Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)=O.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CS(=O)(=O)c1nc2ccccc2[nH]1
Reactant: CN(C)CCN
Product: CN(C)CCNc1nc2ccccc2[nH]1

Procedure:
27.2 G. (0.139 moles) of 2-methanesulfonyl benzimidazole and 26.5 g. (0.3 moles) of N,N-dimethylethylene diamine are combined and heated at 170°-175° C. for 5 hours. The mixture is then cooled and concentrated in vacuo. The residue is dissolved in methylene chloride washed with saturated sodium chloride, dried over sodium sulfate and evaporated to dryness affording 22 g. of N,N-dimethyl-N'-(2-benzimidazolyl)-1,2-ethane diamine compound which is recrystallized from benzene yielding 20.3 g. with a m.p. of 143.5-145.5.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[ClH:23]>CO>[ClH:23].[ClH:23].[ClH:23].[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(CCF)CC2)CC1
Agent: Cl
Solvent: CO
Product: FCCN1CCN(C2CCNCC2)CC1
Reaction time: 3 h

Procedure:
1,1-Dimethylethyl 4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinecarboxylate (28.95 g, 91.78 mmol) was dissolved in 76 mL of MeOH and 76 mL 37% HCl was added. Reaction was stirred for 3 h and then concentrated in vacuo and to give 1-(2-fluoroethyl)-4-(4-piperidinyl)piperazine trihydrochloride (˜29 g) which was then dissolved in DMSO (200 mL). K2CO3 (63 g, 459 mmol) was added followed by 4-fluoro-2-(methyloxy)-1-nitrobenzene (15.7 g, 91.8 mmol) and the reaction mixture was heated to 80° C. and allowed to stir overnight. The mixture was then poured into H2O and extracted with EtOAc (3×). The combined organics were dried with MgSO4, filtered, and concentrated in vacuo. The resulting solids were triturated with diethyl ether to give the title compound of step E (27.13 g, 81%). MS (M+H, ES+) 367.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[NH2:17][C:16]1[C:4]([C:2]#[N:3])=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:23]([NH:22][CH2:20][CH3:21])=[O:24]
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CCN=C=O
Agent: [Cl-]
Product: CCNC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 209a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 209bW) and ethyl isocyanate in 100% yield as a white solid. MS 289 (MH+).
Reaction SMILES: [CH3:1][C:2]([O:39]C(=O)C)([CH3:38])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:37])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH:34]([CH3:36])[CH3:35])[N:13]=3)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[OH:39][C:2]([CH3:38])([CH3:1])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:37])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH:34]([CH3:35])[CH3:36])[N:13]=3)[CH2:6]1)=[O:4]
Reactant: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-isopropylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidin-1-yl}-2-oxoethyl ester (56 mg, 0.17 mmol) and LiOH (84 μL, 0.33 mmol, 4M solution) in THF (3 mL) and MeOH (1 mL) was allowed to stir at r.t. for 18 h. Further LiOH (495 μL, 1.98 mmol, 4M solution) and the mixture stirred at 50° C. for 5 days. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) then partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 854 as a white solid (62 mg, 70%). LCMS (method I): RT 3.15 min, [M+H]+ 533.4. 1H NMR (DMSO, 400 MHz): δ 7.87-7.86 (1 H, m), 7.65-7.64 (1 H, m), 7.25-7.24 (2 H, m), 5.02 (1 H, brd s), 4.57 (1 H, t, J=8.92 Hz), 4.25 (4 H, brd s), 4.18 (1 H, dd, J=10.40, 5.66 Hz), 4.03 (1 H, t, J=9.00 Hz), 3.91-3.90 (1 H, m), 3.76 (4 H, t, J=4.59 Hz), 3.72 (3 H, s), 3.68 (1 H, dd, J=9.99, 5.41 Hz), 3.22-3.21 (3 H, m), 1.36 (3 H, s), 1.34 (3 H, s), 1.25 (6 H, d, J=2.06 Hz)
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N:14]=[C:15]=[S:16])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[NH2:18][NH:19][C:20](N)=[NH:21].C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:21][C:20]1[N:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:5][CH:6]=2)[C:15]([SH:16])=[N:18][N:19]=1
Reactant: N=C(N)NN
Reactant: S=C=Nc1ccc(C2CC2)c2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
Compound 3 (447 mg, 2.1 mmol) was dissolved in 3 mL of dimethylformamide, aminoguanidine hydrochloride salt (355 mg, 3.2 mmol) and diisopropyl ethylamine (0.56 mL, 3.2 mmol) were added and the mixture stirred at 50° C. for 18 hours. The mixture was then concentrated and to the resulting residue was added 2M aqueous sodium hydroxide solution (10 mL). The mixture was stirred at 50° C. for 18 hours and then cooled to room temperature. The resulting mixture was then neutralized with aqueous 1N HCl and the precipitate (product) collected to give 5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (4). (240 mg, 44% yield)
Reaction SMILES: [C:1]1(C)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:12][CH2:13][CH2:14][CH:15]([C:23]1([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]1=[O:36])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH:41](N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:41][C:5]1[CH:6]=[CH:1][C:2]([S:7]([NH:12][CH2:13][CH2:14][CH:15]([C:23]2([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]2=[O:36])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:8])=[O:9])=[CH:3][CH:4]=1
Reactant: CC(C)CC1(C(CCN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCC(C(=O)OC(C)(C)C)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
Toluenesulfonyl chloride (372 mg) is added to a solution of tert-butyl α-(2-aminoethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 73, step 1; 654 mg, 1.62 mmol), CH2Cl2 (10.0 mL), and diisopropylethylamine (0.34 mL) at 0° C. The solution is stirred at 0° C. for 1 hour and at room temperature for 16 hours. Basic workup (CH2Cl2, NaHCO3, MgSO4) and purification by flash chromatography gives 634 nag (70%) of the title compound as a white solid (mp 136°-138° C.):
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH2:18])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6].[Cl:34][C:35]1[N:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH:18][C:37]([C:36]3[C:35]([Cl:34])=[N:43][CH:42]=[CH:41][CH:40]=3)=[O:38])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(NC(=O)c3cccnc3Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
The title material of Example 17 (100 mg, 0.00025 mol) was dissolved in DMF (2 mL), and to the solution was added 2-Chloronicotinic acid (40 mg, 0.00025 mol), HATU (144 mg, 0.00038 mol), and DIEA (49 mg, 0.00038 mol). The reaction was blanketed with argon and stirred at room temperature for 18 hours. The solution was concentrated in vacuo, and the resulting solid were washed with water and then filtered. The product was then recrystallized from ethanol, and isolated by vacuum filtration. 25 mg. (MW=530.93, 19% yield). LC/MS m/z=531.7 (m+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH3:20])=[O:14])=[CH:11][N:10]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2ccc(C(=O)O)cn2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OCc2ccc(OC)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
6-(4-Methoxybenzyloxy)nicotinic acid (8.10 g, 31.2 mmol) obtained in Step 1 was dissolved in DMF (250 ml), and potassium carbonate (8.64 g, 62.5 mmol) and methyl iodide (3.89 mL, 62.5 mmol) were added thereto, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford methyl 6-(4-methoxybenzyloxy)nicotinate (3.78 g, 44%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1([O:51][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CC[N:64](C(C)C)[CH:65]([CH3:67])[CH3:66]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:64][C@H:65]([CH3:67])[CH2:66][OH:51])=[O:18])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:33])[CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)N[C@H](C)CO)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 37 mg, 0.08 mmol) in DMF (3 ml) was added BOP (42 mg, 0.10 mmol) and DIPEA (16 mg, 0.10 mmol), followed by D-alanol (16 mg, 0.10 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][OH:19])[C:13]=3[CH:26]=2)[CH:5]=[C:4]([F:27])[C:3]=1[C:28]([F:31])([F:30])[F:29]>C(Cl)(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[O:19])[C:13]=3[CH:26]=2)[CH:5]=[C:4]([F:27])[C:3]=1[C:28]([F:31])([F:30])[F:29]
Reactant: OC[C@H](c1ccccc1)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=C[C@H](c1ccccc1)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-β-phenyl-1H-benzotriazole-1-ethanol (1.0 g, 0.0022 mole) in chloroform is treated with MnO2, (1.0 g, 0.0115 mole) stirred at 40° C. for 18 hours and filtered through a bed of diatomaceous earth. The filtrate is concentrated in vacuo to give a residue which is chromatographed using silica gel and 10% tetrahydrofuran in carbon tetrachloride to yield the title product as a white solid, 0.42 g, mp 84°-85° C., characterized by elemental and NMR analyses.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1F)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1.O>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[O:2][CH3:1])[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1
Reactant: CO
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
Methanol (0.462 ml, 11.4 mmol) was added to a stirring suspension of NaH (684 mg, 17.1 mmol) in DMF (10 ml) under an argon atmosphere. The resulting solution was allowed to stir at RT for 20 min. 6-chloro-7-fluoro-8-nitro-9H-β-carboline (500 mg, 1.9 mmol) was added to the stirring solution and the resulting mixture was allowed to stir at RT. Upon addition of H2O, a brown solid precipitated out which was filtered to give the desired 6-chloro-7-methoxy-8-nitro-9H-β-carboline (510 mg, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15]3[C:11](=[N:12][N:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[C:14]=3[CH:24]([CH3:26])[CH3:25])[C:10]2=[O:35])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:36][O:37][C:38](=[O:42])[CH2:39][CH2:40]I>>[CH3:36][O:37][C:38](=[O:42])[CH2:39][CH2:40][C:16]1([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:15]2[C:11](=[N:12][N:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:14]=2[CH:24]([CH3:26])[CH3:25])[C:10](=[O:35])[N:9]1[C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)CCI
Reactant: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Product: COC(=O)CCC1(c2ccc(Cl)cc2)c2c(nn(-c3ccccc3OC)c2C(C)C)C(=O)N1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described for example 74 but using the compound prepared in example 88 and 2 equivalents of 3-iodo-propionic acid methyl ester (Scapens, D.; Adams, H.; Johnson, T. R.; Mann, B. E.; Sawle, P.; Aqil, R.; Perrior, T.; Motterlini, R. Dalton Transactions 2007, 43, 4962-4973). The reaction mixture was stirred for 2 h at rt. The crude material was purified by silica gel column chromatography (heptane/ethyl acetate, 1:0→7:3→2:3) followed by preparative HPLC (Column: XBridge, 30×100 mm. Flow: 30 mL/min. Gradient: 30% to 60% B in 15 min, 60% B for 5 min, 60% to 90% B in 5 min; A=0.1% TFA in water, B=0.1% TFA in acetonitrile). tR: 1.42 min (LC-MS 3); ESI-MS: 596.3 [M+H]+ (LC-MS 3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:18]>C1COCC1.O>[C:2]1([NH:1][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:18])=[O:8])=[O:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCCCC(=O)O1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
Aniline (0.6 g, 6.4 mmol) was added at room temperature to a stirred solution of oxonane-2,9-dione (1.0 g, 6.4 mmol) in THF anhydrous. After stirring at RT for 0.5 h, the resulting mixture was diluted with water (100 mL). The formed white solid was filtered and collected. Purification by silica gel column chromatography using as eluent EtOAc:cyclohexane=80:20 to 100:0 afforded 7-(phenylcarbamoyl)heptanoic acid as a white solid (174 mg, 11% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>CC(N(C)C)=O>[N:64]1([C:20]([C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:23]=[CH:24][C:9]([NH:8][C:6]4[CH:5]=[C:4]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:10][CH:11]=3)[CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1
Reactant: C1COCCN1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)N4CCOCC4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylic acid (Example 20, 0.15 g, 0.38 mmol) in dry DMA (3 mL) was added HATU (0.14 g, 0.38 mmol) and DIEA (0.15 g, 1.13 mmol). The solution was stirred at rt for 0.5 h, followed by addition of morpholine (0.16 g, 1.88 mmol). The resulting solution was stirred at rt overnight, followed by prep-HPLC separation to give 77 mg (35%) pure product. 1H NMR (DMSO-d6) δ 10.79 (s, 1H), 8.40 (s, 1H), 7.85 (m, 2H), 7.74 (m, 2H), 7.60 (m, 3H), 7.21 (m, 2H), 7.00 (m, 2H), 6.59 (s, 1H), 3.49 (m, 8H); MS ES 469 (M+H)+, calcd 469.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[S:17][C:18]([CH3:21])=[N:19][N:20]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C:18]1[S:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:32]5[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=5)[CH:23]=[CH:22][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1nnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a degassed solution of 6-bromo-2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazole (450 mg, 1.094 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (406 mg, 1.313 mmol) and potassium carbonate (454 mg, 3.28 mmol) in dioxane (9 mL) and water (3.0 mL) was added Pd(Ph3P)4 (63 mg, 0.055 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to rt, diluted with water (20 mL), and extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 30 to 100% EtOAc) to afford tert-butyl 4-(2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (443 mg, 0.862 mmol, 79% yield) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.59-7.65 (2H, m), 7.41 (1H, dd, J=8.5, 1.7 Hz), 6.00-6.11 (1H, m), 5.41-5.48 (1H, m), 4.07-4.12 (2H, m), 3.75-3.83 (2H, m), 3.66 (2H, t, J=5.5 Hz), 3.52-3.59 (2H, m), 2.60 (3H, s), 2.53-2.58 (2H, m), 2.19-2.27 (2H, m), 2.06-2.14 (2H, m), 1.50 (9H, s). LCMS (m/z)=514 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]=O)[CH:4]=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]=[CH:21][CH:22]=[O:23])[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cccc2cccnc12
Product: O=CC=Cc1cccc2cccnc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 8-quinolinecarboxaldehyde (prepared as described in J. Am. Chem. Soc. 1997, 119, 8891) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][Mg]Br.O>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([CH3:10])[CH:3]=1
Reactant: C[Mg]Br
Reactant: Cc1cc(Br)ccc1C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1C(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 4-bromo-2-methylbenzaldehyde (1 g, 5 mmol) in tetrahydrofuran (30 mL) was added methylmagnesium bromide (3N in tetrahydrofuran, 2 mL) at −40° C. Then the mixture was stirred at 25° C. for 3 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 1-(4-bromo-2-methylphenyl)ethanol (600 mg, 56%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])[OH:4].[CH3:17][S:18](O)(=[O:20])=[O:19]>CO>[CH3:17][S:18]([O:4][CH:3]([CH2:2][NH2:1])[C:5]1[CH:10]=[C:9]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])(=[O:20])=[O:19]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(O)CN
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COc1ccc(S(N)(=O)=O)cc1C(CN)OS(C)(=O)=O

Procedure:
Starting from (+)-α-aminomethyl-2-methoxy-5-sulphamoylbenzenemethanol treated with 1 equivalent of methanesulphonic acid in 2M solution in methanol, recrystallization in methanol and diethyl ether and drying in a desiccator under vacuum over phosphorus pentoxide, (+)-α-aminomethyl-2-methoxy-5-sulphamoylbenzenemethanol methanesulphonate was obtained.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:10][C:9]([F:22])=[CH:8][CH:7]=2)[CH3:3].CS(C)=[O:25]>C(O)CCC>[F:22][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH:2]([OH:25])[CH3:3])=[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:12]2=[O:21]
Reactant: CS(C)=O
Reactant: CC(Br)c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Solvent: CCCCO
Product: CC(O)c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 120 °C
Yield: 64 %

Procedure:
To a solution of 2-(1-bromoethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (15.0 g, 40.84 mmol) in DMSO (150 ml), n-butanol (7.5 ml) was added and heated to 120° C. for 3 h. The reaction mixture was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as an off-white solid (7.90 g, 64%). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.85 (dd, J=8.1, 3 Hz, 1H), 7.54 (dd, J=9.2, 4.2 Hz, 1H), 7.47-7.37 (m, 2H), 7.15-6.98 (m, 3H), 4.74 (quintet, J=6.8 Hz, 1H), 2.23 (d, J=7.4 Hz, 1H), 1.54 (d, J=6.6 Hz, 3H).