Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[N:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].C1COCC1.Cl>CO>[N:19]1([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C@H:9]3[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[N:18]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: CCOC(=O)[C@H]1CC[C@H](Nc2nccc(-n3ncc4ccccc43)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](Nc2nccc(-n3ncc4ccccc43)n2)CC1
Reaction time: 8 h

Procedure:
A mixture of trans-4-(4-indazol-1-ylpyrimidin-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (2.88 g, 7.9 mmol), aqueous NaOH (2 M, 65 mL) and THF (65 mL) was stirred overnight. MeOH (40 mL) was added, and the reaction mixture stirred for an additional 105 min. Aqueous HCl (1M) was added to reach pH 3, and the resulting solid collected by filtration to give trans-4-(4-indazol-1-yl-pyrimidin-2-ylamino)-cyclohexanecarboxylic acid (2.739 g) without further purification.
Reaction SMILES: Cl[C:2]1[C@@H:3](N)[CH2:4][CH2:5][CH2:6][CH:7]=1.C1(=O)[N:13](N[C@H](C(O)=O)CC2C=CC=CC=2)[C:12](=[O:26])[C:11]2=CC=CC=[C:10]12>>[C:2]1([CH2:10][CH2:11][C:12]([NH2:13])=[O:26])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCCC=C1Cl
Reactant: O=C(O)[C@H](Cc1ccccc1)NN1C(=O)c2ccccc2C1=O
Product: NC(=O)CCc1ccccc1

Procedure:
reacting (S)-2-chloro-cyclohex-2-enylamine with phthalimido-L-phenyalanine derivative to give (S)-N-(2-chloro-cyclohex-2-enyl)-2- 2(S)-1,3-dihydro-1,3-dioxo-isoindol-2-yl)-3-phenyl-propionamide;
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:31](C1C=C2C(=CC=1)NC=C2CC(O)=O)#[N:32]>>[C:31]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:2]=1)[NH:8][CH:7]=[C:6]2[CH2:11][C:12]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=1)=[O:13])#[N:32]
Reactant: N#Cc1ccc2[nH]cc(CC(=O)O)c2c1
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3ccc(C#N)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(5-cyano-1H-indol-3-yl)acetic acid (preparation H) in step 23 (A), the title compound was prepared. 1H-NMR (500 MHz, CD3OD) δ ppm 2.19 (s, 3 H) 4.03 (s, 2 H) 4.56 (s, 2 H) 7.45 (m, 4 H) 7.55 (d, J=8.55 Hz, 1 H) 8.06 (s, 1 H)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:23]/[CH:24]=[C:25](\[CH3:34])/[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>O.CCCCC>[N:1]([CH2:23]/[CH:24]=[C:25](\[CH3:34])/[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C/C(=C\CCl)COC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Product: C/C(=C\CN=[N+]=[N-])COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A solution of 11.43 g (175.86 mmol) of sodium azide (NaN3) and 2.20 g (6.45 mmol) of tetrabutylammonium hydrogenosulfate in 60 ml of water was added to a solution of 12.0 g (58.62 mmol) of (E)-2-(4-Chloro-2-methylbut-2-en yloxy)tetrahydro-2H-pyran in 300 ml of pentane. The reaction mixture was stirred at room temperature overnight. The organic phase was separated and the aqueous phase was extracted with 3×150 ml of Et2O. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give 11.21 g (53.06 mmol, 90% yield) of a mixture of azides isomers. No purification was done as infeasible separation was observed on silica gel. The product was used without further purification for the next step.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:26])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=3)=[N:13]2)=[O:8])[N:6]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([C:37]4[N:33]([CH:28]5[CH2:29][CH2:30][CH2:31][CH2:32][O:27]5)[N:34]=[CH:35][CH:36]=4)[O:3][CH:4]=3)=[O:8])[CH3:26])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(-c2ccnn2C2CCCCO2)n1
Temperature: 100 °C
Yield: 31.4 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide (153 mg, 0.352 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (490 mg, 1.760 mmol), tetrakis(triphenylphosphine)palladium (4.07 mg, 3.52 umol), THF and 2 M Na2CO3 solution were added in a microwave flask and heated at 100° C. for 1 h. The reaction mixture was diluted with DCM and washed twice with NaHCO3 solution. Organic phase was dried and evaporated to dryness. The product was purified twice by Flash-chromatography. Yield 31.4%. m/z [506.0+1].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][OH:26]>CN1CCCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:23]4[CH2:29][CH2:28][CH2:27][C@H:24]4[CH2:25][OH:26])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CCCN1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: CN1CCCC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC[C@H]3CO)c(F)cc2c1=O

Procedure:
A solution of 3.1 g (0.01 mmol) of ethyl 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3-carboxylate and 3.03 g (0.03 mmol) of L-prolinol in 15 ml of N-methylpyrrolidine was stirred at 80° C. for 2.5 hours. The solvent was removed by distillation under reduced pressure and the oily residue was recrystallized from ethyl acetate/ether. The resulting ester was saponified analogously to Example 1A. There was obtained 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[(S)-2-hydroxymethyl-1-pyrrolidinyl]-4-oxoquinoline-3-carboxylic acid, m.p. 209°-210° C.
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([S:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([S:1][C:9]3[CH:14]=[CH:13][C:12]([O:15][S:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:24])=[O:23])=[CH:11][CH:10]=3)=[CH:3][CH:4]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(Sc2ccc(OS(=O)(=O)c3ccccc3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A 100 ml 3-necked oven dried flask is equipped with a magnetic stirring bar and a CaCl2 -Drierite drying tube and is charged with 4,4'-thiodiphenol (5.3 grams, 24.3 mmol), benzenesulfonyl chloride (6.5 ml, 50.9 mmol), 4-dimethylaminopyridene (0.59 grams, 4.8 mmol), and anhydrous pyridine (40 ml). The mixture is stirred at ambient temperature for 18 hours, and at reflux for 4 hours, then is poured into ice-cold water (100 ml) with vigorous stirring, and the yellow oil that separates is extracted into CH2Cl2 (100 ml), and washed with water (100 ml). Drying (MgSO4), filtration and concentration affords a yellow oil. Purification by filtration through a column packed with flash grade silica gel (5"×2" i.d.), eluting with CH2Cl2 (ca. 0.5 l), gives after solvent removal under vacuum 11.8 grams (98 percent yield) of the title compound as a faintly yellowish, thick glass material.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](=[O:24])[CH2:10]1)=O)(C)(C)C.[OH-].[Na+]>>[C:18]1([CH2:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][NH:9][CH2:10][C:11]2=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2ccccc2)C(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CNCCN1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Concentrated hydrochloric acid (4.2 ml) was added to 4-tert-butoxycarbonyl-1-(3-phenylpropan-1-yl)-2-oxopiperazine (3.85 g, 12.1 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. The reaction mixture was basified with 8N-sodium hydroxide and extracted with ethyl acetate. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-(3-phenylpropan-1-yl)-2-oxopiperazine as a colorless oil (2.49 g, 94%).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]1=[O:12])C.[S:13]([NH:23]N)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].CC(O)=O>CCO>[S:13]([N:23]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:12])[C:5]=2[CH:4]=[N:2]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3=O)cc1
Yield: 51.3 %

Procedure:
A solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (55 g, 0.329 mol), 2-tosylhydrazine (61.3 g, 0.329 mol) and AcOH (33 mL) in EtOH (540 mL) was heated for 4 h at 70° C. Removed the solvent under reduced pressure and the residue was recrystallized using PE/EA=5/1 to give 1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (49 g, yield 51.3%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]([NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([C:29](O)=[O:30])[CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:29]([C@@H:25]3[CH2:26][CH2:27][CH2:28][C@H:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:24]3)=[O:30])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a mixture of 4-(3,4-dichlorophenyl)piperazine (350 mg, 1.51 mmol), cis-3-(N-Boc-amino)cyclohexane carboxylic acid (368 mg, 1.51 mmol), HOBt (209 mg, 1.51 mmol) and EDC (291 mg, 1.51 mmol) was added dichloromethane followed by TEA (153 mg, 1.51 mmoL). Upon completion of addition, the resulting solution was allowed to stir overnight. At the conclusion of this period, the reaction mixture was concentrated and then purified via silica gel chromatography (20% to 50% EtOAc/hexanes) to provide the title compound (640 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][N:6]([CH3:10])[C:7](=[O:9])[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:25](OC)(=[O:30])[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH3:29][O:28][C:26](=[O:27])[C:25]([OH:30])=[CH:8][C:7](=[O:9])[N:6]([CH2:5][C:4]1[CH:11]=[CH:12][C:13]([Cl:14])=[C:2]([Cl:1])[CH:3]=1)[CH3:10]
Reactant: CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
A solution of N-(3,4-dichlorobenzyl)-N-methyl-acetamide (0.83 g, 3.57 mmol) in tetrahydrofuran (15 ml) was cooled to −78° C. and treated dropwise with 7.1 ml (7.1 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran. After 20 min, the mixture was treated dropwise with a solution of dimethyl oxalate (0.63 g, 5.35 mmol) in tetrahydrofuran (3 ml), stirred at −78° C. for 1 h and then at 5° C. for another 45 min. The reaction mixture was then quenched by the addition of 1 N hydrochloric acid and ethyl acetate. The organic phase was washed successively with water, saturated sodium bicarbonate and brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 85:15) gave 0.70 g (61% yield) of the title ester as clear oil. 1HNMR 400 MHz (C6D6) δ (ppm); mixture of rotamers: 2.01 and 2.49 (3H, 2 s, NCH3), 3.43 and 3.5 (3H, 2 s, OCH3), 4.0 and 4.4 (2H, 2 s, NCH2), 6.26 and 6.33 (1H, 2 s, CH), 6.62–7.2 (3H, m, aromatics). Anal. calcd for C13H13Cl2NO4: C, 49.08; H, 4.12; N, 4.40. Found: C, 49.38; H, 4.23; N, 4.30.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[C:14]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]4=[N:19][CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:2]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>>[CH3:32][S:33]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[C:14]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]4=[N:19][CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:2]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3NC3CCCCNC3)cnc21
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3NC3CCCCN(S(C)(=O)=O)C3)cnc21

Procedure:
(1-Methanesulfonyl-azepan-3-yl)-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from azepan-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methanesulfonyl chloride, using 4 equivalents of DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[Cl-].[NH4+:17]>C(O)C>[OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: [NH4+]
Reactant: C=CCc1c(O)ccc(C(=O)OC)c1O
Agent: [Cl-]
Solvent: CCO
Product: C=CCc1c(O)ccc(C(N)=O)c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Methyl 2,4-dihydroxy-3-(2-propenyl)benzoate (4.4 g) was added to a mixture of about 10 to 15 ml of saturated ammonium chloride solution and 2 to 3 ml of ethanol. The reaction mixture was stirred overnight at 50° C. The reaction mixture was extracted five times with ethyl acetate, and the organic layer was concentrated under vacuum. The product was crystallized and recrystallized from chloroform. Subsequent chromatography of the precipitated product on a 25 g silica gel column with 40% ethyl acetate/hexane as eluant gave the pure product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.[CH3:11]C1C(C)=C(C)N=C(O)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH3:11])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(Cl)nc(C)c1C
Reactant: Cc1nc(O)nc(C)c1C
Product: CCc1c(C)nc(Cl)nc1C

Procedure:
The title compound was prepared in a manner analogous to Intermediate 17, substituting 5-ethyl-4,6-dimethylpyrimidin-2-ol for 4,5,6-trimethylpyrimidin-2-ol. MS (ESI): mass calculated for C8H11ClN2, 170.06, m/z found 171.1 [M+1]+. 1H NMR (500 MHz, CDCl3): 2.65 (q, J=7.6 Hz, 2H), 2.50 (s, 6H), 1.15 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:21].CN(C)C=O>O>[CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[O:10][CH:11]=[CH:12][CH:13]=3)[O:6][C:7]=2[CH3:8])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:21]
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: COC(=O)c1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (7.13 g), potassium carbonate (3.84 g), methyl 5-formyl-2-hydroxybenzoate (5.0 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 5-formyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as pale-brown crystals (8.67 g, 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH:13]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])C.Cl>O1CCOCC1>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])([O:11][CH2:12][CH:13]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10]
Reactant: CCOC(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Agent: Cl
Solvent: C1COCCO1
Product: O=CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 98000 %

Procedure:
To a stirring solution of N-Fmoc-4-amino-butyraldehyde diethyl acetal (0.050 mmol) in 1,4-dioxane (100 mL) was added aq. HCl (100 ml, 1:1 v/v, H2O: conc. HCl) and the reaction progress was monitored by MS. Upon completion, the organic solvent was removed by rotary evaporation, and the aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with 5% NaHCO3 (2×75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to dryness to yield the desired N-Fmoc-4-amino-butyraldehyde (15.35 g, 0.049 mol, 90.0% yield), which was carried through to the next step without further purification: MS m/e [M+Na]+ calcd 332.1, found 332.0.
Reaction SMILES: OS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:33]([CH:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:36](OCC)=[O:37])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[C:23]2[C:24](=[CH:25][CH:26]=1)[C:27]1([CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[C:33](=[O:34])[C:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:36]2[OH:37]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(Cl)cc2)CCOCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
Concentrated H2SO4 (9.5 mL, 18.0M) was treated with P2O5 (4.25 g, 29.9 mmol). The resulting slurry was stirred at room temperature for 2 hours. The mixture was cooled in an ice bath and treated with a solution of diethyl 2-(4-(4-chlorophenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (1.70 g, 4.44 mmol) in IPAc (3.0 mL). The resulting green solution was aged for 15 minutes and subsequently poured into ice water. The resulting mixture was extracted with IPAc (3×20 mL), and the combined organic extracts were dried (MgSO4). The organic solution was concentrated in vacuo to furnish a brown solid. The crude product was recrystallized from hot heptane to give the title compound as a pale yellow solid (0.81 g). MS m/e=337.2 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[CH3:15][Si:16]([CH3:19])(Cl)[Cl:17]>CCCCCC>[CH3:15][Si:16]([Cl:17])([CH3:19])[CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C[Si](C)(Cl)Cl
Reactant: C1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[Si](C)(Cl)C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.9 %

Procedure:
In a 2-liter flask were charged 50 g (0.43 mol) of indene and 600 ml of dry n-hexane, to which was dripped down 270 ml of a hexane solution of 1.6 M n-butyllithium at 0° C. The mixture was stirred at room temperature for 10 hours, to which was added 111 g (0.86 mol) of dimethyidichlorosilane and the mixture was stirred as was at room temperature for 3 hours. After it was filtered through a G-4 filter, the reaction mixture was distilled under reduced pressure to remove volatile components. The crude product thus obtained was purified by distillation under reduced pressure (100° C., 7 mmHg) under argon atmosphere. As a result, 78 g of the target compound was obtained. Yield: 87%.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:8][CH2:18][C:17]1[C:10]([F:9])=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C#N)c1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Product: N#Cc1cccc(CBr)c1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
NBS (1.729 g, 9.71 mmol) was added to a solution of 2-fluoro-3-methylbenzonitrile (1.25 g, 9.25 mmol) in acetonitrile (25 mL). The obtained mixture was refluxed, and then benzoic peroxyanhydride (0.045 g, 0.18 mmol) was added. The reaction mixture was refluxed overnight, then cooled to r.t. and water was added. The aqueous phase was discarded and the organic phase was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using a gradient of EtOAc in heptane as eluent to give the title compound (1.39 g, 70% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 4.75 (s, 2 H) 7.43 (t, 1 H) 7.93 (t, 2 H); MS (EI) m/z 213 M+.
Reaction SMILES: [CH:1]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]O)=[CH:22][CH:21]=1)([O-:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>CCOCC>[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][C:1]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(CCc1ccc([N+](=O)[O-])cc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
To a solution of triethyl methanetricarboxylate (16.6 g) in ether (350 mL) were added 4-nitrophenethyl alcohol (8.00 g) and triphenylphosphine (25.0 g). 40% Diisopropyl azodicarboxylate/toluene solution (48.4 g) was added dropwise to the mixture under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Insoluble material was removed by filtration, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (12.2 g) as an oil.