Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC.Cl>>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][CH2:5][O:4][CH:1]2[CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-cyclopropoxyethanol (400 mg, 3.92 mmol) DCM (10 mL) were added TsCl (821 mg, 4.31 mmol) and Et3N (0.6 mL, 4.31 mmol). The reaction was stirred at room temperature overnight. Then, 1N HCl was added, and the reaction was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a yellow oil. The oil was purified by preparative TLC to obtain intermediate BP (50 mg) as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:30](Cl)(=[O:32])[CH3:31].CCN(CC)CC>C(Cl)Cl>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][C:30](=[O:32])[CH3:31])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Prepared using General Procedure 4: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile HCl 3 (20 mg, 0.05 mmol) in DCM (0.5 mL) were added acetyl chloride (7 μL, 0.10 mmol) and NEt3 (14 μL, 0.10 mmol). After stirring for 1 h, the solvent was evaporated and the residue was purified by preparative HPLC to provide 11.3 mg (56%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide 21. LCMS-ESI (m/z) calculated for C24H24N4O3: 416.5; found 417.2 [M+H]+, tR=3.56 min. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 7.92 (dd, J=7.7, 1.2 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.83 (d, J=8.6 Hz, 1H), 5.36-5.21 (m, 1H), 4.79 (hept, J=6.0 Hz, 1H), 3.16 (dt, J=17.9, 6.0 Hz, 1H), 3.03 (dt, J=18.2, 6.3 Hz, 1H), 2.10-1.99 (m, 4H), 1.97-1.79 (m, 3H), 1.47 (d, J=6.1 Hz, 6H).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:26][C:27]1[S:31][C:30]([NH:32][C:33]2[C:38]([Cl:39])=[CH:37][C:36]([Cl:40])=[CH:35][C:34]=2[Cl:41])=[N:29][C:28]=1[C:42]([F:45])([F:44])[F:43].CCOCC>C(Cl)Cl>[CH2:2]([N:9]([CH2:26][C:27]1[S:31][C:30]([NH:32][C:33]2[C:34]([Cl:41])=[CH:35][C:36]([Cl:40])=[CH:37][C:38]=2[Cl:39])=[N:29][C:28]=1[C:42]([F:44])([F:43])[F:45])[CH2:10][CH2:11][C:12]([F:14])([F:13])[F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)CCNCc1ccccc1
Reactant: FC(F)(F)c1nc(Nc2c(Cl)cc(Cl)cc2Cl)sc1CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)CCN(Cc1ccccc1)Cc1sc(Nc2c(Cl)cc(Cl)cc2Cl)nc1C(F)(F)F
Reaction time: 12 h
Yield: 94 %

Procedure:
A stirred suspension of benzyl-3,3,3-trifluoropropyl-amine hydrochloride (152.8 mg, 3 equiv.) in methylene chloride (10 mL) at room temperature was treated with diisopropylethylamine (0.132 mL, 3 equiv.). Within a few minutes the mixture became homogeneous and then a 12.5 mg/mL solution of (5-chloromethyl-4-trifluoromethyl-thiazol-2-yl)-(2,4,6-trichloro-phenyl)-amine in ether (8 mL, 0.2525 mmoles) was added all at once. After 12 hours at room temperature, the mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 12% ethyl acetate/hexane, to give the product as a colorless glass (133.6 mg, 94%). 1H-NMR δ (CDCl3) 2.27 (m, 2H), 2.75 (ABq, 2H), 3.62 (s, 2H), 3.74 (s, 2H), 7.28 (m, 5H), 7.48 (s, 2H), 8.75 (br, 1H). Mass spec.: 563.98 (MH+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>C1COCC1.O>[F:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1cncc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
n-Butyl lithium (1.0 eq, 76 mmol, 47.6 mL, 1.6 M in hexanes) was added via dropping funnel to a solution of diisopropylamine (1.05 eq, 80 mmol, 11.2 mL) in THF (300 mL) at −78° C. under nitrogen (N2). The solution was stirred for 30 min at −78° C., then a solution of 3,5-difluoropyridine (1.05 eq, 80 mmol, 9.2 g) in THF (20 mL) was added dropwise via syringe. A beige precipitate was observed to form. The reaction stirred at −78° C. for 90 min then tributyltin chloride (1.0 eq, 76 mmol, 20.7 mL) was added dropwise via syringe and the resulting solution allowed to warm to RT over 2 h. Water (5 mL) was added, then roughly 250 mL of THF was removed on a rotary evaporator. The resulting material was diluted with diethyl ether (350 mL) and washed successively with water (2×200 mL), saturated sodium chloride solution (1×150 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the 3,5-Difluoro-4-tributylstannanyl-pyridine as a colourless oil (27.5 g, 88%). This material was used crude without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](O)=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:49]([O:51][C:52]([C@@:54]1([NH2:59])[CH2:56][C@H:55]1[CH:57]=[CH2:58])=[O:53])[CH3:50].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](=[O:36])[NH:59][C:54]1([C:52]([O:51][CH2:49][CH3:50])=[O:53])[CH2:56][CH:55]1[CH:57]=[CH2:58])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Reactant: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a stirred solution of 4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (48, 3.4 g, 6.20 mmol) in dry DMF (50 mL) was added (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester tosylate (2.23 g, 6.82 mmol) and diisopropylethylamine (2.70 mL, 17.1 mmol). Then, HATU (2.59 g, 6.82 mmol) was added at 0° C. under nitrogen. After 30 min at 0° C., the reaction mixture was successively allowed to warm up to room temperature for 4 h, then diluted with water (150 mL) and extracted with EtOAc (3×150 mL). The organic layers were combined and washed with a saturated solution of NaHCO3, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography (gradient EtOAc/CH2Cl2, 0:1 to 2:8) afforded 3.0 g (70%) of the title product 49: m/z=685 (M+H)+.
Reaction SMILES: C(OC)(=[O:4])C=C.C(P)(C)(C)C.[C:12]([P:16]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([P:16](=[O:4])([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH3:14])([CH3:15])[CH3:13]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CCP(CCC(=O)OC)C(C)(C)C
Agent: CC(C)(C)P
Product: COC(=O)CCP(=O)(CCC(=O)OC)C(C)(C)C

Procedure:
The procedure of Example 1 is again followed except that 860 parts of methyl acrylate are reacted with 452 parts of t-butylphosphine. 4.9 Parts of azobis-1-isovaleronitrile are used as catalyst. The liquid reaction product, t-butyl bis(carbomethoxyethyl)phosphine is oxidized to give t-butyl bis(carbomethoxyethyl)phosphine oxide which is then hydrolyzed. The product, t-butyl bis(β-carboxyethyl)phosphine oxide is isolated as an off-white crystalline solid having a m.p. of 174° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H](C3C=CC=CC=3)C)[CH2:11][C@H:10]2[F:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([N:12]1[CH2:13][C@H:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]2)[C@H:10]([F:22])[CH2:11]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C[C@H]2F)CC1
Solvent: ClCCl
Product: CCOC(=O)C1([C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Yield: 83.7 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]pyrrolidine (5.08 g, 16.63 mmol) was dissolved in dry dichloromethane (50 ml), and benzyl chloroformate (3.56 ml, 25.0 mmol) was added dropwise to the thus prepared solution which was cooled in an ice bath. After 1 hour of heating of the reaction solution under reflux, dichloromethane was evaporated under reduced pressure. Thereafter, the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=3:1, to thereby obtain 4.67 g (83.7%) of the title compound as a colorless oil.
Reaction SMILES: C1(SC2C=CC=C[C:9]=2[C:10](O)=[O:11])C=CC=CC=1.[OH-:17].[K+].[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23]>O.C(O)C>[CH2:10]([OH:11])[CH2:9][O:23][C:22]([CH2:21][CH:20]([OH:17])[C:19]([OH:26])=[O:25])=[O:24]
Reactant: O=C(O)c1ccccc1Sc1ccccc1
Reactant: [OH-]
Reactant: O=C(O)/C=C\C(=O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(CC(O)C(=O)O)OCCO
Temperature: 20 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of methyl 2-(4-(2-chloroethoxy)phenylsulfanyl)benzoate (7.2 g, 22.0 mmol), 1-(4-chlorobenzyl)piperazine (4.6 g, 22.0 mmol), anhydrous potassium carbonate (10.5 g), potassium iodide (0.2 g) and 4-methylpentane-2-one (120 ml) was refluxed for 20 h (the reaction was monitored by TLC and continued till 1-(4-chlorobenzyl)piperazine was not present in the reaction mixture). The hot mixture was filtered, the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel using dichloromethane and chloroform as eluents. Crystallization from a mixture of n-hexane-ether (1:1) provided methyl ester of the title acid (4.2 g, 38.5%), m.p. 106-108° C. For C27H29ClN2O3S (497.1) calculated: 65.24% C, 5.88% H, 7.13% Cl, 5.64% N, 6.45% S; found: 65.62% C, 6.19% H, 7.08% Cl, 5.20% N, 6.35% S. 1H NMR spectrum (CDCl3): CH3(ester) 3.96 s; aromatic H on the phenylsulfanylbenzoic acid moiety: H(6) 8.00 dd (J=2.0, 7.5 Hz); H(3,4,5,3′,5′) 6.68-7.20 m; aromatic H of 4-chlorobenzyl group 7.28 s. A solution of potassium hydroxide (1.7 g) in water (10 ml) was added to a stirred solution of this ester (3.7 g, 7.4 mmol) in ethanol (40 ml) and the mixture was refluxed for 1 h. The residue after evaporation was dissolved in water and acidified with acetic acid, the mixture was cooled down and the formed precipitate was extracted with chloroform. The extract was dried with sodium sulfate, the residue after evaporation was suspended in ethanol (50 ml) and a solution of maleic acid (1.2 g, 10.0 mmol) in ethanol (10 ml) was added and the mixture was stirred for 8 h at 20° C. The insoluble portion was filtered off, washed with ethanol to provide the title hydrogenmaleate (4.0 g, 90.2%), m.p. 194-196 ° C. For C26H27ClN2O3S. C4H4O4 (599.1) calculated: 60.14% C, 5.22% H, 5.92% Cl, 4.68% N, 5.35% S; found: 59.94% C, 5.31% H, 6.01% Cl, 4.51% N,5.26% S.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)(=O)C>[C:8]1([C:7](=[N:6][CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:33])([CH3:34])[O:27]2)[C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CC1(C)OB(CCCCBr)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N=C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 64.3 %

Procedure:
A solution of N-(diphenylmethylene)glycine ethyl ester (8.24 g, 30.8 mmol) and 2-(4-bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.92 g, 33.9 mmol) in freshly distilled THF (77 mL, 0.4 M) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (32.3 mL, 1.0 M in THF). Once the addition was complete, the reaction was warmed to 50° C. and heated for 8 h. After being complete by TLC, the reaction mixture was cooled to 0° C., diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Rapid purification by MPLC (1-15% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave ethyl 2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (8.9 g, 64%). Rf 0.40 (30% ethyl acetate in heptane).
Reaction SMILES: C(O[C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:28])[CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]2=3)=[CH:7][CH:6]=1)C.[OH-].[NH4+:31]>O>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([CH2:12][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([NH2:31])=[O:29])=[CH:10][CH:9]=3)[OH:28])[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: [NH4+]
Reactant: CCOC(=O)c1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C(N)=O)cc2)CCN(C)C1
Temperature: 25 °C

Procedure:
A solution of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoicacid ethyl ester (90 mg, 0.229 mmol) in 25% ammonium hydroxide solution (5 mL) was stirred at 120° C. for 1 h. The progress of reaction was monitored by NMR and LCMS. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzamide (3 mg) which was separated by chiral preparative HPLC to obtain 139a and 139b. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.18 (t, 2H), 7.4 (d, 1H), 7.31 (d, 2H), 7.23 (s, 1H), 7.03 (t, 1H), 5.08 (t, 1H), 4.64 (dd, 1H), 4.33 (m, 2H), 4.21 (dd, 1H), 3.71 (t, 1H), 3.45 (bs, 1H), 3.12 (m, 1H), 3.09 (d, 3H), 2.6 (d, 1H), 2.41 (s, 3H).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:5])[CH3:4].[CH:6](=[O:9])[CH2:7]C.[CH2:10]([Mg]Br)C>>[CH3:7][CH:6]([OH:9])[C:1]#[C:2][CH:3]([OH:5])[CH2:4][CH3:10]
Reactant: CCC=O
Reactant: C#CC(C)O
Reactant: CC[Mg]Br
Product: CCC(O)C#CC(C)O
Yield: 64 %

Procedure:
0.5 mole of 1-butyn-3-ol was coupled with 0.5 mole of propionaldehyde under the influence of ethylmagnesium bromide according to Bull.Soc.Chim.(Fr.) 425 (1956) and 3-heptyne-2,5-diol (b.p. 109°-110° C at 2 mm Hg) was obtained in 64% yield. The alkyne diol was esterified with p-toluene sulfonylchloride as described in Example 1A and 3-heptyne-2,5-ditosylate (m.p. 69.5°-70.5° C) was obtained in 76% yield. The alkyne ditosylate was oxidised with aqueous potassium permanganate as described in Example 2A, at a temperature of 5° C and heptane-3,4-dione-2,5-ditosylate was obtained in 55% yield; m.p. 120°-121.5° C (from tetrachloromethane).
Reaction SMILES: [C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([OH:24])[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(Cl)(Cl)Cl>CC(C)=O.CO>[C:1]([O:4][C:5]12[O:21][N:13]([CH2:14][CH:15]3[CH:17]1[N:16]3[C:18](=[O:20])[CH3:19])[C:12]1[C:7](=[C:8]([O:24][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:9]=[C:10]([CH:22]=[O:23])[CH:11]=1)[CH:6]2[CH2:25][O:26][C:27](=[O:29])[NH2:28])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(O)c1C2COC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)=O
Product: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(OCc3ccccc3)c1C2COC(N)=O
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (80 mg) in acetone (1 ml) were added potassium carbonate (55 mg) and benzyl bromide (47 μl), and the mixture was stirred at 50° C. for 90 minutes. The mixture was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (20:1, v/v) to afford 11-acetyl-6-benzyloxy-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (90 mg).
Reaction SMILES: ClCCl.C(N(S(F)(F)[F:10])CC)C.[CH2:13]([C:20]1[C:25]([O:26][CH2:27][O:28][CH3:29])=[CH:24][CH:23]=[C:22]([N:30]2[CH2:34][CH2:33][C@@H:32](O)[C:31]2=[O:36])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([C:20]1[C:25]([O:26][CH2:27][O:28][CH3:29])=[CH:24][CH:23]=[C:22]([N:30]2[CH2:34][CH2:33][C@@H:32]([F:10])[C:31]2=[O:36])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COCOc1ccc(N2CC[C@@H](O)C2=O)nc1Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(N2CC[C@@H](F)C2=O)nc1Cc1ccccc1
Reaction time: 2 h

Procedure:
3 ml of dichloromethane was added to 0.18 ml of diethylaminosulfur trifluoride. Into the mixture was added dropwise a solution of 3 ml of dichloromethane containing 371 mg of 2-benzyl-3-methoxymethyloxy-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine under cooling in an ethanol/dry ice bath. The mixture was returned to room temperature and stirred for 2 hours. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvents was removed. The residue was subjected to silica gel column chromatography using 17-20% ethyl acetate/hexane as an eluent for separation and purification, to give 116 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([N:22]=[C:23]=[O:24])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].N1C=CC=CC=1>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:22][C:23]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])=[O:24])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19]
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)n2cc(F)c(=O)[nH]c2=O)cc(OC)c1OC
Temperature: 90 °C
Yield: 47.2 %

Procedure:
A mixture of 3.9 g of 5-fluorouracil, 6.27 g of 3, 4, 5-trimethoxyphenylisocyanate and 15 ml of pyridine was heated at 90° C. for 2 hr and, after evaporating pyridine, 100 ml of dichloromethane and 200 ml of hydrochloric acid water were added to it. The insoluble substance produced was combined with the substance dissolved in the dichloromethane. The combined substances were washed with water and then with ethanol, and 4.8 g of 1-(3, 4, 5-trimethoxyphenylcarbamoy)-5-fluorouracil (melting point: 168°-170° C.) was obtained (Compound No. 6). NMR: 3.76 (3H s OCH3) 3.84 (6H s OCH3) 6.64-7.0 (2H b C6H2).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:17]([O:21][C:22]([CH2:24][NH:25][CH:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C>C1COCC1>[C:17]([O:21][C:22]([CH2:24][NH:25][CH:26]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:27]([CH2:16][NH:15][CH:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:28])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)CNC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(Cc1ccccc1I)NC
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1I)NCC(=O)C(Cc1ccccc1)NCC(=O)OC(C)(C)C
Yield: 56.1 %

Procedure:
Ethyl 3-(2-iodophenyl)-2-methylaminopropionate (3.94 g, 12 mmol), 2-(tert-butoxycarbonylmethylamino)-3-phenylpropionic acid (3.7 g, 13 mmol), N-ethyldiisopropylamine (7.8 g, 61 mmol) and EDAC (4.6 g, 24 mmol) were stirred in THF (abs., 50 ml) for 16 h. The reaction solution was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate, washed, dried and concentrated. Purification by column chromatography (SiO2, hexane/ethyl acetate) gave 4.0 g (56%) of the target compound.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][Br:12])=[O:5])[CH2:3][CH2:2]1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[Br-:12].[CH:1]1([C:4]([NH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[O:5])[CH2:3][CH2:2]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(CCCCBr)NC(=O)C1CC1
Solvent: CC#N
Product: O=C(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)C1CC1
Product: [Br-]
Yield: 23.8 %

Procedure:
A mixture of 4.96 g. (20 mmoles) of the N-cyclopropanecarbonyl-5-bromovaleramide prepared above, 7.86 g. (30 mmoles) of triphenylphosphine, and 50 ml. of acetonitrile were heated at reflux temperatures under nitrogen for 112 hours. The mixture was then concentrated and the resultant white foam was purified by column chromatography on Silica gel (Baker 60-200 mesh) using 5% methanol in methylene chloride as eluent. After removal of starting materials and less polar impurities, the desired [4-(cyclopropanecarbonylaminocarbonyl)butyl]triphenylphosphonium bromide was obtained as a white hygroscopic foam weighing 2.42 g. (23.8% yield).