Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:21][S:22]([O:8][CH2:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Triethylamine (1.80 ml) was added to a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (806 mg) in tetrahydrofuran (25 ml). This was cooled on ice under a nitrogen atmosphere, and methanesulfonyl chloride (0.499 ml) was added dropwise, followed by stirring at the same temperature for 30 minutes. The reaction mixture was partitioned after the addition of ethyl acetate (100 ml) and water (70 ml). The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate). The fractions containing the target compound were concentrated to give the title compound (1.05 g, 92.0%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-])=O.N[C:12]1[CH:17]=CC=[CH:14][CH:13]=1.C(N1CCCC1=O)O.ClCC(Cl)=O>>[CH2:17]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])[CH2:12][CH2:13][CH3:14]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S
Agent: O=C(Cl)CCl
Agent: O=C1CCCN1CO
Product: CCCCSc1ccccc1N

Procedure:
2-Butylmercaptoaniline was prepared from -2-nitrothiophenol by a two-step reaction sequence consisting of alkylation followed by reduction corresponding to the procedure described in Example 4. The aniline then was condensed with N-methylolpyrrolidone, followed by reaction with chloroacetyl chloride to yield the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-])=O.N[C:12]1[CH:17]=CC=[CH:14][CH:13]=1.C(N1CCCC1=O)O>>[CH2:17]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])[CH2:12][CH2:13][CH3:14]
Reactant: O=[N+]([O-])c1ccccc1S
Reactant: Nc1ccccc1
Agent: O=C1CCCN1CO
Product: CCCCSc1ccccc1N

Procedure:
2-Butylmercaptoaniline was prepared from -2-nitrothiophenol by a two-step reaction sequence consisting of alkylation followed by reduction corresponding to the procedure described in Example 4. The aniline then was condensed with N-methylol-2-pyrrolidone to yield the desired product.
Reaction SMILES: [CH2:1]=O.[CH2:3]([CH2:5][NH2:6])[OH:4].C([O:10][P:11]([O:16]C(C)C)[O:12]C(C)C)(C)C>C(O)(C)C>[OH:4][CH2:3][CH2:5][NH:6][CH2:1][P:11](=[O:16])([OH:12])[OH:10]
Reactant: C=O
Reactant: NCCO
Reactant: CC(C)OP(OC(C)C)OC(C)C
Solvent: CC(C)O
Product: O=P(O)(O)CNCCO
Yield: 78 %

Procedure:
A solution of paraformaldehyde (4.0 g, 0.122 mole), ethanolamine (12 g, 0.2 mole), triisopropylphosphite (20.9 g, 0.1 mole) and 50 mL of isopropanol was stirred at 90° C. for 16 hours. The isopropanol was removed under vacuum and 50 mL of conc. HCl was added in one portion. The solution was heated at reflux for 6 hours after which time it was assayed by 31P-NMR. N-(2-Hydroxyethyl)aminomethylphosphonic acid was obtained in 78% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O.C(N(C(C)C)CC)(C)C.OP([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:19])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn2ncnc(O)c2c1C
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10 L reactor was charged with 4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (155.1 g, 0.70 mol) and toluene (2.7 L). Phosphorous oxychloride (128.8 g, 78 mL, 0.84 mol) was then added followed by the addition of diisopropylethylamine (94.2 g, 127 mL, 0.70 mol). The reaction mixture was stirred for 5 min at room temperature and then heated at reflux for 20 h. HPLC analysis indicated complete disappearance of starting material. The reaction mixture was then cooled to 0° C. and cold K2HPO4 solution (527 g in 2.4 L of water) was added at a rate to maintain the internal temperature of the reaction mixture below 5° C. The final pH of the mixture was 8. The mixture was then stirred at between 0° C. to 5° C. for 20 min and then at room temperature for 1 h. The organic phase was separated and washed with K2HPO4 solution (85 g in 405 mL of water) and water (345 mL) and then filtered and concentrated in vacuo until yellow solids began to precipitate. Dimethyl formamide (1 L) was added and the remaining toluene was removed in vacuo (bath temperature=38° C., pressure=9 Torr). After concentration, approximately 4% toluene was observable by HPLC.
Reaction SMILES: [OH:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4].[Cl:8][CH2:9][C:10]([N:12]([CH3:16])[C:13](Cl)=[O:14])=[O:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[N:2][OH:1])[CH3:4])[CH3:7].[Cl:8][CH2:9][C:10]([N:12]([CH3:16])[C:13](=[O:1])[O-:14])=[O:11]
Reactant: CN(C(=O)Cl)C(=O)CCl
Agent: CCOC(C)=NO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C(=O)[O-])C(=O)CCl
Reaction time: 2 h
Yield: 167.5 %

Procedure:
To a solution of 5.0 g (0.05 m) of ethyl N-hydroxyacetimidate and 8.5 g (0.05 m) of N-chloroacetyl-N-methyl-carbamoyl chloride dissolved in 75 ml of toluene was added 5.05 g (0.05 m) of triethylamine. After stirring for 2 hours the reaction mixture was filtered through a bed of Celite. The filtrate was concentrated under reduced pressure to afford 10.3 g of a light yellow crystalline solid. m.p. 69°-71° C.
Reaction SMILES: [C:1]([N:8]([CH2:37][CH3:38])[C:9]([NH:11][C:12]1[NH:16][C:15]2[C:17]([C@H:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[C:18]([F:31])[C:19]([C:21]3[CH:22]=[N:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=3)=[CH:20][C:14]=2[N:13]=1)=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=NN=N1.CC(N([P:51]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[O:52]CC1C=CC=CC=1)C(C)C)C.C1C=C(Cl)C=C(C(OO)=[O:76])C=1>C(Cl)Cl>[CH2:61]([O:60][P:51]([OH:52])([O:33][CH2:32][C:17]1[CH:15]=[CH:14][CH:20]=[CH:19][CH:18]=1)=[O:76])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1.[C:1]([N:8]([CH2:37][CH3:38])[C:9]([NH:11][C:12]1[NH:16][C:15]2[C:17]([C@H:32]3[CH2:36][CH2:35][CH2:34][O:33]3)=[C:18]([F:31])[C:19]([C:21]3[CH:22]=[N:23][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:25][CH:26]=3)=[CH:20][C:14]=2[N:13]=1)=[O:10])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: CCN(C(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c([C@H]3CCCO3)c2[nH]1)C(=O)OC(C)(C)C
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: O=P(O)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To Boc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea (25) (12.69 g, 23.58 mmol) and tetrazole (3.304 g, 47.16 mmol) under N2 at 23° C. was added DCM (240 mL) followed by N-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (9.775 g, 9.509 mL, 28.30 mmol). After 3 hours at 23° C., the reaction was cooled to 0° C. then mCPBA (6.977 g, 28.30 mmol) was added. The resulting solution was stirred for 45 min at 0° C. then for 20 min at 23° C. The reaction mixture was then partitioned between DCM (50 mL) and saturated aqueous sodium bicarbonate (400 mL). The organic layer was separated, then washed successively with aqueous sodium bisulfate (63 g in 350 mL water) and saturated aqueous sodium bicarbonate (400 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by MPLC using an ISCO COMBIFLASH brand flash chromatography purification system (330 g silica column) eluting with a 0-100% EtOAc in hexanes linear gradient over 16 column volumes at 200 mL/min. Product containing fractions were evaporated in vacuo to give Boc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea dibenzyl phosphate (26) (11.92 g, 15.11 mmol, 64.09%). ESMS (M+1)=789.2; 1H NMR (300.0 MHz, CDCl3) δ 9.51 (s, 1H), 9.03 (t, J=5.4 Hz, 1H), 8.91 (d, J=1.6 Hz, 2H), 7.73 (d, J=6.5 Hz, 1H), 7.37-7.28 (m, 10H), 5.58 (t, J=7.8 Hz, 1H), 5.17-5.05 (m, 4H), 4.23 (t, J=7.5 Hz, 1H), 4.05 (td, J=7.8, 4.3 Hz, 1H), 3.53-3.44 (m, 2H), 2.39 (dd, J=7.9, 14.5 Hz, 2H), 2.28-2.15 (m, 2H), 1.98 (s, 6H), 1.72 (m, 9H) and 1.31 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.C1(C)C(C)=CC=CC=1.[OH-].[Cs+]>O>[CH:17]1[CH:18]=[CH:19][C:14]([NH:13][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Cs+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 5 °C

Procedure:
Into the reactor previously described are charged 49.7 grams (0.315 moles) of p-nitrochlorobenzene together with 98.7 grams of a 66.4% solution of formanilide recovered from a previous run (0.54 molecular proportions). The solution also contained 0.07 moles of p-nitrochlorobenzene, bringing the total to 0.385 mole. About 50 milliliters of xylene are added, and the mixture heated to refluxing temperature which is about 195°-198° C. To the hot mixture is added at the rate of about 0.4 ml. per minute 82.5 grams (0.55 mole) of cesium hydroxide as a 50% solution in water (165 grams) during which addition the water is continuously removed. The heating is continued for a total time of about five hours, then 250 ml. of xylene is added and the xylene solution washed twice with 200 ml. portions of 90° C. water. The xylene solution is cooled to 5° C., filtered and the cake washed with 60 ml. of 5° C. xylene. There is obtained 40.7 grams of 4-nitrodiphenylamine. The total yield determined as described in Example 1 is 72%. The conversion of p-nitrodiphenylamine is 99.1%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCc1cc(Br)ccc1NS(C)(=O)=O
Reaction time: 15 h
Yield: 79.6 %

Procedure:
4-Bromo-2-ethyl-aniline (2 mL, 14 mmol) dissolved in anhydrous pyridine (35 mL) at room temperature was treated with methylsulfonyl chloride (1.3 mL, 16.8 mmol). The reaction was stirred at that temperature for 15 hours before it was diluted with EtOAc. The mixture was washed with H2O, brine and dried over MgSO4. The solvent was removed in vacuo and the residue was purified with flash chromatography (SiO2, 5-30% EtOAc in hexanes) to afford the desired product (3.1 g, 81% yield). 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J=7.5 Hz, 3 H), 2.61-2.68 (m, 2 H), 3.02 (s, 3 H), 6.36 (s, 1 H), 7.36-7.39 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.[Li][C:15]([CH3:18])([CH3:17])[CH3:16].O=S(Cl)Cl.[CH3:23][CH2:24][O:25]CC>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:24](=[O:25])[CH3:23])[CH:10]=2)[C:5]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH2:3]1
Reactant: [Li]C(C)(C)C
Reactant: CC1(C)CCC(=O)c2ccccc21
Reactant: CCOCC
Solvent: O=S(Cl)Cl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(2-methyl-1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthlen-1(2H)-one ((Compound D15, 353 mg, 1.36 mmol) in 3 ml of dry ether at -78° C. was added dropwise t-BuLi (1 ml, 1.7 mmol, 1.7M solution in pentane). This clear light yellow solution was left at -78° C. for 30 min. Then, freshly distilled SOCl2 (0.15 ml, 2.0 mmol) was added. The reaction mixture was stirred at -78° C. for additional 30 min and thereafter slowly warmed to room temperature. The reaction was quenched by addition of saturated NH4Cl. The white solids were removed by filtration and the clear solution was concentrated to an oil, and purified by column chromatography with ethyl acetate/hexane (1/10) to give the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6](O)=[O:7])#[N:2].C(Cl)(=O)C([Cl:24])=O>ClCCl>[C:1]([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6]([Cl:24])=[O:7])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CC(CCC(=O)O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: N#CC(CCC(=O)Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Dimethyltormamide (1 drop) was added to a suspension of 4-cyano-4,4-diphenylbutanoic acid [(7.8 g, 29 mmol), WO97/24325] and oxalyl chloride (5.2 mL, 60 mmol) in dichloromethane (40 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was azeotroped with toluene (3×50 mL) to afford the crude title compound. The material was used in preparation 60 without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17].N1CCCCC1.[OH:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2>C(O)C>[NH2:17][C:16]1[O:25][C:26]2[C:27]3[CH:28]=[CH:29][CH:30]=[N:31][C:32]=3[CH:33]=[CH:34][C:35]=2[CH:7]([C:6]2[CH:5]=[C:4]([O:10][CH3:11])[C:3]([O:12][CH3:13])=[C:2]([Br:1])[CH:9]=2)[C:15]=1[C:14]#[N:18]
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Oc1cccc2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ncccc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.4 %

Procedure:
To a mixture of 5-bromoveratraldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) in ethanol (2 ml) was added piperidine (0.1 ml, 1 mmol). The mixture was stirred at room temperature for 15 min, then refluxed for 1 h, and cooled to room temperature. To the mixture was added piperidine (0.1 ml, 1 mmol) and 5-hydroxyquinoline (145 mg, 1 mmol). The mixture was refluxed for 1 h, and the solvent was evaporated. The residue was purified by chromatography on silica gel (EtOAc/hexane, 1:2), yielding the title compound (50 mg, 11%). 1H NMR (CDCl3): 8.95 (s, 1H), 8.50 (d, J=9.0, 1H), 7.82 (d, J=9.0, 1H), 7.50 (brs, 1H), 7.30 (s, 1H), 6.92 (s, 1H), 6.76 (s, 1H), 4.82 (brs, 3H), 3.84 (s, 6H).
Reaction SMILES: O=O.[CH3:3]/[C:4](/[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:5]\[CH2:6][OH:7]>CO>[CH3:3][C@H:4]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:12])[CH3:13])[CH2:5][CH2:6][OH:7]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=O
Solvent: CO
Product: CC(C)=CCC[C@@H](C)CCO
Yield: 97.9 %

Procedure:
A 500 ml autoclave was charged in a glove box (O2 content <1 ppm) with 24.0 g (155.6 mmol) of (E)-3,7-dimethylocta-2,6-dien-1-ol, 22 ml of methanol and 100 ml of catalyst solution. This mixture was hydrogenated at 20°, a constant pressure of 60 bar H2 and while stirring intensively. The conversion was 100% after 48 hours. The pale yellow hydrogenation solution was rinsed from the autoclave and evaporated on a rotary evaporator at 60°/17 mbar. The residue was distilled at 65%/0.01 mbar. There were obtained 23.8 g of (R)-3,7-dimethyloct-6-en-1-ol as a colourless oil with an enantiomeric purity of 98.4% e.e.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(C)([O-])C.[K+].[Cl:19][C:20]1[C:21](F)=[CH:22][C:23]([F:33])=[C:24]([CH:32]=1)[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:26]>CS(C)=O>[C:1]12([CH2:11][O:12][C:21]3[C:20]([Cl:19])=[CH:32][C:24]([C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:26])=[C:23]([F:33])[CH:22]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
To a mixture of adamantan-1-ylmethanol (1.00 g, 6.0 mmol) in anhydrous dimethyl sulfoxide (40 mL) was added potassium t-butoxide (1.68 g, 15.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min followed by the addition of 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (1.62 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was cooled to 0° C. and quenched with hydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate (200 mL). The organic layer was washed with water (2×40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the crude product was purified by silica gel column chromatography using 10-60% ethyl acetate (containing 0.2% acetic acid) in hexanes as an eluent to afford the title compound as a white solid (1.17 g, 46%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.77 (d, J=7.5 Hz 1H), 7.23 (d, J=12.5 Hz, 1H), 3.72 (s, 2H), 3.35 (s, 3H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H); 13C NMR (75 MHz, DMSO-d6) δ 162.3 (d, J=2.2 Hz), 159.8 (d, JC-F=255 Hz), 158.3 (d, JC-F=11 Hz), 130.6 (d, JC-F=4 Hz), 116.8 (d, JC-F=3 Hz), 113.6 (d, JC-F=14 Hz), 102.7 (d, JC-F=28 Hz), 79.1, 41.2, 38.5, 36.4, 33.4, 27.3; MS (ES−) m/z 414.1, 416.1 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>ClCCl>[ClH:12].[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)nc1
Solvent: ClCCl
Product: Cc1ccc(CCl)nc1
Product: Cl
Reaction time: 2 h

Procedure:
To (5-methyl-pyridin-2-yl)-methanol (310 g) in dichloromethane (1.2 L) was added thionyl chloride (200 mL) dropwise over 1.5 hours. The reaction was stirred for 2 hours, and then concentrated under vacuum. Ethyl acetate (1 L) was added, and the mixture was again concentrated to dryness. Additional ethyl acetate (1.5 L) was added, and the suspension was stirred for 30 minutes and then filtered to isolate the desired product as a solid, which was dried under nitrogen.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH2:5].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH:5][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
Mix L-serine methyl ester (6.6 mmol) and pyridine (60 mL). Add, by dropwise addition, benzyl chloroformate (7.3 mmol) and stir overnight. Remove excess pyridine in vacuo and dissolve the residue in a two-phase mixture of ethyl acetate/water. Separate the organic phase and extract the aqueous phase with additional ethyl acetate (2×). Wash the combined organic phases with water, then brine and dry (MgSO4). Evaporate the solvent in vacuo to give N -(benzyloxycarbonyl)-L-serine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.CO.[BH4-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OC1CCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
Charged 5-fluoro-2,3-dihydroinden-1-one (486 mg, 3.22 mmol), methanol (8 mL) and dichloromethane (4 mL) to a flask, the mixture was cooled to 0° C. and NaBH4 (119 mg, 3.22 mmol) was added in portions. The reaction mixture was stirred at 0° C. for 15 min, warmed up to room temperature and stirred for 30 min. Added water, extracted with ethyl acetate twice, and washed the organic phase with brine and dried with anhydrous Na2SO4, concentrated to give the title compound (488 mg, 100%). 1H NMR (400 MHz, CDCl3): δ 1.94-2.02 (1H, m), 2.46-2.55 (1H, m), 2.76-7.84 (1H, m), 3.01-3.08 (1H, m), 5.20 (2H, t, J=5.6 Hz), 6.89-6.93 (2H, m), 7.32-7.36 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.O([Si](C)(C)C)[K:21]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][NH:14][CH2:15][C:16]([F:17])([F:18])[F:19])[C:9]([O-:11])=[O:10])=[CH:6][CH:7]=1.[K+:21]
Reactant: C[Si](C)(C)O[K]
Reactant: COC(=O)C(CNCC(F)(F)F)c1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C([O-])C(CNCC(F)(F)F)c1ccc(Cl)cc1
Product: [K+]
Reaction time: 18 h
Yield: 117.6 %

Procedure:
A solution of methyl 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (235 mg, 0.795 mmol) in TI-IF (3.0 mL) was treated with KOTMS (153 mg, 1.19 mmol) at room temperature. The reaction was allowed to stir 18 hours to completion, and the mixture was diluted with ether. The resulting precipitate was isolated by filtration and placed under high vacuum for two hours to afford the potassium 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (299 mg, 118%, excess salts) as a white solid. LCMS (APCI+) m/z 282.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
A mixture of 2,2-diphenylpropionic acid (0.200 mmol, 45.2 mg), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (0.200 mmol, 60.7 mg), 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide (EDC, 0.400 mmol, 62.0 mg) and 4-dimethylaminopyridine (5.00 mg) was dissolved in CH2Cl2/DMF (1.00/0.100 mL) and the mixture was shaken on an orbital J-KEM shaker at room temperature for 12 h. The reaction mixture was concentrated in vacuo, purified by preparative TLC [silica, CH2Cl2:ammonia (2.0 M in methanol) 100:5] to afford the desired product (43.8 mg, 42% yield): 1H NMR (400 MHz, CDCl3) δ 7.50–7.43 (br, 1H), 7.43–7.39 (br, 1H), 7.39–7.18 (m, 12H), 6.89 (d, 1H, J=7.7 Hz), 6.23 (br, 1H) 3.42–3.32 (m, 2H), 2.85 (d, 2H, J=10.8 Hz), 2.50 (quintet, 1H, J=7.4 Hz), 2.45–2.36 (m, 1H), 2.28 (t, 2H, J=6.4 Hz), 1.99 (s, 3H), 1.96–1.82 (m, 2H), 1.78–1.60 (m, 4H), 1.60–1.47 (m, 2H), 1.23 (d, 6H, J=7.0 Hz); ESMS m/e: 512.4 [M+H]+.