Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH2:25][CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Li+]>O1CCCC1.CO>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]=1[CH2:25][CH3:26])=[O:31]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cc3c(c2n1Cc1ccccc1)CCC3
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCC3
Temperature: 40 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A solution 2-[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-benzyl-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (10 mg, 0.023 mmol) in 1:1 tetrahydrofuran/methanol (3 mL) was treated with 1 M aqueous lithium hydroxide solution (1.5 mL) The resulting mixture was warmed to 40° C. and stirred for 2 h. The mixture was concentrated in vacuo and treated with dilute hydrochloric acid. The resulting precipitate was collected via vacuum filtration. The solid was slurried with methanol, and the resulting solid collected via vacuum filtration to provide 5 mg (52%) of the title product as a white solid. 1H NMR (CDCl3) δ 7.25 (m, 3H), 7.03 (bs, 1H, —NH), 6.90 (d, J=6 Hz, 2H), 6.57 (s, 1H), 6.45 (bs, 1H, —NH), 5.50 (s, 2H), 4.77 (s, 2H), 2.90 (m, 6H), 2.04 (quintet, J=7 Hz, 2H), 1.18 (t, J=7 Hz, 3H); TOS MS ES+ exact mass calculated for C24H25N2O5 (p+1): m/z=421.1763. Found: 421.1767.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.P(Br)(Br)[Br:12].O>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=1[F:10]
Reactant: OCc1c(F)cncc1F
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Fc1cncc(F)c1CBr
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
To a solution of (3,5-difluoropyridin-4-yl)methanol (3.5 mmol) in anhydrous chloroform (15 mL) was added dropwise a solution of phosphorus tribromide (330 μL, 3.5 mmol) in anhydrous chloroform (5 mL) at 0° C. The mixture was stirred for 6 hours at room temperature. Water was added, and the reaction was extracted 3 times with dichloromethane. The combined organic phases were washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 4-(bromomethyl)-3,5-difluoropyridine was obtained as pale yellow solid (600 mg, 83% yield for 2 steps) and used in the next step without purification; 1H NMR (400 MHz, MeOd4): δ 4.59 (s, 2H), 8.42 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)=[O:13]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)cc1

Procedure:
To a solution of 4-hydroxy-1-napthaldehyde (172 mg, 1.0 mmol) in DCM (10 mL) was added copper (II) diacetate (181 mg, 1.0 mmol), 4-cyanophenyl boronic acid (441 mg, 3.0 mmol), triethylamine (0.7 mL, 5.0 mmol) and 4 Å molecular sieves. After 48 h at rt the mixture was filtered. Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane 3:7). The resulting solid was washed with ether (10 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound: δH (CDCl3) 7.06 (1H, d), 7.21 (2H, d), 7.49 (1H, t), 7.62-7.82 (3H, m), 7.96 (1H, d), 8.28 (1H, d), 9.36 (1H, d), 10.33 (1H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10]([Cl:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C[Si](Cl)(C)C>C(O)CCC>[Cl:11][C:10]1[C:5]2[C:4]([NH:12][CH:13]3[CH2:16][CH2:15][CH2:14]3)=[N:3][C:2]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[N:7][C:6]=2[NH:8][CH:9]=1
Reactant: Clc1nc(NC2CCC2)c2c(Cl)c[nH]c2n1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Clc1c[nH]c2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CCC3)c12
Temperature: 116 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
A mixture of 2,5-dichloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (23 mg, 0.089 mmol), 6-aminoindazole (40 mg, 0.30 mmol) and TMSCl (0.040 mL, 0.32 mmol) in nBuOH (2 mL) was stirred at 116° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (8 mg). MS 354.0, 356.0 (M+H, Cl pattern); UV 201.4, 246.2, 307.9 nm.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:11]([O:16][CH2:17][CH:18]1[O:20][CH2:19]1)(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:21]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23].N(C(C)(CC)C([O-])=O)=NC(C)(CC)[C:37]([O-])=[O:38]>CCCCCCC.C(C(C)=O)C(C)C>[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:11]([O:16][CH2:17][CH:18]1[O:20][CH2:19]1)(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:21]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23].[C:1]([O:6][CH:7]([CH3:10])[CH2:8][O:38][CH3:37])(=[O:5])[CH3:2]
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: C=C(C)C(=O)OC(C)(C)C
Agent: C=C(C)C(=O)OCC1CO1
Agent: C=C(C)C(=O)OCc1ccccc1
Solvent: CCCCCCC
Solvent: CC(=O)CC(C)C
Product: COCC(C)OC(C)=O
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 42.7 g (0.3 mol) of tert-butyl methacrylate, 21.3 g (0.15 mol) of glycidyl methacrylate, 26.4 g (0.15 mol) of benzyl methacrylate and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in propylene glycol monomethyl ether acetate, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A′-9 (tert-butyl methacrylate/glycidyl methacrylate/benzyl methacrylate) as a propylene glycol monomethyl ether acetate solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)[CH:6]=[CH:5]2.ClC1C(Cl)=CC(C(O)=O)=C(C=O)C=1.[C:33]([O:37][C:38](=[O:56])[CH2:39][C@H:40]([NH2:55])[CH:41]([OH:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:56])[CH2:39][C@H:40]([NH:55][C:15](=[O:17])[C@@H:14]([N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:13])[CH2:18][CH3:19])[C:41](=[O:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: CC[C@@H](C(=O)O)n1ccc2cc(Cl)c(Cl)cc2c1=O
Agent: O=Cc1cc(Cl)c(Cl)cc1C(=O)O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2cc(Cl)c(Cl)cc2c1=O

Procedure:
This compound was prepared using (S)-2-(6,7-dichloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid (synthesized from 4,5-dichloro-2-formyl-benzoic acid [prepared as described in methods R-T] using procedures similar to those described in methods A-E) and (3S)-3-Amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods H-J) using procedures similar to those described in methods F-G. The title compound was isolated as a white solid (94% last step); IR (solid) 1784.5, 1734.7, 1650.1, 1610.2, 1585.4, 1515.7, 1490.8, 1426.0, 1216.9, 1172.1, 1092.5, 933.1 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.80 (3H, t), 1.90-1.98 (1H, m), 2.04-2.12 (1H, m), 2.55-2.79 (2H, m), 4.56-4.71 (1H, m), 5.08-5.41 (3H, m), 6.67 (1H, d), 7.56-7.59 (2H, m), 8.07 (1H, brs), 8.25 (1H, d), 8.85-8.95 (1H, 2×d), 12.73 (1H, brs); 19F NMR (376 MHz, d6-DMSO) (proton decoupled) δ −140.93, −140.95, −140.99, −141.01, −141.04, −141.07, −141.10, −156.76, −156.79, −156.82, −156.85, −156.89, −156.91; MS ES (+): 577.14 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:12]=[CH2:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=C[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-].[Si:22]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Si:22]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:24])[CH3:23].[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:23][CH2:13]1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Solvent: CCOCC
Product: CCOC(=O)C1([C@H](CO)NC(=O)OC(C)(C)C)CC1
Yield: 87.9 %

Procedure:
Palladium(II) acetate (168 mg, 0.75 mmol) was dissolved in an ether solution (50 ml) of t-butyldimethylsilyl ether of (2R)-N-t-butoxycarbonyl-2-amino-3-butenol (3) (4.34 g, 15.0 mmol) and to this was added an ether solution (100 ml) of ethyl diazoacetate (17.1 g, 150 mmol) and palladium(II) acetate (168 mg, 0.75 mmol) over 3 hours. The insoluble material in the reaction mixture was filtered off and the filtrate was concentrated under reduced pressure to give an oily product. Purification of the product by column chromatography over silica gel (20% ether/hexane) afforded t-butyldimethylsilyl ether of (2R)-N-t-butoxycarbonyl-2-(ethoxycarbonylcyclopropyl)glycinol (4) as an oil (4.00 g, 87.9%). Compound (4) thus obtained was dissolved in ethanol (70 ml) and CSA (10 mg) was added to this solution then the mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was subjected to medium pressure column chromatography over silica gel (50% ether/hexane) 932 mg of (2R,3S,4S)-N-t-butoxycarbonyl-2-(ethoxycarbonylcyclopropyl)glycinol (5), 175 mg of its stereoisomer (6) and 560 mg of a mixture of inseparable stereoisomer.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.C(Cl)Cl>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:13]4[CH:12]=[CH:11][C:10]([CH2:9][N:3]5[C@H:4]([CH3:8])[CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[CH:15][CH:14]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: C[C@@H]1CCC[C@H](C)N1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)cc1
Yield: 38.7 %

Procedure:
A degassed mixture of (2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]piperidine (685 mg, 2.08 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (389 mg, 1.04 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (127 mg, 0.16 mmol) in saturated sodium carbonate solution (1 mL) and THF (10 mL) was heated under reflux for 18 h. The cooled reaction mixture was diluted with DCM (50 mL) and washed with water (25 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g column, ISCO, 0-15% methanol in DCM) to afford the title compound as an off-white solid (181 mg, 39%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=2.2 Hz, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.69 (d, J=0.9 Hz, 1H), 8.29 (d, J=0.9 Hz, 1H), 7.68-7.63 (d, J=8.1 Hz, 2H), 7.56-7.50 (m, 2H), 4.00 (s, 2H), 2.65-2.51 (m, 2H), 1.72-1.56 (m, 4H), 1.46-1.30 (m, 2H), 1.25 (d, J=6.2 Hz, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([CH3:12])=O.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=[N:14][OH:15])[CH3:12]
Reactant: NO
Reactant: CC(=O)c1cc2ccccc2o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Twenty six grams (g) (162 millimoles (mmol)) of commercially available 2-benzofuranylmethylketone was dissolved in 300 milliliters (ml) of methanol, and 16.9 g (243 mmol) of hydroxylamine hydrochloride and 20.4 g (243 mmol) of sodium hydrogencarbonate were added thereto. The resulting mixture was stirred at room temperature for 8 hours. Then, φml of water was added and the methanol was distilled away under reduced pressure. Precipitated crystals were filtered off and washed with water to yield 27.8 g of 2-benzofuranylmethylketone oxime having the following formula (yield, 98%). ##STR26##
Reaction SMILES: [C:1](O)(=O)C.C(O)(=O)C.[NH:9]1[CH2:12][CH:11]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:22])=[C:16]3[C:15]([I:23])=[N:14]2)[CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[OH-].[Na+]>ClC(Cl)C>[I:23][C:15]1[C:16]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:22])[N:13]([CH:11]2[CH2:12][N:9]([CH3:1])[CH2:10]2)[N:14]=1
Reactant: CC(=O)O
Reactant: Nc1ncnc2c1c(I)nn2C1CNC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of to 1-(3-azetanyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.165 g, 0.0005 mol) and sodium triacetoxyborohydride (0.15 g, 0.00073 mol) in dichloroethane (15 mL) was added a 37% solution of formaldehyde in 0.016 mL, 0.000572 mol) at room temperature. The mixture was stirred at room temperature under an atmosphere of nitrogen for 16 hours. Additonal formaldehyde (37% in water, 0.016 mL, 0.000572 mol) and sodium triacetoxyborohydride (0.15 g, 0.00073 mol) were added, and the mixture was stirred at room temperature for 2 days. An aqueous 5N solution of sodium hydroxide (1 mL) was added to the mixture. The solvent was removed under the reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure. Majority product was still in aqueous layer. The aqueous layer and the residue from organic layer were combined. The solvent was removed, and the residue was carried to the next step without purification. TLC (methanol/dichloromethane=10:90) Rf 0.48 MS: MH+ 331
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=1
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of cis-methyl 4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylate (2.51 g, 8.00 mmol) in dioxane (10 mL) was added 4N aqueous HCl (52.0 mL, 208 mmol), and the resulting mixture was stirred at 60° C. for 3 hours. The mixture was concentrated to dryness to afford cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid hydrochloride as a yellow solid (2.69 g, 100% yield). MS m/z=300.2 [M+H]. Calc'd for C12H14ClN3O4: 299.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)=[C:4]([OH:32])[CH:3]=1.Br[CH:34]([CH3:37])[C:35]#[N:36]>>[C:35]([CH:34]([CH3:37])[O:32][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH3:31])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)#[N:36]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Reactant: CC(Br)C#N
Product: CC(C#N)Oc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 49, from N-[4-(4-fluoro-2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 48) and 2-bromopropionitrile (CAS RN 19481-82-4). Off-white solid (74%). MS (ESI): m/z =512.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[C:9]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:22]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17](Br)[CH2:18][CH3:19])=[N:15][N:16]=3)[C:7]=2[C:6]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:5][CH:4]=1)[CH3:2].[CH3:37][NH:38][CH3:39].[I-].[Na+]>>[CH2:1]([C:3]1[C:8]2[C:9]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:22]=3)=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17]([N:38]([CH3:39])[CH3:37])[CH2:18][CH3:19])=[N:15][N:16]=3)[C:7]=2[C:6]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(S(C)(=O)=O)c2c1C(c1cc(Cl)cc(S(=O)(=O)CC)c1)=NCc1nnc(C(Br)CC)n1-2
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Product: CCc1ccc(S(C)(=O)=O)c2c1C(c1cc(Cl)cc(S(=O)(=O)CC)c1)=NCc1nnc(C(CC)N(C)C)n1-2

Procedure:
In the manner given in Example 1, 7-ethyl-10-methylsulfonyl-1-(α-bromopropyl)-6-(3-ethylsulfonyl-5-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 7-ethyl-1-[α-(dimethylamino)propyl]-10-methylsulfonyl-6-(3-ethylsulfonyl-5-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([CH3:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[C:16]([CH3:32])[C:15]=2[F:33])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[N:11]1([C:14]2[C:23]([CH3:24])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:26][CH2:27]3)=[C:16]([CH3:32])[C:15]=2[F:33])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1c(F)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1c(F)c(N2CCNCC2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 53.4 %

Procedure:
To a solution of 7-(4-benzyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg) in ethanol (20 ml) is added 10% Pd-C (50 mg) and the catalytic reduction is carried out at 70° C. under atomospheric pressure. After filtering off the 10% Pd-C, the filtrate is concentrated. The residue is recrystallized from dimethylformamide to give 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (64 mg), m.p. 185°-187° C., as pale yellow needles.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[N-:8]=[N+:9]=[N-:10].[Na+].[Cl-].[NH4+]>CO.O>[N:8]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7])=[N+:9]=[N-:10]
Reactant: C1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NC1CCCCC1O
Temperature: 72 °C

Procedure:
A mixture of cyclohexene oxide (2 g, 20.4 mmol), sodium azide (1.86 g, 30.6 mmol), and ammonium chloride (2.16 g, 40.8 mmol) in methanol/water (61 mL/6 mL) was heated to 72° C. for 16 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give pure product. (2.3 g, 80%). EI-MS m/z 242 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.[OH-].[Na+]>C(O)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]([Br:15])=[CH:13][N:14]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2nccs2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ncc(Br)s2)CC1
Yield: 68.1 %

Procedure:
A solution of 4-acetyl-1-(thiazol-2-yl)piperazine (3.1 g) and N-bromosuccinimide (2.9 g) in acetic acid (14 ml) was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid (2.9 g). The obtained pale-brown solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give the title compound (2.1 g) as a pale-brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:6]([C:7]([NH:9][NH2:10])=[O:8])[C:5]=1[OH:14])([O-:3])=[O:2].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:18]1([C:15](=[N:10][NH:9][C:7](=[O:8])[C:6]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)[OH:14])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccccc1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(=NNC(=O)c1cccc([N+](=O)[O-])c1O)c1ccccc1
Temperature: 22.5 °C
Reaction time: 14 h
Yield: 93.6 %

Procedure:
A solution of 1.0 g (5 mmol) of 3-nitrosalicylohydrazide in 50 ml of anhydrous ethanol were treated with 0.6 g (5 mmol) of acetophenone and with a catalytic amount of p-toluenesulfonic acid. After the mixture had been stirred for 14 hours at approximately 20 to 25° C. and the solvent had been distilled off, 1.4 g of the title compound (90% of theory) were obtained as colorless crystals of m.p.: 163-168° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.Cl.[NH2:18][C@@H:19]([CH2:23][OH:24])[C:20]([NH2:22])=[O:21].C(N(CC)CC)C>>[OH:24][CH2:23][C@H:19]([N:18]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:20]([NH2:22])=[O:21]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=O)[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 52 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (2 g, 0.01 mol), methanol (40 mL, 1 mol), (S)-2-amino-3-hydroxypropanamide hydrochloride (2.2 g, 0.016 mol) and triethylamine (2.55 mL, 0.0183 mol) and stirred at 52° C. overnight. The product precipitated out and was filtered and dried to yield the pure product as a yellow solid. MS m/z=278.3 (M+H).