Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu](I)I>[C:7]1([N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1c[nH]nn1
Reactant: Ic1ccccc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ccnn2)cc1
Temperature: 110 °C

Procedure:
1,2,3-Triazole (5 g), iodobenzene (9.72 ml) and copper iodide (0.68 g) was taken in dry DMF under Nitrogen atmosphere. 1,2-(N,N-dimethyl) cyclohexyl diamine (1.02 g) and potassium phosphate (30.73 g) was added into above mixture. The reaction mixture was reflux at 110° C. for over night. TLC was checked no starting material and the reaction mixture was filtered through celite. The filtrate was diluted with water and product was extracted with dichloromethane. The organic layer was evaporated and the crude product was purified by column chromatography using 60-120 silica gel and pet ether \ ethyl acetate as eluent to give 1-phenyl-1H-1,2,3-triazole as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[CH:44]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:42][C:43]2[CH:44]=[C:45]([CH3:49])[CH:46]=[CH:47][CH:48]=2)=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(Oc2ccnc(Br)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)c2cccc(Oc3ccnc(Br)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-(2-bromo-pyridin-4-yloxy)-benzoic acid (170 mg, 0.58 mmol), HATU (265 mg, 0.69 mmol), m-toluidine (93 mg, 0.87 mmol) and N,N-diisopropylethylamine (164 mg, 1.28 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 20 minutes. The mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 3-(2-Bromo-pyridin-4-yloxy)-N-m-tolyl-benzamide as off-white solid. Yield: 150 mg, 68%.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[C:13]([N:15]2[C:19]3[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[O:25][CH:26]2[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>ClCCl>[NH:28]1[CH2:27][CH:26]([O:25][C:16]2[N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[N:14]=3)[C:19]3[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:18]=3[N:17]=2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Nc1nccc(-n2c(OC3CNC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 1130 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise into a solution of tert-butyl 3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidine-1-carboxylate (250 mg, 0.49 mmol, 90%) in dichloromethane (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hr. Triethylamine was then added to adjust the pH of the solution to 8. The mixture was concentrated under vacuum to give 2 g (88%) of 4-[2-(azetidin-3-yloxy)-6-bromo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as dark red oil: LC-MS: m/z=+361 (M+H)+.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[CH2:9](O)[CH2:10][CH2:11][CH2:12][OH:13]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O:5][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH3:2]
Reactant: CCP(=O)(O)CCO
Reactant: OCCCCO
Solvent: Cc1ccccc1
Product: CCP(=O)(CCO)OCCCCO
Yield: 79.9 %

Procedure:
414 g (3.0 mol) of ethyl(2-hydroxyethyl)phosphinic acid (produced as in Example 7) are at 80° C. dissolved in 400 ml of toluene and admixed with 594 g (6.6 mol) of 1,4-butanediol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene is removed in vacuo to leave 504 g (80% of theory) of 4-hydroxybutyl ethyl-(2-hydroxyethyl)phosphinate as colorless oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4](=[O:6])[CH3:5].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4](=[O:6])[CH:5]=[CH:11][N:12]([CH3:14])[CH3:13]
Reactant: COC(OC)C(C)=O
Reactant: COC(OC)N(C)C
Product: COC(OC)C(=O)C=CN(C)C
Temperature: 100 °C
Yield: 99.4 %

Procedure:
1,1-Dimethoxypropan-2-one (57.9 g, 0.459 mol) was added to dimethyl formamide dimethyl acetal (54.6 g, 0.459 mol) and the mixture stirred and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool and the volatiles removed by evaporation give the itle compound (79 g) as a red oil. NMR: (CDCl3): 2.90 (d, 3H), 3.10 (d, 3H), 3.40 (s, 6H), 4.56 (s, 1H), 5.34 (1H, d), 7.74 (d, 1H).
Reaction SMILES: [Li].[Cl-].[Al+3].[Cl-].[Cl-].O[CH:7]([C:16]1[O:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.N>O1CCCC1>[CH3:21][C:18]1[O:17][C:16]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:14][CH:15]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(C(O)c2ccc(C=O)cc2)o1
Agent: N
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(Cc2ccc(CO)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.8 %

Procedure:
To a mixture of lithium aluminumhydride (230 mg, 4.9 mmol) and tetrahydrofuran (15 mL) was added aluminum chloride (830 mg, 6.2 mmol) at 0° C., which was stirred for 30 minutes at room temperature. A mixture of 4-(hydroxy-(5-methyl-furan-2-yl)-methyl)-benzaldehyde (320 mg, 1.5 mmol) described in Manufacturing Example 46-1-1 and tetrahydrofuran (5 mL) was added dropwise into the reaction mixture at 0° C., and stirred for 2 hours at that temperature. A 28% aqueous ammonia solution was added dropwise into the reaction mixture at the same temperature to quench the excess reagent. The reaction mixture was cooled to room temperature, and filtered by being passed through a Celite bed. The filtrate was concentrated under a reduced pressure to obtain the title compound (330 mg) as a crude product. This compound was used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1>CO.Cl.[Pd]>[NH2:21][CH2:20][C:16]1[CH:15]=[C:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:23][CH:22]=2)[CH:19]=[CH:18][N:17]=1
Reactant: N#Cc1cc(Cc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cc(Cc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.9 %

Procedure:
10% Degussa Pd on carbon (15 mg, 0.14 mmol) was flushed with nitrogen then diluted in methanol (1 mL). 4-[4-(2-amino-6-phenyl-pyrimidin-4-ylamino)-benzyl]-pyridine-2-carbonitrile (Example 35, 90 mg, 0.24 mmol) in methanol (2 mL) and concentrated HCl (0.03 mL) were subsequently added, and the mixture was flushed again with nitrogen prior to placing a hydrogen balloon on the flask. The mixture was stirred at rt for 3 h then filtered through Celite® and concentrated. The residue was purified by prep HPLC to give N4-[4-(2-aminomethyl-pyridin-4-ylmethyl)-phenyl]-6-phenyl-pyrimidine-2,4-diamine (10 mg, 11%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[NH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C1COCC1>[C:21]([N:4]1[C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[C:2]([Br:1])=[CH:3]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20]
Reactant: Brc1c[nH]c2ccncc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(Br)c2cnccc21
Yield: 122.4 %

Procedure:
Referring now to the Scheme 1 as shown in FIG. 1, a solution of 3.5601 g (18.06 mmol) of 3-bromo-5-azaindole (2) and 0.4651 g (3.8 mmol, 21 mol %) of dimethylaminopyridine (DMAP) in 80 mL of THF was placed in a 250 mL three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling ice bath. A total of 4.7769 g (21.88 mmol, 1.2 eq.) of BOC2O was added to the flask at 17° C., and the resulting mixture was stirred until starting 3-bromo-5-azaindole disappeared, as monitored by TLC (generally, overnight stirring at room temperature). The resulting yellow solution was concentrated on rotavap, washed with 100 mL of saturated sodium bicarbonate, and extracted with dichloromethane (3×80 mL). The organic phase was dried over Na2SO4 and concentrated on rotavap to afford 6.57 g of orange solid. This crude material was purified on CombiFlash using hexane/ethyl acetate as eluent to give 5.25 g (97% yield) of n-boc-3-bromo-5-azaindole (3) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:12][CH2:13][C:14](O)=O>Cl>[Cl:12][CH2:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Product: O=[N+]([O-])c1ccc2nc(CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3,4-diamino-nitrobenzene (15.3 g, 0.10 mole) and chloroacetic acid (14.18 μm, 1.5 eq) in 5.0 N aqueous HCl (80 mL) was heated at reflux for 1 hr. After cooling to RT, the reaction was filtered through celite and the filtrate was stored at 0° C. for 2 days. The crystals that formed, were collected and recrystallized from a mixture of EtOH and water to give 7.2 μm of the hydrogen chloride salt of 2-chloromethyl-5-nitro-benzimidazole. A portion of this salt (528 mg, 2.13 mmole) and morpholine (1.31 mL, 7 eq) in toluene (15 mL) were heated at reflux for 4 hr. After cooling to RT, the reaction was filtered and the filter cake was washed with toluene. The solvent was removed from the filtrate to leave the crude 2-[N-morpholinylmethyl]-5-nitro-benzimidazole as an oil. A portion of this material (657 mg) and 10% palladium on charcoal (650 mg) in EtOH (10 mL) was stirred overnight under a hydrogen atmosphere (balloon). Removal of the catalyst by filtration and the solvent left the crude 5-amino-2-[N-morpholinylmethyl]-benzimidazole as an oil. A portion of this material was coupled with 556 as described for 570 to afford 573 (HPLC retention time (YMC ODS S7 3×50 mm): 0.92 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl>>[Cl:1][C:2]1[C:7]([C:8]([CH3:15])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C)(C)c1cccnc1Cl
Agent: Cl
Product: CC(C)(C(=O)O)c1cccnc1Cl
Temperature: 105 °C

Procedure:
Ethyl 2-(2-chloropyridin-3-yl)-2-methylpropanoate (1.43 g, 6.28 mmol) was suspended in concentrated hydrochloric acid (36.5-38.0%, 21.20 mL, 251 mmol) under nitrogen and heated at 105° C. for 20 hours. Additional concentrated hydrochloric acid (15 mL) was added and the reaction heated for another 12 hours. The mixture was concentrated in vacuo and the product was obtained as a brown solid.
Reaction SMILES: [CH:1]1N=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[N:17][C:18]2CCNC[C:23]=2[CH:24]=1>C1COCC1.C(Cl)Cl>[N:8]1([C:6]([N:3]2[CH2:2][CH2:1][C:18]3[N:17]=[CH:16][C:15]([C:14]([F:26])([F:25])[F:13])=[CH:24][C:23]=3[CH2:4]2)=[O:7])[CH:9]=[CH:10][N:11]=[CH:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)n1ccnc1
Temperature: 60 °C
Yield: 88.5 %

Procedure:
To a suspension of CDI (0.949 g, 5.86 mmol) in THF (10 mL) was added 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine (0.988 g, 4.88 mmol) and the reaction mixture was heated at about 60° C. for about 16 h. The reaction mixture was cooled at ambient temperature and concentrated in vacuo to afford a light orange solid. The residue was dissolved in DCM (10 mL), washed with water (2×10 mL), and the organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to give imidazol-1-yl-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone (1.28 g, 88%) as a yellow solid which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 2.10 min; m/z: (M+H)+ 297.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]=2[O:4]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].CCN(CC)CC>C(Cl)Cl>[Br:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([NH:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: Nc1ccc2c(c1)CC(CBr)O2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(CBr)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
(RS)-2-bromomethyl-2,3-dihydro-benzofuran-5-ylamine (410 mg, 1.80 mmol), methansulfonyl-chloride (206 mg, 1.8 mmol), Et3N (182 mg, 1.80 mmol) were dissolved in CH2Cl2 (50 ml) and stirred overnight at room temperature. Solvent was then evaporated and the residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH (95:5) to provide (RS)-N-(2-bromomethyl-2,3-dihydro-benzofuran-5-yl)-methansulfonamide (516 mg, 94%) as an oil. MS: m/e=305.9 (M−H+)
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([O:13]COCC)=[CH:11][CH:10]=[CH:9][N:8]=1.[Br:18][C:19]1[CH:20]=[C:21]2[C:31](=[CH:32][CH:33]=1)[O:30][C:24]1[CH:25]=[N:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:22]2=[N:34]S(C(C)(C)C)=O>C1COCC1>[NH2:34][C:22]1([C:7]2[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[C:23]2[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:24]=2[O:30][C:31]2[C:21]1=[CH:20][C:19]([Br:18])=[CH:33][CH:32]=2
Reactant: CCOCOc1cccnc1Br
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NC1(c2ncccc2O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 71.3 %

Procedure:
Butyllithium solution, 2.5m in hexanes (1.70 mL, 4.24 mmol) was added dropwise to a solution of 2-bromo-3-(ethoxymethoxy)pyridine (0.98 g, 4.24 mmol) in THF 25 mL at −78° C. The reaction was stirred for 25 min. Then N-(7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (1.35 g, 3.26 mmol, prepared as in Example 18b) in THF was added. The reaction was warmed up to RT and stirred for 1 h. The reaction was quenched with aq. ammonium chloride and extracted with EtOAc. The organic phase was separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography with 25-60% EtOAc/Hexane to give 0.94 g of desired product. The resulting material was dissolved in dry MeOH 10 mL and cooled in an ice bath. Hydrochloric acid, 4.0M solution in 1,4-dioxane (20 mL, 80 mmol) was added and mixture was stirred at RT for 4 h. The reaction was quenched with 10% sodium carbonate solution and extracted with DCM three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated to give the desired product which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.COCCOC>[CH:37]1([C:34]2[CH:35]=[CH:36][C:31]([C:29]3[CH:30]=[CH:25][N:26]=[C:27]([C:14]4[C:9]5[O:8][C:6]6[C:5]([C:10]=5[CH:11]=[CH:12][CH:13]=4)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=6)[CH:28]=3)=[CH:32][CH:33]=2)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: Clc1cc(-c2ccc(C3CCCC3)cc2)ccn1
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccc(C5CCCC5)cc4)ccn3)cccc12
Yield: 73.3 %

Procedure:
A mixture of 2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (2.5 g, 8.09 mmol), 2-chloro-4-(4-cyclopentylphenyl)pyridine (2.29 g, 8.89 mmol), Pd2(dba)3 (0.148 g 0.162 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.266 g, 0.647 mmol), potassium phosphate (6.01 g, 28.3 mmol), DME (70 mL) and water (7 mL) was degassed with nitrogen and then refluxed overnight. The mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then further purified by column chromatography using ethyl acetate in hexanes to give 8-(4-(4-cyclopentylphenyl)pyridine-2-yl)-2-methylbenzofuro[2,3-b]pyridine (2.4 g, 73% yield).
Reaction SMILES: N#N.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:13][C:14]1[N:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17].CN([CH:28]=[O:29])C>C1COCC1>[Cl:13][C:14]1[C:15]2[C:16](=[O:17])[NH:18][CH:28]([OH:29])[C:19]=2[C:20]([F:24])=[C:21]([Cl:23])[N:22]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NC(O)c2c(F)c(Cl)nc(Cl)c21
Temperature: 5 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 22-L multi-neck RBF equipped with an overhead stirrer, temperature probe, and N2 inlet/outlet was charged with LiHMDS (10.65 L, 2.5 eq) by N2 pressure. The orange solution was cooled to <0° C. using an ice/brine bath. A separate 12-L RBF was sequentially charged with 2,6-dichloro-5-fluoronicotinamide (890 g, 1.0 eq), anhydrous THF (6.0 L), and anhydrous DMF (1.0 L, 3.0 eq). The resulting solution was added to the LiHMDS solution via a peristaltic pump over a 1 h period, which kept the internal temperature below 5° C. The 12-L flask was rinsed with THF (1.6 L), and the rinse was transferred to the reaction mixture. The mixture was stirred at a temperature<5° C. for 1 h, and the reaction was added to a pre-cooled 2N HCl aq solution via a peristaltic pump at a rate that kept the temperature of the mixture below 22° C. Following the quench, IPAc (14 L) was added and the mixture was stirred for 10 min. The biphasic mixture was separated and the organic layer was stored in a carboy at RT overnight. The organic layer was subsequently washed with water (8.9 L) and was concentrated under reduced pressure to a volume of about 4.5 L. The distillation was continued the next day. Isopropyl acetate (16 L) was added to the slurry and the distillation was continued until about 4.5 L of material remained. The off-white slurry was transferred into a 50-L multi-neck RBF to which was charged heptanes (18 L) via a peristaltic pump over a 45 min period. The resultant slurry was stirred at RT overnight and then filtered through a Buchner funnel with a Sharkskin filter paper. The filter cake was washed with heptanes (2×4.5 L) and then dried under high vacuum at RT for 24 h to afford title compound (913.0 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm 6.11 (dd, J=9.3 Hz, 1.5 Hz, 1 H), 6.95 (d, J=9.3 Hz, 1 H), 9.54 (s, 1 H). [M+H] calc'd for C7H3Cl2FN2O2, 237; found, 237.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([N:6]1[CH:10]=[C:9]([Br:11])[C:8]([CH3:12])=[N:7]1)(=[O:5])=[O:4].[Cl:14][CH2:15][CH2:16][CH2:17]I>C(OCC)C.C(OCCCC)CCC.C1COCC1>[CH3:1][N:2]([CH3:13])[S:3]([N:6]1[C:10]([CH2:17][CH2:16][CH2:15][Cl:14])=[C:9]([Br:11])[C:8]([CH3:12])=[N:7]1)(=[O:4])=[O:5]
Reactant: Cc1nn(S(=O)(=O)N(C)C)cc1Br
Reactant: ClCCCI
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCOCCCC
Product: Cc1nn(S(=O)(=O)N(C)C)c(CCCCl)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
To a solution of 4-bromo-3-methyl-pyrazole-1-sulfonic acid dimethylamide (6.7 g, 25 mmol) in diethyl ether (75 mL) was added dropwise at −78° C. under N2 phenyl lithium (1.8 M, 14.6 mL, 26.3 mmol) in dibutyl ether. After warming to 0° C. for 15 m, the reaction mixture was re-cooled to −78° C. and a solution of 3-chloro-iodopropane (15.3 g, 75 mmol) in 20 mL THF was added dropwise. The reaction was warmed to room temperature and stirred for 3 h before quenching with a saturated aqueous solution of NH4Cl. The quenched reaction mixture was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified over normal phase silica starting with 5% EtOAc in heptane for 10 m and then increasing to 50% EtOAc in heptane for 20 m to give the desired product as a clear oil (3.85 g, 11.2 mmol) MS m/z 346.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][C:23]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)(O)[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH3:32])[N:15]=1)[CH2:12][CH3:13].C(=O)([O-])O.[Na+]>C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH:22]=[C:23]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH3:32])[N:15]=1)[CH2:12][CH3:13]
Reactant: CCN(c1nc(C)cc(N2CCC(O)(c3cccs3)CC2)n1)c1ccc(C(C)C)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CCN(c1nc(C)cc(N2CC=C(c3cccs3)CC2)n1)c1ccc(C(C)C)cc1Br
Yield: 82.4 %

Procedure:
2-[N-(2-Bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(thiophen-2-yl)-4-hydroxypiperidin-1-yl]-6-methylpyrimidine (166 mg) was stirred in 0.5 ml of99% formic acid at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed successively with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1) to give 132 mg of 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino] -4-[4-(thiophen-2-yl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[CH3:5][C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[CH:14][CH:15]=[C:8]2[N:7]=1>CN(C=O)C>[CH3:5][C:6]1[CH:11]=[C:10]([O:2][CH3:1])[N:9]2[N:13]=[CH:14][CH:15]=[C:8]2[N:7]=1
Reactant: CO
Reactant: Cc1cc(Cl)n2nccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)nc2ccnn12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanol (5 ml) was added to a suspension of 0.40 g of 60% sodium hydride in 10 ml of DMF. Then a solution of 1 g of 5-methyl-7-chloropyrazolo[1,5-a]pyrimidine in 5 ml of DMF was added dropwise thereinto at 0° C. and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and the crystals precipitated were collected by filtration and recrystallized from diethyl ether to provide 0.40 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.