Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[NH2:22][C:23]1[C:24]([Cl:32])=[C:25](Cl)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=1.C(N(C(C)C)CC)(C)C>C(O)CCC.CCOC(C)=O>[NH2:22][C:23]1[C:24]([Cl:32])=[C:25]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]3[CH:21]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[C:26](=[O:30])[N:27]([CH3:29])[N:28]=1
Reactant: Cn1nc(N)c(Cl)c(Cl)c1=O
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1c(Cl)c(N)nn(C)c1=O)c1nc2ccc(F)cc2n1-c1ccccc1
Yield: 13.3 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (1.0 g, 3.05 mmol), 6-amino-4,5-dichloro-2-methyl-2H-pyridazin-3-one (J. Het Chem, 5-10 37, 2000) (0.59 g, 3.05 mmol) and diisopropylethylamine (2.1 mL, 12.8 mmol) in butanol (5 mL) was heated to 115° C. in a sealed tube under argon for 19 h. The reaction mixture was cooled and diluted with EtOAc (50 mL) and washed with water (20 mL). The organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 1-8% (9:1 MeOH/0.880 NH3) in DCM then gradient 20-100% EtOAc in cyclohexane). Fractions containing the less polar product were evaporated and freeze dried to give 341 as a yellow solid, (167 mg, 13%). LCMS (Method C): RT 4.01 min [M+H]+ 313.02. 1H NMR δ (ppm DMSO-d6): 7.76 (1H, dd, J=8.81, 4.85 Hz), 7.56-7.40 (5H, m), 7.13 (1H, ddd, J=9.85, 8.80, 2.53 Hz), 6.88 (1H, dd, J=8.91, 2.51 Hz), 5.70 (1H, d, J=9.37 Hz), 5.61-5.60 (1H, m), 5.52 (2H, s), 3.37 (3H, s), 1.59 (3H, d, J=6.56 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:31])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:25])=[O:6].N1C=CC=CC=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[C:38]([NH:1][C:2]1[C:3]([F:31])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:9]([CH3:25])=[CH:10][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:18])([F:17])[F:19])=[CH:12][C:13]=1[CH3:14])=[O:6])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1F
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(NC(=O)c2ccccc2)c1F
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 3-amino-4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-fluoro-benzamide (68 mg, 0.15 mmol) (Example I12) in tetrahydrofuran (2 ml) were added pyridine (36 μl, 0.45 mmol) and benzoyl chloride (21 μl, 0.18 mmol). The reaction mixture was heated in a microwave at 140° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature. A second portion of benzoyl chloride (21 μl, 0.18 mmol) was added and heating repeated at 140° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and then partitioned between sodium hydrogen carbonate (1M) and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase chromatography (eluent: trifluoroacetic acid/water/acetonitrile 1:4:5 to 1:1:8) to give Compound No. D15 of Table D (0.024 g, 28% yield). 1H-NMR (400 MHz, CDCl3): 2.28 (6H, s), 7.33 (2H, s), 7.45-7.96 (9H, m) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][C@H:30]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:31]1>C(Cl)Cl.O>[CH2:35]([N:32]1[CH2:33][CH2:34][C@H:30]([NH:29][C:11](=[O:13])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])[CH2:31]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CCN(Cc2ccccc2)C1
Temperature: -5 °C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
N-(tert-Butoxycarbonyl)-L-alanine (12.8 g) was dissolved in methylene chloride (50 mL) and the solution cooled to -5° C., and treated with N-methylmorpholine (6.7 g). The resulting mixture was stirred and cooled to -5° to -10° C. and a cold (-5° C.) solution of isobutyl chloroformate (8.5 g) in methylene chloride (100 mL) added slowly while keeping the temperature at or below -5° C. The mixture was stirred for another 30 minutes at -5° to -10° C. To this mixture was then added a cold (0° C.) solution of (S)-3-amino-1-benzylpyrrolidine (10.0 g) in methylene chloride (100 mL) while keeping the temperature between 0° and -10° C. The reaction mixture was stirred at 0° to -5° C. for 1 hour and then at 15° to 25° C. for 2 hours. The mixture was treated with 300 mL of demineralized water and the layers separated. The organic phase was extracted with a solution of sodium bicarbonate (18.5 g) in demineralized water (200 mL) followed by demineralized water (300 mL). The organic phase was dried over sodium sulfate (50 g) and the product solution concentrated under vacuum to give 1-benzyl-3-(S)-[2-(S) (tert-butoxycarbonylamino)-propionylamino]pyrrolidine (21.3 g) as an off white solid (mp: 102°-105° C.) which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:38])[NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:25][CH:24]1[CH3:37])=[O:22])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)([O-])O.[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:25][C@H:24]1[CH3:37])=[O:22])=[O:38]
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)CCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)CCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of [2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.110 g, 0.2 mmol) in methylene chloride (3 mL) was added trifluoroacetic acid (0.50 mL). The reaction was stirred for 2 hours at ambient temperature then diluted with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with methylene chloride and the combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.069 g)
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[Na+].[Br:19][CH2:20][CH2:21]Br>O.C(O)C.CC(C)=O>[Br:19][CH2:20][CH2:21][O:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[C:2]([OH:1])[CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCBr)cc1O
Reaction time: 16 h
Yield: 42.5 %

Procedure:
A 2000 mL, 1 neck round-bottomed flask containing a magnetic stir bar is charged with 2,4-dihydroxybenzophenone (85.6 g, 0.40 mol, Aldrich Chemical Co., Milwaukee, Wis.). To this is added a solution of sodium hydroxide (16.0 g) dissolved in 320 mL of water. Next, 1,2-dibromoethane (105.6 g, 0.56 mol) dissolved in 320 ml of ethanol is added. The reaction mixture is heated to reflux with stirring for 16 hours. The reaction vessel is then transferred to a rotary evaporator where the liquids are removed at aspirator pressure at 80° C. A brown solid is obtained which is suspended in 180 mL of acetone and stirred for 1 hour at 45° C. This mixture is filtered and the filtrate poured into 2 L of water containing 20 g of sodium carbonate yielding 65 grams of a tan precipitate. This material is recrystallized from approximately 100 mL of ethanol to give 55.3 g (0.17 mol, 43%) of a light tan solid m.p. 87°-89.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][CH2:5][N:4]([C:7]2[C:11]([N+:12]([O-])=O)=[CH:10][N:9]([CH3:15])[N:8]=2)[C:3]1=[O:16].C1COCC1>[C].[Pd].CO>[NH2:12][C:11]1[C:7]([N:4]2[CH2:5][CH2:6][C:2]([CH3:1])([CH3:17])[C:3]2=[O:16])=[N:8][N:9]([CH3:15])[CH:10]=1
Reactant: Cn1cc([N+](=O)[O-])c(N2CCC(C)(C)C2=O)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(N)c(N2CCC(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A mixture of 3,3-dimethyl-1-(1-methyl-4-nitro-1H-pyrazol-3-yl)pyrrolidin-2-one (170 mg), 10% palladium-carbon (76 mg), THF (2 mL) and methanol (2 mL) was stirred at room temperature for 2 hr under hydrogen atmosphere. The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure to give the title compound (140 mg).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].O=[C:11]1[CH2:14][C:13]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:12]1>C(O)C>[OH:3][N:2]=[C:11]1[CH2:14][C:13]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=NO)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.2 %

Procedure:
0.58 g (8.36 mmol) of hydroxylamine hydrochloride and 1.15 g (8.36 mmol) of potassium carbonate are added to a solution of 1.00 g (4.18 mmol) of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (U.S. Pat. No. 6,498,159) in 60 mL of ethanol, and the mixture is then left stirring at room temperature for 12 hours. After evaporating off the solvent under reduced pressure, the residue is taken up in dichloromethane and water, the aqueous phase is separated out and extracted twice with dichloromethane, and the combined organic phases are dried over sodium sulfate. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia. 0.831 g of pure product is thus obtained in the form of a white powder.
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][N+:7]=1[O-:15]>CO>[Cl:5][C:6]1[CH:11]=[C:10]([O:3][CH3:2])[CH:9]=[CH:8][N+:7]=1[O-:15]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc[n+]([O-])c(Cl)c1
Reaction time: 50 h

Procedure:
Sodium (0.46 g) is dissolved in absolute methanol (50 ml) and the resultant solution of sodium methoxide is added to a solution of 2-chloro-4-nitropyridine-1-oxide (3.5 g, prepared as described in Example 1) in methanol (10 ml). The reaction mixture is allowed to stand at room temperature for 50 hours and is then subjected to rotary evaporation to give 2-chloro-4-methoxypyridine-1-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH:66]1[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([N:66]5[CH2:70][CH2:69][C@@H:68]([OH:71])[CH2:67]5)=[O:25])=[CH:22][C:21]=4[F:29])[C:15]3=[O:30])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.7 %

Procedure:
To a solution of (S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (Example 153, Step B; 0.10 g, 0.22 mmol) in DMF (2 mL) was added HATU (0.17 g, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.66 mmol) and the reaction was stirred for 20 minutes at ambient temperature. (R)-pyrrolidin-3-ol hydrochloride (0.058 g, 0.66 mmol) was added and the reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with EtOAc (30 mL), washed with HCl (1N, 10 mL), NaOH (1N, 10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by reverse phase HPLC. The combined fractions were diluted with EtOAc (50 mL) and washed with 1 N NaOH (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum to give (S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one (0.038 g, 0.072 mmol, 33% yield). Mass spectrum (apci) m/z=521.0 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][NH:6]1.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].[OH-].[Na+]>O.C1COCC1>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]
Reactant: COC(=O)[C@@H]1CC(O)CN1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 4-hydroxyproline methyl ester hydrochloride (Rosen et al, Synthesis, 40, 1988) (60.4 mMol) in water (10 ml) and THF (20 ml), at 0° C., was added dropwise allyl chloroformate (70 mMol) in THF (20 ml). The solution was maintained at a slightly basic pH by the simultaneous addition of 4N sodium hydroxide (144 mMol). The mixture was stirred at 0° for 1 hour. The aqueous layer was separated and washed, twice, with dichloromethane (25 ml). The organic layers were combined, dried and evaporated to give N-allyloxycarbonyl hydroxyproline methyl ester as a pale yellow oil (86%): NMR (CDCl3) 2.2(m, 3H); 3.58(m, 2H); 3.73(2d, 3H); 4.54(m, 4H); 5.25(m, 2H); 5.9(m, 1H): M/S CI (M+H)+ =230.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([CH2:20][CH2:21][CH3:22])=[C:9]([CH:17]=[CH:18][CH:19]=1)[C:10]([O:12]C(C)(C)C)=[O:11].O>C1(C)C=CC=CC=1>[OH:6][C:7]1[C:8]([CH2:20][CH2:21][CH3:22])=[C:9]([CH:17]=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11]
Reactant: CCCc1c(OC)cccc1C(=O)OC(C)(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(O)cccc1C(=O)O
Temperature: -25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Add boron tribromide (305.6 mL, 305.6 mmol) dropwise while maintaining the temperature below 0° C. to a solution of tert-butyl 3-methoxy-2-propyl-benzoate (61.2 g, 244 mmol) in toluene (428 mL) which has been cooled to −25° C. Stir at −5° C. for 3 h. Add water (100 mL) dropwise, raising the temperature to 7° C., and stir 30 min. Concentrate the mixture in vacuo and then suspend the semisolid in water (200 mL). Stir 1 h and filter the suspension through a glass frit. Wash the collected solid with water and dry the solid to yield the title compound (43.1 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.0 Hz, 1H); 7.16 (t, J=8.0 Hz, 1H); 6.99 (d, J=7.7 Hz, 1H); 5.0 (bs, 2H); 2.98 (t, J=7.7 Hz, 2H), 1.64 (m, 2H); 1.02 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1.[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[CH:5][N:6]=1
Reactant: Cc1ncc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ncc(-c2cc(Oc3ccc(N)nc3)ccn2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.5 %

Procedure:
A 0° C. mixture of 2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)oxazole (323 mg, 1.083 mmol) and NH4Cl (2.317 g, 43.3 mmol) in MeOH (8 mL) and THF (8 mL) was treated portion-wise with zinc dust (708 mg, 10.83 mmol), allowed to warm to RT and stirred overnight. The mixture was diluted with EtOAc, warmed slightly, the solids removed via filtration through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to dryness, treated with EtOAc, heated to reflux, the solids removed via hot filtration and the filtrate concentrated to dryness to afford 5-((2-(2-methyloxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (324 mg, 112%). 1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J=5.7 Hz, 1H), 7.83 (d, J=2.9 Hz, 1H), 7.60 (s, 1H), 7.31 (dd, J=8.9, 3.0 Hz, 1H), 7.06 (d, J=2.5 Hz, 1H), 6.83 (dd, J=5.7, 2.5 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.07 (s, 2H), 2.46 (s, 3H); MS (ESI) m/z: 269.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>CC#N>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(N)cc2ccoc12
Solvent: CC#N
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(NS(=O)(=O)c2ccccc2Cl)cc2ccoc12

Procedure:
The title product was prepared according to the procedure of Example 121, Step 4, starting from tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-1-carboxylate (obtained in Example 121, Step 3) and 2-chlorobenzenesulfonyl chloride (0.043 g, 0.2 mmol). Yield: 0.017 g (26%). HPLC 94% RT=2.01 min (System A; 10-97% MeCN over 3 min), 98% RT=1.85 min (System B; 10-97% MeCN over 3 min). MS (ESI+) m/z 534.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][N:73]3[C:84](=[O:91])[C@@H:85]([NH2:90])[C:86]([CH3:89])([CH3:88])[CH3:87])=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:90][C@H:85]([C:84]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:54][CH2:55][CH2:56][CH2:57]3)(=[O:60])=[O:59])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:82])([CH3:81])[C:76]32[CH2:79][CH2:78][CH2:77]3)[CH2:74]1)=[O:91])[C:86]([CH3:89])([CH3:88])[CH3:87])[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](N)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCCCC1
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: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCCCC1)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 15 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(1-methyl-cyclohexyl)-acetic acid (0.217 g; 0.80 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.38 g; 1.00 mmol) in DCM (10 mL) was stirred for 20 min at ambient temperature. After addition of DIPEA (0.698 mL; 4.00 mmol) and (5R,8S)-7-((S)-2-Amino-3,3-dimethyl-butyryl)-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.400 g; 0.67 mmol) in DCM (10 mL) the reaction mixture was stirred for 15 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.91 min; M/z=818 [M+H], HPLC (method A3) Rt=7.18 min
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[C:10]([NH:11][C:12]2[C:13]3[O:28][CH2:27][CH2:26][C:14]=3[N:15]=[C:16]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[N:17]=2)=[CH:9][CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C:16]2[N:17]=[C:12]([NH:11][C:10]3[C:5]([C:4]([OH:29])=[O:3])=[CH:6][N:7]=[CH:8][CH:9]=3)[C:13]3[O:28][CH2:27][CH2:26][C:14]=3[N:15]=2)[CH:23]=1
Reactant: CCOC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-nicotinic acid ethyl ester (100 mg, 0.24 mmol, 1 eq) in MeOH (5 ml) was added a 1 N NaOH(aq) solution (290 μl, 0.29 mmol, 1.2 eq) and the reaction mixture was refluxed for 5 h. The solution was cooled to r.t. and concentrated in vacuo. Water (20 ml) was added to the crude material and the aqueous layer was acidified to pH 4. The solid was filtered, washed with water (2×5 ml) and dried overnight to afford 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-nicotinic acid (88 mg, 94%) as a cream colored solid.
Reaction SMILES: [F:1][C:2]([F:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][O:4][CH2:5][CH2:6][C:7]([F:13])([F:12])[CH2:8][CH2:9][CH:10]=C.FC(F)(CCOCCCCC1C=CC=CC=1)CCC=[O:26]>>[F:1][C:2]([F:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][O:4][CH2:5][CH2:6][C:7]([F:13])([F:12])[CH2:8][CH2:9][CH:10]=[O:26]
Reactant: C=CCCC(F)(F)CCOCC(F)(F)c1ccccc1
Reactant: O=CCCC(F)(F)CCOCCCCc1ccccc1
Product: O=CCCC(F)(F)CCOCC(F)(F)c1ccccc1
Yield: 60 %

Procedure:
Obtained from Intermediate 85 (0.80 g, 2.7 mmol) by the procedure described in Intermediate 17. Purification by column chromatography with silica gel eluting with ethyl acetate/n-hexane (1:5) gave the title compound (0.48 g, 60%) as oil.