Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(Cl)[Cl:2].[P+3].[Cl:5][C:6]1[C:15]2[N:16]=[C:17]([OH:23])[N:18]([CH2:19][CH2:20][CH2:21]O)[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.O>CN(C=O)C>[Cl:5][C:6]1[C:15]2[N:16]=[C:17]([OH:23])[N:18]([CH2:19][CH2:20][CH2:21][Cl:2])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: OCCCn1c(O)nc2c(Cl)nc3ccccc3c21
Reactant: ClOCl
Agent: [P+3]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1nc2c(Cl)nc3ccccc3c2n1CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
Phosphorus(III) oxychloride (7.9 g, 52 mmol) was added dropwise to a stirred solution of 4-chloro-1-(3-hydroxypropyl)-1H-imidazo[4,5-c]quinolin-2-ol (12 g, 43 mmol) in DMF (150 mL), and the reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and additional phosphorus(III) oxychloride (7.9 g) was added. The reaction was stirred overnight at room temperature and then cooled to approximately 0° C. Water (300 mL) was slowly added, and a precipitate formed. The mixture was stirred for several minutes, and the precipitate was isolated by filtration, washed with water and diethyl ether, and dried in a vacuum oven to provide 8.2 g of 4-chloro-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-2-ol.
Reaction SMILES: C[N+:2]([O-])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12]N=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C[Si](C#[N:22])(C)C.CN(C)C(Cl)=O.[N+:29]([CH2:32][CH3:33])([O-])=O>>[C:32]([C:33]1[N:22]=[C:15]([CH2:10][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH:14]=[CH:13][CH:12]=1)#[N:29]
Reactant: CC[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)[N+](C)([O-])c1ccccn1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Product: CC(C)(C)OC(=O)NCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
A mixture of tert-butyl methyl(2-pyridyl)carbamate N-oxide (14.1 g, 63 mmol), trimethylsilyl cyanide (12.5 g, 126 mmol), N,N-dimethylcarbamoyl chloride (13.5 g, 125 mmol) and nitroethane (120 ml) was stirred at room temperature for 48 hrs. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (10:1, v/v) and recrystallized from ethyl acetate-hexane to give the titled compound (11.3 g, 77%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13](Br)[CH:12]=1)[CH3:9].[CH2:21]([Li])[CH2:22][CH2:23]C.CCCCCC.[Cl-].[NH4+].[O:34]1CCCC1>CC(C)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:8]([CH2:7][CH:6]=[CH:5][C:4]#[C:3][C:2]([CH3:20])([CH3:19])[CH3:1])[CH3:9])=[CH:12][C:13]=1[CH2:21][CH:22]([OH:34])[CH3:23]
Reactant: [Li]CCCC
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1ccc(F)c(Br)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(O)Cc1cc(CN(C)CC=CC#CC(C)(C)C)ccc1F
Temperature: -78 °C
Yield: 58.5 %

Procedure:
Compound 28 (1.00 g; 2.96 mmol) was dissolved in tetrahydrofuran (15 ml). While the solution was stirred at −78° C. under nitrogen atmosphere, n-butyl lithium in n-hexane (1.63 M: 1.8 ml; 2.97 mmol) was added dropwise. The mixture was stirred for 10 minutes, and acetone (2 ml) was added dropwise thereto. The mixture was gradually brought to room temperature, and saturated aqueous ammonium chloride solution was added dropwise thereto, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→3:1), to thereby yield 0.55 g of the target compound as yellow oily matter (yield: 58.5%).
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.Br[CH2:15]C(=O)CC.C(O)C>[Pt](=O)=O.CO>[CH2:2]([C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1)[CH3:15]
Reactant: CCC(=O)CBr
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCO
Product: CCc1cn2c(n1)CNCC2

Procedure:
2-Ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 1-bromo-2-butanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:25])[NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][NH:20]3)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[NH:20]1[C:21]2[C:17](=[C:16]([CH2:15][NH:14][C:13]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH:10]([CH3:12])[CH3:11])[CH:8]=3)=[O:25])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)O
Reaction time: 15 h

Procedure:
A mixture of 5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-isopropyl-thiophene-2-carboxylic acid methyl ester (126 mg, 0.35 mmol), lithium hydroxide monohydrate (150 mg, 3.53 mmol), THF (4 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 115.6 mg (96%). MS m/e 344.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20](Br)[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[Sn](CCCC)(CCCC)CCCC.CN1C=CC=C1.[Cl-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:28]5[N:27]([CH3:26])[CH:31]=[CH:30][CH:29]=5)[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: Fc1ccc(CCN2CCC(n3ccc4ccc(Br)cc43)CC2)cc1
Agent: Cn1cccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1cccc1-c1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 57.5 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindole (0.2 g) was dissolved in toluene (2.50 ml). Next, 1-methyl-2-tributylstannylpyrrole (1.44 g) synthesized in accordance with the method described in Tetrahedron Lett., 4407 (1986). with the use of 1-methylpyrrole and tributylthin chloride was added thereto and the resultant mixture was heated under reflux for 3 hr under nitrogen atmosphere. After adding ethyl acetate, the mixture was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.115 g) as a yellow oil (yield: 57.28%).
Reaction SMILES: [CH2:1]([C:3]([CH:5]1[CH2:7][CH2:6]1)=O)[CH3:2].[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])#[N:9]>>[C:8]([C:10](=[C:3]([CH:5]1[CH2:7][CH2:6]1)[CH2:1][CH3:2])[C:11]([O:13][CH3:14])=[O:12])#[N:9]
Reactant: COC(=O)CC#N
Reactant: CCC(=O)C1CC1
Product: CCC(=C(C#N)C(=O)OC)C1CC1
Yield: 20.9 %

Procedure:
Similarly to Example 3a), a solution of 4 g (40.8 mmol) of cyclopropyl ethyl ketone and 2.4 g (24 mmol) of methyl cyanoacetate was reacted to give 0.9 g (21% yield) of methyl 2-cyano-3-cyclopropylpent-2-enoate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([Br:14])=[CH:7][C:6]=1[F:15])[CH:2]=[CH2:3].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(O)C>[CH2:1]([O:4][C:5]1[C:6]([F:15])=[CH:7][C:8]([Br:14])=[CH:9][C:10]=1[NH2:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOc1c(N)cc(Br)cc1F
Yield: 55 %

Procedure:
A mixture of Example 89A (1.3 g, 4.71 mmol), tin chloride dihydrate (5.3 g, 23.5 mmol) and triethylamine (13.1 mL, 94.2 mmol) in ethanol (50 mL) was heated at 70° C. for 6 hours, cooled. The insoluble material was filtered off and extensively washed with ethyl acetate. The combined filtrate was concentrated, and the residue was purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane to provide the desired product (638 mg, 55%). MS (DCI/NH3) m/z 247.82 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 4.41 (d, J=5.93 Hz, 2 H) 5.20 (dd, J=10.45, 1.72 Hz, 1 H) 5.30 (dd, J=17.31, 1.72 Hz, 1 H) 5.43 (s, 2 H) 6.03 (m, 1 H) 6.56 (dd, J=10.29, 2.50 Hz, 1 H) 6.66 (dd, J=2.34, 1.72 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([NH2:34])=[N:36][CH:37]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.273 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as an off-white solid (0.20 g, 73%). MS (ISP) 559.2 [(M+H)+]; mp 220° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(Cl)CCl>[C:17]([N:24]1[CH2:25][CH2:26][N:27]([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:28][CH2:29]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-nitro-5-trifluoromethyl-benzoic acid (4.13 g), 4-Boc-piperazine (2.97 g), EDC (3.88 g), HOBt (2.74 g), DIEA (3.33 ml) in CH2Cl2 (120 ml) was stirred at RT for 3 h. The mixture was diluted with CH2Cl2 (100 ml), washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (hexane, CH2Cl2:hexane 1:2) to give the compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([CH:18]=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1Cc2ccccc2N(Cc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1Cc2ccccc2N(Cc2ccccc2)C1

Procedure:
5.4 g of 1-benzyl-3(R,S)-hydroxymethyl-1,2,3,4-tetrahydroquinoline are reacted with 2.8 ml oxalyl chloride, 3.0 ml dimethylsulfoxide and 12 ml triethylamine analogously to Example 29b). Purification by means of FC is carried out over 500 g of silica gel (mobile phase D): Rf (D)=0.26; Rf (B)=0.41.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:14][NH:15][C:16](=O)[CH:17]([N:19]2[CH:28]=[CH:27][C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]2=[O:29])[CH3:18])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si](N=[N+]=[N-])(C)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[C:3]2[N:4]([C:16]([CH:17]([N:19]3[CH:28]=[CH:27][C:26]4[N:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]3=[O:29])[CH3:18])=[N:15][N:14]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: CC(C(=O)NNc1ncc(-c2cnn(C)c2)cc1F)n1ccc2ncccc2c1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nnc2c(F)cc(-c3cnn(C)c3)cn12)n1ccc2ncccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)propanehydrazide (400 mg, 982 μmol) and triphenylphosphine (386 mg, 1.4 mmol) were taken up in THF (9.8 mL). TMS-azide (195 μl, 1.4 mmol) was added, followed by slow addition of DEAD (233 μl, 1.4 mmol) and the reaction was stirred at room temperature for 1 hr until complete. The reaction was concentrated and purified via MPLC with a gradient 100% DCM to 90% DCM/10% MeOH/1% NH4OH to yield racemic 6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one (220 mg, 57% yield) as a tan solid. Separated by preperative SFC (ChiralPak® OJ-H, (20×150 mm, 5 □m), 20% MeOH, 80% CO2, 0.2% DEA; 100 bar system pressure; 70 mL/min; tr: 3.5 min) to yield (R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-1,6-naphthyridin-5(6H)-one (60 mg, 15% yield). On the basis of previous crystallographic data and potency recorded for related compound in the same program, the absolute stereochemistry has been assigned to be the R enantiomer. MS m/z=390.2 [M+H], calc 389.14 for C20H16FN7O. 1H NMR (400 MHz, CHLOROFORM-d) □ ppm 2.16 (d, J=5.18 Hz, 3 H) 3.97 (s, 3 H) 6.82 (d, J=6.55 Hz, 1 H) 7.01-7.13 (m, 2 H) 7.41-7.49 (m, 1 H) 7.54 (d, J=6.26 Hz, 1 H) 7.61 (s, 1 H) 7.71 (s, 1 H) 8.33 (s, 1 H) 8.78 (d, J=7.73 Hz, 1 H) 8.93 (s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31](O)=[O:32])[CH:26]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:31]([C:27]3[CH:26]=[C:25]([CH2:24][NH:23][C:21](=[O:22])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH:30]=[CH:29][N:28]=3)=[O:32])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccnc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 116.7 %

Procedure:
To a stirred solution of 4-(4-chlorophenoxy)piperidine hydrochloride (98 mg, 0.34 mmol), 4-(((tert-butoxycarbonyl)amino)methyl)picolinic acid (100 mg, 0.34 mmol), and N,N-diisopropylethylamine (0.14 mL, 0.79 mmol) in N,N-dimethylformamide (2 mL) was add HBTU (225 mg, 0.60 mmol) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into water (5 mL). This was extracted with ethyl acetate (5 mL) and washed with water (5 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) to give 177 mg (>99% yield) of the title compound as slight brown syrup.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(N2CCOCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A solution of (±)-cis-4-(-2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.531 g, 2.00 mmol) from Example 4 and morpholine (0.526 g, 6.04 mmol) in ethanol (6 mL) was stirred at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature before the addition of 2 mL of 1.0 N NaOH. Concentration of the mixture afforded the crude product which was purified by elution from a silica gel column using 5% methanol in chloroform (0.62 g, 98%). Crystallization of such a sample from ethanol-water gave a white powder; m.p. 165-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([CH2:8][NH:9][C:10]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[O:11])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:11][C:10]([C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C(=O)NCC(=O)c2ccc(Cl)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ncc(-c3ccc(Cl)cc3)o2)cc1
Yield: 80 %

Procedure:
In the same manner as in Example 106, ethyl 4-[N-(4-chlorobenzoylmethyl)carbamoyl]benzoate was reacted with phosphorus oxychloride to obtain ethyl 4-[5-(4-chlorophenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethyl acetate-isopropyl ether. Yield: 80%. Pale yellow prisms. Melting point: 195 to 197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:15]I>>[Cl:1][C:2]1[CH:8]=[C:7]([I:15])[CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4]
Reactant: II
Reactant: Nc1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1c(Cl)cc(I)cc1Cl
Temperature: 60 °C
Reaction time: 72 h

Procedure:
2,6-Dichloroaniline (16.2 g, 0.1 mol) is suspended in a solution of sodium bicarbonate (8.6 g, 0.1 mol in 100 mL of water) and warmed to 60° C. Elemental iodine (25.4 g, 0.1 mol) is added portionwise and the resulting mixture stirred at 60° C. for 3 days. After cooling to room temperature, the reaction mixture is partitioned between CH2Cl2 (250 mL) and saturated sodium bisulfite solution (500 mL). The aqueous layer is re-extracted with additional CH2Cl2 (250 mL) and the combined organic layers dried (MgSO4) and concentrated by rotary evaporator. The residual oil is purified by flash chromatography (9:1 hexanes/EtOAc) to give 2,6-dichloro-4-iodoaniline (m.p. 100–102° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([N:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)=[CH:40][CH:39]=3)[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)c2ccc(N3CCOCC3)cc2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(4-morpholin-4-yl-benzoyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 4-morpholinobenzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 570.1 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:18]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]O)=[CH:22][CH:21]=1)#[N:19]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: N#Cc1ccc(CCO)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(C#N)cc2)cc1)OCC
Reaction time: 2 h
Yield: 62.2 %

Procedure:
3-{4-[2-(4-Cyanophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester was synthesized using the same method as in Example 38(c) using 2-ethoxy-3-(4-hydroxyphenyl) propanoic acid ethyl ester (described in Example 20b) (6.62 g; 27.78 mmole) and p-cyanophenethyl alcohol (2.73 g; 18.52 mmole). The reaction was interrupted after 2 hours. Purification by chromatography on silica gel using first dichloromethane and then petroleum ether:diethyl ether as eluants gave a mixture of product and starting material which was dissolved in ethyl acetate and washed with sodium hydroxide (1 N). The organic phase was washed with water, dried (sodium sulfate), filtered and the solvent as evaporated to give 4.23 g (yield 62%) of 3-{4-[2-(4-cyanophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.[C:21]1([CH2:27][C:28](Cl)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C1COCC1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:4](=[O:20])[C:3]=1[CH2:28][CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1CCc1ccccc1

Procedure:
The title compound was prepared as described in General Method 5 using 2.0 mmol of 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one, 2.1 mmol of phenylacetyl chloride, 2.1 mmol of triethylamine, and 10 mL of THF, followed by 10 mL of toluene and catalytic DMAP. Chromatography of the residue afforded 1.5 mmol of the intermediate 3-acyl compound. Reduction of this acyl derivative was accomplished with 3 mmol of sodium cyanoborohydride. The product was triturated from ether (m.p. 158°-159° C.). 1H NMR (DMSO-d6) δ2.31 (m, 4H), 3.37 (m, 2H), 6.93 (d, 1H), 7.07-7.17 (m, 3H), 7.24-7.28 (m, 2H), 7.35 (m, 8H).