Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:9]2[N:8]([CH:15]2[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH2:16]2)[C:7](=[O:25])[C:6]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCCC1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:9]2[N:8]([C@H:15]2[CH2:24][CH2:23][C@H:18]([OH:19])[CH2:17][CH2:16]2)[C:7](=[O:25])[C:6]=1[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:31][CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (6.4 g), 3N hydrochloric acid (40 mL) and tetrahydrofuran (40 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (30 mL) and methanol (30 mL), sodium borohydride (0.67 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (4.9 g, 83%).
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(N=NC(C#N)(C)C)(C#N)C>O1CCOCC1>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Solvent: C=Cc1ccccc1
Product: C=Cc1ccc(O)cc1

Procedure:
300 g of p-t-butoxystyrene, 30 g of styrene, and 1.6 g of azobis-iso-butylonitrile were dissolved in 330 g of dioxane, and reacted for 12 hours under a nitrogen atmosphere at 70° C. After the reaction, unreacted monomers were removed to obtain a copolymer of p-hydroxystyrene and styrene. This resin was hydrolyzed with an acid to produce 180 g of a copolymer of p-hydroxystyrene and styrene with Mw of 18,000. NMR measurement confirmed that the molar ratio of p-hydroxystyrene and styrene was 85:15.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][C:24]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: Cc1ccc(C)cc1
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1ccc(C)c(C(=O)c2ccccc2)c1
Reaction time: 16 h

Procedure:
Benzoic acid (20 g, 0.16 mole), p-xylene (100 mL), and trifluoromethanesulfonic acid (5 mL) were heated at reflux in a 300 mL flask equipped with a Dean-Stark trap. After 16 hours, the mixture was extracted with 100 mL of 6% aqueous sodium hydroxide, washed with water, dried over magnesium sulfate and evaporated to give 15.4 g (0.073 mole) of 2,5-dimethylbenzophenone. The aqueous sodium hydroxide extract was acidified to give 8.1 g (0.066 mole) of unreacted benzoic acid.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[C@H:28]5[C@H:26]([CH2:27]5)[C@H:25]([NH:29]C(=O)OCC)[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[Si](I)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[C@H:28]5[C@H:26]([CH2:27]5)[C@H:25]([NH2:29])[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: CCOC(=O)N[C@@H]1C[C@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)[C@@H]2C[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)I
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@H]4C[C@@H](N)[C@H]5C[C@H]54)n23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl (1S,2R,4S,5R)-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan-2-ylcarbamate (0.16 g, 0.34 mmol, prepared using GG from Preparation #KK.1, A from Preparation #9 with HATU and TEA, C with TEA) in DCM (2.3 mL) was added trimethylsilyl iodide (0.11 mL, 0.75 mmol). After stirring at ambient temperature for about 24 h, additional trimethylsilyl iodide (0.11 mL, 0.75 mmol) was added and the reaction mixture was heated to about 40° C. for about 4 days. The reaction mixture was cooled to ambient temperature, followed by the addition of saturated aqueous NaHCO3 (20 mL). The mixture was stirred for about 5 min and the layers were separated. The aqueous layer was further extracted with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford (1S,2R,4S,5R)-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[3.1.0]hexan-2-amine that contained 1 molar equiv DCM (0.17 g, 100%): LC/MS (Table 2, Method a) Rt=1.76 min; MS m/z: 409 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:21].[H-].[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[CH2:32]Cl.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:32][C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[Cl:24])=[O:19])[C:3]=1[Cl:21]
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)OCc3ccc(Cl)cc3Cl)n2)c1F
Reaction time: 24 h
Yield: 35 %

Procedure:
4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared by the methods described in U.S. Pat. No. 7,314,849 B2; 828 mg, 2.5 mmol) was dissolved in DMF (4 mL). Sodium hydride (NaH, 60% dispersion in mineral oil; 154 mg, 3.85 mmol) was added portion wise. To the mixture was added 2,4-dichloro-1-(chloromethyl)benzene (586 mg, 3.0 mmol). The reaction mixture was allowed to stir for 24 hours (h). Water was added to the reaction mixture, and the aqueous phase was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried with Na2SO4, filtered, and concentrated. Purification by normal phase chromatography gave a white solid (440 mg, 35%): mp 165-168° C., 1H NMR (400 MHz, CDCl3) δ 7.68 (dd, J=8.6, 7.8 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 5.50 (s, 2H), 4.83 (s, 2H), 3.97 (d, J=0.8 Hz, 3H); ESIMS m/z 489 ([M−H]).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[S:16]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]Br)=[CH:22][CH:21]=1)(=[O:19])(=[O:18])[NH2:17]>>[S:16]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:22][CH:21]=1)(=[O:18])(=[O:19])[NH2:17]
Reactant: NS(=O)(=O)c1ccc(CCBr)cc1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Product: NS(=O)(=O)c1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 10.5 %

Procedure:
1-(Piperidin-4-yl)indoline (300 mg) and 4-sulfamoylphenethyl bromide (400 mg) were treated as in Example 2 to give the title compound (60 mg) as a pale yellow powder (yield: 10%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([N:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)[S:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:43](P(=O)(OCC)OCC)[P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47].CN(C)C=O.[H-].[Na+]>O>[CH2:46]([O:45][P:44](/[CH:43]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([N:28]4[CH2:29][CH2:30][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:33]4)[S:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:48][CH2:49][CH3:50])=[O:51])[CH3:47]
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)s2)CC1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a mixture of ethyl 1-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate (0.30 g), tetraethyl methylenediphosphonate (0.16 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 25 mg) at room temperature. The mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]piperidine-4-carboxylate as a colorless oil (0.29 g, yield 78%) from a fraction eluted with ethyl acetate-hexane (9:1, v/v).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[N:15]=[C:14]4[CH2:16][CH2:17][CH2:18][CH2:19][C:13]4=[C:12]3[CH2:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[N:15]=[C:14]4[CH2:16][CH2:17][CH2:18][CH2:19][C:13]4=[C:12]3[CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCBr
Reactant: C1=C(OCc2ccccc2)C=C2N=C3CCCCC3=C2C1
Product: CCCCCCCCC1C=C(OCc2ccccc2)C=C2N=C3CCCCC3=C21
Yield: 92.9 %

Procedure:
Using the procedure of Example 9, 6.9 g of 1,2,3,4-tetrahydro-7-phenylmethoxy -9H-dibenzo[b,d]pyrrole from Example 57 was alkylated with 1-bromooctane (5.25 g) giving 9.0 g (92.8%) of 1,2,3,4-tetrahydro-7-phenylmethoxy-9-octyl-9H-dibenzo[b,d]pyrrole as a yellow oil after chromatographic purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:82][C@H:83]1[O:88][C@@H:87]([CH3:89])[CH2:86][NH:85][CH2:84]1>CN(C=O)C.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:85]3[CH2:84][C@H:83]([CH3:82])[O:88][C@H:87]([CH3:89])[CH2:86]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:20])[CH:14]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(c1cccnc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3cccnc3)cc2)C[C@H](C)O1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g (3.96 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.12 g (0.198 mmol), cis-2,6-dimethylmorpholine 0.37 g (3.3 mmol) and Pd (dba)3 60 mg (0.066 mmol) in 3 ml DMF, followed by work up and HPLC purification to yield yellow title compound.
Reaction SMILES: [CH3:1][N:2]([NH:12][C@H:13]([C:17]([NH:19]C(OC(C)(C)C)=O)=[O:18])[CH2:14][S:15][CH3:16])[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[ClH:27]>C(OCC)(=O)C>[ClH:27].[CH3:1][N:2]([NH:12][C@H:13]([C:17]([NH2:19])=[O:18])[CH2:14][S:15][CH3:16])[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: CSC[C@H](NN(C)c1ccc2c(c1)OCO2)C(=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CSC[C@H](NN(C)c1ccc2c(c1)OCO2)C(N)=O
Yield: 86 %

Procedure:
After 6.323 g (17.183 mmol) of (N-methyl-1,3-benzodioxol-5-ylamino)-N-t-butoxycarbonyl-S-methyl-L-cysteinamide were dissolved in 100 ml of ethyl acetate, an excess of hydrochloric acid was ebulated. A precipitate so precipitated was collected by filtration, washed with ether, and then dried under reduced pressure, whereby 4.5 g of (N-methyl-1,3-benzodioxol-5-ylamino)-S-methyl-L-cysteinamide hydrochloride were obtained (yield: 86%).
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.CO.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]2=O)=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][CH:36]([N:20]3[CH2:21][CH2:22][C@@H:18]([NH:17][C:2](=[O:1])[CH2:3][NH:4][C:5](=[O:16])[C:6]4[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:14])([F:15])[F:13])[CH:7]=4)[CH2:19]3)[CH2:35][CH2:34]2)=[CH:29][CH:28]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: COc1ccc(N2CCCCC2=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (306 mg, 0.97 mmol; prepared according to WO2004/050024A2) in methanol (757 μL, 1.87 mmol) at room temperature was added 1-(6-methoxypyridin-3-yl)piperidinone (200 mg, 0.971 mmol) followed by sodium triacetoxyborohydride (247 mg, 1.16 mmol); the reaction mixture was stirred for 16 hours. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (465 mg, 95%) as a white solid. 1H-NMR (CD3OD) δ: 1.59-1.86 (m, 3H), 2.00-2.14 (m, 2H), 2.21-2.48 (m, 2H), 2.64-2.84 (m, 4H), 2.95-3.10 (m, 2H), 3.26-3.38 (m, 2H), 3.49-3.60 (m, 2H), 3.84 (s, 3H), 4.03 (s, 2H), 4.36-4.48 (m, 1H), 6.73 (d, J=9.3 Hz, 1H), 7.46 (dd, J=9.0, 3.0 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 8.14 (d, J=8.1 Hz 1H), 8.22 (s, 1H). MS m/z: 506 (M+1).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([CH3:29])[CH:6]=[C:5]([O:30][CH3:31])[C:4]=1[CH3:32].[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH:44]=O)[CH3:43])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH3:44])[CH:43]=[CH:9][C:8]1[C:3]([Cl:2])=[C:4]([CH3:32])[C:5]([O:30][CH3:31])=[CH:6][C:7]=1[CH3:29])[CH3:34]
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1C
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1Cl

Procedure:
By the procedure of Example 1, 6-chloro-4-methoxy-2,5-dimethylbenzyl-triphenylphosphonium chloride is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to obtain 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester of melting point 106°-107° C.
Reaction SMILES: [OH:1][C@@H:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].O[C@@H](C)C(OCC)=O.[CH2:20](N1CCNCC1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>C[O-].[Na+]>[CH2:20]([N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([OH:1])[CH3:11])[CH2:10][CH2:9]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](O)C(=O)N1CCNCC1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCOC(=O)[C@H](C)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](O)C(=O)N1CCN(Cc2ccccc2)CC1

Procedure:
Scheme 4 shows the synthesis of intermediate (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V from (S)-ethyl 2-hydroxypropanoate 7. 1-Benzylpiperazine and 7 were reacted in sodium methoxide and methanol to give (S)-1-(4-benzylpiperazin-1-yl)-2-hydroxypropan-1-one 8, isolated from AMBERLITE® IRC-748 resin or oxalic acid, followed by the activated charcoal treatment (Example 10). Reductive cleavage removal of the benzyl group from 8 was effected by palladium catalysis with either hydrogen gas (Method A) or cyclohexene (Method B) to give intermediate (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one 6 (Example 11). The oxalate salt was formed from 6 with oxalic acid in ethanol and tetrahydrofuran to give V (Example 11).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([CH:13]=[CH2:14])[CH:10]=[C:9]([N+:15]([O-])=O)[CH:8]=2)=[N:5][N:4]=[N:3]1>CO.[OH-].[OH-].[Pd+2]>[CH2:13]([C:11]1[CH:10]=[C:9]([CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH:12]=1)[NH2:15])[CH3:14]
Reactant: C=Cc1cc(-c2nnnn2C)cc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(N)cc(-c2nnnn2C)c1
Reaction time: 4 h
Yield: 95.7 %

Procedure:
A mixture of impure 1-methyl-5-(3-nitro-5-vinylphenyl)-1H-tetrazole (17.0 g) and palladium hydroxide on charcoal (3.0 g) in methanol (50 mL) was shaken under a hydrogen atmosphere (50 psig) for 4 hours. The mixture was filtered and the filtrate was concentrated under vacuum to provide an amber solid (14.3 g). 1H NMR (300 MHz, CDCl3) δ6.90 (s, 1H), 6.87 (s, 1H), 6.73 (s, 1H), 4.16 (s, 3H), 3.95 (bs, 2H), 2.65 (q, J=7 Hz, 2H), 1.22 (t, J=7 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.C1(N2C3C=CC(C(O)=O)=CC=3N=C2C2C=C3C(=CC=2)N=C(C2C=CC=CC=2)C=C3N(C)C)CCCCC1.[N:75]1([CH2:80][CH2:81][CH2:82][NH2:83])[CH:79]=[CH:78][N:77]=[CH:76]1>>[CH:30]1([N:10]2[C:9]3[CH:36]=[CH:37][C:6]([C:4]([OH:3])=[O:5])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[C:16]3[NH:83][CH2:82][CH2:81][CH2:80][N:75]2[CH:79]=[CH:78][N:77]=[CH:76]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Agent: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(NCCCn4ccnc4)c3c1)n2C1CCCCC1

Procedure:
In this reaction 102 mg (0.2 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used in the same reaction sequence as that used for Compound 481. The nucleophile used was 3-imidazol-1-yl-propylamine. Yield: 31 mg.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]Br>ClCCl>[CH2:1]([N:8]1[C:16]([Br:24])=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: COC(=O)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Solvent: ClCCl
Product: COC(=O)CNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-Benzyl-2-chloroadenine (0.30 g, 1.12 mmol), glycine methyl ester hydrochloride (0.72 g, 5.73 mmol) and diisopropylethylamine (1.48 g, 11.47 mmol) were added to n-butanol (10 ml), and the mixture was stirred in an autoclave at 150° C. for 19 hours. The solvent was removed and the residue was poured into water. The solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography to give 9-benzyl-2-methoxycarbonylmethylaminoadenine (0.06 g) as a brown tar. Thus obtained 9-benzyl-2-methoxycarbonylmethylaminoadenine was dissolved in dichloromethane (10 ml) and to the solution was added bromine (0.05 ml) in an ice bath. The mixture was stirred at room temperature for 1 hour. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography to give 9-benzyl-8-bromo-2-methoxycarbonylmethylaminoadenine (0.06 g) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:19]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:19]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(Cc1nc(CCCCCNc2ccccn2)co1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(Cc1nc(CCCCCNc2ccccn2)co1)c1ccccc1
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a solution of ethyl (±)-3-phenyl-4-[4-[5-(pyridin-2-yl)amino- 1-pentyl]-1,3-oxazol-2-yl]butanoate (75 mg, 0.18 mmole) in 1:1 THF/H2O (2 mL) was added 1.0 N LiOH (0.27 mL, 0.27 mmole). After 18 hr, the pH was adjusted to 6 using 10% HCl; then the solution was concentrated under reduced pressure to remove the THF. The solution was chromatographed on a C-18 Mega Bond Elut® column (50 mL H2O then 200 mL 20% CH3CN/H2O containing 0.1% TFA). Fractions containing the product were pooled and lyophilized to give the title compound (43 mg, 61%) as a yellow gum: MS (ES) m/e 394 (M+H)+. Anal. Calcd for C23H27N3O3.0.098 CF3CO2H: C, 68.85; H, 6.75; N, 10.38. Found: C, 69.23; H, 7.00; N, 9.98.
Reaction SMILES: [F:1][C:2]12[CH2:7][C:5]([C:8]([O:10]C)=[O:9])([CH2:6]1)[N:4](C)[CH2:3]2.Cl>C(Cl)Cl>[F:1][C:2]12[CH2:7][C:5]([C:8]([OH:10])=[O:9])([CH2:6]1)[NH:4][CH2:3]2
Reactant: COC(=O)C12CC(F)(CN1C)C2
Agent: Cl
Solvent: ClCCl
Product: O=C(O)C12CC(F)(CN1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
To a solution of methyl 1-fluoro-3-methyl-3-azabicyclo[2.1.1]hexane-4-carboxylate (AR4) (150 mg, 0.57 mmol) in CH2Cl2 (1.0, mL) was added an aqueous of HCl (6.0N, 8.0 mL). The reaction mixture was heated to reflux and stirred for 3 hours. After cooled to room temperature, the solution was filtered. The filtrate was evaporated in vacuo, and the residue was washed with MeCN to give 4-fluoro-2-aza-bicyclo[2.1.1]hexane-1-carboxylic acid as a white solid (45 mg). LC/MS: calc'd 146 (MH+), exp 146 (MH+).