Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(O)[C:8]#[C:9][C@:10]2([O:18][CH3:19])[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:19][O:18][C@@:10]1([C:9]#[C:8][CH:7]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1
Reactant: CO[C@]1(C#CC(O)(c2ccccc2)C2CCCCC2)CN2CCC1CC2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CO[C@]1(C#CC(c2ccccc2)C2CCCCC2)CN2CCC1CC2
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
1-cyclohexyl-3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-2-propyn-1-ol 201 (150 mg, 0.42 mmol) was dissolved under argon in CH2Cl2 (20 ml) and then cooled to −40° C. Neat Et3SiH (203 μL, 1.27 mmol) was added dropwise. After 5 minutes, neat BF3.OEt2 (376 μL, 1.27 mmol) was slowly added to the mixture. After 15 minutes, the reaction was slowly left to room temperature, then quenched with saturated aqueous K2CO3 solution after 45 minutes and diluted with ether. The organic phase was dried over Na2SO4 and evaporated to dryness to give (3R)-3-(3-cyclohexyl-3-phenyl-1-propynyl)-1-azabicyclo[2.2.2]oct-3-yl methyl ether 112 (mixture of diastereomers) as a colorless oil (140 mg, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:50])=[O:51])[CH:45]=[CH:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 90.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.19 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (intermediate 3) (84.8 mg, 0.285 mmol) in sodium carbonate (60.5 mg, 0.57 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (13.3 mg, 0.019 mmol) and toluene/ethanol/water (12/6/2 ml) to afford 106 mg of the crude product which was taken as such for next step. MS: m/z=615.7 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][O:40][C:41]1[N:42]=[C:43]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])[CH:3]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Yield: 57.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (190 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmols) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 20%, dichloromethane-ethyl acetate) to give 61 mg (59% yield) of the title compound. Purity 632%.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH2:12][CH3:13].[C:14](O)(=[O:16])[CH3:15].Br>O>[CH2:11]([C:4]1[C:5]([OH:9])=[C:6]([C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][C:3]=1[OH:2])[CH2:12][CH3:13]
Reactant: CC(=O)O
Reactant: CCCc1c(OC)cccc1OC
Agent: Br
Solvent: O
Product: CCCc1c(O)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
1,3-Dimethoxy-2-propylbenzene (0.90 g, 5.0 mmol), glacial acetic acid (150 ml), and 48% aqueous hydrobromic acid (15 ml, 133 mmol) were combined and stirred at reflux temperature for three days. The mixture was allowed to cool to room temperature; poured into water (500 ml), and the aqueous solution extracted with ether (500 ml, 2×). The ether layers were combined, washed with brine, dried over magnesium sulfate, filtered and taken to dryness in vacuo. Flash chromatography as in Example 10 (plus an additional step of 5% ethyl acetate in hexane) yielded the title product: n.m.r.: δ12.97 (s, 1H), 7.52 (d, 1H), 6.38 (d, 1H), 5.79 (s, 1H), 2.63 (t, 2H), 2.56 (s, 3H), 1.58 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][N:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([NH2:6])=[N:8][CH:9]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1ccc(CNc2ccc(C3(C)CCOCC3)cn2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2ccc(N)nc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To an ice cold solution of N-(2,4-dimethoxybenzyl)-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (100 mg, 0.29 mmol) in DCM (6 mL) was added 10 mL 30% TFA in DCM solution. The resulting solution was stirred at 0° C. for 15 min. The solvent was removed via vacuum. The resulting residue was redissolved in ethyl acetate, and the organic solution was washed with 1M NaOH, brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silicagel (ISCO) eluting with 0-100% ethyl acetate in heptane to give 5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (50 mg, 0.26 mmol, 89% yield) as white color solid. LCMS (m/z): 193 (MH+), 0.35 min.
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[CH:5]1([CH3:15])[CH2:10][CH2:9][CH:8]([CH:11]([CH3:13])[CH3:12])[CH:7]([OH:14])[CH2:6]1>ClCCl>[Cl:2][P:1]([Cl:4])[O:14][C@@H:7]1[CH2:6][C@H:5]([CH3:15])[CH2:10][CH2:9][C@H:8]1[CH:11]([CH3:13])[CH3:12]
Reactant: ClP(Cl)Cl
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OP(Cl)Cl
Temperature: -30 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
The phosphorus trichloride (56.0 ml, 87.89 g, 0.640 mol) was added to dichloromethane (anhydrous) under argon gas to obtain a solution. The solution was cooled to −30° C. and (−)-menthol (1R,2S,5R) (10.00 g, 0.0640 mol) was added portion wise over 10 mins. The solution was allowed to warm to ambient temperature and was allowed to stir at ambient temperature for 16 hours. The solvent was removed in vacuo to obtain a colourless oil (16.46 g). The crude product was used directly in the subsequent step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]3=[O:24])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.N1C=CC(C2C=CC=C3C=2CCN=C3)=CC=1>>[CH:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][C:12]3=[O:24])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)C(=O)C1
Agent: C1=NCCc2c1cccc2-c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCN=C3)C(=O)C1

Procedure:
Intermediate 18 was prepared from Intermediate 18A as described for Intermediate 17. MS (ESI) m/z: 330.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[Cl:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][CH:22]=[N:23]2)=[C:19]([NH2:26])[N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:19]([NH2:26])[N:18]=1
Reactant: ClCc1cccnc1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc2c1ncn2Cc1cccnc1
Temperature: 80 °C

Procedure:
Potassium carbonate (1.1 g, 8 mmol) and 3-chloromethylpyridine hydrochloride (660 mg, 5 mmol) were added to a DMF solution (30 ml) comprising 2-chloroadenine (520 mg, 3 mmol), and the resultant was stirred while heating at 80° C. for 3 hours. The reaction solution was concentrated under reduced pressure, water was added thereto, and the precipitated solid was collected by filtration. Thus, 2-chloro-9-(3-pyridylmethyl)adenine was obtained (yield: 759 mg). Sodium (750 mg, 30 mmol) was added to butanol (50 ml), and the temperature of the mixture was raised to 90° C. to completely dissolve sodium therein. Subsequently, 2-chloro-9-(3-pyridylmethyl)adenine (430 mg, 1.5 mmol) was added thereto, and the resultant was heated under reflux for 2 hours. The solvent was concentrated under reduced pressure, water was added to the residue, and concentrated hydrochloric acid was added dropwise under ice cooling to neutralize the solution. Liquid separation was carried out with the addition of methylene chloride, and the organic layer was concentrated under reduced pressure. Acetic acid (30 ml) was added to the residue to dissolve it, bromine (660 mg, 5.5 mmol) was added thereto, and the resultant was allowed to react at room temperature all day and night. The reaction solution was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1). Thus, 310 mg of 8-bromo-2-butoxy-9-(3-pyridylmethyl)adenine was obtained. Subsequently, the title compound was obtained in the same manner as in Reference Example 3 and Example 1.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[F:8]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)C(=O)Nc1cc(F)c(Br)cc1-c1ccccn1
Agent: O=S(=O)(O)O
Product: CC(C)(C)C(=O)Nc1c(-c2ccccn2)cc(Br)c(F)c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To an ice-cold solution of N-(4-bromo-5-fluoro-2-(pyridin-2-yl)phenyl)pivalamide (17.5 g, 50.0 mmol) in conc. H2SO4 (50.0 mL) was added drop wise fuming HNO3 (10.0 mL). The resulting mixture was stirred at 0-10° C. for 1 h. After completion of reaction (by TLC), the mixture was poured onto 500 mL of crushed ice and stirred for 30 min followed by extraction with EtOAc (3×500 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude was triturated with Et2O to obtain the desired product as a yellow solid (15.0 g, 76%). MS: 396.23 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:10][OH:11])=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(CO)NCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(CO)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 2-benzylamino-2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](S)[O:8][C:4]=2[CH:3]=1.[K].[Cl:13]Cl>ClC1C=CC=CC=1>[Cl:13][C:7]1[O:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: ClCl
Reactant: Sc1nc2ccc(Cl)cc2o1
Agent: [K]
Solvent: Clc1ccccc1
Product: Clc1ccc2nc(Cl)oc2c1
Reaction time: 12 h
Yield: 91 %

Procedure:
223.5 g (1 mole) of potassium 6-chloro-2-mercaptobenzoxazole are suspended in 500 ml of chlorobenzene and 180 g (2.5 moles) of chlorine gas are added in the course of 3 hours at a temperature of approx. 25° C. Stirring is continued for 12 hours at room temperature and excess chlorine is blown out of the mixture by means of nitrogen. The precipitated potassium chloride is filtered off and rinsed with approx. 200 ml of chlorobenzene. The filtrate is then distilled. When the sulfur dichloride and chlorobenzene have been distilled off, 171 g (91% of theory) of 2,6-dichlorobenzoxazole are obtained, having a melting point of 49°-51° C. and a boiling point of 124°-128.5° C. under approx. 25 mbars.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])[CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[O:13]1.C(=O)(O)[O-].[Na+]>>[F:5][C:6]1[C:11]([CH:12]2[CH2:16][CH2:15][C:14](=[O:17])[O:13]2)=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])[CH:7]=1
Reactant: O=C1CCC(c2ccc(NC(=O)c3ccccn3)cc2F)O1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCC(c2cc([N+](=O)[O-])c(NC(=O)c3ccccn3)cc2F)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fuming nitric acid (3 ml) was added to N-(3-fluoro-4-(5-oxotetrahydrofuran-2-yl)phenyl)pyridine-2-carboxamide (600 mg) obtained in (step 4), and the reaction liquid was stirred at room temperature for 2 hours. With cooling with ice, aqueous saturated sodium bicarbonate was added to the reaction liquid to make it basic, and extracted with ethyl acetate. This was dried with anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting residue was washed with chloroform/hexane mixed solvent to obtain the entitled compound.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([NH:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)=[O:16])[CH:4]=[C:3]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[OH-].[Na+]>FC(F)(F)C(O)=O>[NH2:20][CH2:19][CH2:18][NH:17][C:15]([C:5]1[C:6]2=[C:14]3[C:9](=[CH:8][N:7]2[C:2](=[O:1])[CH:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:4]=1)[CH:10]=[CH:11][CH:12]=[CH:13]3)=[O:16]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)C1=CC(c2ccccc2)C(=O)n2cc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.4 %

Procedure:
A suspension of 0.9 g of tert.-butyl [2-(4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxamido)ethyl]carbamate in 1.6 ml of trifluoroacetic acid was stirred at room temperature. The reaction was finished after about 15 minutes and the reaction mixture was treated slowly with 36 ml of 0.25N sodium hydroxide solution, whereby the product crystallized out. The product was stirred for a short time and then filtered off under suction. After chromatography on silica gel with methylene chloride/methanol (9:1 and 2:1) and recrystallization from methanol there was obtained 0.31 g of N-(2-aminoethyl)-4,5-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxamide with a m.p. of 216°-218°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30].C(=O)=O.CC(C)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: O=C=O
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
2-[3-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (5.885 g, 22.64 mmol) and dichloromethane (135 mL) were combined. 4-Methylmorpholine (5.0 mL , 45.48 mmol, 2 eq.) was added. The mixture was cooled in a dry-ice/acetone bath and a solution of 3,4,5-trimethoxy-benzoyl chloride (5.22 g, 22.63 mmol) in dichloromethane (100 mL) was added dropwise. After the addition was complete, the dry-ice/acetone bath was changed to an ice bath and the mixture was stirred for 1 h. The solution was extracted with 1N HCl (50 mL), 5% NaHCO3 (50 mL), and H2O (50 mL) . The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel (400 g) eluting with ethyl acetate and then 6% methanol in dichloromethane to give the title compound:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:13](=O)[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][CH:9]([C:19]([O:21][CH3:22])=[O:20])[O:8][C:7]=2[CH:23]=1.C(O)C.C(OCC)(=O)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][CH:9]([C:19]([O:21][CH3:22])=[O:20])[O:8][C:7]=2[CH:23]=1
Reactant: [H][H]
Reactant: COC(=O)C1Oc2ccccc2C(=O)c2ccc(OC)cc2O1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C1Oc2ccccc2Cc2ccc(OC)cc2O1

Procedure:
Methyl 3-methoxy-12H-dibenzo[d,g][1,3]-dioxocin-12-one-6-carboxylate (1.35 g, 4.3 mmol) was combined with 35 ml of ethanol, 15 ml of ethyl acetate, 6 ml of acetic acid, and 0.70 g of 5 percent palladium on carbon catalyst and the suspension was placed on a Parr hydrogenator under 50 psi of hydrogen for 18 hours. The catalyst was removed by filtration and the filtrate was diluted with 300 ml of ether and 100 ml of water and the layers separated. The organic layer was extracted with 3-100 ml portions of water and 2-100 ml portions of saturated aqueous sodium bicarbonate and was then dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was purified by preparative liquid chromatography on silica gel eluting with a 15:85 mixture of ether and hexane to obtain 0.76 g (59 percent of theory) of the title compound as a white powder melting at 93°-95° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]([CH2:38][CH3:39])[CH2:40][CH3:41])=[CH:17][N:16]=1
Reactant: CCN(CC)CCC(=O)Nc1cnc(N)c2c(-c3ccc(N)c(OC)c3)csc12
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Product: CCN(CC)CCC(=O)Nc1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-Amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-diethylaminopropionamide, and the procedure described in General Procedure F. m/z (M+H)+571.3.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].N12CCCN=C1CCCCC2.CCOC(C)=O>C1COCC1>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:2]1
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Temperature: 50 °C
Yield: 104 %

Procedure:
A solution of cyclohex-2-enone (3.05 mL, 30 mmol) and diethyl malonate (4.58 mL, 30.0 mmol) in THF (30 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (4.52 mL, 30.0 mmol) and heated at 50° C. for 16 h. The cooled mixture was poured into EtOAc and washed sequentially with 1M aqueous HCl and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated to give diethyl 2-(3-oxocyclohexyl)malonate as an oil (8.0 g), used without further purification. Mass spectrum m/z 257 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH2:50]O)[CH2:48][OH:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=3)[CH:32]=2)[O:11][C:10]1([CH2:48][OH:49])[CH3:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3OC(C)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 70 °C
Yield: 108.2 %

Procedure:
To a stirred solution of bis-tosylate of {(3S,4R,5S,6S)-3,4,5-Tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-hydroxymethyl-tetrahydro-pyran-2-yl}-methanol (250 mg, 0.20 mmol) in dry THF (15 mL) was added lithium aluminum hydride (40 mg, 0.80 mmol) at 0° C. and heated at 70° C. for 16 hour. The excess lithium aluminum hydride was quenched with saturated aqueous sodium sulfate solution and filtered through celite bed. The filtrate was concentrated and purified by using silica gel column chromatography (30% ethyl acetate in hexane) to furnish 150 mg of {(3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-methyl-tetrahydro-pyran-2-yl}-methanol.