Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11]1O[CH:12]1[CH3:13].S(=O)(=O)(O)O>>[CH2:1]([O:8][CH2:13][C:12]1[CH:11]=[CH:4][CH:3]=[CH:2][CH:1]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC1CO1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2297.75 g (21.24 moles) of benzyl alcohol was placed in a dry, stirred pressure vessel fitted with a nitrogen inlet. A catalytic amount (6 g) of KOH was added as a 40% aqueous solution. The vessel was purged with nitrogen and heated to 110° C. Vacuum was applied for 1 hour to remove the water vapors from the headspace of the vessel, and the mixture was further heated to 130° C. After 3702.25 g (63.74 moles) of propylene oxide were added, the reaction mixture was stirred for additional 3 hours to complete the reaction. The progress of the reaction was monitored by the uptake of the reagent and the measurement of the pressure in the vessel. The reaction mixture was cooled to 110° C., and a vacuum was applied for approximately 1 hour. To neutralize KOH in the reaction mixture, 29 g of 25% sulfuric acid was added. The mixture was stirred for 10 minutes, and the pH was adjusted to 5.7. Upon cooling, PPG-3 Benzyl Ether, a thin light yellow liquid, was isolated as the major product.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([OH:10])=O)(=[O:5])[C:2]([CH3:4])=[CH2:3].CN(C)C=O.S(Cl)([Cl:18])=O>>[C:1]([O:6][CH2:7][C:8]([Cl:18])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCC(=O)Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Into a 100-mL reaction vessel with a condenser were added 30 g (purity: 46%, 95.1 mmol) of methacryloyloxyacetic acid (prepared in a method described in International Publication No. 96/41841 and the like), 347 mg (4.8 mmol/0.05 eq) of dimethylformamide and 47.6 g (380.5 mmol/4.0 eq) of thionyl chloride. The resulting solution was stirred at 70° C. for 1 hour and subjected to distillation purification, thereby obtaining 10.0 g of target methacryloyloxyacetyl chloride. The purity of the target product was 70%; and the yield of the target product was 45%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.O=P(Cl)(Cl)Cl.CN([CH:23]=[O:24])C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:23]=[O:24])=[C:4]2[N:3]=1
Reactant: Clc1cc(NC2CC2)n2nccc2n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-chloro-N-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (156 mg, 0.75 mmol) in DMF was added POCl3 (205 μl, 2.25 mmol). The mixture was stirred at room temperature for 3 hours. Ice was added to quench excess POCl3 then the mixture was neutralized with 1M NaOH. DCM was added and the product was extracted three times. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. Some residual DMF could not be removed. LCMS (M+1=237)
Reaction SMILES: [N+:1]([C:4]1[C:13]([CH2:14][P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])([O-:3])=[O:2].[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[C:13]([CH2:14][P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: CCOP(=O)(Cc1cccc(C(=O)OC)c1[N+](=O)[O-])OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(Cc1cccc(C(=O)O)c1[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl 2-nitro-3-(diethylphosphonomethyl)benzoate (7.3 gm) was dissolved in absolute ethanol (44 mL) containing sodium hydroxide (0.89 gm) and allowed to stir at room temperature for 48 hours. The solvent was removed on a rotory evaporator and the residue dissolved in water (150 mL) and extracted with ethyl acetate (100 mL). The aqueous layer was acidified with 1N HCl and the turbid solution extracted with 3×chloroform (75 mL). The chloroform layers were combined, dried (MgSO4) and concentrated to a yellow solid. 1H NMR data CDCl3, TMS 1.28 (t, 6H), 3.27 (d, 2H), 4.09 (p, 4H), 7.57 (t, 1H), 7.83 (d, 1H), 7.98 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5](I)=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[C:18]([N:25]1[CH2:28][C:27](=[O:29])[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:25]1[CH2:28][C:27]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][C:6]=2[CH2:8][OH:9])([OH:29])[CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: OCc1cc(Cl)ncc1I
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2cnc(Cl)cc2CO)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
To a stirred solution of (2-chloro-5-iodo-pyridin-4-yl)-methanol (2 g, 7.44 mmol, 1 eq) in dry THF (20 mL) was added i-PrMgCl.LiCl complex (1.3M in THF, 13.7 mL, 17.8 mmol, 2.4 eq) at −20° C. in drop wise manner over period of 10 minutes. Pre-dissolved solution of N-boc-3-azetidinone (1.53 g, 8.9 mmol, 1.2 eq) in dry THF (10 mL) was added at −20° C. to above reaction mixture. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After maximum consumption of starting material, reaction mixture was cooled to 0° C., quenched with 10% citric acid solution (20 mL) and extracted with ethyl acetate (3×50 mL). Combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown oil (2.2 g, crude). Crude compound was purified by column chromatography by using silica gel (100-200 mesh). Desired compound was eluted at 20% ethyl acetate in hexane to afford title compound as yellow solid (0.45 g, 19%). 1H NMR (400 MHz, CDCl3) δ: 1.38 (s, 9H), 3.96 (d, J=8.8 Hz, 2H), 4.38 (d, J=9.32 Hz, 2H), 4.53 (d, J=5.64 Hz, 2H), 5.53 (t, J=5.32 Hz, 1H), 6.40 (s, 1H), 7.57 (s, 1H), 8.33 (s, 1H). LC-MS (m/z): 314.9 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[ClH:15]>O>[Cl:15][C:10]1[C:9]2[O:12][CH2:13][C:7]3[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=3[C:8]=2[CH:7]=[C:6]2[CH:5]=[CH:4][C:3]([OH:14])=[CH:2][C:11]=12
Reactant: Cl
Reactant: COc1ccc2ccc(O)c(Cl)c2c1
Solvent: O
Product: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1Cl

Procedure:
A mixture of Example 9 (2.25 g, 6.92 mmol) and pyridiumium hydrochloride (21.9 g, 162 mmol) was heated to 184° C. for 2 hrs. The reaction mixture was allowed to cool and poured into water (300 mL) and extracted with ethyl acetate (2×200 mL), washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed and the product was chromatographed (40% ethyl acetate-hexanes) to afford a white solid which was triturated with methylene chloride (25 mL) to afford 1.2 g (58%); mp 230–231° C.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][C:20]=1[Cl:21].[BH4-].[Na+]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][NH:24][CH2:11][C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:13])([F:1])[O:3][C:4]=3[CH:10]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: [BH4-]
Agent: [Na+]
Product: FC1(F)Oc2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2O1

Procedure:
[2-(3,4-dichloro-phenyl)-ethyl]-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-amine was synthesized in analogy to the above procedure using 100 mg of 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde (0.54 mmol), 102 mg of 2-(3,4-dichloro-phenyl)-ethylamine (0.54 mmol) and 31 mg of sodium borohydride (0.81 mmol). The isolated colorless semisolid (98 mg, 51%) was used in the following step without further purification. MS (ISP) 360.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:20][CH2:21][CH:22]=[CH:23][CH2:24]Br>CN1C(=O)CCC1>[Br:20][CH2:21][CH:22]=[CH:23][CH2:24][O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc([N+](=O)[O-])c(OCC=CCBr)c1
Temperature: 45 °C

Procedure:
A mixture of 2,5-dinitrophenol (4.0 g), potassium carbonate (4.6 g), NMP (40 mL) and 1,4-dibromo-2-butene (14.0 g) is heated to 45° C. for 2 hr. Extraction in the normal fashion and Kugelrohr distillation of the excess dibromide (0.1 mm Hg, 80° C.) gives 1-bromo-4-(2,5-dinitrophenyloxy)but-2-ene (mp 81-83° C.).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][NH:7][C:8]([C:10]1[N:19]([CH2:20][CH2:21][CH2:22]Cl)[C:18](=[O:24])[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)=[O:9].[H-].[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:37][C:35]([F:36])([F:38])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:1])[F:39])[CH:34]=1)[CH2:6][N:7]1[CH2:22][CH2:21][CH2:20][N:19]2[C:10](=[C:11]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=3[C:18]2=[O:24])[C:8]1=[O:9]
Reactant: Cc1ccc(-c2c(C(=O)NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(CCCCl)c(=O)c3ncccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c3n(c(=O)c4ncccc24)CCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.6 %

Procedure:
A mixture of N-[3,5-bis(trifluoromethyl)benzyl]-7-(3-chloropropyl)-7,8-dihydro-5-(4-methylphenyl)-8-oxo-6-pyrido [3,4-b]pyridinecarboxamide (66 mg), sodium hydride (60% oily) (84 mg) and THF (3 ml) was stirred at room temperature for 14 hours. 2 N-HCl was added to the reaction mixture, which was then made basic with aqueous potassium carbonate and thereafter extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was removed by distillation. Thus, the entitled compound was obtained as colorless crystals (35 mg).
Reaction SMILES: [BH4-].[Na+].[C:3](O)(=O)[C@@H]([C@H](C(O)=O)O)O.[C:13]1([C:19](=[O:23])[C:20]([OH:22])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1>[OH:23][C@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]([O:22][CH3:3])=[O:21]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: O=C(O)C(=O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](O)c1ccccc1
Temperature: 70 °C
Reaction time: 67 h
Yield: 93.9 %

Procedure:
To a dispersion of 1.0 g (26.3 mmol) of sodium borohydride in THF (80 ml), there was added 3.95 g (26.3 mmol) of L-(+)-tartaric acid, and the mixture was heated under reflux for four hours in an oil bath at 70° C. with stirring. The resulting mixture was cooled in a cryostat at -20° C., a solution of 1.0 g (6.6 mmol) of phenylglyoxylic acid in THF (5 ml) was added dropwise with stirring over a period of ten minutes, and stirring was continued for 67 hours. The reaction mixture was cooled in an ice bath, 30 ml of 1N HCl was added, and stirring was further continued for 30 minutes. After distilling off the solvent under reduced pressure, the residue was extracted twice with 20 ml ether, and the combined extract was washed with 50 ml of a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The dried solution was concentrated to about 30 ml, and an ethereal solution of diazomethane was added to the concentrate to esterify the reaction product. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography, giving 1.03 g of methyl (R)-(-)-2-hydroxy-2-phenylacetate as a fraction in ethyl acetate:n-hexane (1:5). Its specific rotation [α]D21 was -100.0° (cl. 09, MeOH). The synthesis yield was 93% and the optical yield was 65% e.e. (see Reference 3).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:18]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=2[F:40])=[CH:29][CH:28]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C[C@@H](OC1C=CC(Br)=CC=1F)CCCCC.C(C1C=CC(C2C=CC(Br)=CC=2F)=CC=1)CCCCCCC>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:36]2[CH:37]=[CH:38][C:33]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:28][CH:29]=3)=[C:34]([F:40])[CH:35]=2)=[CH:12][C:11]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2F)cc1
Reactant: CCCCCCCCOc1ccc(Br)cc1F
Agent: CCCCCCCCc1ccc(-c2ccc(Br)cc2F)cc1
Agent: CCCCC[C@@H](C)Oc1ccc(Br)cc1F
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(OCCCCCCCC)c(F)c3)cc2F)cc1
Yield: 13.9 %

Procedure:
Except that 3.6 g of 4-octyloxy-3-fluorobromobenzene obtained in Example 3 (a) and 2.2 g of 4-octyloxy-2'-fluoro-4'-bromobiphenyl obtained in Example 2 (c) were used in place of 3.4 g of (R) -4-(1-methylhexyl)oxy-3-fluorobromobenzene and 2.2 g of 4-octyl-2'-fluoro-4 '-bromobiphenyl used in Example 1 (e), respectively, the operation was performed in the same manner as in Example 1 (e) to obtain 0.42 g (13.9%) of 4,4"-dioctyloxy-3,3 '-difluoro-p-terphenyl.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]2[NH:15][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[NH:18][N:17]=3)=[N:13][C:12]=2[CH:26]=1.C=O.[BH3-][C:30]#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH3:30])[CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]2[NH:15][C:14]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=4)[NH:18][N:17]=3)=[N:13][C:12]=2[CH:26]=1
Reactant: C[C@H]1CNCCN1c1ccc2[nH]c(-c3n[nH]c4cc(Cl)ccc34)nc2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H]1CN(C)CCN1c1ccc2[nH]c(-c3n[nH]c4cc(Cl)ccc34)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[6-((2S)-2-methylpiperazinyl)benzimidazol-2-yl]-6-chloro-1H-indazole (1 equivalent) is dissolved in a mixture of MeOH and acetic acid (10: 1), on molecular sieves. Paraformaldehyde (10 equivalents) is added in one portion. The reaction mixture is stirred at room temperature overnight then solid NaCNBH3 is added in small portions. The reaction mixture is refluxed for 5 hours, cooled to room temperature, filtered, and concentrated under reduced pressure. The residue is dissolved in dichloromethane and washed with saturated aqueous NaHCO3. The organic solution is dried over Na2SO4, and the solvent removed under reduced pressure to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:30][C:31](Br)=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[C:10](=[C:11]4[C:2](=[CH:3][CH:4]=3)[NH:1][C:31](=[O:32])[CH2:30][O:12]4)[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: O=C(Br)CBr
Reactant: CC(C)c1oc2c(O)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(Cl)cc1)NC(=O)CO3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 7-amino-3-(4-chlorophenyl)-8-hydroxy-2-isopropyl-chromen-4-one (250 mg, 0.75 mmol), CDCl3 (1 ml), saturated NaHCO3 solution (1.5 ml) and bromoacetylbromide (169 mg, 0.85 mmol) is stirred vigorously at room temperature for 5 min and then passed through an Isolute™ phase separator to separate the organic phase, which is then treated with dimethylformamide (1 ml) and K2CO3 (115 mg, 0.85 mmol) and heated in a microwave at 90° C. for 15 min. The reaction mixture is partitioned between CH2Cl2 and water. The organic phase is washed with water and brine, dried (MgSO4) and concentrated in vacuo, followed by crystallisation from methanol. The product is partitioned between ethyl acetate and water to remove traces of dimethylformamide. The organic phase is dried (MgSO4), concentrated in vacuo and crystallised from methanol to yield the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH3:13])[CH:7]=1)[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH3:13])[CH:7]=1)[CH2:3][OH:4]
Reactant: Cc1cc(C(N)C(=O)O)ccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C(N)CO)ccc1Cl
Yield: 101.4 %

Procedure:
To 2-amino-2-(4-chloro-3-methylphenyl)acetic acid (1.7 g, 8.5 mmol) in tetrahydrofuran (0.4 M) at 0° C. was added lithium aluminum hydride (2 M, 8.5 mL, 17 mmol) dropwise. The reaction was refluxed for 18 hours. The reaction was cooled and quenched with ice water. The reaction was extracted with ethyl acetate, washed with water, and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow solid (1.6 g, quantitative): 1H NMR (300 MHz, DMSO-d6) δ 7.44-7.23 (m, 2H), 7.18 (dd, J=8.2, 2.2 Hz, 1H), 4.77 (bs, 2H), 3.81 (dd, J=7.8, 4.8 Hz, 1H), 3.53-3.14 (m, 3H), 2.30 (s, 3H); ESIMS m/z 186 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35][NH2:36])([CH3:29])([CH3:28])[CH3:27]>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:36][CH2:35][CH2:34][CH2:33][NH:32][C:31](=[O:37])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 27 %

Procedure:
A 1,4-dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (300 mg, 0.48 mmol) obtained in Example 54 and t-butyl(3-aminopropyl)carbamate (400 μl) was stirred at 120° C. for 2 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (71 mg, 27%) as an oil.
Reaction SMILES: C(OC([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:41][CH2:42][O:43][CH3:44]>C(OCC)(=O)C>[CH3:44][O:43][CH2:42][CH2:41][N:15]1[C:11]([CH2:10][CH2:9][NH:8][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:14]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)n[nH]1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1nc(-c2ccccc2)nc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 140.2 %

Procedure:
5-[2-Bis(tert-butoxycarbonyl)aminoethyl]-3-phenyl-[1,2,4]triazole (96 mg, 247 μmol; example 22, step 1) and potassium carbonate (85.4 mg, 618 μmol) were combined with DMF (1 mL) and the mixture was stirred for 30 min at RT. 1-Bromo-2-methoxyethane (34.3 mg, 23.2 μL, 247 μmol) was added and the mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled down to RT, a second portion of 1-bromo-2-methoxyethane (34.3 mg, 23.2 μL, 247 μmol) and potassium carbonate (34.2 mg, 247 μmol) were added and the mixture was stirred at 60° C. for another 4 h. The reaction mixture was poured into ethyl acetate (25 mL) and the organic phase was washed with water (3×10 mL) and brine (1×15 mL). The aqueous layers were back-extracted with ethyl acetate (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo to give 120 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless oil (29 mg, 83.7 μmol, 33.9%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:15]1(O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.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>C1COCC1>[CH:15]1([O:1][C:2]2[C:7]3[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OC1CCCCC1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)c2c(OC3CCCCC3)cccc2O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a cold mixture of 5-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (1 g, 5.21 mmol) and cyclohexanol (1.98 g, 19.8 mmol) and triphenyl phosphine (2.46 g, 9.38 mmol) in THF in an ice bath was added diisopropyl azodicarboxylate (DIAD) (1.94 g, 9.59 mmol). Resulting mixture was stirred at 0° C. for 15 min and then at rt for 1 h. Reaction mixture was concentrated and the residue was purified by silica gel chromatography (eluting with 50%-100% CH2Cl2 in hexanes) to provide the title compound (0.97 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.36 (t, J=8.2 Hz, 1H), 6.60 (d, J=8.6 Hz, 1H), 6.47 (d, J=8.2 Hz, 1H), 4.39 (m, 1H), 1.93-1.37 (m, 10H), 1.69 (s, 6H).
Reaction SMILES: C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[N:12]1([CH2:16][C@H:17]([OH:22])[C:18](OC)=[O:19])[CH2:15][CH2:14][CH2:13]1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[N:12]1([CH2:16][C@H:17]([OH:22])[C:18]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=2)=[O:19])[CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)[C@@H](O)CN1CCC1
Reactant: Nc1ccccn1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccn1)[C@@H](O)CN1CCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
Trimethylaluminium (8.31 mL, 16.62 mmol) was added to pyridin-2-amine (1.360 g, 14.45 mmol) in toluene (30 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-Methyl 3-(azetidin-1-yl)-2-hydroxypropanoate (Intermediate BC2) (2.3 g, 14.45 mmol) in toluene (10 mL) and THF (5 mL) was added and the resulting solution was allowed to warm to room temperature and then heated at 60° C. for 8 hours. The reaction cooled and 20% Rochelle salt (50 mL) added followed by EtOAc (50 mL) and the mixture stirred at ambient temperature overnight. The organic phase separated and the aqueous phase re-extracted with EtOAc (2×50 mL). The organic phases were combined, dried (MgSO4) and evaporated to afford the product (2.7 g) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCl)cc1
Yield: 99.3 %

Procedure:
To a solution of 4′-hydroxyacetophenone (101 g, 0.74 mole) in acetone (800 mL) was added 1-bromo-2-chloroethane (638 g, 4.45 mole) followed by K2CO3 (307 g, 2.22 mole). The reaction was heated to reflux for 48 h then filtered. The K2CO3 was washed with acetone (1 L) and the filtrate was evaporated. The residue was then partitioned between EtOAc (800 mL) and 1N NaOH (250 mL). The organic layer was washed with 1N NaOH (250 mL) then dried aid evaporated to yield 146 g of the desired product (99% yield).