Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:12]4[N:13]([CH:20]=[N:21][CH:22]=4)[CH:14]=[CH:15][C:16]=3[C:17]([OH:19])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:55][O:56][C:57]([CH3:61])([CH3:60])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([CH3:61])([CH3:60])[O:56][NH:55][C:17]([C:16]1[CH:15]=[CH:14][N:13]2[CH:20]=[N:21][CH:22]=[C:12]2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:23])=[O:19]
Reactant: CC(C)(CO)ON
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CO)ONC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.9 %

Procedure:
A suspension of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (0.11 g, 0.35 mmol), EDCI (0.081 g, 0.42 mmol), HOBt (0.057 g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and 2-aminooxy-2-methyl-propan-1-ol hydrochloride (0.055 g, 0.39 mmol) in DMF (1.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 ml). The organic layer was washed with water (5 mL), followed by brine (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 40%, ethyl actetate in DCM) to give a yellow solid, which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (11 mg, 8%). LCMS (method A): RT=7.57 min, [M+H]+=399. 1H NMR (DMSO-d6): 10.37 (1H, s), 8.28 (1H, s), 7.79 (1H, dd, J=7.35, 0.95 Hz), 7.14 (1H, s), 7.02-6.93 (1H, m), 6.91 (1H, d, J=8.28 Hz), 6.82 (1H, s), 6.27 (1H, s), 1.99-1.90 (1H, m), 1.15 (6H, s), 0.99-0.92 (2H, m), 0.73-0.67 (2H, m).
Reaction SMILES: F[C:2]1[C:3](=[O:20])[N:4]([CH2:12][C:13]2[N:17]([CH3:18])[C:16](=[O:19])[NH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[F:21][CH:22]([F:32])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([OH:31])[CH:30]=1)[C:26]#[N:27].C([O-])([O-])=O.[K+].[K+]>O>[F:21][CH:22]([F:32])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][C:2]2[C:3](=[O:20])[N:4]([CH2:12][C:13]3[N:17]([CH3:18])[C:16](=[O:19])[NH:15][N:14]=3)[CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9])[CH:30]=1)[C:26]#[N:27]
Reactant: Cn1c(Cn2ccc(C(F)(F)F)c(F)c2=O)n[nH]c1=O
Reactant: N#Cc1cc(O)cc(C(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1c(Cn2ccc(C(F)(F)F)c(Oc3cc(C#N)cc(C(F)F)c3)c2=O)n[nH]c1=O
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 3-fluoro-1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-4-(trifluoromethyl)pyridin-2(1 H)-one (8-8; 30 mg; 0.103 mmol), 3-(difluoromethyl)-5-hydroxybenzonitrile (8-7; 34.7 mg; 0.205 mmol) and K2CO3 (28.4 mg; 0.205 mmol) was heated to 75° C., and stirred overnight. After cooling to room temperature, the mixture was diluted with water and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by mass-directed HPLC provided 2.1 mg (0.0048 mmol; 4.6%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO): δ 11.70 (s, 1 H); 7.90 (d, J=7.3 Hz, 1 H); 7.80 (d, J=8.5 Hz, 2 H); 7.57 (s, 1 H); 7.05 (t, J=55.2 Hz, 1 H); 6.69 (d, J=7.3 Hz, 1 H); 5.17 (s, 2 H); 3.10 (s, 3 H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH2:40]([S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43])[CH3:41].C(SCCCO)C.Cl.Cl.CS(CCCN1CCNCC1)(=O)=O>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:51]3[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])[CH2:49][CH2:50]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: CCSCCCO
Agent: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(=O)(=O)CC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(3-ethanesulfonyl-propyl)-piperazine dihydrochloride (prepared from 3-ethylsulfanyl-propan-1-ol in an analogous manner as the method described for 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride, Ding, Q. et al. WO2007063013) to give the title compound. HR-MS (ES, m/z) calculated for C38H50Cl2N5O4S [(M+H)+] 742.2955, observed 742.2952.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([Cl:13])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH3:18][O:19][CH2:20]Cl.O>C1COCC1>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([Cl:13])[C:5]([O:12][CH2:18][O:19][CH3:20])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(OC)c(Cl)c1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1c(C(=O)OC)cc(Br)c(OC)c1Cl
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of methyl 5-bromo-3-chloro-2-hydroxy-4-methoxybenzoate (5.00 g) in THF (120 mL) was added sodium hydride (1.01 g) under ice-cooling, and the mixture was stirred for 1 hr under nitrogen atmosphere. To this reaction mixture was added dropwise chloromethyl methyl ether (1.63 g), and the mixture was stirred at 20° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.08 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][C:3]=1[O:19][CH3:20].[CH:21]1([Mg]Br)[CH2:23][CH2:22]1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH:21]1([CH:6]([C:5]2[CH:17]=[CH:18][C:2]([F:1])=[C:3]([O:19][CH3:20])[CH:4]=2)[CH:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[CH2:23][CH2:22]1
Reactant: Br[Mg]C1CC1
Reactant: COc1cc(C=C2C(=O)OC(C)(C)OC2=O)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(C2CC2)C2C(=O)OC(C)(C)OC2=O)ccc1F
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of (5-(4-fluoro-3-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.00 g) in THF (20 mL) was added dropwise a 1.0 M solution of cyclopropylmagnesium bromide in THF (53.5 mL) at 0° C., and the mixture was stirred for 1 hr. 3N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was stirred for 15 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.40 g) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[OH-].[K+].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1(C)C=CC=CC=1>[CH2:21]([N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cc1ncc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCCBr
Product: CCCCCCCCCCCCn1ccnc1C
Temperature: 60 °C

Procedure:
After the reaction is completed, the reaction mixture contains a solution comprised of the 1-alkylimidazole and inorganic materials dissolved in the non-reactive aromatic solvent. The dissolved inorganic materials are unreacted base and inorganic salts which would be expected to form in the alkylation reaction. In addition, substantial amounts of insoluble unreacted base and inorganic salt are dispersed in the solution. For example, if imidazole is alkylated with 1-bromobutane in the presence of potassium hydroxide in toluene, the product mixture would contain a 1-butylimidazole-toluene solution in which are dissolved small amounts of potassium bromide and unreacted potassium hydroxide and undissolved potassium bromide and potassium hydroxide dispersed in the 1-butylimidazole-toluene solution. The solid inorganic material can be separated from the toluene solution by any means known to those skilled in the art such as by filtration. Inorganic material as defined above dissolved in the toluene solution can be removed by any means known to those skilled art such as by washing the organic phase with aqueous brine solutions. The imidazole product may be isolated from the solvent or may remain dissolved therein. The product imidazole can be isolated by any means known to those skilled in the art such as by distillation of the solvent. In a preferred embodiment of the present invention, about 1.5 moles of 2-methylimidazole and about 1.9 moles of potassium hydroxide powder are mixed with about 536 mL of toluene and heated to about 60° C. for 30 minutes with stirring. The temperature is then raised to 90° C. and about 1.36 moles of 1-bromododecane are added over 60 minutes. After the addition is complete, the reaction mixture is then maintained at 90° C. until the 1-bromododecane is no longer observable by GC analysis of the reaction mixture. The reaction mixture is then cooled and the organic phase and inorganic phases separated by filtration. The organic phase is washed with four 500 mL portions of brine and the toluene is removed at 40° C. under vacuum leaving a 99 mole % yield of N-dodecyl-2-methylimidazole relative to 1-bromododecane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:11])=[CH:5][CH:4]=1.C(O)(=O)[C@H](C1C=CC=CC=1)O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@H:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(C)NCc2ccccc2)cc1
Agent: O=C(O)[C@@H](O)c1ccccc1
Product: COc1ccc(C[C@@H](C)NCc2ccccc2)cc1
Yield: 17.6 %

Procedure:
A sample of 3.02 g (11.8 mmol) of 1-(4′-methoxyphenyl)-2-benzylaminopropane (42) was reacted with 1.8 g (11.8 mmol) (S)-(+)-mandelic acid to give 530 mg (35% based on enantiomeric abundance) of the free amine after workup. 1H NMR (CDCl3) δ□ 1.10 (d, 3H, J=6.3 Hz), 2.57-2.76 (m, 2H), 2.88-2.94 (m, 1H), 3.79 (s, 3H), 3.72-3.88 (m, 2H), 6.82 (d, 2H, J=8.7 Hz), 7.07 (d, 2H, J=8.4 Hz), 7.15-7.31 (m, 5H); MS (APCI+) m/z (rel): 256 (100); [α]D=−30.4° (c=1.25 MeOH).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].CN1CCOCC1>C(#N)C>[CH2:12]([O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:25])[CH3:26])[NH:22][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[CH3:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(C)Br
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
Leucine benzyl ester para-toluene sulphonic acid salt (113 g) in dry acetonitrile (800 ml) was treated with methyl 2-bromopropionate (62.7 ml) and N-methyl morpholine (100 ml) under reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue in ethyl acetate washed with brine, dried (Na2SO4) and evaporated. Chromatography of the resulting oil on silica in 1:4 ethyl acetate-hexane gave N-[1-(R)-methoxycarbonylethyl]-L-leucine benzyl ester (45 g) as the faster running fraction. This material was treated exactly as described above in Example 2 to give the title compound.
Reaction SMILES: [CH2:1]=[C:2]=[CH2:3].C=C1CCC1=C.[CH2:10]=[C:11]1[CH2:14][C:13](=[CH2:15])[CH2:12]1>>[CH2:1]=[C:2]1[CH2:3][CH2:12][C:13](=[CH2:15])[CH2:14][C:11]1=[CH2:10]
Reactant: C=C1CC(=C)C1
Reactant: C=C=C
Agent: C=C1CCC1=C
Product: C=C1CCC(=C)C(=C)C1

Procedure:
The system was first purged with nitrogen. The power to the fluidized bed was turned on and its temperature was brought to 450°-470° C. Allene was introduced into the system from the allene cylinder at a rate of 80-100 grams/hour. The allene supply from the cylinder was shut off two to three hours before the end of a dimerization run in order that the allene present in the system could be used up, with little allene remaining in the reservoir a the end. At the end of the day, the power to the fluidized bed was turned off, the system was allowed to cool, and the accumulated crude liquid-product was poured into a bottle and weighed. Approximately 3 grams of phenothiazine was added per kilogram of crude liquid product to inhibit polymerization and oxidation of the dimers and trimers. The crude product was then analyzed by gas chromatography for peaks corresponding to two allene dimers, 1,2dimethylenecyclobutane (1,2-DMCB) and 1,3-dimethylenecyclobutane (1,3-DMCB), and the allene trimer 1,2,4-trimethylenecyclohexane (TMCH). Data from seven hot tube reaction runs are shown in Table 1.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[N:7]=[N+:8]([O-:20])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH3:19])[CH2:16]3)=[CH:12][C:10]=2[N:11]=1.C[OH:23].C(Cl)Cl>>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[N:7]=[N+:8]([O-:20])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH3:19])[CH2:16]3)=[CH:12][C:10]=2[N+:11]=1[O-:23]
Reactant: CO
Reactant: CC1Cc2cc3nc(NCCN(C)C)n[n+]([O-])c3cc2C1
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1)[n+]([O-])c(NCCN(C)C)n[n+]3[O-]

Procedure:
H2O2 (70%, 0.65 mL, ca. 12.9 mmol) was added dropwise to a stirred solution of TFAA (1.8 mL, 12.9 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 96 (371 mg, 1.3 mmol) and TFA (0.50 mL, 6.5 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 96 (181 mg, 49%) and (ii) 1,4-dioxide 97 (103 mg, 26%) as a red solid: mp (MeOH/DCM) 149-151° C.; 1H NMR δ 8.09 (s, 1H, H-9), 8.07 (s, 1H, H-5), 7.52 (br s, 1H, NH), 3.58-3.64 (m, 2H, CH2N), 3.14-3.27 (m, 2H, CH2), 2.63-2.75 (m, 3H, CH, CH2), 2.59 (br t, J=6.0 Hz, 2H, CH2), 2.28 [s, 6H, N(CH3)2], 1.18 (d, J=6.2 Hz, 3H, CH3); 13C NMR δ 155.6, 149.4, 145.5, 138.0, 128.9, 115.8, 111.8, 57.4, 45.0 (2), 41.4, 40.4, 38.7, 34.8, 20.1. Anal. calcd for C15H21N5O2.½CH2Cl2: C, 54.6; H, 6.3; N, 19.9. Found: C, 54.4; H, 6.0; N, 19.8%.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH2:17][CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][N:20]3[CH3:24])[C:15](=O)[CH2:14][O:13][C:12]=2[CH:26]=1>C1COCC1>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][CH2:17][N:16]1[CH2:15][CH2:14][O:13][C:12]2[CH:26]=[C:8]([NH2:7])[CH:9]=[CH:10][C:11]1=2
Reactant: CN1CCCC1CCN1C(=O)COc2cc(N)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC1CCN1CCOc2cc(N)ccc21
Reaction time: 8 h
Yield: 83.6 %

Procedure:
A solution of LiAlH4 (4.21 mL, 4.212 mmol, 1.0 M solution in THF) was treated dropwise with 7-amino-4-(2-(1-methylpyrrolidin-2-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (0.29 g, 1.053 mmol) in dry THF (5 mL) at 0° C. The resulting mixture was brought to room temperature and stirred overnight. The reaction was carefully quenched with the sequential addition of water (0.16 mL), 2 N NaOH solution (0.16 mL), and water (0.16 mL). The reaction was filtered after stirring for 30 minutes at room temperature and washed with CH2Cl2 (3×10 mL). The combined CH2Cl2 layers were evaporated, and the crude material was purified by column chromatography (5:95 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound (0.23 g, 84%) as a syrup. 1H NMR (DMSO-d6) δ 1.28-1.45 (m, 2H), 1.56-1.65 (m, 2H), 1.75-2.10 (m, 4H), 2.18 (s, 3H), 2.88-2.95 (m, 1H), 3.03-3.10 (m, 4H), 4.08 (t, 2H, J=4.8 Hz), 4.36 (s, 2H), 6.00 (d, 1H, J=2.4 Hz), 6.06 (dd, 1H, J=2.4, 8.5 Hz), 6.43 (d, 1H, J=8.4 Hz); ESI-MS (m/z, %): 262 (MH+, 100), 163 (33), 112 (42).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[NH2:35][C:36]1[C:41]([N+:42]([O-])=O)=[C:40]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][C:52]([NH:54][C:55]3[S:56][CH:57]=[CH:58][N:59]=3)=[O:53])[CH2:47][CH2:46]2)[C:39]([Br:60])=[CH:38][N:37]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:69]([CH:71]1[CH2:73][CH:72]1[C:74]([O:76][CH2:77][CH3:78])=[O:75])=O>C(O)C.CN(C=O)C>[Br:60][C:39]1[C:40]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][C:52](=[O:53])[NH:54][C:55]3[S:56][CH:57]=[CH:58][N:59]=3)[CH2:47][CH2:46]2)=[C:41]2[N:42]=[C:69]([CH:71]3[CH2:73][CH:72]3[C:74]([O:76][CH2:77][CH3:78])=[O:75])[NH:35][C:36]2=[N:37][CH:38]=1
Reactant: CCOC(=O)C1CC1C=O
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1c1nc2c(N3CCN(CC(=O)Nc4nccs4)CC3)c(Br)cnc2[nH]1
Reaction time: 16 h
Yield: 25.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (63 mg, 0.14 mmol), DMF (1.3 mL), ethanol (0.2 mL), 1M Na2S2O4 (3 eq, 0.43 mmol, 0.43 mL) and ethyl 2-formyl-1-cyclopropanecarboxylate (1.1 eq, 0.16 mmol, 0.021 mL). After 16 h, concentration in vacuo and preparation by preparative tlc (EtOAc—CH2Cl2-MeOH, 50:50:2) gave the product (19 mg, 25%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 1.21 (t, J=7.1 Hz, 3H, CH2CH3), 1.56 (app. quintet, J=4.6 Hz, 1H, cyclopropane CHAHB), 1.64-1.67 (m, 1H, cyclopropane CHAHB), 2.26 (app. quintet, J=5.0 Hz, cyclopropane CH), 2.73 (br s, 4H, piperazine N(CH2)2), 3.38 (s, 2H, NCH2CO), 3.57 (br s, 4H, piperazine N(CH2)2), 4.13 (q, J=7.1 Hz, 2H, CH2CH3), 7.23 (d, J=3.5 Hz, 1H, thiazole H-4 or H-5), 7.48 (d, J=3.5 Hz, 1H, thiazole H-4 or H-5), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 11.86 (br s, 1H, CONH or imidazo[4,5-b]pyridine NH), 12.94 (br s, 1H, CONH or imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1F.[CH3:14][O-:15].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:15][CH3:14]
Reactant: CCS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Br)c(OC)c1
Temperature: 100 °C
Yield: 75 %

Procedure:
In a sealed vessel 1-bromo-4-(ethylsulfonyl)-2-fluorobenzene (Preparation 19, 34.89 g, 0.131 mol) was dissolved in MeOH (400 mL) and sodium methoxide (35.3 g, 0.653 mol) was added. The reaction was heated at 100° C. for 12 hours and then allowed to cool to room temperature. The reaction mixture was diluted with water (750 mL) and the aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and reduced to dryness to give a solid. The crude was purified by silica gel column chromatography eluting with cyclo-hexane/EtOAc gradient from 95/5 to 8/2 to afford the title compound as colourless solid in 75% yield, 27.32 g.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:14]2CC2C=CC=CC=2)=[O:12])[CH:7]=[CH:8][CH:9]=1>C1COCC1.[Pd]>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:22])([CH3:24])[CH3:23])[NH:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (97 mg, 0.19 mmol) in THF (1 mL) was added Pd/C (10%, 20 mg). The solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere overnight. The catalyst was removed through a pad of Celite and washed with THF. Solvent was concentrated and the crude residue was purified by preparative HPLC (Waters SunFire C18-ODB 5 μm, 19×50, 5-100% CH3CN/H2O in 17 min, 100% CH3CN for 3 min, CH3CN and H2O containing 0.1% TFA, flow: 20 mL/min) to give the desired compound. MS (LC/MS): 419 [M+H]+; tR (HPLC conditions b): 5.28 min.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][NH2:38])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][NH:38][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCCCC1CCCCN1CCCCC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCCC2CCCCN2CCCCC2)c2ccccc21
Yield: 36 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[4-(piperidin-l-yl)butyl]-piperidin-l-yl]ethanamine in a yield of 36% of theory. Colourless crystals, m.p. 154°-155° C. (acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[N:10][C:9]2[NH:8][C:7](=[O:15])[CH2:6][S:5][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([N:22]=[CH:23][C:24]([S:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]3)=[N:25]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([N:22]=[CH:23][C:24]([S:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH:34]([NH:37][C:12]([C:11]4[C:2]([Cl:1])=[CH:3][C:4]5[S:5][CH2:6][C:7](=[O:15])[NH:8][C:9]=5[N:10]=4)=[O:14])[CH2:35][CH2:36]3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)nc2N1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4nc5c(cc4Cl)SCC(=O)N5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (9 mg, 12% yield) following Scheme 3 and in analogy to Example 35 using 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (31 mg, 0.12 mmol, 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40 mg, 0.12 mmol, 1.0 eq) as starting materials.