Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:38]([C:34]2[S:33][CH:37]=[CH:36][CH:35]=2)=[O:39])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)c2cccs2)c1=O

Procedure:
This compound was prepared from 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 2-thiophenecarbonyl chloride employing methods similar to those described in Example 400 and was obtained as a white solid: ES+ MS: 553 (M+H+).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25]>C(Cl)Cl>[C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 27 %

Procedure:
(+,−) Cis-2-Phenyl-cyclopentylamine (0.43 g, 2.7 mmol, from preparations 5 or 7) was dissolved in 15 mL of methylene chloride and cooled to 0° C. under nitrogen. 0.52 mL (3.5 mmol) of DBU was added followed by 0.39 mL (3.5 mmol) of isopropylsulfonyl chloride. Stirring was allowed to continue for 3 days while warming to room temperature. The reaction was washed with 1N HCl and the organic phase dried over sodium sulfate. Filtered, and concentrated in vacuo to a crude brown solid which was a 4:1 mixture of cis:trans by NMR. The isomers were purified by radial chromatography eluting with methylene chloride. 195 mg (27%) of the title compound (cis isomer) was isolated as a white solid as well as 15 mg of the more polar trans isomer. The NMR was consistent with the assigned structure.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][C@@H:2]1[OH:3].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C>C(O)C>[S:29]([O:8][CH2:7][C@H:5]1[O:6][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@@H:2]([OH:3])[CH2:4]1)([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)C[C@@H]2O)c(=O)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](O)[C@H](n3ccc(=O)[nH]c3=O)O2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
With moisture excluded, a solution consisting of 228 mg. (1.0 millimoles) of 1-(3-deoxy-β-D-threopentofuranosyl)-uracil [Prepared according to the method described by Horwitz et al., J. Org. Chem. 31, pp. 205--211 (1966)] and 2.5 ml. pyridine was chilled to 0° C. and a solution consisting of 236 mg. (1.24 millimoles) p-toluenesulfonyl chloride and 2.5 ml. pyridine was added dropwise while the temperature of the reaction mixture was maintained at 0° C. The reaction vessel was securely sealed and set aside at 3° to 5° C. for about 16 hrs. Afterwards, a small portion of crushed ice was added to the reaction mixture and refrigeration was continued for about 1 to 2 hrs. This mixture was further diluted with 50 ml. of ice-cold water and the dilute aqueous solution was extracted three times with 30 ml. portions of chloroform. The chloroform extracts were combined and dried over anhydrous sodium sulfate. After removing the chloroform by evaporation under reduced pressure, the residue thus obtained was dissolved in hot absolute ethanol. Some decolorizing charcoal was added to the ethanol solution, the charcoal was removed by filtration, and the filter was washed with hot absolute ethnol. The ethanol was removed from the combined filtrate and washings under reduced pressure, and the residue thus obtained was azeotroped with absolute ethanol under reduced pressure. There was thus obtained 182.8 mg. of 1-(5-O-tosyl- 3-deoxy-β-D-threopentofuranosyl)uracil as an amorphous solid.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])([CH3:38])[CH3:37]>C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:8][C:7]1[CH:15]=[CH:16][C:4]([C:1]2[O:3][C:47](=[O:48])[C:46]([S:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH:36]([CH3:37])[CH3:38])=[C:50]([OH:51])[CH:2]=2)=[CH:5][CH:6]=1)[CH3:14]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using ethyl (4-acetyl-phenoxy)acetate (2.14g, 9.67 mmol), trimethylsilyl triflate (4.48 mL, 23.20 mmol), triethylamine (12.93 mL, 38.6 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (2.00g, 6.45 mmol) m.p. 194°-196° C.; ; 1H NMR (400 MHz, DMSO-d6) δ 1.57 (m, 9H), 3.41 (m, 1H), 4.81 (q, 2H), 4.89 (s, 2H), 6.75 (s, 1H), 6.90 (d, 1H), 7.05 (m, 4H), 7.26 (d, 1H), 7.79 (d, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:41]1[CH2:43][CH2:42]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+].O>O1CCCC1>[CH:41]1([N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]3([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:15]=2)=[O:13])[CH2:42][CH2:43]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (284) (430 mg, 0.69 mmol) in tetrahydrofuran (20 mL) was added 1N HCl (3.5 mL. 3.48 mmol) at room temperature and the reaction mixture was stirred for 30 min. After completion of the reaction, solid NaHCO3 was added, basified up to pH 8. Water (10 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The organic part was dried and concentrated to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (285) (300 mg, 88.4%) as a light yellow sticky mass.
Reaction SMILES: CC([C@H]1[N:9]2[CH2:10][CH2:11][CH2:12][C@:8]2([CH2:13][CH:14]=[CH2:15])[C:7](=[O:16])[O:6]1)(C)C.[ClH:17]>CO.O>[ClH:17].[CH:13]([C@:8]1([C:7]([OH:16])=[O:6])[CH2:12][CH2:11][CH2:10][NH:9]1)=[CH:14][CH3:15]
Reactant: C=CC[C@]12CCCN1[C@H](C(C)(C)C)OC2=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CC=C[C@]1(C(=O)O)CCCN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(1,1-Dimethylethyl)-5,6,7,7a-tetrahydro-7a-(2-propenyl)-(3S-cis)-1H,3H-pyrrolo[1,2-c]oxazol-1-one (7.98 g) was dissolved in a mixture of methanol (170 ml) and water (40 ml). Silica gel (20 g) was added and the reaction was stirred for 24 h at ambient temperature. The silica was removed by filtration, washed with methanol (100 ml) and water (50 ml) and the filtrate and washes were combined, then evaporated to leave an oil which was taken up in 1M HCl (100 ml). The solution was washed with CH2Cl2 (4×50 ml) then evaporated to dryness. Residual water was removed by azeotropic evaporation with methanol to leave a brown solid (5 g) which was dried in vacuo over P2O5, leached with boiling chloroform and crystallised from methanol to give the title compound (3.68 g) m.p. 180°-183° , [α]D +50° (MeOH, C=1%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)=[O:17])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)CC1

Procedure:
In the same manner as in Reference Example 2, N-tert-butoxycarbonyl-L-glutamine and 1-methylpiperazine were condensed to obtain a crystal of 1-(N-tert-butoxycarbonyl-L-glutaminyl)-4-methylpiperazine (7.0 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[OH:32][CH:31]([C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:30][CH2:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)C1CCCC1
Reactant: O=CCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)C1(C(O)CCCCc2ccccc2)CCCC1
Temperature: -40 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Diisopropylamine (17.5 mL, 124 mmol) is dissolved in THF (80 mL), cooled to -40° C. and 2.38 M n-butyl lithium in hexanes (52 mL, 124 mmol) is added over 5 minutes. The reaction is allowed to warm to 0° C. and cyclopentanecarboxylic acid (6.7 mL, 62 mmol) in THF (60 mL) is added over 5 minutes. The reaction is heated at 40° C. for 1 hour. The reaction is cooled to -78° C. and 5-phenylpentanal (10 g, 62 mmol) in THF (20 mL) is added dropwise over 15 minutes. The cooling bath is removed and the reaction is allowed to stir at room temperature overnight. The reaction is acidified with 2 N HCl (120 mL) and the organics are removed in vacuo. The resulting aqueous mixture is extracted with CH2Cl2 (200 mL) and this organic layer is dried over MgSO4. The solution is concentrated in vacuo, and the resulting residue is purified by column chromatography (silica, 50% ether in petroleum ether) to yield 1-(1-hydroxy-5-phenylpentyl)cyclopentanecarboxylic acid (13.1 g, 77%): 1H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.19-7.15 (m, 3H), 3.53-3.46 (m, 1H), 2.64-2.58 (m, 2H), 2.20-2.13 (m, 1H), 2.07-1.99 (m, 1H), 1.95-1.73 (m, 1H), 1.67-1.49 (m, 8H), 1.44-1.32 (m, 3H); MS (EI) m/e 276 (M+).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[C:14]1[CH:24]([CH3:26])[CH3:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:30]=[O:31])C>CCOC(C)=O>[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[C:15]([CH:30]=[O:31])=[C:14]1[CH:24]([CH3:26])[CH3:25])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2cc(C(C)C)n(Cc3ccccc3)c2c1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2c1
Reaction time: 0.5 h

Procedure:
POCl3 (0.48 ml, 5.23 mmol) was added dropwise to anhydrous DMF (2 ml) at 0° C. under argon. After stirred for 30 min, this solution was added dropwise to a solution of 1-benzyl-2-isopropyl-6-methoxy-1H-indole (Compound 4, 583 mg, 2.09 mmol) in anhydrous DMF (8 ml) at 0° C. under argon. The reaction was stirred for 1 h at 0° C. and 30 min at room temperature, diluted with EtOAc, washed with aqueous NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a light yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:32]1[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]1)=[O:19])=[N:5]2
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 82 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 82%). 1H NMR (300 MHz, DMSO-d6): δ 3.62-3.66 (m, 8H), 4.06 (s, 3H), 7.07 (d, J=9.0 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.76-7.80 (m, 2H), 8.11 (d, J=9.0 Hz, 2H), 9.46 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][C:16]1[C:17]([CH2:23][NH2:24])=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:24][CH2:23][C:17]2[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cnc(CN)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B, reaction of N-Boc-4-piperidone, C-(3,5-dimethylpyridin-2-yl)-methylamine and NaBH(OAc)3 in CH2Cl2 gave 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH2:15][CH3:16]>CN(C)C=O.CCOCC>[C:1]([N:8]([CH2:9][C:10]#[CH:11])[CH2:15][CH3:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Di-tert-butyl dicarbonate (42.8 g, 196 mmol) in dichloromethane (100 mL) was added dropwise to a solution of propargylamine (11.02 g, 200 mmol) in dichloromethane (200 mL) at room temperature with magnetic stirring. After 2 h, the reaction mixture was washed with aqueous 1N hydrochloric acid (300 mL) and saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layers were washed with dichloromethane (300 mL). The dichloromethane solutions were combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 40S, EtOAc-hexanes V/V 1:9 as solvent) to give crude N-Boc-propargylamine. (32.32 g). The crude N-Boc-propargylamine (3.1 g, 20 mmol) was dissolved in dry dimethylformamide (20 mL) with magnetic stirring and cooled in an ice-water bath. Sodium hydride (0.61 g, 24 mmol) was added in small portions. After stirring for 15 min., iodoethane (3.74 g, 24 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. then diluted with ether and extracted with water and saturated brine. The aqueous layers were back washed with ether and the ether layers were combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 40M, ethyl acetate-hexanes as solvent to give N-Boc-N-ethylpropargylamine. (Yield 3.19 g, 87%).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.CO.[OH-].[Na+].Cl>O>[NH:36]1[C:32]([C:29]2[CH:28]=[CH:27][C:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:21][CH:22]=3)=[CH:31][CH:30]=2)=[N:33][N:34]=[N:35]1
Reactant: COC(=O)CCCCCCCCCCCCCCCOc1ccc(-c2ccc(-c3nnn[nH]3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCCCCCCCCCOc1ccc(-c2ccc(-c3nnn[nH]3)cc2)cc1
Yield: 96.1 %

Procedure:
A mixture of 16-(4′-(5-tetrazolyl)biphenyl-4-yloxy)hexadecanoic acid methyl ester (2.87 g, 5.66 mmol), MeOH (30 ml), and a solution of NaOH (1.51 g, 37.8 mmol) in water (2.0 ml) was stirred at 70° C. After 4 d water (100 ml) and 1N HCl (50 ml) were added, and the product was filtered, washed with water, coevaporated with MeCN/PhMe, and dried under reduced pressure. 2.68 g (96%) of 16-(4′-(5-tetrazolyl)biphenyl-4-yloxy)hexadecanoic acid was obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)=[CH:9][C:8]=2[Cl:19])=[N:5][N:6]=1.[CH3:20][N:21]1[CH2:28][C@@H:27]2[C@@H:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1>CN1C(=O)CCC1.C(Cl)Cl>[Cl:19][C:8]1[CH:9]=[C:10]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]([N:25]2[CH2:26][C@@H:27]3[C@@H:23]([CH2:22][N:21]([CH3:20])[CH2:28]3)[CH2:24]2)=[N:6][N:5]=1
Reactant: CN1C[C@H]2CNC[C@H]2C1
Reactant: Cn1cc(-c2ccc(-c3nnc(Br)s3)c(Cl)c2)cn1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN1C[C@@H]2CN(c3nnc(-c4ccc(-c5cnn(C)c5)cc4Cl)s3)C[C@@H]2C1
Temperature: 120 °C
Reaction time: 16 h
Yield: 12.7 %

Procedure:
A stirred suspension of 2-bromo-5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (70 mg, 0.197 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (75 mg, 0.590 mmol) in NMP (0.5 mL) was heated to 120° C. and the resulting solution was stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (20 mL). The organic phase was separated and the aqueous phase was re-extracted with DCM (20 mL). The combined organic phases were concentrated in vacuo to afford the crude product as a dark brown oily residue. The crude material was purified by mass directed preparative HPLC under acidic conditions (TFA modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a light brown solid (10 mg, 13% yield). LC-MS: Rt 0.79 min; MS m/z 401.4 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.99-8.03 (m, 2H), 7.84 (d, J=2.02 Hz, 1H), 7.65-7.69 (m, 1H), 3.88 (s, 3H), 3.70 (dd, J=10.61, 8.08 Hz, 2H), 3.36 (dd, J=10.61, 3.03 Hz, 2H), 2.99 (br. s., 2H), 2.55 (br. s., 4H), 2.25 (s, 3H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.21 (d, J=8.08 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.57 (d, J=2.02 Hz, 1H), 7.46 (dd, J=8.34, 1.77 Hz, 1H), 3.99 (s, 3H), 3.79 (dd, J=9.85, 7.83 Hz, 2H), 3.53 (d, J=11.12 Hz, 2H), 3.12 (br. s., 2H), 2.76 (br. s., 2H), 2.58 (d, J=8.08 Hz, 2H), 2.41 (br. s., 3H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](=[O:21])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][NH:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28]1)=[O:26])[CH3:23]>ClCCl>[CH2:14]([O:13][C:11]([CH2:10][C:9]([N:31]1[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28][CH:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:32]1)=[O:21])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CNc2ccccc2O1
Reactant: O=C(Cl)CC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)CC(=O)OCc2ccccc2)c2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
54.6 mmol (7.6 ml) of triethylamine and 35.9 mmol (7.64 g) of benzyl 3-chloro-3-oxopropanoate are added to 17.1 mmol (3.53 g) of 2-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine (described in J. Heterocyclic Chem., 1985, 22, 177) in 35 ml of dichloromethane. The reaction mixture is stirred at room temperature for 1 hour. After hydrolysis and extraction with dichloromethane, the organic phase is concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (2/8) as eluant to yield the expected compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].Cl.[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([S:17][CH3:16])=[CH:19][CH:20]=1)#[N:2]
Reactant: CSc1ccc(CN)cc1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CSc1ccc(CN=C(NC#N)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.40 g, 2.1 mmol) was dissolved in methanol (15 ml), and 4-methylthiobenzylamine hydrochloride (0.60 g, 3.2 mmol) and triethylamine (0.43 g, 4.2 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was then concentrated under reduced pressure. The residual concentrate was extracted with ethyl acetate (50 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was crystallized from methanol-diethyl ether to give the title compound (0.29 g, 1.0 mmol, yield: 49%) as colorless crystals.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([NH:17][C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: CCCCN
Solvent: CCOC(C)=O
Product: CCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Following the procedure of Example 1 above and using trans-2-phenyl-1-cyclopropanecarbonyl chloride and n-butylamine (and ethyl acetate in place of benzene), the title compound was prepared as a waxy white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nn1cccc1
Product: Fc1cnc(Cl)nc1Nn1cccc1

Procedure:
In like manner to the preparation of 2-chloro-N-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 1-aminopyrrole to produce 2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 11.39 (s, 1H), 8.35 (d, 1H, J=3.5 Hz), 6.83 (t, 2H, J=2.3 Hz), 6.07 (t, 2H, J=2.3 Hz). LCMS: ret. time: 18.95 min.; purity: 97%; MS (m/e): 213 (MH+).