Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])[CH:3]=[CH2:4].CO[C:32]([O:37]C)([N:34]([CH3:36])[CH3:35])[CH3:33]>C1(C)C=CC=CC=1>[CH3:36][N:34]([CH3:35])[C:32](=[O:37])[CH2:33][CH2:4]/[CH:3]=[CH:2]/[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29]
Reactant: C=CC(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C/CCC(=O)N(C)C)ccc21
Yield: 76.6 %

Procedure:
A mixture of methyl 4-[5-(1-hydroxyallyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.8 g), N,N-dimethylacetamide dimethyl acetal (0.542 g, redistilled) in dry toluene (20 ml) was stirred and heated under reflux, under an atmosphere of nitrogen for 5 hr. The cooled solution was introduced directly onto a column of silica gel and the product purified by flash chromatography, eluting with ethyl acetate, to give methyl E-4-[5-[5-(dimethylamino)-5-oxopent-1-enyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.72 g, 77%) as an oil: partial NMR (250 MHz, DMSO-d6): 0.81(t, 3H, CH2CH3), 1.75(m, 2H, CH2CH3), 2.45(m, 4H, CH2CH2CO), 2.82(s, 3H, NCH3), 2.98(s, 3H, NCH3), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.0(m, 4H, ArCH2Ar', NCH2), 6.2(d of t, 1H, CH2CH=CH), 6.45(d, J=15.8 Hz, 1H, CH2CH=CH).
Reaction SMILES: [NH2-].[Na+].[C:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CCOCC>[C:19]1([C:18](=[O:17])[CH2:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[O:5])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1cccc2ccccc12
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)c1cccc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
9.5 gr of 50% slurry of sodium amide was suspended in 100 ml of anhydrous ether in a 250 ml round bottom flask that was equipped with a magnetic stir bar and a condenser. To this suspension was added 10.2 gr of solid acetonaphthone and continued stirring for 5 min at room temperature. After 5 minutes, 8.16 gr of methylbenzoate was added in one lot as a neat liquid. At this point, the reaction flask was transferred to an oil bath and the bath temperature was raised so that the contents reflux gently in ether for 3 hours. The contents were then poured onto 300 gr of solid ice and the pH was adjusted to 7.0 with conc. HCl while stirring. The ether layer was separated and the aqueous layer was extracted with 150 ml aliquots of ether twice. Combined ether layers were dried over a bed of anhydrous sodium sulfate and concentrated on rotavapor to about 100 ml and let it sit at RT. The recrystallized solid was filtered, washed with ether and dried to obtain 10.6 gr of solid diketone.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:28](OCC)=[O:29])=[CH:16][C:15]([F:33])=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:35][NH2:36]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:29])[C:17]=4[CH:16]=[C:15]([F:33])[CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccccc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CN(C)Cc1ccc(C2Nc3cc(F)cc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of compound ethyl 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg, 0.18 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The solvent was removed in vacuum; the crude product was purified by chromatography to obtain the title compound as a yellow solid (22 mg, yield 30%). LC-MS (ESI) m/z: 415 (M+1)+. 1H-NMR (400 MHz, DMSO-d) δ (ppm): 2.14 (s, 6H), 3.36 (s, 2H), 4.18-4.21 (d, J=8.8 Hz, 1H), 4.67-4.69 (d, J=9.2 Hz, 1H), 6.81-6.84 (m, 1H), 6.99-7.01 (m, 2H), 7.08-7.19 (m, 8H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([Cl:30])[CH:17]=1.Cl>O1CCCC1>[Cl:30][C:18]1[CH:17]=[C:16]([CH2:15][CH:8]([C:3](=[O:7])[CH2:4][CH2:5][CH3:6])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:21]=[CH:20][C:19]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1Cl
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(Cl)c1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (0.50 g) in tetrahydrofuran (20 mL) was added dropwise a solution of ethyl butyrylacetate (2.40 g) in tetrahydrofuran (10 mL). After stirring for 30 min, 4′-(bromomethyl)-2′-chlorobiphenyl-2-carbonitrile (2.30 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(2-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(2-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (1.35 g) and 28% sodium methoxide (4.09 g) in methanol (30 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (1.95 g, 73%) as a white solid.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Brc1ccccn1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccn1)O2

Procedure:
This compound was prepared by reacting rac-3,4-dihydro2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-bromopyridine as described in Example 14. The compound was isolated by chromatography as in Example 14 and was crystallized from ethyl acetate to give colorless crystals with m.p. 179°-181° C.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:19]([CH2:40][OH:41])[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]([O:50][C@H:51]1[C@@H:63]([O:64][C:65](=[O:72])[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C@H:62]([O:73][C:74](=[O:81])[C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[C@@H:61]([CH2:82][O:83][C:84](=[O:91])[C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[O:60][C@@H:52]1OC(=N)C(Cl)(Cl)Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:19]([CH2:40][O:41][C@H:52]2[O:60][C@H:61]([CH2:82][O:83][C:84](=[O:91])[C:85]3[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=3)[C@@H:62]([O:73][C:74](=[O:81])[C:75]3[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=3)[C@H:63]([O:64][C:65](=[O:72])[C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[C@@H:51]2[O:50][C:42](=[O:49])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: N=C(O[C@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask was added 2-azidoethyl 2,3,4-tri-O-benzoyl-α-D-mannopyranoside (720 mg, 1.282 mmol), 2,3,4,6-tetra-O-benzoyl-1-O-(2,2,2-trichloroethanimidoyl)-α-D-mannopyranose (1.14 g, 1.539 mmol) and 4 Å molecular sieves (300 mg). To the above mixture was added CH2Cl2 (10 mL). The reaction mixture was cooled to -78° C. To the above mixture was added TMSOTf (23.2 μL, 0.128 mmol). The mixture was allowed to gradually warm to 0° C. and stirred for 30 min. The reaction was then quenched with sat. NaHCO3, and the mixture was filtered through a pad of Celite. The filtrate was diluted with CH2Cl2 (20 mL), washed with brine and water. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (80 g), eluting with 0-100% EtOAc in hexanes, to give the title product. LC-MS Method A: m/e=1157.64 [M+18] and 1163.52 [M+Na]; Rt=3.01 min. 1H NMR (CDCl3) δ 7.2-8.3 (m, 25H), 6.0 (t, 1H), 5.8 (t, 1H), 5.7 (m, 2H), 5.4 (s, 1H), 5.38 (m, 1H), 5.2 (s, 1H), 4.7 (dd, 1H), 4.6 (dd, 1H), 4.45 (m, 1H), 4.35 (dd, 1H), 3.9-4.0 (m, 2H), 3.8 (m, 2H), 3.7 (m, 1H), 3.4 (m, 2H).
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH2:20][CH2:21][CH3:22])=[C:18]([C:23]([OH:25])=O)[N:17]=[N:16]2)=[CH:11][CH:10]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C1C=C[C:29]2N(O)N=[N:32][C:30]=2[CH:31]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:30]1([NH:32][C:23]([C:18]2[N:17]=[N:16][N:15]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:8])=[CH:14][CH:13]=3)[C:19]=2[CH2:20][CH2:21][CH3:22])=[O:25])[CH2:31][CH2:29]1
Reactant: CCCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
1-{4-[(Pentylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (487 mg, 1.41 mmol) obtained in Example 57b), HOBt (193 mg, 1.41 mmol, 1.0 eq.) and cyclopropylamine (0.131 ml, 1.84 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (1:1, 7.5 ml), WSC (332 mg, 1.70 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a white powder. This was crystallized from methanol-ethyl acetate to give the title compound as a white powder (298 mg, 0.777 mmol, 55.1%). The mother liquor was concentrated, and crystallized from diethyl ether to give the title compound as a white powder (225 mg, 0.587 mmol, 41.6%).
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18](NC3C=C4C(=CC=3)C(CC(O)=O)CC4)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.C1(C)C(N=C=S)=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C([OH:62])C>>[C:1]1([CH3:34])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:19])=[O:62])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc4c(c3)CCC4CC(=O)O)cc2o1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccccc1N=C=S
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-amino-3-hydroxy-phenylacetate (3.3 g, Reference Example 3) and o-tolylisothiocyanate (2.5 mL) in ethanol (150 mL) was stirred at room temperature for about 2 hours. After standing at room temperature overnight the mixture was evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3, v/v) to give a yellow foam. A solution of this material in ethanol (150 mL) was treated with dicyclohexylcarbodiimide (3.0 g) and the mixture was heated at reflux temperature for 2 hours. The mixture was evaporated and the residue subjected to short column chromatography on silica eluting with a mixture of 5-10% tert-butyl methyl ether in dichloromethane to remove dicyclohexylurea. The resulting light yellow oil was dissolved in ethanol (100 mL) and the solution was treated with sodium hydroxide solution (15 mL, 1M) then heated at reflux temperature for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was acidified to pH 1 by addition of concentrated hydrochloric acid. The resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (1.8 g) as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[NH2:42][C:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[C:43]([C:45]1[CH:50]=[C:49]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])[CH:48]=[CH:47][CH:46]=1)(=[O:44])[NH2:42]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3cccc(C(N)=O)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 47.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (5.6 mL), and the solution was added with (3-aminocarbonylphenyl)boronic acid (89 mg, 0.54 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (17.6 mg, 0.0216 mmol), potassium carbonate (93.0 mg, 0.675 mmol) and water (0.049 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(3-carbamoylphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (36.1 mg, yield 47%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:22][CH2:23][OH:24].[CH2:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][N:31]=1)(=[O:29])=[O:28])[CH3:26]>>[CH2:25]([S:27]([C:30]1[N:31]=[CH:32][C:33]([C:10]2[CH:9]=[CH:8][C:7]([C:5]3[O:6][C:2]([CH3:1])=[C:3]([CH2:22][CH2:23][OH:24])[N:4]=3)=[CH:12][CH:11]=2)=[CH:34][CH:35]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Reactant: CCS(=O)(=O)c1ccc(I)cn1
Product: CCS(=O)(=O)c1ccc(-c2ccc(-c3nc(CCO)c(C)o3)cc2)cn1

Procedure:
The titled compound is prepared substantially in accordance with the procedure of Intermediate 9 using 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (See Intermediate 3) and 2-Ethanesulfonyl-5-iodo-pyridine (See Intermediate 22). MS (m/e) 373.3 (M+1)
Reaction SMILES: NC1N=C(NC2O[C@H](CO)[C@@H](O)[C@H]2[OH:11])N=C(P(O)(OO)=O)C=1N.N[C:25]1[N:30]=[C:29]([NH:31][CH:32]2[O:38][C@H:37]([CH2:39][O:40][P:41]([OH:44])([OH:43])=[O:42])[C@@H:35]([OH:36])[C@H:33]2[OH:34])[C:28]([NH2:45])=[C:27]([OH:46])[N:26]=1>>[NH2:45][C:28]1[C:27](=[O:46])[NH:26][C:25](=[O:11])[NH:30][C:29]=1[NH:31][CH:32]1[O:38][C@H:37]([CH2:39][O:40][P:41]([OH:44])([OH:43])=[O:42])[C@@H:35]([OH:36])[C@H:33]1[OH:34]
Reactant: Nc1nc(NC2O[C@H](CO)[C@@H](O)[C@H]2O)nc(P(=O)(O)OO)c1N
Reactant: Nc1nc(O)c(N)c(NC2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)n1
Product: Nc1c(NC2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)[nH]c(=O)[nH]c1=O

Procedure:
As noted above, in bacteria and fungi, GTP cyclohydrolase II (EC 3.5.4.25) catalyzes the reaction of GTP with a purine to produce 2,5-Diamino-6-hydroxy-4-(5′phosphoribosylamino)-pyrimidine; diaminohydroxyphosphoribosylaminopyrimidine deaminase (EC 3.5.4.26) catalyzes the reaction of 2,5-Diamino-6-hydroxy-4-(5′phosphoribosylamino)-pyrimidine to produce 5-amino-6-(5-phosphoribosylamino)uracil; 5-amino-6-(5-phosphoribosylamino)uracil reductase (EC 1.1.1.193) catalyzes the reaction of 5-amino-6-(5-phosphoribosylamino)uracil to produce 5-Amino-6-(5′phosphoribitylamino)uracil; lumazine synthase catalyzes the reaction of 5-Amino-6-(5′phosphoribitylamino)uracil to produce 6,7-Dimethyl-8-ribityl lumazine; and riboflavin synthase (EC 2.5.1.9) catalyzes the reaction of 6,7-Dimethyl-8-ribityl lumazine to produce riboflavin
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH:3]([F:5])[F:4].[O:16]([C:23]1[CH:24]=[C:25]([NH:29][CH2:30][CH:31](O)[C:32]([F:35])([F:34])[F:33])[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Zn+2].[I-].[I-].C1(C)C=CC=CC=1>[O:16]([C:23]1[CH:24]=[C:25]([N:29]2[CH2:30][CH:31]([C:32]([F:33])([F:34])[F:35])[O:11][CH:10]2[C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:4])[F:5])[CH:8]=2)[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC(CNc1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [I-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: FC(F)C(F)(F)Oc1cccc(C2OC(C(F)(F)F)CN2c2cccc(Oc3ccccc3)c2)c1
Yield: 91.7 %

Procedure:
A toluene solution (5 mL) of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.45 g, 2.0 mol) and N-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.60 g, 2.0 mmol) was refluxed in the presence of molecular sieves and ZnI2 (˜5 mg) for 18 h under N2. The reaction mixture was filtered to remove the sieves, and the filtrate was diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to give 0.92 g (92%) of the desired 3-(3-phenoxyphenyl)-2-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-5-(trifluoromethyl) oxazolidine product as a colorless oil. The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) in the 1H NMR spectrum. HRMS calcd. 502.1253 [M+H]+, found: 502.1220.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]#[CH:18])[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:30][N:31]=[C:32]=[O:33]>C(Cl)Cl>[CH3:30][NH:31][C:32](=[O:33])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][CH2:16][C:17]#[CH:18])[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: C#CCN=C1CCc2c1n(C)c1ccc(O)cc21
Reactant: CN=C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCN=C1CCc2c1n(C)c1ccc(OC(=O)NC)cc21
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (3.4 g) in CH2Cl2 (15.0 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (326 mg) followed by the dropwise addition of methyl isocyanate (0.8 g) in CH2Cl2 (5.0 ml). The reaction was monitored via TLC and after 1.0 hour, the solution was concentrated and the crude product was purified via flash chromatography eluting with hexane/acetone (2:1). The product which precipitated out of the pure fractions was collected to give 4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate (1.2 grams) and the fractions were concentrated to give an additional 0.9 gram.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(CCOC2CCCCO2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Sodium hydride (1.27 g of a 50% suspension in mineral oil, 26.4mmol) was added to a solution of 4-hydroxypyridine (2.5 g, 26 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (5.0 g, 23.9 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), in DMF (5 ml) was added and the mixture heated at 80° C. for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 1-[2-(tetrahydropyran-2-yloxy)ethyl]-1,4-dihydro-4-pyridone (1.5 g, 28%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH:14]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:29])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=O>CO.O1CCCC1>[NH2:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:14][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:29])[CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)(=[O:11])=[O:12]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1cccc(-c2cccc(C(=O)NCCN3CCCC3)c2)c1
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(CCNCc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(2-Aminoethyl)benzene sulfonamide (2.37 g) and molecular sieves 3A (4.0 g) were added to a solution of 3′-formyl-N-[2-(1-pyrrolidinyl)ethyl][1,1′-biphenyl]-3-carboxamide (3.81 g) in methanol (50 ml), and the mixture was stirred at room temperature for 1.5 hours. After the reaction mixture was diluted with tetrahydrofuran (THF), the molecular sieves were filtered off, and the filtrate was concentrated under reduced pressure. The residues were dissolved in a mixed solvent (100 ml) of methanol-THF (1:1), and sodium borohydride (0.89 g) was added thereto. The reaction mixture was stirred at room temperature for 5 hours, and then the solvent was evaporated under reduced pressure. The residues were diluted with water and extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residues were crystallized from hexane, whereby the title compound (3.71 g) was obtained.