Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[C:6](I)=[CH:7][O:8]2.[NH:17]1[CH:21]=[CH:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[CH:21]=[CH:20][C:19]([C:7]2[O:8][C:9]3[C:4]([C:5](=[O:16])[CH:6]=2)=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)=[N:18]1
Reactant: c1cn[nH]c1
Reactant: COc1cc(OC)c2c(=O)c(I)coc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3cc[nH]n3)oc2c1
Temperature: 0 °C
Yield: 89.6 %

Procedure:
A mixture of 5,7-dimethoxy-3-iodochromone (166 mg) prepared in Example 16, pyrazole (136 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours-with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (122 mg; yield=90.0%) as white bulk crystals. Melting point: 197°-198° C. Mass spectrum (M+): 272. 1 H-NMR(CDCl3, δ ppm): 6.77 (s, 1H, H3), 6.55 (d, 1H, H6), 7.81 (s, 1H, H8), 8.12 (s, 1H, H3'), 6.41 (d, H4'), 6.54 (s, 1H, H5'), 3.96 (s, 3H, 5MeO), 4.06 (s, 3H, 7MeO).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:22]2[C:21](=[O:23])[N:20]([CH2:24][CH3:25])[CH2:19][C:18]([CH3:27])([CH3:26])[O:17][C:16]=2[N:15]=[C:14]([S:28][CH3:29])[N:13]=1.O>C1COCC1>[CH2:1]([O:8][C:12]1[C:22]2[C:21](=[O:23])[N:20]([CH2:24][CH3:25])[CH2:19][C:18]([CH3:26])([CH3:27])[O:17][C:16]=2[N:15]=[C:14]([S:28][CH3:29])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCN1CC(C)(C)Oc2nc(SC)nc(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CC(C)(C)Oc2nc(SC)nc(OCc3ccccc3)c2C1=O
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
6.20 ml of benzyl alcohol (59.64 mmol) are placed in 400 ml of anhydrous THF. The solution is cooled to 4° C. in an ice bath and 2.39 g of 60% sodium hydride (59.64 mmol) are added portionwise. The reaction mixture is stirred at 4° C. for 15 minutes. 15 g of 4-chloro-6-ethyl-8,8-dimethyl-2-methylsulfanyl-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzo cyclohepten-5-one (49.70 mmol) dissolved in 400 ml of anhydrous THF are added dropwise. After stirring for 2 hours at 4° C., 400 ml of water are added and the THF is evaporated off. The aqueous phase is extracted twice with 300 ml of DCM, and the organic phases are combined and washed with 400 ml of water and then 400 ml of brine. The organic phase is dried over Na2SO4, filtered and concentrated. The residue is chromatographed on silica gel with a gradient of ethyl acetate in heptane ranging from 30% to 50%. 18.6 g of 4-benzyloxy-6-ethyl-8,8-dimethyl-2-methylsulfanyl-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzocyclohepten-5-one are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@H:20]3[C@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21]3)=[C:13]([NH2:29])[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>>[OH:25][C@@H:24]1[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21][C@H:20]1[N:17]1[CH:16]=[N:15][C:14]2[C:18]1=[N:19][C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)=[N:12][C:13]=2[NH2:29]
Reactant: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(-n2cc(C(=O)O)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
Compound 12 (0.05 mg, 0.12 mmol) was dissolved in one equivalent of 1N NaOH. The solution was allowed to stir at Rt for 2 h, then acidified to pH 4. The resulting precipitate was filtered and washed with water and ether. 1HNMR (CD3OD) Δ3.75 (m, 1 H), 3.90 (m, 1 H), 4.13 (d, 1 H), 4.43 (d, 1 H), 4.64 (m, 1H), 6.05 (d, 1H), 8.10 (s, 1H), 8.35 (s, 1 H), 9.05 (s, 1 H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:18][C:15]2[CH:14]=[N:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=3)=[CH:17][N:16]=2)=[CH:24][CH:23]=1)[CH2:20][CH3:21]
Reactant: CCCc1ccc(CBr)cc1
Reactant: CCCCCc1ccc(-c2cnc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCc1ccc(-c2cnc(OCc3ccc(CCC)cc3)cn2)cc1

Procedure:
A mixture of 10.4 g of 5-(4-pentylphenyl)-2-pyrazinol (obtainable analogously to Japanese Preliminary Published Application 144,770/84), 7.7 g of p-n-propylbenzyl bromide, 8.6 g of potassium carbonate and 50 ml of dimethylformamide is heated at 90° for 10 hours. Customary working up gives 5-(4-n-pentylphenyl)-pyrazin-2-yl p-n-propylbenzyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21]CC2C=CC=CC=2)[CH2:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2OCc2ccccc2)CC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2O)CC1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
A suspension of 3.42 g of 4-(2-benzyloxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10c) (8.94 mmol) and 342 mg of 10% palladium-carbon (50% wet) in methanol (90 ml) was stirred under a hydrogen atmosphere at room temperature for six hours. Hydrogen in the reaction vessel was replaced by nitrogen. Then, palladium-carbon was separated by filtration and washed with methanol. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=1/1) to obtain 2.6 g of the title compound (yield: quant.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[C:11]#[N:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N:16]([CH3:17])[CH3:15])=[CH:6][C:5]=1[C:11]#[N:12]
Reactant: COC(=O)c1ccc(F)cc1C#N
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1C#N
Temperature: 60 °C
Reaction time: 9 h
Yield: 85 %

Procedure:
To a stirred solution of 4.03 g (22.5 mmol) 2-Cyano-4-fluoro-benzoic acid methyl ester (J. Med. Chem., 35; 24; (1992); 4613-4627) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 9 h at 60° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 9a was obtained in 85% yield (3.90 g, 19.1 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A mixture of 6 g of the syn isomer of ethyl 2-(2-bromoethoxyimino)-2-(2-tritylamino-4-thiazolyl)-acetate, 60 ml of methyl ethyl ketone and 2.141 g of sodium iodide was refluxed for 70 minutes and was then evaporated to dryness under reduced pressure. The residue was taken up in 120 ml of methylene chloride and the solution was washed 5 times with 40 ml of water. Each of the wash waters were reextracted with 2 ml of methylene chloride and the combined organic phase were dried and evaporated to dryness. The resin residue was added to ether and the solution was evaporated to dryness under reduced pressure to obtain 6.22 g of the syn isomer of ethyl 2-(2-iodoethoxyimino)-2-(2-tritylamino-4-thiazolyl)acetate melting at 110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:25](=[O:26])[O:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)OC(=O)Cl
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Solvent: C1CCOC1
Product: CC(C)OC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 0.89 mmol) and TEA (360 mg, 3.6 mmol) in THF (200 mL) at −20° C. was slowly added iso-propyl chloroformate (97.5 mg, 0.89 mmol) in THF (10 mL). Then the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Gemini 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.04% NH3OH; B-MeCN] B %: 10%-35%, 25 min) to give the title compound (230 mg, 43%). 1H NMR DMSO 400 MHz δ 9.17 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.33 (q, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.12 (q, 1H), 6.47 (s, 1H), 6.36 (q, 1H), 6.00 (s, 2H), 4.85 (s, 2H), 4.77 (q, 1H), 4.50 (s, 2H), 1.19 (d, J=6.0 Hz, 6H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C@@H:5]1[CH2:10][CH:9]([C@H:11]([NH:17][C:18]([O:20][CH3:21])=[O:19])[C:12]([O:14]CC)=[O:13])[CH2:8][C@@H:7]([CH3:22])[O:6]1>O.C1COCC1>[CH3:4][C@@H:5]1[CH2:10][CH:9]([C@H:11]([NH:17][C:18]([O:20][CH3:21])=[O:19])[C:12]([OH:14])=[O:13])[CH2:8][C@@H:7]([CH3:22])[O:6]1
Reactant: CCOC(=O)[C@@H](NC(=O)OC)C1C[C@@H](C)O[C@H](C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)O)C1C[C@@H](C)O[C@H](C)C1
Reaction time: 0.67 h
Yield: 104.1 %

Procedure:
Lithium hydroxide hydrate (8.51 g, 203 mmol) in H2O (270 mL) was added dropwise to a stirred solution of (S)-ethyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonyl-amino)acetate (27.7 g, 101 mmol) in THF (405 mL) over 65 min, while maintaining an internal temperature <5° C. The reaction mixture was stirred in an ice bath for 40 min and then in a water bath at RT for 5 h. The reaction mixture was partially concentrated to remove the THF and then partitioned between water (250 mL) and DCM (250 mL). The aqueous layer was adjusted to pH=2 with 1 N HCl (205 mL), and then extracted with isopropyl acetate (7×250 mL). The combined extracts were washed with brine (1×600 mL), dried (MgSO4), filtered and concentrated. The resulting viscous oil was treated with toluene (100 mL) and ether (75 mL), evaporated and dried in vacuo to afford Cap-2 (25.8 g, with 0.33 eq. of toluene) as a white foam. Chiral SFC purity >99.9% (Chiralpak AD-H (25×0.46 cm, 5 μm) 5% EtOH in CO2, 3 mL/min, 35° C., 220 nm, 100 bar). HPLC purity 95.6% (Column: Sunfire C8 75×4.6 mm ID; 2.5 μm; 40° C.; Mobile Phase: A=Water w/0.1% Formic Acid; B=CH3CN w/0.1% Formic Acid). LC/MS (ES+) 228.1 (M+H—H2O)+. By 1H-NMR the material contained about 0.33 eq. of toluene. 1H-NMR (400 MHz, CDCl3) δ 5.29 (d, J=8.6 Hz, 1H), 4.46-4.25 (m, 2H), 3.82 (dd, J=9.7, 5.9 Hz, 1H), 3.74 (s, 3H), 2.46-2.30 (m, 1H), 1.76-1.55 (m, 2H), 1.51-1.35 (m, 1H), 1.29 (d, J=6.8 Hz, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.18-1.06 (m, 1H). 13C-NMR (101 MHz, CDCl3) δ 174.1, 156.7, 68.3, 64.4, 57.5, 52.2, 35.8, 32.6, 30.3, 21.6, 16.7.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.O.[NH2:14][NH2:15]>C(O)CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:12])[NH:15][N:14]=[C:8]2[CH3:9]
Reactant: CC(=O)c1cc(Br)c(F)cc1F
Reactant: NN
Solvent: O
Solvent: OCCO
Product: Cc1n[nH]c2cc(F)c(Br)cc12
Temperature: 160 °C
Reaction time: 26 h
Yield: 67 %

Procedure:
To a solution of 1-(5-bromo-2,4-difluorophenyl)ethanone (4.9 g) in ethylene glycol (15 ml) was added hydrazine monohydrate (1.2 g) at room temperature, and the mixture was stirred at 160° C. for 26 hr. The reaction mixture was cooled to room temperature, and the insoluble material was removed. The filtrate was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[CH:21]1([CH2:24][NH:25][C:26]2[N:31]([CH3:32])[C:30](=[O:33])[C:29]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=3)=[CH:28][N:27]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CC([O-])(C)C.[K+]>CN(C=O)C>[CH:21]1([CH2:24][NH:25][C:26]2[N:31]([CH3:32])[C:30](=[O:33])[C:29]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[N:8]([CH2:7][C:6]6[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=6)[N:9]=[C:10]([CH3:18])[C:11]=45)=[C:36]([F:41])[CH:35]=3)=[CH:28][N:27]=2)[CH2:23][CH2:22]1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: Cn1c(NCC2CC2)ncc(-c2ccc(O)c(F)c2)c1=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(NCC6CC6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a 15 mL capacity reaction tube were added 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (20 mg, 0.07 mmol; prepared according to the procedure of Example 43, Step E) and 2-(cyclopropylmethylamino)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one (22.1 mg, 0.077 mmol) and the solids were dissolved in DMF (1 mL) under nitrogen. Potassium carbonate (10.6 mg, 0.0765 mmol) was added, followed by KOtBu (0.077 mL, 0.077 mmol, 1M solution in THF). The reaction tube was sealed and the reaction mixture was stirred at 110° C. for 1 hour. The reaction mixture was partitioned between water (5 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with a second portion of ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate and evaporated to afford 37.5 mg of a red semi-solid. The crude product was purified by silica gel chromatography (Biotage 12M) eluting with 2% MeOH/DCM to afford a red colored glass (23.8 mg, 63%). LRMS (APCI pos) m/e 541.3 (M+1).
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:30]=[CH:29][C:21]([C:22](OC(C)(C)C)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.Cl.[NH2:32][C@H:33]([C:38]([NH2:40])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36]>>[NH2:40][C:38]([C@@H:33]([NH:32][C:22](=[O:23])[C:21]1[CH:29]=[CH:30][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:3]3[C:4]4[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=4[CH2:6][O:7][C:2]3=[O:1])[CH2:13][CH2:14]2)=[CH:19][CH:20]=1)[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:39]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)cc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)cc1)C(N)=O

Procedure:
The title compound was prepared from the product of example 161 step (i) (0.06 g) and (S)-leucinamide hydrochloride (0.056 g) using the method of example 161 step (ii). Purification was by chromatography eluting with (5:1) ethyl acetate/dichloromethane. Yield 0.01 g as a solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[CH3:22]I.O>CS(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH3:22])[CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CI
Reactant: Fc1ccc(-c2cc[nH]c2-c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1ccc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a mixture of 1.5 g (0.038 mole) of 60% sodium hydride dispersion and 100 ml DMSO was added dropwise a solution of 5.1 g (0.02 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole in 25 ml DMSO. After the mixture was stirred one hour at room temperature, 5.6 g (0.04 mole) of methyl iodide was added dropwise. The mixture was stirred at room temperature overnight, then poured into water and extracted with ether. The ether extracts were backwashed with water three times, then dried and concentrated. The crude solid was recrystallized from hexane to give 4.3 g of product, m.p. 129°-129.5°.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([CH3:15])[CH:6]=1>C1COCC1>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[C:7]([CH3:15])[CH:6]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1S(=O)(=O)N(C)C
Yield: 100.7 %

Procedure:
To a mixture of 40% dimethylamine (aqueous, 2.5 mL, 20 mmol) in THF (2.5 mL) added 4-bromo-2-methylbenzenesulfonyl chloride (0.27 g, 1.0 mmol) with stirring. After 5h the reaction mixture was partitioned between DCM (50 mL) and water (50 mL), washed with water (2×50 mL) and brine (50 mL), dried (anhyd Na2SO4) and concentrated under reduced pressure to provide the title compound (0.28 g, quant) as a colorless liquid, which was used without purification in the next step. 1H-NMR (CDCl3) δ 7.74 (1H, d, J=8.3), 7.49 (1H, d, J=1.8), 7.46 (1H, dd, J=1.8, 8.3), 2.80 (6H, s), 2.60 (3H, s); Rf=0.38 (silica, 1:4 EtOAc/Hex).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]I>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:20])[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=S(=O)(NCC1CCCO1)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC1CCCO1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4.30 g of 4-bromo-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide (compound D2) are dissolved in 150 ml of dry tetrahydrofuran. 590 mg of sodium hydride (strength 60 wt. % dispersion in mineral oil) are added in portions to the solution. After 15 min, 1.67 ml of methyl iodide are slowly added and the reaction mixture is stirred at room temperature for 20 hours. Subsequently, the suspension is concentrated in vacuo, extracted using 200 ml of ethyl acetate and 100 ml of half-saturated brine (sodium chloride solution). The organic layer is dried using Na2SO4, filtered with suction, and concentrated in vacuo to yield 4.53 g of the title compound as an oil. ESI-MS: 334.2/336.0 (MH+, 100%:98%). TLC: Rf=0.78 (dichloromethane/ethanol 20:1 parts by volume).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[CH2:14][CH2:15]1
Reactant: Nc1ccccn1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Product: c1ccc(NCC2CCN(c3ccc(CN4CCCC4)cc3)CC2)nc1

Procedure:
Prepared from the product of Example 16 and 2-aminopyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.Cl>>[Cl:12][C:8]1[CH:7]=[C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:5])[CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1cccc(Cl)c1
Agent: Cl
Product: O=C(c1cccc(Cl)c1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 125 °C
Yield: 29.9 %

Procedure:
To a stirred melt of 10.0 g (0.043 mole) of 2-amino-3'-chlorobenzophenone under an atmosphere of nitrogen gas was added at 115°-120° C. in two portions at 20 min intervals, 6.3 g (0.040 mole) of 2-chloro-3-nitropyridine. The reaction mixture was heated at 125° C. for 4 hr and then poured into 250 ml of hot 3N hydrochloric acid under vigorous agitation. The mixture was cooled, the aqueous portion decanted and the residue was dissolved in 150 ml of methylene chloride. The methylene chloride solution was washed in sequence five times with 30 ml portions of 3N hydrochloric acid, once with 30 ml of 5% aqueous sodium hydroxide, once with 30 ml of saturated aqueous sodium chloride solution. The washed methylene chloride solution was dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropyl ether, yielding 4.23 g (28%) of dark yellow solid, m.p. 124°- 125° C.