Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH2:22][CH3:23])=[N:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:24]([C@H:2]1[NH:1][C:27](=[O:29])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH2:22][CH3:23])=[N:20][O:21][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1noc2cccc(Oc3ccc(NC(=O)[C@H](N)CC)cn3)c12
Solvent: ClCCl
Product: CCc1noc2cccc(Oc3ccc(N4C(=O)N[C@H](CC)C4=O)cn3)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2R)-2-amino-N-{6-[(3-ethyl-1,2-benzisoxazol-4-yl)oxy]-3-pyridinyl}butanamide (Intermediate 35) was dissolved in dichloromethane (1.0 ml) and TEA (0.004 ml, 0.03 mmol) was added. The reaction mixture was cooled down to 0° C. and triphosgene (1.3 mg, 4.49 μmol) dissolved in 0.1 ml of dichloromethane was added. The reaction mixture was stirred at that temperature for 30 minutes. The mixture was quenched with 0.5 ml of water and water was removed by addition of sodium sulphate. The organic phase was pipetted off and evaporated and the crude obtained was charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/EtOAv (from 1/0 to 7/3, then 7/3, then from 7/3 to 1/1, the 1/1, then from 1/1 to 0/1) to afford the title compound (1.3 mg).
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:20]([Cl:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=3[Cl:25])[CH:11]=[CH:10][C:9]=2[OH:26])(=[O:7])=[O:6])[CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:22][C:18]1[CH:17]=[C:16]([Cl:25])[C:15]([O:14][C:12]2[CH:11]=[CH:10][C:9]([OH:26])=[C:8]([S:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)(=[O:7])=[O:6])[CH:13]=2)=[C:20]([Cl:21])[CH:19]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC3CC3)c2)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC3CC3)c2)c(Cl)c1
Reaction time: 12 h
Yield: 61.5 %

Procedure:
To a solution of 2-cyclopropylmethanesulfonyl-4-(2,6-dichloro-4-nitro-phenoxy)-phenol (76 mg, 0.18 mmol) in ethanol (2 mL) was added catalyst 10% Pd/C (27 mg). The mixture was hydrogenated under 45 psi at RT for 12 h. The mixture was filtered through Celite and concentrated to give the title compound of Step E (43 mg) as a solid. The title product of Step E was used in the next step without further purification. MS (APCI−) Calc.: 387.0, Found: 386.2 (M−1).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=1[NH2:16])(=O)C.[N:17]([O-])=O.[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[NH:4]1[C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[N:16]=[N:17]1
Reactant: COC(=O)Cc1ccc(NC(C)=O)c(N)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
Methyl 4-acetamido-3-aminophenylacetate (77 g, 0.373 mol) was taken up in a mixture of acetic acid (210 ml) and water (210 ml) and cooled to below 5° C. A solution of sodium nitrite (38.63 g, 0.559 mol) in water (200 ml) was added dropwise, and once the addition was complete the mixture was stirred for 4 hours, warming slowly to room temperature. The mixture was diluted with ethyl acetate and the insoluble material removed by filtration. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated in vacuo, to give a viscous residue (51 g) which was then dissolved in a solution of methanol (400 ml) previously saturated with hydrogen chloride and the mixture stirred for 2 hours. The solvent was removed in vacuo, the residue taken up in water, neutralised with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to afford methyl 5-benzotriazoleacetate (35 g) as a reddish liquid which crystallised on standing.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:46]2[N:47]=[C:48]([NH:51]C=O)[S:49][CH:50]=2)[C:7]([NH:9][C@@H:10]2[C:44](=[O:45])[N:12]3[C:13]([C:28]([O:30][CH:31]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])=[C:14]([CH2:17][S:18][C:19]4[N:24]([CH3:25])[C:23](=[O:26])[C:22](=[O:27])[NH:21][N:20]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[NH2:51][C:48]1[S:49][CH:50]=[C:46]([C:6](=[N:5][O:4][CH:1]2[CH2:2][CH2:3]2)[C:7]([NH:9][C@@H:10]2[C:44](=[O:45])[N:12]3[C:13]([C:28]([O:30][CH:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:29])=[C:14]([CH2:17][S:18][C:19]4[N:24]([CH3:25])[C:23](=[O:26])[C:22](=[O:27])[NH:21][N:20]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:47]=1
Reactant: Cn1c(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3SC2)n[nH]c(=O)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1c(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(N)n4)[C@H]3SC2)n[nH]c(=O)c1=O
Temperature: 35 °C
Yield: 33.6 %

Procedure:
To a suspension of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.10 g) in a mixture of methanol (7.5 ml) and tetrahydrofuran (4 ml) was added concentrated hydrochloric acid (0.44 ml) and the mixture was stirred at 35° C. for an hour. The mixture was poured into a mixture of ethyl acetate (100 ml) and ice-water (100 ml) and adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous solution of sodium chloride and water successively and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (30 g) using a mixture of chloroform and methanol (30:1 V/V) as an eluent to give benzhydryl 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (356 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([CH3:13])=[CH:4][N:3]=1.Cl[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C=O)C.O.N1C=CC=CC=1>[CH3:13][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]2[N:3]([CH:4]=1)[CH2:15][CH2:16][S:17](=[O:19])(=[O:18])[N:1]=2
Reactant: CCOC(=O)c1cc(C)cnc1N
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C1=CC(C)=CN2CCS(=O)(=O)N=C12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-amino-5-methylpyridine-3-carboxylate (368 mg) in DMF (20 mL) were added pyridine (0.66 mL) and 2-chloroethanesulfonyl chloride (0.32 mL), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added water (50 mL) and sodium carbonate (1 g), sodium chloride was saturated and the mixture was extracted 3 times with ethyl acetate. The extracts were collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (111 mg) as a brown solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]([CH3:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1>>[CH3:15][N:16]([CH3:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:6]2[CH:7]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[NH:27][CH:28]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:22])=[CH:19][CH:18]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Product: CN(C)c1ccc(C(=O)N2c3ccccc3-c3ccccc3C2c2c[nH]c3ccccc23)cc1

Procedure:
(4-Dimethylamino-phenyl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 4-dimethylaminobenzoyl chloride, and indole according to GP 2. Yield, 55%. (+)-ESI-MS: m/z=444 [M+H]+, 327. [M-indole+H]+, 148.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O>CN1CCN(C)C1=O>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C:11]1[N:1]=[C:2]2[CH:3]=[C:4]([Cl:8])[N:5]=[CH:6][N:7]2[CH:10]=1)[CH3:18]
Reactant: CCOC(=O)NC(=O)CCl
Reactant: Nc1cc(Cl)ncn1
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)Nc1cn2cnc(Cl)cc2n1
Temperature: 130 °C
Yield: 9.4 %

Procedure:
A solution of 6-amino-4-chloropyrimidine (1) (0.504 g, 3.89 mmol) and N-chloroacetylurethane (0.770 g, 4.65 mmol) in 1,3-dimethyl-2-imidazolidinone (10 mL) was heated to 130° C. under nitrogen for 3 h. N-Chloroacetylurethane (0.770 g, 4.65 mmol) was added and the mixture was heated to 130° C. under nitrogen for a further 3.5 h. The black oily solution was poured onto ice (200 g) and the aqueous solution was extracted with ethyl acetate (3×250 mL). The organic fractions were combined, removal of solvent in vacuo gave an oily solid which was triturated with ether. Filtration of the solid and washing with ether gave urethane (2) (88 mg, 9%) as a solid. APCI-MS Found [M+H]+=241, 243.
Reaction SMILES: [CH2:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([P:22](=[O:25])([O-:24])[O-:23])[NH:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH3:19])[C:13]([CH3:21])([CH3:20])[CH2:12]1)[CH3:2].CC[O-].[Na+].O.O.[Ni:32](Cl)Cl>C(O)C>[Ni:32].[OH2:23].[CH2:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([P:22](=[O:23])([OH:24])[OH:25])[NH:10][CH:11]1[CH2:12][C:13]([CH3:20])([CH3:21])[N:14]([CH3:19])[C:15]([CH3:18])([CH3:17])[CH2:16]1)[CH3:2].[CH2:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([P:22](=[O:23])([OH:24])[OH:25])[NH:10][CH:11]1[CH2:12][C:13]([CH3:20])([CH3:21])[N:14]([CH3:19])[C:15]([CH3:18])([CH3:17])[CH2:16]1)[CH3:2]
Reactant: CCCCCCCCC(NC1CC(C)(C)N(C)C(C)(C)C1)P(=O)([O-])[O-]
Reactant: Cl[Ni]Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCC(NC1CC(C)(C)N(C)C(C)(C)C1)P(=O)(O)O
Product: [Ni]
Reaction time: 3 h

Procedure:
18.8 g (0.05 mol) of the ethyl-1-[(1,2,2,6,6-pentamethyl-4-piperidyl)-amino]-n-heptyl-phosphonate from Example 2 are dissolved in 400 ml of ethanol with the addition of 3.40 g (0.05 mol) of sodium ethylate. A solution of 4.14 g (0.025 mol) of nickel chloride dihydrate in 100 ml of ethanol is added dropwise to this solution at 25° and the mixture is stirred at 25° for 3 hours. The sodium chloride which has precipitated out is now filtered off, the solvent is evaporated off and the residue is extracted with ether. After volatilising the solvent, the extract is dried for 10 hours at a temperature of 60° and under a pressure of 11 mm Hg. Ni-di-{ethyl-1-[(1,2,2,6,6-pentamethyl-4-piperidyl)-amino]-n-heptyl-phosphonate}-monohydrate is obtained as a green-yellow solid product. It is soluble in hexane at room temperature.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])[N:6]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:23][C:9]1[N:8]([CH2:7][C:5]2[N:6]=[C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[S:3][CH:4]=2)[C:16]2[C:11]([CH:10]=1)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(Br)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 310D using 1-[(2-bromo-1,3-thiazol-4-yl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 311B) and [3-(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 466 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:12][CH:11]=1.NO.[OH-].[K+].CO>C1COCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[CH:11][CH:12]=2)(=[O:18])=[O:19])=[CH:25][CH:24]=1
Reactant: COC(=O)CCCCCSc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCCSc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of the 6-(4-(4-chlorobenzenesulfonylamino)-phenylsulfanyl)-hexanoic acid methyl ester (300 mg, 0.7 mmol) in distilled THF (10 mL) containing 50% aqueous hydroxylamine (0.4 mL, 6.3 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1.2 mL, 1M, 1.2 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×15 mL) and the combined extracts were washed with brine (15 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The solid residue was recrystallised from ethyl acetate/diethyl ether to give the title compound (200 mg, 66%) as a white powder, mp 160-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:11](=[O:36])[N:12]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)=[O:4].[CH3:37][C:38]([CH3:54])([CH3:53])[C:39]([O:41][NH:42][C:43]([CH:45]([CH2:49][CH:50]([CH3:52])[CH3:51])[C:46](O)=[O:47])=[O:44])=[O:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:46](=[O:47])[CH:45]([C:43](=[O:44])[NH:42][O:41][C:39](=[O:40])[C:38]([CH3:53])([CH3:37])[CH3:54])[CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:7][N:6]1[C:11](=[O:36])[N:12]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)=[O:4]
Reactant: CC(C)CC(C(=O)O)C(=O)NOC(=O)C(C)(C)C
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1C[C@@H](N)C[C@H]1C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1C[C@@H](NC(=O)C(CC(C)C)C(=O)NOC(=O)C(C)(C)C)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
(2S,4S)-4-Amino-1-{pentyl-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]carbamoyl}-pyrrolidine-2-carboxylic acid methyl ester (2.0 g, 3.0 mmol) and 2-(2,2-dimethyl-propionyloxycarbamoyl)-4-methylpentanoic acid (1.2 g, 1.4 equiv) were dissolved in DMF (20 mL). DIPEA (2 mL, 3.5 equiv) was added, followed by HATU (1.4 g, 1.2 equiv). The mixture was stirred for 16 hours at room temperature and then partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was re-extracted with EtOAc (100mL). The combined organics were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, and evaporated to afford the title compound (2.2 g, 3 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C38H52N8O7, 732.9. found 733.5.
Reaction SMILES: S(O[CH2:6][C@@:7]12[CH2:22][O:21][C@@H:9]([C@H:10]([N:12]3[CH:19]=[C:18]([CH3:20])[C:16](=[O:17])[NH:15][C:13]3=[O:14])[O:11]1)[C@@H:8]2[OH:23])(C)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH2:6][C@@:7]12[CH2:22][O:21][C@@H:9]([C@H:10]([N:12]3[CH:19]=[C:18]([CH3:20])[C:16](=[O:17])[NH:15][C:13]3=[O:14])[O:11]1)[C@@H:8]2[OH:23])=[N+:25]=[N-:26]
Reactant: Cc1cn([C@@H]2O[C@@]3(COS(C)(=O)=O)CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn([C@@H]2O[C@@]3(CN=[N+]=[N-])CO[C@@H]2[C@@H]3O)c(=O)[nH]c1=O

Procedure:
A dimethylformamide (3.0 ml) solution of Compound 3 (27 mg, 0.078 mmol) and sodium azide was stirred for 1.5 hours at room temperature and for 2 hours at 100° C. in a stream of nitrogen. The solvent was distilled off under reduced pressure, and then a small amount of water was added to the residue, followed by extracting the mixture with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain Compound 4 (28 mg, quant. in 2 steps) as a yellow oily substance.
Reaction SMILES: [N-]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:20]([OH:22])=O)=[CH:8][CH:7]=1.[NH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][NH2:29]>>[CH:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:20]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][NH:29][C:20]([C:9]2[C:4]3[C:5](=[CH:16][C:17]4[C:2]([N:3]=3)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:6]=[CH:7][CH:8]=2)=[O:22])=[O:22])=[CH:8][CH:7]=1
Reactant: NCCNCCN
Reactant: O=C(O)c1cccc2cc3ccccc3nc12
Reactant: c1c[n-]cn1
Product: O=C(NCCNCCNC(=O)c1cccc2cc3ccccc3nc12)c1cccc2cc3ccccc3nc12
Yield: 84 %

Procedure:
Reaction of acridine-4-carboxylic acid imidazolide with N,N-bis(2-aminoethyl)amine as above, followed by crystallization of the crude product from MeOH/H2O, gave bis[2-(acridine-4-carboxamido)ethyl]amine (34) (84%). 1H NMR [(CD3)2SO] δ 11.57 (t, J=5.0 Hz, 2 H, 2×CONH), 8.80 (s, 2 H, H-9), 8.46 (d, J=7.1 Hz, 2 H, H-3), 8.08 (d, J=8.4 Hz, 2 H, ArH), 7.92 (d, J=8.7 Hz, 2 H, ArH), 7.79 (d, J=8.1 Hz, 2 H, ArH), 7.55 (t, J=7.7 Hz, 2 H, ArH), 7.41 (t, J=7.6 Hz, 2 H, ArH), 7.27 (t, J=7.4 Hz, 2 H, ArH), 3.73 (q, J=5.5 Hz, 4 H, 2×NHCH2), 3.11 (t, J=5.6 Hz, 4 H, CH2NHCH2). The trihydrochloride salt crystallized from MeOH/EtOAc/HCl, mp 182-184° C. Anal. (C32H27N5O2.3HCl) C, H, N, Cl.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[O:10][C:9]1=[O:17]>C(#N)C>[CH:1]([NH:4][CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[O:10][C:9]1=[O:17])([CH3:3])[CH3:2]
Reactant: O=c1oc2cccnc2n1CCBr
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NCCn1c(=O)oc2cccnc21

Procedure:
0.1 mol of isopropylamine and 0.01 mol of 3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolved beforehand in 40 cm3 of acetonitrile, are introduced into a 100-cm3 ground-necked round-bottomed flask equipped with a reflux condenser. The mixture is heated to reflux for 15 hours. After cooling, the precipitate obtained is drained, dried and recrystallized.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([OH:15])=O)[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:30]C(OCC(C)C)=O.[C:38]1([CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.CN(C=O)C>[NH2:1][C@H:2]([C:13]([NH:47][CH2:46][CH2:45][CH:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:15])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[ClH:30]
Reactant: CC(C)COC(=O)Cl
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)NCCC(c1ccccc1)c1ccccc1
Product: Cl
Temperature: 0 °C

Procedure:
0.62 g (2 mmol) of Boc-Thr(Bzl)-OH were dissolved in 10 ml DCM, 2 mmol of triethylamine were added and the solution was cooled to 0° C. With stirring, 2 mmol of isobutyl chloroformate were slowly added. The cooling bath was removed, the solution was stirred for 15 minutes and 2.5 mmol of 3,3-diphenylpropylamine in 2 ml of DMF were added and stirred at room temperature for 1 hour. The solution was evaporated, dissolved in ethyl acetate and extracted with 0.5M KHSO4 solution, sat. NaHCO3 solution and brine, dried with MgSO4 and evaporated. The oily product was dissolved in 10 ml of DCM, and 10 ml of a 4M solution of hydrochloric acid in dioxane were added. After 10 minutes the solvents were evaporated, the product hydrochloride was precipitated with diethyl ether, filtered off, washed with diethyl ether and dried in vacuo to give a white solid. MS analysis: (M+H)+: found 403.1, calc. 403.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9](C2C=CC=CC=2N)=[CH:10][CH:11]=1)[CH3:2].C([N:32]([CH2:35][CH3:36])CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C1COCC1.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([N:8]2[C:9]([C:5]3[CH:4]=[CH:36][C:35]([NH:32][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:7][CH:6]=3)=[CH:10][CH:11]=[C:7]2[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:29])=[C:20]([CH3:28])[CH:21]=1)(=[O:27])[NH2:26]
Reactant: CCOC(=O)CCc1ccc(-c2ccccc2N)n1-c1ccc(C(N)=O)cc1C
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2ccc(NS(C)(=O)=O)cc2)n1-c1ccc(C(N)=O)cc1C
Reaction time: 18 h

Procedure:
Under nitrogen atmosphere, 3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(amino-phenyl)-1H-pyrrole-2-yl]-propionic acid ethyl ester (11A, synthesis described in Scheme 4 where R1=4-carbamoyl-2-methylphenyl) (51 mg, 0.13 mmol) was dissolved in 1 mL anhydrous THF. Triethylamine (0.04 mL, 0.26 mmol) and then methane sulfonylchloride (0.01 mL, 0.13 mmol) were added. After 18 hrs, 0.01 mL methane sulfonylchloride was added to push the reaction to completion. After another 18 hrs, the reaction was diluted with water and extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC plate (5% MeOH/CH2Cl2). 14B, ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonamido)phenyl)-1H-pyrrol-2-yl)propanoate was isolated, rf=0.17 (28 mg, 50%).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][N:21]1[CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][N:9]([C:38](=[O:39])[CH2:37][N:21]3[CH2:22][CH2:23][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:20]3=[O:19])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C2(c3ccccc3)CCCNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCCC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 24A (0.48 g, 2.00 mmol) in dichloromethane was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.59 g, 2.00 mmol) under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.77 g, 4.00 mmol) and N,N-dimethylpyridin-4-amine (0.024 g, 0.20 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.13-7.37 (m, 20H), 4.16 (s, 2H), 4.11 (s, 2H), 3.33-3.40 (m, 2H), 3.24 (t, J=6.4 Hz, 2H), 2.63 (t, J=6.4 Hz, 2H), 2.39-2.46 (m, 2H), 1.29-1.37 (m, 2H); MS (DCI+) m/z 515 (M+H)+.