Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH:6]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[CH:9]=1)[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1>O>[CH2:2]([O:4][C:5](=[O:25])[CH:6]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:40]([C:35]2[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=2)(=[O:42])=[O:41])[CH:9]=1)[CH3:3]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)OCC
Reaction time: 8 h
Yield: 36.7 %

Procedure:
2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-prop ionic acid ethyl ester hydrochloride(110 mg, 0.294 mmol) and sodium carbonate (93.5 mg, 0.882 mmol) were dissolved in water (1.5 mL) and 3,5-dichlorobenzenesulfonylchloride (86.7 mg, 0.353 mmol) was added. This mixture was stirred overnight. The reaction was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound (59 mg, 37%). MS (CI) m/z 545.7 (M+1)
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.Cl[CH2:19][C:20](=[O:22])[CH3:21]>C1COCC1>[O:22]=[C:20]([CH3:21])[CH2:19][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CSc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Mercapto-benzoic acid (5.0 g, 32.3 mmol) and triethylamine (11.3 mL, 81.1 mmol) were dissolved in THF at 0° C. Chloroacetone (2.7 mL, 33.9 mmol) was then added and the reaction was allowed to slowly warm to room temperature as it stirred overnight. Standard aqueous workup afforded the title compound which was brought forward to the next step without further purification.
Reaction SMILES: [Si](Br)(C)(C)C.CS(C)=O.[S:10]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=O)=[CH:11]1.[CH3:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]2[S:30]C(C3C=CC=CC=3)=C[N:33]=2)[CH:25]=[CH:26][CH:27]=1)[CH3:20]>CC#N>[CH3:20][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]2[S:30][C:15]([C:12]3[CH:13]=[CH:14][S:10][CH:11]=3)=[CH:16][N:33]=2)[CH:25]=[CH:26][CH:27]=1)[CH3:18]
Reactant: CN(C)Cc1cccc(Nc2ncc(-c3ccccc3)s2)c1
Reactant: O=CCc1ccsc1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: CS(C)=O
Product: CN(C)Cc1cccc(Nc2ncc(-c3ccsc3)s2)c1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Me3SiBr (0.23 mL, 1.75 mmol, 1.1 equiv) and DMSO (0.12 mL, 1.75 mmol, 1.1 equiv) are added sequentially and dropwise to a cold (−35° C.) solution of 3-thiophenylacetaldehyde (200 mg, 1.59 mmol) in CH3CN (3.0 mL), under an argon atmosphere. The resulting mixture is allowed to warm to 0° C., to stir for 50 min, then to warm to room temperature and to stir for 10 min. CH3CN (5.0 mL) is added to the reaction mixture, followed by addition of (3-dimethylaminomethyl-phenyl)-thiourea (Example 2) (333 mg, 1.59 mmol). The reaction mixture is heated to reflux for 1 h, allowed to cool to RT and concentrated in vacuo. MPLC (CH3CN/H2O/TFA) purification affords the title compound: ES-MS: 316.0 [M+H]+; single peak at tR=3.19 min (System 2).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]([OH:11])[N:10]=2.[NH2:19][NH2:20].O1CCOCC1>C(OCC)(=O)C>[NH:19]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]([OH:11])[N:10]=2)[NH2:20]
Reactant: NN
Reactant: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1
Temperature: 100 °C

Procedure:
To a flask was added 6-chloro-3-phenylpyrido[2,3-b]pyrazin-2-ol (8-2, 3.41 g, 13.23 mmol), anhydrous hydrazine (5.0 mL, 159 mmol), and finally 1,4 Dioxane (60 mL). The stirred reaction mixture was then heated to 100° C. in a hot oil bath under an atmosphere of nitrogen with an air cooled reflux condenser attached. Upon completion of the reaction the mixture was cooled to room temperature, suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-3 as an orange/tan foam. HRMS (M+H)+: observed=254.1041, calculated=254.1037.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])=[O:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1.[Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][C@@H:60]2[CH2:62][O:61]2)=[CH:54][C:53]=1[N:63]([S:67]([CH3:70])(=[O:69])=[O:68])C(=O)[O-])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[CH2:25][NH:24][C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][NH:4][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]3[CH:56]=[CH:57][C:52]([OH:51])=[C:53]([NH:63][S:67]([CH3:70])(=[O:69])=[O:68])[CH:54]=3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: NCC1CCN(S(=O)(=O)c2ccc(NC(=O)NCc3cc(F)ccc3F)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1N(C(=O)[O-])S(C)(=O)=O)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(NC(=O)NCc4cc(F)ccc4F)cc3)CC2)ccc1O
Yield: 7.5 %

Procedure:
N-(4-{[4-(aminomethyl)-1-piperidinyl]sulfonyl}phenyl)-N′-(2,5-difluorobenzyl)urea formate (0.285 g, 0.535 mmol) was reacted with 2-{[t-butyl(diphenyl)silyl]oxy}-5-[(2S)oxiranylmethoxy]phenyl(methylsulfonyl)carbamate (0.322 g, 0.535 mmol) according to example 37 to give the title compound (0.03 g, 0.04 mmol).
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11](=[O:51])[N:12]([CH2:40][C:41]1[CH:50]=[CH:49][C:44]2[O:45][CH2:46][CH2:47][O:48][C:43]=2[CH:42]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][C:22]2=[O:39])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].[N:58]1[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=1>O.C(OCC)(=O)C>[C:6]([O:10][C:11](=[O:51])[N:12]([CH2:40][C:41]1[CH:50]=[CH:49][C:44]2[O:45][CH2:46][CH2:47][O:48][C:43]=2[CH:42]=1)[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:61]3[CH:62]=[CH:63][N:58]=[CH:59][CH:60]=3)=[CH:23][C:22]2=[O:39])[CH2:17][CH2:18]1)([CH3:7])([CH3:8])[CH3:9]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OS(=O)(=O)C(F)(F)F)c3ccccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(-c3ccncc3)c3ccccc32)CC1
Temperature: 120 °C
Reaction time: 1.33 h
Yield: 33.6 %

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.14 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-(trifluoromethanesulfonyl)oxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.24 mL of 2.0 mol/L aqueous sodium carbonate solution, 12 mg of tetrakis triphenylphosphine palladium and 39 mg of 4-pyridineboronic acid were added, and stirred at 120° C. under nitrogen atmosphere for 80 min. The reaction mixture was cooled to the room temperature, ethyl acetate and water were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1], to give 42 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-4-(pyridin-4-yl)quinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)=[O:25]
Reactant: NC1CCN2CCc3ccccc3C2C1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)NC2CCN3CCc4ccccc4C3C2)cc1

Procedure:
By a procedure analogous to that of Example 1, 2-amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine is reacted with p-methylphenyl isocyanate to give the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:21])[CH2:15][CH2:16][S:17]C(=O)C)=[O:4]>CO.[OH-].[K+]>[SH:17][CH2:16][CH2:15][C:14]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH:5]1[C:3]([OH:4])=[O:2])=[O:21]
Reactant: COC(=O)C1Cc2ccccc2N1C(=O)CCSC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1Cc2ccccc2N1C(=O)CCS
Temperature: 25 °C

Procedure:
The solutions of 4.0 g of 1-(3-acetylthiopropanoyl)-indoline-2-carboxylic acid methyl ester in 20 ml of methanol and 18.5 ml of 2.11N aqueous potassium hydroxide are each deoxygenated by bubbling nitrogen through them for 10 minutes. Then the latter solution is added to the former and the mixture stirred at room temperature under nitrogen. After 2 hours it is quenched with 50 ml of 1N hydrochloric acid and extracted twice with 100 ml of diethyl ether. The combined extracts are dried and evaporated, to give the 1-(3-mercaptopropanoyl)-indoline-2-carboxylic acid melting at 140°-142°.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[O:7][C:6]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:5][CH2:4]1.[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Br)[CH2:23][CH3:24]>>[C:37]([C:34]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][S:1][CH2:2][CH:3]2[O:7][C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:5][CH2:4]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:35]=1[OH:36])(=[O:39])[CH3:38]
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OC(CS)CS1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)O2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 64 (1.0 g, 0.003 mol), (3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (described in U.S. Pat. No. 4,565,882, Example 14) (1.1 g, 0.0033 mol) and anhydrous potassium carbonate (1.6 g) in methyl ethyl ketone (15 ml) The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 1.54 g (90%) of the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([OH:26])=O)[C:13]2=[O:27])=[O:10])[CH:5]=[C:4]([Cl:28])[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN1C(=O)CCC1>[Cl:28][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)=[O:26])[C:13]2=[O:27])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)nc(Cl)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCN(C(=O)Cn2c(=O)c3ccccc3n(CC(=O)Nc3cc(Cl)nc(Cl)c3)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of {1-[(2,6-dichloro-pyridin-4-ylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (13.5 mg, 0.0318 mmol) in dry NMP (1.5 ml), HATU (13.3 mg, 0.035 mmol) is added followed by triethylamine (4.89 μL, 0.035 mmol). The orange solution is stirred at RT for 10 minutes, then treated with 1-methyl piperazine (3.89 μL, 0.035 mmol). The reaction mixture is stirred at RT and monitored by HPLC/LCMS until the starting material is consumed. The reaction mixture is partitioned between EtOAc (5 ml) and water (5 ml). The organic layer is separated and washed with brine (5 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by passing down a 5 g Isolute™ SCX2 (solid-supported sulfonic acid resin) cartridge, eluting with DCM (20 ml), MeOH (20 ml), and 7N NH3 in MeOH. The basic ammonia wash is concentrated in vacuo to afford the title compound as a white solid, [M+H]+ 505.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH2:14][OH:15].CO>O1CCCC1.C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:14]/[OH:15])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: NO
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCO
Product: O/N=C/c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)benzaldehyde (93.9 mg, 0.45 mmol) in tetrahydrofuran (0.9 mL) and ethanol (0.9 mL) was added hydroxylamine (50% in water, 0.20 mL) and the reaction was maintained at room temperature for 36 hours. Methanol (3.0 mL) was added, the solvent was removed in vacuo, and the residue was triturated with toluene (2×1 mL) to afford the title compound as a solid. Yield: 101 mg, 0.45 mmol, 100%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(morpholin-4-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C28H27N3O4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH3:18])=[C:16]([NH:19][C:20]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=[CH:22][C:21]=2[N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl[C:42]1[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([NH2:49])[N:43]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[NH2:49][C:44]1[N:43]=[C:42]([C:24]2[CH:23]=[CH:22][C:21]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:20]([NH:19][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]=3[CH3:18])[CH:25]=2)[CH:47]=[C:46]([CH3:48])[N:45]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(N3CCOCC3)c(Nc3c(C)c(-c4ccccc4F)nc4ccccc34)c2)nc(N)n1
Temperature: 120 °C

Procedure:
A solution of 2-(2-fluorophenyl)-3-methyl-N-(2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinolin-4-amine (100 mg, 0.185 mmol; described herein), 4-chloro-6-methylpyrimidin-2-amine (26.6 mg, 0.185 mmol), sodium carbonate (58.9 mg, 0.556 mmol), dichlorobis(triphenylphosphine)-palladium(ii) (13.0 mg, 0.019 mmol), 1,4-dioxane (4.0 mL), and water (1.0 mL) was heated in a microwave at 120° C. for 60 min. The mixture was then cooled to rt and partitioned between EtOAc and water. The organic layer was dried (magnesium sulfate) and concd, and chromatography afforded N-(5-(2-amino-6-methyl-4-pyrimidinyl)-2-(4-morpholinyl)phenyl)-2-(2-fluorophenyl)-3-methyl-4-quinolinamine. 1H NMR (400 MHz, TFA) δ ppm 8.32 (1H, dd, J=8.8, 2.2 Hz), 7.95-8.17 (5H, m), 7.72 (2H, m), 7.55 (1H, m), 7.40-7.48 (1H, m), 7.24-7.37 (2H, m), 4.30-4.47 (4H, m), 4.07-4.25 (4H, m), 2.60 (3H, s), 2.09 (3H, br. s.). Mass Spectrum (ESI) m/e=521.1 (M+1).
Reaction SMILES: N1CCCC1.C(=O)([O-])N.[CH2:10]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([N:34]4[CH2:39]C[CH:37](N5CCCC5)[CH2:36][CH2:35]4)=[O:33])[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14])[CH3:11]>CN(C)C=O>[CH2:10]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([N:34]4[CH2:39][CH2:37][CH2:36][CH2:35]4)=[O:33])[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14])[CH3:11]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Agent: NC(=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCCC4)c3)ccc21
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and pyrrolidine (0.36 ml, 4.3 mmol) were added to a mixture (0.461 g) of phenyl N-(4-(1-(ethylamino)carbonyl)-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 77; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as crystals (245 mg, 0.623 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[ClH:18]>O1CCOCC1>[ClH:18].[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C1CCN(c2ccncc2)CC1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
2.95 g (12.6 mmol) of ethyl 1-(4-pyridyl)-4-piperidinecarboxylate was stirred in 100 ml of dioxane. 50 ml of 1 N hydrochloric acid was added to the obtained mixture, and they were stirred at 95° C. for 20 hours. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=N.O[N:45]=[C:46]([NH2:48])[CH3:47]>ClCCl.O1CCOCC1.O>[CH3:47][C:46]1[N:48]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[O:16][N:45]=1
Reactant: CC(N)=NO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1noc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (5.00 g, 21.83 mmol), 1-hydroxybenzotriazole (2.95 g, 21.83 mmol) and N-methylmorpholine (4.8 mL, 43.67 mmol) were dissolved in dichloromethane (100 mL), under argon, and (3-dimethylaminopropyl)carbodiimide hydrochloride (4.60 g, 24.0 mmol) and N′-hydroxyethanimidamide (1.62 g, 21.83 mmol) were added. The mixture was stirred at room temperature overnight then water (50 mL) was added and the mixture stirred for 30 minutes. The organics were separated, dried and the solvent evaporated to give a yellow oil which was redissolved in 1,4-dioxane (100 mL) and heated to 100° C. for 3 hours, cooled and the solvent evaporated to give crude tert-butyl 4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate as a brown oil (5.74 g, 98.5%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:35]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(O)cc3OCC3CC3)ncnc12
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: O=C(NC1CCN(C(=O)CO)CC1)c1c[nH]c2c(-c3cc(F)c(O)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-hydroxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A188) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:42][C:43](O)=[O:44])[CH:28]=[CH:29][C:30]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41])=[O:33].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:43](=[O:44])[CH2:42][C:27]3[CH:28]=[CH:29][C:30]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[O:33])=[C:25]([O:24][CH3:23])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)[CH3:2]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CC1(c2ccc(N)cc2)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1(c2ccc(NC(=O)Cc3ccc(NC(=O)Nc4ccccc4C)c(OC)c3)cc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
A solution of [2-(4-amino-phenyl)-indan-2-yl]-acetic acid ethyl ester (0.158 g, Reference Example 10) in dimethylformamide (2 mL) was treated with a solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.169 g) in dimethylformamide (2 mL) which had been treated with diisopropylethylamine (1.3 mL) and a solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.223 g) in dimethylformamide (2 mL). After stirring at room temperature for 2 hours the reaction mixture was evaporated and the residue was partitioned between ethyl acetate (30 mL) and hydrochloric acid (30 mL, 0.5N). The organic phase was washed with hydrochloric acid (30 mL, 0.5N), then with saturated sodium hydrogen carbonate solution (30 mL), then dried over magnesium sulfate and then evaporated. The residual beige coloured solid was subjected to chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:1, v/v) to give the title compound (0.06 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(C)(C)C)=[C:11]([F:22])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl>CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:10][C:11]=1[F:22]
Reactant: CC(C)(C)C(=O)Nc1ccc(Oc2ccnc(N)c2)cc1F
Agent: Cl
Solvent: CO
Product: Nc1cc(Oc2ccc(N)c(F)c2)ccn1
Yield: 53.6 %

Procedure:
A solution of N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)pivalamide (70 mg, 0.23 mmol) in 3 mL of MeOH was added 2 mL of 6 N HCl. The mixture was then heated at reflux for 48 h. After cooling down, the solvent was removed under reduced pressure and the residue was purified by solid extraction (Waters Oasis® MCX extraction cartridge) to give 4-(4-amino-3-fluorophenoxy)pyridin-2-amine (27 mg, 54% yield). MS(ESI+): m/z 220.21 (M+H)+.