Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:25]([O:27]C)=[O:26])=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[Li+].[OH-].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:25]([OH:27])=[O:26])=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2cc(-c3ccccc3)c(-c3ccc(OC)cc3)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc3cc(C(=O)O)ccc3cc2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 58.8 %

Procedure:
Methyl 2-(4-methoxyphenyl)-3-phenylquinoline-7-carboxylate (40 mg, 0.11 mmol, 1.00 equiv), LiOH (13 mg, 0.54 mmol, 5.00 equiv), methanol (5 mL), and water (0.5 mL) were placed in a 50-mL round-bottom flask and stirred for 5 hr at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 10 mL of H2O, and the pH adjusted to 4-5 with 1N HCl. The resulting solids were collected by filtration and dried in an oven under reduced pressure, yielding 23 mg (59%) of 2-(4-methoxyphenyl)-3-phenylquinoline-7-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Cl.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.[CH2:38]=O.[OH-].[Na+]>C(#N)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:10][C:11]([CH2:38][N:33]3[CH2:34][CH2:35][N:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:36])[F:37])[CH:25]=4)[CH2:31][CH2:32]3)=[C:12]2[CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1
Reactant: C=O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1c(CN2CCN(c3cccc(C(F)(F)F)c3)CC2)cc(-c2ccc(Cl)cc2)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 64.3 %

Procedure:
To a stirred solution of 1,2-bis(4-chlorophenyl)-5-methylpyrrole (1.76 g, 0.006 mol, as obtained in Step-2) in acetonitrile (18 ml) was added a mixture of 1-(3-trifluoromethylphenyl) piperazine hydrochloride (1.55 g, 0.006 mol), 40% formaldehyde (0.45 ml, 0.006 mol) and acetic acid (5.23 ml) drop-wise. After the completion of addition, the reaction mixture was stirred at room temperature for 3-4 hours. The reaction mixture was neutralized with NaOH (20% aq. soln.) and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate extract was washed with water (2×50 ml), brine (1×30 ml), dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained was purified by column chromatography over silica gel using ethyl acetate hexane (80:10) as eluent to give 2.1 g (66.24%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:38])[C@@H:11]([N:17]1[C:21](=[O:22])[C@@H:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32]C(C)(C)C)=[CH:25][CH:24]=2)[NH:19][C:18]1=[O:37])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C[Si](I)(C)C.CO>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:38])[C@@H:11]([N:17]1[C:21](=[O:22])[C@@H:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][CH:28]=2)[NH:19][C:18]1=[O:37])[CH2:12][C:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OCCOC(C)(C)C)cc2)C1=O
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OCCO)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (S)-2-{(R)-4-[4-(2-tert-butoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide (295 mg, 0.46 mmol) in dichloromethane (3 mL) at 0° C. under an atmosphere of dry argon was slowly added a solution of trimethylsilyl iodide (183 uL, 1.3 mmol) in dichloromethane (1 mL). The reaction mixture stirred at ambient temperature for 2 hours. Methanol (0.5 mL) was added to quench the reaction. The reaction mixture extracted with dichloromethane and the organic layer was washed sequentially with saturated aqueous sodium carbonate, 5% aqueous sodium thiosulfate, brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 100% hexane up to 50% ethyl acetate/50% hexane over 30 minutes. Concentration of the product containing fractions gave (S)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide as a white solid (126 mg, 47%).
Reaction SMILES: [C:1]1([C:7]([C:48]2[CH:53]=[CH:52][C:51]([N:54]([CH3:56])[CH3:55])=[CH:50][CH:49]=2)([PH2:46]=O)[C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[C:28]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[PH2:29]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCCC)CCCC)CCC.C1([SiH](Cl)Cl)C=CC=CC=1.[OH-].[Na+]>>[C:1]1([C:7]([C:48]2[CH:49]=[CH:50][C:51]([N:54]([CH3:56])[CH3:55])=[CH:52][CH:53]=2)([PH2:46])[C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[C:28]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[PH2:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)c1ccc(C([PH2]=O)(c2ccccc2)c2ccc3ccccc3c2-c2c(C([PH2]=O)(c3ccccc3)c3ccc(N(C)C)cc3)ccc3ccccc23)cc1
Agent: Cl[SiH](Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: CN(C)c1ccc(C(P)(c2ccccc2)c2ccc3ccccc3c2-c2c(C(P)(c3ccccc3)c3ccc(N(C)C)cc3)ccc3ccccc23)cc1
Temperature: 145 °C
Yield: 75 %

Procedure:
19.87 g (25.8 mmol) of 2,2'-bis(phenyl4-dimethylaminophenyl-phosphinylmethyl)-1,1'-binaphthyl and 15.5 ml (66 mmol) of tributylamine are initially charged in 80 ml of degassed, dry o-xylene in an argon atmosphere while stirring and 9.4 ml (65 mmol) of phenyldichlorosilane are added dropwise. The mixture is subsequently heated at 145° C. for 7 hours while stirring. The reaction mixture is cooled, admixed with 50 ml of degassed 32% strength sodium hydroxide solution and the phases are separated. The organic phase is concentrated and the solid formed is filtered off and recrystallized from acetonitrile. This gives 14.3 g of colorless crystals, corresponding to a yield of 75%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=C(Cl)C=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.C(O)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=2[N:32]2[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)C1CCN(c2c(N)cncc2F)CC1
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Temperature: 95 °C
Yield: 77.9 %

Procedure:
6-chloro-1H-benzo[d][1,2,3]triazol-1-yl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (45 g, 129.4 mmol) and tert-butyl 1-(3-amino-5-fluoropyridin-4-yl)piperidine-4-carboxylate 27 (40.1 g, 135.9 mmol) were slurried in pyridine (675 ml). The mixture was heated at 95° C. under nitrogen until the reaction was complete (determined by HPLC analysis). The mixture was cooled and ethanol (450 ml) was added dropwise. The mixture was filtered and the filter cake washed with ethanol (2×70 ml). The damp cake was dried to give the product 28 as a yellow crystalline solid (47.7 g, 78%); 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.58 (s, 1H), 9.51 (dd, 1H), 8.72 (dd, 1H), 8.25 (d, 1H), 6.81 (s, 2H), 3.15-2.93 (m, 4H), 2.55-2.47 (masked signal, 1H), 2.02-1.91 (m, 4H), 1.47 (s, 9H); 19F NMR (500 MHz, DMSO-d6) δ −153.5, −136.3; MS (ES+) 474.2.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[N:27]([CH2:30][CH:31]=[CH2:32])=C=S>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:27][CH2:30][CH:31]=[CH2:32])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCN=C=S
Solvent: CC#N
Product: C=CCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.50 g, 1.31 mmol) in CH3CN, was added neat 3-isothiocyanatoprop-1-ene (0.155 g, 1.2 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of 1:1 EtOAc and hexanes, providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-allylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.410 g, 81% yield) 1H NMR (500 MHz, CDCl3) δ 1.98 (s, 3H), 2.00 (s, 3H), 2.03 (s, 3H), 2.05 (s, 3H), 3.81-3.83 (m, 1H), 4.02-4.08 (m, 3H), 4.21 (dd, 1H, J=4.6, 12.5 Hz), 5.06-5.15 (m, 3H), 5.20-5.30 (m, 2H), 5.72 (d, 1H, J=8.6 Hz), 5.75-5.8 (s, 1H), 6.42-6.52 (m, 2H).
Reaction SMILES: C(O)(=O)C.[Cl-:5].[Li+].[S:7](=[O:9])=[O:8].F[B-](F)(F)F.[N+](=[C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)=[N-]>O1CCOCC1.C(#N)C.[Cu]Cl>[Cl:5][S:7]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][C:18]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:9])=[O:8]
Reactant: [N-]=[N+]=C1C=CC(C(N)=O)=CC1OCCc1cccc2ccccc12
Reactant: O=S=O
Reactant: [Cl-]
Agent: Cl[Cu]
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: C1COCCO1
Product: NC(=O)c1ccc(S(=O)(=O)Cl)c(OCCc2cccc3ccccc23)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of acetic acid (8 mL) and dioxane (8 mL) at 0° C. was added lithium chloride (0.36 g, 8.46 mmol) and copper (I) chloride (0.042 g, 0.42 mmol). Sulfur dioxide (40 mL) was then condensed into this mixture by means of a cold finger at −78° C. A solution of 4-diazo-3-(2-naphthalen-1-yl-ethoxy)-benzamide fluoroborate in dioxane (20 mL) and acetonitrile (5 mL) was added in one portion to the sulfur dioxide mixture. The reaction was stirred at 0° C. for 3 hours and then heated to 65° C. overnight. The reaction was then cooled to room temperature and poured onto ethyl acetate (500 mL) and washed with water (50 mL), 1N sodium hydroxide (50 mL), saturated sodium bicarbonate (50 mL), and saturated sodium chloride (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 4-(chlorosulfonyl)-3-(2-naphthalen-1-yl-ethoxy)-benzamide as an orange oil. 1HNMR(300 MHz, CDCl3) 8.00 (d, 1H), 7.87 (d, 1H), 7.78 (d, 1H), 7.68 (d, 1H), 7.57 (s, 1H), 7.40 (m, 4H), 6.21 (bs, 1H), 4.49 (t, 2H), 3.64 (t, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:32](OCC)(=[O:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34].[Cl-].[NH4+]>O1CCCC1>[CH2:36]([O:35][C:33](=[O:34])[C:32]([C:15]1[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:38])[CH3:37]
Reactant: CC(C)(C)C(=O)Nc1cccc(N2CCN(Cc3ccccc3)CC2)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(NC(=O)C(C)(C)C)cccc1N1CCN(Cc2ccccc2)CC1
Temperature: 15 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
Under a nitrogen atmosphere, a solution of N-[3-(4-benzyl-piperazin-1-yl)-phenyl]-2,2-dimethyl-propionamide (2.4 g, 6.8 mmol) and N,N,N′N′-tetramethylethylenediamine (3.2 g, 27.4 mmol) in tetrahydrofuran (24 mL) was stirred for 15 minutes at 0° C., n-butyllithium (2.5M in hexane) (11 mL, 27.5 mmol) was added dropwise, and the mixture stirred for 3 hours at 15° C. The mixture was then cooled to −78° C., and diethyl oxalate (4.0 g, 27.4 mmol) was added. The mixture was stirred at −20° C. for 30 minutes, poured into a saturated aqueous solution of ammonium chloride (50 mL), and the product extracted into ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to yield 4.5 g of crude product as a light brown oil. Purification by chromatography (150 g silica gel, 2% methanol in chloroform) afforded the title compound (1.5 g, 3.3 mmol, 49% yield) as a straw colored oil; this compound was confirmed by the following mass spectrometry results: EI M+ @ m/z 451 and (+)FAB [M+H]+ @ m/z 452, [M+Na]+ @ m/z 474.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C2CN(Cc3ccccc3)CCO2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C2CNCCO2)c1
Yield: 56.1 %

Procedure:
In a 250 mL round-bottomed flask, 4-benzyl-2-(3-methoxyphenyl)morpholine (2.3 g, 8.12 mmol) and palladium hydroxide on carbon (285 mg, 406 μmol) were combined in methanol (15 ml). The suspension was stirred at room temperature under a balloon of hydrogen overnight. The system was evacuated with argon 3 times. The reaction mixture was filtered through Celite, and the filtercake washed several times with methanol. The combined filtrate and washes were concentrated in vacuo to afford 2-(3-methoxy-phenyl)-morpholine (0.88 g, 56%) which was directly used for next step. (M+H)+=194 m/e.
Reaction SMILES: [C:1]1([CH:7]2[S:12](=[O:14])(=[O:13])[NH:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([F:24])[CH:17]=1.[H-].[Na+].O>CN(C)C(=O)C.CCOC(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:11]2[CH2:10][CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:12]2(=[O:14])=[O:13])=[C:18]([F:24])[CH:17]=1
Reactant: O=S1(=O)NCCCC1c1ccccc1
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=S1(=O)C(c2ccccc2)CCCN1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 6-phenyl-1,2-thiazinane 1,1-dioxide (300 mg, 1.42 mmol) and 4-bromo-1-(bromomethyl)-2-fluorobenzene (456 mg, 1.7 mmol) in N,N-dimethylacetamide (5 mL) at 0° C. was added sodium hydride (60% in mineral oil) (68 mg, 1.85 mmol) and the reaction was stirred at room temperature for 2 hours. Water was added and the reaction was diluted with EtOAc, washed with brine, dried with MgSO4, filtered and purified by silica gel column chromatography (0-60% EtOAc/heptane) to give 2-(4-bromo-2-fluorobenzyl)-6-phenyl-1,2-thiazinane 1,1-dioxide (396 mg, 70% yield). LCMS (ESI), m/z, 398 [M+H]+.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[CH:3][CH:2]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=4)=[N:11][C:10]=13)=[O:18])[CH2:24]2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.7 %

Procedure:
A mixture of 2-p-tolylbenzoxazole-4-carboxylic acid (62 mg, 0.24 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (66 mg, 0.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg, 0.49 mmol) and 1-hydroxybenzotriazole (66 mg, 0.49 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (0.16 mL, 0.98 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-p-tolylbenzoxazole-4-carboxamide (25 mg, 27%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.10 (d, J=7.0 Hz, 1H), 8.20 (dd, J=7.5, 0.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 2H), 7.68 (dd, J=8.0, 1.0 Hz, 1H), 7.45 (t, J=7.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 4.64-4.55 (m, 1H), 3.17-3.11 (m, 2H), 2.70-2.60 (m, 2H) 2.56 (s, 3H), 2.48 (s, 3H), 2.08-1.98 (m, 2H), 1.75-1.50 (m, 3H), 1.25-1.17 (m, 3H); MS (ESI+) m/z 390 (M+H); HPLC>99% (AUC), tR=13.37 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:35][C@@H:34]4[C@@H:30]([CH2:31][NH:32][CH2:33]4)[CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][CH3:48]>C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][C@@H:30]4[C@@H:34]([CH2:33][N:32]([CH2:47][CH3:48])[CH2:31]4)[CH2:35]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CCBr
Reactant: O=C(Nc1cn(CC(=O)N2C[C@H]3CNC[C@H]3C2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1C[C@@H]2CN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)C[C@@H]2C1
Product: Cl
Temperature: 50 °C

Procedure:
To a solution of cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide (100 mg, 0.18 mmol) in acetonitrile (4 mL) was added potassium carbonate (37 mg, 0.27 mmol) and bromoethane (20 μL, 0.27 mmol). The reaction was heated at 50° C. for 2 hours and then allowed to cool to room temperature. The mixture was applied directly to an SCX-2 cartridge. Elution with 2M ammonia in MeOH gave the desired product. The product was purified by HPLC (Method 1) and the pure fractions were combined as passed through an SCX-2 cartridge. Elution with 2M ammonia in MeOH gave the free base on evaporation of the solvent. The solid was dissolved in 1.25M methanolic HCl and then the volatiles were evaporated. The HCl salt was crystallised from MeOH/Et2O and obtained as a white solid (32 mg, 40%). LCMS (Method 5) [M+H]+=585.0, RT=2.88 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.44 (d, 1H, J=35.0 Hz), 9.79-9.74 (m, 1H), 9.35 (dd, 1H, J=1.3, 7.0 Hz), 8.69 (dd, 1H, J=1.5, 4.2 Hz), 8.67 (s, 1H), 8.31 (d, 1H, J=3.8 Hz), 7.64 (dd, 1H, J=2.5, 8.8 Hz), 7.57 (d, 1H, J=2.6 Hz), 7.47 (d, 1H, J=8.9 Hz), 7.30 (dd, 1H, J=4.3, 7.0 Hz), 7.27 (t, 1H, J=73.6 Hz), 5.22-5.10 (m, 2H), 3.43 (s, 12H), 3.84-2.77 (m, 12H), 1.29-1.19 (m, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=4)[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:3][CH2:2]1.C1C(=O)N([Br:34])C(=O)C1.CCOC(C)=O>C(Cl)Cl>[Br:34][C:7]1[C:8]2[CH:9]=[N:10][C:11]([NH:14][C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:25])([CH3:23])[CH3:24])=[CH:20][CH:21]=3)=[CH:12][C:13]=2[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:6]=1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc3c(ccn3CC3CC3)cn2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3CC2CC2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To an ice-cooled solution of N-(1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide (Example 9, 75 mg, 0.215 mmol) in DCM (4 ml) was added NBS (38.2 mg, 0.215 mmol). The reaction mixture was stirred at 50° C. for 1 h, and then subjected to chromatography (NH—SiO2, EtOAc). The fractions were concentrated in vacuo and purified by preparatory HPLC to give the title compound N-(3-bromo-1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide (60 mg, 0.14 mmol, 65% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.40-0.48 (m, 2 H) 0.52-0.59 (m, 2 H) 1.20-1.32 (m, 1 H) 1.46 (s, 6 H) 4.05 (d, J=7.07 Hz, 2 H) 5.17 (s, 1 H) 7.59 (d, J=8.59 Hz, 2 H) 7.74 (s, 1 H) 8.02 (d, J=8.59 Hz, 2 H) 8.40 (s, 1 H) 8.51 (s, 1 H) 10.69 (s, 1 H); m.p. 193-194° C.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Si:14]([CH3:17])([CH3:16])[CH3:15].C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1>[F:6][C:7]1[C:12]([F:13])=[C:11]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:10]=[CH:9][C:8]=1[Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)c1cccc(F)c1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc([Si](C)(C)C)c(F)c2F)OC1(C)C
Temperature: -75 °C
Yield: 60.1 %

Procedure:
A solution of sec-butyllithium (1.4 M in cyclohexane; 19.17 mL, 26.8 mmol) was added to THF (53.7 mL) cooled to −75° C. To this solution was added (2,3-difluorophenyl)-trimethylsilane (prepared as in Heiss, C. et al. Eur. J. Org. Chem. 2007, 4, 669-675; 5.0 g, 26.8 mmol) dropwise keeping the temperature below −70° C. The resulting reaction mixture was stirred at −75° C. for 45 min after which time 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.49 g, 29.5 mmol) was added dropwise keeping the temperature below −70° C. The reaction mixture was then allowed to warm to 25° C. and was partitioned between Et2O and H2O. The aqueous phase was acidified to pH 3 with 12 Normal (N) HCl. The product was extracted with Et2O, and the organic phase was dried and concentrated under vacuum to provide the title compound as a white solid (5.03 g, 60%): 1H NMR (300 MHz, CDCl3) δ 7.42 (ddd, J=7.3, 4.4, 0.7 Hz, 1H), 7.09 (ddd, J=7.3, 4.1, 0.9 Hz, 1H), 1.36 (s, 12H), 0.32 (d, J=0.9 Hz, 9H); EIMS m/z 312.