Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9](=[O:15])[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:20][N:21]([CH3:23])[CH3:22])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: CS(=O)(=O)CC(=O)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1cccc(C(F)(F)F)c1)S(C)(=O)=O
Yield: 99.4 %

Procedure:
2.5 g of m-trifluoromethyl-α-methanesulfonylacetophenone and 1.4 g of N,N-dimethylformamide dimethylacetal were dissolved in 40 ml of toluene, and the resulting mixture was heated under reflux for 2 hours. The solvent was distilled away under reduced pressure. The residue was treated with column chromatography on silica gel, thereby obtaining 3 g of 1-(3-trifluoromethylbenzoyl)-1-methanesulfonyl-2-(N,N-dimethylamino)ethene (Compound 205).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 300 mg, 0.84 mmol) and triphenylphosphine (288 mg, 1.09 mmol) in methylene chloride (6.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (192 mg, 1.09 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyridine (220 mg, 1.68 mmol) and 2,6-lutidine (0.42 mL, 3.36 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL) and water (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (265 mg, 67%) as a white foam: [α]23589=−35.71° (c=0.35, chloroform); EI-HRMS m/e calcd for C21H22Cl2N2O4S (M+H)+ 469.0750, found 469.0754.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH3:40])=[N:6][C:7]=2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl>O1CCOCC1>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH3:40])=[N:6][C:7]=2[N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidine-1-carboxylate (0.36 g, 0.66 mmol) in 1,4-dioxane (10 mL) was added a 4M solution of hydrogen chloride in 1,4-dioxane. The reaction mixture was then stirred at room temperature for 1 hour. The resulting suspension was then filtered. The collected solid was washed 1,4-dioxane and dried under vacuum to give 520 (hydrochloride salt) as an off-white solid (0.34 g, quant.). LCMS m/z: 484.2 (MH+)
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23]([C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)c1ccc(-c2csc(Cl)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a solution of 5.0 g (19.0 mmole) of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole and 57 mL of tetrahydrofuran at −78 degrees, was added, over 10 minutes, 9.5 mL of 2.5 M n-butyl lithium in hexanes solution. After 30 minutes, 1.1 mL of 2.5 M n-butyl lithium in hexanes solution was added The mixture was stirred for 2 hours and then 10.63 mL (107.8 mmole) of ethyl chloroformate was added quickly to a rapidly stirring solution. After 15 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 22 minutes. The reaction was quenched by the addition of 75 mL of 1M hydrochloric acid, stirred for 5 minutes and then diluted with 500 mL of ethyl acetate. The ethyl acetate layer was washed twice with 75 mL of water, once with 75 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting dichloromethane-hexanes (gradient 10:90-50:50) to give 4.94 g of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][C:21]3[N:25]([CH3:26])[C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=4)=[N:23][N:22]=3)=[CH:16][C:15]=2[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:25]([CH3:26])[C:21]([S:20][C:17]3[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:45])=[O:3])=[CH:7][CH:8]=4)=[C:15]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:16]=3)=[N:22][N:23]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(=O)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCOc1cc(Sc2nnc(-c3ccc(C(C)(C)C)cc3)n2C)ccc1CNc1ccc(CC(=O)O)cc1

Procedure:
A solution of ethyl(4-{4-[5-(4-tert-butylphenyl)-4-methyl-4H-[1,2,4]-triazol-3-yl sulfanyl]-2-heptyloxybenzylamino}phenyl)acetate obtained in Example 1 (2.5 g, 4 mmol) of a 2M aqueous potassium carbonate solution (32 ml) in methanol (65 ml) is heated under reflux for 3 hours. The organic phase is acidified at room temperature with a 2N hydrochloric acid solution to pH 5. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator. The product is purified by chromatography on a silica column, eluted with a heptane/ethyl acetate 4:6 mixture. After evaporation of the solvents, 1.7 g (70%) of the expected compound are recovered in the form of a yellow amorphous solid.
Reaction SMILES: CC1(C)CCC(N2C(=O)C3C(=CC=CC=3)C2=O)C=C1.BrN1C(=O)CCC1=O.Br[C@@H]1[C@@H](O)C(C)(C)CC[C@H]1N1C(=O)C2C(=CC=CC=2)C1=O.Br[C@H]1[C@H](O)C(C)(C)CC[C@@H]1N1C(=O)C2C(=CC=CC=2)C1=O.[Br:70][C@@H:71]1[C:76]([CH3:78])([CH3:77])[CH2:75][CH2:74][C@@H:73]([N:79]2[C:87](=[O:88])[C:86]3[C:81](=[CH:82][CH:83]=[CH:84][CH:85]=3)[C:80]2=[O:89])[C@H:72]1[OH:90]>C(Cl)(Cl)Cl.C(O)C>[Br:70][C@H:71]1[C:76]([CH3:78])([CH3:77])[CH2:75][CH2:74][C@H:73]([N:79]2[C:87](=[O:88])[C:86]3[C:81](=[CH:82][CH:83]=[CH:84][CH:85]=3)[C:80]2=[O:89])[C@@H:72]1[OH:90]
Reactant: CC1(C)CC[C@@H](N2C(=O)c3ccccc3C2=O)[C@@H](O)[C@@H]1Br
Agent: CC1(C)C=CC(N2C(=O)c3ccccc3C2=O)CC1
Agent: CC1(C)CC[C@@H](N2C(=O)c3ccccc3C2=O)[C@H](Br)[C@H]1O
Agent: CC1(C)CC[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](Br)[C@@H]1O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC1(C)CC[C@H](N2C(=O)c3ccccc3C2=O)[C@H](O)[C@H]1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of 2-(4,4-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (11.59 g, 45.4 mmol) in chloroform (110 mL) and ethanol (3.83 mL) was added N-bromosuccinimide (10.34 g, 58.1 mmol) as a solid over a few min at ambient temperature. After addition was complete, the reaction mixture was stirred at ambient temperature overnight under nitrogen. The reaction mixture was washed with 1 M aqueous solution of sodium thiosulfate (100 mL). The aqueous layer was extracted with chloroform (100 mL) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. To this oil was added 150 mL THF (150 mL) and a 1N aqueous solution of hydrochloric acid (30 mL). The resulting mixture was stirred at ambient temperature for 2 h. The THF was removed under reduced pressure and the remaining aqueous layer was diluted with ethyl acetate (150 mL) and 75 mL of a 1:1 water:saturated aqueous sodium bicarbonate solution mixture. The layers were separated and the aqueous was back-extracted aqueous with ethyl acetate (75 mL). The combined ethyl acetate layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that was purified by silica gel chromatography (0-25% ethyl acetate/hexane) to afford a mixture of 2-((1R,2S,3S)-2-bromo-3-hydroxy-4,4-dimethylcyclohexyl)isoindoline-1,3-dione, 2-((1S,2R,3R)-2-bromo-3-hydroxy-4,4-dimethylcyclohexyl)isoindoline-1,3-dione, 2-((1R,2R,3R)-3-bromo-2-hydroxy-4,4-dimethylcyclohexyl)isoindoline-1,3-dione, and 2-((1S,2S,3S)-3-bromo-2-hydroxy-4,4-dimethylcyclohexyl)isoindoline-1,3-dione (11.4 g, 32.4 mmol, 71.3% yield). MS (ESI) m/z 374.5 [M+1]+ and 376.5 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C(O)C>[CH3:41][C:5]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:11][CH:12]=1)[C:4]([OH:42])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3cccc(C(F)(F)F)c3)C(=O)N2C)cc1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2cccc(C(F)(F)F)c2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.3 %

Procedure:
To a solution of the esters obtained from Step A (270 mg) in absolute ethanol (4.5 ml) is added 5N NaOH (1.9 ml, 9.5 mmol), and the mixture stirred for 20 hours at ambient temperature. The mixture is poured into 1N HCl, then extracted with ethyl acetate (2×20 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified is purified by flash chromatography on a Biotage silica cartridge (gradient elution, 3:1 hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate to yield a foam (78 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:14]2[N:15]=[C:11]([C:10]3[C:2]([CH3:1])=[N:3][N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=34)[S:12][C:13]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccc(F)cc1
Yield: 67.7 %

Procedure:
Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (500 mg, 1.2 mmol) produced in Example 15-B(i), (4-fluorophenyl)boronic acid (480 mg, 3.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (75 mg, 0.091 mmol), cesium carbonate (700 mg, 2.2 mmol), water (2 mL) and 1,2-dimethoxyethane (30 mL) as starting materials and in the same manner as in Example 13-B(iii), the title compound (310 mg, 73%) was obtained as a brown solid.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:26][CH3:27])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C@@H:21]2[CH2:25][CH2:24][O:23][CH2:22]2)=[C:9]([NH2:28])[N:8]=1)[CH2:3][CH2:4][CH3:5].ClCCCCN1C(OC)=NC2C1=NC(O[C@@H](C)CCC)=NC=2N.O1CC[C@H](N)C1>>[CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:26][CH3:27])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C@H:21]2[CH2:25][CH2:24][O:23][CH2:22]2)=[C:9]([NH2:28])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCN[C@@H]3CCOC3)c2n1
Agent: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: N[C@H]1CCOC1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCN[C@H]3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 40 from 9-(4-chlorobutyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine and (3S)-tetrahydro-3-furanamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10]>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[C:9]([OH:12])(=[O:11])[CH3:10].[C:9]([OH:12])(=[O:11])[CH3:10].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1
Reactant: CC(=O)OC(C)=O
Agent: O=Cc1cccnc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)O

Procedure:
Pyridine-3-carboxaldehyde (5.45 g, 0.051 mol) was dissolved in an excess of acetic acid anhydride (10 ml) and 4 drops conc. sulfuric acid added under stirring. The resulting red mixture was allowed to react at 70-75° C. for 7 days. The cooled, black coloured reaction mixture was diluted with CHCl3, washed twice with 10% aqueous NaHCO3 and then several times with brine. The organic phase was dried (MgSO4) and evaporated. The black crude product was dissolved in CHCl3, and impurities precipitated as pentane was added. Precipitates were removed. The solution was evaporated and the residual product distilled (Kugelrohr) under reduced pressure (140° C./0.2 mbar) to give a colourless oil. 1H- and 13C NMR (CDCL3), d (ppm) rel. to TMS: 8.80, 8.68, 7.83 and 7.37 (m, 4×1H, Ar-H), 7.73 (s, 1H, CH(OAc)2) and 2.14 (s, 6H, CH3); 168.443 (C=O), 150.778, 148.154, 134.303, 131.172 and 123.253 (Ar), 87.988 (CH(OAc)2) and 20.587 (CH3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1Br.[Cl:17][C:18]1[CH:19]=[C:20]([C@H:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=2[F:39])=[O:29])[CH2:25][OH:26])[CH:21]=[CH:22][CH:23]=1>>[NH2:1][C:2]1[C:3]([C:33]2[CH:34]=[CH:35][C:30]([C:28]([NH:27][C@@H:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)[CH2:25][OH:26])=[O:29])=[C:31]([F:39])[CH:32]=2)=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: O=C(N[C@H](CO)c1cccc(Cl)c1)c1ccc(B(O)O)cc1F
Reactant: CN1CCC(c2cnc(N)c(Br)c2)CC1=O
Product: CN1CCC(c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)c2)CC1=O

Procedure:
Following Step 6 in Scheme 47, using (+/−)-4-(6-amino-5-bromopyridin-3-yl)-1-methylpiperidin-2-one and (S)-(4-((1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)boronic acid, 4-(2-amino-5-(1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained as a diastereomeric mixture (inseparable) (35%). LCMS (m/z): 497.3 (MH+), 0.59 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (m, 1H), 7.9 (m, 1H), 7.82 (m, 1H), 7.52-7.39 (m, 3H), 7.39-7.32 (m, 2H), 7.3 (m, 1H), 5.19 (m, 1H), 3.88 (m, 2H), 3.60-3.38 (m, 3H), 3.21-3.08 (m, 1H), 2.72-2.58 (m, 1H), 2.57-2.41 (m, 1H), 2.21-1.95 (m, 2H). The diastereomeric mixture was separated by chiral SFC (ChiralPak 5mic AD column, 4.6×100 (mm), 5 mL/min, EtOH+0.1%, DEA=45% in 5 min). The polar diastereomer, 4-(2-amino-5-((R)-1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained at Rt=1.82 min. The less polar diastereomer, 4-(2-amino-5-((S)-1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained at Rt=2.35 min. The absolute stereochemistry for both diastereomers was assigned arbitrarily.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].C(O)C.[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[C:25](=[O:48])[N:26]([CH:36]3[CH2:41][CH2:40][C:39](=[CH:42][C:43](OCC)=[O:44])[CH2:38][CH2:37]3)[C:27]3[N:28]([N:33]=[CH:34][N:35]=3)[C:29]=2[CH2:30][CH2:31][CH3:32])=[CH:19][CH:18]=1)#[N:10]>O1CCCC1>[OH:44][CH2:43][CH:42]=[C:39]1[CH2:40][CH2:41][CH:36]([N:26]2[C:25](=[O:48])[C:24]([CH2:23][C:20]3[CH:21]=[CH:22][C:17]([C:12]4[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:18][CH:19]=3)=[C:29]([CH2:30][CH2:31][CH3:32])[N:28]3[N:33]=[CH:34][N:35]=[C:27]23)[CH2:37][CH2:38]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=CC(=O)OCC)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=CCO)CC2)c2ncnn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
A mixture of calcium chloride (1.6 g), sodium borohydride (1.1 g), tetrahydrofuran (40 mL) and ethanol (40 mL) was stirred at 0° C. for 1 hr. A solution (20 mL) of ethyl (4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexylidene)acetate (1.9 g) in tetrahydrofuran was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was extracted with 1 N hydrochloric acid and ethyl acetate, and the obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.9 g, 49%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f15) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.Cl[C:22]1[N:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:22]4[N:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=4)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(Cn2nc(C)c3c(Oc4ncc([N+](=O)[O-])cn4)ccnc32)cc1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 30.2 %

Procedure:
A 100 mL flask was charged with 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1.00 g, 3.71 mmol obtained from Example 5, step B), 2-chloro-5-nitropyrimidine (0.592 g, 3.71 mmol), cesium carbonate (1.21 g, 3.71 mmol) and DMF (20 mL). The solution was allowed to stir overnight at room temperature for 16.5 hours. The crude product was isolated by filtration and flash chromatography (EtOAc/Hexane 1:2) to afford 0.44 g (29%) of the desired product. LRMS M+1 (393.0) observed.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11]O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[I-:24].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[I:24][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: [I-]
Reactant: OCC1CCC2(CC1)OCCO2
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Product: ICC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.60 g, 9.29 mmol) in methylene chloride (50 mL) was treated with 4-(dimethylamino)pyridine (1.26 g, 10.22 mmol) and p-toluenesulfonyl chloride (1.86 g, 9.75 mmol). The reaction mixture was stirred at 25° C. for 2 h, and was then washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in acetone (30 mL) and treated with sodium iodide (4.73 g, 31.53 mmol). The reaction was heated under reflux for 2 h, cooled to 25° C., and then concentrated in vacuo. The resulting residue was suspended in ethyl acetate (50 mL), washed with water (2×15 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 19/1 hexanes/ethyl acetate) afforded 8-iodomethyl-1,4-dioxa-spiro[4.5]decane (2.32 g, 88.6%) as a colorless oil.
Reaction SMILES: C1(S(O[CH:11]2[CH2:24][N:23]3[C:14](=[N:15][C:16]4[C:21]([C:22]3=[O:25])=[CH:20][CH:19]=[C:18]([Br:26])[CH:17]=4)[CH2:13][CH2:12]2)(=O)=O)C=CC=CC=1.[CH3:27][NH:28][CH3:29]>C(#N)C.O>[Br:26][C:18]1[CH:17]=[C:16]2[C:21]([C:22](=[O:25])[N:23]3[CH2:24][CH:11]([N:28]([CH3:29])[CH3:27])[CH2:12][CH2:13][C:14]3=[N:15]2)=[CH:20][CH:19]=1
Reactant: CNC
Reactant: O=c1c2ccc(Br)cc2nc2n1CC(OS(=O)(=O)c1ccccc1)CC2
Solvent: CC#N
Solvent: O
Product: CN(C)C1CCc2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-yl benzenesulfonate (0.15 g, 0.34 mmol, 1 equiv) and excess aq. dimethylamine in acetonitrile (6 mL) was stirred at 70° C. for 3 hours. After it was cooled to rt, the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.