Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([CH2:8][C:9]([OH:11])=O)[CH2:7][CH2:6]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:21][C@@H:20]2[CH2:22][NH:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][NH2:31])[C:25]=2[C:32]([F:35])([F:34])[F:33])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O.C1COCC1>[CH:5]1([CH2:8][C:9]([NH:31][NH:30][C:26]2[C:25]([C:32]([F:33])([F:35])[F:34])=[C:24]([NH:23][CH2:22][C@H:20]3[CH2:21][C@@H:19]3[C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=3)[CH:29]=[CH:28][N:27]=2)=[O:11])[CH2:6][CH2:7]1
Reactant: NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Reactant: O=C(O)CC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(CC1CC1)NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Reaction time: 1 h
Yield: 51.8 %

Procedure:
A solution of thionyl chloride (0.713 mL, 8.23 mmol) and 2-cyclopropylacetic acid (0.247 g, 2.468 mmol) in methylene chloride (10 mL) was heated to reflux for 30 min. The solution was cooled and concentrated. The residue was dissolved in EtOAc (10 mL) and added to a stirred mixture of N-(((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)-2-hydrazinyl-3-(trifluoromethyl)pyridin-4-amine (0.56 g, 1.646 mmol) in EtOAc (10 mL), THF (10 mL), and sat'd Na2CO3 (10 mL). The mixture was stirred for 1 h. The reaction was diluted with EtOAc. The organic layer was separated, washed with aqueous sodium bicarbonate, washed with brine, dried over MgSO4, and concentrated to give the crude product. The crude product was purified by silica gel chromatography to give 2-cyclopropyl-N′-(4-((((1S,2S)-2-(4-fluorophenyl)-cyclopropyl)methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)acetohydrazide (360 mg, 49%) as a light yellow gum. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.90 (d, J=6.0 Hz, 1H), 7.74 (br. s., 1H), 7.09-6.86 (m, 4H), 6.19 (d, J=6.0 Hz, 1H), 5.40-5.16 (m, 1H), 3.34-3.09 (m, 2H), 2.29 (d, J=7.0 Hz, 3H), 1.88 (dt, J=9.1, 4.9 Hz, 2H), 1.44-1.30 (m, 1H), 1.13-1.02 (m, 2H), 1.01-0.93 (m, 1H), 0.72-0.55 (m, 2H), 0.27 (d, J=5.8 Hz, 2H). LCMS M+1=423.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.7 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (71.0 mg, 62%).
Reaction SMILES: [CH2:1]([C:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:15])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])([O-])=O.[K+].[K+]>CCOCC>[CH2:1]([C:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:15])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C(Cc2ccccc2)CCCC1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OC1C=C(Cc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A solution of 3-benzyl-2-cyclohepten-1-one (3.1 g, 18 mmol) in either 100 mL) was slowly added to a suspension of lithium aluminum hydride (LAH) (684 mg, 0.87 mol) and ether (100 mL) at 0° C. under N2. The resulting mixture was stirred overnight at ambient temperature and cooled to 0° C. Saturated K2CO3 solution was added to quench the excess LAH, the mixture was filtered through Celite and washed with several portions of ether. The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the title compound (3 g, 93%) as a colorless oil. NMR (CDCl3):3.32(ABq,J=6 Hz,2H, benzylic protons), 4.42 (bs, 1H, CHOH), 5.58 (bs, 1H, olefinic proton), 7.22 (m, 5H, aromatic protons).
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][C:11]([Br:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Br:15][C:11]1[N:10]=[CH:9][C:8]2=[N:7][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[CH:14]=[C:13]2[CH:12]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2cc(Br)ncc2n1
Product: CC(C#N)(Cn1cc2cc(Br)ncc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-bromo-2H-pyrazolo[3,4-c]pyridin-2-yl)-2-methylpropionitrile (100 mg, described in Example 199) and 4-trifluoromethylthiobenzoyl chloride (92 mg), the title compound was isolated as a white solid (150 mg, 87%). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, DMSO-d6): 1.69 (s, 3H), 5.20 (d, J=13.5 Hz, 1H), 5.27 (d, J=13.5 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 8.04 (d, J=1.2 Hz, 1H), 8.54 (d, J=0.6 Hz, 1H) and 9.05 (d, J=1.1 Hz, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13]C)=O.C(O)C.O.[NH2:19][NH2:20]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:19][NH2:20])=[O:13]
Reactant: NN
Reactant: COC(=O)c1ccc2ccccc2c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2ccccc2c1
Yield: 88 %

Procedure:
First, 5.0 g of methyl 2-naphthoate and 20 mL of ethanol were put in a four-neck flask, and stirred. Then, 5 mL of hydrazine monohydrate (NH2NH2.H2O) was added to this mixture, and heated and stirred at 80° C. for 5 hours to be reacted. After the reaction, the solution was added to 100 mL of water, whereby a solid was precipitated. The resulting suspension was subjected to suction filtration to give a solid. This solid was recrystallized from a mixed solvent of chloroform and hexane, so that 4.4 g of 2-naphthohydrazide was prepared as a white solid with a yield of 88%. The synthetic scheme of Step 1 is shown by (a-12).
Reaction SMILES: [Cl-].[Li+].[CH2:3]([N:9]1[CH:14]=[C:13](I)[C:12]([CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[C:10]1=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21]1([Sn](CCCC)(CCCC)CCCC)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C(OCC)(=O)C>[CH2:3]([N:9]1[CH:14]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]([CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[C:10]1=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCCCCCn1cc(I)c(C)c([N+](=O)[O-])c1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCn1cc(-c2ccccc2)c(C)c([N+](=O)[O-])c1=O
Yield: 72.2 %

Procedure:
A mixture of bis(triphenylphosphine)Pd(II) chloride (0.014 g), lithium chloride (0.067 g), 1-hexyl-5-iodo-4-methyl-3-nitro-2-pyridone (0.15 g, 0.41 mmol) and phenyltributyltin (0.11 mL, 0.62 mmol) in THF (15 mL) was heated under reflux for 2 days. The mixture was cooled, diluted with ethyl acetate, and washed with aqueous potassium fluoride and water. The organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (petroleum ether/methylene chloride 1/1 to methylene chloride gradient) gave 1-hexyl-4-methyl-3-nitro-5-phenyl-2-pyridone (0.093 g, 72%). 3-Amino-1-hexyl-4-methyl-5-phenyl-2-pyridone. A mixture of 1-hexyl-4-methyl-3-nitro-5-phenyl-2-pyridone (0.093 g, 0.30 mmol) and 10% Pd/C in ethyl acetate (100 mL) was hydrogenated at 45 psi in a Parr apparatus for 4 hours. The catalyst was removed by filtration, and the solvent was evaporated to give 3-amino-1-hexyl-4-methyl-5-phenyl-2-pyridone (0.083 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH2:30]([CH2:32][NH2:33])[OH:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:33][CH2:32][CH2:30][OH:31])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: Cc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ccc(-c2cc3cc(CNCCO)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 80.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (54.0 mg, 0.138 mmol) was dissolved in acetonitrile (4.3 mL), and the solution was treated with ethanolamine (0.034 mL, 0.55 mmol), acetic acid (0.158 mL, 2.76 mmol) and sodium triacetoxyborohydride (58.0 mg, 0.276 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-methyl-7-{1-(tert-butoxycarbonyl)-5-[(2-hydroxyethylamino)methyl]indol-2-yl}isoindolinone (48.5 mg, yield 81%).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([C:16]([O:18][CH3:19])=[O:17])[CH2:4]2)[CH2:2]1.[Li+].[CH3:21]C([N-]C(C)C)C.C1COCC1.CCCCCCC.IC.[NH4+].[Cl-]>C1COCC1>[CH3:21][C:5]1([C:16]([O:18][CH3:19])=[O:17])[N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:7][CH2:8][C:3]2([CH2:2][CH2:1]2)[CH2:4]1
Reactant: COC(=O)C1CC2(CCN1C(=O)OC(C)(C)C)CC2
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CC2(CCN1C(=O)OC(C)(C)C)CC2
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
6-tert-butyl 5-methyl 6-azaspiro[2.5]octane-5,6-dicarboxylate (D4) (420 mg, 1.56 mmol) was dissolved in THF (25 ml) and the solution was cooled at −78° C. prior addition of LDA 2M sol in THF/heptane (1.16 ml, 2.34 mmol). The red solution was left stirring at −78° C. for 40 min before adding iodomethane (0.146 ml, 2.34 mmol). The reaction was allowed to warm to RT and left stirring for 3 hrs. The resulting yellow-orange solution was treated with NH4Cl sat. sol. (5 ml) and extracted with Et2O (3×50 ml). Collected organic phases were washed with NaCl sat. sol. and dried over Na2SO4. Collected organics after solvent evaporation, afforded a residue which was purified by Biotage SNAP-Si (25 g) eluting with DCM. Collected fractions after solvent evaporation afforded the title compound (D5) (320 mg)
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:14]([O-:16])=O)[C:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[C:17]1(OC2C=CC=CC=2)C=CC=C[CH:18]=1>C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:17][CH3:18])=[O:12])=[C:14]2[OH:16]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=C([O-])C(=CNc1ccc(Br)nc1)C(=O)[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccc(Br)nc2c1O

Procedure:
Diethyl(2-(((6-bromopyridin-3-yl)amino)methylene)malonate (36 g, 0.105 mol) was added to boiling diphenyl ether (185 mL) in batches over 5 min, and reacted under reflux for 45 min. After confirming a disappearance of the raw materials by a thin layer chromatography plate (ethyl acetate:petroleum ether=1:3), cooled and poured into petroleum ether to precipitate a solid. The reaction mixture was suction filtered to give 17.1 g of a khaki solid.
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]2[N:27]=[C:26]([N:28]3[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:13]1)=[O:11].N1C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>C(Cl)(Cl)Cl>[ClH:1].[C:47]([N:31]1[CH2:32][CH2:33][CH2:34][N:28]([C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([NH:17][C@H:14]3[CH2:15][CH2:16][N:12]([C:10](=[O:11])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:13]3)[N:27]=2)[CH2:29][CH2:30]1)(=[O:49])[CH3:48]
Reactant: O=C(Cc1ccccc1-c1ccccc1)N1CC[C@H](Nc2nc(N3CCCNCC3)c3ccccc3n2)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccccc4-c4ccccc4)C3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113.9 %

Procedure:
t-Butyl 4-(2-((S)-1-(2-biphenyl-2-ylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)-[1,4]diazepane-1-carboxylate (0.53 g) synthesized in the same manner as in Example 1 was dissolved in ethyl acetate (3 mL), followed by addition of a solution (2.2 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred overnight. Precipitated solids were collected by filtration and then washed with hexane to obtain 2-biphenyl-2-yl-1-((S)-3-(4-[1,4]diazepan-1-ylquinazolin-2-ylamino)pyrrolidin-1-yl)ethanone dihydrochloride (0.15 g). (2) 2-Biphenyl-2-yl-1-((S)-3-(4-[1,4]diazepan-1-ylquinazolin-2-ylamino)pyrrolidin-1-yl)ethanone di hydrochloride (40 mg) was suspended in chloroform (3 mL), followed by addition of pyridine (12 mg) and acetic anhydride (8.5 mg), and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform/methanol=10:1) to obtain the title compound (compound 1-210) (46 mg). The resulting purification product was dissolved in ethyl acetate (1.0 mL), followed by addition of a solution (0.015 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred to obtain the title compound (compound 1-212) (12 mg).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([C:12]2([OH:16])[CH2:15][O:14][CH2:13]2)[S:8]([NH2:11])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[CH2:23]([O:25][C:26](OCC)(OCC)OCC)C>C(O)(=O)C>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([CH:7]2[C:12]3([CH2:13][O:14][CH2:15]3)[O:16][C:23]([O:25][CH3:26])=[N:11][S:8]2(=[O:10])=[O:9])=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)C(c1ccc(-c2ccccc2)cc1)C1(O)COC1
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(c2ccc(-c3ccccc3)cc2)C2(COC2)O1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 0.17 g of biphenyl-4-yl-(3-hydroxyoxetan-3-yl)methanesulfonamide in 4 ml of tetraethoxymethane and 1 ml of acetic acid was stirred at 90° C. for 3 hours. The solvent was removed under reduced pressure. This gave the crude product, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[S:23]1[C:27]([CH:28]=O)=[CH:26][N:25]=[CH:24]1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:28][C:27]1[S:23][CH:24]=[N:25][CH:26]=1)[CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Reactant: O=Cc1cncs1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2Cc1cncs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
To a solution of 1G (94 mg, 0.3 mmol) and thiazole-5-carbaldehyde (67.9 mg, 0.6 mmol) (prepared following the procedures described in Alessandro Dondoni, et al, Synthesis, 11, 998-1001, (1987)) in a mixed solvents of TFA (0.75 mL) and CH2Cl2 (0.75 mL) was added Et3SiH (0.096 mL, 0.6 mmol). The resulting mixture was stirred at RT under argon for 18 h, then concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3, then extracted with EtOAc (3×20 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (50-90%) in hexane to give the title compound as an off-white solid (70 mg, 57%). HPLC: 99% at 5.43 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4), Flow rate at 2.5 mL/min, UV detection at 220 nm). MS (ES): m/z 411 [M+H]+; Chiral HPLC 100% e.e.; retention time=32.9 min; Conditions: AD (4.6×250 mm); Eluted with 40% isopropanol in hexane for 50 min at 1 mL/min.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: OCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(Oc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To the solution of (4-(4-fluorophenoxyl)phenyl)methanol (7 g, 32.1 mmol) and pyridine (5.19 mL, 64.2 mmol) in dichloromethane (DCM) (100 mL) was added sulfurous dichloride (7.63 g, 64.2 mmol) dropwise at 0° C. After addition the mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3 solution (40 mL×2) and brine (40 mL), the organic phase was dried over Na2SO4, filtered and concentrated to leave the crude product, which was purified by column chromatography (silica-gel, elution with PE: EtOAc=6:1) to afford the pure 1-(chloromethyl)-4-(4-fluorophenoxyl)benzene (2.2 g, 8.83 mmol, 27.5% yield) as light yellow oil. LCMS: rt=1.56 min, [M+H+]=237
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1I.[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.CCO.O.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>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=1
Reactant: O=C1OC(COc2ccon2)CN1c1ccc(I)c(F)c1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1OC(COc2ccon2)CN1c1ccc(-c2ccc(CO)cc2)c(F)c1

Procedure:
A degassed mixture containing 3-(3-fluoro-4-iodo-phenyl)-5-(isoxazol-3-yloxymethyl)-oxazolidin-2-one (1.0 g, 2.48 mmol), 4-(hydroxymethyl)phenylboronic acid (0.46 g, 3.00 mmol) and Pd(PPh3)4 in toluene (24 mL), EtOH (8 mL) and H2O (8 mL) was heated to reflux for 15 h. The reaction was concentrated, the crude residue was suspended in H2O, filtered and dried in vacuo to give 3-(2-fluoro-4′-hydroxymethyl-biphenyl-4-yl)-5-(isoxazol-3-yloxymethyl)-oxazolidin-2-one. This crude material was dissolved in CH2Cl2 (10 mL) and Hunig's base (0.88 mL, 5.3 mmol), then MsCl (0.32 mL, 2.65 mmol) was added and the mixture was stirred at room temperature for 15 h. The reaction was partitioned between dilute sodium bicarbonate (NaHCO3, 20 mL) and CH2Cl2 (30 mL). The two layers were separated and the organic phase was washed with saturated ammonium chloride (NH4Cl, 1×20 mL) and H2O (1×20 mL) and dried over Na2SO4. The solvent was evaporated and the crude was purified on silica gel eluting with 0–3% MeOH in CH2Cl2 to give benzyl chloride 107 as white crystalline solid (0.46 g; 43% yield over the last two steps). LCMS (ESI) m/z 403 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC#CCCCCCCCl
Reactant: Cc1cccnc1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1cccc(C)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 3-picoline (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in a vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 3-picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (82%). 1HNMR (300 MHz, CDCl3, ppm) 9.36 (s, 1H), 9.18 (d, 1H), 8.24 (d, 1H), 8.00 (dd, 1H), 4.92 (t, 2H), 2.62 (s, 3H), 1.95-2.18 (m, 6H), 1.15-1.25 (br, 10H), 0.90 (t, 3H); 13CNMR, 145.51, 144.12, 144.78, 139.46, 127.56, 80.44, 79.42, 61.75, 31.72, 31.16, 28.65, 28.04, 25.52, 21.92, 18.75, 18.55, 18.40, 13.63.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[Cl:17][C:18]([Cl:22])([Cl:21])[CH2:19]O.Cl.CN(C)CCCC(N=C=N)C.C(Cl)Cl>O.CCOC(C)=O>[CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:19][C:18]([Cl:22])([Cl:21])[Cl:17])=[O:9]
Reactant: Cc1cc(C)c(C)c(OCCCC(=O)O)c1
Reactant: OCC(Cl)(Cl)Cl
Agent: CC(CCCN(C)C)N=C=N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(C)c(OCCCC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2,3,5-trimethylphenoxy)butyric acid (4.82 mg) dimethylaminopyridine (DMAP, 0.26 g), 2,2,2-trichloroethanol (2.50 ml), 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (4.57 g) and CH2Cl2 was stirred at room temperature overnight. The reaction mixture was poured into a mixture of AcOEt and water. The separated AcOEt was washed with dil. HCl, sat. NaHCO3, water, and brine, and dried over MgSO4, and then evaporated to give 2,2,2-trichloroethyl 4-(2,3,5-trimethylphenoxy)butyrate (8.11 g) as an oil compound.
Reaction SMILES: [CH:1]([C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[O:6][C:7](=[CH:10]OC)[C:8]#[N:9])([CH3:3])[CH3:2].[S:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([NH2:30])=[NH:29])[CH2:23][CH2:22]1>>[CH:1]([C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[O:6][C:7]1[C:8]([NH2:9])=[N:29][C:28]([NH:27][CH:24]2[CH2:25][CH2:26][S:21][CH2:22][CH2:23]2)=[N:30][CH:10]=1)([CH3:2])[CH3:3]
Reactant: N=C(N)NC1CCSCC1
Reactant: COC=C(C#N)Oc1cc(OC)c(OC)cc1C(C)C
Product: COc1cc(Oc2cnc(NC3CCSCC3)nc2N)c(C(C)C)cc1OC

Procedure:
5-(2-Isopropyl-4,5-dimethoxy-phenoxy)-N*2*-(tetrahydro-thiopyran-4-yl)-pyrimidine-2,4-diamine was prepared according to the procedure of example 5, using 2-(2-isopropyl-4,5-dimethoxy-phenoxy)-3-methoxy-acrylonitrile (prepared using the procedure of Example 4) together with N-(tetrahydro-thiopyran-4-yl)-guanidine from Preparation 1.