Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]#[N:30].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[C:3]([O:27][CH2:28][C:29]#[N:30])[CH:4]=[CH:5]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCC(=O)c1c(-c2ccc3c(-c4ccccc4)c(OCC#N)ccc3c2)oc2ccccc12
Temperature: 70 °C
Reaction time: 22 h
Yield: 48.1 %

Procedure:
Following the procedure described in Step 1 of Example 1, 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile (0.480 g, 1.04 mmol) was coupled to phenylboronic acid (0.448 g, 3.67 mmol) using [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (0.0918 g, 0.112 mmol) in presence of potassium carbonate (0.290 g, 2.10 mmol) in dioxane (10 mL) and water (1.0 mL). The reaction mixture was stirred at 70° C. for 22 hours. Purification by flash chromatography (Biotage apparatus) using 7.5-10% tert-butyl methyl ether in hexane furnished the title compound (0.230 g). 1HNMR (300 MHz, DMSO-d6): δ8.5 (s, 1H), 8.3 (d, 1H, J=9.2 Hz), 8.05 (d, 1H, J=7.7 Hz), 7.7-7.85 (m, 3H), 7.35-7.6 (m, 9H), 5.25 (s, 2H), 2.75 (t, 2H, J=7.7 Hz), 1.5-1.6 (m, 2H), 1.1-1.3 (m, 2H), and 0.75 ppm (t, 3H, J=7.7 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][O:17][CH3:18])=[CH:12][CH:13]=2)[O:8][CH2:7][C:6]1([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[CH:22][CH:21]=1)[CH3:19].[F:30][C:31]([F:47])([C:43]([F:46])([F:45])[F:44])[CH2:32][CH2:33][CH2:34][S:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=O)=[O:36].C([BH3-])#N.[Na+].C(Cl)(Cl)Cl.CO.O.N>CO.O>[CH3:18][O:17][CH2:16][O:15][C:11]1[CH:10]=[C:9]2[C:14]([CH:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][S:35]([CH2:34][CH2:33][CH2:32][C:31]([F:47])([F:30])[C:43]([F:44])([F:45])[F:46])=[O:36])[C:6]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][O:28][CH3:29])=[CH:24][CH:25]=3)([CH3:19])[CH2:7][O:8]2)=[CH:13][CH:12]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCN)cc1
Reactant: O=CCCCCS(=O)CCCC(F)(F)C(F)(F)F
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCNCCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc1
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a solution of (3RS,4RS)-4-(3-aminopropyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (80 mg, 0.20 mmol) and 5-(4,4,5,5,5-pentafluoropentylsulfinyl)pentanal (80 mg, 0.19 mmol) in methanol (5 ml) was added a solution of sodium cyanoborohydride (12 mg, 0.19 mmol) in methanol (5 ml), which was then stirred at 0 for 2 hours. The reaction solution was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to preparative TLC on silica gel using chloroform/methanol/ammonia water (7/1/0.1) as a mobile phase to give (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-{3-[N-5-(4,4,5,5,5-pentafluoropentylsulfinyl)pe ntylamino]propyl}chroman (38 mg, yield 28%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][C@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[N:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CN1C(=O)CCC1.CCOC(C)=O>[O:29]=[C:28]1[NH:26][N:27]=[C:1]([C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([NH:13][C@H:14]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]4)[N:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccnc23)C1
Reactant: CCOC(=O)NN
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccnc23)C1
Temperature: 175 °C
Yield: 32.5 %

Procedure:
To (S)-tert-butyl 3-((6-cyano-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate (210 mg, 0.619 mmol) in NMP (1.5 mL) was added ethyl hydrazinecarboxylate (258 mg, 2.475 mmol). The reaction mixture was heated at 175° C. for 2 days and was then cooled, diluted with EtOAc, and washed with aqueous NH4Cl. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 35-60% ACN in water (acid mode) to give the title compound (80 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:51]([NH:53][CH3:54])=[O:52])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH:31]3[C:39]4[C:34](=[CH:35][C:36](CCCO[Si](C(C)(C)C)(C)C)=[CH:37][CH:38]=4)[CH2:33][CH2:32]3)S(C3C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=3)(=O)=O)[CH:9]=2)=[CH:6][N:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.C(N)(C)C.[CH2:80]1C[O:83][CH2:82][CH2:81]1>>[NH2:1][C:2]1[C:3]([C:51]([NH:53][CH3:54])=[O:52])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([CH2:80][CH2:81][CH2:82][OH:83])[CH:38]=4)[CH2:33][CH2:32]3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: C1CCOC1
Reactant: CNC(=O)c1nc(-c2cccc(CN(C3CCc4cc(CCCO[Si](C)(C)C(C)(C)C)ccc43)S(=O)(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)cnc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CC(C)N
Product: CNC(=O)c1nc(-c2cccc(CNC3CCc4ccc(CCCO)cc43)c2)cnc1N
Reaction time: 0.5 h
Yield: 33 %

Procedure:
3-Amino-6-[3-({[5-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-2,3-dihydro-1H-inden-1-yl][(3,5-dinitrophenyl)sulfonyl]amino}methyl)phenyl]-N-methyl pyrazine-2-carboxamide (600 mg, 0.77 mmol) was dissolved in THF and refluxed for an hour in the presence of tetrabutylammonium fluoride in THBF. The reaction mixture was partitioned with water and extracted with ethyl acetate (10 mL×3) and dried over MgSO4. Filteration and concentration under vacuum gave tan oil, which was subjected to the solution of dichloromethane and isopropylamine. After being stirred for 30 min, the solvent was removed in vacuo and purified by flash column chromatography to give the 3-amino-6-[3-({[6-(3-hydroxypropyl)-2,3-dihydro-1H-inden-1-yl]amino}methyl)phenyl]N-methylpyrazine-2-carboxamide (110 mg, 33% yield): 1H NMR (400 MHz, CD3OD): δ 8.59 (s, 1H), 8.06 (bs, 1H), 7.91 (s, 1H), 7.52 (m, 1H), 7.40 (m, 2H), 7.11 (d, 1H), 7.08 (s, 1H), 7.03 (d, 1H), 4.32 (d, 1H), 3.66 (t, 2H), 3.02 (d, 3H), 2.99 (m, 1H), 2.81 (m, 1H), 2.69 (t, 2H), 2.44 (m, 1H), 1.90 (m, 4H), 1.32 (m, 3H), 0.82 (m, 2H); MS (EI) for C25H29N5O2: 432.23 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1.[CH3:31][NH2:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH:32][CH3:31])[CH2:13][C:12]=2[CH:11]=[C:10]([O:29][CH3:30])[CH:9]=1
Reactant: CN
Reactant: COc1cc2c(c(-c3ccccc3C)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(OC)cc(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.055 g, 54%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.135 g, 0.32 mmol) and methylamine (0.099 g, 3.2 mmol). mp 167-169° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:6]=1.[Br:11]Br>C(Cl)(Cl)Cl.OS([O-])=O.[Na+]>[Br:11][C:5]1[N:6]=[C:2]([CH3:1])[S:3][C:4]=1[NH:7][C:8](=[O:10])[CH3:9]
Reactant: BrBr
Reactant: CC(=O)Nc1cnc(C)s1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1sc(C)nc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
To a solution of N-(2-methylthiazol-5-yl)acetamide (0.4 g, 2.6 mmol) in CHCl3 (30 mL) was added Br2 (0.15 mL, 2.8 mmol), then the solution was stirred at room temperature for 12 h to give a brown solution. The reaction mixture was diluted with saturated NaHSO3 solution. The aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated to afford a yellow solid. The resulting mixture was deposited onto silica gel and loaded onto a silica gel column and eluted with PE/EA(1:1) to give the title compound (400 mg, yield 67%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.Cl.Cl[CH2:20][CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:20][CH2:21][C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)=[CH:17][CH:16]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: ClCCc1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(OCCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
240 mg (60% in oil, 6 mmol) of sodium hydride are added to a solution of 2.34 g (12 mmol) of 4-hydroxybenzophenone in 10 ml of dimethylformamide. The mixture is stirred at room temperature for 1 hour under nitrogen. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalytic amount) are then added. The mixture is heated at 100° C. for 2 days and the solvent is then evaporated under reduced pressure. Dilute hydrochloric acid is added to the oily residue and the excess hydroxybenzophenone is extracted with diethyl ether. The aqueous solution is basified with potassium carbonate and the product is extracted with diethyl ether. The title compound is converted to the dioxalate. Crystallization from an ethanol/diethyl ether (2/1) mixture gives a pure product, M.p.: 193°-194° C.
Reaction SMILES: [CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[N:17]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[C:16]1=[O:38])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].Cl.N1C=CC=CC=1.[OH-].[NH4+]>O>[CH3:3][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[N:17]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=2)[C:16]1=[O:38])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:1]
Reactant: COc1cccc([C@H]2C[C@@H](NC(C)(C)c3cccc(C(F)(F)F)n3)C(=O)N2c2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(N[C@@H]1C[C@H](c2cccc(O)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 185 °C
Yield: 32.6 %

Procedure:
Add (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-methoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (1.9 g, 3.4 mmol) to pyridine hydrochloride (28.6 g, 247.8 mmol). Plunge the mixture into a 185° C. oil bath and heat for 2 hours. Cool to ambient temperature and dilute with water (175 mL). Make the pH basic by ammonium hydroxide addition and extract with EtOAc. Wash with brine, dry over sodium sulfate, filter and concentrate the organic to residue. Purify the residue by silica gel chromatography (20%-30% EtOAc-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-hydroxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (0.58 g, 32%) as a white foam. LC-MS ESI m/z: 524.2 (M+H)+, Tr=2.91 min., method 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.C1CCN2C(=NCCC2)CC1.CN(C)C=O.[F:33][C:34]1[CH:35]=[C:36]2[C@:43]3([C:47](=[O:48])[NH:46][C:45](=[O:49])[NH:44]3)[CH2:42][C@@H:41]([C:50](Cl)=[O:51])[O:40][C:37]2=[CH:38][CH:39]=1>>[CH2:10]([CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:50]([C@@H:41]2[CH2:42][C@@:43]3([C:47](=[O:48])[NH:46][C:45](=[O:49])[NH:44]3)[C:36]3[C:37](=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=3)[O:40]2)=[O:51])[CH2:9][CH2:8]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCN1CCC(Cc2ccccc2)CC1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)NCCN3CCC(Cc4ccccc4)CC3)Oc3ccc(F)cc32)N1
Temperature: -30 °C
Reaction time: 15 h
Yield: 49.9 %

Procedure:
A mixture of N-(2-aminoethyl)-4-benzylpiperidine (13.0 g, 59.6 mmol), 1,8-diazabicyclo[5,4,0]-7-undecene (10.9 g, 71.7 mmol) and N,N-dimethylformamide (90.0 ml, 1.16 mol) was chilled to -30° C. To the mixture was added over 30 minutes a solution of (2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example, 18.0 g, 60.3 mmol) in N,N-dimethylformamide (90.0 ml, 1.16 mol) and the mixture was stirred for 15 hours at temperature of 15°-25° C. After distilling off the solvent, the reaction mixture was chromatographed on silica gel, eluted with CH2Cl2 /MeOH (9/1) and evaporated in vacuo to dryness to give the desired compound (14.3 g, 50.0%) as colorless amorphous substance.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[C:25]([F:34])=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:23][C:24]1[C:25]([F:34])=[C:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1cccc(Cl)c1F
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(Cl)c2F)c2c(N)ncnc21
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (65.3 mg, 0.192 mmol), (3-chloro-2-fluorophenyl)acetic acid (36.3 mg, 0.192 mmol), HATU (73.2 mg, 0.192 mmol) in DMF (2 mL) was added Hunig's base (0.134 mL, 0.770 mmol). The mixture was stirred overnight. The reaction was poured into water, and off-white solid formed. The solid was filtered to give the title compound as an off-white solid. It has 0.75 eq. of DMF based on NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25-3.31 (m, 2H), 3.94 (s, 3H), 4.04 (s, 2H), 4.32 (t, J=8.46 Hz, 2H), 7.20-7.26 (m, 1H), 7.33 (d, J=1.52 Hz, 1H), 7.35 (s, 1H), 7.44 (d, J=8.08 Hz, 1H), 7.50-7.57 (m, 2H), 8.14 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.[I:44]N1C(=O)CCC1=O>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([I:44])[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2ncn3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(I)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 70 °C

Procedure:
To a solution of 6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (288 mg, 0.000512 mol) in THF (10 mL, 0.1 mol) was added N-Iodosuccinimide (0.576 g, 0.00256 mol), and the mixture was heated at 70° C. overnight. The reaction was cooled, quenched by addition of saturated aqueous NaHSO3 and the mixture was extracted with DCM (3×), washed with water, brine dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes) to obtain 271 mg (76.9%). Reference: Nolsoe, J. M. J.; Gundersen, L-L.; Rise, F. Acta Chemica Scandinavica, 1999, 53, 366-372.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-])=O)=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:13]([O-])=O.[Na+].Cl[Sn]Cl.[OH-].[Na+]>CC(O)=O.O.Cl>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:9]=[N:13][NH:7]2)=[CH:4][C:3]=1[NH2:10]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc2cn[nH]c2cc1Cl
Temperature: 15 °C
Reaction time: 28 h
Yield: 19.1 %

Procedure:
5-Chloro-2-methyl-4-nitroaniline (1.0 g, 5.3 mmol, 1.0 equiv) was dissolved in AcOH (46 mL) and cooled to 15° C. NaNO2 (0.37 g, 5.3 mmol, 1.0 equiv) was dissolved In H2O (1 mL) and added all at once via pipet. The reaction was warmed to room temperature and stirred for 28 hours. The reaction mixture was concentrated en vacuo to provide an orange solid, which was azeotroped several times with hexanes. The solid was dissolved in EtOH (12 mL) and added to a solution of SnCl2 (3.4 g, 18 mmol, 3.4 equiv) in 6N HCl (12 mL) The reaction mixture was heated to 60° C. for two hours, then cooled to room temperature and basified with 50% NaOH. The resulting precipitate was removed by filtration and washed with EtOAc. The filtrate was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over Na2SO4. The solution was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography (25% EtOAc/CH2Cl2) to afford 170 mg (19%) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:13](=[O:26])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[C:4]([F:29])[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[CH:41]=[C:42]([N:46]=[C:47]=[O:48])[CH:43]=[CH:44][CH:45]=1>O1CCOCC1>[Cl:39][C:40]1[CH:41]=[C:42]([NH:46][C:47]([NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[C:16]4[CH2:15][N:14]([CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)[C:13](=[O:26])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[C:4]([F:29])[CH:3]=2)=[O:48])[CH:43]=[CH:44][CH:45]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)cc4F)ccnc3NC2=O)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)Nc5cccc(Cl)c5)cc4F)ccnc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
57 (20 mg, 0.05 mmol), DIEA (304, 0.15 mmol), and 3-chlorophenyl isocyanate (9.4 mg, 0.06 mmol) were suspended in dioxane (2 mL), and stirred overnight at room temperature. The crude product was purified directly via HPLC. LC-MS (M+H=548, obsd.=548).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([NH2:16])=O)[CH:7]=[CH:6]2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]#[N:16])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)C(N)=O)ccc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(C(C)C#N)ccc2c1

Procedure:
In 50 ml of dry THF, were suspended 3.0 g of oa (6-methoxy-2-naphthyl)-propanamide, followed by adding thereto 8.3 g of trifluoroacetic anhydride and then stirring at room temperature for 12 hours. The resulting reaction mixture was poured into 200 ml of iced water, and then precipitated white solid was filtered off. After purifying with silica gel column, the product was recrystallized twice with ethanol to obtain 2.1 g of oa (6-methoxy-2-naphthyl)propanonitrile (Compound No. 1-1) of this invention.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:8][NH2:9])[N:5]=[N:4][N:3]=1.[Cl:33][CH2:34][CH2:35][CH2:36][S:37](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:39])=[O:38]>>[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:9][CH2:8][CH:7]([N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:39])=[O:38]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)n1nnnc1C
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)n1nnnc1C

Procedure:
2-(5-Methyl-1H-tetrazol-1-yl)-3-octadecylcarbamoyloxypropylamine IVi2 is allowed to react and worked up by the same procedure as described in (4). m.p. 74°-77° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:6]([N+:19]([O-])=O)[CH:5]=1)([O-])=O.[H][H].CCOCC>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:6]([NH2:19])[CH:5]=1
Reactant: Cc1ccc(C=Cc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(CCc2ccc(N)cc2N)cc1

Procedure:
1.4 g of 1,3-dinitro-4-[2-(4-methylphenyl)ethenyl]benzene prepared as described by S. Saravanan and P. Srinivasan, Synth. Commun. 31(6), pages 823-826 (2001) was dissolved in 50 mL of ethanol and hydrogenated using 0.2 g of Pd/C 10% for 4 hours at 8 bar of hydrogen pressure. The catalyst was then filtered off, and the filtrate was evaporated to dryness. This gave a brownish oil which upon addition of 10 mL of ether crystallized. Yield: 1.1 g of yellowish oil.
Reaction SMILES: CC(CCCCCOC(C1C(C(OCCCCCC(C)C)=O)=CC=CC=1)=O)C.CC(N)C1C=CC=CC=1.[F:38][C:39]1[CH:44]=[C:43]([C:45](=[CH2:49])[C:46]([OH:48])=[O:47])[CH:42]=[CH:41][C:40]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1C=CC=CC=1.C(O)C>[F:38][C:39]1[CH:44]=[C:43]([CH:45]([CH3:49])[C:46]([OH:48])=[O:47])[CH:42]=[CH:41][C:40]=1[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: C=C(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: CC(C)CCCCCOC(=O)c1ccccc1C(=O)OCCCCCC(C)C
Agent: CC(N)c1ccccc1
Solvent: CCO
Solvent: c1ccccc1
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
DIOP (64.8 mg.) was added to a solution of DTDR (46 mg.) in benzene (9 ml.) under nitrogen and the mixture allowed to stand for 15 minutes. This complex was then added to a mixture, prepared by adding ethanol (16 ml.) followed by (-)-α-methylbenzylamine (24 mg.) in ethanol (2 ml.) to the product of Example 2 (0.5 g.), under hydrogen. The reaction mixture was stirred under hydrogen for 51/2 hours at room temperature and then kept under hydrogen overnight. The solution was concentrated under reduced pressure and the residue treated with ether and aqueous 10% potassium carbonate. The ether extract was treated with the potassium carbonate extract, which was then acidified. The oil which separated, solidified and was extracted with ether and the extract dried, filtered, evaporated and the product recrystallised from light petroleum (b.p. 60°-80° C.) to give 2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 101°-103° C., having an optical rotation [α]D20 +35.5° C. representing 89% of the (+) isomer in the product.