Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Cl-].[C:3](=[Zr+2:6]([CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:21]1)[CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8]1)([CH3:5])[CH3:4]>O=[Pt]=O.C(Cl)Cl>[Cl-:1].[Cl-:1].[C:3](=[Zr+2:6]([CH:20]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[C:22]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:21]1)[CH:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8]1)([CH3:4])[CH3:5]
Reactant: CC(C)=[Zr+2](C1C=C(C(C)(C)C)c2ccccc21)C1C=C(C(C)(C)C)c2ccccc21
Agent: O=[Pt]=O
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)=[Zr+2](C1C=C(C(C)(C)C)C2=C1CCCC2)C1C=C(C(C)(C)C)C2=C1CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 167.2 %

Procedure:
In a 100 ml glass-autoclave were introduced 0.66 g of rac-isopropylidene-bis(3-t-butyl-indenyl)zirconiumdichloride, 40 mg of PtO2 and 50 ml of CH2Cl2. 5 atm of H2 were pressurized in and the mixture was stirred for 4 hours at room temperature. The mixture was filtered, the filtrate brought to dryness and 0,56 g of a yellow solid was isolated, which was further purified by washing with hexane and Et2O. 0,22 g of a yellow powder were thus obtained. IH-NMR (CDCl3): 5.3(s), 2.6-2.9(m), 2.2-2.4(m), 1.85(s), 1.4-1.8(m), 1.3(s).
Reaction SMILES: [Cl-].[CH2:2]1[CH2:12][CH2:11][N:10]2[C:5](=N[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1.[C:13]1(C)[C:14](C)=CC=C[CH:18]=1>>[CH2:11]([N:10]1[CH2:9][CH2:8][CH2:7][CH2:4][CH2:5]1)[C:12]1[CH:2]=[CH:3][CH:14]=[CH:13][CH:18]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccccc1C
Agent: [Cl-]
Product: c1ccc(CN2CCCCC2)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
Chloride 12 (23.0 g, 1.0 equiv) was combined with DBU (20.4 g, 2 equiv) in 400 mL xylene and stirred at 100° C. until TLC examination indicated complete reaction (ca. 5 h). The reaction was concentrated to dryness in vacuo. The residue was dissolved in methylene chloride and extracted with water (1×). The organic solvent was removed in vacuo and the residue was flash chromatographed in 10% ethyl acetate/methylene chloride to afford 11.8 g (60%) of 11 as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=4)[C:11]=3[CH:23]=2)=[N:4][N:3]=1.S(Cl)([Cl:26])=O>ClCCCl>[Cl:26][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[C:11]3[CH:23]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(CO)cc4)c3c2)o1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1nnc(-c2ccc3occ(-c4ccc(CCl)cc4)c3c2)o1

Procedure:
To a solution of [4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenyl]methanol (204 mg, 0.66 mmol) in 1,2-dichloroethane (5 mL) was added thionyl chloride (0.240 mL, 3.33 mmol), and the resulting mixture was heated under reflux for 1 hr. After cooling, the reaction mixture was concentrated under reduced pressure to give crude 2-[3-[4-(chloromethyl)phenyl]-1-benzofuran-5-yl]-5-methyl-1,3,4-oxadiazole as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[S:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[N:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[S:11][CH3:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCC(=S)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC(CNC(=O)OC(C)(C)C)=N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.1 g (2.43 mmol) of 4-benzyl 1-tert-butyl N-[(1-tert-butoxyformamido)thioacetyl]-L-aspartate, 1.95 ml of methyl iodide and 0.92 g of potassium carbonate in 50 ml of acetone is stirred at room temperature overnight. Thereafter, the solvent is distilled off under reduced pressure and the residue is taken up in ether. The organic phase is washed with water, dried over sodium sulphate and evaporated. 4-Benzyl 1-tert-butyl N-[2-(1-tert-butoxyformamido)-1-(methylthio)ethylidene]-L-aspartate is obtained as a mixture of the E- and Z-isomers; MS: 467 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([S:6][CH:7]1[N:10]([CH2:11][C:12]([O:14]C)=[O:13])[C:9](=[O:16])[CH2:8]1)[CH:4]=[CH2:5].Cl>C(O)C.O>[CH2:3]([S:6][CH:7]1[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9](=[O:16])[CH2:8]1)[CH:4]=[CH2:5]
Reactant: C=CCSC1CC(=O)N1CC(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCSC1CC(=O)N1CC(=O)O
Temperature: 25 °C

Procedure:
2.34 g of potassium hydroxide dissolved in a mixture of 285 ml of ethanol and 15 ml of water were added to 6.0 g of methyl 2-(4-allylthioazetidin-2-on-1-yl)acetate with stirring at room temperature. The solution was poured into 720 ml 1M hydrochloric acid, extracted into dichloromethane (2.650 ml), the organic layer extracted with saturated sodium bicarbonate solution and the aqueous phase acidified to pH1 with 5M hydrochloric acid. This solution was extracted into dichloromethane (5×650 ml), dried with MgSO4 and evaporated to leave a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][NH:36][CH3:37])[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][N:36]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH3:37])[CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CNCCc1cccc(OCc2ccccc2)c1
Product: CN(CCc1cccc(OCc2ccccc2)c1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and 1-[3-(benzyloxy)phenyl]-2-(methylamino)ethane was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared as a pale yellow crystal having a melting point of 78 to 78.5° C.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].CCN(C(C)C)C(C)C.Br[CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][N:25]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:26][CH2:27][C:21]=4[CH:20]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1C#N
Reactant: CCOC(=O)CCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
2-[(1-Methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 18) (200 mg, 0.534 mmol), DIPEA (0.327 ml, 1.869 mmol) and ethyl 4-bromobutanoate (0.153 ml, 1.068 mmol) were stirred at room temperature in DMF (10 ml) for 5 hours, the reaction mixture then heated to 60° C. for 5 h, the reaction mixture was allowed to stand overnight at room temperature, further ethyl 4-bromobutanoate (0.076 ml, 0.534 mmol) was added and the reaction mixture heated at 60° C. for 6 hours. The reaction mixture was partitioned between ethylacetate (˜30 ml) and water (˜30 ml) and the aq. layer extracted once more with ethylacetate (˜40 ml). The combined organics were concentrated in vacuo to yield the title compound (218 mg, 0.402 mmol) as an orange oil. MS (ES): C28H32N4O4 requires 488; found 489 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:8]1[C:7]([CH3:14])([CH3:13])[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:16]=[CH:17][CH3:18]
Reactant: COc1ccc2c(c1)C(=O)CC2(C)C
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1C(=O)c2cc(OC)ccc2C1(C)C
Yield: 38 %

Procedure:
A solution of 12.1 g of 6-methoxy-3.3-dimethyl-1-indanone, 11.1 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 67 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). In addition to 4.64 g of educt, there were obtained 5.86 g (38%) of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-dimethyl-1-indanone as a yellow oil.
Reaction SMILES: [C:1]([C:4]#[CH:5])([CH3:3])=[CH2:2].C([Li])CCC.[CH:11]([CH:13]=[CH2:14])=[O:12].[NH4+].[Cl-]>CCCCCC.O1CCCC1>[CH3:2][C:1](=[CH2:3])[C:4]#[C:5][CH:11]([OH:12])[CH:13]=[CH2:14]
Reactant: C#CC(=C)C
Reactant: C=CC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC(O)C#CC(=C)C
Temperature: 25 °C

Procedure:
10 g Isopropenylacetylene are taken up in abs. tetrahydrofuran and under an inert gas 94.5 ml of 1.6M solution of n-butyllithium in hexane added dropwise at -20°. The mixture is then cooled to -78° and 8.5 g of acrolein added dropwise. The reaction mixture is warmed to room temperature, poured into saturated aqueous NH4Cl and repeatedly extracted with ether. The organic phase is washed, dried and concentrated in vacuum. An oil is obtained.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([I:9])=[C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:25]=[N:26][N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)=[CH:14][CH:13]=2)[CH:6]=[C:5]([CH3:48])[N:4]=1>ClCCl.CO>[ClH:1].[CH3:2][C:3]1[C:8]([I:9])=[C:7]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:25][N:26]=[N:27][N:28]=3)=[CH:16][CH:17]=2)[CH:6]=[C:5]([CH3:48])[N:4]=1
Reactant: Cc1cc(NCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(I)c(C)n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(I)c(C)n1
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (0.5 ml) was added to a suspension of 2,6-dimethyl-3-iodo-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methylamino]pyridine (A) (215 mg) in dichloromethane/methanol (4 ml) (1:3 v/v) and the mixture stirred for 30 minutes. Volatile material was removed by evaporation and the residue purified by recrystallisation from methanol to give 2,6-dimethyl-3-iodo-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methylamino]pyridine hydrochloride as a white solid, m.p. 238°-240° C. (decomposition); NMR (d6 -DMSO): 2.4(s,3H), 2.7(s,3H), 4.7(d,2H), 6.6(s,1H), 7.1(d,2H), 7.3(d,2H), 7.4-7.7(m,4H), 8.0(t,1H); mass spectrum (positive fast atom bombardment (+ve FAB), DMSO/nitrobenzyl alcohol): 483(M+H)+ ; microanalysis, found: C,48.1; H,4.1; N,16.1%; C21H19N6I.HCl requires: C,48.6; H,3.9; N,16.2%.
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[OH2:15]>O1CCOCC1>[C:1]([C:6]1[S:10][C:9](/[CH:11]=[C:12](\[CH3:13])/[CH:14]=[O:15])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O
Reactant: CCOC(=O)c1ccc(C=C(C)C)s1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(/C=C(\C)C=O)s1
Yield: 176.3 %

Procedure:
A mixture of 3.8 g (17.2 mmol) of 1-(5-carbethoxythien-2-yl)-2-methyl-1-propene and 5.0 g (45 mmol) of SeO2 in 60 mL of dioxane and 0.8 mL (44 mmol) of H2O was degassed three times under argon and heated under reflux for 45 min. Cooling, filtration over Celite, and concentration gave 6.8 g of a light-brown solid, which was diluted with 50 mL of Et2O and filtered. The filtrate was concentrated and passed over a column of 150 g of silica gel (15% EtOAc/hexane) to give 2.35 g (60% yield) of the aldehyde as a pale yellow solid, a portion of which was recrystallized from EtOAc/hexane to give white needles, mp 98° C: IR (mull) 1720, 1680, 1620, 1380, 1290, 1250, 1180, 1160, 1100, 1020, 890, 850, 815, 750 cm-1 ; 1H NMR (CDCl3) δ1.42 (t, J=7 Hz, 3, CH2CH3), 2.17 (s, 3, C=CCH3), 4.47 (q, J=7 Hz, 2, CH2CH3), 7.40 (d, J=4 Hz, 1, 3' C=CH), 7.43 (s, 1, C=CH), 7.83 (d, J=4 Hz, 1, 4' C=CH), 9.63 (s, 1, CHO); MS calcd for C11H12O3S 224.0507, found 224.0519.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]([NH:36][CH3:37])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([N:36]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:37])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNC(C)(C)C
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)C(C)(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N-tert-butylmethylamine (55 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 519 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8].O.NN>CO.[Ni]>[Br:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CNc1cc(Br)ccc1N
Temperature: 80 °C

Procedure:
5-bromo-N-methyl-2-nitroaniline (1.5 g) was dissolved in methanol (60 mL) by heating to 80° C. Hydrazine hydrate was added (3.2 mL) followed by Raney Nickel (50% slurry in water, 6 drops) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was filtered through Celite® and concentrated under reduced pressure, providing 5-bromo-N1-methylbenzene-1,2-diamine as an amber oil. This product was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:10]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)SCCCS2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[OH2:25]>C(OCC)(=O)C>[OH:9][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:25]
Reactant: O
Reactant: OC(Cc1ccccc1)C1(c2ccccc2)SCCCS1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
To a solution of 2-phenyl-1-(2-phenyl-[1,3]-dithian-2-yl)-ethanol (23) (2.50 g, 7.9 mmol) in 100 mL of a 9:1 mixture of acetonitrile and water was added mercuric perchlorate hydrate (4.1 g, 10.3 mmol). The resulting mixture was stirred at room temperature for 5 minutes and thin layer chromatography indicated that the reaction was completed. The mixture was diluted with ethyl acetate, filtered through a pad of Celite and the filtrate was washed with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel, (20% ethyl acetate in hexanes) to afford 1.32 g (74%) of the title compound (25). 1H NMR (CDCl3, 400 MHz): δ 2.90 (dd, J=14.4, 7.0 Hz, 1H), 3.20 (dd, J=14.4, 4.0 Hz, 1H), 3.70 (d, J=6.8 Hz, 1H), 5.35 (m, 1H), 7.28-7.11 (m, 5H), 7.53 (m, 2H), 7.65 (m, 1H), 7.93 (d, J=7.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC(C)I
Reactant: O=c1nc(Cl)cc2n1CCN2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1CCn2c1cc(Cl)nc2=O
Yield: 53.5 %

Procedure:
A mixture of 7-chloro-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (700 mg, 4.08 mol), 2-iodopropane (1.04 g, 6.12 mmol) and Cs2CO3 (2.66 g, 8.16 mmol) in acetonitrile (15 mL) was refluxed for 3 h, filtered and concentrated to remove solvent to get crude product (700 mg) without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1.[Na+].[I-].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:21]([O:20][P:19]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1)([O:23][CH2:24][CH3:25])=[O:26])[CH3:22]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1cn2cc(CCl)ccc2n1
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)c1cn2cc(CP(=O)(OCC)OCC)ccc2n1
Yield: 42.6 %

Procedure:
By the method of Example 6, the product from Example 11 (2.66 g, 11.1 mmol) was treated with NaI (1.67 g, 11.1 mmol) and triethyl phosphite (2.03 g, 12.2 mmol). Workup produced 1.61 g (43%) of title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12](=[O:13])[CH:11]2[CH:6]([CH:7]3[O:14][CH:10]2[CH:9]=[CH:8]3)[C:5]1=[O:15].CCN(CC)CC.[Br:23][C:24]([CH3:29])([CH3:28])[C:25](Br)=[O:26]>C1COCC1>[O:13]=[C:12]1[N:4]([CH2:3][CH2:2][O:1][C:25](=[O:26])[C:24]([Br:23])([CH3:29])[CH3:28])[C:5](=[O:15])[CH:6]2[CH:11]1[CH:10]1[O:14][CH:7]2[CH:8]=[CH:9]1
Reactant: O=C1C2C3C=CC(O3)C2C(=O)N1CCO
Reactant: CC(C)(Br)C(=O)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)OCCN1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a 250 mL of round bottom flask were added 2 (2.0 g, 9.55 mmol) and Et3N (1.44 mL, 10.54 mmol) in 100 mL of THF. The mixture was cooled to 0° C., and a solution of 2-bromo isobutyryl bromide (2.34 g, 10.0 mmol) in 25 mL of THF was added dropwise (30 min) to the reaction mixture. The white suspension was stirred for 3 h at 0° C. and subsequently at ambient temperature for overnight. The ammonium salt was filtered off and the solvent was removed under reduced pressure to give a pale-yellow residue that was further purified by column chromatography over silica gel eluting with EtOAc/hexane (1:4) to give compound as a white solid. Yield: 2.5 g (91%). EIMS m/z 338.0 for [M+Na]+C14H16NO5BrNa calculated 380.02. 1H NMR (500 MHz, CDCl3, δ) 6.52 (s, 2H, CH═CH, bridge protons), 5.27 (s, 2H, —CHO, bridge-head protons), 4.33 (t, J=10.5 Hz, 2H, NCH2CH2OC═O), 3.77 (t, J=10.5 Hz, 2H, NCH2CH2OC═O), 2.87 (s, 2H, CH—CH, bridge protons), 1.90 (s, 6H, C(CH3)2—Br). 13C NMR (500 MHz, CDCl3, δ): 175.8, 171.3, 136.5, 80.8, 62.1, 55.6, 47.4, 37.5, 30.5.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl.C(O[CH:11]=[NH:12])C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]([NH2:25])[NH:23][N:24]=1.[C:26]([OH:29])(=[O:28])[CH3:27]>C(Cl)Cl>[C:26]([OH:29])(=[O:28])[CH3:27].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]([NH:25][CH:11]=[NH:12])[NH:23][N:24]=1
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Reactant: CCOC=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N=CNc1cc(-c2ccccc2Cl)n[nH]1

Procedure:
To a vigorously stirred solution of saturated aqueous Na2CO3 (50 mL) and methylene chloride (50 ml) was added solid ethylformimidate hydrochloride salt (8.98 g, 82 mol). After stirring for several minutes the aqueous layer was separated and extracted with additional methylene chloride (3×50 ml). The combined organic layers were dried (MgSO4) and filtered. To the stirred solution was added 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-9a; 5.27 g, 27 mmol) in methylene chloride (50 mL) and then glacial acetic acid (2.67 ml, 46.6 mmol), dropwise. A cloudy precipitate began to form as the acetic acid was added. After stirring overnight, the solids were collected by vacuum filtration, washed with methylene chloride, and then dried, in vacuo, to give intermediate I-3A-9b, contaminated with ˜25% of the corresponding dimer (MW=396; 2 pyrazoles+1 formamidine), as a solid (5.7 g, 75%): +APcI MS (M+1) 221.1; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.62-7.30 (m, 4H), 6.48 (s, 1H), 1.92 (s, 3H).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[O:20][C:19]=2[CH3:34])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:27][CH:28]=3)[O:20][C:19]=2[CH3:34])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:15])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccc(OC(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: Cc1oc(-c2ccc(OC(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 95.5 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(cyclohexyl{2-methyl-5-[4-(trifluoromethoxy)phenyl]-3-furyl}methoxy)benzoic acid (119 mg) as well as ethyl 3-(methylamino)propanoate (39 mg) to give the title compound (134 mg, 96%) as an amorphous compound.