Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH3:25])[N:22]([CH2:26][CH:27]3[CH2:29][O:28]3)[N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[NH3:30]>>[NH2:30][CH2:29][CH:27]([OH:28])[CH2:26][N:22]1[C:23]([CH3:25])=[CH:24][C:20]([C:17]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([CH:16]=2)[C:4]([NH:6][CH2:7][C:8]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:5])=[N:21]1
Reactant: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)nn1CC1CO1
Reactant: N
Product: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)nn1CC(O)CN
Temperature: 67 °C

Procedure:
A mixture of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-methyl-1-oxiranylmethyl-1H-pyrazol-3-yl)-benzamide (0.4 g, 0.96 mmol) in methanolic ammonia (20 mL, 7.0 N) was heated to 67° C. in a sealed tube for 16 h. The mixture was concentrated in vacuo, and the residue was triturated with diethyl ether-ethyl acetate to afford the title compound (0.12 g). LCMS (m/z) 435.3 M+1.
Reaction SMILES: [CH3:1][N:2]([CH2:40][CH2:41][NH:42]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[C:3]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:39])[C@@H:17]4[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:18]4[C:19]=3[C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])[CH2:11]2)[S:8][CH:9]=1)=[O:4]>O1CCCC1>[NH2:42][CH2:41][CH2:40][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[C:7]([N:10]2[CH2:11][CH:12]([S:14][C:15]3[C@H:16]([CH3:39])[C@@H:17]4[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:18]4[C:19]=3[C:20]([OH:22])=[O:21])[CH2:13]2)[S:8][CH:9]=1)=[O:4]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N(C)CCNC(=O)OCc5ccc([N+](=O)[O-])cc5)cs4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SC3CN(c4nc(C(=O)N(C)CCN)cs4)C3)[C@H](C)[C@H]12
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-[1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (267.5 mg, 0.33 mmol) (obtained as described in Example 63(1)) in a mixture of tetrahydrofuran (14 ml) and distilled water (6.7 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (300 mg) at 30° C. in a water bath for 1.5 hours. After checking the completion of the reaction, the reaction mixture was filtered and to the filtrate were added ethyl acetate-tetrahydrofuran (1:1) and distilled water. The mixture was shaken in a separatory funnel. The aqueous layer was separated, washed with the above-mentioned mixed solvent, and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water→5% acetonitrile in distilled water→10% acetonitrile in distilled water→15% acetonitrile in distilled water),and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-(1-{4-[N-(2-aminoethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (81.6 mg, yield 51%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[C:29]([CH3:33])=[N:28]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH:11]3[CH2:15][NH:14][CH2:13][CH:12]3[CH2:23]2)=[N:7][C:2]([NH:32][C:30]2[C:29]([CH3:33])=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Cc1nn(C)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CC3CNCC3C2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole2(1H)-carboxylate (573.1 mg, 1.54 mmol) and 1,3-dimethylpyrazol-4-amine hydrochloride (458.8 mg, 3.11 mmol) in dioxane (10 mL) was added trifluoroacetic acid (856.4 mg, 7.51 mmol). The reaction mixture was stirred at 100° C. overnight and adjusted to pH=10 with a saturated Na2CO3 solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM=1/10) to give the title compound as a beige solid (256.8 mg, 48.1%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:21](=[O:32])[CH2:20]3)(=[O:18])=[O:17])=[CH:13][C:12]=2[CH:33]=1.Cl.Cl[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:40]5[CH:39]=[CH:38][N:37]=[CH:36][CH:41]=5)[CH2:30][CH2:31]4)[C:21](=[O:32])[CH2:20]3)(=[O:18])=[O:17])=[CH:13][C:12]=2[CH:33]=1
Reactant: Clc1ccccn1
Reactant: O=C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CCN1CC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)c2cc3cc(Cl)ccc3o2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 37.1 %

Procedure:
To sodium bicarbonate solution were added 4-(5-chlorobenzofuran-2-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (215 mg) and chloropyridine hydrochloride (144 mg), and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (15 ml), and the mixture was allowed to react at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution 15:1) to give colorless solid of 4-(5-chlorobenzofuran-2-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone (87 mg), which was treated with hydrochloric acid to give colorless solid of the title compound (80 mg) as hydrochloride salt.
Reaction SMILES: [N:1]([C:4]1([CH3:10])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=C=O.[ClH:11]>C1COCC1>[ClH:11].[CH3:10][C:4]1([NH2:1])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CC1(N=C=O)CCOCC1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(N)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A solution of 4-isocyanato-4-methyltetrahydro-2H-pyran (D10) (520 mg, 3.68 mmol) in THF (30 mL) was treated with 5 M hydrochloric acid (4.05 mL, 20.3 mmol) and stirred at room temperature overnight. The mixture was then concentrated under vacuum to yield the title compound (D11) (820 mg, 3.52 mmol, 95% yield) as a pale green solid.
Reaction SMILES: Cl[CH2:2][CH:3]1[S:9][CH2:8][CH2:7][CH2:6][CH2:5][S:4]1.[OH-].[Na+].[CH3:12][NH2:13]>>[S:4]1[CH2:5][CH2:6][CH2:7][CH2:8][S:9][CH:3]1[CH2:2][NH:13][CH3:12]
Reactant: CN
Reactant: ClCC1SCCCCS1
Agent: [Na+]
Agent: [OH-]
Product: CNCC1SCCCCS1
Reaction time: 18 h

Procedure:
A 40% by weight aqueous solution of methylamine (100 ml) and 2-chloromethyl-1,3-dithiepane (50 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture is stirred for a period of about 18 hours. After this time sodium hydroxide (18 grams) is added with stirring over a period of about 3 hours. Stirring is then continued for an additional period of about 16 hours. The organic phase of the reaction mixture is then separated, is washed with aqueous potasssium carbonate and dried over anhydrous magnesium sulfate. The dried product is then distilled under reduced pressure to yield the desired product N-(1,3-dithiepan-2-ylmethyl)-N-methylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:29])[CH:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:9]=[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[NH:15][C:16](=[O:18])[NH:17][C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1>[Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:9]=[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[NH:15][C:16](=[O:18])[NH:17][C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)[nH]c4c3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: O=C1Nc2ccc(Cl)cc2C(c2ccc3[nH]c(=O)[nH]c3c2)=NC1Cc1ccccc1Cl
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 44.3 %

Procedure:
(Z)-7-Chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (200 mg, 0.35 mmol) was dissolved in anhydrous anisole (4 mL) under a nitrogen atmosphere, aluminum chloride (280 mg, 2.1 mmol) was added and the mixture was heated to 85° C. for 1 hour. The solution was cooled to ambient temperature, poured onto ice, rinsing the flask with ethyl acetate and water. The mixture was slurried for 10 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate, decanted and concentrated in the presence of silica gel. The residue was chromatographed on silica gel eluting with 70-100% ethyl acetate in hexanes switching to a gradient of 0-10% methanol in ethyl acetate to give (Z)-7-chloro-3-(2-chlorobenzyl)-5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (70 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 3.46 (d, 2H) 3.76 (t, 1H), 6.90 (m, 2H), 7.01 (s, 1H) 7.21-7.64 (m, 7H), 10.70 (s, 1H), 10.74 (s, 1H), 10.85 (s, 1H); ESI m/z measured 451.0736 [M+H+], calculated 451.0729.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:10][NH:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To the solution of 5-fluoro-N-methyl-2-nitrobenzamide (178 mg, 0.9 mmol) and morpholine (94 mg, 1.2 eq) in anhydrous DMF (3.0 mL) was added Cs2CO3 (350 mg, 1.2 eq). The mixture was stirred at 100° C. in an oil bath overnight. The mixture was cooled and the solvent was removed to obtain the crude which was purified by silica gel chromatography to obtain the desired compound N-methyl-5-morpholino-2-nitrobenzamide (206 mg, isolated yield 86%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1.C(=O)(O)[O-].[K+]>O1CCCC1>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:15]=2)[N:8]=[CH:7]1
Reactant: NCCc1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NCCc2c[nH]cn2)nc1

Procedure:
0.5 g (4.5 mmol) of histamine and 0.77 g (4.5 mmol) of 6-chloro-3-carbomethoxypyridine are stirred with potassium bicarbonate in 20 ml of tetrahydrofuran at 21° C. for 24 h and then heated at reflux for 24 h. The mixture is evaporated and the white solid residue is chromatographed through silica gel, using a chloroform/methanol (4/1) mixture as eluent. The fractions containing the pure product are combined and evaporated and the resulting oily residue is treated with a methanol solution of oxalic acid. Addition of ether provides the title compound in the form of the oxalate salt, M.p.: 209°-210° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC=CC=1>C(N(CC)CC)C>[CH3:7][N:8]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNc1ccccc1
Reactant: CC(C)CCBr
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)CCN(C)c1ccccc1
Yield: 63.4 %

Procedure:
121 g of isoamyl bromide were added dropwise to a mixture of 86 g of N-methyl-aniline, 500 ml of anhydrous benzene and 81 g of anhydrous triethylamine and the mixture was refluxed for 100 hours and was filtered. The filtrate was washed with water, dried and evaporated to dryness. The residue was distilled to obtain 90 g of N-methyl-N-(3-methylbutyl)-aniline boiling at 132° C. at 18 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1.[C:24](=S)=[S:25].[OH-].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[O:16][C:24]([SH:25])=[N:18][N:17]=3)=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1
Reactant: S=C=S
Reactant: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1cc(Br)ccc1Nc1c(-c2nnc(S)o2)cn2ccnc2c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
7-(4-Bromo-2-fluoro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid hydrazide (50 mg, 0.13 mmol) was suspended in ethanol (2.5 mL) and cooled to 0° C. Carbon disulfide (22 mg, 0.29 mmol) was added, followed by powdered potassium hydroxide (7 mg, 0.13 mmol). The reaction mixture was stirred under N2 for 1 hour at 0° C. and then for 30 minutes at room temperature. The reaction mixture was then brought to reflux and stirred under N2 for 5 days. The reaction mixture was diluted with water and acidified to pH 1-2 with aqueous 1 M HCl. This mixture was then extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4 and concentrated. Purification of the crude product was achieved by flash column chromatography (gradient of dichloromethane to 15:1 dichloromethane/methanol) and then trituration with diethyl ether and dichloromethane to yield the desired product (17 mg, 31%) as a yellow solid. MS ESI (+) m/z 440, 442 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.16 (s, 1H), 8.08 (br s, 1H), 7.73 (s, 1H), 7.49 (d, 1H), 7.15 (d, 1H), 6.59 (t, 1H). 19F (376 MHz, DMSO-d6)−128.7 (s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[OH:22])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([OH:25])[CH3:24].C(OC(=O)C)(=O)C>[Fe].C(O)(=O)C>[C:23]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:12])=[C:14]([OH:22])[CH:15]=1)(=[O:25])[CH3:24]
Reactant: CCO
Reactant: CN(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(N(C)C(=O)OCc2ccccc2)c(O)c1
Temperature: 80 °C

Procedure:
3.3×10-2 mole (10 g) of 2-(N-benzyloxycarbonyl -N-methylamino)-5-nitrophenol is added to 40 g of iron powder in 60 ml of 96° strength ethanol mixed with 20 ml of acetic acid brought to 80° C., the temperature being maintained at 80° C. When the addition is complete, heating is maintained for 30 minutes. The inorganic salts present in the reaction medium are removed by filtration while hot. The filtrate is diluted with 800 ml of ice-cold water. 3.7×10-2 mole (3.5 ml) of acetic anhydride is then added. The expected product crystallizes after 3 hours. After filtration and drying, the product obtained is recrystallized from a water/ethanol mixture. It then melts at 174° C.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:13])[C@H:7]([CH3:12])[NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[S:23](Cl)(=[O:25])=[O:24]>>[CH2:3]([O:5][C:6](=[O:13])[C@H:7]([CH3:12])[NH:8][CH2:9][CH2:10][NH:11][S:23]([C:15]1[S:14][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1)(=[O:24])=[O:25])[CH3:4]
Reactant: CCOC(=O)[C@H](C)NCCN
Reactant: O=S(=O)(Cl)c1nc2ccccc2s1
Agent: Cl
Product: CCOC(=O)[C@H](C)NCCNS(=O)(=O)c1nc2ccccc2s1

Procedure:
N-(2-Aminoethyl)-alanine ethylester 2HCl, prepared as described by Puschl (A. Puschl et al., Tetrahedron, 1998, 39, 4707.), was reacted with benzothiazole-2-sulfonyl chloride as per the procedure of Example 1 to give the title compound. 1H NMR (500 MHz; DMSO-d6) δ 8.27 (d, 1H), 8.18 (d, 1H), 7.69˜7.62 (m, 2H), 4.01 (q, 2H), 3.17 (q, 1H), 3.13 (t, 2H), 2.61 (m, 1H), 2.49 (m, 1H), 1.13 (t, 3H), 1.06 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:18]2[CH2:19][CH2:20][N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(N2CCN(c3ccccn3)CC2)nn1
Yield: 45.3 %

Procedure:
A mixture of 3.3 parts of 3,6-dichloropyridazine, 3.3 parts of 1-(2-pyridinyl)piperazine, 1.5 parts of sodium hydrogencarbonate and 120 parts of ethanol was stirred and refluxed over weekend. The reaction mixture was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and tetrahydrofuran, yielding 2.5 parts (45.3%) of 3-chloro-6-[4-(2-pyridinyl)-1-piperazinyl]pyridazine; mp. 194.7° C. (compound 213).
Reaction SMILES: [I-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:30][CH:27]4[CH2:29][CH2:28]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: NC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-chloro-1-[(cyclopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.N1CCCC1>Cl[Pd]Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:29]2[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd]Cl
Solvent: C1CCNC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCC#Cc2ccc(Br)cc2)cc1
Yield: 33.8 %

Procedure:
General procedure A was followed using the product from step 3 Example 1 (266 mg, 0.803 mmol), p-bromo iodobenzene (156.5 mg, 0.669 mmol), PdCl2 (2.5 mg, 0.014 mmol), pyrrolidine (0.277 mL, 3.34 mmol), water (0.844 mL) to give the title compound (110 mg, 33.8%).
Reaction SMILES: [CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:39][C:40]([F:47])([F:46])[CH2:41][CH2:42][C:43](O)=[O:44].C(N1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(OCC)(=O)C.O>[CH:1]([N:4]1[C:32](=[O:33])[C:31]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:29][CH3:30])[C:18]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])=[CH:19][C:20]=4[C:11]3=[C:10]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)[C:9]=2[CH2:8][N:7]([C:43](=[O:44])[CH2:42][CH2:41][C:40]([F:47])([F:46])[F:39])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)CCC(F)(F)F
Reactant: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Agent: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1-c1c(C)nn(C)c1C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(=O)CCC(F)(F)F)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 26 mg of 10q, 10 mg of trifluorobutyric acid, 15 μl of N-ethyl morpholine and 20 mg of TBTU was stirred at RT for 1 hr. The turbid mixture readily became homogeneous. After one hour, water and ethyl acetate were added and the mixture was stirred for ½ hr. The organic layer was once washed with 1N NaOH and twice with 5% aq. NH4Cl, dried and concentrated. The residue was treated with diethyl ether, from which 25 mg of 10t crystallized, Mp: 256-258° C. Rf 0.25 (heptane/acetone). MS-ESI: [M+1] 654.18
Reaction SMILES: [CH:1]([C:4]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)([C:30](=[O:32])[NH2:31])[N:5]1[C:11](=[O:12])[CH:10]([NH:13][C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[C:9](=[O:25])[NH:8][C:7]2[CH:26]=[CH:27][CH:28]=[CH:29][C:6]1=2)([CH3:3])[CH3:2].Br[C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.[K+].C([O-])(=O)C>CN(C=O)C.[Cu]>[CH:1]([C:4]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)([C:30](=[O:32])[NH2:31])[N:5]1[C:11](=[O:12])[CH:10]([NH:13][C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[C:9](=[O:25])[N:8]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:7]2[CH:26]=[CH:27][CH:28]=[CH:29][C:6]1=2)([CH3:3])[CH3:2]
Reactant: Brc1cccnc1
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)C(=O)Nc3ccccc32)cc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)C(=O)N(c3cccnc3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 11.9 %

Procedure:
To a solution of 1H-Indole-2-carboxylic acid {1[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo-2,3,4,5-tetrhydro-1H-benzo[b][1,4]diazepine-3-yl}amide (0.14 g, 0.26 mmol) and 3-bromopyridine (40 μL, 0.42 mmol)in DMF (1 mL) was added copper powder (46 mg, 0.73 mmol) and acetic acid potassium salt (38 mg, 0.73 mmol). The heterogenous solution was stirred at 100° C. for 15 h and subsequently hot filtered through celite and washed with methanol. The resulting precipitate was filtered and purified by RPHPLC (40-60% C. over 30 min) to yield the title compound (19 mg) as a white lyophile: Tr=8.7 min (40-60% C. over 30 min); 1HNMR (d6 -Acetone, 300 MHz) δ 10.98 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 7.85 (d, 1H, J=8.8), 7.5 (m, 15H), 5.68 (d, 1H, J=7.6), 5.02 (m, 1H), 4.65 (ABq, 2H, J=16.8, 135), 4.02 (s, 3H), 2.19 (d, 3H, J=2.0), 2.18 (d, 3H, J=2.0); low resolution MS(FAB) m/e 617 (MH+).