Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCCBr)(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([O:16][C:17]([C:19]1[C:20]([S:36][CH3:37])=[N:21][N:22]2[CH:27]=[C:26]([CH2:28][O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[CH:25]=[CH:24][C:23]=12)=[O:18])[CH3:15]>C(Cl)(Cl)Cl>[CH2:14]([O:16][C:17]([C:19]1[C:20]([S:36][CH3:37])=[N:21][N:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:28][O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[C:27]=12)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1c(SC)nn2cc(COC3CCCCO3)ccc12
Agent: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(SC)nn2cccc(COC3CCCCO3)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The compound of Example 14 (45.6 g) was dissolved in ethanol (500 mL). To this solution, carbon disulfide (10.3 mL) and dimethylsulfuric acid (16.3 mL) were added. An aqueous solution (100 mL) of potassium hydroxide (14.5 g) was then slowly added dropwise over 1.5 hours. Subsequently, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to give a yellow oil (6.78 g). The oily product (8.64 g) was dissolved in chloroform (200 mL). To this solution, bromoethyl acetate (6.66 mL) was added and the resulting mixture was stirred for 6 hours at room temperature. Subsequently, the solvent was evaporated and the residue was washed with diethyl ether to give a yellow oil. The oily product was dissolved in chloroform (290 mL). To the solution, potassium carbonate (20.0 g) was added and the resulting mixture was stirred for 16 hours at room temperature. Subsequently, the mixture was filtered and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=8:1) gave an inseparable mixture of the title compound and 3-ethoxycarbonyl-2-methylthio-6-(tetrahydropyrane-2-yl oxymethyl)-pyrazolo[1,5-a]pyridine as a yellow oil (3.71 g, 0.6:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Cl:18])[C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Cl:18])[CH:15]([OH:17])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)C(Cl)=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)C(Cl)=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of 55 (1.24 g, 4.53 mmol) in ethanol (25 mL) was treated with sodium borohydride (102 mg, 2.72 mmol) at 25° C. After 1 h, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (40 mL), carefully treated with 5% aqueous hydrochloric acid (1×25 mL), the layers separated, and dried (MgSO4). The resulting solution was concentrated in vacuo to afford 56 (902.1 mg, 72%) as a colorless residue that was used without further purification. MS 298 (M+Na).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Si:29]([O:36][C@@H:37]([CH3:65])[C@@H:38]([NH:53][C:54]1[C:62]2[CH:61]=[CH:60][S:59][C:58]=2[C:57]([C:63]#[N:64])=[CH:56][CH:55]=1)[C:39]([NH:41][NH:42][C:43](=O)[C:44]1[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=1)=[O:40])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[Si:29]([O:36][C@@H:37]([CH3:65])[C@@H:38]([NH:53][C:54]1[C:62]2[CH:61]=[CH:60][S:59][C:58]=2[C:57]([C:63]#[N:64])=[CH:56][CH:55]=1)[C:39]1[O:40][C:43]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[N:42][N:41]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
To a solution of triphenylphosphine (275 mg, 1.43 mmol) in DCM (24 mL) was added I2 (363 mg, 1.43 mmol) at 0° C. After I2 was dissolved completely, Et3N (0.40 mL, 2.87 mmol) was added, followed by a solution of N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(7-cyanobenzo[b]thiophen-4-ylamino)butanoyl)-4-cyanobenzohydrazide (380 mg, 0.71 mmol) in DCM (12 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 10 min. The reaction was quenched with saturated sodium thiosulfate (3 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by flash chromatography to provide the title compound 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (360 mg, 98%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.22 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.73 (d, J=5.5 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 5.89 (d, J=8.6 Hz, 1H), 5.12 (m, 1H), 4.74 (m, 1H), 1.61 (d, J=6.2 Hz, 3H), 1.05 (s, 9H), 0.26 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CO>[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Solvent: CO
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c(C)c2C)cc1

Procedure:
The compound is prepared from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g para-methylaniline in the manner described in Example 82A. Title compound is obtained after FC in CH2Cl/Methanol 19/1; m.p. 68-70° C. 1H-NMR (250 MHz, CDCl3): δ=8.45 (s, wide, 2H); 7.45 (d, 2H); 7.10 (“d”, wide, 4H); 6.10 (s, wide, 1H); 4.25 (s, 2H); 2.30 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 305 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9](CCCCCCCCCCCCCCC)[C:5]=1[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:30])=O.CN(C)C=O>CCCCCC>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:30])=[O:7])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)Cl

Procedure:
To a stirred solution of 2-Ethoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Ethoxy-benzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: IC1C2C(=NC=NC=2N)N([C@H]2CC[C@H](N3CCN(C)CC3)CC2)N=1.CC1(C)C(C)(C)OB(C2C=CC(NC3OC4C=CC=CC=4N=3)=CC=2)O1.[NH2:50][C:51]1[N:56]=[CH:55][N:54]=[C:53]2[N:57]([C@H:77]3[CH2:82][CH2:81][C@@H:80]([N:83]4[CH2:88][CH2:87][N:86]([CH3:89])[CH2:85][CH2:84]4)[CH2:79][CH2:78]3)[N:58]=[C:59]([C:60]3[CH:65]=[CH:64][C:63]([NH:66][C:67]4[O:68][C:69]5[CH:75]=[CH:74][CH:73]=[CH:72][C:70]=5[N:71]=4)=[C:62](F)[CH:61]=3)[C:52]=12>>[NH2:50][C:51]1[N:56]=[CH:55][N:54]=[C:53]2[N:57]([C@H:77]3[CH2:78][CH2:79][C@H:80]([N:83]4[CH2:84][CH2:85][N:86]([CH3:89])[CH2:87][CH2:88]4)[CH2:81][CH2:82]3)[N:58]=[C:59]([C:60]3[CH:61]=[CH:62][C:63]([NH:66][C:67]4[O:68][C:69]5[CH:75]=[CH:74][CH:73]=[CH:72][C:70]=5[N:71]=4)=[CH:64][CH:65]=3)[C:52]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Agent: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)cc2)OC1(C)C
Agent: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-1,3-benzoxazol-2-amine was prepared from trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.036 g, 0.082 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine (0.034 g, 0.10 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white powder (0.021 g, 50%): 1H NMR (DMSO-d6, 400 MHz) δ 10.86 (s, 1H), 8.23 (s, 1H), 7.93 (d, 2H), 7.66 (d, 2H), 7.51 (t, 1H), 7.25 (t, 1H), 7.16 (t, 1H), 4.65 (m, 1H), 3.51 (m, 1H), 2.67-1.91 (m, 17H), 1.49-1.46 (m, 2H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.17 min., 100%; m/z 524 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])O.[Na+].O.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([C:24](=O)[CH2:25]Br)=[CH:16]1>C(O)CC>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([C:24]2[N:8]=[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[CH:25]=2)=[CH:16]1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(CBr)c1coc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: Brc1ccc2nc(-c3coc4ccccc34)cn2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
In a glass tube, 250 mg of 1-(benzofuran-3-yl)-2-bromoethanone, 181 mg of 5-bromopyridin-2-ylamine and 105 mg of sodium hydrogencarbonate are dissolved in 15 ml of n-propanol. The tube is closed and heated at 80° C. for 20 h. After cooling, 20 ml of water are added and the reaction mixture is stirred for 1 hour at ambient temperature. A precipitate forms, and is recovered by filtration, washed with water and then with diisopropyl ether, and dried in a desiccator under reduced pressure. 250 mg of compound are obtained.
Reaction SMILES: Cl.[CH:2]1([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)(=O)C(C)(C)C.CN1CCOCC1.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl.O>[C:32]([O:36][C:37](=[O:38])[NH:39][CH2:40][C:41]([N:9]1[CH2:10][CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]1[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:42])([CH3:35])([CH3:33])[CH3:34]
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCc2ccccc2C1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g) was dissolved in methylene chloride (20 mL), and pivaloyl chloride (0.98 mL) and 4-methylmorpholine (2.2 mL) were added thereto under ice-cooling. The reaction liquid was stirred at room temperature for 30 minutes and then ice-cooled, and [(tert-butoxycarbonyl)amino]acetic acid (1.54 g) was added thereto. The reaction liquid was stirred at room temperature for 14 hours and then water was added thereto, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain tert-butyl[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]carbamate (1.49 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:34]=[CH:33][C:17]([C:18]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[NH:7][CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:46]([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:47].Cl>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[O:19])=[CH:33][CH:34]=3)=[CH:11][CH:12]=2)[N:7]([C:46]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:47])[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2NC[C@@H]1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCNCC4)cc3)cc2N(C(=O)Oc2ccccc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A reaction vial was charged with (S)-tert-butyl 4-(4-(1-acetyl-2-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)benzoyl)piperazine-1-carboxylate (0.2 M in 1,2-dichloroethane, 100 μL, 0.02 mmol), N,N-diisopropylethyl amine (25 μL, 0.14 mmol), and phenyl chloroformate (6.23 mg, 0.04 mmol), and the mixture was shaken at 50° C. for 2 h. Methanol (50 μL) was added and the mixture was shaken at 50° C. for 10 min. HCl (4 M in dioxane, 0.075 mL, 0.30 mmol) was added and the reaction was shaken at 50° C. for 2 h. The mixture was concentrated and the residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford phenyl (S)-4-acetyl-3-methyl-7-(4-(piperazine-1-carbonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 499.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([C:13]1[N:17](COCC[Si](C)(C)C)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)[OH:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:14]1[C:15]2[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=2[N:17]=[C:13]1[CH:11]([C:3]1[C:4]([F:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1])[OH:12]
Reactant: COc1ccc(F)c(C(O)c2nc3ccccc3n2COCC[Si](C)(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(F)c(C(O)c2nc3ccccc3[nH]2)c1F

Procedure:
A solution of (2,6-difluoro-3-methoxyphenyl)[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol (1.4 g) in tetrahydrofuran (20 mL) is refluxed for 15 h with tetrabutylammonium fluoride (10 mL of a 1M solution in tetrahydrofuran). The mixture is then concentrated under reduced pressure and purified by chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 95/5) to afford the pure (1H-benzimidazol-2-yl)-(2,6-difluoro-3-methoxyphenyl)methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>>[C:10]([N:9]=[C:12]([NH2:13])[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)#[N:11]
Reactant: N#C[N-]C#N
Reactant: Nc1cccc(Cl)c1
Agent: [Na+]
Product: N#CN=C(N)Nc1cccc(Cl)c1

Procedure:
3-Chloroaniline and sodium dicyanamide were processed as described in Example 71A to provide the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:24]2[C:29](=[O:30])[CH2:28][CH2:27][C@H:26]([NH:31]C(=O)OC(C)(C)C)[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1.O1CCOCC1>Cl>[NH2:31][C@@H:26]1[CH2:25][N:24]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)[N:4]=2)[C:29](=[O:30])[CH2:28][CH2:27]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C)c(N3C[C@@H](NC(=O)OC(C)(C)C)CCC3=O)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C)c(N3C[C@@H](N)CCC3=O)n2)n1
Yield: 30.2 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[3-methyl-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-6-oxo-3-piperidyl]carbamate (63 mg, 0.12 mmol) in hydrogen chloride (4 mol/l) in 1,4-dioxane (2.0 ml, 8.0 mmol) and 1,4-dioxane 2.0 mL was stirred at RT 18 h. The reaction was concentrated in vacuum. The crude product was submitted for reverse phase HPLC to give 221 15 mg 29% yield. MS (ESI) m/z: 415.1. 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 9.48 (s, 1H), 9.35 (s, 1H), 8.73 (s, 1H), 8.64 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 4.27 (s, 1H), 3.86 (s, 1H), 3.59 (d, J=33.7 Hz, 1H), 3.40 (s, 1H), 2.68 (t, J=18.2 Hz, 3H), 2.20 (d, J=13.0 Hz, 3H), 2.10 (s, 1H), 1.85 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C@@H:55]([CH3:73])[CH2:56][N:57]1[CH:61]=[CH:60][C:59]([C:62]2[CH:69]=[C:68]([F:70])[C:65]([C:66]#[N:67])=[C:64]([Cl:71])[C:63]=2[F:72])=[N:58]1>CN(C=O)C.O.CCOC(C)=O>[Cl:71][C:64]1[C:63]([F:72])=[C:62]([C:59]2[CH:60]=[CH:61][N:57]([CH2:56][C@@H:55]([NH:54][C:7]([C:5]3[NH:6][C:2]([CH3:1])=[N:3][CH:4]=3)=[O:9])[CH3:73])[N:58]=2)[CH:69]=[C:68]([F:70])[C:65]=1[C:66]#[N:67]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2F)n1
Reactant: Cc1nc(C(=O)O)c[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ncc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3F)n2)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
2-Methyl-1H-imidazole-4-carboxylic acid (0.202 mmol, 0.026 g) was dissolved in DMF (5 ml) under nitrogen atmosphere. EDCI (0.202 mmol, 0.039 g), DIPEA (0.270 mmol, 0.035 g) and HBTU (0.034 mmol, 0.013 g) were added and the resulting mixture was stirred for 20 min at RT. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3,6-difluorobenzonitrile (0.135 mmol, 0.04 g) dissolved in DMF (2 ml) was added and the resulting mixture was stirred at RT for 3 days. The mixture was diluted with water and EtOAc, washed with 2M Na2CO3, water and brine. The combined organics were dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.0324 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4) δ ppm 1.23 (d, 3H), 2.38 (s, 3H), 4.28-4.47 (m, 2H), 4.48-4.58 (m, 1H), 6.77-6.82 (m, 1H), 7.46 (s, 1H), 7.77 (d, 1H), 7.83-7.96 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.94 g, 7.8 mmol; described herein), 2-(tributylstannyl)pyridine (2.9 mL, 7.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.69 g, 0.59 mmol) in toluene. The reaction was stirred at 100° C. for 18 h, then cooled to rt, concentrated, and the resulting residue triturated with hexanes. Column chromatography afforded 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=291.0 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.[CH:11]1([C:14]2[N:19]=[C:18]([C:20]3[NH:37][C:23]4=[N:24][C:25]([N:28]5[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34](O)=[O:35])[CH2:29]5)=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:17]=[CH:16][N:15]=2)[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:11]1([C:14]2[N:19]=[C:18]([C:20]3[NH:37][C:23]4=[N:24][C:25]([N:28]5[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]([N:2]([CH3:3])[CH3:1])=[O:35])[CH2:29]5)=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:17]=[CH:16][N:15]=2)[CH2:13][CH2:12]1
Reactant: CNC
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of dimethylamine (175 μmol) in N,N-dimethylformamide (200 μL) was added triethylamine (35 μL, 250 μmol) and (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (200 μL, 50 μmol, 0.25M in N,N-dimethylformamide) followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (250 μL, 100 μmol, 0.4M in N,N-dimethylformamide). The reaction mixture was stirred at 50° C. for 16 h. The solvent was removed by Speedvac and the residue was purified via HPLC to afford the title compound. MS API-ES+ (M+H) 392; HPLC retention time 2.43 min (Method C).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[C:17]([NH2:32])[N:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)C.O1CCOCC1.[OH-].[Na+]>>[NH2:32][C:17]1[N:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:33])=[O:3])=[CH:7][CH:8]=2)[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)Cc1ccc(Nc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncnc(Nc2ccc(CC(=O)O)cc2)c1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a vial with stirbar were added {4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-acetic acid ethyl ester (1430.0 mg; 3.084 mmol; 1.0 eq.) dissolved in dioxane (15.0 ml; 176.040 mmol; 57.1 eq.), and aqueous sodium hydroxide (2 N, 9.3 ml; 18.504 mmol; 6.0 eq.). The reaction mixture was stirred at room temperature for 1.5 h. The reaction was quenched by the addition of water, and washed once with EtOAc. The aqueous phase was acidified with 1N hydrochloric acid. The precipitate was filtered and dried in vacuo to afford (4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid (1.11 g, 85% yield) as white solid. The filtrate was extracted with EtOAc (2×). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford (4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid (265 mg, 19% yield) as white solid. MS: m/z=413 [M+H]+. 1H-NMR (DMSO-d6) δ 12.20 (bs, 1H), 8.05 (s, 1H), 7.41-7-39 (m, 4H), 7.34-7.32 (d, 2H), 7.16-7.11 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[OH:36])[CH2:5][NH:6][C:7]1[N:12]=[C:11]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]([NH:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].[Br:43][CH2:44][CH2:45][CH2:46]Br>CC(C)=O>[Br:43][CH2:44][CH2:45][CH2:46][O:36][C:35]1[CH:34]=[CH:33][C:4]([CH2:5][NH:6][C:7]2[N:12]=[C:11]([O:13][CH2:14][C:15]([F:17])([F:16])[F:18])[N:10]=[C:9]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[CH:22][CH:21]=3)[N:8]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: BrCCCBr
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
To a dry 30 mL vial equipped with a stir bar was added tert-butyl 4-((4-((3-chloro-4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (1.80 g, 3.18 mmol), potassium carbonate (1.32 g, 9.55 mmol) and acetone (16 mL). To the mixture was added 1,3-dibromopropane (3.37 ml, 25.5 mmol). The vial was placed in a 60° C. heating block with stirring for 2.5 h. The mixture was cooled to room temperature and then concentrated in vacuo. The resulting solid residue was subjected to SiO2 chromatography (hexanes:EtOAc 85:15 to 75:25) to afford tert-butyl 4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate as a colorless solid (1.60 g, 78%). MS m/z=646.25 (M+H)+.