Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1C=CC=CC=1.Cl.[O:9]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([Cl:24])[C:17]=2[Cl:25])=[O:15])=[CH:10]1>N1C=CC=CC=1>[O:9]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:24])[C:17]=2[Cl:25])=[O:15])=[CH:10]1
Reactant: COc1ccc(C(=O)c2ccoc2)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccoc1)c1ccc(O)c(Cl)c1Cl
Temperature: 210 °C
Reaction time: 1 h

Procedure:
A molten bath of pyridine HCl is prepared by adding 16 ml of concentrated HCl (0.186 mole) to 14.2 g of pyridine and heating the mixture to 210° C. under nitrogen and allowing the H2O to distill out. The anisole (5.0 g) is added in portions and heating is continued for one hour and the solution poured over ice and extracted with ethyl acetate. Drying and evaporation gives 4-(3-furoyl)-2,3-dichlorophenol, mp 138°-142° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([CH2:21][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]2)=[CH:27][CH:26]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ccn(Cc3ccc(-c4ccccc4)cc3)c12
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To methyl 1H-indole-7-carboxylate (1.5 g) was added DMF (15 mL), and potassium tert-butoxide (1.5 g) was added thereto under ice-cooling, followed by stirring for 10 minutes. 4-(Bromomethyl)biphenyl (2.8 g) was added thereto, followed by stirring at room temperature for 19 hours. The reaction mixture was again ice-cooled, and a 10% aqueous citric acid solution (20 mL) was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=97/3-95/5) to obtain methyl 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylate (2.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>C(#N)C>[CH2:21]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:20][CH:19]=[CH2:18]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCOc1ccc([N+](=O)[O-])cc1

Procedure:
To an acetonitrile (20 mL) solution of 4-nitrophenol (0.423 g; 3.04 mmol) and potassium carbonate (1.11 g; 8.02 mmol), 4-bromo-1-butene (0.827 g; 6.13 mmol) was added, and the mixture was refluxed and then reacted for 17 hours. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by flash column chromatography using methylene chloride, and then the effluent was concentrated to obtain 4-(3-butenyloxy)nitrobenzene (1) (0.571 g, 97% of yield, a light yellow oil) represented by the following formula.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:21](=[O:23])[CH3:22])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc(C2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 4-(4-bromophenyl)piperidine (400 mg, 1.70 mmol) in dichloromethane (20 mL) was added triethylamine (340 mg, 3.40 mmol) and acetic anhydride (500 mg, 5.10 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue. The material was partitioned between water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was washed two additional times with ethyl acetate (30 mL). The combined organics layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (260 mg, 60% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.27 (d, 2H), 6.91 (d, 2H), 4.63 (d, 1H), 3.77 (d, 1H), 3.00 (t, 1H), 2.57-2.42 (t, 2H), 1.97 (s, 3H), 1.75-1.68 (m, 2H), 1.47-1.40 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:36])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:29])[CH:22]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:36])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:29])[CH:22]=1
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Yield: 87 %

Procedure:
In a manner similar to that of Example (18e), by reaction of 400 mg (26% by mass) of 10% palladium-on-charcoal, 1.54 g (3.16 mmol, 1 eq) of methyl (E)-3-[2-benzyloxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]acrylate in 20 ml of methanol and 5 mL of ethyl acetate, and after crystallization from pentane, 1.1 g of methyl 3-[2-hydroxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate are obtained in solid form. Yield=87%
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:35]1([NH2:45])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1>CN(C=O)C.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:45][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1nccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Nc2nccc3ccccc23)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-amino-3-nitrobenzoic acid (546 mg), EDCI (576 mg) and HOBt (405 mg) in DMF (7 mL) was added isoquinolin-1-ylamine (432 mg) and the mixture was stirred at ambient temperature for 18 h. Water was added and the orange precipitate was filtered to give 4-amino-N-isoquinolin-1-yl-3-nitrobenzamide.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16](OC)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[C:9]1[CH:19]=[CH:20][C:21]1[O:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[N+:25]=1[CH2:26][CH3:27])[CH3:7].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:43]([N+:45]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[S:47][C:46]=1[CH3:54])[CH3:44].C(N(CC)CC)C>C(#N)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16]([CH:54]=[C:46]2[N:45]([CH2:43][CH3:44])[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[S:47]2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[C:9]1[CH:19]=[CH:20][C:21]1[O:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[N+:25]=1[CH2:26][CH3:27])[CH3:7]
Reactant: CC[n+]1c(C)sc2ccccc21
Reactant: CCn1c(C=Cc2oc3ccccc3[n+]2CC)c2ccccc2c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1C(=Cc2c3ccccc3c(C=Cc3oc4ccccc4[n+]3CC)n2CC)Sc2ccccc21

Procedure:
2-[2-(2-Ethyl-3-methoxyisoindol-1-yl)vinyl]-3-ethyl-benzoxazolium perchlorate (1.0 g) and 3-ethyl-2-methylbenzothiazolium p-toluenesulfonate (0.9 g) were dissolved in acetonitrile. Triethylamine was added and the reaction mixture stirred until the absorption at 520 nm disappeared. The reaction mixture was evaporated to dryness and chromatographed on silica gel. After recrystallization of the product from methanol, the melting point was 180° C. CH3CN λ max 625 nm.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=C[CH:8]=1.C[CH:14]([S:49][C:50]1[NH:54][N:53]=[N:52][N:51]=1)[C:15]1[CH2:16][S:17][C@@H:18]2[C@H:38]([NH:39]C(=O)CC3SC=CC=3)[C:37](=[O:48])[N:19]2[C:20]=1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].CO>C(Cl)Cl>[NH2:39][C@@H:38]1[C:37](=[O:48])[N:19]2[C:20]([C:21]([O:23][CH:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:15]([CH2:14][S:49][C:50]3[N:54]([CH3:8])[N:53]=[N:52][N:51]=3)[CH2:16][S:17][C@H:18]12
Reactant: c1ccncc1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Yield: 81.5 %

Procedure:
A suspension of phosphorus pentachloride (416 mg) in dry methylene dichloride (10 ml.) was stirred at 23° and a solution of pyridine (0.16 ml.) added. The warm suspension was stirred for 10 minutes, and cooled to 0°, and treated, over 10 minutes, with a solution of diphenylmethyl 3-(1-methyltetrazol-5-ylthiomethyl)-7β-(2-thienylacetamido)-ceph-3-em-4-carboxylate (619 mg) in methylene dichloride (15 ml.). After stirring for a further 45 minutes, during which time the temperature was allowed to rise to 23°, the solution was added, over 5 minutes, to a stirred and cooled (0°) mixture of methanol (5 ml.) and methylene dichloride (15 ml.). The resulting solution was stirred for a further 10 minutes, and washed with N-hydrochloric acid (20 ml.), and stirred for 30 minutes with saturated sodium bicarbonate solution (50 ml.). The organic phase was separated, and washed with saturated aqueous sodium bicarbonate (25 ml.), and treated with some charcoal. The mixture was filtered through a pad of kieselguhr, and the filtrate evaporated to a gum (640 mg.), which was triturated with ether (20 ml) to give the amine as an off-white solid (403 mg, 81.5%), λmax. (CHCl3) 268.5 nm (ε 7,700), νmax. (CHBr3) 3416 and 3350 (NH2), 1780 (β-lactam), and 1720 cm.-1 (CO2R), τ (CDCl3) values include 5.00 and 5.15 (C-6H and C-7 H, two doublets, J 5 Hz.), 6.14 (CH3 -), and 7.59 (NH2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:2]=1.Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:11][CH2:10]2)[CH:2]=1
Reactant: c1cncc(C(OC2CCNCC2)c2ccsc2)c1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2cccnc2)c2ccsc2)CC1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(3-pyridyl)-3-thienylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(3-pyridyl)-3-thienylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:6]=[CH:5][N:4]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)[CH:6]=[CH:5][N:4]=1
Reactant: C1COCCN1
Reactant: CSc1nccc(-c2cc(OS(=O)(=O)C(F)(F)F)nnc2-c2cccc(C(F)(F)F)c2)n1
Product: CSc1nccc(-c2cc(N3CCOCC3)nnc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 80 °C

Procedure:
Compound 74 (180 mg, 0.363 mmol) and morpholine (˜1 mL) were combined under Argon and heated to 80° C. for 2 h. Purification by flash column chromatography (hexane ethyl acetate 50:50) gave Compound 75 as an oil: 104 mg (0.240 mmol, 66%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][C:11]#[N:12].[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH:21]=O)=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:11]([NH2:12])=[N:20][C:18]2[N:19]=[C:14]([NH2:13])[N:15]=[CH:16][C:17]=2[CH:21]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1c(Cl)ccc(Cl)c1Cl
Product: Nc1ncc2cc(-c3c(Cl)ccc(Cl)c3Cl)c(N)nc2n1

Procedure:
The title compound was prepared according to Example 1, starting from 1.0 g of (2,3,6-trichloro)-phenyl-acetonitrile and 0.6 g of 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 320-322° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:10]1[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:22]#[N:23])([CH3:9])[CH3:8].[CH2:28](I)[CH2:29][CH2:30][CH3:31]>CN(C=O)C>[CH2:28]([N:12]1[C:11]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:22]#[N:23])=[C:10]([CH:7]([CH3:9])[CH3:8])[C:15](=[O:16])[NH:14][C:13]1=[O:17])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCI
Reactant: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(Oc2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
Potassium carbonate (9.3 mg, 0.0067 mmol, 1.0 eq.) was added to 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzonitrile (103) (23 mg, 0.0.08 mmol, 1.2 eq.) in 1.0 mL DMF. The reaction mixture was stirred at room temperature for 10 minutes, and n-butyl iodide (7.6 μL, 0.0.067 mmol) was added. The reaction mixture was filtered and purified by reverse phase HPLC (MeCN/water) to give a white powder (3.8 mg, 17%). LC-MS shows 342.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 8.37 (br, 1H), 7.28 (s, 1H), 7.08 (s, 1H), 6.98 (s, 1H), 3.42 (t, 2H), 2.71 (m, 1H), 2.42 (s, 3H), 1.60 (m, 2H), 1.28 (m, 2H), 1.17 (d, 6H), 0.88 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:33](=[O:34])[CH2:32][O:31][C:30]5[CH:36]=[CH:37][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCc2nc3c(N4CCNCC4)ncnc3s2)cc1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3ncnc4sc(CCc5ccc(F)cc5)nc34)CC2)cc1
Yield: 39 %

Procedure:
This compound was prepared from 2-(4-fluorophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidine using 4-methoxyphenoxyacetic acid in a yield of 39%, according to the procedure for the synthesis of example 50.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH:23]1([CH2:26][NH:27][CH3:28])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH:23]1([CH2:26][N:27]([CH3:28])[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH2:25][CH2:24]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CNCC1CC1
Solvent: Cc1ccccc1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)CC1CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A solution of methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (100 mg, 0.31 mmol) and cyclopropylmethyl(methyl)amine (260 mg, 3.1 mmol) in toluene (5 mL) was heated at 110° C. in a sealed tube for 24 hrs. The solution was concentrated to an oily residue which was dissolved in MeOH (5 mL). To this solution was added 10 N NaOH solution (1 g). The mixture was stirred and refluxed for 1 hr and then cooled to RT. The pH was carefully adjusted to 6.5 and the resulting mixture was concentrated to a residue. The residue was diluted with MeOH (10 mL) and filtered. The solids were washed with additional MeOH (10 mL). The filtrate was concentrated to an oily residue and chromatographed on silica gel (90% MeOH, 10% pH 7 buffer [potassium phosphate based] to give a foam. The foam was then chromatographed on reverse phase C18 silica gel [40-63 microns (mesh 230-400); 60 Å; 500 m2/g; pore volume 0.8 ml/g] using 80% MeOH/10% DI H2O to give the title compound (32 mg) as a beige solid: 1HNMR (400 MHz, CD3OD): δ 0.29 (2H, s), 0.73 (2H, s), 1.05 (1H, m), 2.77 (5H, m), 3.51 (2H, t, J=4.2 Hz), 4.45 (2H, t, J=4.2 Hz), 7.79 (1H, s), 7.92 (2H, m), 8.43 (1H, s), 8.64 (1H, s). [M+H] Calc'd for C16H20N4O2, 301. Found, 301.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[S:7])([CH3:3])[CH3:2].[OH:13][CH:14]1[CH2:17][O:16][CH2:15]1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:13][CH:14]1[CH2:17][O:16][CH2:15]1)=[S:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1C(=S)Cl
Reactant: OC1COC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)c1ccccc1C(=S)OC1COC1
Reaction time: 3 h
Yield: 89 %

Procedure:
##STR16## A mixture of 12.9 g of 2-isopropylthiobenzoyl chloride and 20 ml of absolute toluene is added dropwise to a mixture of 4.44 g of 3-hydroxyoxetane, 6.64 g of pyridine and 60 ml of absolute toluene at a temperature of 15° to 20° C. The suspension formed is stirred at a temperature of 20°-25° C. for 2 hours and at a temperature of 40°-45° C. for a further 3 hours. Adding water to the reaction mixture, washing the organic phase with water and drying and evaporating it gives 12.6 g of oxetan-3-yl 2-isopropylthiobenzoate as a pale yellow oil.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1>O1CCCC1>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][CH:3]=[O:2])[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)#[N:16]
Reactant: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1

Procedure:
A solution of 10.1 g of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile in 200 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 1 hour while stirring. The reaction mixture was subsequently partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated, there being obtained 9.8 g of 2-[trans-4-(p-cyanophenyl)cyclohexyl]acetaldehyde as a light yellowish, crystalline residue.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:12]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: C1CNC1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To a solution of 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg, 1.98 mmol) in tetrahydrofuran (10 mL) was added azetidine (141 mg, 0.17 mL, 2.48 mmol) and diisopropylethyl amine (307 mg, 0.42 mL, 2.38 mmol) drop wise and the resulting mixture was stirred at room temperature for 24 h. The solution was concentrated and the residue dissolved in dichloromethane (50 mL), washed with water (50 mL). The aqueous layer was extracted with methylene chloride (2×50 mL) and the organic phases combined and dried over magnesium sulfate. The resulting mixture was filtered and evaporated and the residue purified by flash chromatography (40 g, 1% to 5% methanol in dichloromethane) to give 5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole (349 mg, 90%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) as the catalyst and using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]1([S:12][C:13]2[CH:14]=[C:15]([CH:45]=[CH:46][CH:47]=2)[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][C@@H:30]([C:32]3[CH:43]=[CH:42][C:35]4[O:36][C:37]([CH3:41])([CH3:40])[O:38][CH2:39][C:34]=4[CH:33]=3)[O:29][C:28]2=[O:44])[CH2:11][CH2:10][CH2:9][CH2:8]1>C(O)C.O>[CH:7]1([S:12]([C:13]2[CH:14]=[C:15]([CH:45]=[CH:46][CH:47]=2)[CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][C@@H:30]([C:32]3[CH:43]=[CH:42][C:35]4[O:36][C:37]([CH3:41])([CH3:40])[O:38][CH2:39][C:34]=4[CH:33]=3)[O:29][C:28]2=[O:44])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(SC5CCCC5)c4)C(=O)O3)ccc2O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(S(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Sodium periodate (333 mg) was added to a solution of (5R)-3-[6-(2-{[3-(cyclopentylthio)benzyl]oxy}ethoxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (230 mg) in ethanol (12 ml) and water (4 ml). The mixture was stirred at room temperature under nitrogen for 3 h. and the ethanol evaporated in vacuo. The aqueous phase was diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) filtered, and evaporated in vacuo. The residue was purified on a 10 g silica SPE cartridge, eluting with a stepped gradient of 10% to 100% ethyl acetate-cyclohexane, to give the title compound (201 mg). LCMS RT=3.54 min.