutes. The reaction was washed with NaHCO3 solution, water, brine and dried with Na2SO4. The solution was evaporated to give N-CBZ-amino-1-(methylsulfonyloxymethyl)cyclopropane as an off white solid. This solid was mixed with above 6-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide and Cs2CO3 (250 mg) in DMA (4 ml). The reaction was heated at 100° C. for 10 hours and mixed with EtOAc and water, then filtered, further extracted with EtOAc. The combined organic layer was evaporated and purified with silica gel column to give the titled product. Mass: (M+1), 578
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[F:20][C:18]1[C:17]([F:21])=[CH:16][N:15]([C:8]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:6]([OH:5])[CH:7]=2)[CH:19]=1
Reactant: CC(C)(C)Oc1cc(-n2cc(F)c(F)c2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1O
Yield: 95.6 %

Procedure:
A mixture of 1-(3-tert-butoxy-4-nitrophenyl)-3,4-difluoro-1H-pyrrole (8.30 g), TFA (30 mL) and THF (60 mL) was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane/ethyl acetate (10/1) to give the title compound (6.43 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[S:8].[H-].[Na+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[S:8])=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=S)c1ccccc1CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=S)c1ccccc1CCCOCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To an ice bath cooled solution of methyl 2-(3-hydroxyprop-1-yl)thiobenzoate (3.7 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in oil, 719 mg) and the solution was stirred at the same temperature for 30 minutes. 4-Methoxybenzyl chloride (2.56 g) was added to the solution and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with ethyl acetate (100 ml) and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a crude oil. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate=10:1) to give methyl 2-[3-(4-methoxyphenyl)methoxyprop-1-yl]thiobenzoate (2.13 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].[N+](C1C=CC(OC2C=CC=CC=2)=CN=1)([O-])=O>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Product: COc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Yield: 99.8 %

Procedure:
Compound 430A (7.34 g, 100%) was prepared from 1-fluoro-4-nitro-benzene (4.23 g, 30.0 mmol) and 2-methoxy-phenol (3.72 g, 30.0 mmol) by a route analogous to that used for the preparation of compound 429B. It is a bright yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:17]=[C:16]2[CH2:27][CH2:28][CH2:29][C:15]=12>CO.ClCCl>[Cl:26][C:22]1[CH:21]=[C:20]([C:18]2[N:17]=[C:16]3[CH2:27][CH2:28][CH2:29][C:15]3=[C:14]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=3)[CH:19]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 86.4 %

Procedure:
An 18-mL vial was charged with methyl 4-aminobenzoate (20 mg, 0.13 mmol, 2 eq.) and 4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (20 mg, 0.066 mmol, 1 eq. See step 1 of EXAMPLE 1). The mixture was dissolved in a mixture of MeOH (1 ml) and dichloromethane (2 ml). After the volatile material was removed under reduced pressure, the residue was heated at 150° C. under argon for 1 hr. After cooling to room temperature, the reaction mixture was partitioned between NaHCO3 aq. (10 ml) and ethyl acetate (10 ml). The organics was separated and dried over MgSO4. The solvent was removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using dichloromethane followed by ethyl acetate as eluent to give the desired product methyl 4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoate (21.6 mg, 86% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38](OS(C(F)(F)F)(=O)=O)[N:37]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:38]4[N:37]=[C:36]([CH3:35])[C:45]5[C:40]([CH:39]=4)=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)cc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)cc2ccccc12
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (97.5 mg, 0.208 mmol), trifluoromethanesulfonic acid 1-methylisoquinolin-3-yl ester (62.3 mg, 0.214 mmol), and Pd(PPh3)4 (15 mg, 0.013 mmol) in 1,4-dioxane (3.2 mL, 41 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (135 mg, 0.413 mmol) in H2O (0.95 mL, 53 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water and brine, and dried over MgSO4. The EtOAc extract was diluted with DCM (to give DCM:EtOAc≈1:1) and filtered through a plug of silica gel. The silica gel was then washed with DCM:EtOAc 1:2, DCM:EtOAc 1:5, and EtOAc until no more product eluted. Filtrate/washings that contained product were concentrated in vacuo. The crude material was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→DCM:EtOAc 2:1→DCM:EtOAc 1:1→DCM:EtOAc 1:2→EtOAc]. Mixed fractions were combined, concentrated in vacuo, and purified by prep. TLC [20×20 cm plates, 500 μm, eluting with 2% MeOH/DCM (1×) and 4% MeOH/DCM (3×)]. Clean material from prep. TLC was combined with pure fractions from the column chromatography and dried in vacuo, yielding the title compound as viscous, yellow oil. 1H NMR (400 MHz, CDCl3): δ=8.26 (d, J=2.0 Hz, 1H), 8.15 (dd, J=0.8, 8.4 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J=0.4 Hz, 1H), 7.72 (ddd, J=1.2, 7.2, 8.2 Hz, 1H), 7.66 (d, J=0.4 Hz, 1H), 7.62 (ddd, J=1.2, 6.8, 8.2 Hz, 1H), 6.49 (brs, 2H), 4.38-4.20 (m, 3H), 3.03 (s, 3H), 2.92 (brt, J=12.0 Hz, 2H), 2.19 (brd, J=12.0 Hz, 2H), 1.98 (dq, J=4.4, 12.2 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=485.18 (100) [MH+], 429.06 (39) [MH+-isobutene]. HPLC: tR=2.76 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[Cl:16][C:17]1[C:18]([OH:28])=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[C:21]([Cl:23])[CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][S:24]([C:19]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:17]([Cl:16])[C:18]=2[OH:28])(=[O:25])=[O:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To a solution of 2-amino-indan-2-carboxylic acid ethyl ester (3.14 g, 15.3 mmol) and 3,5-dichloro-2-hydroxy-benzenesulfonyl chloride (1 g, 3.82 mmol) in anhydrous DCM (dichloromethane, 20 mL) is added DIPEA (631 μL, 3.82 mmol). The resulting solution is stirred at RT for 1 hour. The reaction solution is diluted in DCM (50 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (30) as white solid (450 mg, 27%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1.[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([O-:32])=[O:31].C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=2)[CH:7]=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)Cc1cncn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 55 °C

Procedure:
To a solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (23, 274 mg, 0.736 mmol) in acetonitrile (10 ml) was added 4-nitrobenzylbromide (159 mg, 0.736 mmol) and heated to 55° C. for 16 h. After this time, the reaction was cooled to room temperature, treated with ethyl acetate (20 ml) and the resulting precipitate was filtered. The filtrate was concentrated to dryness in vacuo and the residue was redissolved in acetonitrile (4 ml) and heated to 65° C. for 3 h. After this time, the reaction mixture was evaporated to dryness and combined with initial precipitate. This residue was dissolved in methanol (5 ml) and heated to reflux for 30 min. The resulting solution was evaporated in vacuo and the residue was purified by flash chromatography (2-5% methanol/methylene chloride gradient elution) to provide 16.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21].Cl>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CCN(CC)CC1CCCCN1CCN
Agent: Cl
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2csc(C)c21
Yield: 55 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and (+)-2-[2-[(diethylamino)methyl]-piperidin-l-yl]ethanamine in a yield of 55% of theory. Colourless crystals, m.p. 131°-132° C. (acetonitrile); [α]D20 =-13.66° (dilute aqueous hydrochloric acid).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:29]([C:25]5[S:24][CH:28]=[CH:27][CH:26]=5)=[O:30])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccs1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Reaction time: 8 h

Procedure:
To a mixture of 0.40 g (1.55 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline and 2 ml of dimethylformamide at 0° C. is added 0.23 g (1.55 mmol) of 2-thiophencarbonylchloride. The reaction mixture solution is allowed to stir overnight while slowly reaching room temperature. The reaction mixture is then diluted with water producing a tan precipitate which is collected by filtration, washed with water and dried to yield 0.282 (50%) of the title compound as a tan solid: m.p.>250° C.; IR (KBr) 3420, 1640, 1440 cm-1 ; NMR (DMSO-d6) δ14.1 (s, 1H), 9.6 (s, 1H), 8.6 (d, 1H), 8.3 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.2 (d, 1H), 5.0 (s, 2H), 4.0 (t, 2H), 3.1 (m, 2H); m/e 368 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][CH2:46][OH:47])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:41]3[CH2:42][CH2:43][N:38]([CH2:44][CH2:45][CH2:46][OH:47])[CH2:39][CH2:40]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCCN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCO)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-piperazin-1-yl-propan-1-ol (Acros) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C35H45N6O3Cl2 [(M+H)+] 667.2925, observed 667.2923.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC#N.O>[CH3:9][NH:8][C:6]1[N:7]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=[C:4]([NH:10][C@@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]2)[N:5]=1
Reactant: C1CCNCC1
Reactant: CNc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)O)CC2)n1
Solvent: O
Solvent: CC#N
Product: CNc1nc(N[C@H]2CC[C@@H](C(=O)O)CC2)nc(N2CCCCC2)n1
Temperature: 80 °C

Procedure:
To the crude solution of cis-4-(4-chloro-6-(methylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (˜0.38 mmol) in CH3CN/H2O (1/1, 5 ml) was added piperidine (188 μL, 5 equivalents). The reaction mixture was heated at 80° C. overnight. The reaction solution was condensed and the crude was acidified and purified by RP-HPLC (Luna 5μ C8(2), 100×21 mm, 15-60% CH3CN/H2O, 0.1% TFA, 17 min) to give the product (34.9 mg). MS (ES+): m/e 335.22 [M+H]+.
Reaction SMILES: [F:1][C:2]1(F)[C:7]([N:8]2[CH2:13][CH2:12][C:11]([F:16])([CH2:14][OH:15])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH2:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[F:16][C:11]1([CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(C2=CC=C(N3CCC(F)(CO)CC3)C(F)(F)C2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(COS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 75 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[3-fluoro-4-(4-fluoro-4-hydroxymethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.76 mmol) with methanesulfonyl chloride (0.91 mmol) in dichloromethane (10 ml) at 10° C. in presence of triethylamine (1.3 mmol) followed by purification by using silica gel column chromatography in 75% yield. M.P. 182-183° C. and MS (M+1)=462 (MH+, 100%) M.F.=C19H25F2N3O6S.
Reaction SMILES: [CH3:1]C1CCOC(=O)CCCCCCOCC1.[CH3:17][CH:18]1[CH2:33][CH2:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:17][C:18]1([CH3:1])[CH2:33][CH2:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CC1CCOCCCCCCCC(=O)OCC1
Reactant: CC1CCOCCCCCCC(=O)OCC1
Product: CC1(C)CCOCCCCCCCC(=O)OCC1

Procedure:
Odor: Relatively weak, powdery musk-like, woody-herby.--IR (film): ν=1734 cm-1 (νC=O), 1117/1154 cm-1 (νasO--C--C), 1252 cm-1 (νasC--C(=O)--O), 1366 cm31 1 (δCH3), 1046 cm-1 (νasC--O--C).--1H-NMR (CDCl3): δ=0.94 (s, 6H, 12-Me2), 1.31-1.42 (m, 6H, 4-H2 -6-H2), 1.50-1.57 (m, 4H, 3-,7-H2), 1.69 (t, J=7.2 Hz,2H, 11-H2), 1.71 (dd, J=10.0 and 6.8 Hz, 2H, 13-H2), 2.30 (t, J=6.6 Hz, 2-H2), 3.39 (t, J=5.2 Hz, 8-H2), 3.46 (t, J=6.2 Hz, 10-H2), 4.16 (t, J=7.0 Hz, 2H, 14-H2). --13C-NMR (CDCl3): δ=23.72, 24.91 (t, C-3,-6), 26.41/27.89 (t, C-4,-5), 28.59 (2q, 12-Me2), 29.05 (t, C-7), 31.77 (s, C-12), 34.59 (t, C-2), 38.86/40.57 (t, C-11,-13), 61.93 (t, C-14), 67.66/69.88 (t, C-8,-10), 174.15 (s, C-1).--MS (El): m/z (%)=55 (100) [C4H7⊕ ], 69 (72) [C5H9⊕!, 81 (40) [C6H9⊕ ], 97 (59) [C6H9O⊕]113 (27) [C7H13O⊕]125 (27) [C8H13O⊕ ], 141 (15) [M⊕ --C6H9O--H2O], 183 (2) [M⊕ --C4H7 --H2O]227 (1)[M⊕ --CHO], 256 (1) [M⊕].--C15H28O3 (256.39): calculated C 70.27, H 11.01; found C 70.15, H 10.87.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:32]([C:29]3[CH:28]=[CH:27][C:26]([Br:25])=[CH:31][N:30]=3)=[O:33])[CH:18]=2)([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cccc(N)c2)(C(F)F)COC1
Product: CC(C)(C)OC(=O)NC1=NC(c2cccc(NC(=O)c3ccc(Br)cn3)c2)(C(F)F)COC1

Procedure:
[5-(3-Amino-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester and 5-bromo-pyridine-2-carboxylic acid were coupled according the procedure described in example 51m). 1H-NMR (360 MHz, CDCl3): 9.92 (s, 1H, NH), 8.73 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 7.88 (m, 2H), 7.45 (m, 1H), 7.31 (m, 1H), 5.92 (t, 1H, CHF2), 4.84 (d, 1H), 4.65 (d, 1H), 4.31 (d, 1H), 3.96 (d, 1H), 1.52 (s, 9H); MS: 525 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:14])[C:10]=2OC)=[CH:6][CH:5]=[CH:4][C:3]=1[S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18].[CH3:23][C:24]1[O:28][C:27]([CH:29]([NH2:35])[C:30]2([CH3:34])[CH2:33][O:32][CH2:31]2)=[CH:26][CH:25]=1>CO>[OH:1][C:2]1[C:7]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:14])[C:10]=2[NH:35][CH:29]([C:27]2[O:28][C:24]([CH3:23])=[CH:25][CH:26]=2)[C:30]2([CH3:34])[CH2:31][O:32][CH2:33]2)=[CH:6][CH:5]=[CH:4][C:3]=1[S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18]
Reactant: COc1c(Nc2cccc(S(=O)(=O)N(C)C)c2O)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(S(=O)(=O)N(C)C)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 70.1 %

Procedure:
A mixture of 284 mg (0.87 mmol, 1 eq) of 2-hydroxy-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)-N,N-dimethylbenzenesulfonamide and 318 mg (1.75 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 20 ml of methanol was heated at 50° C. for 3 days. The reaction medium was concentrated. The residue was taken up in ethyl acetate and was washed twice with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 0.29 g of product was obtained in the form of an ochre solid. Yield=70%, HPLC=98.68%, Mp=123° C.