Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CO.C(OC([N:11]([C:39]1[C:48]([N+:49]([O-:51])=[O:50])=[CH:47][CH:46]=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1)=O)(C)(C)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:29]2[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:16]3[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:39]4[C:48]([N+:49]([O-:51])=[O:50])=[CH:47][CH:46]=[CH:45][C:40]=4[C:41]([O:43][CH3:44])=[O:42])=[CH:18][CH:17]=3)=[N:26][N:27]=[N:28]2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccc(OC)cc2)cc1
Temperature: 3 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
To hydrogen chloride-methanol (30%; 26.9 g, net 8.08 g, 222 mmol) was added methyl 2-(N-tert-butoxycarbonyl-N-{(2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate (compound 20a, 5.00 g, 7.68 mmol) over 13 min by four portions at 4-5° C. The mixture was stirred at about 3° C. for 2 hr, and warmed to 9° C. over 1 hr. The reaction was monitored by TLC (eluent: toluene/ethyl acetate (2:1)). The reaction mixture was cooled to 3° C., and saturated aqueous sodium hydrogen carbonate solution (180 mL) was added dropwise thereto at 30° C. or lower. The mixture was extracted twice with ethyl acetate (450 mL, 250 mL), and the combined organic layers were washed with saturated brine (200 mL), dried over magnesium sulfate (10 g), and concentrated under reduced pressure at 40° C. or lower. To the concentrate was added chloroform, and the solvent was evaporated under reduced pressure in a bath at 40° C. to give methyl 2-[({2′-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-nitrobenzoate (compound 21a, 4.27 g, 101%) as a yellowish brown amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([O:22][CH3:23])=[C:15]([O:24][CH3:25])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[C:13]2[CH:14]=[C:15]([O:24][CH3:25])[C:16]([O:22][CH3:23])=[C:17]([NH:19][S:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)(=[O:37])=[O:36])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c(OC)c([N+](=O)[O-])c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cccc(Cl)c3)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(3-Chloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=489.2 (M+H+), was prepared in analogy to example 1, steps A to D. Step A was performed using 3,4-dimethoxy-5-nitro-benzoyl chloride and yielded 4-(3,4-dimethoxy-5-nitro-benzoylamino)-benzoic acid ethyl ester. This was reduced to 4-(3,4-dimethoxy-5-nitro-benzoylamino)-benzoic acid ethyl ester in step B. This was coupled with 3-chloro-benzenesulfonyl chloride in step C, yielding 4-[3-(3-chloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=C[CH:2]=1.[CH:8](=[O:11])[CH2:9][CH3:10].N1CCCC[CH2:13]1.C(O)(=O)C>O>[CH3:13][C:6]1[C:1]([CH3:2])([CH3:7])[CH:10]([CH2:9][CH:8]=[O:11])[CH2:4][CH:5]=1
Reactant: C1CCNCC1
Reactant: Cc1ccccc1
Reactant: CCC=O
Solvent: CC(=O)O
Solvent: O
Product: CC1=CCC(CC=O)C1(C)C
Temperature: 25 °C

Procedure:
3.04 kg of campholene aldehyde and 2 kg of toluene were introduced into a 10-liter glass reactor and 2.9 kg of propionaldehyde, 170 g of piperidine and 120 g of glacial acetic acid were added with stirring at room temperature. The mixture was then refluxed for 4 hours on a water separator, 680 ml of water of reaction being removed from the circuit. Analysis of a sample of the reaction mixture by gas chromatography revealed a percentage content of 15% of unreacted educt. Accordingly, another 85 g of piperidine and 60 g of glacial acetic acid were added. After refluxing for another hour, another 120 g of water were removed from the circuit and the educt was completely reacted.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.[CH2:21]([O:23][C:24]([C:26]1[N:27]=[CH:28][O:29][C:30]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2OC(C)(C)O[C:41](=[O:43])[CH:42]=2)[CH:32]=1)=[O:25])[CH3:22].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([O:23][C:24]([C:26]1[N:27]=[CH:28][O:29][C:30]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH2:42][C:41](=[O:43])[NH:19][C:9]3[CH:10]=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:32]=1)=[O:25])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: CCOC(=O)c1ncoc1-c1cccc(C2=CC(=O)OC(C)(C)O2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncoc1-c1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (164 mg) and 5-[3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-phenyl]-oxazole-4-carboxylic acid ethyl ester (Example L6) (206 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (63 mg).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[I-].[Na+]>C1C=CC=CC=1>[CH2:35]([CH:20]1[C:19](=[O:24])[CH2:18][C:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[O:22][C:21]1=[O:23])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3ccccc3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.7 %

Procedure:
DBU (28.6 ul, 0.191 mmol) was added to a solution of 6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (55 mg, 0.174 mmol, described below) in benzene (1.9 ml), under an atmosphere of argon. Benzyl bromide (21 ul, 0.174 mmol) was then added. The reaction mixture was stirred at room temperature for 20 minutes, followed by the addition of 5 crystals of sodium iodide. The reaction mixture was stirred for a further 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (9.0 mg). 1H NMR (CDCl3): δ 1.43-1.80 (bm, 8H), 2.20 (m, 2H), 2.24 (m, 1H), 2.72 (m, 2H), 3.06 (m, 3H), 3.30 (m, 1H), 3.76 (m, 4H), 6.72 (d, J=8.64 Hz, 2H), 6.78 (d, J=8.64 Hz, 2H), 6.94 (m, 3H), 7.23 (m, 2H). Exact Mass: Calcd, 406.51; Found, 406.21.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([CH:29]3[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37](OCC)=[O:38])[CH2:31][CH2:30]3)[C:19]3[N:20]([N:25]=[C:26]([CH3:28])[N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH2:43]([Mg]Br)[CH3:44].Cl.O1CC[CH2:50][CH2:49]1>>[CH2:49]([C:37]([OH:38])([CH2:43][CH3:44])[CH2:36][O:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:18]2[C:17](=[O:42])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[C:26]([CH3:28])[N:27]=[C:19]23)[CH2:30][CH2:31]1)[CH3:50]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(=O)OCC)CC2)c2nc(C)nn12
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Agent: Cl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)(CC)CC)CC2)c2nc(C)nn12
Reaction time: 1 h

Procedure:
Ethyl [(4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (0.6 g) was dissolved in tetrahydrofuran (15 mL), and ethylmagnesium bromide (3.0 M diethyl ether solution, 1.7 mL) was added at 0° C. After stirring at the same temperature for 1 hr, 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.4 g, 55%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Li]CCCC.CCCCCC.F[C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1COCC1>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][S:28]([C:25]2[CH:26]=[CH:27][C:22]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:37][CH:36]=1
Reactant: NCCN1CCOCC1
Reactant: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(NCCN2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
N-(2aminoethyl)morpholine (293 μL, 2.25 mmol) was dissolved in THF (7.5 mL) and was cooled down to −78° C. A 2.5N solution of nBuLi in hexane (1 mL, 2.5 mmol) was added dropwise. After 5 min. at −78° C., the mixture was stirred 1 h at −40° C. N-aryl-benzenesulfonamide building block XIII, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (214 mg, 0.75 mmol), was added as a solid. The reaction mixture was stirred 2 h at room temperature, then overnight at 60° C. The reaction was quenched at room temperature with NH4Cl saturated solution in water (5 mL). The desired product was extracted with three portions of ethyl acetate (3×10 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The crude product was purified by flash chromatography, using pure ethyl acetate as eluent. The desired product, e.g. N-(4-chlorophenyl)-4-{[2-(4-morpholinyl)ethyl]amino}benzenesulfonamide (184.2 mg, 62% yield) was obtained as a colorless oil, in 97% purity by BPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=3[O:34][CH2:35]OC)[O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.BrCC1C2N=C(C3C=C(OC)C=CC=3OC)OC=2C=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=3[O:34][CH3:35])[O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CN(Cc3ccccn3)Cc3ccccn3)cccc2o1
Agent: COc1ccc(OC)c(-c2nc3c(CBr)cccc3o2)c1
Product: COc1ccc(OC)c(-c2nc3c(CN(Cc4ccccn4)Cc4ccccn4)cccc3o2)c1

Procedure:
4-bis(2-pyridylmethyl)aminomethyl-2-(2,5-dimethoxy phenyl)benzoxazole (F22) was prepared in a similar manner for the preparation of 4-bis(2-pyridylmethyl)aminomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F18) using 4-bromomethyl-2-(2,5-dimethoxyphenyl)benzoxazole (F14) (522 mg, 1.5 mmol) instead of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) in 91% (640 mg); 1H-NMR (400 MHz, CDCl3) δ3.88 (s, 4H), 3.95 (s, 6H), 4.23 (s, 2H), 7.01–7.07 (m, 2H), 7.13 (dd, 2H, J=8.0, 5.0 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.49 (d, 1H, J=7.5 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.64–7.68 (m, 3H), 7.80 (d, 2H, J=8.0 Hz), 8.52 (d, 2H, J=5.0 Hz).
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([NH2:29])[CH2:26][CH2:25][N:24]1[C:30](=[O:45])[C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]([C:56](O)=[O:57])=[CH:48][CH:47]=1.C(N(CC)CC)C>C(Cl)Cl>[F:43][C:41]([F:44])([F:42])[C:33]1[CH:32]=[C:31]([CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=1)[C:30]([N:24]1[CH2:25][CH2:26][C@H:27]([NH:29][C:56]([C:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:46]=[CH:47][CH:48]=2)=[O:57])[CH2:28][C@H:23]1[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:45]
Reactant: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.95 g (11.6 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride are added at 0° C. to a solution of 4.16 g (9.67 mmol) of (2R,4S)-2-benzyl-1-(3,5-bis-trifluoromethyl-benzoyl)-4-piperidineamine [EP 532 456 A1, Example 38 f], 1.84 g (10.6 mmol) of quinoline4-carboxylic acid and 3 ml (21.3 mmol) of triethylamine in 30 ml of methylene chloride and the ice bath is removed after 10 minutes. The reaction mixture is stirred for 4 hours at room temperature and then diluted with methylene chloride. The organic phase is extracted with aqueous 10% citric acid and with 1 N potassium carbonate solution, washed with brine, dried over magnesium sulfate and concentrated to dryness by evaporation. The crude product is chromatographed on silica gel with methylene chloride/acetone (7:3). The title compound is crystallised from methylene chloride/ether/hexane in the form of white crystals. M.p.: 187° C.; TLC: methylene chloride/acetone (7:3) Rf =0.48, FD-MS: M+ =585; [alpha]D=+9.9 (c=1, methylene chloride); analysis: calc.: C=63.59%, H=4.30%, N=7.18%, F=19.47%, found: C=63.50%, H=4.40%, N=7.16%, F=19.45%. ##STR15##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:16][O:17][C:18]1[CH:42]=[CH:41][C:21]([CH2:22][O:23][C:24]2[C:25](B(O)O)=[CH:26][C:27]3[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=3[CH:33]=2)=[CH:20][CH:19]=1>>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][C:6]=1[C:25]1[C:24]([O:23][CH2:22][C:21]2[CH:41]=[CH:42][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:33][C:32]2[C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29][C:28]([CH3:37])([CH3:36])[C:27]=2[CH:26]=1
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Reactant: COc1ccc(COc2cc3c(cc2B(O)O)C(C)(C)CCC3(C)C)cc1
Product: COc1ccc(COc2cc3c(cc2-c2cc(C=CC(=O)O)ccc2O)C(C)(C)CCC3(C)C)cc1
Yield: 51.7 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 2.0 g (5.5 mmol) of 3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid obtained above, 930 mg (49%) of the expected compound were obtained in the form of a colorless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[C:17]([Cl:18])=[C:16]([N:19]([CH3:23])[CH2:20][CH2:21][OH:22])[CH:15]=[CH:14][N:13]=1.[H-].[Na+].Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33]([N+:36]([O-:38])=[O:37])=[CH:34][N:35]=2)[N:32]=1.O>CN(C)C=O.O1CCCC1>[ClH:18].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[C:17]([Cl:18])=[C:16]([N:19]([CH3:23])[CH2:20][CH2:21][O:22][C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:33]([N+:36]([O-:38])=[O:37])=[CH:34][N:35]=3)[N:32]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CN(CCO)c1ccnc(CSc2nc3ccccc3[nH]2)c1Cl
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCOc1ccc2ncc([N+](=O)[O-])n2n1)c1ccnc(CSc2nc3ccccc3[nH]2)c1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-{[2-(1H-benzimidazol-2-ylsulfanylmethyl)-3-chloropyridin-4-yl]-methylamino}-ethanol (7.5 g, 21.5 mmol) in dimethylformamide (75 ml) is treated with sodium hydride (1.4 g 80% strength suspension) and stirred for 1 h at room temperature. Then 6-chloro-3-nitro-imidazo[1,2-b]pyridazine (4.3 g, 21.5 mmol) in tetrahydrofurane (50 ml) is added dropwise over a period of 20 min and stirring is continued for another 2 h. The solution is treated with water (750 ml) and extracted extensively with ethyl acetate. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed (silica, toluene/dioxane/ammonia 2:1:0.1) and crystallized from ethyl acetate. The crude product is dissolved in boiling 2-pronanol (250 ml) and treated with charcoal. After filtration and cooling to 35° C., a saturated solution of hydrogen chloride in diethyl ether (1.5 ml) is added and the mixture is cooled to 4° C. The precipitate is filtered, washed with 2-propanol and dried in vacuo to give the title compound as a faintly yellow solid, 3.6 g (31%). M.p. 211-2° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[CH:5]=[N:4]1)[CH3:2].C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:5]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:11]=2[N:3]([CH2:1][CH3:2])[N:4]=1
Reactant: CCn1ncc2ncncc21
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Br)c2ncncc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of 1-ethyl-1H-pyrazolo[4,3-d]pyrimidine (300 mg) in DMF (6 mL) was added NBS (721 mg) at room temperature, and the mixture was stirred at 80° C. overnight. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (310 mg). 1H NMR (300 MHz, CDCl3) δ 1.62 (3H, t, J=7.3 Hz), 4.54 (2H, q, J=7.3 Hz), 9.14 (1H, s), 9.17 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH2:19])[CH2:14]1)[C:8]([CH3:20])=[N:7]2.[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[NH2:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][C@H:13]([NH:12][C:9]2[C:8]([CH3:20])=[N:7][C:6]3[C:11]([N:10]=2)=[C:2]([C:28]2[NH:27][C:26]4[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=4[CH:29]=2)[CH:3]=[CH:4][CH:5]=3)[CH2:14]1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: Cc1nc2cccc(Br)c2nc1N[C@H]1CCC[C@@H](N)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](N)C1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
A mixture of (1S,3R)—N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483b, 1.62 g, 4.83 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 2.53 g, 9.65 mmol), dichlorobis(p-dimethylaminophenylditbutylphosphine)palladium (II) (0.171 g, 0.24 mmol), and potassium phosphate (3.07 g, 14.48 mmol) in 1,4-dioxane (38.6 mL)/water (9.65 mL) was sparged with nitrogen for 3 min and was stirred at 80° C. for 45 min. The reaction mixture was diluted with water (200 mL), added to a separatory funnel, and extracted with 3:2 chloroform/IPA (5×100 mL); the combined organic layers were separated, dried over Na2SO4, and concentrated. The crude product in 10% MeOH/DCM was loaded onto the column and was purified via automated flash chromatography (silica gel) with 100% DCM to 50% 2 M ammonia in MeOH/DCM to give (R)-2-(3-4(1S,3R)-3-aminocyclohexyl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (483, 1.59 g, 4.07 mmol, 84% yield) as a brown amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.16 (m, 1H) 1.29-1.42 (m, 3H) 1.43 (d, J=6.65 Hz, 3H) 1.82 (d, J=11.15 Hz, 2H) 1.99-2.18 (m, 3H) 2.55 (s, 3H) 2.82 (t, J=10.27 Hz, 1H) 3.33 (br. s., 1H) 4.04-4.14 (m, 1H) 4.56 (q, J=6.52 Hz, 1H) 7.03 (s, 1H) 7.13 (br. s., 1H) 7.34 (t, J=7.82 Hz, 1H) 7.60 (dd, J=7.92, 1.08 Hz, 1H) 7.64 (s, 1H) 7.86-7.91 (m, 1H) 12.08 (br. s., 1H). MS (ESI, pos. ion) m/z: 391.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28]C4CCCCO4)=[CH:21][C:20]=3[CH3:35])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:40])[O:4][N:3]=1.Cl.O1CCOCC1>O1CCCC1.CO>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][OH:28])=[CH:21][C:20]=3[CH3:35])[CH2:36][CH:37]([CH3:39])[CH3:38])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[C:5]([CH3:40])[O:4][N:3]=1
Reactant: Cc1cc(OCCOC2CCCCO2)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(OCCO)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutyl-N-(2-methyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)benzenesulfonamide (51.2 mg, 0.089 mmol) in tetrahydrofuran (THF) (4 mL) stirred at room temperature was added a solution of 4M HCl in dioxane (4 mL, 16.00 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. The sample was dissolved in 1:1 MeOH:DMSO 1 mL and purified by Open Access Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required product, 27 mg as colourless oil which solidified. LCMS (M+1) 489, RT 1.14 mins.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([CH3:50])[CH2:47][CH2:46][N:45]([CH3:48])[C:44]2=[O:49])=[N:41][CH:42]=1>>[CH3:48][N:45]1[CH2:46][CH2:47][C:43]([C:40]2[N:41]=[CH:42][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:38][CH:39]=2)([CH3:50])[C:44]1=[O:49]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN1CCC(C)(c2ccc(Br)cn2)C1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C)CCN(C)C3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 65 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 3-(5-bromo-pyridin-2-yl)-1,3-dimethyl-pyrrolidin-2-one following a procedure analogous to that described in Example 1. Yield: 65% of theory; LC (method 3): tR=3.06 min; Mass spectrum (ESI+): m/z=542 [M+H]+.