Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=1[CH3:23])=[O:9]
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2F)c(C)c1
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a solution of 5-bromo-2-fluorobenzoic acid (3.50 g, 15.9 mmol) in CH2Cl2 (50 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (2.86 g, 15.9 mmol, see preparation 12) and N,N-diisopropylethylamine (8.35 ml, 47.9 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 20.5 ml, 31.9 mmol) is added via syringe and stirred at ambient temperature. After 36 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 10% ethyl acetate in hexane to give the title compound as a white solid (4.20 g, 69%). Mass spectrum (m/z): 380.2 (M+1).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5](=[O:19])[CH2:6][O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]=[CH2:18])[O:10]1)[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(O)=[O:28]>C(Cl)Cl>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:19])[CH2:6][O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]2[CH2:18][O:28]2)[O:10]1)[CH2:21][CH3:22]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: C=CCOCC1CCC(COCC(=O)N(CCC)CCC)O1
Solvent: ClCCl
Product: CCCN(CCC)C(=O)COCC1CCC(COCC2CO2)O1
Reaction time: 72 h
Yield: 92.2 %

Procedure:
5.0 g of N,N-dipropyl-2-[[tetrahydro-5-[(2-propenyloxy)methyl]-2-furanyl]methoxy]acetamide (0.016 mole) is dissolved in 300 ml of methylene chloride and 3.20 g of m-chlorobenzoic acid (1 equivalent @ 85% tech) is added at room temperature. The mixture is then stirred at 30° for 72 hours under nitrogen. The precipitated m-chlorobenzoic acid is removed via filtration. The methylene chloride mixture is then washed with 2×200 ml portions of saturated potassium carbonate solution and dried over anhydrous sodium sulfate. The methylene chloride is removed in vacuo yielding 4.86 g (92%) of the above compound as a pale yellow liquid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.ClC(OCC)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26].Cl>C(Cl)(Cl)Cl>[ClH:8].[NH2:26][CH2:25][CH2:24][NH:27][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[Cl:8]
Reactant: NCCN
Reactant: O=C(O)c1ccccc1Cl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NCCNC(=O)c1ccccc1Cl
Temperature: 0 °C
Yield: 108.9 %

Procedure:
22.1 ml (0.16 mol) of triethylamine are added dropwise at 10° to a suspension of 23.5 g (0.15 mol) of 2-chlorobenzoic acid in 200 ml of chloroform. 14.8 ml (0.155 mol) of ethyl chloroformate are then added dropwise at the same temperature. After completion of the addition (1 hour), the mixture is poured on to ice/water. The chloroform phase is separated, dried over magnesium sulfate and gently concentrated to about 60 ml. The thus-obtained solution is added dropwise at 10° to a solution of 40.1 ml (0.6 mol) of ethylenediamine in 400 ml of chloroform. After completion of the addition, the difficulty soluble neutral constituents are filtered off, the filtrate is concentrated and excess ethylenediamine is removed in a high vacuum. The residue obtained (31.5 g) is converted into the hydrochloride which is purified by recrystallization from ethanol/ether. There are obtained 19.2 g of N-(2-aminoethyl)-2-chlorobenzamide hydrochloride (see Example 6 of German Offenlegungsschrift 2.362.568), m.p. 155°-158°. An analytically pure sample melts at 159°-161°.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@@H:15]2[CH2:16][CH2:17][C@@H:12]([C@@H:13]([OH:19])[C@H:14]2[OH:18])[N:11]1C(OC(C)(C)C)=O)=[O:9])#[N:2].[ClH:27]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:27].[OH:18][C@@H:14]1[C@H:13]([OH:19])[C@@H:12]2[CH2:17][CH2:16][C@H:15]1[C@@H:10]([C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[C:1]#[N:2])=[O:9])[NH:11]2
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)N2CCC[C@H]2C#N)[C@@H]2CC[C@H]1[C@@H](O)[C@H]2O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: N#C[C@@H]1CCCN1C(=O)[C@H]1N[C@H]2CC[C@@H]1[C@H](O)[C@@H]2O
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (1S,3S,4S,5S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-5,6-dihydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate obtained in Example 1-4 (122 mg) in chloroform (1 mL), was added 4N HCl in dioxane (3 mL) at room temperature. The reaction mixture was stirred for 15 minutes and the organic solvent was removed in vacuo. The residue was triturated with ethyl acetate to give the target compound as a white powder (100 mg).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([OH:8])=[O:7])[CH:2]=[CH2:3].Br[CH2:10][C:11]#[N:12].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][CH2:5][C:6]([O:8][CH2:10][C:11]#[N:12])=[O:7])[CH:2]=[CH2:3]
Reactant: N#CCBr
Reactant: C=CCOCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOCC(=O)OCC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
2-(Allyloxy)acetic acid (0.500 g, 4.31 mmol) was dissolved in dichloromethane (20 ml), and 2-bromoacetonitrile (2.06 g, 17.18 mmol) and triethylamine (0.87 g, 8.61 mmol) were slowly added at room temperature. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford cyanomethyl 2-(allyloxy)acetate (0.40 g, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:30])[CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
A solution of ethyl 2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (104 mg, 0.27 mmol) in THF (2.7 mL) was cooled to 0° C. and treated with methyl iodide (0.084 mL, 1.35 mmol) and NaHMDS (0.41 mL, 1 M solution in THF, 0.41 mmol). After stirring for 16 h at room temperature, additional methyl iodide (0.042 mL, 0.77 mmol) was added and the mixture was warmed to 35° C. for 6 hours. The reaction was quenched with saturated NH4Cl solution (2 mL), diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, sat'd aq sodium chloride, dried over MgSO4 and concentrated. Purification by column chromatography (5-40% ethyl acetate in heptane) gave ethyl 2-(tert-butoxycarbonyl(methyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (59 mg, 55%). Rf 0.34 (20% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 4.72-4.68, 4.43-4.38 (m, 1H, rotamers), 4.15 (q, J=7.3 Hz, 2H), 2.81, 2.77 (s, 3H, rotamers), 1.87-1.61 (m, 2H), 1.53-1.23 (m, 28H), 0.78 (t, J=7.3 Hz, 2H). ESI MS found for C20H38B1N1O6 m/z [400.5 (M+1)].
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]2[C:17]2[CH:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CC#N>[CH3:36][O:35][C:31](=[O:34])[CH:32]=[CH:33][C:20]1[CH:19]=[CH:18][C:17]([CH:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:15][CH2:16][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][CH:21]=1
Reactant: C=CC(=O)OC
Reactant: O=S(=O)(Oc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1)C(F)(F)F
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1

Procedure:
Prepared by Heck coupling 7b and methyl acrylate in accordance with the general method described in Example IV. Yield (76%); APcI m/z: 410 (M+H+CH3CN+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12].[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1)[C:8](=[O:11])[C:7]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2c(F)cccc21
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(Cc2cccc(F)c2)c2c(F)cccc21
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.3 g, 7.3 mmol) was dissolved in dimethylformamide (14 mL) and NaH (0.30 g, 8 mmol) was added and the mixture was stirred 30 minutes then 3-fluorobenzyl bromide (1.5 g, 8.0 mmol) was added. The mixture was stirred 4 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-20% ethyl acetate in hexane) to afford 1.7 g (81%) of 7-fluoro-1-(3-fluorobenzyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][NH:4][C:3]1=[S:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].[H-].[Na+].C(OCC)(=O)C>CCO>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][S:18][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][N:4]=1
Reactant: ClCCCCBr
Reactant: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc2c(-c3nnc(SCCCCCl)n3C)cccc2n1
Yield: 79 %

Procedure:
4-Methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (400 mg) was reacted with 1-bromo-4-chloro-butane (0.233 ml) and NaH (60%, 69 mg) in absolute EtOH (6.5 ml) at reflux for 45 min. Ethyl acetate was added, the insoluble salts were filtered off and the solvent was evaporated under reduced pressure. The crude was purified on silica gel (eluent: ethyl acetate to ethyl acetate/acetone, 1/1) affording the desired compound as pale yellow solid (430 mg, 79% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:13][CH:12]=1)[CH3:22]
Reactant: CCO
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)cc1

Procedure:
A suspension of 300 g of 4-trifluoromethylcinnamic acid (J. Org. Chem. 43:980 (1980) and 25 ml of concentrated sulfuric acid in 1.7 liters of ethanol is heated to reflux for 24 hours. The solution is concentrated, cooled, and filtered to give as a white solid, 4-trifluoromethylcinnamic acid ethyl ester, mp 40°-41° C.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=1)(=O)=O.[NH2:16][C@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>COCCOC>[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([C:5]2[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=2)[CH2:18]1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: N[C@H]1CCNC1
Solvent: COCCOC
Product: CCOC(=O)c1cnc(N2CC[C@H](N)C2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
The methylsulfone 149 (450 mg, 1.95 mmol) was added to a solution of 3-(S)(−) aminopyrrolidine (253 mg, 2.93 mmol) in DME (10 ml). The reaction mixture was stirred for 10 min at room temperature and the solvent was evaporated. The remaining solid was dissolved in dichloromethane, the solution was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound 150 as a yellow solid (416 mg, 90% yield). 1H NMR: (DMSO) δ (ppm): 8.76 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 3.70-3.53 (m, 4H), 3.26 (dd, J=11.3, 3.9 Hz, 1H), 2.07-1.98 (m, 1H), 1.75-1.67 (m, 3H), 1.29 (t, J=7.0 Hz, 3H). LRMS (ESI): (calc.) 236.1; (obt.) 237.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1>C(Cl)(Cl)Cl.O1CCCC1.[O-2].[O-2].[Mn+4]>[O:12]=[C:9]1[NH:8][C:7]2[CH:13]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=2[S:11][CH2:10]1
Reactant: O=C1CSc2ccc(CO)cc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Yield: 72.2 %

Procedure:
A stirred solution of the alcohol (b) (3.5 g) in chloroform (150 ml) and tetrahydrofuran (300 ml) was treated with manganese dioxide (7.8 g) for 18 hours and was filtered and evaporated to give a white solid (2.5 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[F:15])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:24]1([N:27]2[CH2:32][C:31]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[O:30][CH2:29][C:28]2=[O:38])[CH2:26][CH2:25]1>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH:6]([C:7]1[C:12]([F:13])=[CH:11][C:10]([Br:14])=[CH:9][C:8]=1[F:15])[N:35]1[CH2:36][CH2:37][C:31]2([O:30][CH2:29][C:28](=[O:38])[N:27]([CH:24]3[CH2:25][CH2:26]3)[CH2:32]2)[CH2:33][CH2:34]1)(=[O:3])[CH3:2]
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Reactant: CC(=O)OCC(Br)c1c(F)cc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC(c1c(F)cc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 2-bromo-2-(4-bromo-2,6-difluorophenyl)ethyl acetate (1.013 mmol) in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (3.04 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (1.115 mmol). The reaction was stirred at room temperature overnight. The reaction solution was diluted with water (100 mL) and was extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude title compound as a yellow solid (405 mg of 80% pure material as estimated by 1H NMR, 65% yield). MS(ES)+ m/e 487.2/489.3 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[C@@H:17]([NH2:20])[CH2:18][OH:19].CCN(CC)CC.[CH3:29][C:30]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:20][C@H:17]([C@H:16]([OH:21])[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:18][O:19][Si:33]([C:30]([CH3:32])([CH3:31])[CH3:29])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC=C[C@@H](O)[C@@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 4 h
Yield: 40.1 %

Procedure:
To a solution of D-erythro-sphingosine (46 mg, 0.153 mmol) in CH2Cl2 (1.5 mL) at room temperature, Et3N (32 μL, 0.230 mmol), TBDPSCl (44 μL, 0.169 mmol) and 4-DMAP (ca. 5 mg, cat.) were added. After stirring for 4 h, the reaction was quenched with H2O (10 mL), extracted with EtOAc (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography on silica (hexane/EtOAc 5:1 to 100% EtOAc) to obtain 136 as a colorless oil (33 mg, 40% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: CCc1cc2c(NCc3ccccc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:17][N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)=[N:3][CH:4]=1
Reactant: Nn1cccc1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(Nn3cccc3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine was reacted with 1-aminopyrrole to provide 5-fluoro-N4-(3-hydroxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.95 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), 7.99 (d, 1H, J=3.5 Hz), 7.22 (d, 1H, J=8.2 Hz), 6.94 (br s, 1H), 6.89 (t, 1H, J=8.2 Hz), 6.70 (dd, 2H, J=2.3 and 4.7 Hz), 6.38 (d, 1H, J=8.2 Hz), 5.99 (t, 2H, J=2.3 and 4.7 Hz). LCMS: ret. time: 18.23 min.; purity: 94%; MS (m/e): 286 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[C:6]([NH2:11])=[CH:7][C:8]=1[O:9][CH3:10].[F:13][C:14]([F:21])([F:20])[CH:15]([OH:19])[C:16](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:12][C:16]([CH:15]([OH:19])[C:14]([F:21])([F:20])[F:13])=[N:11][C:6]=2[CH:7]=1
Reactant: COc1cc(N)c(N)cc1OC
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nc(C(O)C(F)(F)F)[nH]c2cc1OC
Temperature: 108 °C

Procedure:
4,5-Dimethoxy-benzene-1,2-diamine (2.02 g; 12.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (2.67 g; 18.5 mmoles) were suspended in 6N HCl (5 mL; 30 mmoles) and water (4 mL) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (40 mL) and with ethyl acetate (40 mL), then sodium bicarbonate (3.84 g; 46.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (40 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude dark orange solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a bright orange solid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[C:8](O)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:14][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCC#CCCO
Reactant: CCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC#CCCOC(=O)CCCCC
Temperature: 25 °C

Procedure:
Into a 250 ml reaction flask equipped with condenser, stirrer, heating mantle, thermometer and Dean Stark trap is placed 29.4 grams (0.3 moles) of 3-hexyn-1-ol; 34.8 grams (0.3 moles) of n-hexanoic acid; 100 ml toluene and 0.2 ml concentrated sulfuric acid. With stirring, the reaction mass is refluxed for a period of four hours. At the end of the four hour period, the reaction mass is then cooled to room temperature and washed with two volumes of 10% sodium carbonate followed by two volumes of saturated sodium chloride solution. The reaction mass is then distilled on a one plate short path column yielding the following fraction:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
Compound A2 (0.13 mmol, 50 mg), and ethyl chloroformate (0.13 mmol, 13 μL) were dissolved in DMF (1 mL) and triethylamine (0.36 mmol, 50 μL). The reaction was heated in a microwave at 80° C. for 4 minutes. The mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo provided Compound A10 as a yellow solid (50 mg, 89%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.97 (s, 1H), 8.20 (s, 1H), 7.77 (d, 2H), 7.66 (d, 2H), 5.41 (heptet, 1H), 3.96 (q, 2H), 3.47 (m, 4H), 2.88 (s, 3H), 1.72 (m, 4H), 1.08 (t, 3H). LCMS (ESI), m/z 466.3 (M+H+, 100%).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:19][O:20][CH2:21][CH2:22]O.C(P(CCCC)CCCC)CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[OH:57])[CH2:46][C:45]1([CH3:59])[CH3:58])=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1(C)C=CC=CC=1.O>[C:37]([O:41][C:42]([N:44]1[CH2:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[O:57][CH2:22][CH2:21][O:20][CH3:19])[CH2:46][C:45]1([CH3:59])[CH3:58])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2O)CC1(C)C
Reactant: COCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
518 mg of 1,1′-(azodicarbonyl)dipiperidine (2.05 mmol), 156 mg of 2-methoxyethanol (2.05 mmol) and 0.42 ml of tributylphosphine (2.05 mmol) were added to a solution of 400 mg of 4-(2-hydroxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10d) (1.36 mmol) in toluene (14 ml), and the mixture was stirred at 100° C. for three hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=1/2) to obtain 444 mg of 4-[2-(2-methoxyethoxy)phenyl]-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester (yield: 86%).