Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[NH:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>>[NH2:45][CH:42]1[CH2:43][CH2:44][N:39]([C:16]2[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]3[CH:12]=[CH:11][C:10](=[O:38])[N:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:14]=3[N:15]=2)[CH2:40][CH2:41]1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NC1CCNCC1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(N2CCC(N)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 32 %

Procedure:
The title compound was prepared from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide and 4-piperidinamine according to General Procedure for Sulfoxide/Sulfone Displacement, described above. The concentrated reaction mixture was purified via reversed-phase HPLC to give the desired compound as a light tan powder (0.041 g, 32%). HPLC indicated the material to be >95% pure (m.p. 183.8-187.9): LC-MS m/z 573 (M+H)+, 1.79 min (ret time).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]1)#[CH:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([CH3:23])=[CH:18][N:17]=1>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[N:21]=[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10]2)[C:19]([CH3:23])=[CH:18][N:17]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1C#Cc1ccccc1C1(C(N)=O)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (2.29 g, 12.4 mmol), 2,4-dichloro-5-methylpyrimidine (2.62 g, 16.1 mmol), CuI (0.047 g, 0.25 mmol) and PdCl2(PPh3)2 (0.087 g, 0.12 mmol) in dioxane (25 mL) was bubbled with N2 for 10 minutes. Et3N (10 mL) was added and the mixture was stirred under nitrogen at 70° C. for 1 hour. The reaction mixture was cooled and adsorbed onto silica. Purification by column chromatography (Biotage Isolera, 120 g SiO2, 0-10% MeOH in CHCl3) gave the title compound A39 as a yellow oil (1.85 g, 48%). LCMS-D: rt 3.24 min; m/z 312 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([O-])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:20]([O:22][CH3:23])=[O:21].[K+].C1C=CC=CC=1.CN(C)C=O.S(Cl)([Cl:38])=O>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([Cl:38])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(N=Nc2ccc(S(=O)(=O)[O-])cc2)ccc1O
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N=Nc2ccc(S(=O)(=O)Cl)cc2)ccc1O

Procedure:
17.6 g of potassium 4-(4-hydroxy-3-carbomethoxy-phenylazo)-benzenesulphonate, 30 ml of benzene, 2 ml of dimethylformamid and 6 ml of thionyl chloride are heated to the boiling point under reflux for 30 min. The mixture is cooled, and cold water and 100 ml of petroleum ether are added with rapid stirring. The product is filtered off and washed with water and dried, whereupon 15.4 g of the title compound are obtained. The melting point is 137° - 138° C. after recrystallization.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][CH2:14][CH2:15][OH:16]>>[C:1]([O:16][CH2:15][CH2:14][CH2:13][C:12]([F:11])=[C:17]([F:19])[F:18])(=[O:3])[CH3:2]
Reactant: OCCCC(F)=C(F)F
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)OCCCC(F)=C(F)F
Temperature: 25 °C
Yield: 90.6 %

Procedure:
31.7 g (0.41 mol) of acetyl chloride were added dropwise to a two-necked round-bottomed flask, cooled in an ice bath, equipped with a reflux condenser (connected to a trap comprising potassium carbonate) and comprising 50.1 g (0.36 mol) of 4,5,5-trifluoropent-4-en-1-ol. The reactivity of the two reactants was monitored by sparging of the trap by HCl. After the completion of the addition, the mixture was stirred at ambient temperature until HCl was no longer being evolved (approximately 4 hours). After distillation, 59.3 g (0.326 mol) of 4,5,5-trifluoro-4-pentenyl acetate (colourless liquid) were obtained. Boiling point=56-58° C./21 mmHg. (Yield=91%.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](Cl)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20].[CH:21]1[C:26]([NH2:27])=[CH:25][C:24]2[NH:28][N:29]=[CH:30][C:23]=2[CH:22]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:27][C:26]3[CH:25]=[C:24]4[C:23]([CH:30]=[N:29][NH:28]4)=[CH:22][CH:21]=3)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCCl
Yield: 90 %

Procedure:
The title compound was prepared by the procedure of Example 166 using 0.311 g of 7-(3-chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.147 g of 6-aminoimidazole, 0.128 g of pyridine hydrochloride and 12 ml of ethoxyethanol to give 0.367 g (90%) of the desired product. MP 280-285° C. mass spectrum (electrospray m/e): M+H=407.9.
Reaction SMILES: ClC1C(=O)N(C2C=CC=CC=2)N=CC=1Cl.[Cl:16][C:17]1[C:18](=[O:30])[N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]=[CH:21][C:22]=1[SH:23].S.[Na].[CH2:33](Cl)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[Na+].[OH-].[NH4+]>>[CH2:33]([S:23][C:22]1[CH:21]=[N:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18](=[O:30])[C:17]=1[Cl:16])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=c1c(Cl)c(S)cnn1-c1ccccc1
Reactant: ClCc1ccccc1
Agent: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Agent: S
Agent: [NH4+]
Product: O=c1c(Cl)c(SCc2ccccc2)cnn1-c1ccccc1

Procedure:
Compounds of the type IV are known, but the conventional methods of preparation entail two stages, starting from the dihalo compound II, or give undesirable by-products. Chem. Abstr. 68, (1968), 2906 c describes the preparation of 4-chloro-5-mercapto-2-phenylpyridazin-3(2H)-one (V) starting from 4,5-dichloro-2-phenylpyridazin-3(2H)-one (II, R1 =C6H5, X=Cl) and sodium hydrogen sulfide, the product (V) being reacted with benzyl chloride and sodium hydroxide and ammonium hydroxide to give the desired compound 5-benzylthio-4-chloro-2-phenyl-pyridazin-3-(2H)-one. ##STR5##
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[C:4]([N+:16]([O-])=O)[C:3]=1[CH3:19].[CH2:20](OC(OCC)N(C)C)C.N1CCCC1.O.NN>CN(C=O)C.C1COCC1.[Ni].CO>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:19]=[CH:20][NH:16]2
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1Cl
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCNC1
Product: Clc1c(OCc2ccccc2)ccc2[nH]ccc12
Temperature: 110 °C
Yield: 77.2 %

Procedure:
To a solution of 2-chloro-3-benzyloxy-6-nitro-toluene (5.00 g, 18.0 mmol) in DMF (25 ml) was added dimethylformamide diethyl acetal (3.14 g, 21.3 mmol) and pyrrolidine (1.51 g, 21.3 mmol), and the mixture was heated at 110° C. for 3 hours under nitrogen. Evaporation under high vacuum at 70° C. gave a deep-red oil which was dissolved in THF (35 ml) and methanol (35 ml) and treated with Raney nickel (0.4 ml) and then hydrazine hydrate (1.30 ml), while stirring at room temperature under nitrogen. The temperature rose to 45° C., and was maintained there by gently warming on an oil bath. A further quantity of hydrazine hydrate (1.30 ml) was added after 30 minutes, and stirring at 45° C. was continued for another hour. The mixture was allowed to cool, filtered through celite, evaporated to a brown oil and purified by chromatography (SiO2 ; C6H14 /CHCl3) to give 4-chloro-5-benzyloxyindole as a yellow oil (3.58 g).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][CH:15]=[CH:16][CH2:17]Cl>>[Cl:14][CH:15]=[CH:16][CH2:17][C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:9]
Reactant: Cc1cc(C)cc(C)c1
Reactant: ClC=CCCl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(CC=CCl)c(C)c1

Procedure:
30 g (0.25 mol) of mesitylene and 0.7 g of aluminum chloride are introduced. 5.55 g (0.05 mol) of 1,3-dichloropropene (cis/trans) are then added dropwise at 20°-25° C. with cooling.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31](F)=[CH:30]C=CC=3F)(=[O:25])=[O:24])C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([CH:56]=[CH:57][CH:58]=2)[NH2:55])[CH:38]=[CH:37][N:36]=1.C1(S(Cl)(=O)=O)CC1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([NH:55][S:23]([CH:26]3[CH2:31][CH2:30]3)(=[O:24])=[O:25])[CH:56]=[CH:57][CH:58]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)C1CC1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (150 mg, 0.383 mmol) and cyclopropanesulfonyl chloride (0.039 mL, 0.383 mmol) the title compound of Step A was obtained as a yellow solid (125 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 8.27-8.39 (m, 1H), 7.54 (td, J=7.6, 1.7 Hz, 1H), 7.22-7.42 (m, 2H), 6.62-6.72 (m, 1H), 5.30 (s, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.52 (t, J=4.6 Hz, 4H), 2.59-2.70 (m, 1H), 0.75-0.93 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[N+:17]([O-])=[O:18])=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO.CN(C=O)C.O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([C:5]3[CH:20]=[CH:21][C:2]([NH2:1])=[CH:3][CH:4]=3)[N:17]([OH:18])[C:9]=2[CH:10]=1)([O-:16])=[O:15]
Reactant: Nc1ccc(CNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc3ccc([N+](=O)[O-])cc3n2O)cc1
Temperature: 60 °C
Yield: 90 %

Procedure:
To a solution of N-(4-aminobenzyl)-2,4-dinitroaniline (7) (21.6 g, 74.9 mmol) in anhydrous EtOH (300 mL) and anhydrous DMF (75 mL) was slowly added sodium methoxide (30% w/w) (69.1 g, 375 mmol) at room temperature under argon atmosphere, followed by heating to 60° C. for 2 hours. After cooling to ambient termperature, the solution was diluted with water (700 mL) and then acidified with saturated citric acid. The resulting precipitate was collected on a sintered funnel while rinsing with water. The crude product was recrystallized in hot EtOH to afford 18.1 g as a brown solid in 90% yield.
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:23])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:22][CH2:21][NH:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2.C([O:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:23])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:22][CH2:21][N:20]([CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCCc2cc(-c3csc(C4CCNC4)n3)ccc21
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCCc2cc(-c3csc(C4CCN(CCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out starting from 4-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-pyrrolidin-3-ylthiazole hydrobromide and 4-bromobutyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O1CC[N:21]([CH:24]=[CH:25][CH2:26][CH3:27])CC1>C(Cl)Cl>[CH2:26]([C:25]1[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:21][CH:24]=1)[CH3:27]
Reactant: CCC=CN1CCOCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Reaction time: 72 h
Yield: 56.9 %

Procedure:
Diethyl ethoxymethyleneoxalacetate (3.17 g, 0.013 mol) is added to a solution of 1-morpholinobutene (1.84 g, 0.013 mol) dissolved in CH2Cl2 (40 mL) at 0°. The solution is concentrated in vacuo, and ammonium acetate (50 g), ammonium hydroxide (10 mL), tetrahydrofuran (20 mL) and 95% ethanol (20 mL) are added. The solution is heated to reflux for 30 minutes, then held at 3° for 72 hours. The reaction solution is then partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo to give the product (1.85 g, 0.0074 mol, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.B.[Na]>C(O)C>[CH2:31]([NH:1][C:2]1[CH:3]=[C:4]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:30])[CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=Cc1ccccc1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(N)c3c(c2)CCC(=O)N3)CC1
Agent: B
Agent: [Na]
Solvent: CCO
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cc3c(c(NCc4ccccc4)c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
In 10 ml of ethanol was dissolved 1 g of 8-amino-6-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}-3,4-dihydrocarbostyril. Thereto was added 0.3 g of benzaldehyde. The mixture was refluxed by heating, for 4 hours in an oil bath. The reaction mixture was allowed to cool and then mixed with 0.15 g of sodium boron hydride. The mixture was stirred at room temperature for 4 hours and subjected to distillation under reduced pressure to remove the solvent. The residue was mixed with water. The mixture was extracted with methylene chloride. The extract was dried with anhydrous sodium sulfate and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: methylene chloride/methanol=100/1~50/1~20/1). The eluate was subjected to distillation to remove the solvent. The residue was recrystallized from ethanol-n-hexane to obtain 0.8 g of 8-benzylamino-6-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}-3,4-dihydrocarbostyril as a light yellow powder having a melting point of 144.5°-145.5° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([CH3:13])[C:11]=2[N:12]=1.C(OC([C:28]1[NH:29][CH:30]=[CH:31][CH:32]=1)=O)(C)(C)C.C([O-])(=O)C.[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN1CCCC1=O>[CH2:19]([N:6]1[C:7](=[O:18])[C:8]2[CH:17]=[CH:16][CH:15]=[N:14][C:9]=2[N:10]([CH3:13])[C:11]2[N:12]=[C:2]([C:28]3[NH:29][CH:30]=[CH:31][CH:32]=3)[CH:3]=[CH:4][C:5]1=2)[CH3:20]
Reactant: CC(C)(C)OC(=O)c1ccc[nH]1
Reactant: CCN1C(=O)c2cccnc2N(C)c2nc(Cl)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCN1C(=O)c2cccnc2N(C)c2nc(-c3ccc[nH]3)ccc21
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-5,11-dihydro-5-ethyl-11-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.21 g), (t-butoxycarbonyl)pyrrole (0.25 g), potassium acetate (0.20 g), Pd(PPh3)2Cl2 (0.030 g), and 1-methyl-2-pyrrolidinone (2.5 mL) were heated in a sealed tube at 140° C. for 14 h. After removing the solvent, water was added and the product was extracted with CH2Cl2, dried (anhyd Na2 SO4), filtered, and evaporated. The residue was chromatographed over silica gel (ethyl acetate/methylene chloride, 1:9) and was further purified by preparative plate chromatography (ethyl acetate/methylene chloride, 1:9) to give, after recrystallization from ethyl acetate/hexanes, 0.020 g of the title compound, mp 161°-162° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].C(N(CC)CC)C.O>C(Cl)Cl>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1cc([N+](=O)[O-])ccc1F
Yield: 100 %

Procedure:
A solution of methoxyacetyl chloride (5.85 ml) in methylene chloride (50 ml) was added dropwise to a solution of 2-fluoro-5-nitroaniline (5.06 g) and triethylamine (8.92 ml) in methylene chloride (150 ml) under an argon atmosphere. The resultant mixture was stirred at ambient temperature for 5 hours, then poured into water and extracted with methylene chloride. The organic phases were washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to yield N-(2-fluoro-5-nitrophenyl)-2-methoxyacetamide as a solid (7.7 g, 100%); NMR: 3.26 (s, 2H), 4.5 (s, 3H), 7.57 (t, 1H), 8.03 (m, 1H), 8.82 (m, 1H), 9.83 (s, 1H); m/s: M+H+ 229.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J28) (271 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (346 mg, 79%).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[N:19]=[C:18]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[Cl-].[NH4+]>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[N:19]=[C:18]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[CH2:26][CH2:27]3)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)n2)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(N)cc4)CC3)n2)cc1OC
Reaction time: 2 h
Yield: 90 %

Procedure:
To an ethanol (70 ml) and water (25 ml) mixed solution of 2.5 g of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-nitrophenyl)piperazine were added 0.15 g of ammonium chloride and 3.1 g of reduced iron, followed by 2 hours of heating under reflux. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. An aqueous sodium hydrogen carbonate solution was added to thus obtained residue, followed by extraction with chloroform. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and further, crystallization was carried out from acetonitrile-ethyl acetate to obtain 2.1 g of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-aminophenyl) piperazine as pale pink crystals.
Reaction SMILES: ClC1C=CC(S(N(C2C=C(Cl)C=CC=2Cl)[C@H](C)CCN2CCSC2[C:20]([OH:22])=[O:21])(=O)=O)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:57]2[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=2[Cl:64])[C@H:43]([CH3:56])[CH2:44][CH2:45][CH2:46][N:47]2[CH2:51][CH:50](CC(O)=O)[S:49][CH2:48]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1.[OH-].[K+].[K+].[Br-]>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([C:57]2[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=2[Cl:64])[C@H:43]([CH3:56])[CH2:44][CH2:45][CH2:46][N:47]2[CH2:51][CH:50]([C:20]([OH:22])=[O:21])[S:49][CH2:48]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: C[C@H](CCCN1CSC(CC(=O)O)C1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[C@H](CCN1CCSC1C(=O)O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Product: C[C@H](CCCN1CSC(C(=O)O)C1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 45 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-(4-(5-carboxy-3-thiazolidinyl)-1(R)-methylbutyl)benzenesulfonamide was prepared analogous to 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(2-carboxy-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide by reacting 4-chloro-N-(2,5-dichlorophenyl)-N-(4-(5-carboxymethyl-3-thiazolidinyl)-1(R)-methylbutyl)benzenesulfonamide with 50% aqueous KOH. Yield=45%; White powder: IR (KBr) 1467, 1350, 1167, 1094, 754, 622 cm−1; MS (ESI+), 537 (M+H)+.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([CH2:15][OH:16])[N:13](C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11][C@H:10]1[OH:27])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[NH:13]1[C@H:14]([CH2:15][OH:16])[C@@H:9]([OH:8])[C@H:10]([OH:27])[CH2:11][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](OCc2ccccc2)[C@H]1CO
Agent: [Pd]
Solvent: CC(=O)O
Product: OC[C@H]1NCC[C@@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
4-O-Benzyl-N-benzyloxycarbonyl-1,5-imino-1,2,5-trideoxy-D-arabino-hexitol (25) (325 mg, 0.877 mmol) was dissolved in acetic acid (8 ml) and stirred under hydrogen at atmospheric pressure with palladium black (100 mg). After 18 hours, the solution was filtered and evaporated. Subsequent purification by flash chromatography (CMAW) and ion exchange gave 1,5-imino-1,2,5-trideoxy-D-arabino-hexitol as the hydrochloride salt (158 mg, 98%) a white crystalline solid, m.p. (methanol-ether) 173°-175° C., [α]20D +17.9° (c, 0.78 in water); νmax (KBr disc) 3370, 1615, 1390, 1055, 935 and 660 cm-1 ; 1H NMR (D2O) δ 1.58 (1H, dddd, H-2, J2,2' 14.2 Hz, J2,3 11.4 Hz, J2,1 13.6 Hz, J2,1' 4.6 Hz); 2.06 (1H, dddd, J2',1' 2.4 Hz, J2',3 4.8 Hz, J2',1 3.2 Hz); 2.90-3.01 (2H, m, H-5, H-1); 3.30 (1H, ddd, H-1', J1,1' 13.2 Hz); 3.38 (1H, dd, H-4, J3,4 9.2 Hz, J4,5 10.5 Hz); 3.57 (1H, ddd, H-3); 3.73, 3.79 (2H, 2×dd, H-6,6', J6,6' 12.7 Hz, J5,6 5.2 Hz, J5,6' 3.4 Hz). 13C NMR δ29.33 (t, C-2); 42.66 (t, C-1); 58.53 (t, C-6); 60.68 (d, C-5); 70.39, 71.24 (2×d, C-3, C-4). m/z: 148 (M+H+, 100%), 116 (10%), 72 (8%). Also characterized as free base, m.p. (acetone-water) 178°-180° C., [lit.20 180°-184° C.], [α]20D +21.0° (c 0.3 in water) [lit.20 +24.7 (c 0.4 in water)]; 1H NMR δ 1.28 (1H, dddd, H-2), 1.81 (1H, dddd, H-2'), 2.40 (1H, ddd, H-1), 2.83 (1 H, ddd, H-1'), 2.99 (1H, dd, H-4), 3.37 (1H, m, H-3), 3.46 (1H, dd, H-6), 3.68 (1H, dd, H-6'); 13C NMR δ 33.45 (t, C-2), 43.30 (t, C-1), 61.59 (d, C-5), 62.45 (t, C-6), 73.98 (2×d, C-3,4).