Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C@H:5]([C@H:11]([OH:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C.[ClH:28]>C(O)C>[ClH:28].[NH2:4][C@H:5]([C@H:11]([OH:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](NC(C)=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](N)C(=O)OCC
Temperature: 26 °C
Reaction time: 15.5 h
Yield: 62 %

Procedure:
Ethyl (2R, 3R)-2-acetylamino-3-hydroxyoctadecanoate (1.00 g, 2.59 mmol) synthesized in the same method as Example 13 was suspended in an ethanol solution of about 30 wt % of hydrogen chloride, and the mixture was stirred for 15.5 hours in refluxing condition. After ethanol (10.0 mL) was added thereto, the mixture was cooled to 26° C. The precipitated solid was filtered to obtain 0.61 g of the title compound (yield: 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH2:24][NH:25][N:26](CC4C=CC(OC)=CC=4)[C:19]=23)[CH:10]=1.FC1C=CC(F)=CC=1C1N=C(C)C(C)=C(NC2C3C(=CN(CC4C=CC(OC)=CC=4)N=3)N=CC=2)C=1.[C:71]([OH:77])([C:73]([F:76])([F:75])[F:74])=[O:72]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[C:11]([NH:17][C:18]2[C:19]3[C:20](=[CH:24][NH:25][N:26]=3)[N:21]=[CH:22][CH:23]=2)[CH:10]=1.[C:71]([OH:77])([C:73]([F:76])([F:75])[F:74])=[O:72]
Reactant: COc1ccc(CN2NCc3nccc(Nc4cc(-c5cc(F)ccc5F)nc(C)c4C)c32)cc1
Agent: COc1ccc(Cn2cc3nccc(Nc4cc(-c5cc(F)ccc5F)nc(C)c4C)c3n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cc(F)ccc2F)cc(Nc2ccnc3c[nH]nc23)c1C
Temperature: 70 °C

Procedure:
N-(6-(2,5-Difluorophenyl)-2,3-dimethylpyridin-4-yl)-1-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and N-(6-(2,5-difluorophenyl)-2,3-dimethylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine was combined in TFA (5 mL) and heated at 70° C. for 12 hours. The reaction mixture was evaporated to give a residue which was purified via preparative HPLC using a gradient of 5-30% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to give the title compound as a TFA salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.93 (s, 1H) 2.24 (s, 1H) 2.42 (s, 3H) 2.75 (s, 3H) 6.96 (br. s., 1H) 7.23-7.33 (m, 2H) 7.60 (s, 1H) 7.61-7.68 (m, 1H) 8.44 (s, 2H). MS [M+H] found 352.1
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].[CH:41]1([B-](F)(F)F)[CH2:43][CH2:42]1.[K+].Cl[C:50]1[CH:51]=[C:52]([CH:62]=[O:63])[CH:53]=[C:54]2[C:59]=1[O:58][C:57]([CH3:61])([CH3:60])[CH2:56][CH2:55]2>C1(OC)CC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:41]1([C:50]2[CH:51]=[C:52]([CH:62]=[O:63])[CH:53]=[C:54]3[C:59]=2[O:58][C:57]([CH3:60])([CH3:61])[CH2:56][CH2:55]3)[CH2:43][CH2:42]1
Reactant: F[B-](F)(F)C1CC1
Reactant: CC1(C)CCc2cc(C=O)cc(Cl)c2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CC1(C)CCc2cc(C=O)cc(C3CC3)c2O1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A vial was charged with Pd(OAc)2 (7.99 mg, 0.04 mmol), XPhos (25.5 mg, 0.05 mmol), potassium carbonate (148 mg, 1.07 mmol), potassium cyclopropyltrifluoroborate (58.0 mg, 0.39 mmol) and 8-chloro-2,2-dimethyl-3,4-dihydro-2H-chromene-6-carbaldehyde (80 mg, 0.36 mmol). The mixture was dissolved in cyclopropylmethyl ether (1.62 mL) and water (0.16 mL) and purged with Ar. The reaction mixture was then stirred at 100° C. overnight, cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under vacuum, and the crude residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to afford the desired product as a pale-yellow oil.
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[CH2:30]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][C:39]=1[F:47])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:43])=[CH:40][C:39]=1[F:47])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(F)c1
Product: C[C@@H](COc1ncc(NC(=O)c2ccc(OCc3ccccc3)c(F)c2)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 4-(benzyloxy)-3-fluorobenzoic acid, and in the same manner as in Step A of Example 4, Step D of Example 83 and Step B of Example 123, the title compound was obtained.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[CH3:5])C.Cl.[NH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[NH2:18].C(N(CC)CC)C.O>ClCCl.CO>[Cl:14][C:10]1[CH:9]=[C:8]([C:7]2[N:17]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[N:18]=[C:4]([CH3:5])[N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(C)=NC(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nc(-c2cccc(Cl)c2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reaction time: 8 h
Yield: 70.9 %

Procedure:
N-(1-ethoxy-ethylidene)-3-chloro-benzamide 472 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3-chloro-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (517 mg, yield: 71%) was obtained as a solid phase.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][OH:27].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][OH:27])[CH2:14][CH2:13]1
Reactant: Fc1c(C2CCNCC2)cccc1C(F)(F)F
Reactant: OCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1.1 mmol) and 2-iodoethanol (0.16 ml, 2.0 mmol). Yield: 0.35 g (66%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 224-226° C. MS m/z (relative intensity, 70 eV) 291 (M+, 1), 260 (bp), 217 (5), 189 (3), 177 (7).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13]OS(C)(=O)=O)[O:9][C:8]=2[CH:19]=1)([O-:3])=[O:2].C([O-])(O)=O.[Na+].Cl.[NH:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([C:32]2[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=2)[CH2:27]1.O>CN(C=O)C.C(#N)C.CCCCCCC.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([C:32]4[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=4)[CH2:27]3)[O:9][C:8]=2[CH:19]=1)([O-:3])=[O:2]
Reactant: Oc1cccc([C@H]2CCCNC2)c1
Reactant: CS(=O)(=O)OC[C@H]1COc2ccc([N+](=O)[O-])cc2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CN1CCC[C@H](c3cccc(O)c3)C1)CO2

Procedure:
Methanesulfonic acid (R)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester (0.98 mmol, 0.28 g) was dissolved in the mixture of DMF (2.8 ml) and acetonitrile (2.8 ml). NaHCO3 (2.92 mmol, 0.25 g) and (R*)-3-(piperidin-3-yl)phenol hydrochloride was added. The mixture was refluxed 4 h and after cooling water (15 ml) was added. The water phase was extracted twice with ethyl acetate and washed with water and brine. Evaporation to dryness gave 0.36 g of the crude product. Flash chromatography, using heptane/EtOAc as eluent and crystallisation (CHCl3) gave 83 mg of the desired product.
Reaction SMILES: [NH2:1][C@H:2]([CH2:4]O)[CH3:3].C(N(CC)CC)C.[CH3:13][O:14][P:15](Cl)([O:17][CH3:18])=[O:16].C(Cl)Cl.CO.[NH4+].[OH-].C(Cl)(Cl)Cl.CO.[NH4+].[OH-].[O-][Mn](=O)(=O)=O.[K+].CS(Cl)(=O)=O.[OH-].[K+]>ClCCl>[CH3:13][O:14][P:15]([N@:1]1[CH2:4][C@@H:2]1[CH3:3])(=[O:16])[O:17][CH3:18]
Reactant: C[C@H](N)CO
Reactant: COP(=O)(Cl)OC
Agent: O=[Mn](=O)(=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COP(=O)(OC)[N@]1C[C@@H]1C
Temperature: 41 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
A 500 mL, 3-neck flask equipped with an overhead mechanical stirrer and pressure equalizing addition funnel was charged with L-alaninol (12.5 g, 166.4 mmol), triethylamine (29 mL, 208 mmol, 1.25 equiv) and dichloromethane (125 mL). The reaction solution was cooled to +2° C. and treated with dimethoxyphosphoryl chloride (20 mL, 183 mmol, 1.10 equiv) over 40 minutes while maintaining an internal temperature >+8° C. The reaction mixture was stirred with ice bath cooling for 1 hour at which point the reaction was complete by TLC analysis (silica gel, 93:6:1 DCM/MeOH/NH4OH and 6/3/1 CHCl3/MeOH/NH4OH; KMnO4 stain). Additional triethylamine (25.5 mL, 182.5 mmol, 1.10 equiv) was added to the reaction mixture and methanesulfonyl chloride (14.9 mL, 191 mol, 1.15 equiv) was added drop-wise over 45 minutes while maintaining an internal temperature <+10° C. The resulting reaction mixture was stirred with ice bath cooling for 1.0 hour after which time TLC analysis indicated the reaction was complete. Potassium hydroxide solution (3 M, 220 mL, 650 mmol, 4.0 equiv) was slowly added to the stirred reaction mixture while maintaining an internal temperature <+16° C. The reaction was continued with agitation for 6 hours, after which time the aqueous layer was separated and discarded. Saturated NaHCO3 solution (35 mL) was added and the biphasic mixture heated to 40-42° C. Distillation was started and a first fraction of 90 mL of dichloromethane was collected. When the temperature reached 50° C., a second fraction was collected until the batch temperature was 65° C. The mixture was heated at 65° C. for another 1 hour and then cooled to ambient temperature. Dichloromethane (90 mL) was added and the mixture stirred for 10 minutes before separation. The dichloromethane layer was concentrated under reduced pressure. The residue was dissolved in heptanes (15 mL) and concentrated under reduced pressure to remove the residual water. This azeotropic drying was repeated two more times. The resulting 4a was obtained as a light yellow liquid (20.9 g, 76% yield, 95.40% GC purity). A colorless sample was prepared by short path distillation (80-85° C.@15 mm Hg vacuum). Optical rotation c=1.00, ethanol, 25.0° C., +39.3°. 1H NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 3.76 (s, 3H), 2.65-2.50 (m, 1H), 2.42-2.31 (m, 1H), 1.92 (dt, J=3.6, 1.2 Hz, 1H), 1.28 (dd, J=5.4, 1.2 Hz, 3H).
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:38][OH:39].C[O-].[Na+]>C(O)(=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:39][CH3:38])[N:21]=1
Reactant: CO
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 98 %

Procedure:
To a 250 mL dry round-bottomed flask was charged (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (12, 7.50 g, 14.26 mmol). Anhydrous methanol (30 mL) was added and a white suspension was formed. At 50° C., a solution of sodium methoxide in methanol (25%, 19.7 mL, 64.17 mmol) was added via a dry syringe under a nitrogen atmosphere. A white cloudy reaction mixture was formed. After 3.5 h at 50° C., the reaction was complete with no starting material left as shown by TLC test. The mixture was cooled down to room temperature and neutralized by addition of glacial acetic acid (3 mL). A white solid was filtered out and washed with methanol (3×5 mL). The filtrate was mixed with 20 g of silica gel and concentrated to dryness. The mixture was loaded in line with a silica gel cartridge and separated via column chromatography using a gradient of methanol in dichloromethane 0 to 15% MeOH. The product eluted out at 12% methanol in dichloromethane. The product containing fractions were combined, concentrated under reduced pressure and dried under vacuum (0.2 mmHg, 50° C., 24 h) to a white powder solid (4.45 g, 98% yield), mp 199-202° C.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C=CC([CH:15]2[NH:19][C:18]([C:20]3[CH:25]=[CH:24]C(OC)=CC=3OCC)=NC2C)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:51][CH2:50]N(C)[CH2:48][CH2:47]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH2:64]C2CCCC2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:47][CH2:48][CH:15]([N:19]4[CH2:18][CH2:20][CH2:25][CH2:24]4)[CH2:50][CH2:51]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH3:64])=[CH:37][CH:38]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-1H-imidazole, trifluoroacetate salt (Example 17) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 525.2635, calculated for C29H38N4O3Cl [(M+H)+]525.2627.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[CH:4]([C:19](=[O:22])[CH2:20][CH3:21])[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)CC(=O)OC
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)C(C(=O)CC)C(=O)OC
Temperature: 2 °C
Yield: 104.4 %

Procedure:
5.21 g=5.02 ml (39.2 mmol) of 3-oxo-pentanoic acid methyl ester were dissolved in 30 ml of CH2Cl2, the solution was cooled to 2° C. and 3.81 g (39.2 mmol) of anhydrous magnesium chloride were added in small portions. Then, 6.21 g=6.34 ml (78.4 mmol) of pyridine were added to this suspension between 2° C. and 5° C., followed by 3.89 g=3.67 ml (41.2 mmol) of propionyl chloride. The reaction mixture was warmed up to RT and 1 hour later poured into crashed ice, acidified with HCl (25%) to pH 1-2 and extracted twice with Et2O. The organic phases were dried over magnesium sulfate, filtered and evaporated to give 7.62 g of title compound as light yellow oil. MS: 185.1 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:30])=[C:15]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:36]4[CH:35]=[N:34][C:33]([O:32][CH3:31])=[N:38][CH:37]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])[C:14]=1[F:30])(=[O:22])=[O:21]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(c1cccc(NS(=O)(=O)c2ccccc2F)c1F)c1c[nH]c2ncc(Br)cc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ncc(-c2cnc3[nH]cc(C(=O)c4cccc(NS(=O)(=O)c5ccccc5F)c4F)c3c2)cn1
Temperature: 160 °C
Yield: 25.5 %

Procedure:
In a microwave vial, N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fluoro-benzenesulfonamide (21, 100 mg, 0.203 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (22, 72 mg, 0.305 mmol) and tetrakis-(triphenylphosphine) palladium(0) (10 mg) are combined with potassium carbonate (0.609 mL, 1M aqueous, 0.609 mmol) and 0.6 mL of acetonitrile. The reaction mixture is heated in a microwave at 160° C. for 15 minutes. The mixture is filtered through celite, and the celite is washed with water and ethyl acetate. The aqueous layer is separated from the filtrate and extracted with ethyl acetate. The organic portions are combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1518, 27 mg). MS (ESI) [M+H+]+=521.95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:19][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: CN(C[C@H](c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C[C@@H](N)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 89.3 %

Procedure:
To a solution of (S)-tert-butyl (2-(3-chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate (1.96 g, 4.72 mmol) in ethanol (15.75 mL) was added hydrazine hydrate (2.296 mL, 47.2 mmol). The reaction mixture was heated at 60° C. for 2 h. The reaction mixture was then filtered through Celite pad and the filtrate was concentrated. The residue was re-dissolved in ethanol and filtered through Celite® pad to remove extra white solid. NMR showed there was impurity in crude material. The crude product was filtered through a plug of silica, washed by DCM/EtOAc (2:1 ratio) and flashed with DCM/EtOAc (20% methanol, 0.5% NH3 in methanol) (1:1 ratio) to provide (s)-tert-butyl (2-amino-2-(3-chlorophenyl)ethyl)(methyl)carbamate (1.2 g, 89% yield). LCMS (m/z): 285.1 (MH+), 0.65 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (s, 1H) 7.26 (3H), 4.20 (br. s., 1H), 2.85-2.77 (m, 3H), 1.51-1.38 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1.N1C=CC=CC=1.[S-:28][C:29]#[N:30].[K+].BrBr>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[C:10]([S:28][C:29]#[N:30])=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2cccc(Cl)c2)n1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc(O)c1SC#N
Temperature: 0 °C

Procedure:
The product of Example 3 (0.5 g), pyridine (0.21 ml) and potassium thiocyanate (0.6 g) were dissolved in DMF (10 ml) and cooled to 0° C. Bromine (74 μl) was added before the cooling bath was removed and the reaction mixture allowed to warm to room temperature. After 1 h water (50 ml) was added and the mixture extracted with EtOAc (3×30 ml). The combined extracts were dried (MgSO4), filtered, evaporated and purified by silica gel chromatography (10% methanol/DCM) to yield the title product as a white solid. Yield 0.3 g.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[CH2:31]([C:34]1[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=1[O:36][CH2:37][C@@H:38]1[CH2:40][O:39]1)[CH:32]=[CH2:33]>>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:40][C@H:38]([OH:39])[CH2:37][O:36][C:35]3[CH:41]=[CH:42][CH:43]=[CH:44][C:34]=3[CH2:31][CH:32]=[CH2:33])=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: C=CCc1ccccc1OC[C@@H]1CO1
Solvent: O=CO
Product: C=CCc1ccccc1OC[C@@H](O)CNCCc1ccc(NC2CCN(C(=O)NCCCCCCCC)CC2)cc1
Yield: 14 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.40 g, 0.95 mmol) was reacted with (2S)-2-[(2-allylphenoxy)methyl]oxirane (0.125 g, 0.713 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.060 g, 0.1 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:10]2[N:11](COC)[CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.C(OCN1C=CN=C1C(C1C=CC(Cl)=CC=1)(C1C=CC=CC=1)O)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: COCn1ccnc1C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: OC(c1ccccc1)(c1ccc(Cl)cc1)c1nccn1COCc1ccccc1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1ncc[nH]1

Procedure:
Using the procedure described in Example VIC but substituting an equivalent amount of α,α-bis(p-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol for the 1-[(benzyloxy)-methyl]-α-(p-chlorophenyl)-α-phenylimidazole-2-methanol, α,α-bis(p-fluorophenyl)imidazole-2-methanol was obtained. Melting point 198°-200° C.