Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH2:34][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)=[N:33][C:26]=2[NH:25]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
To a solution of 297 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one and 159 mg of 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazine-6-carbaldehyde in 4 mL of chloroform and 1 mL of methanol, 0.11 mL of acetic acid was added, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture, 299 mg of sodium triacetoxyborohydride was added, and the mixture was stirred for 1.5 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and an eluent of chloroform:methanol (mixing 5% of 28% ammonium water)=87:13 to obtain 275 mg of 1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)oxazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a yellow foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=O)[N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3([CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:16][CH2:15]3)[C:6]=12.Cl.[NH2:29]O.C([O-])(=O)C.[Na+].CC(OC(C)=O)=O.C([O-])(O)=O.[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:26]#[N:29])[N:5]2[C:6]=1[C:7]1([CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])[CH2:18][CH2:19]1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=1
Reactant: Cc1cc(C=O)n2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: Cc1cc(C#N)n2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
To a solution of 3′-methyl-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbaldehyde (25 mg, 0.07 mmol) in ethanol (125 μL) at 60° C. was added an aqueous solution of hydroxylamine hydrochloride (20.7 mg, 0.30 mmol) and sodium acetate (41.2 mg, 0.50 mmol) in water (125.0 μL). The solution was stirred at 60° C. for 2 hours. The reaction was cooled to 25° C., water added and the precipitate that formed was collected by filtration. The solids were washed thoroughly with water and dried under vacuum, dissolved in Ac2O (119.1 μL, 1.26 mmol) and heated at 140° C. for 5 h. The reaction was cooled to 25° C., poured onto ice, basified by addition of solid NaHCO3 until no more foaming occurred and extracted with dichloromethane (3×5 mL). The organic phases were combined, dried, filtered and concentrated to yield a residue that was purified by silica gel chromatography using a gradient of 0.5-45% EtOAc in hexanes to yield 3-methyl-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbonitrile (10 mg, 40%). ESI-MS m/z calc. 375.1. found 376.3 (M+1)+; Retention time 2.01 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22].[CH3:25][S:26]([O-:28])=[O:27].[Na+].N1CCC[C@H]1C(O)=O>CS(C)=O.O.[Cu](I)I>[CH3:25][S:26]([C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])(=[O:28])=[O:27]
Reactant: CS(=O)[O-]
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCN1C(=O)C2(COc3cc(S(C)(=O)=O)ccc32)c2ccccc21
Temperature: 100 °C
Yield: 5 %

Procedure:
A mixture of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.60 g, 1.55 mmol), sodium methanesulfinate (0.19 g, 1.86 mmol), copper iodide (0.03 g, 0.16 mmol), and L-proline (0.04 g, 0.31 mmol) in dimethyl sulfoxide (3.00 mL) was heated at 100° C. for 2 days under N2. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (4×15.0 mL). The combined organics was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/3) to give the title compound (0.03 g, 46%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.46-7.48 (m, 1H), 7.38 (dt, 1H), 7.34 (dt, 1H), 7.13-7.02 (m, 2H), 6.94 (d, 1H), 6.86 (d, 1H), 5.03 (d, 1H), 4.78 (d, 1H), 3.87-3.64 (m, 2H), 3.02 (s, 3H), 1.79-1.68 (m, 2H), 1.41-1.32 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.1, 161.2, 142.6, 142.1, 135.4, 131.5, 129.5, 124.3, 124.0, 123.5, 120.7, 109.5, 109.0, 80.5, 57.7, 44.5, 40.6, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 386.5 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>C(Cl)Cl.FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)cc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution mixture of the obtained tert-butyl 2-(2-hydroxy-4-phenylbenzamido)-4-phenylbenzoate in methylene chloride (6 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 3 hours and 10 minutes. Trifluoroacetic acid (2 mL) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.076 g of 2-(2-hydroxy-4-phenylbenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: Cl.[CH2:2]([N:4]=[C:5]=NCCCN(C)C)C.[C:13]([O:17][C:18]([N:20]1[CH2:27][C@@H:26]([OH:28])[CH2:25][C@H:21]1[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].O.ON1C2C=CC=CC=2N=N1.CNC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CCCCCC.C(Cl)(Cl)Cl.O1CCCC1>[CH3:2][N:4]([CH3:5])[C:22]([C@@H:21]1[CH2:25][C@H:26]([OH:28])[CH2:27][N:20]1[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])=[O:23]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
9.95 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice cooling to a 100 mL tetrahydrofuran solution of 10.0 g of (4S)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline and 8.77 g of 1-hydroxybenzotriazole monohydrate, and the reaction mixture was stirred for 30 minutes at the same temperature. 15.6 g of a 50% dimethylamine aqueous solution was than added to the reaction solution, after which the reaction mixture was stirred for 1 hour at room temperature. 100 mL of chloroform and 50 mL of a 5% potassium carbonate aqueous solution were added to the reaction solution, liquid separation was performed, the aqueous layer was extracted with chloroform (30 mL×2), and the combined organic layer was washed with 30 mL of saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1 to 10/0; v/v) to obtain 8.66 g of the titled compound (colorless solid).
Reaction SMILES: [Li]CCCC.C([Mg]Br)C.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[N:15]=[CH:14]2.CN([CH:24]=[O:25])C>C1(C)C=CC=CC=1.C1COCC1>[CH3:20][N:16]1[C:17]2[C:13](=[CH:12][C:11]([CH:24]=[O:25])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: Cn1ncc2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: CC[Mg]Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1ncc2cc(C=O)ccc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A suspension of n-BuLi (7.33 mL, 11.73 mmol) and ethylmagnesium bromide (5.76 mL, 5.76 mmol) in toluene (30 mL) was stirred at −30° C. for 30 min, and then a solution of 5-bromo-1-methyl-1H-indazole (2.25 g, 10.66 mmol) in THF (5 mL) was added. After 1 h, anhydrous DMF (4.95 mL, 64.0 mmol) was added at −10° C. The reaction mixture was allowed to warm to rt and stirred for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution and concentrated in vacuo. The residue was diluted with water, extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (hexane:EtOAc=10:1) to give the title compound as a white solid (1.37 g, 76%). 1H-NMR (400 MHz, DMSO-d6) δppm 10.02 (s, 1H), 8.41 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H), 7.78 (d, 1H), 4.09 (s, 3H). LCMS (method A): [MH]+=161, tR=4.00 min.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:26][C:27]1[O:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH:33]=2)=[N:29][C:28]=1[CH2:43][CH2:44][O:45]S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:45][CH2:44][CH2:43][C:28]4[N:29]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[C:34]([C:38]6[S:39][CH:40]=[CH:41][CH:42]=6)[CH:33]=5)[O:31][C:27]=4[CH3:26])=[CH:9][CH:8]=3)[C:4]([OH:25])=[O:3])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3cccs3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc3c(c2)OCO3)C(=O)O)cc1

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-yloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 58, Part C), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (0.030 mmol) (see Ex. 5, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.19 (t, 1H, J=1.71 Hz), 7.85–7.82 (m, 1H), 7.67–7.63 (m, 1H), 7.42 (t, 1H, J=7.82 Hz), 7.38–7.37 (m, 1H), 7.28–7.26 (m, 1H), 7.13 (d, 2H, J=8.79 Hz), 7.06 (dd, 1H, J=4.88 Hz, J=3.42 Hz), 6.79 (d, 2H, J=8.79 Hz), 6.60 (d, 1H, J=8.30 Hz), 6.40 (d, 1H, J=2.44 Hz), 6.32 (dd, 1H, J=8.30 Hz, J=2.44 Hz), 5.87 (d, 2H, J=0.98 Hz), 4.19 (t, 2H, J=6.11 Hz), 3.15 (d, 1H, J=14.17 Hz), 3.04–3.01 (m, 3H), 2.39 (s, 3H), 1.30 (s, 3H);HRMS (ES+) m/z exact mass calcd for C33H30NO7S 584.1743, found 584.1744.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:16](Br)=[C:15](Br)[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2-c1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccc(F)cc2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-7-cyano-4-hydroxy-1-(4-fluoro-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 326 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1CC1C=CC=CC=1.[ClH:17]>CO>[ClH:17].[CH3:1][N:2]([CH3:16])[CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1
Reactant: CN(C)C[C@@H]1CCCN1Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CN(C)C[C@@H]1CCCN1
Yield: 119.8 %

Procedure:
N,N-Dimethyl-1-[(2S)-1-(phenylmethyl)-2-pyrrolidinyl]methanamine (3.730 g, 17.08 mmol) was dissolved in a mixture of MeOH (100 mL) and 1N HCl (35 mL, 34.16 mmol), degassed and placed under argon. 10% Pd/C (1.119 g) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through a fiberglass filter, washing with MeOH. The filtrate was concentrated in vacuo to provide pure N,N-dimethyl-1-[(2S)-2-pyrrolidinyl]methanamine hydrochloride (3.3701 g, >99%). LCMS: (M+H)+: 129.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]([O:8]C)=[O:7].[OH-].[Na+:11]>CO>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]([O-:8])=[O:7].[Na+:11]
Reactant: COCOCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOCC(=O)[O-]

Procedure:
Methyl methoxymethyloxyacetate (19.06 g) in methanol (20 ml.) is treated with aqueous sodium hydroxide (57 ml. of a 2.5 N solution) over a period of 30 minutes. The methanol is evaporated under reduced pressure and the aqueous residue lyophilized giving sodium methoxymethyloxyacetate. The sodium salt is dispersed in benzene (250 ml.) and treated with pyridine (1 ml.). Oxalyl chloride (30 ml.) is added with ice-bath cooling. The resulting mixture is stirred in the cold until gas evolution ceases, then at room temperature for 5 minutes. The mixture is filtered and evaporated under reduced pressure to remove excess oxalyl chloride and benzene. Distillation of the residue gives methoxymethyloxyacetyl chloride.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3([OH:21])[CH2:20][CH2:19][C:14]4(OCC[O:15]4)[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>C1COCC1>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3([OH:21])[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]3)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OC1(c2ccc(N3CCC3)nc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccc(N3CCC3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-(6-Azetidin-1-ylpyridin-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (35 mg) was dissolved in THF (1.2 mL), and then 3 M HCl (0.8 mL) was added at rt. The resulting solution was stirred at rt for 2 h, then basified with 6 N NaOH in ice bath to PH=10. The aqueous layer was extracted with CH2Cl2×3. The combined organic layers were dried, filtered and rotary evaporated to provide 28 mg (97%) of white solid product w/o further purification. MS (M+H+)=247.0.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][N:16]=2)=[CH:9][C:8]=1[O:27][CH3:28])(=O)[CH3:2].COC(=NS([N+](CC)(CC)CC)(=O)=O)[O-]>C1COCC1>[Cl:13][C:11]1[CH:12]=[C:7]([C:6]2[O:29][C:1]([CH3:2])=[N:4][N:5]=2)[C:8]([O:27][CH3:28])=[CH:9][C:10]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][N:16]=1
Reactant: CNc1nc(Nc2cc(OC)c(C(=O)NNC(C)=O)cc2Cl)ncc1C(F)(F)F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CNc1nc(Nc2cc(OC)c(-c3nnc(C)o3)cc2Cl)ncc1C(F)(F)F
Yield: 42.2 %

Procedure:
A mixture of N′-acetoyl-5-chloro-2-methoxy-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzohydrazide (68 mg, 0.16 mmol), and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess reagent) (75 mg, 0.32 mmol) in THF (4 mL) was irradiated in the microwave at 150° C. for 30 min. An additional portion of Burgess reagent (75 mg, 0.32 mmol) was added and the reaction was irradiated a further 30 min at 150° C. in the microwave. The reaction mixture was concentrated and the crude residue purified via silica gel column chromatography (0-100% ethyl acetate/isohexane) to afford a residue that was triturated with diethyl ether/methanol yielding N2-(2-chloro-5-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine as a white solid (28 mg, 43%). HPLC (15 cm_Formic_Ascentis_HPLC_CH3CN): at 9.15 min. LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=415 at 4.00 min. 1H NMR (400 MHz, CDCl): δ 8.62 (s, 1H); 8.25 (s, 1H); 7.95 (s, 1H); 7.80 (s, 1H); 5.34 (s, 1H); 4.01 (s, 3H); 3.15 (d, J=4.7, 3H); 2.61 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24]C)=[O:23]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:21][C:22]([OH:24])=[O:23])[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NS(=O)(=O)c2ncccc2C)cn1
Reactant: COC(=O)CBr
Product: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1

Procedure:
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid (6-methoxy-pyridin-3-yl)-amide with methyl bromoacetate
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:8]=1.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33](Cl)=[O:34].CC(O)C>CCOCC>[Br:27][C:28]1[CH:36]=[C:32]([C:33]([C:7]2[C:15]3[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=3[NH:9][CH:8]=2)=[O:34])[CH:31]=[N:30][CH:29]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(c1cncc(Br)c1)c1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
n-BuLi (11.3 mL, 2.5 M in Hexane, 28.3 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 25.7 mmol) in Et2O (250 mL) at −78° C. and stirred for 0.5 h. 5-Bromo-nicotinoyl chloride (6.8 g, 30.8 mmol) was added to the reaction mixture slowly and stirred for 3 h, warmed to room temperature, and stirred for an additional 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl (150 mL) and stirred for 30 min. The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organic layers were washed with brine (300 mL), dried (Na2SO4), filtered, and concentrated in vacuo to provide a crude solid. Trituration with 2-propanol provided the title compound as a pure white solid (7.5 g, 86%). MS: 337.5/339.5 (MH+); HPLC Rf: 4.02 min. (HPLC method 4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:32][CH:33]=[CH:34][C:7]=4[C:6]=2[CH:35]=1)[NH:10][C:11]=3[C:16]1[CH2:17][CH:18]2[N:24](C(OC(C)(C)C)=O)[CH:22]([CH:23]=1)[CH2:21][CH2:20][CH2:19]2.FC(F)(F)C(O)=O>ClCCl>[CH:18]12[NH:24][CH:22]([CH2:21][CH2:20][CH2:19]1)[CH:23]=[C:16]([C:11]1[NH:10][C:9]3[C:8]4[C:12]=1[CH2:13][N:14]([CH3:15])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:35][C:6]=1[C:7]=4[CH:34]=[CH:33][N:32]=3)[CH2:17]2
Reactant: CN1Cc2c(C3=CC4CCCC(C3)N4C(=O)OC(C)(C)C)[nH]c3nccc(c23)-c2cc(F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(C3=CC4CCCC(C3)N4)[nH]c3nccc(c23)-c2cc(F)ccc21

Procedure:
A solution of Example 99C (1.135 g, 2.392 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature for 30 minutes, and concentrated in vacuo. The crude product (LC-MS 375.2 (M+H)+) was directly used for next step.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[NH:8][C:9](=[O:11])[CH3:10].C(O)(=O)C>S(=O)(=O)(O)O>[F:5][C:6]1[CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[C:13]([F:16])=[CH:12][C:7]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(F)ccc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of nitric acid (21.85 mL) and sulfuric acid (28.5 mL) is added dropwise to a mixture of 2',5'-difluoroacetanilide (44.2 g, 0.281 mol) and acetic acid (19 mL) in sulfuric acid (190 mL) while maintaining the reaction mixture temperature below 10° C. After the addition is complete, the reaction mixture is stirred at 0° C. for one hour and poured onto cracked ice (2 L). The aqueous mixture is filtered to obtain a solid. The solid is air dried and recrystallized from ethanol to give the title product as a yellow, crystalline solid, mp 188°-189° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:27]([O:29]CC#N)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCON=C(C(=O)OCC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
A mixture of 8.69 g of the product of Step A in 52 ml of dioxane was cooled on an ice bath and 17.1 ml of N sodium hydroxide solution were added thereto dropwise over 20 minutes. Spontaneous heating occured and then 10.5 ml of 2 N hydrochloric acid were added thereto. The dioxane was distilled and only water remained as solvent. 20 ml of water and 30 ml of ether were added thereto and the mixture was stirred for 15 minutes and was vacuum filtered. The crystals were rinsed with water and ether and dried to obtain 4.32 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-cyanomethoxyimino-acetic acid melting at about 180° C. with decomposition.