Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:15]3=[N:16][CH:17]=2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3]1.C(Cl)(=O)C>CO>[CH3:1][C@H:2]1[C@@H:7]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: CC1COCCC1NC(=O)Nc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Solvent: CO
Solvent: CC(=O)Cl
Product: C[C@@H]1COCC[C@@H]1NC(=O)Nc1cnc2[nH]ccc2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
1-(3-Methyl-tetrahydro-pyran-4-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.065 g, 0.16 mmol) was suspended in MeOH and cooled down to 0° C. At that temperature the acetyl chloride (0.4 mL) was added. After the addition was complete the orange solution was allowed to warm up and stirred at 40° C. overnight. The solvent was evaporated and the remaining solid was dried under high vacuum. The orange solid was taken up in MeOH:H2O:Et3N 8:1:1 and stirred at RT for 1 hour. The solvent was evaporated. The remaining off-white solid was absorbed onto SiO2 and purified by SiO2 chromatography (12 g SiO2, DCM/magic (DCM:MeOH:NH4OH 60:10:1) 0-25% magic). Obtained 0.023 g of cis-1-(3-methyl-tetrahydro-pyran-4-yl)-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as an off-white solid, yield: 52%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][O:14][CH2:15][C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C=O)C>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][N:23]=[CH:24][C:16]=1[CH2:15][O:14][CH3:13]
Reactant: COCc1cnccc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cnccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
A mixture of 0.40 g of 2-amino-4-(trifluoromethyl)phenol, 0.38 g of 3-methoxymethyl isonicotinic acid, 1.30 g of BOP reagent, 0.30 g of triethylamine, and 20 ml of DMF was stirred at room temperature for four hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.64 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3(methoxymethyl)isonicotinamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH3:18][N:19](C=O)C.N.C1(C)C=CC=CC=1>O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: COCCc1ccc(-c2ccc(I)cc2)cc1
Reactant: CN(C)C=O
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Product: COCCc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 149 °C
Reaction time: 6 h

Procedure:
Into a 200 ml three-neck flask were added 4'-(β-methyloxyethyl)-4-iodobiphenyl obtained in Step C (20 g, 0.59 mol), cuprous cyanide (6.2 g, 0.688 mol) and DMF (67 ml), and the mixture was reacted together under reflux with stirring at 149° C. for 6 hours. After completion of the reaction, the reaction liquid was cooled down to room temperature and 29% aqueous ammonia (20 ml) was added, followed by agitation. Toluene (50 ml) and water (100 ml) were then added and the reaction liquid was subjected to suction-filtration. The toluene layer of the filtrate was washed with 6 N-hydrochloric acid and then with sodium hydroxide aqueous solution and further with water till the layer became neutral. The resulting toluene layer was dried with anhydrous sodium sulfate (10 g), and passed through an active alumina layer, followed by distilling off toluene, recrystallizing the residual crystals from methanol (30 ml), filtering and drying to obtain objective 4'-(β-methyloxyethyl)-4-cyanobiphenyl (3 g) having a melting point (C-I point) of 50.7° C. When this product was mixed with 4'-octyloxy-4-cyanobiphenyl and the mixture was subjected to measurement for N→I point, its N→I point through extrapolation was -5° C. (With the above product alone, measurement of N→I point was impossible.) The values of the elemental analysis of the product accorded well with the calculated values thereof as follows:
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@H:23]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>>[CH2:49]([O:48][CH:47]([O:51][CH2:52][CH3:53])[C@@H:46]([N:34]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[C:32](=[O:33])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH3:54])[CH3:50]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 94 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-4-oxobutanoate IV-16) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][NH:5][C:6]([C:8]1[C:13]([OH:14])=[CH:12][C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][N:9]=1)=[O:7].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][NH:5][C:6]([C:8]1[C:13]([OH:14])=[CH:12][C:11]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=2)=[CH:10][N:9]=1)=[O:7]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)CNC(=O)c1ncc(OS(=O)(=O)C(F)(F)F)cc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)c1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 85 °C
Yield: 53 %

Procedure:
To a degassed solution of [(3-hydroxy-5-trifluoromethane-sulfonyloxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester, 5, (0.30 g, 0.84 mmol) in 1,4-dioxane (10 mL) at room temperature under N2 is added 3-chlorophenylboronic acid (0.196 g, 1.26 mmol), Pd(dppf)Cl2 (0.068 g, 0.0084 mmol) and K3PO4 (0.195 g, 0.92 mmol). The resulting suspension is heated in a sealed tube at 85° C. for 16 hours. After this time, the mixture is cooled to room temperature and concentrated under reduced pressure. The residue is then treated with 1M HCl (1 mL) and diluted with EtOAc. The organic layer is separated, washed with H2O, saturated aqueous NaCl and concentrated under reduced pressure. The crude material is purified over silica (EtOAc:heptane 3:7). The resulting solid can be crystallized from EtOAc/heptane to afford 0.143 g (53% yield) of the desired compound as a colorless solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.77 (1H, s), 8.36 (1H, t, J=5.7 Hz), 8.24 (1H, d, J=1.8 Hz), 7.50-7.53 (1H, m), 7.39-7.42 (2H, m), 7.34-7.37 (2H, m), 4.20 (2H, d, J=5.9 Hz), 3.76 (3H, s). HPLC-MS: m/z.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CN)c1
Reactant: Clc1cnc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ncc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example 16 starting with rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. MS (ESI) 426.4 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH:21]1([C:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][NH:34][CH2:35][CH2:36][N:37]([CH3:38])[CH3:39])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-1H-indole-6-carboxylate in DCM/H2O (2:1; 0.15 M), a stoichiometric excess of TFA was added dropwise and the solution was stirred at RT overnight. The volatiles were removed in vacuo, the residue taken up in Et2O, scratched and concentrated in vacuo again (2×) to drive off residual TFA. The crude was used in the next step without further purification; MS (ES+) m/z. 492 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH3:16])[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH3:16])[C:7]([OH:9])=[O:8]
Reactant: CCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCCNc1ccc(C(=O)O)cc1N

Procedure:
A mixture of 4.5 parts of 3-nitro-4-(propylamino)-benzoic acid and 80 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off, 100 parts of acetic acid are added to the filtrate and the whole is evaporated, yielding 4.5 parts of 3-amino-4-(propylamino)benzoic acid as a residue.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7](O)=O)=[N:3]1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[F:32][C:33]1[CH:58]=[CH:57][CH:56]=[CH:55][C:34]=1[O:35][C:36]1[CH:37]=[C:38]([NH2:54])[C:39]([NH2:53])=[CH:40][C:41]=1[O:42][C:43]1[CH:44]=[N:45][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:47][CH:48]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C)C=O>[F:32][C:33]1[CH:58]=[CH:57][CH:56]=[CH:55][C:34]=1[O:35][C:36]1[C:41]([O:42][C:43]2[CH:44]=[N:45][C:46]([S:49]([CH3:52])(=[O:50])=[O:51])=[CH:47][CH:48]=2)=[CH:40][C:39]2[NH:53][C:7]([C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)=[N:54][C:38]=2[CH:37]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2F)cn1
Reactant: Cn1ccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cn1ccc(-c2nc3cc(Oc4ccccc4F)c(Oc4ccc(S(C)(=O)=O)nc4)cc3[nH]2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 mg of 1-methyl-1H-pyrazole-3-carboxylic acid, 6.0 mg of hydroxybenzotriazole and 8.5 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added to a dimethylformamide (0.5 ml) solution of 15 mg of 4-(2-fluoro-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 200, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with chloroform, washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and 3 mg of p-toluenesulfonic acid was added to the resulting residue, and the reaction liquid was stirred at 120° C. for 2 hours. The reaction liquid was diluted with ethyl acetate, washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=15/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(N(CC)CC)C.C1COCC1.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([S:49]([CH3:48])(=[O:51])=[O:50])[CH2:34][CH2:35]1)=[O:28]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NC2CCN(S(C)(=O)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
To a mixture of the compound of Example 77 (200 mg, 0.423 mmol), triethylamine (423 μL, 3.18 mmol) and THF (10 mL) was added methanesulfonyl chloride (98.3 μL, 1.27 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). Recrystallization of the obtained solid from ethyl acetate gave the title compound (141 mg, 61%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][N:10](COCC[Si](C)(C)C)[C:7]2=[N:8][CH:9]=1)([O-])=O>C(OCC)(=O)C>[C:14]1([NH:13][C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)[NH:10][N:11]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)CCOCn1nc(Nc2ccccc2)c2cc([N+](=O)[O-])cnc21
Solvent: CCOC(C)=O
Product: Nc1cnc2[nH]nc(Nc3ccccc3)c2c1
Temperature: 25 °C
Yield: 20.7 %

Procedure:
SnCl2 dihydrate (0.243 g, 1.28 mmol) was added to a suspension of 5-nitro-N-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (0.099 g, 0.257 mmol) in ethyl acetate (25 mL), and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NaHCO3 (25 mL). The resulting suspension was filtered through a pad of celite, and the filter cake was washed with ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:1), hexanes/ethyl acetate (1:2) to give N3-phenyl-1H-pyrazolo[3,4-b]pyridine-3,5-diamine (0.012 g, 21% over 3 steps) as solids.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:23]1[C:35]2[NH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[C:25]([C:36]2[C:41]3[O:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:40]=3[CH:39]=[CH:38][CH:37]=2)[CH:24]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>CCCCCC.C1(C)C=CC=CC=1>[CH:39]1[C:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[O:42][C:41]=2[C:36]([C:25]2[CH:24]=[CH:23][C:35]3[N:34]([C:2]4[CH:7]=[CH:6][C:5]([C:8]5[N:9]([C:17]6[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=6)[C:10]6[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=6[N:12]=5)=[CH:4][CH:3]=4)[C:33]4[C:28]([C:27]=3[CH:26]=2)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:37][CH:38]=1
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3oc3ccccc34)cc12
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-n2c(-c3ccc(-n4c5ccccc5c5cc(-c6cccc7c6oc6ccccc67)ccc54)cc3)nc3ccccc32)cc1
Yield: 71 %

Procedure:
To a 100-mL three-neck flask were added 0.70 g (1.0 mmol) of 2-(4-bromophenyl)-3-phenylbenzimidazole and 0.67 g (1.0 mmol) of 4-(9H-carbazol-3-yl)dibenzofuran, and the air in the flask was replaced with nitrogen. To this mixture were added 15 mL of toluene, 0.10 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution), 0.48 g (4.3 mmol) of sodium tert-butoxide. This mixture was degassed while being stirred under reduced pressure. This mixture was stirred at 110° C. for 20 hours. After the stirring, the mixture was washed twice with about 30 mL of water, and the mixture was separated into an organic layer and an aqueous layer. Then, the aqueous layer was subjected to extraction twice with about 30 mL of toluene. The organic layer and the solution of the extract were combined and washed once with about 100 mL of saturated brine. The obtained organic layer was dried over magnesium sulfate, and this mixture was subjected to filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina. The obtained filtrate was concentrated to give a brown solid. The obtained brown solid was purified by silica gel column chromatography (a developing solvent in which the ethyl acetate/toluene ratio was 5:95), and further recrystallized from hexane/toluene, so that 0.86 g of a pale brown solid was obtained in 71% yield. The synthesis scheme of Step 2 is illustrated in (b-2).
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>>[C:3]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:29]2[O:31][CH2:30]2)=[CH:24][CH:25]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)c1c(-c2ccc(O)cc2)oc2ccccc12
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)c1c(-c2ccc(OCC3CO3)cc2)oc2ccccc12

Procedure:
To a mixture of 1.6 g. (0.04 mol.) of sodium hydroxide and 3.7 g. (0.012 mol.) of 3-benzoyl-2-p-hydroxyphenylbenzofuran was added with stirring 10.2 g. (0.11 mol.) of epichlorohydrin. The reaction mixture was refluxed for 1.5 hours, then it was cooled and extracted with methylene chloride. The extract was dried (MgSO4) and concentrated to give a residue which, after chromatography, gave 3-benzoyl-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8](O)=[O:9].CCN(CC)CC.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:31]#[N:32])=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>C1COCC1.O>[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:31]#[N:32])=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)=[O:9]
Reactant: C[C@](O)(CBr)C(=O)O
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@](O)(CBr)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 3 h
Yield: 75.7 %

Procedure:
Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooled solution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoic acid (51.13 g, 0.28 mol) in 300 mL of THF under an argon atmosphere. The resulting mixture was stirred for 3 h under the same condition. To this was added Et3N (39.14 g, 0.39 mol) and stirred for 20 min under the same condition. After 20 min, 5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF were added and then the mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure to give a solid which was treated with 300 mL of H2O, extracted with EtOAc (2×400 mL). The combined organic extracts were washed with saturated NaHCO3 solution (2×300 mL) and brine (300 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure to give a solid which was purified from column chromatography using CH2Cl2/EtOAc (80:20) to give a solid. This solid was recrystallized from CH2Cl2/hexane to give 55.8 g (73.9%) of (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide as a light-yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2].C(Cl)(Cl)Cl>C(O)(=O)C>[C:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cnc2ccccc2c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)NC1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
Borane-pyridine complex (320 mg, 3.5 mmol) was added to a solution of 3-acetamidoquinoline (320 mg, 1.7 mmol) in acetic acid (20 ml) and the mixture was stirred at room temperature for 18 h. Chloroform (150 ml) was added and the mixture was washed with 2N sodium hydroxide solution, water and brine. The organic phase was dried and reduced. Chromatography (80% EtOAc/20% 60-80 pet. ether) afforded 3-acetamido-1,2,3,4-tetrahydroquinoline (180 mg, 55%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[S:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[CH3:17]I>CO>[NH2:16][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[CH:14][N:6]2[CH2:5][O:4][CH2:3][CH2:2][OH:1])=[C:11]([S:15][CH3:17])[N:10]=1
Reactant: CI
Reactant: Nc1nc2c(ncn2COCCO)c(=S)[nH]1
Solvent: CO
Product: CSc1nc(N)nc2c1ncn2COCCO
Yield: 38 %

Procedure:
A mixture 9-(2-Hydroxyethoxymethyl)thioguanine (0.7 g), methyl iodide (0.2 ml), Dowex HCO3- resin (1.7 g) and methanol (200 ml) was stirred overnight at room temperature. The resin was removed by filtration, washed with methanol and the combined filtration evaporated, and the residue recrystallized from isopropanol and then from acetone to give 2-amino-6-methylthio-9-(2-hydroxyethoxymethyl)purine, m.p. 188°-191° C. in 38% yield.