Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.BrC[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
1-methyl piperazine (805 μl, 7.6 mmol) was added to a solution of 4-(bromomethyl)benzonitrile (1 g, 5.1 mmol) and TEA (1.4 ml, 10.2 mmol) in DCM (15 ml) and the resulting mixture was stirred at room temperature for 24 hours. The solution was then diluted with DCM, washed with a 5% NaHCO3 solution and then with H2O. The organic phase was dried over Na2SO4 and evaporated to dryness to give 0.73 g of 4-(4-methyl-piperazin-1-yl)-benzonitrile as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH3:22])=[N:18][N:19]=[C:20]1[CH2:21][N:29]1[C:25](=[O:35])[C:26]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]2[C:28]1=[O:30]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, a mixture of 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 2',5-dichloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 262°-265°C.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1Cl)(=[O:10])=[O:9])([CH3:3])[CH3:2].[H-].[Na+].[OH2:24]>>[CH:1]([O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:12]=1[OH:24])(=[O:10])=[O:9])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)OCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-(2-isopropoxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.635 g, 4.58 mmol), 60% NaH (0.41 g, 13.74 mmol) and water (0.099 mL, 5.50 mmol) were reacted. The crude product (1.676 g) was carried on to the next step without purification. LC-MS (m/z) 340 (M-H)+.
Reaction SMILES: [CH3:1][C@:2]12[CH2:21][CH2:20][C@H:19]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:3]2=[O:4].C(OCC)(OCC)O[CH2:24][CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:24]([O:14][C:13]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:11](=[CH:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:2]2([CH3:1])[C@H:7]3[CH2:6][CH2:5][C:3]2=[O:4])[CH:12]=1)[CH3:25]
Reactant: CCOC(OCC)OCC
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1

Procedure:
Androstenedione (5 g.) was dissolved in dry benzene (20 ml). Triethyl orthoformate (6 ml) was added, followed by p-toluenesulphonic acid (250 mg) and the solution left at room temperature for ten minutes. The benzene solution was washed with aqueous sodium hydroxide (10%), followed by water, dried (anhydrous Na2SO4) and evaporated under reduced pressure to give a pale yellow solid (5.5 g.). This solid was recrystallized from ethanol to give 3-ethoxy-androsta-3,5-dien-17-one (4.3 g.) as white needles, m.p. 146°-149°. ##STR13##
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].O1CCCC1.[CH3:18][CH:19]([CH2:25][CH2:26][CH2:27][CH3:28])[C:20](OCC)=[O:21]>C(O)(=O)C>[O:21]=[C:20]([CH:19]([CH3:18])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(C)C(=O)CP(=O)(OC)OC

Procedure:
n-Butyllithium (150 ml.) is slowly added to a solution of dimethyl methylphosphonate (25.6 g.) in 475 ml. of tetrahydrofuran (THF) at about -65° C. To the mixture is added a solution of racemic ethyl 2-methylhexanoate (18.4 g.) in 50 ml. of THF, and the resulting mixture is stirred at -70° C. for 2 hrs. Then, 16 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with dichloromethane (about 400 ml.) and water (about 50 ml.), shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound, 16.7 g., b.p. 126°-129° C./1 mm.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]#[C:14][C:15](=[O:18])[CH2:16][CH3:17])[O:4]1.[NH2:19][OH:20]>C(O)C>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13](=[N:19][OH:20])[CH2:14][C:15](=[O:18])[CH2:16][CH3:17])[O:4]1
Reactant: CCC(=O)C#C[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: NO
Solvent: CCO
Product: CCC(=O)CC(=NO)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 22 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pent-1-yn-3-one (550 mg) and hydroxylamine (50% solution in water) (0.2 ml) in ethanol (10 ml) was stirred overnight at 22° C. The mixture was concentrated in vacuo to afford the title compound as a yellow oil (554 mg).
Reaction SMILES: [C:1]([C:4]1([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH2:6][CH:5]1[CH:7]=[CH2:8])(=[O:3])[CH3:2].[Br-].C([N+](CCCC)(CCCC)CCCCCCCCCCCCCCCC)CCC>>[C:12]1([NH:11][C:9]([C:4]2[CH2:6][CH:5]([CH:7]=[CH2:8])[O:3][C:1]=2[CH3:2])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC1CC1(C(C)=O)C(=O)Nc1ccccc1
Agent: CCCCCCCCCCCCCCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C=CC1CC(C(=O)Nc2ccccc2)=C(C)O1

Procedure:
1-Acetyl-2-vinylcyclopropanecarboxanilide (2 grams) was combined with 0.5 grams tributylhexadecylammonium bromide and heated for six hours to obtain essentially complete conversion to 4-phenylcarbamyl-5-methyl-2-vinyl-2,3-dihydrofuran. ##STR21##
Reaction SMILES: FC(F)(F)S(OC1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]2[C:8]=1[C@@:9]1([CH3:30])[C@H:18]([CH2:19][S:20]2)[C@:17]2([CH3:27])[C@H:12]([C:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]1)(=O)=O.[CH3:33][C:34]([O-:36])=[O:35].[K+]>CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C(Cl)Cl>[CH3:26][O:25][C:23]1[CH:22]=[C:21]2[C:8]([C@@:9]3([CH3:30])[C@H:18]([CH2:19][S:20]2)[C@:17]2([CH3:27])[C@H:12]([C:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]3)=[C:33]([C:34]([OH:36])=[O:35])[CH:24]=1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Reactant: CC(=O)[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc2c(c(C(=O)O)c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Temperature: 60 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl trifluoromethanesulfonate (32) (1.5 g, 3.0 mmol), KOAc (1.1 g, 12 mmol), Pd(OAc)2 (0.3 g, 2 mmol), dppf:CH2Cl2 1:1 (0.97 g, 1.3 mmol) was prepared in DMSO (15 mL) and purged with N2. The reaction mixture was subjected to carbon monoxide via a balloon. The mixture was stirred at 60° C. for 18 h. The reaction was cooled to room temperature and quenched with water, acidified with 1 M HCl and extracted with EtOAc. The organic layer was concentrated to dryness. The crude product was purified by flash chromatography on silica gel (CH2Cl2/EtOAc, 1:1) to yield (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (74) (0.40 g, 34%) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]([O:14]CC)=O.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][C:23]#[N:24])=[CH:20][CH:19]=1>>[C:23]([CH2:22][C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:12](=[O:14])[CH2:11][C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)=[CH:19][CH:20]=1)#[N:24]
Reactant: CCOC(=O)Cc1nc2ccccc2n1C
Reactant: N#CCc1ccc(N)cc1
Product: Cn1c(CC(=O)Nc2ccc(CC#N)cc2)nc2ccccc21
Yield: 74.9 %

Procedure:
1.14 g of ethyl 2-(1-methylbenzimidazol-2-yl)acetate and 970 mg of 4-aminobenzylcyanide were subjected to a condensation reaction to obtain 1.19 g of 4′-cyanomethyl-2-(1-methylbenzimidazol-2-yl)acetanilide.
Reaction SMILES: S(=O)(=O)(O)O.C(O/[CH:9]=[CH:10]/[C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:29](=[CH:30][CH:31]=1)[CH2:28][C:18]1([C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]1=O)[CH2:17]2)=[O:12])C.[OH-].[Na+]>>[OH:12][C:11]1[CH:10]=[CH:9][C:31]2[C:14](=[CH:15][C:16]3[CH2:17][C:18]4([C:26]5[C:21](=[N:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[CH:19]4)[CH2:28][C:29]=3[CH:30]=2)[N:13]=1
Reactant: CCO/C=C/C(=O)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc2cc3c(cc2n1)CC1(C=Nc2ncccc21)C3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To stirred concentrated sulfuric acid (25 mL) at 0° C. was added (±)-(2E)-3-ethoxy-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acrylamide from Step A (2.20 g, 6.30 mmol) portionwise. The resulting mixture was stirred at 0° C. for 10 min then poured onto ice and adjusted to pH=9 by careful addition of 10 N aqueous NaOH. The precipitate was isolated by filtration, washed with H2O, and dried to give the title compound. MS: m/z=304 (M+1).
Reaction SMILES: C(OC(N1CC[C@@H](C2C=CC=CC=2)[C@@H](C(O)=O)C1)=O)(C)(C)C.C(OC(N1CC[C@@H](C2C=CC=CC=2)[C@@H](C([N:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[CH2:46][CH2:45]2)=O)C1)=O)(C)(C)C>>[CH3:57][C:51]1[CH:52]=[CH:53][C:54]([CH3:56])=[CH:55][C:50]=1[N:47]1[CH2:46][CH2:45][NH:44][CH2:49][CH2:48]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CC[C@H]3c3ccccc3)CC2)c1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](c2ccccc2)[C@@H](C(=O)O)C1
Product: Cc1ccc(C)c(N2CCNCC2)c1

Procedure:
In analogy to example 1, step 1, from (3R,4R)-4-phenyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (CAS Reg. No.: [197900-84-8]) and 1-(2,5-dimethylphenyl)piperazine was prepared (3R,4R)-3-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester as a white foam, MS: 478.27 ([M+H])+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@H:13]3[C:14]([F:19])([F:18])[CH2:15][CH2:16][CH2:17][C@H:12]3[O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1>>[NH2:20][C:10]1[O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C:14]([F:18])([F:19])[C@@H:13]2[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:27]3[S:28][C:24]([Cl:23])=[CH:25][CH:26]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2CCCC(F)(F)[C@@H]21
Reactant: O=C(O)c1ccc(Cl)s1
Product: C[C@]1(c2cc(NC(=O)c3ccc(Cl)s3)ccc2F)N=C(N)O[C@@H]2CCCC(F)(F)[C@@H]21
Yield: 72 %

Procedure:
The coupling of (4S,4aR,8aR)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,3]oxazin-2-ylamine (intermediate XIIIa-2) and 5-chloro-thiophene-2-carboxylic acid (CAS 24065-33-6) following procedure Q yielded the title compound as a white solid (72% yield). MS: m/z=458.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[O:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:16]3[O:17][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc(Cl)o1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)o1
Yield: 97.2 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (3.2 g, 19.1 mmol) (Alfa) was reacted with 5-chloro-2-furaldehyde (2.5 g, 19.1 mmol) (Aldrich) and piperidine (1.89 mL, 19.1 mmol) in methanol to give E/Z-6-chloro-3-(5-chloro-furan-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 5.2 g, 97%)
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH2:5]([N:12]1[CH2:18][CH:17]2[C:19](=O)[CH:14]([CH2:15][CH2:16]2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.CN.[OH-].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:5]([N:12]1[CH2:13][CH:14]2[CH:19]([NH:2][CH3:1])[CH:17]([CH2:16][CH2:15]2)[CH2:18]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: CNC1C2CCC1CN(Cc1ccccc1)C2
Reaction time: 2.5 h
Yield: 49 %

Procedure:
A mixture of sodium cyanoborohydride (35.0 g, 0.557 mol) and zinc chloride (37.9 g, 0.278 mol) in methanol (500 mL) was added dropwise to a mechanically stirred mixture of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (Preparation A; 120 g, 0.557 mol) and methylamine hydrochloride (151 g, 2.23 mol) in methanol (1.0 L) at 25° C. under nitrogen. After 2.5 h of stirring, 6 N NaOH (90 mL) was added dropwise. The mixture was filtered through a pad of Celite®, washing with methanol (500 mL). The filtrate was concentrated in vacuo. Water (500 mL) was added, and the aqueous mixture was extracted with ethyl acetate (3×500 mL). The combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed, eluting with methanol dichloromethane (1:10), to afford 63.0 g (49%) of the sub-title compound as a solid.
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1>CO>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1
Reactant: O=C(CN1CCCC1)Nc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc(NCCN2CCCC2)cc1
Reaction time: 8 h

Procedure:
A 1 M solution of BH3 in tetrahydrofuran (7.7 ml, 7.7 mmol) was added dropwise to N-(4-bromo-phenyl)-2-pyrrolidin-1-yl-acetamide (0.22 g, 0.77 mmol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride was added. The aqueous was extracted twice with ethyl acetate and the organics were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the desired product. Yield 0.18 g, 86%. LCMS method: 2, RT: 4.62 min; MI: 267-269 [M+1].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+].[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O.O1CCOCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]3[C:7]([OH:9])=[O:8])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
To a stirred mixture of (S)-piperidine-2-carboxylic acid (1.0 g, 7.75 mmol) and Na2CO3 (1.65 g, 15.50 mmol) in water (10 mL) was added a solution of FMOC-Cl (3.0 g, 11.63 mmol) in 1,4-dioxane (10 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and washed with MTBE (25 mL). The aqueous layer was acidified with 1M aqueous HCl (10 mL) to pH 2 and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (1.41 g) as an off-white solid. The crude product was used in the next step without purification.
Reaction SMILES: [C:1]1([CH:7]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][CH2:28][C:29]3[CH:44]=[CH:43][C:32]([C:33]([O:35]CC4C=CC=CC=4)=[O:34])=[CH:31][CH:30]=3)=[O:26])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:45]2[C@H:49]([OH:50])[C@H:48]([OH:51])[C@@H:47]([C:52]([NH:54][CH2:55][CH3:56])=[O:53])[O:46]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:57]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][CH2:28][C:29]3[CH:44]=[CH:43][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)=[O:26])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:45]2[C@H:49]([OH:50])[C@H:48]([OH:51])[C@@H:47]([C:52]([NH:54][CH2:55][CH3:56])=[O:53])[O:46]2)[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCc4ccc(C(=O)OCc5ccccc5)cc4)nc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCc4ccc(C(=O)O)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 19.2 %

Procedure:
A solution of benzyl 4-[({[(2-{[(6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-yl)carbonyl]amino}ethyl)amino]carbonyl}amino)methyl]benzoate (Preparation 55) (150 mg, 0.18 mmol) in ethanol (10 ml) was hydrogenated at room temperature over 10% w/w palladium-on-carbon (30 mg) for 28 hours at 414 KPa. The catalyst was removed by filtration through Arbocel (trade mark) and solvent evaporated under reduced pressure to afford the title compound as a white powder (26 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](I)[CH3:37]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:36][CH3:37])[CH:24]=1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: CCI
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(OC)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in example 83 using 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.62 g) and ethyl iodide (0.13 mL) as starting materials, 5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.55 g) was obtained. By the reaction and treatment of this compound (0.40 g) in the same manner as in Example 133, N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.30 g) was obtained. melting point: 211-213° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:7](=[O:9])[CH:8]=1.[OH-].[NH4+:15]>>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:15]=1
Reactant: CCCOc1coc(CO)cc1=O
Reactant: [NH4+]
Agent: [OH-]
Product: CCCOc1cnc(CO)cc1O
Temperature: 90 °C

Procedure:
A mixture of 2-hydroxymethyl-5-propoxy-pyran-4-one (30.0 g, 0.163 mole), 150 mL ammonium hydroxide is stirred and heated in a sealed vessel at 90° C. for 2 hours. The reaction mixture is cooled, evaporated to dryness in-vacuo, taken up in 15% methanol in chloroform and passed thru a pad of magnesol and silica gel eluting with the same solvent. The eluate is evaporated, treated with acetone, filtered, washed with acetone and air dried to give a-grey solid, 8.03 g, (80%), m.p. 159-60° C.; MS (ES+): m/z 184.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1)[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])[CH3:2].[CH2:25]([NH:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:16]1[CH:21]=[C:20]([N:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH3:31])[N:19]=[C:18]([CH3:23])[N:17]=1)[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])[CH3:2]
Reactant: CCOC(=O)CN(c1cc(Cl)nc(C)n1)c1c(C)cc(C)cc1C
Reactant: CCCCNCC
Solvent: CS(C)=O
Product: CCCCN(CC)c1cc(N(CC(=O)OCC)c2c(C)cc(C)cc2C)nc(C)n1
Temperature: 135 °C
Yield: 122.2 %

Procedure:
A mixture of [(6-chloro-2-methylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amino]-acetic acid ethyl ester (85 mg, 0.244 mmol) and N-butyl-ethylamine (0.17 ml, 1.1 mmol) in 4 ml DMSO was heated at 135° C. for 15 hours. An additional 1 ml of N-butyl-ethylamine was added and the reaction was heated at that temperature for an additional 15 hours (tlc showed no starting material). The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 123 mg of a light amber oil. The oil was purified through silica gel chromatotron using 5% ethyl acetate in hexane as eluent to give 92 mg (91%) of the title compound as a white glass. 1H NMR (CDCl3) δ 6.94 (s, 2H), 4.69 (s, 1H), 4.23 (s, 2H), 4.22 (q, 2H), 3.35 (q, 2H), 3.15 (t, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.21 (s, 6H), 1.3-1.5 (m, 2H), 1.34 (t, 3H), 1.1-1.3 (m, 2H), 1.01 (t, 3H), 0.80 (t, 3H) ppm.
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8]1.[Li]CCCC.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>[NH4+].[Cl-]>[CH3:6][N:7]1[C:11]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)=[C:10]([CH3:12])[CH:9]=[N:8]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cnn(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
At 0° C., to above THF solution of 1,4-dimethylpyrazole was added n-BuLi (2.5M in hexane, 58.5 mL, 146 mmole). The reaction solution was stirred for 2 hour at RT and then cooled to −78° C. [J. Heterocyclic Chem. 41, 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.2 g, 146 mmole). After 15 min at −78° C., the reaction was allowed to warm to 0° C. and stir for 3 h. The reaction was diluted with saturated NH4Cl solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford the title compound as a brown solid (21 g, 78%) which was used directly without further purification: LC-MS: 141 (M−C6H12)+, 223 (M+H)+. 1H NMR (CDCl3): δ 7.28 (s, 1H), 4.03 (s, 3H), 2.22 (s, 3H), and 1.32 (s, 12H).