Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[F:17])C>ClC(Cl)C>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[F:17]
Reactant: CN(C)CCCCOCc1cc(Br)ccc1F
Solvent: CC(Cl)Cl
Product: CNCCCCOCc1cc(Br)ccc1F

Procedure:
In a 10 ml flask, under a nitrogen atmosphere, N,N-dimethyl-4-[2-fluoro-5-bromobenzyloxy]butylamine (215 mg, 0.707 mmol) was dissolved in dichloroethane (2.0 ml). To this solution ACE•Cl (0.305 ml, 2.83 mmol) was added and the resulting mixture was heated to reflux. The reaction mixture was refluxed for four hours. The prgress of the reaciton was monitored by thin layer chromatography. The mixture was refluxed for an additional 16 hours. The solvents were removed in vacuo and the residue was taken up in methanol. The methanol solution was refluxed for 1.5 hours and the solvents were removed by evaporation. The residue was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C1COCC1.C(N(CC)CC)C.F[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N+:29]([O-:31])=[O:30]>C(OCC)(=O)C.CN(C=O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N+:29]([O-:31])=[O:30])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1cc(F)ccc1[N+](=O)[O-]
Yield: 71.5 %

Procedure:
To a mixture of 13.96 g of a glycine ethyl ester hydrochloride, 30 ml of THF, 10.11 g of triethylamine and 30 ml of DMF, 15.91 g of 2,4-difluoronitrobenzene was added, followed by heating under reflux for 3 hours under an argon gas stream. After cooling of the reaction mixture and dilution with ethyl acetate, the insoluble matter precipitated was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed successively with water and brine, and then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The resulting residue was recrystallized from ethanol to give 17.32 g (71.5%) of N-(2-nitro-5-fluorophenyl)glycine ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=[C:17]([NH2:24])[CH:16]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:24][C:17]2[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[N:18]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CCCc1cc(C)cc(N)n1
Solvent: CC#N
Product: CCCc1cc(C)cc(Nc2cc(Cl)nnc2C(=O)OCC)n1
Temperature: 130 °C
Yield: 28881.6 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (335 mg, 1.52 mmol) in acetonitrile (5 mL) was added 4-methyl-6-propylpyridin-2-amine (342 mg, 2.27 mmol) and the mixture heated in a sealed tube at 130° C. for 72 h. The mixture was cooled, concentrated in vacuo, and then purified by chromatography (silica, 10 to 35% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (147 mg, 439 mmol, 29%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.61 (s, 1H), 9.26 (s, 1H), 6.74 (s, 1H), 6.61 (s, 1H), 4.58 (q, J=7.1 Hz, 2H), 2.76 (t, J=7.5 Hz, 1H), 2.35 (s, 3H), 1.84 (m, 2H), 1.53 (t, J=6.9 Hz, 3H), 1.03 (t, J=7.3 Hz, 3H), MS (EI/CI) m/z: 335.0 [M+H].
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.Cl.[CH2:21]([NH:28][CH2:29][P:30]([O:35][CH2:36][CH3:37])(=[O:34])[O:31][CH2:32][CH3:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>CN(C)C=O>[CH2:21]([N:28]([CH2:29][P:30](=[O:34])([O:35][CH2:36][CH3:37])[O:31][CH2:32][CH3:33])[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN(Cc1ccccc1)Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)OCC
Yield: 46.1 %

Procedure:
1.0 g (3.05 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitroquinoxaline, 1.1 g (3.66 mmol) of diethyl benzylaminomethanephosphonate hydrochloride and 1.9 ml (10.98 mmol) of N-ethyldiisopropylamine are stirred at room temperature for about 18 hours and at 80° C. for a further 3 hours in 10 ml of dimethylformamide under argon. After addition of ethyl acetate, the mixture is extracted with water and brine, the aqueous phases are washed with ethyl acetate, and the organic phases are combined, dried using sodium sulfate, filtered on a suction filter and concentrated. The evaporation residue is chromatographed on silica gel using hexane-ethyl acetate (1:1). 0.71 g (46%) of diethyl N-benzyl-N-(2,3-dimethoxy-7-nitroquinoxalin-5-ylmethyl)aminomethylphosphonate is obtained.
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].[S:9]1C=C[C:11](C=O)=[CH:10]1>>[O:8]=[C:7]1[C:3]2[CH:11]=[CH:10][S:9][C:4]=2[CH:5]=[CH:6][NH:2]1
Reactant: O=Cc1ccsc1
Reactant: Cn1cccc1C=O
Product: O=c1[nH]ccc2sccc12

Procedure:
The synthesis of this compound was accomplished with the same sequence of reactions as used to prepare IIIc, except that the starting material (X) is 3-thiophenecarboxaldehyde. The multiple step preparation of the positional isomer IIIc' was complicated, however, in that the Curtius-type rearrangement reaction (Example 4) gave the desired VI intermediate compound in low yield as the major product of this reaction was a sym-triazine by-product which resulted from trimerization of the isocyanate intermediate. Nonetheless, application of the reactions outlined in Scheme 1 resulted in production of the IIIc' product, which was a brown gum and was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:24])[CH:23]=1.C(O)(C(F)(F)F)=O>>[O:24]=[C:22]1[O:21][CH2:20][C:19]([N:3]2[CH:4]=[CH:5][C:6]3([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]3)[C:2]2=[O:1])=[CH:23]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=CN(C3=CC(=O)OC3)C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C(N2C=CC3(CCNCC3)C2=O)CO1

Procedure:
The title compound was prepared from tert-Butyl 1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]dec-3-ene-8-carboxylate using TFA in an analogous fashion to that described for 1-19, Step B. LC/MS: [(M+1)]+=235
Reaction SMILES: [CH2:1]([O:3][CH:4]=[C:5]([F:11])[C:6]([O:8]CC)=[O:7])[CH3:2]>[OH-].[Na+]>[CH2:1]([O:3][CH:4]=[C:5]([F:11])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC=C(F)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOC=C(F)C(=O)O
Temperature: 25 °C
Yield: 54 %

Procedure:
The fleshly prepared ethyl 3-ethoxy-2-fluoroacrylate (12, R9 =ethyl, 16.49 g, 0.10 mole) was refluxed in 100 mL of 2N NaOH for 1 hour. After cooling to room temperature, the aqueous solution was washed with hexane (100 mL). The water layer was adjusted to pH 3-4 by addition of 10% HCl and extracted with a mixture of ether and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. Evaporation of solvents yielded crude 3-ethoxy-2-fluoroacrylic acid (13, R7 =ethyl, 7.81 g, 0.054 mole) which was dissolved in 53 mL 1N NaOH, then water was evaporated and the residue was dried under vacuum at 85° C. overnight to give the sodium salt (13, R9 =ethyl). This salt was suspended in 100 mL of ether and treated with SOCl2 (4.68 mL, 0.064 mole, 1.2 eq). After reflux for 6 hours, the mixture was concentrated and distilled to give 3-ethoxy-2-fluoroacryloyl chloride (14, R9 =ethyl, bp 102°-107° C./14 mmHg, 6.55 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[CH:21]1([CH2:24][NH2:25])[CH2:23][CH2:22]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:25][CH2:24][CH:21]2[CH2:23][CH2:22]2)=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: NCC1CC1
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCCN(CC(=O)NCC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and 1-cyclopropylmethane amine: 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.8 Hz, 1H), 6.93 (d, J=2.6 Hz, 1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 6.00 (bs, 1H), 3.99 (s, 2H), 3.43 (t, J=7.7 Hz, 2H), 3.12 (t, J=6.8 Hz, 2H), 1.70 (m, 2H), 0.99 (t, J=7.5 Hz, 3H), 0.87 (m, 1H), 0.44 (m, 2H), 0.13 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][O:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:26](=[O:34])[C:27]2[C:32]([CH3:33])=[N:31][O:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: CCC(c1nc2onc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(c1nc2onc(C)c2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
A solution of the compound from Example 1 Step 6 (60 mg, 0.10 mmol) in CH2Cl2 (2.5 mL) at room temperature was treated with Et3SiH (150 mL) followed by TFA (1.0 mL). The reaction mixture was stirred for 0.5 h then concentrated under vacuum to the desired product as a colorless film (32 mg, 65%); 1H NMR (DMSO-d6) δ 7.62 (s, 1H), 7.25 (m, 7H), 7.22 (s, 1H), 5.77 (d, J=16.5 Hz, 1H), 5.39 (s, 1H), 4.90 (d, J=15.9 Hz, 1H), 3.40 (t, J=7.0 Hz, 2H), 2.92 (s, 3H), 2.54 (s, 3H), 2.09 (m, 1H), 1.92 (m, 1H), 1.91 (m, 1H), 1.89 (t, J=7.0 Hz, 3H), 0.68 (m, 1H); LC/MS (ESI): 474 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][CH2:35][C:36]([N:38]([CH3:46])[C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][CH2:35][C:36]([N:38]([C:39]2[CH:44]=[CH:43][C:42]([NH:45]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:41][CH:40]=2)[CH3:46])=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C(=O)CCN1CCCCC1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CCN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-(piperidin-1-yl)-ethyl)-carbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=5:1) C32H34N4O4
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[O:21][CH:22]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)=[CH:28][CH:27]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Clc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Yield: 76 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(4-chlorophenyl) oxazole to give 2-(4-chlorophenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 76%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 116-117° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1>CC(O)=O>[Br:1][C:5]1[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1ccc(C(=O)O)s1
Solvent: CC(=O)O
Product: Cc1sc(C(=O)O)cc1Br
Reaction time: 5 h

Procedure:
A solution of bromine (725 uL, 14.1 mmol) in AcOH (2.8 mL) was added dropwise to 5-methyl-2-thiophenecarboxylic acid (2 g, 14.1 mmol) and FeCl3 (456 mg, 2.81 mmol) in AcOH (28 mL) at 25° C. After 5 h, the solution was poured onto ice and the precipitate was filtered and washed with water affording the title compound (3 g, quant.) as a yellow powder: LCMS (ES) m/z 222 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].[C:13](Cl)(=[O:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([O:12][CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: Cc1c(CO)cccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Yield: 85.8 %

Procedure:
To 600 mL of toluene in a Morton reaction flask was added 100 g (0.598 mol) of 2-methyl-3-nitrophenylmethanol with stirring. The solution was heated to reflux, and 100 mL of toluene was removed by distillation into a Dean Stark trap. The solution was cooled, and 48.3 mL of pyridine was added. After further cooling with an ice-water bath, 51.6 g (0.658 mol) of acetyl chloride was added dropwise. Upon complete addition, the reaction mixture was allowed to warm to ambient temperature, and was stirred for 16 hours. The reaction mixture was heated under reflux for 3.5 hours, cooled to ambient temperature, then poured over 1 L of ice. When the ice had melted, the organic layer was separated, and the aqueous layer washed with three portions of 300 mL each of toluene. The toluene wash was combined with the organic layer, and the whole was washed with two portions of 250 mL each of aqueous 2 N hydrochloric acid, 250 mL of saturated aqueous solution of sodium chloride, two portions of 250 mL each of an aqueous 2 N solution of sodium hydroxide, and finally, 250 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to distillation using a Kugelrohr distilling system to give 107.3 g of 2-methyl-3-nitrophenylmethyl acetate, b.p. 120° C./0.25 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]=[C:8]([NH:10][CH:11]=[C:12]([C:18]([O:20]CC)=[O:19])[C:13](OCC)=[O:14])[S:9][C:5]=2[CH:4]=1.[OH-:25].[Na+].O>C(O)C>[SH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:24]=[CH:23][C:6]=1[N:7]1[C:13](=[O:14])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][NH:10][C:8]1=[O:25]
Reactant: [OH-]
Reactant: CCOC(=O)C(=CNc1nc2ccc(OC)cc2s1)C(=O)OCC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2c(=O)[nH]cc(C(=O)O)c2=O)c(S)c1

Procedure:
25 g. Diethyl N-(6-methoxybenzthiazol-2-yl)-aminomethylenemalonate are introduced into a solution of 36 g. sodium hydroxide, 360 ml. water and 120 ml. ethanol which has been heated to 70° C. and the reaction mixture is heated under reflux for 30 minutes. A part of the ethanol is then removed in vacuo, filtered and, after cooling, the filtrate is acidified with 2 N hydrochloric acid. 1-(2-Mercapto-4-methoxyphenyl)-5-carboxypyrimidine-2,6-dione is obtained in a yield of 14.7 g. (70% of theory). According to the melting point and the IR, UV and NMR spectra, the product is identical with the compound prepared according to Variant I.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4]1=[O:13])[CH3:2].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Sn](Cl)(Cl)(Cl)Cl.ClC1C=CC=CC=1>CCOC(C)=O>[C:14]([C:7]1[C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4](=[O:13])[N:3]([CH2:1][CH3:2])[C:8]=1[CH3:9])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCn1c(C)cc(=O)n(CC)c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CCn1c(C)c(C(=O)c2ccccc2)c(=O)n(CC)c1=O
Temperature: 25 °C

Procedure:
1,3-Diethyl-6-methylpyrimidine-2,4(1H,3H)-dione (step 1)(680 mg, 3.73 mmol), benzoyl chloride (1.299 mL, 11.20 mmol) and tin(IV) chloride (1.314 mL, 11.20 mmol) were combined in chlorobenzene (30 mL, 295 mmol) and the mixture heated at reflux for 16 h. The reaction mixture was cooled to RT and diluted with EtOAc. The mixture was washed with 2M NaOH(aq) until basic. The organic phase was washed with brine, dried over sodium sulphate and evaporated under vacuum. The residue was dissolved in DCM and evaporated onto silica. The silica was deposited onto a 10 g silica cartridge and the system eluted with 10% EtOAc/hexane, 20% EtOAc/hexane, 40% EtOAc/hexane and 50% EtOAc/hexane. Product elutes at 40% EtOAc/hexane. Fractions were concentrated under vacuum to yield the title compound as an off white solid;
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][CH:28]=2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:27][CH:28]=3)=[CH:35][CH:36]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a mixture of ethyl 3-[3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 4-(4-chloromethylphenoxymethyl)-2-phenyloxazole (450 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration, and ethyl 3-[3-ethoxy-1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (616 mg, yield: 86%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 80–81° C.
Reaction SMILES: CC(=CC)C.Cl[O-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[O:29])[S:20][CH:21]=2)=[CH:13][CH:12]=1.P([O-])(O)(O)=[O:31].[K+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:31])=[O:29])[S:20][CH:21]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2csc(CCCCCCC=O)n2)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(-c2csc(CCCCCCC(=O)O)n2)cc1
Reaction time: 0.67 h
Yield: 92.4 %

Procedure:
Add 2-methyl-2-butene (7.0 mL) and sodium hypochlorite (2.51 g, 27.75 mmol) to a solution of 7-[4-(4-methoxyphenyl)thiazol-2-yl]heptanal (4.02 g, 13.25 mmol) and potassium dihydrogen phosphate (3.10 g, 22.78 mmol) in tert-butanol (60 mL) and water (12 mL) at room temperature. Stir the mixture for 40 minutes, dilute with ethyl acetate (500 mL) and wash with brine (3×200 mL). Dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1:19), and triturate the residue with hexanes/methylene chloride to afford 7-[4-(4-methoxyphenyl)thiazol-2-yl]heptanoic acid (3.91 g, 88%): APCI MS m/z 320 [C17H21NO3S+H]+.
Reaction SMILES: [CH3:1][C@H:2]([C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=C)[C@H:3]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C[N+]1([O-])CC[O:30]CC1.O>C1COCC1.CCOC(C)=O.O=[Os](=O)(=O)=O>[CH3:1][C@@H:2]([C:18](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:3]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C=C(c1ccccc1)[C@@H](C)[C@H](NC(=O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)c1ccccc1)[C@H](NC(=O)C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To olefin 16 (903.4 mg, 2.53 mmol) in THF (25 mL) under N2 was added NMO (60% wt solution in H2O, 0.90 mL, 5.06 mmol) and OsO4 (4% wt solution in H2O, 1.50 mL, 0.25 mmol). The solution was stirred at ambient temperature for 16 h, and NaIO4 (2.16 g, 10.12 mmol) was then added, followed by H2O (2.7 mL). Stirring was continued for 4 h, and the reaction mixture was then diluted with EtOAc (200 mL) and washed with 10% Na2S2O3 (4×50 mL). The combined washings were extracted with EtOAc (50 mL). The organic solutions were combined and washed with 5 M NaCl (20 mL) and dried, and the solvent was evaporated. The residue was separated by chromatography (silica gel, 30 g; 9:1 hexane-EtOAc) and led to 0.632 g (70%) of 18 as a colorless solid: mp 127-128° C.; Rf0.19 (95:5 hexane-EtOAc); [α]23D−39.0 (c 1.05, CH3OH); 1H NMR δ 7.92 (2H, dd, J=7.5 and 1.3 Hz), 7.60 (1H, tt, J=7.5 and 1.3 Hz), 7.49 (2H, t, J=7.6 Hz), 7.03 (1H, br d, J=6.7 Hz), 4.72 (1H, dd, J=7.4 and 4.8 Hz), 4.13 (1H, m), 1.49 (9H, s), 1.36 (3H, d, J=7.2 Hz); 13C NMR δ 200.0, 168.3, 156.9 (q), 135.5, 133.6, 128.8, 128.4, 83.8, 55.0, 42.9, 27.8, 14.2; MS APCI+ m/z 360.1417 [M+H]+ (calcd for C17H21F3NO4, 360.1423); anal. C, 56.39%, H, 5.60%, N, 3.96%, calcd for C17H20F3NO4, C, 56.82%, H, 5.61%, N, 3.90%.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:7])[C:5]#[CH:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[CH:18])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:3][CH:4]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]#[CH:18])[N:12]=[CH:11][N:10]=1)[C:5]#[CH:6]
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: C#CC(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1cc(OC(C)C#C)ncn1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.1 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.12 g of 3-butyn-2-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 0.6 ml of a tetrahydrofuran solution containing 0.4 g of 4-chloro-6-(2-propynyloxy)pyrimidine was slowly added dropwise. The mixture was further stirred at 0° C. for 4.5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(1-methyl-2-propynyloxy)-6-(2-propynyloxy)pyrimidine (the present compound (11)).