Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[OH:35])[N:19]=2)[CH2:13]1)C1C=CC=CC=1.N#N>[Pd].CCO.CCOC(C)=O>[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[OH:35])[N:19]=2)[CH2:13]1
Reactant: Cc1ccc2c(N3CCCC(CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc2c(N3CCCC(CN)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of benzyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (1.75 g, 3.63 mmol) and EtOH/EtOAc (50 mL/20 mL) was heated to obtain a homogeneous solution. After cooling to room temperature, Pd/C (175 mg, 10% wt Pd on carbon) was added and the flask was sealed with a septum. The same flask was 3 times charged with N2 and evacuated under vacuum. The mixture was then stirred under an H2 atmosphere at ambient pressure for 1 h. The product was collected by filtration through a plug of Celite, eluting with MeOH. The filtrate was concentrated to a yellow solid (1.26 g) to give 2-(4-(3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol. LC/MS: m/z 349.3 (M+H)+ at 1.80 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[Br:9]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[Br:9][C:7]1[NH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: O=[N+]([O-])c1cc[nH]c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c[nH]c(Br)c1

Procedure:
To a tetrahydrofuran solution (10 mL) of 3-nitro-1H-pyrrole (520 mg, 4.64 mmol), 1,3-dibromo-5,5-dimethylhydantoin (730 mg, 2.55 mmol) was added at −78° C. and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure and water was added to the resultant residue, followed by extraction from the resultant mixture with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [CH2:1]([NH:3][Si:4]([NH:11][CH2:12][CH3:13])([NH:8][CH2:9][CH3:10])[NH:5][CH2:6][CH3:7])[CH3:2].[C:14]1(C)C=CC=C[CH:15]=1>>[CH2:9]([NH:8][Si:4]([NH:5][CH2:6][CH3:7])([NH:11][CH2:12][CH3:13])[N:3]([CH2:14][CH3:15])[CH2:1][CH3:2])[CH3:10]
Reactant: Cc1ccccc1
Reactant: CCN[Si](NCC)(NCC)NCC
Product: CCN[Si](NCC)(NCC)N(CC)CC

Procedure:
A three-necked flask in which the internal atmosphere was sufficiently replaced with nitrogen gas was charged with 50 ml of a THF solution of diethylamine (0.1 mol/50 ml). The solution was cooled to −10° C. while stirring and 100 ml of a THF solution of BuMgCl (0.1 mol/100 ml) was slowly added dropwise using a dripping funnel. After the addition, the mixture was reacted at 40° C. for two hours to complete the reaction. A slurry of Mg salt of diethylamine obtained in this manner was slowly added to 50 ml of a 0.09 mol/50 ml toluene solution of tetrakis(ethylamino)silane synthesized according to the method of Example 33 at −10° C. while stirring. After the addition, the mixture was allowed to react at 50° C. for two hours. The reaction product was centrifuged in a nitrogen stream to separate a solid from liquid. The solid was washed twice with toluene. The solution was concentrated and purified by distillation under reduced pressure. Tris(ethylamino)(diethylamino)silane thus obtained was subjected to elementary analysis to confirm that the compound consists of C: 41.32% (51.67%), H: 12.10% (12.14%), and N: 23.98% (24.10%), wherein the percentages of the parentheses are theoretical values.
Reaction SMILES: N[C:2]1SC=C(/C(=N/OC)/C(O)=O)N=1.O.ON1C2C=CC=CC=2N=N1.C1(N=[C:32]=[N:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)CCCCC1>CN(C)C=O>[CH3:2][N:33]([CH3:32])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 254 %

Procedure:
A mixture of 1.00 g (5.00 mmol) of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid, 0.76 g (5.00 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 1.14 g (5.50 mmol) of dicyclohexylcarbodiimide and 20 ml of N,N-dimethylformamide was stirred at room temperature for 2 hours. The obtained white solid was filtered and the filtrate was cooled to 0° C. The filtrate was added to mixed solution of 2.5 g (5.00 mmol) of 7-amino-3-(2,3-cyclopenteno-4-carbamoyl-1-pyridinium)methyl-3-cephem-4-carboxylate hydroiodic acid obtained in Preparation Example 24, 10 ml of N,N-dimethylformamide and 1.6 ml (12.70 mmol) of N,N-dimethylaniline. The mixture was stored at room temperature overnight and the precipitate was removed therefrom. The residue was dropped into 500 ml of diethylether with stirring. The precipitate was filtered, triturated with 100 ml of acetone and filtered again. The crude product thus obtained was dissolved in 100 ml of water and insoluble material was discarded by filtration. The resultant was freeze-dried to obtain 1.0 g of the same compound as obtained in Method a (yield: 37%).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16](Br)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].[K+].[Br-]>>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)C(=O)Nc1nc(O)c2cc(C#C[Si](C)(C)C)cnc2n1
Yield: 81 %

Procedure:
2-Pivaloylamino-4-hydroxy-6-trimethylsilylethynylpyrido[2,3-d]pyrimidine is prepared in 81% yield from 2-pivaloylamino-4-hydroxy-6-bromopyrido[2,3-d]pyrimidine and trimethylsilylacetylene analogously to Example 2B. m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 0.29 (s, 9H), 1.35 (s, 9H), 8.36 (brs, 1H), 8.57 (d, 1H, J=2.45 Hz), 8.92 (d, 1H, J=2.45 Hz); IR (KBr) 3200, 2970, 2170, 1680, 1620, 1545, 1475, 1440, 1380, 1275, 1250, 1145, 930, and 845 cm-1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:26])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C)C=O.O>[CH:35]1([CH2:34][N:23]2[CH2:22][CH2:21][CH:20]([O:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[C:10](=[O:26])[CH2:11][CH2:12]4)[CH2:25][CH2:24]2)[CH2:37][CH2:36]1
Reactant: O=C1CCc2cc(OC3CCNCC3)ccc2N1c1ccc(F)cc1
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(OC3CCN(CC4CC4)CC3)ccc2N1c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
A suspension of 1-(4-fluorophenyl)-6-(piperidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one hydrochloride prepared in Example 7-(3) (0.30 g), potassium carbonate (0.55 g) and (bromomethyl)cyclopropane (0.32 g) in N,N-dimethylformamide (10 mL) was stirred at 100° C. for 6 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1) and preparative TLC (on a single plate of 2 mm thickness, developing solvent: chloroform/methanol=9/1) to give the titled compound (0.11 g, 35%) as a colorless amorphous substance.
Reaction SMILES: F[B-](F)(F)F.[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N+]#N.[CH3:16][S-:17].[Na+].N#N>CC#N>[Br:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[S:17][CH3:16]
Reactant: N#[N+]c1ccc(Cl)cc1Br
Reactant: C[S-]
Agent: F[B-](F)(F)F
Agent: N#N
Agent: [Na+]
Solvent: CC#N
Product: CSc1ccc(Cl)cc1Br
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A cold (0° C.) solution of 2-bromo-4-chlorobenzenediazonium tetrafluoroborate (5.0 g, 16.3 mmol) in CH3CN (50 mL) was treated portion wise with sodium thiomethoxide (1.15 g, 16.4 mmol) and a strong evolution of gas (N2) was observed. The mixture was warmed up to 23° C., stirred for 0.25 hours and filtered. The filtrate was concentrated in vacuo; the residue was taken up in CH2Cl2, stirred and the solution was then filtered. The CH2Cl2 filtrate was concentrated in vacuo affording a brown syrup that was distilled under vacuum to provide the purified title compound; bp 125° C./0.4 mm, 1.4 g, 37%. 1H NMR (CDCl3) δ7.56 (d, J=2.5 Hz, H-3, 1H), 7.30 (dd, J=2.5 Hz, J=8.6 Hz, H-5, 1H), 7.07 (d, J=8.6 Hz, H-6, 1H), 2.49 (s, CH3, 3H). IR 1569, 1544, 1450, 1434, 1371,1248, 1105, 1024, 868, 803, 784 cm31 1. Anal. Calcd. for C7H6BrClS: C, 35.39; H, 2.55. Found: C, 34.89; H, 2.51.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.O.[NH2:21][NH2:22]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4](=[N:21][NH2:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: NN
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1cc([N+](=O)[O-])ccc1N)c1ccccc1Cl

Procedure:
In the manner given in Preparation 1, 2-amino-2'-chloro-5-nitrobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-2'-chloro-5-nitrobenzophenone hydrazone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:16][C:4]3[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(-c2nc(C)c(C)cc2O)n1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
5,6,6′-Trimethyl-[2,2′]bipyridin-3-ol (300 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.26 g), 4-dimethylaminopyridine (513 mg), and cesium carbonate (1.37 g) were suspended in dimethyl sulfoxide (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (483 mg, yield 72%).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.CCN(CC)CC.[C:13](Cl)([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14]>C(Cl)Cl>[CH:28]1[C:29]2[CH:17]([CH2:16][O:15][C:13]([N:1]3[CH2:5][CH:4]=[CH:3][CH2:2]3)=[O:14])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: C1=CCNC1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CC=CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 3-pyrroline (25.0 g, 0.36 mol) in CH2Cl2 (500 mL) at 0° C. was added Et3N (60 mL, 0.42 mol), followed by Fmoc-Cl (103 g, 0.39 mole) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then 30 minutes at it. The reaction mixture was partitioned between H2O (250 mL) and CH2Cl2 (150 mL×3). The organic phase was washed with brine and dried over Na2SO4. The solvent was evaporated, and the residue was purified on silica gel using 5 to 70% EtOAc in hexanes as eluting solvents to afford 2,5-dihydro-pyrrole-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (99 g, 95%) as a white solid. MS m/z 314.0 ([M+Na]+).
Reaction SMILES: N.C[N:3](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:44]=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:42]([O:50][CH:51]([CH3:53])[CH3:52])=[CH:41][C:36]=3[C:37]=2[C:38](O)=[O:39])=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:44]=[C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[C:42]([O:50][CH:51]([CH3:53])[CH3:52])=[CH:41][C:36]=3[C:37]=2[C:38]([NH2:3])=[O:39])=[CH:29][CH:28]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)Oc1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc2c(C(N)=O)c(-c3ccc(F)cc3)oc2cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Ammonia (6.1 ml, 12.2 mmol, 2M in MeOH) was added to a stirring solution of HATU (1.1 g, 2.95 mmol) and 2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxylic acid (1.0 g, 2.46 mmol) in DMF (20 ml) at 0° C. It was allowed to warm to rt and stir for 1 hr. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (925 mg, 93%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.30-1.37 (m, 6H) 2.98 (s, 3H) 4.64-4.77 (m, 1H) 7.19 (s, 1H) 7.30-7.41 (m, 2H) 7.54 (s, 1H) 7.63-7.71 (m, 1H) 7.89 (s, 1H) 7.93-8.02 (m, 2H) 8.85 (s, 1H). LC-MS retention time: 1.26 min; m/z (MH+) 407. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([NH:5][NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][N:2]=1.[C:14](Cl)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[C:14]([N:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]2[CH:1]=[N:2][N:3]=[C:4]2[NH:5]1)(=[O:16])[CH3:15]
Reactant: c1ccc2c(c1)NNc1nncn1-2
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1Nc2nncn2-c2ccccc21
Yield: 70 %

Procedure:
A mixture of 7.0 g (0.040 mole) of 4,5-dihydro-s-triazolo[3,4-c]benzo-as-triazine, 3.1 g (0.04 mole) of acetyl chloride and 50 ml of toluene is refluxed under nitrogen atmosphere. The reaction mixture is cooled. The title compound, melting at 220° C., is obtained with a yield of 70%. The product does not show melting point depression in admixture with the compound prepared according to Example 8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@H:4]1[O:50][C@@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]5)=[CH:37][CH:36]=4)[C:18]4[C:23]([C:24]=3[CH3:25])=[CH:22][C:21]([O:26]CC3C=CC=CC=3)=[CH:20][CH:19]=4)=[CH:12][CH:11]=2)[C@:7]([C:52](=[O:54])[CH3:53])([OH:51])[C@@:6]([C:56](=[O:58])[CH3:57])([OH:55])[C@@H:5]1[O:59][C:60](=[O:62])[CH3:61]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:63])[C@H:4]1[O:50][C@@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][N:44]5[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]5)=[CH:39][CH:40]=4)[C:18]4[C:23]([C:24]=3[CH3:25])=[CH:22][C:21]([OH:26])=[CH:20][CH:19]=4)=[CH:12][CH:11]=2)[C@:7]([C:52](=[O:54])[CH3:53])([OH:51])[C@@:6]([C:56](=[O:58])[CH3:57])([OH:55])[C@@H:5]1[O:59][C:60](=[O:62])[CH3:61]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc(-c3c(C)c4cc(OCc5ccccc5)ccc4n3Cc3ccc(OCCN4CCCCC4)cc3)cc2)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(-c3c(C)c4cc(O)ccc4n3Cc3ccc(OCCN4CCCCC4)cc3)cc2)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@H]1OC(C)=O
Yield: 98.9 %

Procedure:
Glycosidated indole 33 (34 g, 0.039 mol) in 400 mL THF/MeOH (1:1) was treated with 10% Pd/C (5.4 g) and hydrogenated in a Parr apparatus at 50 psi for 30 h. The mixture was filtered through Siluflock and 0.34 g of L-Ascorbic acid was added to the filtrate. The cake of Siluflock was washed with THF and the combined filtrates were concentrated to yield product 35 (29.8 g, 98%) as a yellowish-white solid: 1H NMR (CDCl3) δ 6.95 (m, 11 H), 5.34 (m, 2 H), 5.14 (d, 1 H, J=2 Hz), 5.01 (s, 2 H), 4.21 (m, 1 H), 4.06 (t, 2 H), 2.83 (t, 2 H), 2.62 (br s, 4 H), 2.13 (s, 3 H), 1.65 (t, 4 H), 1.44 (br s, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]1[CH2:25][CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13][C@@H:12]1[CH2:25][CH2:26][O:27][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@@H](CCO)C1
Solvent: CN(C)C=O
Product: COCC[C@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of [(1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(hydroxyethyl)-cyclohexyl]-carbamic acid benzyl ester (0.42 g, 1.07 mmol) in DMF (4 mL) was charged with iodomethane (20 mL) and Ag2O (1.24 g, 5.35 mmol) and stirred at RT for 14 h. The mixture was filtered and the filtrate was diluted with sat. NaHCO3 and minimum EtOAc. The mixture was separated (organic on bottom). The aqueous was extracted with EtOAc, and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford [(1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(methoxyethyl)-cyclohexyl]-carbamic acid benzyl ester (0.255 g). MS found: (M+H)+=429.2.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8](S(C)(=O)=O)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1nc(S(C)(=O)=O)ncc1C(N)=O
Reactant: N[C@@H]1CCC[C@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(N[C@@H]2CCC[C@H](O)C2)ncc1C(N)=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of 4-(tert-butylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (250 mg, 0.918 mmol; synthesis described herein) and (1S,3R)-3-aminocyclohexanol (138 mg, 1.2 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in NMP (10 mL) was added DIEA (374 mg, 2.9 mmol). The resulting mixture was stirred at 100° C. overnight. The reaction mixture was purified by preparative HPLC to give the desired product (212.2 mg, 0.69 mmol, yield 75%). 1H NMR (400 MHz, CDCl3) δ ppm 8.86 (brs, 1H), 8.12 (s, 1H), 5.53 (brs, 3H), 3.93-3.91 (m, 1H), 3.88-3.82 (m, 1H), 2.27-2.25 (m, 1H), 1.92-1.85 (m, 3H), 1.47 (s, 9H), 1.42-1.25 (m, 4H); MS (ESI) m/z=308.2 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[S:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: S=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
In a three-necked, 500 ml flask provided with reflux condenser and mechanical stirrer, 25.3 g 4,5-diphenyl-4-oxazolin-2-thione, 27.6 g anhydrous potassium carbonate, 14.5 ml ethyl bromoacetate and 200 ml absolute ethanol were refluxed for 5 hours with vigorous stirring. The mixture was cooled to room temperature, filtered and washed with absolute ethanol on the filter. The filtrate was evaporated to dryness in vacuo and the residue was suspended in 150 ml ether and 150 ml water. The ethereal phase was separated, dried on anhydrous sodium sulphate, filtered and evaporated to dryness in vacuo to give 23 g ethyl S-(4,5-diphenyloxazol-2-yl)-mercaptoacetate as an oil which was recrystallized from an anhydrous ether-petroleum ether mixture: m.p. 53°-55° C; yield = 67.9%.
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH:8]=[C:9]([C:14]1[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:16]=3[CH:15]=1)[CH2:10]2)=O)C.O.NN.[OH-].[K+].O>C(O)CO>[CH3:24][O:23][C:22]1[C:16]2[CH:15]=[C:14]([C:9]3[CH2:10][CH:11]4[NH:6][CH:7]([CH2:13][CH2:12]4)[CH:8]=3)[S:18][C:17]=2[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)N1C2C=C(c3cc4c(OC)cccc4s3)CC1CC2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1cccc2sc(C3=CC4CCC(C3)N4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of (±)-8-ethoxycarbonyl-3-(4-methoxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-ene (0.719 g, 2.09 mmol), hydrazine hydrate (0.51 mL, 10.4 mmol) and KOH (0.700 g, 12.5 mmol) in ethylene glycol (15 mL) was heated at reflux in a sand bath for 3 h. The reaction mixture was then cooled to room temperature and stirred overnight. The reaction mixture was poured into water (20 mL). This mixture was extracted with Et2O (3×30 mL). The combined organic layers were washed with 1.0 N HCl (1×175 mL). The layers were separated and the aqueous layer was basified with 2.5 N NaOH (25 mL). This layer was extracted with EtOAc (2×275 mL). The combined organic layers were then dried over MgSO4, concentrated, and the residue was purified by medium pressure chromatography (silica gel, 7% (10% conc. NH4OH in MeOH)/CH2Cl2] to give the intermediate title compound as an orange semi-solid (0.574 g, quantitative yield). mp (oxalate) 204-207° C. IR (KBr) 3400 (br) cm−1. Ion Spray MS 272 (M+H)+; 255 (M-16)+(base peak).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=O)[C:2]1=2.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([Cl:16])=[O:12])[C:2]1=2
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
2,3-Dihydrobenzo[b]furan-7-oic acid (3 g) (see Preparation 32) was suspended in anhydrous dichloromethane (30 ml) and oxalyl chloride (3.5 g) added, followed by addition of dimethylformamide (3 drops). The mixture was stirred at room temperature for 2.5 hours, the solvent then removed under reduced pressure, the resulting residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was again dissolved in dichloromethane and the solvent removed under reduced pressure to give 2,3-dihydrobenzo[b]furan-7-oyl chloride as a pink solid (3.3 g).