Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH3:29])[C:12]2[O:16][C@@H:15]([CH3:17])[C@@H:14]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[C:13]=2[C:27]=1[CH3:28])C1C=CC=CC=1>CCCCCC>[CH:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:14]2[C:13]3[C:27]([CH3:28])=[C:9]([NH2:8])[C:10]([CH3:30])=[C:11]([CH3:29])[C:12]=3[O:16][C@H:15]2[CH3:17])=[CH:19][CH:20]=1)([CH3:26])[CH3:25]
Reactant: Cc1c(C)c2c(c(C)c1NCc1ccccc1)[C@H](c1ccc(C(C)C)cc1)[C@H](C)O2
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1N)[C@H](c1ccc(C(C)C)cc1)[C@H](C)O2
Yield: 83 %

Procedure:
Using (cis)-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 349, (cis)-5-bromo-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran was synthesized in the same manner as in Reference Example 23. Using this compound, (cis)-N-benzyl-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine were synthesized in the same manner as in Reference Example 24. Using this compound, the title compound was synthesized in the same manner as in Reference Example 30. Yield 83%. Melting point: 91-92° C. (hexane).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:42]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][N:29](CC5C=CC(OC)=CC=5)[CH:30]=4)[CH:24]=3)[CH:20]=[CH:19]2)[CH:12]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[CH:42]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][NH:29][CH:30]=4)[CH:24]=3)[CH:20]=[CH:19]2)[CH:12]=1)=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(N7CCN(C)CC7)cc(C(C)(C)C)c6)ccc5C)ccn4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C)CC3)cc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
68 mg (76% pure, 79 μmol) of the compound of Example 57A were initially charged in 0.32 ml of trifluoroacetic acid and stirred at 80° C. for 3 h. The mixture was then purified directly by preparative HPLC (Method 29). The product fractions were concentrated under reduced pressure and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. This gave 41 mg (97% of theory) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=1>C(O)(=O)C.[Pt]=O>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5]1
Reactant: CCOC(=O)c1cc(CCO)ccn1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(CCO)CCN1

Procedure:
A mixture of 8.37 g of ethyl 4-(2-hydroxyethyl)-pyridine-2-carboxylate in 130 ml acetic acid and 4 g platinum oxide is hydrogenated at 50 lbs/in2. Filtration, concentration in vacuo, neutralization with potassium carbonate and extraction with methylene chloride yields an oil that is purified by flash chromatography using methylene chloride/methanol saturated with ammonia (20:1) to yield ethyl 4-(2-hydroxyethyl)-piperidine-2-carboxylate.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[C:15](=[O:16])[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[C:8]=1[NH2:17].[NH2:18][C:19]1[C:20]([Cl:27])=[C:21]([OH:26])[C:22]([CH3:25])=[CH:23][CH:24]=1.N.OO>O.C(O)C>[NH2:17][C:8]1[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:15](=[O:16])[C:7]=1[N:6]=[C:24]1[CH:23]=[C:22]([CH3:25])[C:21](=[O:26])[C:20]([Cl:27])=[C:19]1[NH2:18]
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: Nc1c(N)n2n(c1=O)CCCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CC1=CC(=Nc2c(N)n3n(c2=O)CCCC3)C(N)=C(Cl)C1=O

Procedure:
0.68 mmol of 2,3-diamino-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazin-1-one methanesulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.68 mmol of 3-amino-2-chloro-6-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: O.Cl[CH2:3][CH:4]([OH:10])[CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[Na+:11].O.[SH-:13].[Na+]>CN(C=O)C>[SH:13][CH2:3][CH:4]([OH:10])[CH2:5][S:6]([O-:9])(=[O:8])=[O:7].[Na+:11]
Reactant: [SH-]
Reactant: O=S(=O)([O-])CC(O)CCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)([O-])CC(O)CS
Yield: 172.6 %

Procedure:
To sodium 3-chloro-2-hydroxypropanesulfonate hydrate (2.0 g), sodium hydrosulfide hydrate (0.42 g) was added in 10 mL DMF. The mixture was refluxed overnight. When the reaction mixture was cooled down, white solid was isolated, rinsed with ether and acetone to obtain 1.9 g crude sodium 3-mercapto-2-hydroxypropane sulfonate. The crude product was dissolved in water and preferentially precipitated the desired product by adding acetone. The precipitated product was then filtered and dried under vacuum to get 1.04 g of the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Br:20])=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[C:15]=2[C@H:23]([OH:30])[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Br:20])=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[C:15]=2[C@H:23]([O:30][C:2]([CH3:7])([CH3:3])[CH3:1])[C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(Cc3ccccc3)CC2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(Cc3ccccc3)CC2)c1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 168.3 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (1.35 g, 2.84 mmol) and 0.27 mL of 70% HClO4 in DCM (25 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel. The reaction was then diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-25% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 1.27 g (84%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.30-7.27 (m, 2H), 7.20-7.18 (m, 3H), 6.12 (br. s, 1H), 4.93-4.88 (m, 1H), 3.79-3.74 (m, 1H), 3.20 (t, J=12.5 Hz, 1H), 2.97-2.95 (m, 1H), 2.74 (br. s, 1H), 2.60 (d, J=5.1 Hz, 2H), 2.51 (s, 3H), 2.40 (s, 3H), 1.68 (br. s, 2H), 1.60-1.57 (m, 1H), 1.36-1.29 (m, 2H), 1.18 (d, J=6.2 Hz, 3H), 1.11 (s, 9H), 1.06 (d, J=6.2 Hz, 3H). UPLC (M+H)=533.3.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[Cl:22]>CN(C=O)C>[Cl:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
NaH (288 mmol) was suspended in DMF (370 mL) at 0° C. under an atmosphere of nitrogen. Dimethyl malonate (261 mmol) in DMF (30 mL) was added dropwise over a period of 20 min. at 0° C. and stirring was continued at 0° C. for 30 min. Then 1,2-dichloro-4-nitrobenzene (130 mmol) in DMF (35 mL) was added dropwise at 0° C. over a period of 20 min. The mixture was stirred at 70° C. for 15 h. The reaction mixture was cooled to room temperature and quenched with NH4Cl. The solution was successively washed with EtOAc (1×100 mL, 1×250 mL) and water (2×150 mL). To facilitate separation of the layers, sat. aq. NaCl (20 mL) was added. The organic layer was separated and washed with sat. aq. NaCl (2×100 mL). The aqueous layer was backextracted with EtOAc (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was recrystallized from EtOH to give dimethyl 2-(2-chloro-4-nitrophenyl)malonate as a solid (74%).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[S:22])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[CH:6][CH:7]=2)=[CH:18][CH:19]=1)#[N:13]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: N#Cc1ccc(N=C=S)cc1
Product: N#Cc1ccc(NC(=S)Nc2ccc(NNC=O)cc2)cc1

Procedure:
Procedure (18.) was employed with 1-formyl-2-(4aminophenyl)hydrazine (1.5 g, 0.01 mole) and 4-cyanophenyl isothiocyanate (1.6 g, 0.01 mole). Yield 2.2, g (71%), m.p. 180°-182° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:43]4[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 77.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (44 mg, 0.21 mmol), sodium carbonate (22 mg, 0.21 mmols) and bis(triphenylphosphine)palladium(II) dichloride (6 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 37 mg (74% yield) of the title compound. Purity 100%.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:11]1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:11]1
Reactant: CC(=O)OC[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
HCl 4M in dioxane (5 mL) was added at RT to a solution of racemic trans acetic acid 3-tert-butoxycarbonylamino-cyclohexylmethyl ester (theoretically 7.37 mmol) in 10 mL of DCM. The resulting mixture was stirred at RT for 4 hours before being evaporated to give 1.5 g of racemic trans acetic acid-3-amino-cyclohexylmethyl ester hydrochloride (>95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:4]=2[C:3]=1[CH3:14].B>O1CCCC1>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[C:3]=1[CH3:14]
Reactant: Cc1c(Br)cc(F)c2c1NC(=O)CO2
Agent: B
Solvent: C1CCOC1
Product: Cc1c(Br)cc(F)c2c1NCCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.3 %

Procedure:
An ice cold mixture of 6-bromo-8-fluoro-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (510 mg, 1.961 mmol) in Tetrahydrofuran (THF) (8 mL) was treated with borane 1M in THF (2.94 mL, 2.94 mmol) (1.5 eq) and then stirred at ambient temperature for 150 minutes. The mixture was cooled to 0° C. and then quenched slowly with 1N NaOH (5 mL×10). The mixture was extracted with ethyl acetate, washed with 1N NaOH, dried over sodium sulfate, filtered and then concentrated to afford 6-bromo-8-fluoro-5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (450 mg) as a light brown solid which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) d=6.77 (d, J=10.1 Hz, 1 H), 4.28-4.25 (m, 2 H), 3.77 (br. s., 1 H), 3.52 (m, 2 H), 2.16 (s, 3 H); LC/MS (m/z) ES+=245.99 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:23])[NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C@@H:8]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:16]([NH:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC1CCCCC1)C(=O)Nc1nccs1
Yield: 93.9 %

Procedure:
A solution of compound 12A (8.89 g, 25 mmol) in TFA (15 ml) was maintained at ambient temperature for 30 minutes. TFA was evaporated. Residue was dissolved in 5% aq. sodium bicarbonate (200 ml) and extracted with EtOAc (2×150 ml). Organic layer was washed with brine (150 ml), dried over anh. MgSO4 and evaporated in vacuum to provide target material (5.95 g, 94%) as light yellow solids. LC-MS [M+H] 254.1 (C12H19N3OS+H, requires 254.37).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20](Cl)[C:19]([CH3:26])=[C:18]([CH3:27])[N:17]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:19]([CH3:26])=[C:18]([CH3:27])[N:17]=1
Reactant: CC(C)(C)OC(=O)NCCOCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (2 3.1 g, 113 mmol) in N,N-dimethylformamide (100 mL) was added over a 1 hour period to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25.02 g, 113 mmol) in N,N-dimethylformamide (400 mL) containing triethylamine (24 mL, 175 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. The N,N-dimethylformamide was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with water (3×100 ml), dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (450 g of silica gel eluting sequentially with 3/1 hexanes/ethyl acetate (1.2 L), 2/1 hexanes/ethyl acetate (1.2 L), and 1/1 hexanes/ethyl acetate (1 L)) to provide 20.67 g of tert-butyl 2-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethoxy}ethylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25][CH3:26])=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:27]([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:27][C:3]1[CH:4]=[C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25][CH3:26])=[O:24])[CH:14]=3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COC(=O)c1ccc2nc(-c3ccc(N)c([N+](=O)[O-])c3)c(N(C)C(C)C)nc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2nc(-c3ccc(N)c(N)c3)c(N(C)C(C)C)nc2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 2-(4-amino-3-nitrophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (900 mg, 2.28 mmol) in methanol (40 mL) was added iron (1.28 g, 22.8 mmol) and NH4Cl (1.81 g, 34.2 mmol). After stirring for 6 h at 60° C., the solids were filtered out. The filtrate was concentrated under vacuum to give a residue which was dissolved in water (200 mL), extracted with dichloromethane (3×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 2-(3,4-diaminophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as yellow solid (635 mg, crude).
Reaction SMILES: [C:1]1([C:7](=[N:17][O:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][CH2:19][O:18][N:17]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(c1ccccc1)c1c[nH]c2cnccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCON=C(c1ccccc1)c1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.5 %

Procedure:
A mixture of tert-butyl 2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methylene]amino]oxy]ethylcarbamate (Example 111) (385.8 mg, 0.94 mmol), trifluoroacetic acid (4 mL) and methylene chloride (2 mL) was stirred at room temperature for 6 h. The solvent was removed in vacuo. The crude material was purified and free based using SCX-2 to give phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone O-(2-aminoethyl)oxime (220 mg, 84%) as an off-white foam: 1H NMR (500 MHz, CD3OD) δ2.97-3.02 (2H, m), 3.20-3.31 (2H, m), 6.75-6.77 (0.6H, m), 7.19 (0.4H, m), 7.40-7.49 (5H, m), 7.91-7.92 (0.6H, m), 8.07-8.20 (1.5H, m), 8.70-8.72 (1H, m); ESI MS m/z 281 [C16H16N4O+H]+; HPLC (Method A) >99% (AUC), Isomeric ratio 58:42, tR=12.5 and 12.2 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][N:7]([S:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=2[CH:5]=[C:4]([C:23]([OH:25])=O)[CH:3]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:36]=[CH:37][C:27]([NH:26][C:23]([C:4]2[CH:3]=[C:2]([Cl:1])[C:10]3[O:9][CH2:8][N:7]([S:11]([C:14]4[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=4[O:21][CH3:22])(=[O:13])=[O:12])[C:6]=3[CH:5]=2)=[O:25])=[CH:28][CH:29]=1)[CH3:35]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c(Cl)cc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(Cl)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1

Procedure:
Reaction of 7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. Light yellow solid, MS (ISP)=551.1 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([O:11]C)[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)[CH:21]=4)=[C:15]([CH3:32])[N:14]=3)=[CH:7][N:6]=2)[CH2:3][CH2:2]1.Br>C(O)(=O)C>[CH:1]1([NH:4][C:5]2[NH:10][C:9](=[O:11])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)[CH:21]=4)=[C:15]([CH3:32])[N:14]=3)=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: COc1nc(NC2CC2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc(-c2cnc(NC3CC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A solution of N-cyclopropyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.082 g, 0.191 mmol) in acetic acid (2 mL) was treated with HBr (0.087 mL, 0.764 mmol) and heated at 90° C. for 4 h. The mixture was cooled to RT, treated with ice, neutralized with satd. NaHCO3 and extracted with EtOAc (3×). The combined organics were washed with brine, dried over MgSO4, concentrated to dryness, treated with MeCN, sonicated, heated to near-boiling and allowed to stand at RT overnight. The resulting solid was collected via filtration. The combined aqueous washes were filtered, the solid washed with water, dried and combined with the above-isolated solid to afford 2-(cyclopropylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (35 mg, 44%). 1H NMR (400 MHz, DMSO-d6): δ 11.09 (br s, 1H), 8.68 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.28 (m, 1H), 8.25 (s, 1H), 7.96 (d, J=0.8 Hz, 1H), 7.66 (br s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.73-2.68 (m, 1H), 2.34 (s, 3H), 0.75 (m, 2H), 0.55-0.53 (m, 2H); MS (ESI) m/z: 416.2 (M+H+).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][OH:14])[CH2:9]2)=[CH:4]1.Cl[C:16]1[N:21]([CH3:22])[C:20](=[O:23])[CH:19]=[C:18]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[F:30])[N:17]=1>CN(C)C=O>[F:30][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:24]=1[C:18]1[N:17]=[C:16]([O:14][CH2:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:6]=[CH:7][S:3][CH:4]=3)[CH2:9]2)[N:21]([CH3:22])[C:20](=[O:23])[CH:19]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: OC[C@H]1CCN(c2ccsc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(OC[C@H]2CCN(c3ccsc3)C2)nc(-c2ccncc2F)cc1=O
Reaction time: 0.25 h
Yield: 20 %

Procedure:
To a slurry of sodium hydride (60 wt % in mineral oil, 0.04 g, 1.0 mmol) in N,N-dimethylformamide (2 ml) under nitrogen atmosphere was added (S)-[1-(thiophen-3-yl)pyrrolidin-3-yl]methanol (0.13 g, 0.70 mmol) in N,N-dimethylformamide (1 ml) at room temperature. The resulting mixture was stirred for 15 minutes. To the mixture was added 2-chloro-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.14 g, 0.60 mmol) at room temperature. After the mixture was stirred for 3 hours, the reaction was quenched with water and partitioned between water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=90/10 to 0/100) to afford 6-(3-fluoro-pyridin-4-yl)-3-methyl-2-[(3S)-1-thiophen-3-yl-pyrrolidin-3-ylmethoxy]-3H-pyrimidin-4-one (0.045 g, 0.12 mmol, 19%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7]O)[CH2:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH3:9][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][N:33]2[C:29](=[O:39])[C:30]3[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:34])[CH2:4][CH2:3]1
Reactant: CC1(C)CC[C@@H](CO)O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC[C@@H](CN2C(=O)c3ccccc3C2=O)O1
Temperature: 8 °C

Procedure:
To a stirred solution of (S)-(5,5-dimethyltetrahydrofuran-2-yl)methanol (14 g, 108 mmol) and PPh3 (33.8 g, 129 mmol) in THF (140 ml) under N2 was added phthalimide (17.40 g, 118 mmol) to give a suspension. The mixture was cooled to 8° C. and DIAD (27.2 ml, 140 mmol) was added dropwise over 30 mins keeping internal T<10° C. The resulting white slurry was diluted with water (100 ml) and extracted with EtOAc (100 ml). The organics were washed with sat. NaHCO3 (100 ml), brine (100 ml) and dried (MgSO4) and concentrated under reduced pressure. Purification by chromatography on silica eluting with 0-20% EtOAc/iso-hexane afforded the title compound as a white crystalline solid;