Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([CH2:43][CH2:44][N:45]4[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 42.9 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (108 mg, 0.23 mmol), 2-(methyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (Example 131, step D) (52 mg, 0.21 mmol), and p-toluenesulfonic acid (107 mg, 0.56 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and neutralized with 1 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (61 mg, 0.09 mmol, 37%). 1H NMR (400 MHz, CDCl3) δ ppm 9.47 (d, J=6.97 Hz, 1H), 8.27-8.31 (m, 2H), 8.26 (d, J=5.50 Hz, 1H), 7.98-8.06 (m, 2H), 7.81 (d, J=8.07 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.80 Hz, 1H), 7.51 (t, J=7.70 Hz, 1H), 7.32-7.40 (m, 1H), 7.18-7.26 (m, 1H), 6.98 (t, J=8.25 Hz, 2H), 6.89 (t, J=6.78 Hz, 1H), 6.78-6.84 (m, 2H), 6.60 (d, J=5.50 Hz, 1H), 3.93 (s, 3H), 2.76-2.85 (m, 2H), 2.43-2.75 (m, 10H), 2.32 (s, 3H). MS (ESI): 675 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([S:28]([CH3:31])(=[O:30])=[O:29])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.CO>C(Cl)Cl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (268.4 mg, 0.579 mmol) in methylene chloride (3 mL) at ambient temperature was added HCl (4M in 1,4-dioxane, 4.34 mL, 17.4 mmol) and the resulting solution was stirred at RT for 5 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]butanamide as a solid. 7.8 mg. LCMS: (M+1) 380.1.
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[CH3:50][O:51][C:52]([NH:54][C@@H:55]([C@H:59]1[CH2:63][CH2:62][O:61][CH2:60]1)[C:56](O)=[O:57])=[O:53]>>[CH3:46][O:45][C:44]([NH:43][C@H:3]([C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[C@@H:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:56](=[O:57])[C@@H:55]([NH:54][C:52]([O:51][CH3:50])=[O:53])[C@H:59]3[CH2:63][CH2:62][O:61][CH2:60]3)=[CH:23][CH:22]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:16][CH:17]=1)=[O:41])=[O:42])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:47]
Reactant: COC(=O)N[C@H](C(=O)O)[C@H]1CCOC1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccccc2)cc1)C(C)(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc2)c2ccccc2)cc1)[C@H]1CCOC1
Yield: 67 %

Procedure:
The product of Example 10A (0.035 g, 0.052 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid were processed as in Example 25B to give 0.030 g (67%) of the title compound as a thick oil. 1H NMR (500 MHz, DMSO-D6) δ ppm 0.91 (s, 9 H) 1.66 (ddd, J=20.03, 7.21, 7.10 Hz, 1 H) 1.77-1.88 (m, 6 H) 1.90-1.99 (m, 2 H) 2.06-2.14 (m, 2 H) 3.48 (s, 6 H) 3.54-3.65 (m, 4 H) 3.66-3.75 (m, 3 H) 3.78-3.85 (m, 1 H) 4.14-4.22 (m, 2 H) 4.38 (dd, J=8.09, 5.04 Hz, 2 H) 4.53 (s, 4 H) 6.51 (t, J=7.25 Hz, 1 H) 6.60 (d, J=8.09 Hz, 2 H) 6.99-7.06 (m, 3 H) 7.12 (d, J=7.48 Hz, 4 H) 7.45 (d, J=7.93 Hz, 4 H) 7.55 (d, J=7.93 Hz, 1 H) 9.93 (d, J=6.26 Hz, 2 H); MS ESI− m/z 852.5 (M−H)−.
Reaction SMILES: B1(C)[O:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H]2N1CCC2.B.CSC>C1(C)C=CC=CC=1.C(Cl)Cl.C1COCC1>[CH:20]1([CH2:15][C@@H:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: B
Solvent: CSC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O[C@@H](CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
A solution of 2.7 mL of 1.0 M (R)-2-methyl-CBS-oxazaborolidine solution in toluene in 4 mL of CH2Cl2 at −25° C. was treated with 1.4 mL of 2.0 M borane.methyl sulfide in THF and stirred cold for 10 min. A solution of 501 mg (2.66 mmol) of cyclopentylmethylene phenyl ketone (from EXAMPLE 20, Step B) in 2 mL of CH2Cl2 was added over 25 min and the resulting mixture was stirred cold for 45 min. The reaction was quenched by pouring it into cold (−25° C.) MeOH. The quenched reaction was warmed to rt and stirred for 45 min until gas evolution ceased. The mixture was concentrated and the residue dissolved in 20 mL of MeOH and concentrated again. Flash chromatography on silica gel using 17:3 v/v hexanes/EtOAc afforded 413 mg (81%) of the title compound: RF: 0.53 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.10-1.17 (m, 2H), 1.47-1.89 (m, 9H), 4.69 (m, 1H), 7.25-7.35 (m, 5H).
Reaction SMILES: ClCCCl.[Br:5][C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[CH3:21][NH:22][CH2:23][CH3:24]>O1CCCC1.CN(C)C=O>[CH2:23]([N:22]([CH3:21])[C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([Cl:16])=[C:14]([Cl:15])[C:6]=1[Br:5])[CH3:24]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1Br
Reactant: CCNC
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCN(C)C(=O)c1ccc(Cl)c(Cl)c1Br
Temperature: 0 °C
Yield: 76.7 %

Procedure:
200 ml of 1,2-dichloroethane, 14 g (0.052 mol) of 2-bromo-3,4-dichlorobenzoic acid and 2 ml of N,N-dimethylformamide are introduced successively into a 500 ml round-bottomed flask. 11.5 ml of thionyl chloride (0.078 mol) are then run in dropwise with stirring and while cooling at 0° C. When the addition is finished, the reaction mixture is heated progressively to 55° C. over 2 hours and then evaporated to dryness. The residue is taken up in 50 ml of tetrahydrofuran and then poured dropwise into a solution containing 13 ml (0.15 mol) of N-methylethylamine in 50 ml of tetrahydrofuran maintained at a temperature below 10° C. When the addition is finished, the reaction mixture is stirred at room temperature for one hour and then evaporated to dryness. The residue is taken up in dichloromethane and washed successively with 1N HCl and distilled water. After drying over magnesium sulfate, the organic phase is evaporated under reduced pressure to provide 12.4 g (yield: 80%) of N-ethyl-N-methyl-2-bromo-3,4-dichlorobenzamide in the form of a white solid melting at 71° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][PH:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[O-:20].[Na+]>>[C:1]1([CH2:7][CH2:8][P:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])[OH:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-]Cl
Reactant: O=[PH](CCc1ccccc1)CCc1ccccc1
Agent: [Na+]
Product: O=P(O)(CCc1ccccc1)CCc1ccccc1
Reaction time: 1 h

Procedure:
The resultant compound of Example 9 (250 mg, 0.97 mmol) was added to 10 ml of 5.25% sodium hypochlorite. The resulting solution was stirred vigorously for 1 h, acidified, extracted with chloroform, washed with 1N HCl and saturated brine, dried over MgSO4, and concentrated in vacuo to give 217 mg (82%) of the desired compound (Rf 0.12, 20% methanol in chloroform) as a glass. 1H NMR (CDCl3) δ2.0-2.1 (m, 4H), 2.9-3.0 (m, 4H), 7.15-7.4 (m, 10H). Mass spectrum (M+H)+ =275.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)#[N:22].C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([C:21]#[N:22])[CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#Cc1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)c1
Yield: 17 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.22 mmol), 3-cyanobenzaldehyde (32.0 mg, 0.244 mmol, and Ammonium acetate (34.2 mg, 0.444 mmol) were reacted to produce 17.15 mg (17%) of the title compound. (300 MHz, DMSO-d6) 13.49 (s, 1H), 8.49 (s, 1H), 8.43 (d, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.82-7.74 (m, 2H), 7.23 (s, 1H), 6.40 (m, 2H), 5.18 (t, J=17 Hz, 9 Hz, 1H), 2.90 (s, 1H), 2.79 (s, 1H), 2.63 (d, J=9 Hz, 1H), 2.24 (d, J=9 Hz, 1H), 1.38 (d, J=9 Hz, 1H). MS=451 (M+2), HPLC: 2.43 min. (G Method)
Reaction SMILES: [N:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]([C:9](N(OC)C)=[O:10])[CH2:2]2.[CH3:15][Li].[Br-].[Li+].P(=O)(O)(O)O>O1CCCC1.C(OCC)C>[C:9]([C:3]1[CH2:2][N:1]2[CH2:8][CH:5]([CH:4]=1)[CH2:6][CH2:7]2)(=[O:10])[CH3:15]
Reactant: [Li]C
Reactant: CON(C)C(=O)C1=CC2CCN(C1)C2
Agent: O=P(O)(O)O
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1=CC2CCN(C1)C2
Temperature: -70 °C

Procedure:
A solution of (±)1-azabicyclo[3.2.1]oct-3-en-3-yl-N-methoxy-N-methylcarboxamide (D8) (0.40 g, 2.0 mmole) in dry tetrahydrofuran (20 ml) was cooled to -70° C., under a nitrogen atmosphere, and treated dropwise over 15 minutes with methyllithium (1.47 ml of a 1.5 m solution in diethyl ether as the complex with lithium bromide, 2.2 mmole). The temperature was maintained at -70° C. for 30 minutes, and then allowed to warm to 0° C. over 1.75h. The reaction was cooled to -20° C. and poured into a 1M solution of orthophosphoric acid (20 ml) cooled below 0° C. The organic layer was separated, and the aqueous phase was saturated with potassium carbonate, and extracted exhaustively with chloroform. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give a pale yellow oil (0.33 g) which was distilled in a kugelrohr at 150° C./0.1 mmHg to give the title compound (D10) as a colourless liquid (0.28 g, 93%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[C:45]2[N:44]=[C:43]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[N:42]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[C:45]3[N:44]=[C:43]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[N:42]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:41]=3[CH:40]=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCc1nc2c(CCl)cccc2n1COCC[Si](C)(C)C
Product: COCCCc1nc2c(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc2n1COCC[Si](C)(C)C

Procedure:
Analogously to Method D, 2.1 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 1.81 g of 4-chloromethyl-2-(3-methoxypropyl)-1-(2-trimethylsilanylethoxymethyl)-1H-benzoimidazole are reacted. The title compound is obtained as a yellowish oil. Rf=0.37 (3:1 EtOAc-heptane); Rt=6.04.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([C@@H:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:23])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([C@@H:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:23])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of compound 286 (0.22 g, 0.44 mmol) in 10 mL of CH3OH was added 0.1 g of Pd—C (10%, wet). The mixture was hydrogenated at room temperature for 16 h. The catalyst was removed by filtration through a pad of celite. The filtrate was concentrated to afford compound 287 as a solid (0.15 g, 83%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2]>N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Product: CCOC(=O)Cc1ccc(CN)cc1
Reaction time: 0.75 h

Procedure:
0.5 g (2.6 mmol) of ethyl (4-cyanophenyl)acetate was dissolved in 70 ml of ethanolic ammonia solution and hydrogenated, at room temperature and under standard pressure, over Raney nickel. After 45 minutes, the mixture was filtered and evaporated. This resulted in 0.42 g (82%) of ethyl (4-aminomethylphenyl)acetate. MS (ES+): m/e=194.11
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH2:17][NH:18][CH3:19])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CC1C=CC=C(C)N=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:19])[S:35]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
To a solution of t-butyl 2-(2-bromo-4-((methylamino)methyl)phenoxy)acetate (2) (4.4 g, 13.4 mmol, 1 eq) in DCM (50 mL) was added 2,6-lutidene (3.1 ml, 26.8 mmol, 2 eq) and 4-fluorobenzenesulfonyl chloride (2.9 g, 14.7 mmol. 1.1 eq, Aldrich, Milwaukee, Wis., USA). After the mixture was stirred for 18 h at room temperature, it was washed with 1 N HCl (100 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The washed DCM layer was dried over Na2SO4 and concentrated in vacuo. Silica gel purification (linear gradient of 0% EtOAc/hexanes to 100% EtOAc/hexanes) of the resultant residue yielded 2.95 g (44.8%) of t-butyl 2-(2-bromo-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (3) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 7.82 (m, 2H), 7.44 (d, 1H), 7.22 (m, 3H), 6.72 (d, 1H), 4.57 (s, 2H), 4.04 (s, 2H), 2.58 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [C:1]1([C:11]([O:13]CC)=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CCO>[CH2:9]([O:8][C:6]([C:1]1([C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 0.1 %

Procedure:
To a solution of diethyl 1,1-cyclopentane dicarboxylate (2.5 g, 11.68 mol) in EtOH (10 ml) was added dropwise a solution of KOH (654 mg, 11.68 mmol) in EtOH (10 ml) over 1/2 hour. The resulting mixture was stirred at room temperature for 96 hr, concentrated under vacuum, and partitioned between H2O and EtOAc. The aqueous layer was acidified with concentrated HCl and extracted with EtOAc. The EtOAc extracts were washed (brine), dried (Na2SO4), filtered, and concentrated under vacuum to give the product (1.73 g) as a clear oil.
Reaction SMILES: [H-].[Na+].C([O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([C:13]2[CH:14]=[C:15]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)=[O:12])=[CH:9][CH:8]=1)(=O)C>C(O)C.O1CCCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([C:13]2[CH:14]=[C:15]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)=[O:12])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC(C)=O)cc2)c2ccccn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)c2ccccn12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (4.38 g) was added to an ice cold solution of ethyl 4-[1-(4-acetoxybenzoyl)indolizin-3-yl]butyrate (36.1 g) in a mixture of ethanol (200 ml) and tetrahydrofuran (200 ml). The mixture was stirred for 20 minutes at 0° C. and evaporated. The residual solution was poured into a mixture of diluted hydrochloric acid and ice, and extracted with a mixture of chloroform and methanol (10:1). The organic layer was washed with a sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and evaporated. The residue was washed with ethyl acetate and diethyl ether to give ethyl 4-[1-(4-hydroxybenzoyl)indolizin-3-yl]butyrate as yellow powder (29.3 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH:10]([CH3:12])[CH3:11].FC(F)(F)C(O)=O.[N:20]1([CH2:24][CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=3)[N:28]=[C:27]2[CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:20]1([CH2:24][CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=3)[N:28]=[C:27]2[CH:42]2[CH2:43][CH2:44][N:45]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[O:9][CH:10]([CH3:12])[CH3:11])[CH2:46][CH2:47]2)[CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)Oc1c(N)ncnc1Cl
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)Oc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h
Yield: 55.7 %

Procedure:
A reaction mixture of 6-Chloro-5-isopropoxy-pyrimidin-4-ylamine (40.00 mg; 0.21 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (133.13 mg; 0.21 mmol; 1.00 eq.), and Cs2CO3 (277.84 mg; 0.85 mmol; 4.00 eq.) in DMSO 5.0 ml was stirred at 120° C. for 2 days, purified the product by HPLC, collected title compound 64 mg, yield 45.5%. LC-MS: (M+1=548, obsd.=548).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C#N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1C1CCNCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(1-tertbutoxycarbonylpiperidin-4-yl)benzonitrile (1.7 g, 5.9 mmol) in ethyl acetate (˜50 ml), cooled to 0° C. was added hydrogen chloride gas, bubbled vigorously for 5 minutes. The reaction mixture was stirred for 10 minutes at 0° C., purged with argon and concentrated. Flushing with ethyl acetate×3 and concentration gave 2-(piperidin-4-yl)benzonitrile hydrochloride;
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[C:19]([CH3:22])[N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].[NH2:23][C:24]1[N:32]=[C:31]2[C:27]([NH:28][CH:29]=[N:30]2)=[C:26](Br)[N:25]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:23][C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][NH:30]2)=[C:26]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:21][CH:20]=[C:19]([CH3:22])[N:7]3[C:8](=[O:18])[C:9]=2[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH3:3])[N:25]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1csc2nc(C(C)Nc3nc(N)nc4[nH]cnc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 110 °C
Yield: 52.3 %

Procedure:
A mixture of optical pure 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.13 g, 0.40 mmol) made from above, 2-amino-6-bromopurine (0.10 g, 0.47 mmol), and N,N-diisopropylethylamine (0.085 mL, 0.49 mmol) in ethanol (1 mL) was heated at 110° C. overnight. LCMS showed incomplete conversion. An additional 0.5 equivalent of 2-amino-6-bromopurine and 1.0 equivalent of N,N-diisopropylethylamine was added, and the mixture was stirred at 110° C. for another day. The solid was shown to be 2-amino-6-bromopurine by LCMS. The mixture was filtered, and the filtrates were purified on preparative-LCMS ((XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.095 g, 52%). LCMS calculated for C20H17F2N8OS (M+H)+: m/z=455.1. Found: 455.1 1H NMR (DMSO-d6, 400 MHz) δ 7.67 (1H, s), 7.27 (1H, m), 7.17 (3H, m), 7.07 (1H, s), 6.89 (1H, br s), 5.45 (2H, br s), 5.03 (1H, m), 2.63 (3H, s), 1.30 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −111 ppm.