Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[I-].[Na+].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[S:30]>CC(C)=O.C(=O)([O-])O.[Na+].O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([C:3]3[N:31]=[C:29]([NH:28][CH2:27][CH2:26][CH:22]4[CH2:23][CH2:24][CH2:25][N:21]4[CH3:20])[S:30][CH:2]=3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:12][CH:13]=1
Reactant: O=C(CCl)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: CN1CCCC1CCNC(N)=S
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN1CCCC1CCNc1nc(C2(c3ccc(Cl)cc3)CCCCC2)cs1
Temperature: 50 °C

Procedure:
A solution of 2-chloro-1-[1-(4-chloro-phenyl)-cyclohexyl]-ethanone (144.8 mg, 0.53 mmol) and sodium iodide (80 mg, 0.53 mmol) in acetone (4 mL) was stirred at room temperature for 10 min. Next, [2-(1-methyl-pyrrolidin-yl)ethyl] thiourea (100 mg, 0.71 mmol) was added. The resulting mixture was heated at 50° C. overnight. After the mixture was allowed to cool to room temperature, it was diluted with 5% sodium hydrogen carbonate in water and then extracted with ethyl acetate (3×20 mL). The extracts were combined, and dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The crude was purified by column chromatography on silica gel using dichloromethane/2 N ammonia in ethanol (95:5) to give {4-[1-(4-chloro-phenyl)-cyclohexyl]-thiazol-2-yl}-[2-(1-methyl-pyrrolidin-2-yl)-ethyl] amine, 95, as an oil (150 mg, 70%). 1H (CDCl3, 300 MHz) δ 7.30-7.21 (m, 4H), 6.02 (s, 1H), 5.67 (s, 1H), 3.67-1.52 (m, 24H) ppm; 13C (C6D6, 75 MHz) δ 22.9, 23.5, 26.9, 29.4, 30.8, 36.7, 40.8, 43.2, 46.4, 57.4, 64.9, 101.2, 128.7, 129.4, 132.0, 146.8, 160.1, 169.5 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[O:21][CH2:20]1>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:28][C:26]1[CH:25]=[CH:24][C:23]2[O:19][CH2:20][O:21][C:22]=2[CH:27]=1)[CH3:2]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Oc1ccc2c(c1)OCO2

Procedure:
A solution 2-Chloro-nicotinic acid ethyl ester (5.0 grams, 27.0 mmole), cesium carbonate (2.96 grams, 67.5 mmole) and Benzo[1,3]dioxol-5-ol (4.19 grams, 29.7 mmole) in dimethylformamide (80 ml) was heated to 65° C. for 10 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a solid (7.0 g). MW 287.275.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:19])[C:17]#[N:18])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20]I>>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: CC(C#N)c1ccc2oc(-c3ccccc3)nc2c1
Product: CC(C)(C#N)c1ccc2oc(-c3ccccc3)nc2c1

Procedure:
By treatment of 2-(2-phenyl-5-benzoxazolyl)propionitrile with methyl iodide in the manner described in Example 12, there was obtained 2-(2-phenyl-5-benzoxazolyl)isobutyronitrile which, on treatment with concentrated hydrochloric acid as described in Example 1(f), yielded 2-(2-phenyl-5-benzoxazolylisobutyric acid, m.p. 92° -95° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16](Br)=[N:15][C:14]2[C:9]1=[N:10][C:11]([Cl:19])=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:24])CCC>Cl>[NH2:18][C:13]1[N:12]=[C:11]([Cl:19])[N:10]=[C:9]2[C:14]=1[NH:15][C:16](=[O:24])[N:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)nc2c1nc(Br)n2Cc1ccccc1
Reactant: CCCCO
Agent: Cl
Product: Nc1nc(Cl)nc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
The product from Step 3 (2 g, 5.9 mmol) was suspended in 12 N HCl (35 mL) and n-butanol (35 mL) and the mixture heated at 100° C. for 7 h and then allowed to cool to room temperature. The reaction mixture was evaporated to dryness in vacuo, and then partitioned between 2 N NaOH (50 mL) and dichloromethane (50 mL). The organic layer was separated and found to contain some unreacted starting material only and was discarded, while the aqueous layer was neutralized with concentrated HCl and the resulting precipitate collected by filtration and washed with ethyl acetate to give 6-amino-9-benzyl-2-chloro-7,9-dihydro-purin-8-one as an off-white solid (1.5 g, 94%) which was found to be >90% pure and was used with no further purification.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O1CCCC1.C(OCC)C>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1
Yield: 94.8 %

Procedure:
A 25% aqueous solution of dimethylamine (420 mL, 2.3 mol) was diluted with 1000 mL of tetrahydrofuran and added dropwise to a solution of p-bromobenzenesulfonyl chloride (200 g, 0.78 mol) in 700 mL of tetrahydrofuran. The mixture was diluted with diethyl ether and the organic layer was washed with water and saturated aqueous sodium chloride and dried over sodium sulfate. Evaporation of the solvent gave 195.4 g (95%) of 4-bromo-N,N-dimethylbenzenesulfonamide as white crystals, mp 90°-92° C. (lit. 94° C., J. Am. Chem. Soc. 45, 2696 (1923)).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=2)[N:7]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([SH:29])=[N:27][N:28]=2)[CH:25]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([S:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=4)[N:7]=3)=[N:27][N:28]=2)[CH:25]=1
Reactant: Sc1nnc2ccc(Cl)cn12
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cn2nc(Sc3nnc4ccc(Cl)cn34)ccc2n1
Temperature: 120 °C
Yield: 102.6 %

Procedure:
Combined compound 7B (50 mg, 0.14 mmol), 6-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (28 mg, 0.15 mmol), Tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.01 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (14 mg, 0.025 mmol), DIEA (48 uL, 0.28 mmol) and DME (1.4 mL) and heated in a microwave unit at high absorbance, 120° C. for 30 min. The resulting crude material was purified by silica gel using 5% MeOH in DCM. The cleanest fractions were concentrated to give compound 7 (0.06 g; quantitative yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (br. s., 1 H), 8.86-8.82 (m, 1 H), 8.11-8.05 (m, 1 H), 7.89 (d, J=9.3 Hz, 1 H), 7.73 (s, 1 H), 7.66 (dd, J=1.9, 9.7 Hz, 1 H), 7.09 (d, J=9.6 Hz, 1 H), 1.48-1.41 (m, 9 H), ESI-MS:m/z 418.2.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(OC)cc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
p-Methoxyaniline (0.104 g, 0.845 mmol), triethylamine (0.085 g, 0.845 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.143 g, 0.845 mmol) were added to a methylene chloride solution (20 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.158 g, 0.422 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=30:1) and then recrystallized from isopropyl ether to obtain the titled compound (0.066 g, 0.138 mmol, 33%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=2[Cl:26])[CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[Cl:26][C:21]1[N:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:7]1[CH:8]=[CH:9][C:10]([C:11]([F:16])([F:17])[C:12]([F:15])([F:14])[F:13])=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH:6]=1)=[O:27]
Reactant: NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 381 mg (0.93 mmol) N-[3-(2-amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamide in 10 ml CH2Cl2 at 0° C. was added 0.389 ml Et3N and 0.072 ml (0.93 mmol) methanesulfonylchloride. After 5 min, the reaction was stirred at RT for 30 min. The reaction was diluted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, concentrated, and dried under vacuum, yielding the titled compound as a white foamy solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)[C:7]2[N:8]([CH:10]=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:33]=[N+:34]=[N-:35])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:35][N:34]=[N:33][N:28]=3)=[CH:19][CH:20]=2)[C:7]2[N:8]([CH:10]=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nn2cc(C)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1nn2cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 31 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5-methyl-3H-imidazo[1,2-b][1,2,4]triazole (from Steps B and C) with trimethyltin azide according to the procedure of Example 1, Step G, gave a 31% yield of the title compound as a light brown solid, mp 124°-125° C.; homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:27][C:28]#[N:29])[CH2:21][N:20]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:19]4)[CH:17]=3)[N:10]3[CH:30]=[CH:31][N:32]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C([O-])(O)=O.[Na+].[Cl:38]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:38][C:30]1[N:10]2[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:18]4([CH2:27][C:28]#[N:29])[CH2:21][N:20]([CH2:22][C:23]([F:24])([F:26])[F:25])[CH2:19]4)[CH:17]=3)=[N:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][C:9]2=[N:32][CH:31]=1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(-c2cc3ncc(Cl)n3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoro ethyl)azetidin-3-yl)acetonitrile (Example 71, 100 mg, 0.227 mmol) in DCM (1.5 mL) was added saturated NaHCO3 (1.0 mL) followed by N-chlorosuccinimide (46.3 mg, 0.340 mmol) in one portion. The biphasic mixture was vigorously stirred at ambient temperature for 17 hours and was diluted with DCM (2 mL). The solution was washed with H2O, dried over Na2SO4 and eluted through a silica gel plug (EtOAc elution). The solution was concentrated, the residual glass was dissolved in minimal DCM and hexane was added to afford a granular suspension. The suspension was concentrated and the residual solid was washed with warm 25% EtOAc/hexanes and dried in vacuum to afford the title compound (22 mg, 20% yield) as an ivory white powder. MS (apci) m/z=476.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:11][CH2:10]2)=[C:5]([CH3:27])[CH:4]=1)#[N:2].C(#N)C.C(N(CC)CC)C.[CH:38]1[CH:43]=[CH:42][C:41]([O:44][C:45](OC2C=CC=CC=2)=[N:46][C:47]#[N:48])=[CH:40][CH:39]=1>>[C:47](/[N:46]=[C:45](\[O:44][C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1)/[N:20]1[CH2:21][CH2:22][C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[CH3:27])[CH2:10][CH2:11]2)=[O:16])[C@@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19]1)#[N:48]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Temperature: 85 °C

Procedure:
To a stirred solution of methyl (3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (386.500 mg, 1.04334E-3 mol) in anhydrous acetonitrile (6.000 mL, 0.1149 mol) at rt was added triethylamine (0.2923 mL, 0.002087 mol) and diphenyl cyanocarbonimidate (384.4 mg, 0.001565 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 5 hrs. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-90% EtOAc/Hex to give the product (60% in yield). MS (ESI): (M+H)+=515.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]([F:24])([F:23])[F:22])=[CH:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:21]([F:23])([F:22])[F:24])=[CH:11][C:12]=2[S:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:25])=[CH:6][CH:7]=1
Reactant: OO
Reactant: FC(F)(F)c1cc(Sc2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Solvent: CC(=O)O
Solvent: O
Product: O=S(c1ccc(Cl)cc1)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Yield: 65.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(p-chlorophenyl)thio]-5-(trifluoromethyl)pyrrole (2.57 g, 6.6 mmol) and 30% hydrogen peroxide solution (0.83 g, 7.3 mmol) in acetic acid is stirred at room temperature overnight and poured into water. The resultant aqueous mixture is filtered to obtain a solid. A solution of the solid in methylene chloride is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:3 ethyl acetate/hexanes solution gives the title product as a white solid (1.75 g, mp 174°-176° C.)
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([N:14]3[C:18](=[O:19])[CH2:17][CH:16]([C:20]([OH:22])=O)[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.CN.[CH2:28]([N:30](CC)CC)C>CN(C)C=O>[CH3:28][NH:30][C:20]([CH:16]1[CH2:17][C:18](=[O:19])[N:14]([C:11]2[CH:12]=[N:13][C:8]([O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=3)=[CH:9][CH:10]=2)[CH2:15]1)=[O:22]
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)nc2)C1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)nc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.6 %

Procedure:
A solution of 105 mg (0.3 mmol) of (RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid in 5 ml N,N-dimethylformamide is treated with 58 mg (0.35 mmol) of N,N-carbonyl-diimidazole, and the mixture is stirred at RT for 15 min. Thereafter, 26 mg (0.38 mmol) of methylamine hydrochloride and 50 μl (0.35 mmol) of triethylamine are added. After 30 min, the solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 15 mg (15% of theory) of (RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a green oil which solidifies on standing. MS: m/e=344 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:15][N:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:36]1[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[NH:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:36]3[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[CH:37]=3)=[CH:20][CH:19]=2)=[N:15][N:14]=1
Reactant: Oc1ccc(-c2nnc(Nc3cc(C(F)(F)F)ccc3Cl)o2)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cc(C(F)(F)F)ccc4Cl)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
4-(5-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (177.85 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 30 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as an off-white solid (131.1 mg). Yield 56.5%.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16](/[CH:18]=[N:19]/[OH:20])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:22]=[C:23]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.C(OCC)(=O)C.Cl>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16]([C:18]2[CH2:22][C:23]([CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[O:20][N:19]=2)[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O/N=C/c1cc(OCc2ccccc2)ccc1Br
Reactant: C=C(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Reaction time: 2 h
Yield: 82.1 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 16.42 g) was added dropwise to a solution of (E)-1-(5-(benzyloxy)-2-bromophenyl)-N-hydroxymethanimine (3.07 g) and di-tert-butyl 2-methylenesuccinate (2.43 g) in THF (30 mL) at 0 C, and the obtained mixture was stirred at 0 C for 2 hours. The reaction mixture was diluted with ethyl acetate, and 1 M hydrochloric acid was added thereto. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (4.50 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH2:24]C)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:26][O:27]CCOC1N=C(C(O)=O)C=NC=1N1CCCC1.N[C@@H](CC(C)C)CO>>[OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:13]([O:22][CH2:23][CH2:24][O:27][CH3:26])[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Reactant: COCCOc1nc(C(=O)O)cnc1N1CCCC1
Agent: CC(C)C[C@H](N)CO
Product: COCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-(2-methoxy-ethoxy)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid and (S)-2-amino-4-methyl-pentan-1-ol (commercially available). m/z (ES+): 367.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:16][O:17][C:18]([C:20]1[O:24][NH:23][C:22](=O)[CH:21]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[O:24][N:23]=[C:22]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:21]=1)=[O:19]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CO
Reactant: COC(=O)c1cc(=O)[nH]o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of [3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (438 mg, 2.1 mmol) in THF (10 mL) was added 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (300 mg, 2.1 mmol) and triphenylphosphine (658 mg, 2.1 mmol) at room temperature under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.1 mL, 2.5 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. Concentration and purification by chromatography (silica, dichloromethane:methanol=4:1 to 1:4) afforded the title compound (431 mg, 62%) as a white solid. MS: m/e=334.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: OCCC(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCCC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.0 g, 20.3 mmol) in THF (140 mL) were triphenylphosphine (7.97 g, 30.4 mmol) and 3,3,3-trifluoropropan-1-ol (1.96 mL, 22.3 mmol) added. Diisopropyl azodicarboxylate (5.98 mL, 30.4 mmol) was added dropwise and the mixture was left stirring at r.t. overnight. Since there was starting material remaining, 3,3,3-trifluoro-1-propanol (0.892 mL, 10.1 mmol) was added dropwise and stirring was continued. After 30 min the mixture was heated to 40° C. and after 1 h the mixture was concentrated. The product was purified by flash chromatography (0-12% EtOAc in heptane as eluent) to afford 1.08 g (22% yield) of the title compound (containing some diisopropyl azodicarboxylate): 1H NMR (500 MHz, CDCl3) δ 2.65 (qt, 2 H), 2.71-2.77 (m, 2 H), 3.05-3.13 (m, 2 H), 4.23 (t, 2 H), 7.17-7.23 (m, 2 H), 7.40 (d, 1 H); MS (ES+) m/z 245 [M+H]+.