Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1F)=O.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4]([C:2]([CH3:1])=[N:14][NH:15]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 150 °C
Yield: 60 %

Procedure:
To a solution of 2-fluoro-4-methoxyacetophenone (1.90 g, 11.3 mmol) in ethanol (20 ml) was added hydrazine hydrate (1.4 ml, 45.0 mmol) and heated at reflux temperature for 6 h. This mixture was evaporated to a residue and ethylene glycol (10 ml) was added. The mixture was heated at 150° C. for 18 h, cooled to room temperature, diluted with water (50 ml), and extracted with dichloromethane (3×60 ml). The combined extracts were washed with brine (10 ml), dried (MgSO4) and evaporated to a residue, which was crystallized from ethyl acetate to give a solid (1.1 g, 59%): MS(ES) m/z 163 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 5 h
Yield: 82.4 %

Procedure:
A mixture of 2.00 g of 10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 15 ml of ethyl alcohol and 15 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is dissolved in methylene chloride, passed through silica gel and the pad washed with 3:1 ethyl acetate-hexane. The filtrate is concentrated in vacuo to give 1.5 g of the desired product as a yellow solid, m.p. 166-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9](SC)[O:8][C:5]2=[N:6][CH:7]=1.Br[C:14]1[CH:15]=[C:16]([N+:21]([O-])=O)[C:17](O)=[N:18][CH:19]=1.Cl.C(O[CH2:29][CH3:30])(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([N:21]3[CH:15]4[CH2:29][CH2:30][N:18]([CH2:19][CH2:14]4)[CH2:17][CH2:16]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CSc1nc2cc(Br)cnc2o1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: Cl
Product: Brc1cnc2oc(N3CCN4CCC3CC4)nc2c1
Yield: 64 %

Procedure:
The title compound was prepared from 6-bromo-2-methylsulfanyl-oxazolo[5,4-b]pyridine (prepared from 5-bromo-2-hydroxy-3-nitropyridine by the methods described in Examples 4, 5 and 7) by the procedure described in Example 9 in 64% yield: 1H NMR (CDCl3, 400 MHz) δ 7.90 (d, 1H, J=2.1 Hz), 7.59 (d, 1H, J=2.1 Hz), 4.50-4.49 (m, 1h), 3.91 (t, 2H, J=5.8 Hz), 3.18-3.11 (m, 4H), 3.03-2.96 (m, 2H), 2.16-2.08 (m, 2H), 1.85-1.76 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 161.4, 138.8, 125.3, 121.4, 116.7, 116.2, 57.0, 50.6, 46.4, 44.3, 26.8; MS (Cl) m/z 323.0 (M+1); HPLC retention time=3.08 min. The hydrochloride salt was prepared by diluting in ethyl acetate and adding a 2.5 N HCl solution in ethyl acetate: mp>300° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[C:17]1([C@@H:15]([NH:14][C:12]2[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])=[CH:7][CH:6]=3)[CH:9]=[N:10][CH:11]=2)[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H](Nc1cncc(-c2ccc(N)cc2)n1)c1ccccc1
Product: C[C@H](Nc1cncc(-c2ccc(NC(=O)C3CC3)cc2)n1)c1ccccc1

Procedure:
In a method analogous to that reported in example 39, reaction of 6-(4-aminophenyl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine (58 mg, 0.2 mmol) and cyclopropanecarbonyl chloride (25 mg, 0.24 mmol) furnished the pure product after chromatographic purification using ethyl acetate-hexane (3:2) (46 mg, 64%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:14]([CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:35])[NH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])[CH3:13].C(N(CC)CC)C>>[C:12]([CH:14]([CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:35])[NH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])(=[O:11])[CH3:13]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1

Procedure:
Analogously to Example 40A, 250 mg (1.94 mmol) of oxalyl chloride, 330 mg (4.2 mmol) of dimethyl sulphoxide, 750 mg (1.61 mmol) of 2-(1-hydroxyethyl)-N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenyl-pentanamide and 820 mg (8.07 mmol) of triethylamine are reacted to give 2-acetyl-N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenyl-pentanamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16].[BH4-].[Na+]>C(O)C>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH:16][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: COC(CN)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CNCC(OC)OC)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
3--Fluoro-4-methoxybenzaldehyde (5.0 g, 0.0324 mole) was added to aminoacetaldehyde dimethyl acetal (3.53 ml, 0.0324 mole) and the mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled in ice, diluted with ethyl alcohol (50 ml) and sodium borohydride (1.23 g, 0.0324 mole) was added and the mixture was stirred overnight at 25° C. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and the solution was washed with water and brine and then dried with sodium sulfate. The mixture was filtered and the solvent removed under reduced pressure to give N-(3-fluoro-4-methoxybenzyl)-aminoacetaldehyde dimethyl acetal as an oil (6.68 g, 85%).
Reaction SMILES: CC(C)(C)C[C:4](=[O:20])[CH2:5][C@H:6]([C:10]1[O:11][CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=1)[CH2:7][CH:8]=[CH2:9].O.[OH-].[Li+].[OH-].[Li+].C(O)(=O)[CH2:29][C:30]([CH2:35]C(O)=O)([C:32](O)=O)[OH:31]>O1CCOCC1.O>[C:30]([O:31][C:4](=[O:20])[CH2:5][C@H:6]([C:10]1[O:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1)[CH2:7][CH:8]=[CH2:9])([CH3:35])([CH3:32])[CH3:29]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C=CC[C@H](CC(=O)CC(C)(C)C)c1nc(C(=O)OCC)co1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CC[C@H](CC(=O)OC(C)(C)C)c1nc(C(=O)O)co1
Temperature: 0 °C
Reaction time: 4 h
Yield: 228.7 %

Procedure:
Two identical reactions were put on each containing the following: A solution of ethyl 2-[(1R)-1-(4,4-dimethyl-2-oxopentyl)-3-butenyl]-1,3-oxazole-4-carboxylate (Preparation 115) (4.0 g, 12.9 mmol) in 1,4-dioxan (40 ml) and water (20 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (0.8 g, 19.0 mmol). The mixture was stirred at 0° C. for 4 hours. Further lithium hydroxide monhydrate (0.8 g, 19.0 mmol) was added and stirred at 0° C. for 10 minutes. The two reactions were combined and partitioned between ethyl acetate and water. The aqueous layer was neutralised with citric acid (16.3 g, 38.0 mmol) and extracted with ethyl acetate (×3). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a colourless oil (8.3 g).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH3:25])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH3:25])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNC(=O)c1cc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-methylthiophene-2-carboxamide (67.4 mg) in acetonitrile (10 mL) were added sodium iodide (56.7 mg) and chloro(trimethyl)silane (0.192 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (57.4 mg).
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[CH3:11][N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])[N:19]=1)[CH3:13].[CH3:25][N:26](C)[CH2:27]CC1SC=C(CSCCNC2C(OC)=NS(=O)N=2)N=1.CNC>>[CH3:13][N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:21][CH2:22][CH2:23][NH:24][C:3]2[C:7]([N:26]([CH3:27])[CH3:25])=[N:6][S:5](=[O:10])[N:4]=2)[N:19]=1)[CH3:11]
Reactant: COC1=NS(=O)N=C1OC
Reactant: COC1=NS(=O)N=C1NCCSCc1csc(CCN(C)C)n1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: CNC
Product: CN(C)Cc1nc(CSCCNC2=NS(=O)N=C2N(C)C)cs1

Procedure:
When a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A] is reacted with one equivalent of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared in Example 33, Step E] and the resultant 3-{2-[(2-dimethylaminoethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with an excess of dimethylamine according to the procedure described in Example 28, the title compound is thereby produced.
Reaction SMILES: [CH3:1][C:2]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1)([CH3:6])[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C.C(Cl)(Cl)Cl>[CH3:6][C:2]([CH:7]1[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12]1)([CH3:1])[C:3]([O:5][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C(=O)O)C1CCC(=O)CC1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)OCc1ccccc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 2-methyl-2-(4-oxocyclohexyl)propanoic acid (0.184 g, 1 mmol) and DIPEA (0.192 mL, 1.100 mmol) in acetonitrile (1 mL) and CHCl3 (1 mL) was added benzyl bromide (0.131 mL, 1.100 mmol) and the mixture was stirred at rt overnight. The reaction mixture was evaporated to dryness and purified by silica gel FCC (0-5% EtOAC in DCM) to afford benzyl 2-methyl-2-(4-oxocyclohexyl)propanoate as a clear oil (184 mg), which was dissolved in CH2Cl2 (2 mL) was treated with Deoxo-Fluor® (0.442 mL, 2.40 mmol), followed by the addition of EtOH (5.8 mL). The resulting yellowish solution was stirred at rt overnight. The reaction mixture was diluted with sat. NaHCO3 and EtOAc. The organic phase was separated and washed with water, sat. NaCl, dried over anhydrous MgSO4, filtered and dried to yield a yellow oil. The crude product was purified by silica gel FCC (1:1 hexane-DCM) to afford benzyl 2-(4,4-difluorocyclohexyl)-2-methylpropanoate as a clear oil (143 mg) which was hydrogenated (0.053 g of 10% Pd—C, EtOAc) under balloon pressure for 4 h. The suspension was filtered and evaporated to dryness to afford Cap P-21. 1H NMR (500 MHz, CDCl3) δ ppm 2.08-2.23 (2H, m), 1.64-1.85 (5H, m), 1.36-1.54 (2H, m), 1.12-1.29 (6H, m).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH:25][C:43]([C:40]5[C:41](=[O:42])[N:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)[N:37]=[CH:38][CH:39]=5)=[O:44])=[CH:23][C:22]=4[F:28])[CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (100.0 mg, 0.256 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 70.53 mg, 0.301 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (144.3 mg, 0.753 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (101.7 mg, 0.753 mmol), N-ethyl-N-isopropylpropan-2-amine (162.2 mg, 1.255 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (103 mg, 66.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 615 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.41 (m, 2H), 8.23 (d, 1H), 7.98 (d, 1H), 7.60 (m, 2H), 7.39 (m, 2H), 7.24 (m, 3H), 6.46 (d, 1H), 6.28 (m, 1H), 4.04 (s, 4H), 2.78 (m, 2H), 2.52 (m, 2H), 1.98 (m, 2H).
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([Cl:31])[CH:3]=1.C([O:35]B(OC(C)C)OC(C)C)(C)C.C([Li])CCC.C(=O)=O.C(O)(=O)C.OO>O1CCCC1>[CH:25]1([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([C:13]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:28]=[C:29]([Cl:30])[C:2]([OH:35])=[CH:3][C:4]=3[Cl:31])=[O:14])[CH2:16][CH2:17]2)[CH2:27][CH2:26]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: O=C=O
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
To a solution of 1.0 g (1.93 mmol) [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 26) in 20 mL dry tetrahydrofuran was added 0.85 mL (3.72 mmol) triisopropylborate (commercially available, CAS RN 5419-55-6). The solution was cooled to −75° C. using a dry ice bath and 1.50 mL (2.4 mmol) n-butyllithium solution (1.6M in n-hexane) was added over 3 min. to the reaction mixture. Stirring was continued for another 1.5 hours. The dry-ice bath was replaced by an ice bath and 0.98 g (8.17 mmol) acetic acid (50% solution in water) and 0.28 g (2.89 mmol) hydrogen peroxide (35% solution in water) were added. The reaction mixture was stirred at 0° C. for 1 hour, the cooling batch was removed and stirring was continued at room temperature for 20 hours. The solution was poured on 10% aqueous sodium thiosulfate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give 0.575 g (65%) of the title compound as a light brown solid. MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:32])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]2[N:29]=[C:28]([NH2:30])[N:27]=[C:26]([NH2:31])[N:25]=2)=[CH:18][CH:17]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:32])[C:16]1[CH:17]=[CH:18][C:19]([CH:22]=[CH:23][C:24]2[N:25]=[C:26]([NH2:31])[N:27]=[C:28]([NH2:30])[N:29]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=Cc2nc(N)nc(N)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(N)nc(C=Cc2ccc(C(=O)Nc3ccccc3N)cc2)n1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a stirred solution at room temperature of 219 (25 mg, 0.056 mmol) in CH2Cl2 (1.5 mL) was added TFA (0.3 mL, 4.3 mmol). After 30 min, a solution of sat. NaHCO3 was slowly added until pH 8 is reached, CH2Cl2 was removed under reduced pressure, AcOEt was added, and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 10/90) to afford the title compound 220 (19 mg, 0.054 mmol, 98% yield). 1H NMR (300 MHz, acetone-d6) δ (ppm): 8.33, 8.13 (2d, J=7.5 Hz, 1H), 8.22 (d, J=15.9 Hz, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 7.38-6.96 (m, 2H), 7.03 (d, J=15.9 Hz, 1H), 6.94-6.62 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]4[C:16](=[O:57])[NH:17][CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][NH:24][C:25](=[O:56])[CH2:26][N:27]([C:54]=3[CH:55]=4)[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[C:41]([NH2:43])[CH:40]=[CH:39][C:38]=3[N:44]3[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]3)=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]4[C:16](=[O:57])[NH:17][CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][NH:24][C:25](=[O:56])[CH2:26][N:27]([C:54]=3[CH:55]=4)[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[C:41]([NH:43][C:1](=[O:3])[CH3:2])[CH:40]=[CH:39][C:38]=3[N:44]3[CH2:45][CH2:46][N:47]([S:50]([CH3:53])(=[O:51])=[O:52])[CH2:48][CH2:49]3)=[CH:31][CH:30]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CS(=O)(=O)N1CCN(c2ccc(N)cc2COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(N2CCN(S(C)(=O)=O)CC2)c(COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCC=CCCNC5=O)cc2)c1
Reaction time: 12 h
Yield: 62.8 %

Procedure:
Acetyl chloride (4 μL, 0.057 mmol) was added under nitrogen to a solution of 4 (38 mg, 0.051 mmol) and N,N′-diisopropylethylamine (DIPEA; 8.7 μL, 0.062 mmol) in CHCl3 (2 mL). After 12 h, the reaction mixture was successively partitioned between CHCl3 and diluted NaHCO3, dried (Na2SO4) and evaporated. The residue was purified by column chromatography to give 25 mg (61.7%) of the title product 5 as a white powder: m/z=782 (M+H)+. NMR (DMSO-d6): δ (ppm) 1.19-1.35 (m, 4H), 1.68-1.77 (m, 4H), 1.90 (m, 2H), 2.02 (s, 3H, COCH3), 2.18 (m, 2H), 2.33 (m, 2H), 2.50 (m, 1H), 2.75 (m, 2H), 2.92 (s, 3H, SO2CH3), 2.96 (m, 2H), 3.33 (m, 8H), 4.43 (s, 2H, CH2CONH), 5.22 (s, 2H, OCH2), 5.35 (m, 1H), 5.53 (m, 1H), 7.17-7.20 (m, 3H), 7.39-7.60 (m, 5H), 7.69-7.79 (m, 2H), 7.86 (broad s, 1H, NH), 8.33+8.56 (m, 1H, NH), 9.95 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].O.C(Cl)Cl>COC(=O)OC>[Br:9][C:5]1[N:6]=[C:7]([Br:8])[C:2]2[N:3]([CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=2)[CH:4]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CCOC(=O)C(=O)CBr
Solvent: O
Solvent: COC(=O)OC
Solvent: ClCCl
Product: CCOC(=O)c1cn2cc(Br)nc(Br)c2n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
To a stirred solution of 2-amino-3,5-dibrompyrazine (20 g, 79 mmol) in dimethylcarbonate (133 mL) at rt was added ethyl 3-bromo-2-oxopropanoate (17.14 g, 79 mmol) in one portion. After stirring at 110° C. for 3 h, the solution was stirred at rt overnight. Water and DCM were added and the aqueous phase was extracted with DCM. After washing of the organic phase with water, drying over Na2(SO4) and filtration the organic phase was evaporated. Flash chromatography yielded 13.95 g (50.6%) ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate: 1H-NMR (300 MHz, CDCl3): δ=8.30 (s, 1H), 8.27 (s, 1H), 4.48 (q, 2H), 1.43 (tr, 3H) ppm.
Reaction SMILES: O[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>CN(C=O)C>[Cl:14][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1
Reactant: Cc1ncnc(O)c1C(C)C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ncnc(Cl)c1C(C)C
Temperature: 65 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
4-Hydroxy-5-isopropyl-6-methylpyrimidine (12.2 g, 80 mmol) was added to 50 ml phosphorous oxychloride and treated with ca. 0.1 ml DMF. The mixture was heated to 60-70° C. and stirred for 2h. After cooling the excess POCl3 was removed under vacuum, the residue was poured onto ice and the pH of the aqueous layer was adjusted to 7 by addition of NaOH and NaHCO3. The product was taken up in dichloromethane, washed with sat. sodium bicarbonate, dried (Na2SO4) and evaporated. The residue was purified by vacuum distillation to yield 8.5 g (62 percent yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1.CN(C=[O:23])C.[S:24]([Cl:27])(Cl)=[O:25]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([S:24]([Cl:27])(=[O:25])=[O:23])=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CN(C)C=O
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(F)cc1F

Procedure:
2′,4′-Difluorobiphenyl-4-sulfonic acid (12.1 g, 47 mmol) was suspended in thionyl chloride (100 mL). The mixture was heated at reflux for 30 minutes, when a catalytic amount of dry DMF was added and the reaction was heated at reflux for a further 4 hours. The reaction was then cooled and the thionyl chloride evaporated and the residue was then azeotroped with toluene (3×10 mL). The resulting yellow/orange gum was taken up into EtOAc 250 mL) and washed with water (50 mL) and brine (50 mL), and dried over MgSO4. Filtration and evaporation gave the title compound as a brown oil which crystallized on standing (11 g).