Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](OC)=[O:25])=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:36][C:33]3[CH:34]=[N:35][C:30]([C:29]([F:38])([F:28])[F:37])=[CH:31][CH:32]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)nc3)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 37.8 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-6, 0.200 g, 0.493 mmol) and 6-(trifluoromethyl)pyridin-3-amine (0.119 g, 0.740 mmol), trimethyl aluminium (2M solution in toluene) (0.071 g, 0.986 mmol) and dry toluene (5.0 mL) to afford 0.100 g of the desired product. 1HNMR (DMSO-d6): δ 1.58 (s, 6H), 3.09 (s, 2H), 7.39 (m, 3H), 7.53 (m, 1H), 7.89 (d, J=8.4 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.99 (s, 1H), 10.07 (s, 1H), 10.94 (s, 2H); MS [M]+: 536.17.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:54][CH:55]([CH2:68][C:69]1[CH:74]=[CH:73][C:72]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[CH:71][CH:70]=1)[C:56]([NH:58][CH:59]1[CH2:64][CH2:63][CH2:62][N:61]([CH2:65][CH2:66][CH3:67])[CH2:60]1)=[O:57]>CN(C=O)C.C(OCC)(=O)C>[CH2:76]([O:75][C:72]1[CH:73]=[CH:74][C:69]([CH2:68][CH:55]([NH:54][C:10](=[O:12])[CH:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:20])=[CH:19][CH:18]=2)[CH3:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[C:56](=[O:57])[NH:58][CH:59]2[CH2:64][CH2:63][CH2:62][N:61]([CH2:65][CH2:66][CH3:67])[CH2:60]2)=[CH:70][CH:71]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)Cc1ccc(N(C)C)cc1
Reactant: CCCN1CCCC(NC(=O)C(N)Cc2ccc(OCc3ccccc3)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1CCCC(NC(=O)C(Cc2ccc(OCc3ccccc3)cc2)NC(=O)C(CC(C)C)N(C)Cc2ccc(N(C)C)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a solution of (S)-2-[(4-dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid (0.28 g, 1.01 mmol) in 15 mL of DMF was added HBTU (0.38 g, 1.01 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol). The mixture was stirred for 30 minutes at 0° C. A solution of 2-amino-3-(4-benzyloxyphenyl)-N-(1-propyl-piperidin-3-yl)propionamide (0.40 g, 1.01 mmol) in 15 mL of DMF was added to the reaction mixture. The reaction mixture was allowed to reach the room temperature and was stirred for another 30 minutes. The mixture was diluted with 40 mL of ethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO3 (2×10 mL) and saturated solution of brine (2×10 mL). The organic layer was separated, dried with Na2SO4 and evaporated to dryness. The crude residue was purified by chromatography (silica gel, 6:4 hexane/ethyl acetate). The purified product was crystallized from methylene chloride and petroleum ether to give the title compound (0.34 g, 49%) as a white powder; mp 131-133° C.
Reaction SMILES: Br[C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].[S:11](S([O-])=O)([O-:13])=[O:12].[Na+].[Na+].[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20].Cl>O.C(#N)C>[F:9][C:2]([F:10])([S:11]([O-:13])=[O:12])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].[CH2:19]([NH+:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20]
Reactant: O=S([O-])S(=O)[O-]
Reactant: CCN(CC)CC
Reactant: OCCC(F)(F)C(F)(F)Br
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC[NH+](CC)CC
Product: O=S([O-])C(F)(F)C(F)(F)CCO
Temperature: 60 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A 1 L reactor was charged with 100.0 g (0.44 mole/1.0 equivalent) of 4-bromo-3,3,4,4-tetrafluorobutan-1-ol, 300 g of acetonitrile, 250 g of water, 108.2 g (0.62 mole/1.4 equivalent) of sodium dithionite and 53.4 g (0.52 mole/1.2 equivalents) of triethylamine, followed by 4 hours of stirring at 60° C. Upon confirming the termination of the reaction, the reaction liquid underwent cooling and 100 mL of 1N HCl was added thereto, followed by stirring. Subsequently, an organic layer was separated, and then the organic layer was subjected to distillation of the solvent, thereby obtaining 264 g of a target triethylammonium 1,1,2,2-tetrafluoro-4-hydroxy-butane-1-sulfinate. It exhibited a purity of 46% and a yield of 88% at this time.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl.N[C:15]1[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[C:19]([CH:22]=1)[C:20]#[N:21].C([N:32](CC)CC)C>>[C:20]([C:19]1[CH:22]=[C:15]([C:4]2[C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[O:1][C:5]=2[C:6]([NH2:32])=[O:8])[CH:16]=[CH:17][C:18]=1[O:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][OH:27])#[N:21]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CCN(CC)CC
Reactant: CC(C)(CO)COc1ccc(N)cc1C#N
Agent: Cl
Product: CC(C)(CO)COc1ccc(-c2c(C(N)=O)oc3ccccc23)cc1C#N

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]furan-2-carboxylic acid (0.7 g), 5-amino-2-(2,2-dimethyl-3-hydroxypropoxy)benzonitrile monohydrochloride (1.0 g) and triethylamine (0.6 ml), the title compound (0.26 g) was obtained. melting point: 199-201° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1/[C:27](=[N:33]/[O:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)/[C:28]([O:30]CC)=[O:29].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1/[C:27](=[N:33]/[O:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)/[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1/C(=N/OC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 100 °C
Yield: 101.4 %

Procedure:
A solution of ethyl 2-(5-methyl-2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetate (9.8 g) in dioxane (40 ml) and water (40 ml) was treated with sodium hydroxide (2.75 g). The mixture was allowed to warm to 100° C. The reaction mixture was cooled to room temperature, diluted with water, and filtered to give a precipitate. A suspension of the precipitate in water and ethyl acetate was allowed to pH 2.5, the organic phase was washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure to afford (5-methyl-2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino) acetic acid (9.55 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH:16]=[N:15][CH:14]=1
Reactant: Oc1cccc2cnccc12
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cncc(Oc2cccc3cnccc23)c1
Temperature: 240 °C
Yield: 22.9 %

Procedure:
A sealed tube was charged with 5-hydroxyisoquinoline (0.15 g, 1.03 mmol), 3,5-dibromopyridine (0.24 g, 1.03 mmol), potassium carbonate (0.27 g, 2.0 mmol) and DMF (4 mL). The reaction was heated to 240° C. for 10 minutes in a personal chemistry microwave. The reaction was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined extracts were concentrated and the residue was purified by flash column chromatography on silica gel with 2:1 ethyl acetate/hexanes to provide the desired product (0.071 g, 23%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1COCC1.O>[NH2:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH:2]=[O:1])[CH:7]=2)[NH:11][N:10]=1
Reactant: Nc1n[nH]c2ccc(C3OCCO3)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1n[nH]c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 5-(1,3-dioxolan-2-yl)-1H-indazol-3-amine (75 mg, 0.36 mmol) in THF (5 mL) and H2O (0.5 mL) was added p-toluene sulfonic acid (25 mg) and the reaction was stirred overnight at room temperature. Ethyl acetate (75 mL) was added and the solution was washed with sat. sodium bicarbonate (5 mL), brine (2×5 mL), dried over MgSO4 and concentrated to give the title compound as an orange solid (52 mg, 89%). 1H NMR (400 MHz, CD3OD) δ 9.68 (s, 1H), 8.94 (s, 1H), 8.18 (d, 1H, J=7.6 Hz), 7.68 (d, 1H, J=8.4 Hz).
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([S:45]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:14]3[S:13][C:12]([NH:11][C:9](=[O:10])[N:8]([CH:2]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]4)[CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[N:16][CH:15]=3)[CH2:19][CH2:20]2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc(CN2CCN(S(=O)(=O)c3ccccc3)CC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 84.7 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3 -(5-piperazin-1 -ylmethyl-thiazol-2-yl)-urea hydrochloride (36 mg, 0.08 mmol), DIEA (42 μL, 0.24 mmol) and benzenesulfonyl chloride (20 μL, 0.16 mmol) to afford 37 mg (68%) of the desired product after purification.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=2)[CH:9]=1.Cl.[NH2:24][C@H:25]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:40]=[C:39]3[C:34]([CH:35]=[CH:36][N:37]=[C:38]3[Cl:41])=[CH:33][CH:32]=2)[C:26]1=[O:42]>CC#N>[Cl:41][C:38]1[C:39]2[C:34](=[CH:33][CH:32]=[C:31]([CH2:30][N:27]3[CH2:28][CH2:29][C@H:25]([NH:24][S:19]([C:17]4[S:18][C:14]([C:10]5[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=5)=[CH:15][CH:16]=4)(=[O:21])=[O:20])[C:26]3=[O:42])[CH:40]=2)[CH:35]=[CH:36][N:37]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cccnc2)s1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3cccnc3)s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Triethylamine (0.35 mL, 2.5 mmol) is added dropwise to a solution of 5-pyridin-3-yl-thiophene-2-sulfonyl chloride (0.22 g, 0.85 mmol) and 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (0.22 g, 0.71 mmol) in CH3CN (5 mL). The suspension is stirred at room temperature overnight then concentrated to dryness. The residue is diluted with methylene chloride and washed with saturated NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered, concentrated, and then purified by column chromatography eluting with a gradient of 1% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2 to give the product (0.23 g, 0.45 mmol) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][NH:14][CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:18]([BH3-])#N.[Na+]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([CH3:18])[CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CNC[C@@H]21
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C[C@H]2CCN(C(=O)OC(C)(C)C)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3aR,6aR)-hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butyl ester (18.31 g, 0.86 mol) in methanol (450 ml) was added paraformaldehyde (52 g, 1.72 mole) and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride was then added and the mixture was stirred at room temperature for 10 hours, diluted with 1N NaOH (450 ml), extracted with dichloromethane (5×200 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.18 (m, 1H) 3.47-3.59 (m, 1H) 3.34-3.46 (m, 2H) 2.75-2.90 (m, 1H) 2.71(m, 1H) 2.44-2.60 (m, 2H) 2.29 (s, 3H) 1.89-2.06 (m, 1H) 1.65-1.81(m, 1H) 1.42-1.49 (m, 9H). MS: (M+H)+=226.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>>[ClH:1].[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: NCC(O)CO
Reactant: Cc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Product: Cc1ccc(-c2cc(NCC(O)CO)c3ccccc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 255-257° C. and MS: m/e=308 (M+), was prepared from 4-chloro-2-p-tolyl-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: C([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=O)CC.[Li+].[OH-]>CO.C1COCC1>[CH2:25]([C:15]1[N:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][OH:5])=[CH:13][CH:12]=2)[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[N:16]=1)[CH3:26]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)cc(C)nc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 5, 1.75 g, 5.1 mmol) in methanol/THF (v/v, 1:1, 28 mL) was added 4N aqueous LiOH (4.6 mL, 18.4 mmol) and the resulting mixture was stirred at room temperature. After 3 h, the mixture was concentrated. The residue was dissolved in water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2:1 to 0:1) to afford 1.3 g (86%) of the title compound as pale brown solids: 1H-NMR (CDCl3) δ 7.40 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 6.91 (1H, s), 3.81-3.75 (2H, m), 3.47 (1H, br.s), 2.92 (2H, t, J=6.9 Hz), 2.81 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.51 (3H, s), 1.27 (3H, t, J=7.6 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH2:28][C:29](Cl)=[O:30].Cl>C1COCC1>[Br:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH2:28][C:29]([N:6]1[CH:7]=[CH:8][C:3](=[O:2])[CH2:4][CH:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:30]
Reactant: COc1ccncc1
Reactant: COc1cc(Br)c(CC(=O)Cl)cc1OC
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(Br)c(CC(=O)N2C=CC(=O)CC2c2ccccc2)cc1OC
Temperature: -25 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a stirring solution of 4-methoxypyridine (336 mg, 3.08 mmol) in THF (7 mL) at −25° C. was added phenylmagnesium bromide (3M in ether, 1.13 mL, 3.39 mmol) under Ar atmosphere. After 5 minutes a solution of (2-bromo-4,5-dimethoxy-phenyl)-acetyl chloride (904 mg, 3.08 mL) in THF (2 mL) was added slowly. The mixture was stirred at −25° C. for 90 minutes. 2N HCl was added at −25° C., and the mixture was allowed to warm to room temperature and was stirred for 10 minutes. The mixture was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexane/ethyl acetate gradient) gave 1-[2-(2-bromo-4,5-dimethoxy-phenyl)-acetyl]-2-phenyl-2,3-dihydro-1H-pyridin-4-one (742 mg, 57%). MS (M+H) 431.
Reaction SMILES: O[C:2]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.CC1C=CC=C(C)N=1.[F:28][C:29]([F:42])([F:41])[S:30]([O:33]S(C(F)(F)F)(=O)=O)(=[O:32])=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:28][C:29]([F:42])([F:41])[S:30]([O:33][C:3]1[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:2]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2c3ccccc3c3ccccc3c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=S(=O)(Oc1cccc2c3ccccc3c3ccccc3c12)C(F)(F)F
Temperature: -78 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
Under an argon atmosphere, 12.5 g of 2-hydroxytriphenylene and 0.93 g of 4-dimethylaminopiridine were placed in a flask, 200 mL of methylene chloride was added thereto and the reaction solution was cooled to −78° C. 8.22 g of 2,6-dimethylpiridine was added to the reaction solution and then, 17.3 g of trifluoromethanesulfonic acid anhydride was dropwise added thereto. The reaction solution was stirred for 5 hours while increasing temperature of the reaction solution to room temperature. The deposited solid was collected by filtration, washed with water and methanol and then dried to obtain 17.3 g (yield: 90%) of triphenylenyl trifluoromethanesulfonate.
Reaction SMILES: Cl[Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[CH2:12]([O:19][CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CN=C1>CN(C=O)C>[CH2:12]([O:19][CH2:20][C@@H:21]([OH:24])[CH2:22][O:23][Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC[C@H](O)COCc1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@H](O)COCc1ccccc1)(C(C)C)C(C)C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
Chloro(triisopropyl)silane (12.2 mL, 0.057 mol) was added dropwise at 20° C. to a stirred solution of diol 78 (9.52 g, 0.052 mol) and imidazole (5.33 g, 0.078 mol) in DMF (150 mL) and stirring was continued for 16 h. Most of the DMF was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic extract was washed well with water, then brine, and was evaporated to give an oil, which was chromatographed on silica. Elution with petroleum ether gave fore fractions, and then further elution with EtOAc/petroleum ether (1:19) gave (2R)-1-(benzyloxy)-3-[(triisopropylsilyl)oxy]-2-propanol (79) (13.80 g, 78%) as a colourless oil: [α]19 −0.78° (c, 8.93, CHCl3); 1H NMR (CDCl3) δ 7.41-7.27 (m, 5H), 4.55 (s, 2H), 3.90-3.84 (m, 1H), 3.79-3.72 (m, 2H), 3.59-3.51 (m, 2H), 2.52 (d, J=5.1 Hz, 1H), 1.13-1.03 (m, 21H). APCI MS m/z 339 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][OH:12])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:11][OH:12])[C:8]([NH:22][O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@@H](CO)CC1CCCC1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)[C@@H](CO)CC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a mixture of (2R)-3-cyclopentyl-2-(hydroxymethyl)propanoic acid (18.3 g, 106 mmol), O-benzyl hydroxyamine hydrochloride (18.62 g, 117 mmol) and 4-(dimethylamino)pyridine (28.5 g, 233 mmol) in dichloromethane (110 mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (22.3 g, 117 mmol). The mixture was maintained at 0° C. for 3 h. After this time, 500 mL of 1N cold, aqueous HCl solution was added, and the mixture was stirred for another 30 min. The resulting white solid precipitate was collected by filtration. The precipitate was washed with 1N HCl, with water, and with cold DCM. Drying overnight in a vacuum dessicator provided (2R)-3-cyclopentyl-2-(hydroxymethyl)-N-[(phenylmethyl)oxy]propanamide (19.1 g, 65%). LCMS: (M+H)+: 278.1.
Reaction SMILES: I[C:2]1[C:3]([S:12][C:13]2[NH:14][C:15]3[C:20]([N:21]=2)=[C:19]([NH2:22])[N:18]=[CH:17][N:16]=3)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[N:24]([O-])=O.[Na+].NC(N)=O>O>[NH2:24][C:2]1[C:3]([S:12][C:13]2[NH:14][C:15]3[C:20]([N:21]=2)=[C:19]([NH2:22])[N:18]=[CH:17][N:16]=3)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1ncnc2[nH]c(Sc3cc4ccccc4cc3I)nc12
Reactant: O=N[O-]
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Product: Nc1cc2ccccc2cc1Sc1nc2c(N)ncnc2[nH]1
Reaction time: 0.17 h

Procedure:
8-(3-iodonaphthalen-2-ylthio)-9H-purin-6-amine (S13-5). To a suspension of S13-4 (14 mg, 0.0454 mmol) in water (150 μL) at 5° C. was added 6 M HCl (140 μL) over 5 min. Then a solution of NaNO2 (6.3 mg, 0.0908 mmol) in water (70 μL) was added dropwise over 30 min. at below 5° C. The mixture was stirred for an additional 10 min., then urea (1.9 mg, 0.0317 mmol) was added slowly. After 10 minutes, a solution of KI (22.6 mg, 0.136 mmol) in water (70 μL) was added dropwise over 5 min. and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 8:1) to give 8 mg (42%) of S13-5 as a solid. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.51 (s, 1H), 8.17 (s, 2H), 7.75-7.80 (m, 2H), 7.52-7.60 (m, 2H); MS (ESI) m/z 420.01 [M+H]+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:28](OC)=[O:29])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]21.O1[CH2:36][CH2:35][CH2:34]C1>>[Br:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([C:28]([CH:34]2[CH2:35][CH2:36]2)([CH:1]2[CH2:3][CH2:2]2)[OH:29])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Br)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: Br[Mg]C1CC1
Reactant: C1CCOC1
Product: OC(c1ccc(Br)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)(C1CC1)C1CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 0.880 mL, 0.880 mmol) was added to a stirred solution of methyl 9-bromo-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (80.0 mg, 0.176 mmol) in tetrahydrofuran (0.88 mL), and the mixture was stirred at 60° C. for 90 min. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (78.3 mg, 0.154 mmol, 88%).