Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[S:7][CH:8]=1.[CH:15]1([N:18]([CH2:32][C:33]2[O:34][CH:35]=[C:36]([C:38]([OH:40])=O)[N:37]=2)[S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=2[CH3:31])(=[O:21])=[O:20])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C>[CH:15]1([N:18]([CH2:32][C:33]2[O:34][CH:35]=[C:36]([C:38]([N:2]([CH3:1])[CH2:3][C:4]3[N:5]=[C:6]([CH2:9][N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)[S:7][CH:8]=3)=[O:40])[N:37]=2)[S:19]([C:22]2[C:23]([CH3:31])=[CH:24][C:25]([O:29][CH3:30])=[CH:26][C:27]=2[CH3:28])(=[O:21])=[O:20])[CH2:17][CH2:16]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1csc(CN2CCCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)Cc3csc(CN4CCCC4)n3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using N-methyl-1-[2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-4-yl]methanamine (40 mg, 189 μmol), 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (72 mg, 189 μmol), DIPEA (0.1 mL, 575 μmol), EDCI (72 mg, 378 μmol), HOBt monohydrate (58 mg, 378 μmol) and DMF (1.5 mL). The resulting crude compound was purified by FCC eluting with 99:1 DCM:7N NH3 in MeOH.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:27]12([CH:37]3C[NH:41][CH2:40][CH2:39][N:38]3C)[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2.[CH2:44](O)[CH3:45]>>[C:27]12([CH2:37][N:38]3[CH2:45][CH2:44][N:41]([CH2:2][C:3]([N:5]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[C:9](=[O:16])[NH:8][C:7]5[CH:17]=[CH:18][CH:19]=[N:20][C:6]4=5)=[O:4])[CH2:40][CH2:39]3)[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CN1CCNCC1C12CC3CC(CC(C3)C1)C2
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CC34CC5CC(CC(C5)C3)C4)CC2)c2ccccc21

Procedure:
4.4 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 1.8 gm of sodium carbonate and 3.75 gm of 1-(1-adamantyl-methyl-piperazine were reacted in 80 ml of absolute ethanol and worked up in analogy to Example 1. After recrystallization from a mixture of n-propanol and dimethylformamide; M.p.: 284°-287° C. (decomposition).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([CH3:17])[N:11]=1>COCCOC>[BrH:1].[Br:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH2:2][C:3]([C:4]([F:7])([F:6])[F:5])([OH:8])[N:9]=2)[C:12]=1[CH3:17]
Reactant: Cc1nc(N)ccc1Br
Reactant: O=C(CBr)C(F)(F)F
Solvent: COCCOC
Product: Br
Product: CC1=C(Br)C=CC2=NC(O)(C(F)(F)F)CN21
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
A mixture of 1.91 g of 3-bromo-1,1,1-trifluoropropan-2-one and 10 ml of DME was added to a mixture of 1.87 g of 2-amino-5-bromo-6-methylpyridine and 10 ml of DME, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was taken by filtration, washed with 10 ml of DME, and dried to obtain 3.39 g of 6-bromo-5-methyl-2-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridin-2-ol hydrobromide.
Reaction SMILES: C(C1C=CC(C)=CC=1)(C)(C)C.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(O)(=O)C>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([CH:34]=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(C(C)(C)C)cc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C=O)cc1

Procedure:
In 3 mL of acetic acid was dissolved 300 mg of p-t-butyltoluene to give a solution, and the solution was further combined with 150 mg of the catalyst B and 33 mg of N-hydroxyphthalimide, followed by stirring at 100° C. in an oxygen atmosphere for 6 hours. The reaction mixture was analyzed through gas chromatography to find that p-t-butylbenzoic acid and p-t-butylbenzaldehyde were obtained in yields of 55.6% and 4.0%, respectively, with a conversion from p-t-butyltoluene of 76.5%. The catalyst B was separated from the reaction mixture through filtration, washed with ethyl acetate two times, dried at room temperature (25° C.) under reduced pressure, and thereby recovered as a catalyst B1. The cobalt ion concentration and manganese ion concentration in the reaction mixture, from which the catalyst B1 had been separated through filtration, were measured through atomic absorption spectrometry and found to be 21 ppm and 24 ppm, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][N:45]=1>O1CCCC1.CN(C)C=O>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][N:45]=4)[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(c4ccc([N+](=O)[O-])cn4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (120 mg) in a mixture of tetrahydrofuran (1.2 ml) and dimethylformamide (1.2 ml) were added triethylamine (0.068 ml) and 2-chloro-5-nitropyridine (58 mg), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=4:1) and dried under reduced pressure to give the title compound (120 mg).
Reaction SMILES: C(C1C=CC2N=C(N[C:16]([NH:18][CH2:19][CH3:20])=[O:17])SC=2C=1)C1C=CC=CC=1.[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][C:27]=2[N:28]=1.C(N(CC)CC)C.C(N=C=O)C>C1(C)C=CC=CC=1>[CH2:36]([O:35][C:33]([C:31]1[CH:30]=[CH:29][C:27]2[N:28]=[C:24]([NH:23][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[S:25][C:26]=2[CH:32]=1)=[O:34])[CH3:37]
Reactant: CCNC(=O)Nc1nc2ccc(Cc3ccccc3)cc2s1
Reactant: CCOC(=O)c1ccc2nc(N)sc2c1
Agent: CCN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C(=O)OCC)cc2s1
Yield: 82 %

Procedure:
According to the General Procedure for 1-(6-substituted-2-benzothiazolyl)-3-ethylurea compounds, and similar to the synthesis of 1-(6-benzyl-2-benzothiazolyl)-3-ethylurea, a mixture of 2-amino-6-ethoxycarbonyl-benzothiazole, triethylamine and ethyl isocyanate in toluene was reacted to give the desired compound 2.40 g (82%). LC/MS 294.0 (M+1); LC retention time 4.29 min.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]([CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:35](I)[CH:36]=[CH2:37].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]([CH2:24][CH2:25][CH2:26][N:27]([CH2:37][CH:36]=[CH2:35])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=CCI
Reactant: CC(=O)N1CCc2ccc(N(CCCNCc3ccccc3)C(=O)/C=C/c3ccccc3)cc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(CCCN(C(=O)/C=C/c1ccccc1)c1ccc2c(c1)N(C(C)=O)CC2)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of trans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-N-(3-benzylamino-propyl)-3-phenyl-acrylamide (Example 47, 39 mg, 0.090 mmol), allyl iodide (0.01 mL, 0.1 mmol), and diisopropylethylamine (0.03 mL, 0.2 mmol) in CH2Cl2 (3.0 mL) was stirred at rt for 20 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified on silica gel (60% EtOAc/hexanes) to provide the title compound (37 mg, 87%). 1H NMR (500 MHz, CDCl3): 8.13 (s, 1H), 7.65 (d, J=15.5 Hz, 1H), 7.31-7.24 (m, 10H), 7.15 (d, J=7.6 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 6.30 (d, J=16.5 Hz, 1H), 5.84-5.80 (m, 1H), 5.10 (dd, J=17.0, 10.1 Hz, 2H), 4.11 (t, J=7.3 Hz, 2H), 3.84 (br s, 2H), 3.50 (s, 2H), 3.24 (t, J=8.5 Hz, 2H), 3.02 (d, J=6.3 Hz, 2H), 2.46 (t, J=7.1 Hz, 2H), 2.23 (s, 3H), 1.81-1.75 (m, 2H). MS: exact mass calculated for C32H35N3O2, 493.64; m/z found, 494.2 [M+H]+.
Reaction SMILES: ClC1C=C([N+]([O-])=O)C(N)=NC=1Cl.FC(F)(F)C(Cl)=O.[Cl:20][C:21]1[CH:22]=[C:23]([N+:35]([O-:37])=O)[C:24]([NH:28][C:29](=O)[C:30]([F:33])([F:32])[F:31])=[N:25][C:26]=1[Cl:27]>>[OH:37][N:35]1[C:23]2[C:24](=[N:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=2)[N:28]=[C:29]1[C:30]([F:33])([F:32])[F:31]
Reactant: O=C(Nc1nc(Cl)c(Cl)cc1[N+](=O)[O-])C(F)(F)F
Agent: Nc1nc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(F)(F)F
Product: On1c(C(F)(F)F)nc2nc(Cl)c(Cl)cc21

Procedure:
In like procedures, 5,6-dichloro-2-amino-3-nitropyridine was reacted with trifluoroacetyl chloride and the resulting 5,6-dichloro-2-trifluoroacetamido-3-nitropyridine was hydrogenated to obtain 1-hydroxy-5,6-dichloro-2-trifluoromethyl-1H-imidazo(4,5-b)-pyridine, m.p. 207°-208° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[H-].[Na+].[C:14]([Si:20](Cl)([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:11][Si:20]([CH3:22])([CH3:21])[C:14]([CH3:16])([CH3:15])[CH:17]([CH3:19])[CH3:18])=[CH:6][CH:7]=1
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1

Procedure:
This intermediate (hereinafter "intermediate A") was prepared in two steps. 4-Bromophenylacetic acid underwent diborane (B2H6) reduction. A solution of the resulting alcohol then underwent silylation with sodium hydride (NaH) and thexyl dimethyl silyl chloride.
Reaction SMILES: [C:1]([C:3]1([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=4)[CH2:24][CH2:23]3)[C@@H:18]([CH3:35])[CH2:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#N.C[Mg]Br>C1COCC1.CCOCC>[CH3:1][C:3]1([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=4)[CH2:24][CH2:23]3)[C@@H:18]([CH3:35])[CH2:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][CH2:4]1
Reactant: C[C@H]1CN(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2ccc(C(F)(F)F)cc21
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of tert-butyl 4-cyano-4-{(3S)-3-methyl-4-[6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}piperidine-1-carboxylate (0.72 g, 1.3 mmol) in THF (20 mL) was added a 3 M solution of methylmagnesium bromide in ether (4.0 mL). After being stirred at room temperature overnight, the reaction was quenched by addition of water. The resulting solution was extracted with EtOAc twice. The combined EtOAc layers were dried and concentrated. Column chromatography on silica (20-30% EtOAc in hexane) provided the title compound (0.32 g, 50%) as a viscous oil. MS calculated for C26H38F3N3O2: (M+H)+ 482; found 482.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[CH2:32]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1])[CH3:33]
Reactant: CCI
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
A suspension of N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (200 mg), potassium carbonate (161 mg) and ethyl iodide (181 mg) in DMF (5 mL) was stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was recrystallized from hexane/ethyl acetate to give the title compound (167 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[C:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)=[CH:7][N:8]=[C:2]12.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[S:1]1[CH:5]=[CH:4][N:3]2[C:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:22][C@@H:23]5[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]5[OH:29])[S:16][C:12]=4[CH:11]=3)=[CH:7][N:8]=[C:2]12
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cc3cnc4sccn34)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cc3cnc4sccn34)cc2s1
Temperature: 130 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
A mixture of 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole (310 mg, 0.93 mmol), (1R,2R)-2-aminocyclohexanol (321 mg, 2.79 mmol) and DIEA (240 mg, 1.86 mmol) in NMP (10 mL) was stirred for 1 d at 130° C. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 10:1 DCM/MeOH, and the product was further purified by preparative HPLC to afford (1R,2R)-2-((6-(imidazo[2,1-b]thiazol-5-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a brown solid (100 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ 7.84 (d, J=7.2 Hz, 1H), 7.68 (d, J=4.5 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.20 (dd, J=0.9, 4.2 Hz, 1H), 7.10 (dd, J=1.8, 8.4 Hz, 1H), 7.02 (s, 1H), 4.71 (d, J=4.8 Hz, 1H), 4.15 (s, 2H), 3.52-3.49 (m, 1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/z 385 (M+H)+.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F.[C:28]([N:35]1[CH2:38]C(=O)[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([NH:9][CH:10]1[CH2:11][N:12]([CH:14]2[CH2:38][N:35]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:36]2)[CH2:13]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(N2CC(NC(=O)c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
To a solution of 1c (1.45 g, 5.25 mmol) in CH2Cl2 (20 mL) at room temperature was added CF3CO2H (5 mL). The reaction was stirred at room temperature for 1.5 h. The reaction was concentrated and the resulting residue was dissolved in a mixed solution of 1,2-dichloroethane (10 mL) and acetic acid (0.5 mL). To the resulting solution at room temperature was added 1-Boc-azetidin-3-one 1d (0.99 g, 5.79 mmol), followed by Na(OAc)3BH (1.23 g, 5.80 mmol). The reaction mixture was stirred at room temperature for 20 h. Additional 1-Boc-azetidin-3-one 1d (0.50 g, 2.92 mmol) and Na(OAc)3BH (0.62 g, 2.92 mmol) was added. The reaction was stirred for another 6 h before it was quenched by the addition of aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 4% MeOH/CH2Cl2) gave compound 1e (0.93 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:21](F)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[O:35]([CH3:37])[K].CO.[Al]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:21]([O:35][CH3:37])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCOCC4)c(F)cc23)CC1
Reactant: CO[K]
Agent: [Al]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1N1CCOCC1
Yield: 67.2 %

Procedure:
A mixture of 4-(6-Fluoro-7-morpholin-4-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (28.9 mg, 69.5 μmol), as prepared in Example 210a, DMSO (50 μL), and 10M KOMe/MeOH (140 μL, 140 μmol) was stirred in a sealed vial at 100° C. (aluminum block) for 13 hr. The crude reaction was then diluted with toluene and directly loaded onto a silica flash column (1:2 hexanes/EtOAc eluent) to provide the title compound (20.0 mg, 67%). NOe experiments support the assigned regioisomer. Select 1H-NMR resonances and nOes (300 MHz, CDCl3) δ 7.36 (s, 1H), 7.25 (s, 1H), 4.05 (s, 3H), 3.51 (m, 1H). Irradiation of the diagnostic methine proton at δ 3.51 generates an nOe to the quinazoline C5 proton at δ 7.25, but not to the quinazoline C8 proton at δ 7.36. Irradiation of the methoxy protons at δ 4.05 generates an nOe to the C5 proton at δ 7.25, but not to the C8 proton at δ 7.36. This indicates methoxy substitution at C6 of the quinazoline. LC/MS (ESI): calcd mass 428.2, found 429.3 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]2[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[CH3:14][C:6]1([CH3:15])[C:5]2[C:9](=[CH:10][C:2]([N:1]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=2)[N:8]([C:11](=[O:13])[CH3:12])[CH2:7]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone (5 g, 24.5 mmol), 1-bromo-2-(2-bromoethoxy)ethane (6.25 g, 26.9 mmol), and Na2CO3 (5.19 g, 49 mmol) in MeOH (25 mL) was heated to 150° C. in a sealed tube. After 2.5 h, the mixture was cooled to rt. The reaction mixture was diluted with water (100 mL). The resulting solid was filtered, washed with water (300 mL), and dried in the air to give 1-(3,3-dimethyl-6-morpholinoindolin-1-yl)ethanone as a grey solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 7.74 (1H, s), 7.06 (1H, d, J=8.1 Hz), 6.61 (1H, dd, J=8.2, 2.1 Hz), 3.82 (2H, s), 3.67-3.76 (4H, m), 2.95-3.06 (4H, m), 2.13 (3H, s), 1.26 (6H, s). Mass Spectrum (ESI) m/e=275.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1.[Br:26]Br>CCOCC>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH:13]([Br:26])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(C)cccc2C)c1
Reactant: BrBr
Solvent: CCOCC
Product: CCOC(=O)CC(Br)C(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a ice cooled solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C, 3 g, 9 mmol) in dry ether (70 ml) was added dropwise bromine (0.7971 g, 9.9 mmol) diluted in ether (30 ml). After 4 hours of stirring, reaction mixture was concentrated and purified by flash chromatography on silica gel column (EtOAc:Hex, 1:4) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1NC.Br[C:15]1[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([Br:21])[N:20]=1.C[CH2:24][N:25](C(C)C)C(C)C>C(Cl)Cl.O>[Br:21][C:19]1[N:20]=[C:15]([NH:25][CH2:24][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[F:1])[N:9]=[CH:8][CH:7]=[CH:6]3)[C:16]([NH2:22])=[N:17][CH:18]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1cc2cccnc2cc1F
Reactant: Nc1ncc(Br)nc1Br
Solvent: ClCCl
Solvent: O
Product: Nc1ncc(Br)nc1NCc1cc2cccnc2cc1F
Temperature: 120 °C
Yield: 77.5 %

Procedure:
A mixture of N-(7-fluoro-quinolin-6-yl)-methylamine (1.69 g, 9.63 mmol), 3,5-dibromopyrazin-2-amine (2.43 g, 9.63 mmol) and DIPEA (2.96 g, 22.90 mmol) was heated in a microwave to 120° C. for 10 hour. The reaction was diluted with DCM and water. The organic layer was washed with NH4Cl (aq.), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (DCM:MeOH) to give the title compound as a yellow solid (2.60 g, 69%). LCMS (method E): [MH]+=348/350, tR=5.21 min.
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([O:6][CH3:7])[O:4][CH3:5].[F:14][C:15]([F:21])([F:20])[C:16]([O:18]C)=[O:17]>C(OCC)(=O)C>[F:14][C:15]([F:21])([F:20])[C:16]([O-:18])=[O:17].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N+:11]([CH3:15])([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7]
Reactant: CO[Si](CCCN(C)C)(OC)OC
Reactant: COC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CO[Si](CCC[N+](C)(C)C)(OC)OC
Product: O=C([O-])C(F)(F)F

Procedure:
5.0 g of trimethoxysilylpropyldimethylamine and 18 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 4.6 g of methyl trifluoroacetate was dissolved in 24 g of ethyl acetate was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was refluxed over 3 days and therefrom, ethyl acetate was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, trimethoxysilylpropyldimethylamine and methyl trifluoroacetate as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylpropyltrimethylammonium trifluoroacetate.