Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([C:6](=O)[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].CC1(C)C2CCCC(=O)C=2C(C)(C)C1C.CC1(C)C2C(C(=O)C(=O)CC2)C(C)(C)C1C.[C:47]([NH2:50])(=[S:49])[CH3:48]>COCCOCCOC>[CH3:48][C:47]1[S:49][C:7]2[CH2:8][CH2:9][CH:10]3[CH:5]([C:4]([CH3:13])([CH3:12])[CH:3]([CH3:14])[C:2]3([CH3:15])[CH3:1])[C:6]=2[N:50]=1
Reactant: CC1C(C)(C)C2CCCC(=O)C2C1(C)C
Reactant: CC(N)=S
Agent: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Agent: CC1C(C)(C)C2CCC(=O)C(=O)C2C1(C)C
Solvent: COCCOCCOC
Product: Cc1nc2c(s1)CCC1C2C(C)(C)C(C)C1(C)C
Temperature: 130 °C
Reaction time: 24 h

Procedure:
1,1,2,3,3-Pentamethyl-octahydro-inden-4-one is first prepared by the hydrogenation of 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (Cashmeran®) (commercially available at IFF). 1,1,2,3,3-Pentamethyl-hexahydro-indene-4,5-dione is subsequently prepared with 1,1,2,3,3-pentamethyl-octahydro-inden-4-one (prepared as described by Barton in Tetrahedron Letters, 1984, 25(6), pages: 603-606). A 100 mL reaction flask is charged with 1,1,2,3,3-pentamethyl-hexahydro-indene-4,5-dione (10 g, 0.04 mol), thioacetamide (3.5 g, 0.04 mol), and diglyme (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sodium carbonate (10%, 100 mL) followed by twice with brine (30 mL). Diglyme is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 2,6,6,7,8,8-hexamethyl-5,5a,6,7,8,8a-hexahydro-4H-3-thia-1-aza-as-indacene (˜10 g) is obtained.
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[C:7]1[CH:8]=[C:9]([CH:14]2[C:27]3[CH:26]=[CH:25][C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[C:18]=3[NH:17][S:16](=[O:29])(=[O:28])[N:15]2[CH3:30])[CH:10]=[CH:11][C:12]=1[F:13].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:13][C:12]1[CH:11]=[CH:10][C:9]([CH:14]2[C:27]3[CH:26]=[CH:25][C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[C:18]=3[NH:17][S:16](=[O:29])(=[O:28])[N:15]2[CH3:30])=[CH:8][C:7]=1[CH:3]=[O:2]
Reactant: CN1C(c2ccc(F)c(C3OCCO3)c2)c2ccc3cccnc3c2NS1(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1C(c2ccc(F)c(C=O)c2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 70 °C
Yield: 51.6 %

Procedure:
6 M HCl (5 ml) was added dropwise to a solution of 1-(3-[1,3]dioxolan-2-yl-4-fluoro-phenyl)-2-methyl-1,4-dihydro-2H-3-thia-2,4,5-triaza-phenanthrene 3,3-dioxide 421 (390 mg, 0.94 mmol) in THF (10 ml) and the mixture was heated at 70° C. for 3 h. After cooling, the mixture was neutralised with sat K2CO3 and the aqueous phase was extracted with EtOAc (30 ml). The organic phase was washed with brine (10 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (95:5) as the eluent to give the title compound (180 mg, 52%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH:8](O)[CH3:9])[CH3:2]>CCCCCC>[CH2:1]([CH:3]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][NH:5][C:6](=[O:11])/[CH:7]=[CH:8]/[CH3:9])[CH3:2]
Reactant: CCCCC(CC)CNC(=O)CC(C)O
Solvent: CCCCCC
Product: C/C=C/C(=O)NCC(CC)CCCC
Temperature: 170 °C
Yield: 54.7 %

Procedure:
In a flask, 10 g of N-(2-ethylhexyl)-β-hydroxybutyramide semisuccinate was admitted and heated at 170° C. for 4 hours. The reaction mixture was dissolved in n-hexane and the insolubles were removed by filtration. The filtrate was washed first with diluted hydrochloric acid and then with 10% sodium hydroxide solution, and subsequently dried with sodium sulfate. The residue was recrystallized from n-hexane, obtaining 5.01 g of N-(2-ethylhexyl)-crotonamide (yield: 80.1%). This compound showed substantially the same results as those in Example 1.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:20][C@@H:19]1[C:34]([O:36]C)=[O:35]>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:20][C@@H:19]1[C:34]([OH:36])=[O:35]
Reactant: COC(=O)[C@H]1CN(CCCc2cccc(F)c2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4cccc(F)c4)C[C@@H]3C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
0.9 cm3 of 5N aqueous sodium hydroxide was added to a solution of 0.58 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)propyl]piperidine-3-carboxylate in 21 cm3 of methanol and then the mixture was heated at a temperature in the region of 60° C. for 20 hours, on conclusion of which 0.2 cm3 of 5N aqueous sodium hydroxide was added. Heating was subsequently continued for 3 hours. After cooling to a temperature in the region of 25° C., the solution was evaporated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue was taken up in 30 cm3 of water and then treated with 7.8 cm3 of 1N hydrochloric acid. After extracting the aqueous phase with 5 times 10 cm3 of dichloromethane, the aqueous phase was evaporated to dryness under reduced pressure (1 kPa) at a temperature in the region of 60° C. The residue obtained was triturated in 10 cm3 of a dichloromethane/methanol (90/10 by volume) mixture. The insoluble material was filtered off and then the cake was washed with 2 times 5 cm3 of the same mixture. The filtrate was dried over sodium sulfate and then evaporated to dryness under reduced pressure (1 kPa) at a temperature in the region of 40° C. 0.46 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)propyl]piperidine-3-carboxylic acid was obtained in the form of a foamy solid with a pale yellow color which melts at approximately 206° C.
Reaction SMILES: CO[C:3]1([O:14]C)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH:5]=[CH:4]1.[C:16]1([S:22]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[C:26]2[C:3]2([OH:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[CH:5]=[CH:4]2)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reactant: COC1(OC)C=CC(=O)c2ccccc21
Product: O=C1C=CC(O)(c2cc3ccccc3n2S(=O)(=O)c2ccccc2)c2ccccc21
Yield: 20 %

Procedure:
The title compound was prepared from 4,4-dimethoxy-4H-naphthalen-1-one and 1-benzenesulfonyl-1H-indole, according to Method E, described above. Yield 20%; mp 175-177° C.; 1H NMR (CDCl3) δ 8.19-8.23 (dd, J=7 Hz, 1H), 8.02-8.05 (dd, J=9 Hz, 1H), 7.80-7.92 (m, 4H), 7.68-7.73 (t, J=7 Hz, 1H), 7.55-7.64 (m, 2H), 7.42-7.48 (t, J=7 Hz, 2H), 7.25-7.32 (m, 3H), 7.14-7.20 (m, 1H), 6.37 (d, J=11 Hz, 1H); 13C NMR (CDCl3) δ 189.7, 153.9, 149.7, 148.9, 143.7, 143.2, 139.0, 137.9, 135.7, 134.2, 133.7, 133.6, 132.4, 131.6, 131.3, 130.8, 129.4, 126.7, 120.5, 74.9; MS (AP+) m/z 416.07 (M++1), 398.06.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.C(N(CC)CC)C>ClCCl.CN(C=O)C.O.C1(C)C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]2[C:14](=[C:19]([F:20])[CH:18]=1)[NH:13][C:4](=[O:6])[C:3]([C:1]#[N:2])=[C:22]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N#CCC(=O)O
Reactant: Nc1c(F)cc(Cl)cc1C(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1c(-c2ccccc2)c2cc(Cl)cc(F)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 32.6 %

Procedure:
2-Cyanoacetic acid (140 mg, 1.65 mmol) was co-evaporated with toluene two times and then suspended in dichloromethane (3 ml). One drop of DMF was added followed by dropwise addition of oxalyl chloride (304 mg, 206 μl, 2.4 mmol) at 0° C. The reaction mixture was stirred for 15 min at 0° C. and for another 2.5 h at room temperature. The solvent was then removed and the remaining residue was co-evaporated two times with dichloromethane. The residue was again dissolved in dichloromethane (3 ml) and a solution of (2-amino-5-chloro-3-fluoro-phenyl)-phenyl-methanone (374 mg, 1.5 mmol) and triethylamine (152 mg, 209 μl, 1.5 mmol) in dichloromethane (3 ml) was added dropwise at 0° C. The mixture was stirred at room temperature overnight. Then triethylamine (227 mg, 313 μl, 2.25 mmol) was added dropwise and the reaction mixture was stirred for 2 h before dichloromethane and water were added and the phases were separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 80:20-45:55) to afford the title compound (146 mg, 33%) as white solid. MS (ESI): 299.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[C:3]=1[OH:10]
Reactant: O=Cc1cccc(F)c1O
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(F)c1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
After a solution of 3-fluoro-2-hydroxybenzaldehyde (600 mg, 4.28 mmol) in THF (10 ml) was cooled to 0° C., a solution of vinyl magnesium chloride in THF (1.9M, 5.42 ml, 10.3 mmol) was added thereto over 5 minutes. The mixture was gradually warmed to room temperature and stirred at room temperature overnight. The mixture was cooled to 0° C. and a saturated aqueous ammonium chloride solution was added thereto at 0° C. The mixture was extracted with ethyl acetate. The organic layer was combined and successively washed with water and a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate. The solid was removed by filtration and the filtrate was concentrated to obtain 772 mg of 2-fluoro-6-(1-hydroxy-2-propenyl)phenol as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cc(F)c(Cl)cc1F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Fc1cc(CN2CCOCC2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.8 %

Procedure:
4-Chloro-2,5-difluorobenzaldehyde (1 g, 5.66 mmol), morpholine (0.490 ml, 5.66 mmol) and sodium triacetoxyborohydride (1.741 g, 8.21 mmol) were mixed in dichloroethane (17 ml). The mixture was stirred at ambient temperature under argon atmosphere for 3 days. NaHCO3 (aq., sat, 25 ml) was added. The mixture was extracted with dichloromethane (×3). The combined organic phase were dried over MgSO4 filtered and concentrated in vacuo to give 4-(4-chloro-2,5-difluorobenzyl)morpholine (0.600 g, 43%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1.[Na].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[Cl:1][C:2]1[N:7]=[C:6]([O:22][CH2:21][CH2:20][O:19][CH3:18])[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Reactant: COCCO
Agent: [Na]
Product: COCCOc1nc(Cl)ncc1Cc1ccc(C)nc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred solution of 44.6 g (0.176 mol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine from Example 1 in 300 ml of 2-methoxyethanol at 0°-5° was added dropwise over 2 hours a solution of 4.25 g (0.177 g-atom) of sodium metal in 250 ml of 2-methoxyethanol. The solution was stirred for 30 minutes at 5°, concentrated and the resulting oil dissolved in 500 ml of ethyl acetate. The solution was washed with water, dried over sodium sulfate, filtered and concentrated to give 40.4 g (0.137 mol, 78%) of 2-chloro-4-(2-methoxyethoxy)-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine: m.p. 50°-52°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14].[CH2:24](O)[CH3:25]>Cl>[N:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:9]=1[CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([O:15][CH2:24][CH3:25])=[O:14]
Reactant: Nc1ccccc1NC(=O)CC(CC(=O)O)c1ccc(Cl)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CC(Cc1nc2ccccc2[nH]1)c1ccc(Cl)cc1

Procedure:
N-(2-Aminophenyl)-3-(4-chlorophenyl)glutaramic acid (2.04 g) is dissolved in a mixture of ethanol (20 ml) and conc. HCl (5 ml) and heated to reflux overnight. The ethanol is removed in vacuo and the aqueous layer is neutralised with 10M NaOH. Saturated sodium bicarbonate solution (40 ml) is added and the aqueous layer is extracted twice with dichloromethane (50 ml). The combined organic layers are dried (sodium sulfate) and concentrated. The residue is purified by flash chromatography (dichloromethane/3% methanol/1% triethyl amine) on silica gel to afford ethyl 4-(2-benzimidazolyl)-3-(4-chlorophenyl)butanoate (1.39 g) as yellowish solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH:16]([CH3:17])[CH2:15][CH2:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:18]([CH:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:19])[CH:3]=1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:27].[CH3:26][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]([C:4]1[CH:3]=[C:2]([O:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:7]2[C:8]3[CH:16]([CH3:17])[CH2:15][CH2:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=1)[CH3:19]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(C)CC1
Reactant: O=C(O)CCCN1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2C(C)CC1

Procedure:
9-hydroxy-7-(3-methyl-2-octyl)-1,4,4-trimethyl-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran from Example 24 is reacted with γ-piperidinobutyric acid hydrochloride following the procedure of Example 2 to form 7-(3-methyl-2-octyl)-9[4-(piperidino)-butyryloxy]-1,4,4-trimethyl-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran hydrochloride.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]([CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)[C:10]1[N:15]=[C:14]2[NH:16][CH:17]=[C:18]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:13]2=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[ClH:1].[ClH:1].[CH2:2]([N:9]([C:10]1[N:15]=[C:14]2[NH:16][CH:17]=[C:18]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:13]2=[CH:12][CH:11]=1)[CH2:30][CH2:31][OH:32])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)c1ccc2c(-c3[nH]ncc3-c3ccccc3)c[nH]c2n1
Agent: Cl
Product: OCCN(Cc1ccccc1)c1ccc2c(-c3[nH]ncc3-c3ccccc3)c[nH]c2n1

Procedure:
The title compound was synthesized by the hydrogen chloride mediated deprotection of N-benzyl-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(4-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-6-amine as described in Step 2 of Example 5. Purification by preparative TLC then preparative HPLC, followed by salt formation with 2N HCl/MeOH and final isolation by lyophilization from water afforded 2-{benzyl-[3-(4-phenyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl]-amino}ethanol dihydrochloride in 10% overall yield as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cc2)CCOCC1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a solution of 2-(4-bromophenyl)acetonitrile (3.9 g) in tetrahydrofuran (50 mL) was added potassium tert-butoxide (4.9 g) in an ice bath, and the mixture was stirred for 1 hr in an ice bath, 1-bromo-2-(2-bromoethoxyl)ethane (5.8 g) was added thereto at the same temperature, and the mixture was stirred at room temperature for 10 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N+:5]([O-])=[CH:6][CH:7]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1
Reactant: [O-][n+]1ccc(Br)cc1-c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: Brc1ccnc(-c2ccccn2)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred suspension of 4-bromo-2,2′-bipyridyl-N-oxide in 60 mL CHCl3, was added 12 mL PCl3, at room temperature. The mixture was refluxed for 2 h under N2 and then cooled to room temperature. The reaction mixture was poured into 100 mL ice/water. The aqueous layer was separated and saved. The CHCl3, layer was extracted three times with H2O (3×60 mL) and then discarded. The combined aqueous solution was neutralized with NaHCO3 powder to about pH 7-8. The resulting white precipitate was collected by suction filtration, washed with H2O (30 mL) and then dried under vacuum at 50° C. for 24 h. Yield: 85%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[OH:29])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: COc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccc(Br)cc2)c1
Temperature: -78 °C
Yield: 96.6 %

Procedure:
p-Dibromobenzene (7.08 g, 30.0 mmole) was added to 50 ml of anhydrous tetrahydrofuran under nitrogen and the slurry was cooled to -78° C. A solution of n-butyllithium in hexane (1.67M, 18.0 ml, 30 mmole) was added dropwise over 15 minutes. After stirring for ten minutes at -78° C., 3.8 ml (4.1 g, 30 mmole) of m-anisaldehyde was added dropwise over five minutes. After stirring for 15 minutes, the reaction was quenched with 10 ml of saturated aqueous ammonium chloride solution and was allowed to warm to room temperature. The reaction solution was diluted with 300 ml of diethyl ether and washed with three 50 ml portions of 1.0M aqueous sodium bisulfite, followed by 50 ml of 1.0 M sodium hydroxide, 100 ml of water, and 100 ml of saturated sodium chloride. After drying over magnesium sulfate, the solvent was removed to give 8.5 g (97%) of crude (4-bromophenyl)(3-methoxyphenyl)-methanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[NH:17][C:16]3[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:14]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:15]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]=3[N:17]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: BrC1CCCC1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(S(C)(=O)=O)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2c(S(C)(=O)=O)cccc2n1C1CCCC1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-6-(((1S)-1-(7-(methylsulfonyl)-1H-benzimidazol-2-yl)-ethyl)amino)-5-pyrimidinecarbonitrile (110 mg, 0.31 mmol) and cesium carbonate (100 mg, 0.31 mmol) was stirred at rt for 30 min in DMF (2 mL). At this time bromocyclopentane (92 μL, 0.62 mmol) was added. The mixture was stirred at 110° C. in a sealed flask for 18 h. The mixture was cooled to rt and concentrated under reduced pressure. Purification of the residue by flash chromatography over silica gel, using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent gave 4-amino-6-(((1S)-1-(1-cyclopentyl-4-(methylsulfonyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile: 1H NMR (400 MHz, DMSO-d6) δ 8.09 (1H, s), 7.95 (1H, s), 7.94 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=8.0 Hz), 7.43 (1H, t, J=8.0 Hz), 7.35 (2H, br), 5.93-5.85 (1H, m), 5.03-4.95 (1H, m), 3.54 (3H, s), 2.70-2.66 (1H, m), 2.35-2.32 (1H, m), 2.18-1.94 (6H, m), 1.67 (3H, d, J=8.0 Hz); LC-MS (ESI) m/z 426.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C(Cl)(Cl)Cl>[CH2:17]([NH:19][C:20]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:14][N:13]=1)=[O:21])[CH3:18]
Reactant: CCN=C=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Yield: 76.3 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1 g, 4.5 mmol) in chloroform (5 mL), ethyl isocyanate (0.33 mL, 4.5 mmol) was added. The resulting mixture was microwaved at 110° C. for one hour and concentrated to give 1 g of product (white solid). MS (ESP): 292 (M+H+) for C14H22BN3O3; NMR (CDCl3): 1.22 (t, 3H), 1.32 (s, 2H), 3.41 (m, 2H), 6.82 (d, 1H), 7.90 (dd, 1H), 8.52 (s, 1H), 8.62 (s, 1H), 9.40 (s, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH3:31])[C:10]([N:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24]COCCOC)[CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:11])=O)(C)(C)C.[ClH:32]>CCOC(C)=O>[ClH:32].[NH2:8][C@H:9]([CH3:31])[C:10]([N:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([OH:24])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:11]
Reactant: COCCOCOc1ccc2cccc(N(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](N)C(=O)N(C)c1cccc2ccc(O)cc12
Reaction time: 1 h

Procedure:
A solution of (R)-2-(tert-butoxycarbonylamino)-N-{7-[(2-methoxyethoxy)methoxy]naphthalen-1-yl}-N-methylpropionamide, as described above in Step C, (255 mg, 0.59 mmol) in EtOAc (10 mL) at ambient temperature was saturated with HCl (g). After 1 hr, the mixture was concentrated in vacuo to yield the titled product as a pale solid.