Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1.Cl[CH:13]([O:15]C)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH:13]=[O:15])=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2c(c1)CCO2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)OCC2
Reaction time: 4 h
Yield: 46.9 %

Procedure:
A solution of 5-methoxy-2,3-dihydrobenzofuran (44.8 g, 299 mmol) in dry methylene chloride (690 mL) was cooled to 3° under nitrogen and titanium tetrachloride (53.5 mL, 92.34 g, 486 mmol) was added dropwise keeping the internal temperature below 7°. To the resulting mixture was added dropwise dichloromethylmethylether (22.3 mL, 28.34 g, 247 mmol) over one hour with the internal temperature maintained at 7°. The cooling bath was removed and the mixture allowed to stir for four hours, then quenched by the dropwise addition of water (120 mL). The resulting mixture was poured into water (100 mL) and the layers separated. The aqueous layer was washed with methylene chloride (2×250 mL), then the combined organic extracts were washed with 5% NaCl (1000 mL), dried (Na2SO4) and concentrated to a dark oil. Purification by preparation HPLC (Waters Prep 500, 15% ethyl acetate in hexane as eluant) afforded 5-methoxy-2,3-dihydrobenzofuran-6-carboxaldehyde as a pale yellow solid (20.64 g, 38.8%), m.p. 82-84° C.
Reaction SMILES: ON=CC1C=CC([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[O:12])=CC=1.C[O-].[Na+].C(Br)C=CC>O>[CH2:18]([O:17][C:15]([CH2:14][NH:13][C:11](=[O:12])[NH2:10])=[O:16])[CH2:19][CH3:20]
Reactant: CCCOC(=O)CNC(=O)Nc1ccc(C=NO)cc1
Agent: CC=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCCOC(=O)CNC(N)=O

Procedure:
A solution of N-[4-(hydroxyiminomethyl)phenyl]-N'-n-propoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of crotyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the corresponding N-[4-crotyloxyiminomethyl)phenyl]-N'-n-propoxycarbonylmethylurea.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Yield: 96 %

Procedure:
A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-(4-nitrophenyl)acetic acid (1f) (14.1 g, 77.5 mmol), anhydrous methanol (130 mL) and concentrated sulfuric acid (12.0 mL, 216 mmol), and the reaction mixture was heated at reflux for 16 h. After this time, the reaction was concentrated to dryness under reduced pressure. The resulting residue was partitioned between water (500 mL) and diethyl ether (200 mL) and the layers separated. The aqueous phase was extracted with diethyl ether (100 mL). The combined organic phases were washed with saturated aqueous sodium carbonate and dried over magnesium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure and dried to a constant weight under vacuum to afford a 96% yield of 1g (14.6 g) as a white solid: mp 45-46° C.; 1H NMR (500 MHz, CDCl3) δ8.19 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 3.75 (s, 2H), 3.73 (s, 3H). Reference: Tetrahedron 2002, 58, 10113.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3/[C:12](=[CH:19]/[C:20](OC)=[O:21])/[C:11]([F:25])([F:24])[CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:28])[CH:3]=1.[NH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH2:30].[C:38](=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:24][C:11]1([F:25])[CH2:10][CH2:9][N:8]([C:6]([C:5]2[CH:26]=[CH:27][C:2]([N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH2:30])=[CH:3][C:4]=2[CH3:28])=[O:7])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2/[C:12]/1=[CH:19]/[C:20]([CH3:38])=[O:21]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C([O-])[O-]
Reactant: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(Br)cc2C)CCC1(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(N(N)C(=O)OC(C)(C)C)cc2C)CCC1(F)F
Temperature: 100 °C
Reaction time: 4 h
Yield: 46.9 %

Procedure:
To a solution of 2.0 g of the compound of Example 2 in 30 ml of toluene, 22.35 g of tert-butyl hydrazine carboxylate, 1.43 g of cesium carbonate, 400 mg of tris(dibenzylideneacetone)dipalladium (0), and 740 mg of 1,1′-bis(diphenylphosphine)ferrocene were added, and the mixture was stirred at 100° C. for 4 hours. After cooling the reaction solution, insoluble matter was filtered, and EtOAc and 10% citric acid aqueous solution were added to the filtrate to extract it. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate anhydride. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (2:1)) to obtain 1.0 g of tert-butyl 1-(4-{[(5Z)-4,4-difluoro-5-(2-methyl-2-oxoethylidene)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)hydrazine carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11]O.[BrH:13].[Br-].[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C.C(Cl)Cl.C1C=CC=CC=1>[Br-:13].[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Reactant: COc1ccc(Cl)c(CO)c1Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1ccc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1Cl
Reaction time: 36 h
Yield: 97 %

Procedure:
Bromination of (2,6-dichloro-3-methoxyphenyl)methanol with 30% HBr in acetic acid, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 112, except that the reaction time for the displacement was 36 h, gave the phosphonium salt (526) (97%) as a white solid, mp (CH2Cl2/benzene) 242–244° C. 1H NMR (CDCl3) δ 7.83–7.60 (m, 15H), 7.15 (dd, J=9.1, 0.8 Hz, 1H), 6.88 (dd, J=9.0, 2.4 Hz, 1H), 5.41 (d, J=14.3 Hz, 2H), 3.84 (s, 3H). Found: C, 58.68; H, 4.16. C26H22BrCl2OP requires C, 58.67; H, 4.17.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:18]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Yield: 45.2 %

Procedure:
2-Chloro-4-trifluoromethylpyridine (1.0 g), methyl 4-hydroxybenzenecarboxylate (838.3 mg) and potassium carbonate (2.28 g) were suspended in acetonitrile (10 mL), heated under reflux for 27 hours, and methyl 4-hydroxybenzenecarboxylate (838.3 mg) was added thereto and further heated under reflux for 24 hours. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (100 mL), water (100 mL) and saturated saline water (100 mL) in that order, dried with magnesium sulfate, and evaporated under reduced pressure to obtain a pale yellow oil. The resulting oil was purified through silica gel column chromatography (hexane/ethyl acetate=8/2) to obtain the entitled compound (740 mg) as a colorless solid.
Reaction SMILES: [C:1]([CH:3]1[C:8](=[O:9])[CH:7]([CH3:10])[CH2:6][N:5]([C:11]([O:13][CH3:14])=O)[CH2:4]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([OH:29])[CH2:27][OH:28].ClC(Cl)(Cl)C>O>[CH2:26]1[O:29][C:11]([N:5]2[CH2:6][CH:7]([CH3:10])[C:8](=[O:9])[CH:3]([C:1]#[N:2])[CH2:4]2)([O:13][CH3:14])[O:28][CH2:27]1
Reactant: OCCO
Reactant: COC(=O)N1CC(C)C(=O)C(C#N)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)(Cl)Cl
Solvent: O
Product: COC1(N2CC(C)C(=O)C(C#N)C2)OCCO1
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of crude 11 (200 g, 1.02 mol), 4-toluenesulfonic acid (35 g), 1,2-ethanediol (900 ml), and 1,1,1-trichlorethane (1 liter) was refluxed with a water separator overnight. The mixture was cooled, water (1 liter) was added and the phases separated. The aqueous phase was extracted 3 times with dichloromethane, and the combined organic phases were washed once with dilute sodium hydroxide solution and once with saturated sodium chloride solution. Drying over magnesium sulphate and evaporation in vacuo of the organic phase yielded 12 (195 g, 80%) as an oil.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(O)=O.CN.CC(O)=O>C1COCC1.CCO>[CH3:1][NH:2]/[C:3](/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CN
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NC)c1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of methylamine (65.03 mL of a 2M solution in THF, 130.06 mmol) and ethyl benzoylacetate (4.505 mL, 26.01 mmol) in EtOH (26 mL) was added HOAc (7.45 mL, 130.06 mmol). The mixture was then heated to reflux for 15 h. At this time, crude 1H NMR revealed only product and MeNH2—HOAc. The reaction mixture was then cooled to RT, and the solvent was removed in vacuo. The crude reaction was then extracted with 1 N HCl and DCM. The organic layer was then dried over MgSO4, and the solvent was removed in vacuo to yield 5.3 g (99%) of ethyl (2Z)-3-(methylamino)-3-phenylacrylate. The product was used as is in subsequent reactions. 1H NMR (500 MHz, CDCl3) ppm: 8.50 (br s, 1H), 7.40 (m, 3H), 7.35 (m, 2H), 4.59 (s, 1H), 4.15 (q, J=7.0 Hz, 2H), 2.77 (d, J=5.0 Hz, 3H), 2.50 (s, 3H), 1.27 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([BH3-])#[N:2].[Na+].[C:5]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)(=O)[CH2:6][CH2:7][CH3:8].C([O-])(=O)C.[NH4+]>CO>[NH2:2][CH:5]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: [BH3-]C#N
Reactant: CCCC(=O)c1ccc(C(=O)OCC)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC(N)c1ccc(C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (29.8 g, 0.450 mol) was added to a solution of Intermediate 1 (66.1 g, 0.300 mol) and ammonium acetate (236 g, 3.00 mol) in methanol (1000 mL). The solution was fitted with a reflux condenser and heated to 60° C. for 16 h. The solution was allowed to cool to room temperature. The reaction was quenched by dropwise addition of 1N HCl (300 mL) and allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to remove methanol. This mixture was diluted by careful addition of 1N NaOH (500 mL) followed by extraction with dichloromethane (3×500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (methanol/dichloromethane) gave ethyl (+/−)-4-(1-aminobutyl)benzoate (Intermediate 2). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.2 Hz, 2 H), 7.40 (d, J=8.2 Hz, 2 H), 4.38 (q, J=7.2 Hz, 2 H), 3.98 (t, J=6.9 Hz, 1 H), 1.95 (br. s., 2 H), 1.74-1.56 (m, 2 H), 1.40 (t, J=7.1 Hz, 3 H), 1.16-1.37 (m, 2 H), 0.91 (t, J=7.4 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:12][CH3:13])[C:3]=1[S:14][CH3:15].O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[C:3]=1[S:14][CH3:15]
Reactant: COC(=O)c1ccc(Cl)c(SC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C(=O)O)ccc(Cl)c1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of methyl 4-chloro-2-methoxy-3-(methylsulphenyl)benzoate (85% pure, 16.9 g) and lithium hydroxide monohydrate (3.85 g) in aqueous methanol was stirred at room temperature overnight. The mixture was evaporated then treated with water and acidified to pH1. It was extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-chloro-2-methoxy-3-(methylsulphenyl)benzoic acid (14.7 g) as a white solid m.p. 121.3°-122.7° C. NMR (CDCl3) 2.45(s,3H), 4.05(s,3H), 7.3(d.1H), 7.95(d,1H) containing only a trace of 4-chloro-3-(choromethylsulphenyl)-2-methoxybenzoic acid (determined by NMR).
Reaction SMILES: NC1C=C(C=CC=1)C([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=O.C(N(C(C)C)CC)(C)C.C(C1C=CC(C(C2C=CC(CC(C)C)=CC=2)Cl)=CC=1)C(C)C>CN(C)C=O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: Nc1cccc(C(=O)c2c[nH]c3ccccc23)c1
Agent: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2[nH]ccc2c1
Reaction time: 14 h
Yield: 210.1 %

Procedure:
To a solution of 3-(3-aminobenzoyl)indole (1.2 g) in N,N-dimethylformamide (12 ml) were added diisopropylethylamine (1.77 ml) and a solution of bis(4-isobutylphenyl)chloromethane (1.92 g) in N,N-dimethylformamide (5 ml) at 25° C., and the mixture was allowed to stand at the same temperature for 14 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (50 g) eluting with a mixture of ethyl acetate and chloroform (1:20) to give 3-[3-bis(4-isobutylphenyl)methylamino]benzoyl]indole (1.25 g) as pale yellow amorphous powder.
Reaction SMILES: [N:1]([CH:4]([CH3:28])[CH2:5][O:6][CH:7]1[CH2:27][C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]4[CH2:25][CH2:24]4)=[C:17]([Cl:26])[CH:16]=3)[O:14][C:10]=2[CH2:9][CH2:8]1)=[N+]=[N-].C1(P([C:42]2[CH:47]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH2:48]>C1COCC1>[Cl:26][C:17]1[CH:16]=[C:15]([C:13]2[O:14][C:10]3[CH2:9][CH2:8][CH:7]([O:6][CH2:5][CH:4]([NH:1][C:47](=[O:48])[CH3:42])[CH3:28])[CH2:27][C:11]=3[N:12]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][CH:23]1[CH2:25][CH2:24]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(COC1CCc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2C1)N=[N+]=[N-]
Reactant: O
Solvent: C1CCOC1
Product: CC(=O)NC(C)COC1CCc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-azidopropoxy)-2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydro-1,3-benzoxazole (3.40 g) in THF (30 mL) were added triphenylphosphine (2.66 g) and water (5 mL), and the mixture was stirred overnight at 60° C. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). To the obtained oil were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (3.02 g).
Reaction SMILES: COCCOC.[CH2:7]([O:14][CH2:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]1[CH:35]=[O:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:37][C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Br.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:7]([O:14][CH2:15][N:16]1[CH:20]=[C:19]([CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[F:37])[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]1[CH:35]=[O:36])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1ccccc1CBr
Reactant: CCOC(=O)c1c(B2OC(C)(C)C(C)(C)O2)cn(COCc2ccccc2)c1C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(Cc2ccccc2F)cn(COCc2ccccc2)c1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To 100 ml of 1,2-dimethoxyethane solution containing 4.38 g (10.6 mmol) of ethyl 1-benzyloxymethyl-2-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrol-3-carboxylate obtained in Reference example 36-(c) were added 2.60 ml (21.4 mmol) of 2-fluorobenzyl bromide and 100 ml of 2M sodium carbonate aqueous solution, the mixture was degassed under reduced pressure and replaced with argon. Further, 2.47 g (2.14 mmol) of tetrakistriphenylphosphine palladium was added to the mixture, and the resulting mixture was stirred at 50° C. for 3 hours. After completion of the reaction, to the reaction mixture were added water and a saturated aqueous solution of sodium chloride, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 3.80 g of the title compound as a yellowish oil. (Yield: 91%)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70](NCC4C=CC=CN=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3NN=CN3CC)[C@@H](O)[C@H]2O)C=CC=CC=1.[NH2:100][CH2:101][C:102]1[CH:103]=[N:104][CH:105]=[CH:106][CH:107]=1>>[ClH:45].[C:39]1([CH:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:100][CH2:101][C:102]4[CH:103]=[N:104][CH:105]=[CH:106][CH:107]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NCc1cccnc1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCN1C=NNN1[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5ccccn5)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6cccnc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(1-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride. (Example 113) by replacing 2-aminomethyl pyridine with 3-aminomethylpyridine. MS (ES+) m/e 730.50 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[C:28]([O:27][C:25](=[O:26])[NH:24][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:5]3[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[CH:7][C:2]4[NH:1][C:35](=[O:37])[CH2:34][CH2:33][NH:32][C:3]=4[N:4]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23]1)([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(NCCC(=O)O)c(N)cc3-c3ccccc3)cc2)CCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CCN4)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 3-((3-amino-6-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-5-phenylpyridin-2-yl)amino)propanoic acid (100 mg, 0.20 mmol) in dry DMF (1 ml) was added EDC (153 mg, 0.80 mmol) and HOBT (122 mg, 0.796 mmol) under nitrogen. The resulting mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 55% EtOAc in cyclohexane) to give the title compound (68 mg, 71%). 1H NMR (500 MHz, CDCl3): 8.38 (1H, br s), 7.94 (1H, br s), 7.72-7.12 (8H, m), 7.01-6.99 (2H, m), 5.00 (1H, s), 3.68-3.66 (2H, m), 2.82-2.80 (2H, m), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br)
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(Cl)(Cl)Cl.[CH3:22][O:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[CH3:22][O:23][C:24]([NH:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[O:25]
Reactant: Nc1cnc2ccc(Sc3ccccn3)cn12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cnc2ccc(Sc3ccccn3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.0 g. of 3-amino-6-(2-pyridylthio) imidazo [1,2-a] pyridine in 25 ml. of chloroform containing 0.401 g. of triethyl amine is treated dropwise with 0.378 g. of methylchloroformate. The reaction mixture is stirred for 3 hours at room temperature. The chloroform is removed in vacuo and the residue is triturated with water. The solids are collected by filtration, washed well with water and dried. Recrystallization from dimethylformamide-ethane yields pure 3-(methoxycarbonylamino) 6-(2-pyridylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: [NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:3]=1[C:21]#[N:22].[H-].[Na+].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[CH2:45][N:44]([C:47]1[S:48][C:49]([CH2:57][CH2:58][CH2:59]I)=[C:50]([C:52]([O:54]CC)=[O:53])[N:51]=1)[CH2:43][CH2:42]2)=[O:36]>CN(C=O)C.Cl.CS(C)=O.CO>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:59][CH2:58][CH2:57][C:49]3[S:48][C:47]([N:44]4[CH2:43][CH2:42][C:41]5[C:46](=[C:37]([C:35](=[O:36])[NH:34][C:26]6[S:25][C:29]7[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=7[N:27]=6)[CH:38]=[CH:39][CH:40]=5)[CH2:45]4)=[N:51][C:50]=3[C:52]([OH:54])=[O:53])=[CH:18][CH:19]=2)[C:3]=1[C:21]#[N:22]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)n[nH]c1N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To compound 31F (0.132 g, 0.44 mmol) in DMF (4 mL) was added 60% sodium hydride (0.048 g, 1.2 mmol) at 0° C. The solution was stirred for 10 minutes. To this solution was added compound 2C. The solution was stirred at rt for 2 hours. The solution was diluted with conc. HCl (0.5 mL), and heated at 60° C. for 30 minutes. The mixture was diluted with DMSO (5 mL) and MeOH (9 mL). The solid was filtered off. The filtrate was then purified by Prep HPLC to provide 12 mg of the desired product: 1H NMR (DMSO-d6): δ 8.03 (d, J=7.98 Hz, 1H), 7.79 (d, J=7.98 Hz, 1H), 7.67-7.71 (m, 4H), 7.33-7.49 (m, 5H), 7.00 (d, J=8.59 Hz, 2H), 4.84 (s, 2H), 4.03 (t, J=5.98 Hz, 2H), 3.71-3.74 (m, 2H), 3.17-3.20 (m, 2H), 3.01-3.05 (m, 2H), 2.02 (m, 2H). MS (ESI(+)): 677 (M+H).