Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH4:13]>>[CH2:11]([OH:12])[C@H:9]1[O:10][C@H:2]([O:1][C@H:13]2[O:4][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]2[OH:10])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: C
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 45 °C
Reaction time: 96 h

Procedure:
Forty parts by weight of "PINE-DEX #4", a reducing partial starch hydrolysate having an average dextrose equivalent (DE) of 19±1 and an average DP of about 5, prepared by hydrolysing starch, purifying and pulverizing the resultant, available from Matsutani Chemical Ind., Co., Ltd., Kyoto, Japan, was dissolved by heating in 60 parts by weight of water, and the resultant solution was heated to 45° C., adjusted to pH 6.5, mixed with one unit/g reducing partial starch hydrolysate of a non-reducing saccharide-forming enzyme prepared by the method in Experiment 1-1, and incubated for 96 hours, followed by heating the resultant mixture at 100° C. for 10 min to inactivate the remaining enzyme. The solution thus obtained was diluted to give a concentration of about 20%, d.s.b., mixed with 10 units/g reducing partial starch hydrolysate of "GLUCOZYME", a glucoamylase specimen commercialized by Nagase Biochemicals, Ltd., Kyoto, Japan, and incubated for 40 hours, followed by heating the resultant mixture to inactivate the remaining enzyme. The solution thus obtained was in usual manner decolored with activated charcoal, desalted with ion-exchange resins, and concentrated into an about 60% solution containing 29.5% trehalose, d.s.b. The concentrated solution was fed to a jacketed-stainless steel column packed with "CG 6000, Na-form", a strong acidic cation exchange resin commercialized by Japan Organo, Co., Ltd., Tokyo, Japan, and fractionated at 60° C. and SV (space velocity) 0.4, followed by recovering a high trehalose content fraction containing about 90% trehalose, d.s.b. The fraction was concentrated into an about 75% w/w % solution, which was then transferred to a crystallizer, mixed with an about 2% hydrous crystalline trehalose as seed crystal, heated to 50° C., gradually cooled to 25° C. under gentle stirring conditions, and separated by a basket-type centrifuge. The resultant crystals were washed by spraying with a small amount of water to obtain a high-purity hydrous crystalline trehalose with a purity of 99% or higher, d.s.b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])[CH3:32]>CN1CCCC1=O.O>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][N:39]([C:17]2[CH:16]=[C:15]([C:9]([OH:14])([C:10]([F:12])([F:11])[F:13])[CH:8]([C:7]3[CH:6]=[CH:5][C:4]([O:23][S:24]([C:27]([F:28])([F:29])[F:30])(=[O:25])=[O:26])=[CH:3][C:2]=3[Cl:1])[CH3:22])[CH:20]=[CH:19][N:18]=2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)ccn2)CC1

Procedure:
Trifluoro-methanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 135-Step 1, 1.0 g) and piperidine-4-carboxylic acid ethyl ester (0.773 mL) in 1-methyl-2-pyrrolidon (10 mL) were heated at 220° C. in a microwave oven for 30 minutes. The reaction mixture was then diluted with water (100 mL), extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (70 g silica gel, heptane/acetic acid isopropylester 80/20 to 70/30) to give the title compound as light yellow viscous oil (119 mg). MS (m/e)=619.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:15])[O:12][CH:11]([CH2:13][CH3:14])[CH2:10][O:9]2)=[C:4]([O:16][CH:17]([F:19])[F:18])[CH:3]=1.[Br:20]Br>C(Cl)(Cl)Cl>[F:19][CH:17]([F:18])[O:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1([CH2:15][Br:20])[O:12][CH:11]([CH2:13][CH3:14])[CH2:10][O:9]1
Reactant: CCC1COC(C)(c2ccc(Cl)cc2OC(F)F)O1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCC1COC(CBr)(c2ccc(Cl)cc2OC(F)F)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.7 parts of the 2-(4'-chloro-2'-difluoromethoxyphenyl)-2-methyl-4-ethyl-1,3-dioxolane prepared in (a) are dissolved in 100 ml of abs. chloroform and the solution is warmed to 30° C. Under irradiation with a 150 watt spot lamp, 7.3 parts of bromine in 30 ml of abs. chloroform are added dropwise over 1 hour and the reaction mixture is then stirred for 2 hours at room temperature. The reaction mixture is then washed with 2×100 ml of water, dried over sodium sulfate, and filtered. The solvent is removed by evaporation and the oily residue is purified by high vacuum distillation; b.p. 113°-115° C./0.05 mbar.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.CC(OC)(C)C.[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]\[C:49]([OH:51])=[O:50]>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:46]([O-:53])(=[O:52])/[CH:47]=[CH:48]\[C:49]([O-:51])=[O:50]
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Solvent: CCO
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Nilotinib base form A (4.00 g, 7.55 mmol) was stirred with EtOH abs (40 mL, 10V) and the suspension was heated to 80° C. Stirring was continued at the same temperature for 30 min. To the stirred suspension was added a solution of maleic acid (0.96 g, 8.31 mol. 1.1 eq) in EtOH abs (10 mL, 2.5V) in one portion. The resulting mixture was stirred at 80° C. for 1 h and then cooled to room temperature and stirred for another 6 h. The solids were isolated by filtration to give Nilotinib maleate form V. The obtained Nilotinib maleate form V was dried in a vacuum oven (35 mmHg) at 60° C. for 16 hours. The dried product was analyzed by PXRD and was found to be Nilotinib maleate form V. Mono maleate was obtained as confirmed by assay determination.
Reaction SMILES: [NH2:1][C@@:2]1([CH2:9][C:10]#[C:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]>CC#N.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:7][N:4]1[CH2:5][CH2:6][C@:2]2([N:1]=[C:11]([C:12]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)[CH2:10][CH2:9]2)[C:3]1=[O:8]
Reactant: CN1CC[C@@](N)(CC#Cc2nccc(-c3ccc(C(F)(F)F)cc3)n2)C1=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: CN1CC[C@@]2(CCC(c3nccc(-c4ccc(C(F)(F)F)cc4)n3)=N2)C1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
Silver trifluoromethanesulphonate (23.34 mg, 0.0900 mmol) was added to a solution of (3S)-3-amino-1-methyl-3-[3-[4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (which may be prepared as described in Description 8) (340 mg, 0.9100 mmol) in MeCN (10 mL) and the reaction was stirred at 20° C. for 18 hrs. Additional AgOTf (0.1 eq) was added and stirring was continued for 3 days. Additional AgOTf was added and stirring was continued for a further 3 days. The solvent was evaporated and the residue was dissolved in EtOAc/satd. NaHCO3. The phases were separated and the organic layer was dried (Na2SO4) and the solvent evaporated to afford (5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one (D9) (340 mg, 0.9082 mmol, 100% yield) as an amber oil.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[C:13]1([CH2:19][C:20](OC)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[O:21]=[C:20]([CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)Cc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of dimethyl methylphosphonate (2.16 mL, 20 mmol) in anhydrous THF (30 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.75 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl phenylacetate (1.40 mL, 10 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH: CH2Cl2=2:98) to give the product (1.50 g) with colorless oil in 62% yield. 1HNMR (CDCl3, ppm) δ 3.074 (d, J=21 Hz, 2H), 3.760 (s, 3H), 3.762 (s, 3H), 3.86 (s, 2H), 7.31 (m, 5H).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[CH2:2][CH3:3].C([Li])CCC.CON(C)[C:17](=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:17]([C:5]2[N:4]([CH2:1][CH2:2][CH3:3])[CH:8]=[CH:7][N:6]=2)=[O:28])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: CON(C)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCn1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCn1ccnc1C(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 3.7 %

Procedure:
To a solution of 1-propylimidazole (13.5 g) in dry tetrahydrofuran (200 ml) was added dropwise n-butyllithium (1.6 m hexane solution, 91.9 ml) under argon atmosphere at −78° C.,. The mixture as it is was stirred for 30 minutes, and added dropwise to a solution of N-methoxy-N-methyl-2-(4-nitrophenyl)acetoamide (27.5 g) in dry tetrahydrofuran (300 ml) under argon atmosphere at −78° C.,. The mixture was allowed to be at room temperature and stirred overnight, and 6N hydrochloric acid (30 ml.) was added to the mixture at 0° C. The mixture was neutralized with potassium carbonate, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=2:1). The obtained solid was washed with hexane-diisopropyl ether to give 2-(4-nitrophenyl)-1-(1-propylimidazol-2-yl)ethanone (1.25 g) as red crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])[CH:22]=[CH:23][C:24]=2[CH3:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].O.[NH2:36][NH2:37].NN>CCO.C(O)(=O)C>[Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([C:26]3[CH:27]=[C:28]([OH:29])[NH:37][N:36]=3)[CH:22]=[CH:23][C:24]=2[CH3:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)CC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(O)[nH]n2)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylphenyl}-3-oxopropanoate (from Step 1) (0.20 g, 0.37 mmol) in EtOH (5.00 mL) was added hydrazine hydrate (0.01 mL, 0.41 mmol). The reaction mixture was heated at 60° C. with a condensere. After 1 h, additional hydrazine hydrate (0.01 mL) was added. After 2 h, acetic acid (2 drops) was added. At 4 h, additional hydrazine was added (0.1 mL). At 5 h, the reaction appeared to be complete. Left in fridge overnight. Precipitate filtered, washed with hexane, found to be product, a white solid (0.10 g, 54%). 1H NMR (CD3OD/400 MHz) δ 7.66 (m, 2H), 7.45 (m, 2H), 7.05 (t, 2H, J=9.6 Hz), 6.65 (s, 1H), 5.36 (s, 2H), 2.04 (s, 3H), 2.02 (s, 3H). ESHRMS m/z 502.0552 and 504.0569 (M+H calculated for C23H19BrF2N3O3 requires 502.0572 and 504.0555).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([I:34])[CH:28]=1.Cl>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:33][C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][C:29]=3[I:34])=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1F
Reactant: Oc1ccc(F)cc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(F)cc1I
Temperature: 80 °C
Yield: 59 %

Procedure:
To a solution of N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-fluorobenzenesulfonamide (Preparation 52, 100 mg, 0.32 mmol) and potassium carbonate (109 mg, 0.8 mmol) in dimethylformamide (3 ml) was added 4-fluoro-2-iodophenol (Preparation 218, 0.32 mmol) and the reaction heated at 80° C. for 24 hours. The solution was added dropwise into rapidly stirring hydrochloric acid (2M aqueous solution). The fine dark precipitate was filtered and dried in vacuo to afford the title product as a brown solid, 100 mg, 59% yield.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](=[O:14])(=[O:13])[NH2:12])C.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:29](=[O:30])[C:28]2[CH:31]=[CH:32][CH:33]=[C:26]3[C:27]=2[C:22](=[CH:23][CH:24]=[CH:25]3)[C:21]1=[O:34]>>[O:34]=[C:21]1[C:22]2[C:27]3[C:26](=[CH:33][CH:32]=[CH:31][C:28]=3[C:29](=[O:30])[N:20]1[CH2:19][CH2:18][CH2:17][NH:12][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([OH:3])=[O:15])(=[O:13])=[O:14])[CH:25]=[CH:24][CH:23]=2
Reactant: CCOC(=O)c1ccccc1S(N)(=O)=O
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCBr
Product: O=C(O)c1ccccc1S(=O)(=O)NCCCN1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
The compound was prepared according to GP-2 using 2-sulfamoylbenzoic acid ethyl ester 4 and compound 3a. The crude product was purified by flash column chromatography using MeOH—CHCl3 to obtain 5a. 1H NMR (500 MHz, DMSO-d6) δ 9.43 (bs, 2H), 8.49-8.46 (m, 4H), 7.87 (t, J=8.0 Hz, 2H), 7.68 (d, J=7.5 Hz 1H), 7.64 (d, J=8.0 Hz 1H), 7.49 (t, J=7.5 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 4.02 (t, J=7.5, 2H), 2.76 (q, J=7.0 Hz, 2H), 1.90-1.60 (m, 2H). MS (ES−) m/z 437 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CN(C2CCNCC2)C1
Yield: 79 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.75 g, 8.88 mmol) in dichloroethane (80 mL) was added azetidine (0.6 g, 10.53 mmol) and the mixture was stirred at RT for 30 min. Sodium triacetoxyborohydride (3.9 g, 18.44 mmol) was added and the resulting solution was stirred at RT for 18 h. The reaction mixture was partitioned between water and DCM and the layers separated. The organic layer was extracted further with DCM and the combined aqueous layers were concentrated in vacuo. The resultant white semi-solid was suspended in DCM and a saturated aqueous solution of NaHCO3 was added. The layers were thoroughly mixed, the organic layer isolated and the aqueous layer further extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.0 g, 95%). BOC-deprotection of 4-azetidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.67 mmol) using TFA:DCM (1:4) gave the title compound as a yellow oil (185 mg, 79%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:11]=1[CH3:19].[CH3:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[NH2:24]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]([NH:24][C:23]([CH3:26])([CH3:25])[C:22]([O:21][CH3:20])=[O:27])=[O:18])[CH:13]=[CH:12][C:11]=1[CH3:19]
Reactant: Cc1ccc(C(=O)O)nc1Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)C(C)(C)N
Product: COC(=O)C(C)(C)NC(=O)c1ccc(C)c(Nc2ccc(Cl)cc2Cl)n1

Procedure:
The title compound was synthesized in analogy to Example 4 b, using 6-(2,4-dichloro-phenylamino)-5-methyl-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 396.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][OH:25])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(CCO)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Reaction time: 0.08 h

Procedure:
To a solution of 1.2 g of methyl 8-(p-chlorophenylsulfonamido)-4-(2-hydroxyethyl)octanoate in 12 mL methylene chloride is added 1.14 g triphenylphosphine followed by 0.336 g 3-hydroxypyridine. After stirring for 5 minutes, 0.55 mL diethyl azodicarboxylate is added slowly. After 1 hour, solvent is evaporated and the residue subjected to flash chromatography to obtain methyl 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]octanoate, m.p. 57-58°.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)[C:48](=[O:50])[CH3:49])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(c1cccc(CN(C(C)=O)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (104 mg) in THF (2.0 mL) were added N-ethyldiisopropylamine (52 μL) and acetyl chloride (17 μL) at 0° C., and the mixture was stirred at room temperature for 1.5 hr. Ice water was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The is solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (104 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][NH:12]2)[O:9][C:8](=[O:21])[NH:7]1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(OCC)(=O)C>C1COCC1.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[O:9][C:8](=[O:21])[NH:7]1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2Cc3ccccc3CN2)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CN2Cc3ccccc3C[C@@H]2[C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of (4S,5R)-4-(3,5-difluorobenzyl)-5-((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one (Step A(7), 320 mg, 0.93 mmol) in THF (20 mL) was added 4-methoxybenzaldehyde (253 mg, 1.86 mmol) and acetic acid (2 drops). This mixture was stirred at rt overnight. NaBH(OAc)3 (588 mg, 2.78 mmol) was added and the reaction mixture was stirred at rt for 2 days. Ethyl acetate (300 mL) was added and the mixture was washed with aqueous sodium carbonate, H2O, dried (Na2SO4), and concentrated in vacuo. Crude mixture was purified by silica gel Flash Chromatography to give 420 mg of the title compound (80% yield): 1H NMR (CDCl3, 500 MHz) δ 2.57 (1H, t, J=10 Hz), 2.96 (1H, dd, J=5, 20 Hz), 3.17 (1H, dd, J=5, 15 Hz), 3.44-3.50 (2H, m), 3.68 (2H, dd, J=10, 45 Hz), 3.80 (3H, s), 3.84-3.88 (3H, m), 4.66 (1H, dd, J=5, 10 Hz), 5.29 (1H, s), 6.71-6.74 (3H, m), 6.88 (2H, d, J=10 Hz), 6.98 (1H, d, J=5 Hz), 7.15-7.21 (5H, m). MS (ESI) (M+H)+ 465.12.
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:7]([N:17]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCN1CCCC1=O
Reaction time: 22 h
Yield: 83.1 %

Procedure:
18.8 g (0.22 M) of γ-butyrolactone and 34.6 g (0.22 M) of n-decylamine were mixed and heated to 180° in a round bottom flask equipped with a condenser and a Dean-Stark trap for 22 hours. The dark brown reaction mixture was distilled at reduced pressure to yield 40.9 g (82.5%) of colorless product; b.p. 150°-155°/0.5-1 mm.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]=[C:31]([P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]=[C:31]([P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[CH:31]([P:38](=[O:45])([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:1]
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: C=C(CCCCCC)P(=O)(OCC)OCC
Agent: CC(=O)[O-]
Product: CCCCCCC=CP(=O)(OCC)OCC
Reaction time: 36 h

Procedure:
Example 8 was repeated in the same manner as described except that the amount of each of palladium acetate and 1,3-bis(diphenylphosphino)propane was reduced to 1/10 and that the reaction was performed at 100° C. for 36 hours. The proton NMR analysis of the resulting reaction mixture revealed that an isomeric mixture of (a) dimethyl 1-octen-2-yl-phosphonate and (b) dimethyl 1-octen-1-yl-phosphonate was obtained with a yield of 100% and that the weight ratio of the former phosphonate (a) to the latter phosphonate (b) was 98:2.