Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:14]>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:19]2[CH:18]=[CH:17][S:16][C:15]=2[C:13]([O:12][CH3:11])=[O:14])(=[O:21])=[O:22])=[O:25])[N:7]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Temperature: 25 °C

Procedure:
To 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 30 ml of anhydrous acetonitrile was added at ambient temperature, with stirring 3.6 g of 2-methoxycarbonyl-3-thiophenesulfonylisocyanate. The mixture was heated to the boiling point and then allowed to cool to ambient temperature. After stirring for sixteen hours the precipitate present in the mixture was filtered off and washed with anhydrous ethyl ether. The product thus obtained which melted at 165°-173° showed absorption peaks by infrared spectroscopy at 1720 and 1700 cm-1, consistent for the carbonyl groups in the desired product.
Reaction SMILES: [F:1][CH:2]([F:22])[C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH2:15][C:14](=[O:21])[CH2:13][C:12]=1[CH2:11][CH2:10]3.C1C=C[NH+]=CC=1.Br[Br-]Br.O>N1C=CC=CC=1>[F:1][CH:2]([F:22])[C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:4]12[CH3:5])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3
Reactant: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2C(F)F)CC(=O)CC4
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@@H]2C(F)F

Procedure:
The 17β-difluoromethylestr-5(10)-en-3-one is dissolved in pyridine under nitrogen with stirring. Pyridinium bromide perbromide is added over a 5-minute period. The reaction is stirred at 20°-25° under nitrogen for about 2.5 hr. Water is then added and the product extracted with diethyl ether. The diethyl ether extract is washed with water, dilute hydrochloric acid, water, dilute bicarbonate, water, and chromatographed over a silica gel column. The column is eluted with a gradient between 10% ethyl acetate-SSB and 60% ethyl acetate-SSB. The appropriate fractions are pooled and concentrated. The concentrate is rechromatographed and recrystallized from acetone to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[NH:14][N:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[CH2:42][CH2:43][NH2:44].C(N(CC)CC)C>CN(C)C=O.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[NH:14][N:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([NH:44][CH2:43][CH2:42][C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[Cl:39])=[O:6]
Reactant: NCCc1ccccc1Cl
Reactant: O=C(O)c1cc(-n2cn[nH]c2=O)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1Cl)c1cc(-n2cn[nH]c2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a solution of 2-chloro-5-(5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid (0.028 g, 0.117 mmol) in anhydrous dimethyl formamide (DMF) (4 mL) was added 1-hydroxybenzotriazole (0.018 g, 0.14 mmol). After stirring at room temperature for 10 minutes, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.025 g, 0.13 mmol) was added. After stirring at room temperature for 30 minutes, 2-chlorophenethylamine (0.018 g, 0.12 mmol) and triethylamine (0.012 g, 0.12 mmol) were added and the mixture stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed sequentially with water and brine, and dried over sodium sulfate. Removal of solvent in vacuo followed by purification by reverse phase HPLC yielded 0.042 g (10%) of the title compound as a colorless solid. 1H NMR (300 MHz, CDCl3) δ (m, 2H), 3.45 (m, 2H), 7.25 (m, 2H), 7.35 (m, 2H), 7.60 (d, J=7.9 Hz, 1H), 7.76 (s, 1H), 7.78 (s, 1H), 8.43 (s, 1H) and 8.64 (m, 1H). Mass Spectrum (M−H) 3:1 Ratio of 375 and 377.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[CH:7]=1.[C-:26]#[N:27].[K+].[Cl-].[NH4+:30].[OH-].[NH4+]>CO.O>[NH2:30][C:16]1([C:26]#[N:27])[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8]2([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:24][CH3:25])[O:20][CH2:21][CH2:22][O:23]2)[CH2:14][CH2:15]1
Reactant: COc1ccc(Cl)cc1C1(CCCCN2CCC(=O)CC2)OCCO1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(Cl)cc1C1(CCCCN2CCC(N)(C#N)CC2)OCCO1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A mixture of 1-[5-(5-chloro-2-methoxyphenyl)-5,5-ethylenedioxypentyl]-4-piperidone (6.62 g, 18 mmol), potassium cyanide (1.4 g, 35.8 mmol), ammonium chloride (2.46 g, 37 mmol), ammonium hydroxide (14M, 4 mL, 56 mmol), water (25 mL) and methanol (120 mL) was heated 2 hours with stirring at approximately 25° C. and then 5 hours at 60° C. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water (3×) and brine (1×), dried (MgSO4) and concentrated to give 4-amino-1-[5-(5-chloro-2-methoxyphenyl)-5,5-ethylenedioxypentyl]piperidine-4-carbonitrile (5.2 g, 13.1 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.O>CS(C)=O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 24.5 g morpholine and 13.3 g 1-Fluoro-4-nitro-benzene in 30 mL DMSO was heated to 100° C. for 4 h. This solution was poured on to 300 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 19.7 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](=[O:48])([O:44][CH:45]([CH3:47])[CH3:46])[O:40][CH:41](Cl)[CH3:42].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:45]([O:44][C:39]([O:40][CH2:41][CH2:42][O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])=[O:48])([CH3:47])[CH3:46].[CH:45]([O:44][C:39]([O:40][CH:41]([O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])[CH3:42])=[O:48])([CH3:47])[CH3:46]
Reactant: CC(C)OC(=O)OC(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)OC(C)OC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Product: CC(C)OC(=O)OCCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 170.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.275 g, 0.5 mmol) and 4 mL of N,N-dimethylformamide were added into the reaction tube. After stirring until 2a was dissolved, 1-chloroethyl isopropyl carbonate (0.1 g, 0.6 mmol), potassium iodide (0.0415 g, 0.25 mmol) and potassium carbonate (0.083 g, 0.6 mmol) were then added to the solution successively. Upon completion of the addition, the reaction tube was sealed up. The reaction mixture was reacted at 65° C. for 2 hours in an oil bath and monitored by thin layer chromatography until the disappearance of the starting materials, and then the oil bath was removed. After cooling to room temperature, 40 mL of water was added to the reaction tube. The reaction mixture was extracted with ethyl acetate (25 mL×3). Thin layer chromatography showed there was no product in the aqueous phase, and the organic phase was collected, then washed with water (20 mL×2), then the combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 1-isopropoxycarbonyloxy-ethyl ester 37a (0.29 g, yield 85.3%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[O:10][CH3:11].[C-:12]#[N:13].[Na+].[C:15]1([C:21]#[C:22][CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH2:6][C:12]#[N:13])[CH:8]=[CH:9][C:2]=1[O:1][CH2:23][C:22]#[C:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OCC#Cc2ccccc2)cc1
Reactant: COc1cc(CO)ccc1O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC#N)ccc1OCC#Cc1ccccc1
Reaction time: 3 h

Procedure:
A mixture of 4-hydroxy-3-methoxy-benzyl alcohol (17.4 g) and sodium cyanide (6.6 g) in dimethylformamide (250 ml) is stirred under an atmosphere of nitrogen for 3 hours at +120° C. The mixture is then cooled to +60° C. and toluene-4-sulfonic acid 3-phenyl-prop-2-ynyl ester (39 g) in dimethylformamid (50 ml)is added during 5 minutes. It is stirred at +65° C. for another 4 hours. Upon cooling water (800 ml) is added. The mixture is extracted with ethyl acetate (2×500 ml). The organic phases are washed with brine (2×500 ml), dried (MgSO4) and evaporated. The residue is purified by flash column chromatography on silica gel (ethyl acetate/hexane 1:3) and recrystallised from ethyl acetate/hexane. [3-Methoxy-4-(3-phenyl-prop-2-ynyloxy)-phenyl]-acetonitrile is obtained, m.p. 74-75° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:13]([NH:15][CH2:16][C:17]([NH:19][C@H:20]([C:22]([OH:24])=O)[CH3:21])=[O:18])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Cl.[Cl:26][CH2:27]C(CCl)=O.[NH2:32][C@H:33]([C:38]([OH:40])=O)[CH2:34][CH:35]([CH3:37])[CH3:36].ClC(OCC(C)C)=O>>[NH:4]([C:1]([CH3:2])=[O:3])[C@H:5]([C:13]([NH:15][CH2:16][C:17]([NH:19][C@H:20]([C:22]([NH:32][C@H:33]([C:38]([CH2:27][Cl:26])=[O:40])[CH2:34][CH:35]([CH3:36])[CH3:37])=[O:24])[CH3:21])=[O:18])=[O:14])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(CCl)CCl
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)CCl

Procedure:
Ac-Phe-Gly-Ala-LeuCH2Cl was prepared by condensation of N-acetyl-L-phenylalanylglycyl-L-alanine with leucine chloromethyl ketone hydrochloride using a mixed anhydride procedure employing isobutyl chloroformate. Powers et al., Biochem. Biophys. Acta. 480:246-261 (1977), describe an analogous procedure. Crude product was recrystallized from ethyl acetate to provide a white crystalline solid, m.p. 152.4°-153.8° (reported m.p. 167°-168°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:11][N:12]1[CH:16]=[C:15]([C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[N:13]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:26]1[CH2:27][CH2:28][N:23]([C:20]3[N:21]=[N:22][C:17]([C:15]4[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=4)=[CH:18][CH:19]=3)[CH2:24][CH2:25]1)[CH2:6][CH2:5]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5cc(F)ccc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 5, STEP 4, reacting 5-fluoroindoline and 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]([OH:16])=O)[N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:50]1[CH:54]=[CH:53][N:52]=[C:51]1[NH:55][C:56]([C:58]1[C:66]2[NH:65][C:64]([NH2:67])=[N:63][C:62]=2[CH:61]=[CH:60][CH:59]=1)=[O:57]>CN(C=O)C>[NH:52]1[CH:53]=[CH:54][N:50]=[C:51]1[NH:55][C:56]([C:58]1[C:66]2[NH:65][C:64]([NH:67][C:14]([C:9]3[N:10]=[CH:11][C:12]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=4)=[O:16])=[N:63][C:62]=2[CH:61]=[CH:60][CH:59]=1)=[O:57]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: O=C(O)c1cc2ccc([N+](=O)[O-])cc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1)c1cc2ccc([N+](=O)[O-])cc2cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a solution of 44 mg (0.2 mmol) of 7-nitro-isoquinoline-3-carboxylic acid in DMF (1 mL) was added 113 mg (0.3 mmol) of HBTU and DIEA (0.3 mL). The mixture was stirred for 10 min and then 40 mg (0.16 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B) was added. The reaction was heated at 80° C. for 1 h. After the usual work up, the residue was purified by column chromatography eluting with DCM/methanol (v/v=10:1) to afford 8 mg (9%) of 7-nitro-isoquinoline-3-carboxylic acid [7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 443 (M+1)+.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C(C1C=CC=CC=1)(=O)C.O.[CH:18]([Br:20])=[CH2:19].[C:21]([O:24][CH2:25]C)(=[O:23])C>>[Br:20][CH:18]1[CH2:2][CH:3]([C:4]([O:6][CH3:1])=[O:5])[CH:19]1[C:21]([O:24][CH3:25])=[O:23]
Reactant: CCOC(C)=O
Reactant: O=C1C=CC(=O)O1
Reactant: C=CBr
Solvent: O
Solvent: CC(=O)c1ccccc1
Product: COC(=O)C1CC(Br)C1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A solution of 5 g (51 mmol) of maleic anhydride and 0.5 mL (4 mmol) of acetophenone in 50 mL of ethyl acetate was added to a 100 mL pyrex photochemical reaction vessel. The vessel was sealed and purged with nitrogen for 10 min then cooled with tap water while 13.8 g (129 mmol) of vinyl bromide was being added to the ethyl acetate solution. The vessel was then irradiated for 20 h with a 450 Watt medium pressure mercury vapor lamp. The solution was concentrated in vacuo and the residue dissolved in 200 mL of methanol which had been treated with 1 mL of trimethylsilyl chloride. The solution was stirred at ambient temperature overnight and then concentrated to a brown viscous oil. The oil was chromatographed on silica gel (200 g) eluted with 20% ethyl acetate in hexane to give a yellow oil. The oil was purified by short-path distillation using a 1" fractionating column to give 2.5 g (19.5% yield) of the title compound; b.p. 75°-80° C. (0.1 mm Hg); EI-MS, m/e (rel intensity): 220 (M+ -CH3O, 60), 218 (60), 192 (42), 190 (39), 171 (100); 1H NMR (CDCl3) δ 2.60 (m, 1H), 2.82 (m, 1H), 3.56 (td, 1H), 3.72 (m, 6H), 3.94 (t, 0.4H), 4.12 (q, 0.6H), 4.93 (q, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:38](C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:28]1([S:25]([NH:24][C@@H:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([NH:1][CH3:38])[CH:3]=2)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)ccc1O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CNc1cc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)ccc1O
Reaction time: 8 h

Procedure:
(2S)-3-(3-Amino-4-hydroxy-phenyl)-2-benzenesulfonylamino-N-(4-phenyl-butyl)-propionamide (502 mg, 1.07 mmol) is dissolved in dichloroethane (5 mL). 37% formaldehyde (120 mg, 1.47 mmol) and NaBH(OAc)3 (1.1 g, 5 mmol) are added. The mixture is stirred overnight. Saturated NaHCO3 (20 mL) is added and the crude mixture is extracted with ETOAC three times. The organic phase is dried and concentrated in vacuo. The small volume of solution is filtered through silica gel plug to provide a crude solution of (2S)-2-benzenesulfonylamino-3-(4-hydroxy-3-methylamino-phenyl)-N-(4-phenyl-butyl)-propionamide which is used without further purification.
Reaction SMILES: [N+](C1C=C(S(O[CH2:14][C@H:15]2[CH2:17][O:16]2)(=O)=O)C=CC=1)([O-])=O.C(N(CC)CC)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][C:38]=1[Cl:39])[O:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C=O)C>[N:40]([CH2:17][C@@H:15]([OH:16])[CH2:14][N:33]1[CH2:34][CH2:35][CH:30]([O:29][C:28]2[CH:36]=[CH:37][C:38]([Cl:39])=[C:26]([Cl:25])[CH:27]=2)[CH2:31][CH2:32]1)=[N+:41]=[N-:42]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
(2R)-Oxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.1 g, 81.3 mmol) in DMF (300 ml) was treated with triethylamine (22.6 ml, 163.0 mmol) followed by 4-(3,4-dichlorophenoxy)-piperidine (20 g, 81.3 mmol). The mixture was stirred overnight at 60° C. Sodium azide (16 g, 243.9 mmol) was added to the mixture and the reaction was stirred for a further 72 h. The solution was carefully concentrated under vacuum and the residue was diluted with water (600 ml), extracted with ethyl acetate (1500 ml). The organic layer was washed twice with water (500 ml), then brine (200 ml) and concentrated under vacuum to afford an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([C:24](O)=[O:25])[CH:18]=1>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:24]([C:19]1[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[N:20]=1)=[O:25]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(Cl)cc(Cl)n1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4,6-dichloro-pyridine-2-carboxylic acid (CAS RN 88912-25-8) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Colorless solid (7%). MS (ESI): m/z=372.07 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[NH:11][CH:10]=1.[CH2:21](OCC)C>CO>[ClH:3].[NH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[NH:11][CH:10]=1
Reactant: CCOCC
Reactant: O=S(Cl)Cl
Reactant: NCCc1c[nH]c2ccc(C(=O)O)cc12
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2[nH]cc(CCN)c2c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (25 ml) was added to Analar methanol (84 ml) at 0° C. over a period of 1 hour under nitrogen. 3-(2-Aminoethyl)-1H-indole-5-carboxylic acid hydrochloride (2.5 g) in Analar methanol (35 ml) was added at 0° C. and the mixture was heated at reflux under nitrogen for 2.5 hour, cooled to ca. 45° C. and dry diethyl ether (200 ml) was added. The mixture was cooled and left overnight at 0° C. giving the title compound (1.9 g) as white microcrystals m.p. 265.5°-267° C. T.L.C. Silica, ethyl acetate:2-propanol:water:ammonia (25:15:8:2) Rf 0.46.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][NH2:34])[CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH2:34])[CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: NCc1ccccc1C1CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: NCc1ccccc1C1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 48 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.00 g, 4.0 mmol) and 2-(3-pyrrolidinyl)-benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (0.65 g, 48%) as a bright yellow solid, mp 164°-165° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].CN=[C:9]1[S:12][CH2:11][S:10]1.C(N=C1SCS1)(C)C.C(N=C1SCS1)(C)(C)C.C(N=C1SCS1)CCCCCCC>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]=[C:9]1[S:12][CH2:11][S:10]1)[CH3:2]
Reactant: CCOCCN
Reactant: CN=C1SCS1
Agent: CC(C)(C)N=C1SCS1
Agent: CC(C)N=C1SCS1
Agent: CCCCCCCCN=C1SCS1
Product: CCOCCN=C1SCS1

Procedure:
Following this procedure, but substituting the appropriate amine for 2-ethoxyethylamine, yields the compounds listed as follows:Example No. Compound m.p. °C.__________________________________________________________________________67 2-(Methylimino)-1,3-dithietane --68 2-(Isopropylimino)-1,3-dithietane --69 2-(tert-Butylimino)-1,3-dithietane oil70 2-(Heptylimino)-1,3-dithietane oil71 2-(Dodecylimino)-1,3-dithietane 40.5-4272 2-(Cyclohexylimino)-1,3-dithietane 78-8073 2-(Methylallylimino)-1,3-dithietane oil74 2-(Isobutylimino)-1,3-dithietane oil75 2-(1,4-Dimethylpentylimino)-1,3- oil dithietane76 2-(n-Octylimino)-1,3-dithietane oil77 2-(n-Hexylimino)-1,3-dithietane oil__________________________________________________________________________
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(t-butoxycarbonyl) azetidine-3-carboxylic acid (1-1)(AXL016917, 1000 mg, 4.97 mmol) was dissolved in MeOH (5 mL)/Toluene (20 mL) and then cooled to 0° C. TMSCHNN (trimethylsilyldiazomethane) (7.45 mmol) was then added drop-wise over 15 minutes with some bubbling observed. The color started clear and slowly turned yellow. The solution was stirred for 10 minutes at 0° C. and then warmed to room temperature over 30 minutes. The solution was then concentrated and pumped on to remove toluene to afford 1.055 g of 1-t-butyl 3-methyl azetidine-1,3-dicarboxylate (1-2) that was used directly in the next step without being purified (99% crude yield).