Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[S:22]1[C:26]2[C:27]([C:31]3[O:41][C:34]4=[C:35]([NH2:40])[N:36]=[CH:37][C:38](I)=[C:33]4[CH:32]=3)=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[S:22]1[C:26]2[C:27]([C:31]3[O:41][C:34]4=[C:35]([NH2:40])[N:36]=[CH:37][C:38]([C:11]5[CH:10]=[N:9][N:8]([CH:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)[CH:12]=5)=[C:33]4[CH:32]=3)=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[CH:23]1
Reactant: CN1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(I)c2cc(-c3cccc4ccsc34)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6ccsc56)cc34)cn2)CC1
Yield: 33 %

Procedure:
A solution of 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (42.0 mg, 0.14 mmol) and 2-(1-benzothiophen-7-yl)-4-iodofuro[2,3-c]pyridin-7-amine (47.1 mg, 0.12 mmol) in 1,4-dioxane (0.81 mL) and H2O (0.2 mL) was charged with potassium carbonate (25 mg, 0.18 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (0.9 mg, 0.01 mmol) under an atmosphere of nitrogen. The mixture was irradiated in a Biotage microwave reactor at 100° C. for 100 min. The reaction mixture was concentrated in vacuo to a solid. Purification by flash chromatography (0 to 10% 7 N NH3/MeOH:EtOAc afforded 17 mg (33%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.11 (d, J=7.58 Hz, 1H), 8.07 (s, 1H), 7.93 (d, J=8.08 Hz, 1H), 7.88 (d, J=7.07 Hz, 2H), 7.70 (d, J=5.31 Hz, 1H), 7.45-7.55 (m, 3H), 4.27 (dt, J=15.35, 7.86 Hz, 1H), 3.06 (d, J=11.62 Hz, 2H), 2.38 (s, 3H), 2.25-2.34 (m, 2H), 2.13-2.22 (m, 4H); MS (ESI): 431.17 [M+H]+; HPLC tR=0.90 min (TOF: polar—3 min).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:13])[CH:11]=[CH2:12].[Li]CCCC.[B:19](OC(C)C)(OC(C)C)[O:20]C(C)C>C1COCC1>[CH:11]([CH:10]1[O:13][B:19]([OH:20])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)=[CH2:12]
Reactant: C=CC(O)c1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC1OB(O)c2ccccc21
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a suspension of NaH (1.23 g, 28.2 mmol, 1.2 equiv., 60% content) in THF (10 mL) was added a solution of 1-(2-bromophenyl)prop-2-en-1-ol (5.0 g, 23.5 mmol, 1.0 eq) in THF (10 mL) dropwise at 0° C. The mixture was stirred for 1 h, then, cooled to −70° C. n-BuLi (11.3 mL, 28.2 mmol, 1.2 eq., 2.5M in THF) was added. The mixture was stirred for 1 h, then, triisopropyl borate (5.3 g, 28.2 mmol, 1.2 equiv.) was added. The mixture was stirred for 5 h, then, quenched with 2N H2SO4. The mixture was partitioned between brine and ethylacetate. The organic layer was washed over brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to yield 3-vinylbenzo[c][1,2]oxaborol-1(3H)-ol (2.2 g, 57%). LC-MS (m/z)=158.9, 160.9 [M+H]+.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH:14](=[O:17])[CH2:15][CH3:16].CC(O)C>CCCCCC>[CH3:16][C@@H:15]([C@@H:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=[O:17]
Reactant: O=[N+]([O-])/C=C/CCc1ccccc1
Reactant: CCC=O
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@H](C=O)[C@H](CCc1ccccc1)C[N+](=O)[O-]

Procedure:
The title compound was prepared from (E)-(4-nitrobut-3-enyl)benzene and propionaldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 210 nm (2-propanol:hexane=2:98), 1 mL/min, tmajor=15.4 min, tminor=14.4 min, the diastereomeric ratio was determined by
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].I[CH:10]([CH3:12])[CH3:11].[BH4-].[Na+]>CO.O>[CH3:11][CH:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])[CH3:12]
Reactant: CC(C)I
Reactant: OCc1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N1CCCCC1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
In a closed stainless steel tube were heated pyridine-2-methanol (3.27 g, 30 mmol) and 2-iodopropane (3.59 ml, 36 mmol) at 120° C. for 20 hours. A reaction product was dissolved in a methanol-water (10:1) mixture 23 ml) followed by addition of sodium borohydride (1.14 g, 30 mmol). After stirring at room temperature for 3 hours, a reaction solution was concentrated to dryness. To the residue was added water followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The crude product thus obtained was purified by column chromatography on silica gel (SiO2 : 90 g, CHCl3) to give 0.61 g of a product (yield 13%). The substance was then subjected to catalytic hydrogenation (2.7 kg/cm2, 1 hour) at room temperature in ethanol (20 ml) using platinum oxide (0.07 g) as a catalyst. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 0.58 g of the title compound.
Reaction SMILES: C(O[CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)C.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>O>[C:17]([C:19](=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: CCCc1ccc(C(OCC)OCC)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(C=C(C#N)C(=O)OCC)cc1
Yield: 94 %

Procedure:
A mixture of 20.0 g (90 mmole) 4-n-propylbenzaldehyde diethylacetal, 20.4 g (180 mmole) ethyl cyanoacetate, 7.2 g (93.4 mmole) ammonium acetate and 60 ml toluene are heated at reflux for six hours, cooled and poured into water. The resulting mixture was extracted with ethyl ether, dried (MgSO4) and the volatiles evaporated in vacuo to afford 23.0 g crude yellow oil which was purified by chromatography on a silica gel column, eluting with 2:1 methylene chloride/hexane to give 20.58 g (94%) of the desired product. 1H-NMR(CDCl3)ppm(delta): 0.85-1.95 (m, 8H), 2.45-2.70 (t, 2H), 4.15-4.60 (q, 2H), 7.15-8.05 (q, 4H), 8.25 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([NH:8][CH2:9][CH3:10])=[CH:6][N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1.[CH:17]1([C:20]([OH:22])=O)[CH2:19][CH2:18]1.Cl.CN(C)CCCN=C=NCC>ClC(Cl)C>[Cl:2][C:3]1[C:7]([N:8]([CH2:9][CH3:10])[C:20]([CH:17]2[CH2:19][CH2:18]2)=[O:22])=[CH:6][N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: O=C(O)C1CC1
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: CCN(C(=O)C1CC1)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To a solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine monohydrochloride (0.10 g, 0.0.38 mmol) in dichloroethane (0.75 ml) was added cyclopropanecarboxylic acid (0.03 g, 0.38 mmol) and 4-N,N-dimethylaminopyridine (0.14 g, 1.15 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.14 g, 0.77 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the crude product was purified by reverse phase silica gel chromatography eluting with 0-50% acetonitrile/water to give a white solid (0.03 g, 25%); mp 111-119° C.; 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J=2.5 Hz, 1H), 8.63-8.59 (m, 1H), 8.06 (ddd, J=8.3, 2.6, 1.4 Hz, 1H), 8.01 (s, 1H), 7.46 (dd, J=8.3, 4.7 Hz, 1H), 3.73 (q, J=7.2 Hz, 2H), 1.46 (ddd, J=12.6, 8.1, 4.7 Hz, 1H), 1.16 (t, J=7.2 Hz, 3H), 1.04 (t, J=3.7 Hz, 2H), 0.71 (dd, J=7.7, 3.0 Hz, 2H); ESIMS m/z 291 ([M+H]).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1)=[O:29]
Reactant: O=C(OCc1ccccc1)C1CNCCO1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)C1CN(C(=O)CCl)CCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
In a 100-mL round-bottom flask, the benzyl morpholine-2-carboxylate (50%, 1.00 g, 2.3 mmol) as the crude tfa salt was taken up in dichloromethane (8 mL), resulting in a white suspension. N-Ethyl-N-isopropylpropan-2-amine (1.4 ml, 7.9 mmol) was added, and the solid dissolved. The solution was cooled to 0 deg, and 2-chloroacetyl chloride (0.20 ml, 2.5 mmol) was added. The reaction mixture was allowed to warm naturally to ambient temperature where it was stirred for 14 h. The reaction mixture was diluted with DCM (75 mL), and the organic layer was extracted with dilute sodium bicarbonate (2×7 mL) then with half-saturated brine (7 mL), then was dried over sodium sulfate. The residue was purified through silica gel (100 mL) which had been deactivated with TEA (10 mL) using 90% EtOAc-hexane, affording the title compound (474 mg, 1.6 mmol). MS m/z 298 (M+1).
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].Br[C:13]1[CH:14]=[C:15]([S:19]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:21])=[O:20])[CH:16]=[N:17][CH:18]=1>>[CH3:11][C:3]1[N:4]=[C:5]([NH:7][C:8](=[O:10])[CH3:9])[S:6][C:2]=1[C:13]1[CH:18]=[N:17][CH:16]=[C:15]([S:19]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:21])=[O:20])[CH:14]=1
Reactant: CC(=O)Nc1nc(C)c(I)s1
Reactant: O=S(=O)(NCCN1CCOCC1)c1cncc(Br)c1
Product: CC(=O)Nc1nc(C)c(-c2cncc(S(=O)(=O)NCCN3CCOCC3)c2)s1
Yield: 7 %

Procedure:
Using an analogous method to that described in Example 7, N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide was reacted with 5-bromo-N-(2-morpholinoethyl)pyridine-3-sulfonamide to give the title compound (Method A HPLC: retention time 3.7 minutes; 8 mg, 7%); 1H NMR Spectrum: (DMSOd6) 12.27 (1H, br s); 8.91 (1H, d); 8.87 (1H, d); 8.17 (1H, br t); 7.96 (1H, br s); 3.42 (4H, br t); 3.00 (2H, t); 2.40 (3H, s); 2.29 (2H, t); 2.22 (4H, br t); 2.16 (3H, s); Mass Spectrum: M+H+ 426.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:25])[C:14]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(OCC)(=O)C.[ClH:42]>C(OCC)(=O)C.CC(O)C>[ClH:42].[C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH:13]=[C:14]([CH2:26][NH:27][CH3:28])[C:15]([F:25])=[C:16]2[C:17]2[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2C#N)c1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 79 %

Procedure:
To a solution of tert-butyl {[1-[(3-cyanophenyl)sulfonyl]-5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (401 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 17 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as a white solid (yield 276 mg, 79%).
Reaction SMILES: [OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].CS(O[CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=O)=O.O>C1COCC1>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][O:1][C@@H:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1
Reactant: COCCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.8 %

Procedure:
An oven dried flask was charged with (R)-tert-butyl 3-((R)-hydroxy(phenyl)-methyl)piperidine-1-carboxylate (162 mg, 0.557 mmol) and 60% NaH in mineral oil (112 mg, 5 equiv.). The flask was purged with N2 gas, cooled to 0° C. and anhydrous THF (6 mL) was added slowly. After 5 min, the reaction mixture was allowed to warn to rt slowly. A solution of 3-methoxypropyl methanesulfonate (468 mg, 4 equiv.) in anhydrous THF (5 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction was complete. The reaction mixture was cooled to 0° C. and water was added dropwise. After separation, the aqueous layer was extracted with ether (3×). The combined organic layers were washed with 5% aq HCl, satd aq NaHCO3 and brine, and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 4-g silica gel cartridge eluted with a 0-35% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-((R)-(3-methoxypropoxy)(phenyl)-methyl)piperidine-1-carboxylate (196 mg, 97% yield) as a clear oil. LC-MS (3 min) tR=2.19 min, m/z 386 (M+Na).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCCc1ccccc1
Reactant: CC(=O)CC(C)=O
Product: O=C(CCCCCc1ccccc1)CC(=O)CCCCCc1ccccc1

Procedure:
Using 2,4-pentanedione (26.7 g, 0.267 mol) and 1-chloro-4-phenylbutane (110 g, 0.65 mol) obtained in Example 13, (2), the reaction was carried out in the same manner as described in Example 17, (1), and the residue was chromatographed on silica gel (Wako Gel C-200) with benzene/n-hexane (from 4:1 to 10:1) as eluent to afford the title compound as a pale yellow oil which was an ca 1:4 mixture of Keto/Enol as seen by the methylene singlet at δ3.52 ppm and the methine singlet at δ5.44 ppm in the 1HNMR spectrum; yield: 2.5 g.
Reaction SMILES: BrC1C=CC([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:18]3([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=CC=1.Cl.Cl.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][C:39](N3CCNCC3)=[N:40][CH:41]=2)=[CH:32][CH:31]=1.COC(C1(S(Cl)(=O)=O)CCOC(C)C1)=O>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[N:40][C:39]([N:8]3[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:18]4([C:24]([OH:26])=[O:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)(=[O:15])=[O:16])[CH2:10][CH2:9]3)=[N:38][CH:37]=2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Agent: COC(=O)C1(S(=O)(=O)Cl)CCOC(C)C1
Agent: Cl
Product: O=C(O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCOCC1
Yield: 81 %

Procedure:
Prepared according to the method for the preparation of 4-[4-(4-bromophenyl)-piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid, from 5-(4-fluoro-phenyl)-2-piperazin-1-ylpyrimidine dihydrochloride (0.27 g), and 4-chlorosulfonyl-methyltetrahydropyran-4-carboxylic acid methyl ester (0.25 g), to yield the title compound as white solid (0.31 g, 81%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].CCN(CC)CC.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21](=[O:22])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCO)C(=O)OCc1ccccc1
Yield: 75.6 %

Procedure:
A solution of 20.0 g (266.3 mmol) of 2-(methylamino)ethanol was dissolved in 100 mL of CH2Cl2 and treated first with 74.23 mL (532.54 mmol, 2 eq) of Et3N then with 33.8 mL (239.64 mmol, 0.9 eq) of benzylchloroformate within a period of 1.5 h at RT. The reaction was partitioned between Et2O (×3)/aqueous 10% KHSO4 (×2), dried over Na2SO4 and evaporated to yield 37.93 g (68%) of (2-hydroxy-ethyl)-methyl-carbamic acid benzyl ester, MS: 210 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:11][C:12]#[C:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:20]O>>[CH3:2][N:3]([CH2:11][C:12]#[C:13][CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH3:20])=[O:8]
Reactant: CO
Reactant: CN(CC#CCN1CCCC1)C(=O)CCC(=O)O
Agent: Cl
Product: COC(=O)CCC(=O)N(C)CC#CCN1CCCC1
Reaction time: 8 h
Yield: 63 %

Procedure:
Dowex 50 resin (200 mg) which had been activated with HCl was added to a solution of N-Methyl-N-[4-(1-pyrrolidinyl)-2-butynyl]-3-carboxypropanamide (101 mg, 0.40 mmol) in MeOH (2 mL) and the suspension was vigorously stirred overnight. The resin was filtered off and washed thoroughly with TFA. The combined MeOH and TFA washes were evaporated under a stream of N2, neutralized with 2M Na2CO3 solution and the product was extracted into EtOAc (3× mL). The organic layer was dried over Na2CO3, evaporated in vacuo and purified on silica gel (CHCl3 /MeOH/NH4OH, 40/10/1) to give 009 (66.8 mg, 63% yield). MS (CI-NH3), m/e 267 (MH+), 186, 172. 1H NMR (CDCl3) δ1.79 (br s, 4 H), 2.58 (br s, 4 H), 2.64 (m, 4 H), 2.98 & 3.07* (s, 3 H), 3.38 (s, 2 H), 3.68 (s, 3 H), 4.08 & 4.24* (s, 2 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:8][C:7]=1[CH3:15].[S:16]([Cl:20])(=O)(=[O:18])[OH:17]>>[C:12]([NH:11][C:9]1[S:10][C:6]([C:2]2[O:1][C:5]([S:16]([Cl:20])(=[O:18])=[O:17])=[CH:4][CH:3]=2)=[C:7]([CH3:15])[N:8]=1)(=[O:14])[CH3:13]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1nc(C)c(-c2ccco2)s1
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)o2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To N-(5-(furan-2-yl)-4-methylthiazol-2-yl)acetamide (0.443 g) under an ice-salt bath was added sulfurochloridoic acid (ClSO3H, 5 ml). After 30 min, the reaction was poured into crushed ice (150 g). Extraction with dichloromethane (3×30 ml), drying and concentration gave 5-(2-acetamido-4-methylthiazol-5-yl)furan-2-sulfonyl chloride (0.359 g) that was used directly for next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and trimethylacetyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: COc1ccnc(Cl)n1
Reactant: C1CNCCN1
Solvent: O
Solvent: CC#N
Product: COc1ccnc(N2CCNCC2)n1
Yield: 90 %

Procedure:
A suspension of 2-chloro-4-methoxypyrimidine (21.5 g) and piperazine (64.0 g) in acetonitrile (200 ml) was refluxed for 30 min. The reaction mixture was poured into water (500 ml) and extracted with chloroform (400 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (26.0 g) as a pale-yellow oil.
Reaction SMILES: [P:1](=[O:7])([NH2:6])([S:4][CH3:5])[O:2][CH3:3].N1C=CC=CC=1.Cl[S:15][N:16]([CH:23]([CH3:25])[CH3:24])[C:17](=[O:22])[O:18][CH2:19][CH2:20][CH3:21].Cl.N1C=CC=CC=1.S(Cl)Cl>C(Cl)Cl>[CH2:19]([O:18][C:17]([N:16]([CH:23]([CH3:24])[CH3:25])[S:15][NH:6][P:1](=[O:7])([S:4][CH3:5])[O:2][CH3:3])=[O:22])[CH2:20][CH3:21]
Reactant: CCCOC(=O)N(SCl)C(C)C
Reactant: COP(N)(=O)SC
Agent: Cl
Agent: ClSCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)N(SNP(=O)(OC)SC)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 4.0 g (0.028 mol) O,S-dimethyl phosphoramidothioate, 2.2 g pyridine (0.028 mol) and 15 ml of anhydrous methylene chloride, chilled to 0°-5° C., was added dropwise 6.0 g (0.028 mol) propyl (chlorosulfenyl)(isopropyl)carbamate over a period of 15 minutes. Pyridine hydrochloride forms immediately during addition of the sulfenyl chloride. The reaction mixture was stirred for an additional half hour at room temperature after the addition of the sulfenyl chloride.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]([NH:9][C:10]1[S:11][C:12]([S:16](Cl)(=[O:18])=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[CH3:7].C(N(CC)CC)C>C1COCC1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[S:16]([C:12]1[S:11][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[N:14][C:13]=1[CH3:15])(=[O:17])=[O:18]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CNCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N(C)CCO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.9 %

Procedure:
To a stirred solution of 2-(methylamino)-ethanol (0.44 g, 5.86 mmol) in THF (12 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.0 g, 3.92 mmol) and triethylamine (0.6 ml, 4.32 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (dichloromethane/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (0.93 g, 81%) as a white solid. MS (ISP) 294.0 [(M+H)+]; mp 189° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:19][NH:20][C:21]([CH3:34])([CH3:33])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH3:6].[OH-].[Na+]>CO.O1CCCC1>[OH:1][C@H:2]([CH2:19][NH:20][C:21]([CH3:33])([CH3:34])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH3:6]
Reactant: COC(=O)CCc1ccccc1[C@@H](C)OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1CCC(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Methyl 3-[2-[(1R)-1-[(2R)-2-hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]phenyl]propionate (539 mg) obtained in Step 4 was dissolved in methanol (20 ml) and tetrahydrofuran (20 ml), 4N aqueous sodium hydroxide (2.5 ml) was added and the mixture was stirred at 50° C. for 8 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with water, neutralized with 10% aqueous citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (332 mg).