Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[O:51]1[CH2:56][CH2:55][N:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:49]=[CH:50][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:60]6[CH2:61][CH2:62][CH:57]([N:54]7[CH2:55][CH2:56][O:51][CH2:52][CH2:53]7)[CH2:58][CH2:59]6)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:42][CH:43]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCC(N5CCOCC5)CC4)cc3F)cn2)cc1
Yield: 138.9 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 4-morpholinopiperidine (40.2 mg, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-phenyl}-(4-morpholin-4-yl-piperidin-1-yl)-methanone as a brown solid (136 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-308) as a yellow powder (61.8 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[K+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([NH:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:19]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(4-methoxyphenyl)methanamine (1.51 g, 11 mmol) was added in DMF (15 mL), potassium hydroxide was added and stirred at room temperature for 10 minutes. The reaction was cooled to −2° C., 4,6-dichloro-2-methylpyrimidine (1.63 g, 10 mmol) in DMF (5 mL) was added drop-wise at a speed the internal temperature was controlled <0° C. After 30 minutes, the reaction was added ethyl acetate (50 mL), washed with brine (20 mL×2). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 110 gram AnaLogix™ silica gel cartridge eluting with 30% ethyl acetate/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:37]([CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCN
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)NCCOc1ncnc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC
Yield: 89.8 %

Procedure:
According to Example 4a) 100 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide was reacted with 93 mg 1-propanesulfonylchloride to give 110 mg 4-tert.-butyl-N-{6-[2-(1-propanesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=5.43 min, [M−1]−=577.49.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)[S:10][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(Cl)(Cl)Cl>[F:25][C:20]1[CH:19]=[C:18]([NH2:17])[CH:23]=[CH:22][C:21]=1[O:24][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)[S:10][C:3]=12
Reactant: Cc1noc(-c2cc3nccc(Cl)c3s2)n1
Reactant: Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1noc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 48.1 %

Procedure:
A 15 mL sealed tube was charged with 7-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridine (0.113 g, 0.449 mmol), 4-amino-2-fluorophenol (0.071 g, 0.56 mmol), cesium carbonate (0.512 g, 1.57 mmol), and DMF (2.00 ml) and sealed. The reaction mixture was stirred at 90° C. for 18 hours, allowed to cool to room temperature, then diluted with chloroform (50 mL) and washed with water (50 mL), sat. aq. NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield a black solid. The product was purified by silica gel chromatography eluting with 3% methanol in methylene chloride to yield 3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (0.074 g, 48% yield) as a yellow solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([OH:14])=O.Cl.[NH:16]1[CH2:27][S:26][CH2:25][C@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19].C1C2C(=CC=CC=2)CC1CCC(O)=O.Cl.N1CSC[C@H]1C(N1CCCC1)=O>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[CH2:11][C:12]([CH:25]1[S:26][CH2:27][NH:16][C@@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:14]
Reactant: O=C([C@@H]1CSCN1)N1CCSC1
Reactant: O=C(O)C[C@H]1CCc2ccccc2C1
Agent: Cl
Agent: O=C(O)CCC1Cc2ccccc2C1
Agent: O=C([C@@H]1CSCN1)N1CCCC1
Product: O=C(C[C@H]1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCSC1
Yield: 38 %

Procedure:
Colorless crystals of 3-{3-[(S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-thioprolyl}thiazolidine were prepared in the same manner as in Example 25, except that (S)-(-)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and 3-L-thioprolylthiazolidine hydrochloride were used instead of 3-(indan-2-yl)propionic acid and 1-L-thioprolylpyrrolidine hydrochloride, respectively (yield: 38%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[CH:15]=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.C1C(=O)N([I:25])C(=O)C1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([I:25])=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(I)c2n1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
A solution of 5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridine (700 mg, 3.04 mmol) in THF (25 mL) was treated with n-iodosuccinimide (753 mg, 3.34 mmol, Alfa-Aesar). The reaction was stirred at 23° C. under N2. After 30 min, the solution was diluted with EtOAc (250 ml) and washed with brine (175 ml), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 15-40% EtOAc/hexane), affording 5-(2,6-difluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (255 mg, 78%). MS (ESI, pos. ion) m/z: 356.9 (M+1).
Reaction SMILES: CC1N=CN(C2C=C(NC(=O)OC(C)(C)C)C=C(C(F)(F)F)C=2)C=1.[CH3:25][C:26]1[N:27]([C:31]2[CH:32]=[C:33]([NH:41]C(=O)OC(C)(C)C)[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[CH:28]=[CH:29][N:30]=1>>[CH3:25][C:26]1[N:27]([C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:34]=[C:33]([NH2:41])[CH:32]=2)[CH:28]=[CH:29][N:30]=1
Reactant: Cc1nccn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: Cc1cn(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)cn1
Product: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1

Procedure:
Utilising the procedure described in Example 91d, but employing [3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 92c) in lieu of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a colourless crystalline solid, m.p. 127–131° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7]/[C:8](=[CH:12]\[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C1(N)CCCCC1>CO>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/C(=C\CCc1ccccc1)C(=O)O
Solvent: NC1CCCCC1
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A stirred solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (100 g, 0.34 mol), cyclohexylamine (39 ml, 0.34 mol) and [(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ruthenium chloride (0.64 g, 0.69 mmol) in methanol (1000 ml) was heated to 60° C., under hydrogen (60 p.s.i.), for 42 hours and then allowed to cool to room temperature. The mixture was filtered through celite and then concentrated in vacuo to a yellow solid which was purified by re-crystallisation from acetone (850 ml). The resulting solid was partitioned between ethyl acetate (1200 ml) and citric acid solution (10%, 1200 ml) and the organic phase was separated, washed with demineralised water (1200 ml) and concentrated in vacuo to leave the title compound as an oil (80 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23][C:24]1[C:33]([NH2:34])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>C(O)CCCCC.CO>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:34][C:33]3[CH:32]=[C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]4=[CH:25][C:24]=3[N:23]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: Nc1cc2ccccc2cc1N
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCCCCCO
Solvent: CO
Product: O=c1[nH]c2cc3ccccc3cc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 1.07 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 696.3 mg of 2,3-diaminonaphthalene in 3 ml of 1-hexanol is heated to boiling under reflux for 3 hours. The reaction mixture is then cooled and diluted with methanol. The crude product is filtered under suction and recrystallized from N,N-dimethylformamide/water, There is obtained 3-(3,4-dihydroxy-5-nitrophenyl)benzo[g]quinoxalin-2(1H)-one of m.p.>300°.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@@H:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:14][CH2:13][CH2:12][O:11]1)C1C=CC=CC=1>CO.C(O)C.[Pd]>[CH2:17]([O:16][C@H:15]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:9][OH:8])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCO[C@H]1CCCO[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCCCCCCCCCO[C@H]1CCCO[C@H]1CO

Procedure:
1.409 g of dl-cis-2-benzyloxymethyl-3-hexadecyloxytetrahydropyran (prepared as described in Preparation 45) was dissolved in 100 ml of a 1:1 by volume mixture of methanol and ethanol. 0.70 g of a 10% w/w palladium on activated carbon catalyst was then added to the resulting solution. Catalytic reduction using the same procedure as described in Preparation 44 yielded 1.116 g of a crude substance, which was then subjected to column chromatography through 30 g of silica gel. Those fractions eluted with mixtures of diethyl ether and hexane ranging from 1:20 to 1:5 by volume gave 1.031 g of the title compound, melting at 42°-43° C. (after recrystallisation from cold hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:3]=1
Reactant: COc1cccc(CCl)c1
Reactant: Oc1ccc(F)cc1
Product: COc1cccc(Cc2cc(F)ccc2O)c1

Procedure:
Alkylation of 4-fluorophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3′-methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155° C., by the procedure similar to that in Example 18 method B.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13]>CO.O>[NH2:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[N:7]=[C:6]([NH:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:17])=[C:10]([NH2:9])[CH:11]=3)[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1ccc(N)cc1N
Reactant: Clc1ccnc(Cl)n1
Solvent: O
Solvent: CO
Product: Cc1ccc(Nc2ccnc(Nc3ccc(C)c(N)c3)n2)cc1N
Temperature: 70 °C

Procedure:
2,4-Dichloropyrimidine (45 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.13 (s, 1H), 6.95 (d, 2H, J=7.5 Hz), 6.82 (d, 2H, J=1.8 Hz), 6.60 (dd, 2H, J=1.8, 7.5 Hz), 6.17 (s, 1H), 2.12 (s, 6H); LCMS purity: 97.3%; MS (m/e): 321.09 (M+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[N:4]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:21]=2[CH3:37])[CH2:3]1.[CH:39]1[C:44](Cl)=[N:43][C:42]([NH2:46])=[N:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:40]5[CH:39]=[CH:44][N:43]=[C:42]([NH2:46])[N:41]=5)[CH:6]=4)[C:2]([CH3:1])([CH3:38])[CH2:3]3)=[C:21]([CH3:37])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(-c3ccnc(N)n3)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 4-(3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (75 mg, 0.147 mmol), PdCl2(PPh3)2 (10.33 mg, 0.015 mmol), 2-amine-4-chloropyrimidine (21.0 mg, 0.162 mmol) and sodium carbonate (26.5 mg, 0.442 mmol) in 1,4-dioxane (2.0 mL) and water (0.7 mL) and heating in the microwave for 1 h at 120° C. After purification 4-(1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-pyrimidinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.66-8.83 (1H, m), 8.17 (1H, d, J=5.5 Hz), 7.79-7.99 (4H, m), 7.36-7.48 (2H, m), 7.26-7.29 (2H, m), 6.87 (1H, d, J=5.5 Hz), 6.62 (1H, d, J=1.6 Hz), 5.43 (2H, br. s.), 3.82 (2H, s), 2.29-2.44 (3H, m), 1.58 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=477 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=C[C:3]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]2([CH3:24])[CH3:23])=[CH2:9].C(N(CCCC)CCCC)CCC.[C]=O.[C:40]([O:43][CH2:44]C)(=[O:42])[CH3:41]>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:19]1[C:10]([C:8]([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:41]=2[C:40]([O:43][CH3:44])=[O:42])=[CH2:9])=[CH:11][C:12]2[C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][C:16]([CH3:21])([CH3:22])[C:17]=2[CH:18]=1
Reactant: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1I
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1C(=O)OC

Procedure:
A solution of 6-[1-(2-iodophenyl)vinyl]-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (17.2 g, 40 mmol), palladium diacetate (1.02 g, 4.5 mmol) and tributylamine (21.9 ml, 92 mmol) in methanol (500 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=1)[CH3:10])=[O:7].[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1.O>[O:1]([CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:13][N:12]=1)[CH3:10])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1CO)c1ccc(OCC(F)(F)F)cn1
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1COc1ccccc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
To a mixture of (1S*,2S*)-2-(hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cy clopropanecarboxamide (30 mg, 0.094 mmol) and phenol (16.0 mg, 0.17 mmol) in tetrahydrofuran (1 mL), triphenylphosphine (45 mg, 0.17 mmol) and di-tert-butyl azodicarboxylate (28.2 mg, 0.12 mmol) were added successively. After stirring at room temperature for 1 day, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 12.1 mg (33% yield) of the title compound.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)Cc1ccc(CCO)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(CCBr)cc1
Temperature: 25 °C

Procedure:
Phosphorus tribromide (1.42 g) was added, dropwise, to a solution of methyl 4-(2-hydroxyethyl)phenylacetate (2.7 g-see Preparation 21) in carbon tetrachloride (20 ml) at 0°. When the addition was complete, the mixture was allowed to warm to room temperature and then heated under reflux for 2 hours. Ice (100 g) was added and the mixture was partitioned between dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing hexane (40%) then with dichloromethane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 1.02 g.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6](=[O:53])[NH:7][C@H:8]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]4[CH:40]=[N:41][C:42]([N:45]5[CH2:50][CH2:49][NH:48][CH2:47][C@H:46]5[CH3:51])=[CH:43][CH:44]=4)=[O:38])=[CH:32][C:31]=3[CH3:52])=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:13])[CH:9]([CH3:11])[CH3:10].C(N(CC)C(C)C)(C)C.CC(N(C)C)=O.[C:69]([N:72]1[CH2:76][CH2:75][CH2:74][C@@:73]1([CH3:80])[C:77](O)=[O:78])(=[O:71])[CH3:70].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:4][O:5][C:6](=[O:53])[NH:7][C@H:8]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]1[NH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]4[CH:40]=[N:41][C:42]([N:45]5[CH2:50][CH2:49][N:48]([C:77]([C@:73]6([CH3:80])[CH2:74][CH2:75][CH2:76][N:72]6[C:69](=[O:71])[CH3:70])=[O:78])[CH2:47][C@H:46]5[CH3:51])=[CH:43][CH:44]=4)=[O:38])=[CH:32][C:31]=3[CH3:52])=[CH:28][CH:29]=2)=[CH:22][N:23]=1)=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3C)cc2)[nH]1)C(C)C
Reactant: CC(=O)N1CCC[C@@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C(=O)[C@]6(C)CCCN6C(C)=O)C[C@H]5C)nc4)cc3C)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of [(((S)-2-methyl-1-{(S)-2-[5-(2′-methyl-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester tri-HCl (15 mg, 0.019 mmol; Preparation 18) and N,N-diisopropylethylamine (33.1 uL, 0.190 mmol) dissolved in DMA (0.6 mL, 7 mmol) was added (S)-1-acetyl-2-methyl-pyrrolidine-2-carboxylic acid (3.2 mg, 0.019 mmol, Preparation 19) and HATU (11 mg, 0.028 mmol). The reaction mixture was stirred at room temperature overnight, concentrated, dissolved in 1:1 acetic acid:water (4 mL) and purified by preparative HPLC to provide the di-TFA salt of the title compound (9.1 mg). (m/z): [M+H]+ calcd for C46H57N9O6 832.44 found 832.4.
Reaction SMILES: BrC[C:3]1C=CC=C[C:4]=1[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([CH:17]2[CH2:22][CH2:21][CH:20](C3C=CC=CC=3CBr)[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[C-]#[N:32].[Na+].O1CCOCC1>O>[CH:17]1([C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:4][C:3]#[N:32])=[CH:10][CH:11]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(C1CCC(c2ccccc2CBr)CC1)C1CCC(c2ccccc2CBr)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc(C(=O)C2CCCCC2)cc1

Procedure:
Crude α-bromo-p-tolylcyclohexyl ketone (17 g.), sodium cyanide (3 g.), dioxan (80 ml.) and water (20 ml.) were heated under reflux for 4 hours. The mixture when cold was poured into water and extracted with ether. Evaporation of the extracts followed by chromatography on silica gave a solid (1.5 g.) which was crystallised from light petroleum (b.p. 60°-80°) m.p. 102°-103°.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH3:22])=[C:16]([CH3:23])[C:15]=1[CH3:24]>C(Cl)Cl>[CH3:12][O:13][C:14]1[C:15]([CH3:24])=[C:16]([CH3:23])[C:17]([O:21][CH3:22])=[C:18]([CH3:20])[C:19]=1[OH:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C)c(OC)c(C)c1C
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(O)c1C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A solution of 9.4 g of m-chloroperbenzoic acid (70% purity) in 100 ml of methylene chloride was added dropwise, whilst ice-cooling, to a solution of 4.6 g of 1,4-dimethoxy-2,3,5-trimethylbenzene in 20 ml of methylene chloride, and the resulting mixture was stirred at the same temperature for 30 minutes and then at room temperature for 5 hours. At the end of this time, the reaction mixture was washed with a 5% w/v aqueous solution of sodium hydrogensulfite, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed from the reaction mixture by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using benzene and a 50:1 by volume mixture of benzene and ethyl acetate as the eluents, to give 1.3 g of the title compound.