Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[SH:15].C(N(CC)CC)C.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[S:15][CH2:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1oc(-c2ccccc2)cc(O)c1S
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CSc1c(O)cc(-c2ccccc2)oc1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxy-3-mercapto-6-phenyl-2-pyrone (0.175, 0.840 mmol, prepared as in R. F. Harris, J. E. Dunbar, U.S. Pat. No. 3,818,046) in CH2Cl2 (3.0 mL) under an N2 atmosphere was treated with triethylamine (0.12 mL, 0.84 mmol) followed by bromoacetophenone (0.167 g, 0.840 mmol). The mixture was allowed to stir for 30 min. at ambient temperature then the solvent removed in vacuo. The residue was then diluted with diethyl ether and extracted with saturated Na2CO3 (3×50 mL). The aquous layers were then combined, acidifed with conc. HCl, and extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried with Na2SO4, and the solvent removed in vacuo to give the title compound (0.066 g, m.p. 164 -166 ° C.) which was dried in vacuo. 1H NMR (300 MHz, CDCl3) δ9.900 (bs, 1 H), 7.970 (d, 2 H, J=7.1 Hz), 7.810 (d, 2 H, J=8 Hz), 7.615 (t, 1 H, J =4 Hz), 7.505-7.443 (m, 5 H), 6.619 (s, 1 H), 4.334 (s, 2 H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH2:10])[CH2:5][CH2:4]1.[S:11]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[C:18](Cl)[N:17]=2)=[CH:14][C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2>C(O)(C)C.ClCCl>[NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:18]2[N:17]=[C:16]([C:15]3[S:11][C:12]4[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=4[CH:14]=3)[CH:21]=[CH:20][N:19]=2)[CH2:5][CH2:4]1
Reactant: Clc1nccc(-c2cc3ccccc3s2)n1
Reactant: NCC1CCC(CN)CC1
Solvent: CC(C)O
Solvent: ClCCl
Product: NC[C@H]1CC[C@@H](CNc2nccc(-c3cc4ccccc4s3)n2)CC1
Yield: 88 %

Procedure:
4-Aminomethyl-cyclohexylmethyl-amine (cis/trans-mixture, ca. 2:1) (1.28 g, 9.00 mmol) is added to a stirred suspension of 4-benzo[b]thiophen-2-yl-2-chloro-pyrimidine (986 mg, 4.00 mmol) in isopropanol (13 mL) at ambient temperature under nitrogen. The resultant mixture is heated at 110° C. for 20 hours. At ambient temperature the mixture is diluted with dichloromethane (40 mL), washed with 1N NaOH (13 mL), and dried (MgSO4). After concentration and subsequent chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-20%, the title compound is obtained as a 2:1 cis/trans-mixture (1.24 g, 88% yield). ES+(m/z) 353 [M+H].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[N+:6]([C:9]1[CH:10]=[C:11]([OH:17])[C:12](OC)=[CH:13][CH:14]=1)([O-:8])=[O:7].[CH2:18](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][C:11]=1[O:17][CH3:18]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CCCCP(CCCC)CCCC
Reactant: OCCCBr
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OCCCBr
Reaction time: 16 h
Yield: 21 %

Procedure:
A solution of 3-bromo-1-propanol (0.685 g, 4.93 mmol), 4-nitroguaiacol (1 g, 5.91 mmol) and tributylphosphine (1.49 g, 7.36 mmol) in 20 ml tetrahydrofuran was treated with 1,1′-(azodicarbonyl)dipiperidine (1.49 g, mmol), added portionwise over 5 mins, and the resulting mixture stirred for 16 hrs. The solvent was removed in vacuo and the residues partitioned between ethyl acetate (25 ml) and 0.5 M HCl (25 ml). The organic phase was washed with 0.5 M NaOH (4×25 ml), water (25 ml) and saturated brine (25 ml), then dried and concentrated to a pale yellow solid. This was purified by flash chromatography on silica gel (eluting with ethyl acetate-hexane) to give 1-(3-bromo-propoxy)-2-methoxy-4-nitro-benzene as a white solid (300 mg, 21%);
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([N+:21]([O-])=O)[C:16]([CH3:20])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]=1[CH2:24][N:25]([CH3:27])[CH3:26]>[Fe].C(O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][C:16]([CH3:20])=[C:15]([NH2:21])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:5][C:4]=1[CH2:24][N:25]([CH3:26])[CH3:27]
Reactant: Cc1ccc2c(Nc3ccc(Cl)c(CN(C)C)c3)nccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(Nc3ccc(Cl)c(CN(C)C)c3)nccc2c1N
Yield: 59.1 %

Procedure:
Iron (202 mg, 3.25 mmol) and concentrated hydrochloric acid (0.02 mL) were added to ethanol/water (6.5 mL/6.5 mL), followed by refluxing for 1 hour. The mixed reaction solution was added with N-(4-chloro-3-((dimethylamino)methyl)phenyl)-6-methyl-5-nitroisoquinolin-1-amine (241.5 mg, 0.65 mmol) obtained in <Step 3> above, followed by refluxing for 1 hour. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with ethanol and chloroform/2-propanol=3/1 (v/v). The resulting filtrate was distilled under reduced pressure, and dissolved in chloroform/2-propanol=3/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (dichloromethane:methanol=9:1 (v/v)) to obtain the title compound (130.9 mg, 59%).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:6]([NH:5][S:2]([NH:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:20])(=[O:4])=[O:3])=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)CN
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNS(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
A solution of chlorosulfonylisocyanate (Sigma-Aldrich) (5.0 mL, 57.4 mmol) in dichloromethane (100 mL) was cooled to 0° C. Tert-butyl alcohol (4.26 g, 57.4 mmol, 1.0 equiv.) was added dichloromethane (100 mL) via an addition funnel. This solution was stirred at 0° C. for 30 min. Glycine ethyl ester hydrochloride (8.82 g, 63.2 mmol, 1.1 equiv.) was added followed by drop-wise addition of triethylamine (20.0 mL, 144 mmol, 2.5 equiv.) at 0° C. This reaction mixture was stirred at room temperature for 4 h. The reaction was diluted with dichloromethane (100 mL) and washed with 0.1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate and concentrated to give the desired product (13.2 g, 81.4%) as a crude off-white solid, which was used in the subsequent reaction without further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.07 (t, 1H, J=6.1 Hz), 4.08 (q, 2H, J=7.1 Hz), 3.78 (d, 2H, J=6.1 Hz), 1.40 (s, 9H), 1.18 (t, 3H, J=7.1 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12]C)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]#[C:15][Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1C#C)([CH3:23])([CH3:22])[CH3:21].IC1C=CC2C=CS(=O)(=O)C=2C=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:15]#[C:14][C:3]1[CH:2]=[CH:7][C:6]2[CH:12]=[CH:11][S:8](=[O:9])(=[O:10])[C:5]=2[CH:4]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: O=S1(=O)C=Cc2ccc(I)cc21
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)C=C2

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-iodo-1-benzothiophene 1,1-dioxide (Intermediate 236), the title compound was obtained as a yellow solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([NH:9][CH3:10])[N:3]=1.Cl[CH2:12]C=O.[C:15](=[O:18])([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[NH:7][C:15](=[O:18])[C:5]2[CH:6]=[CH:12][N:9]([CH3:10])[C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=CCCl
Reactant: CNc1cc(O)nc(N)n1
Agent: [K+]
Solvent: CO
Product: Cn1ccc2c(=O)[nH]c(N)nc21
Yield: 40.9 %

Procedure:
To a suspension of 2-amino-6-(methylamino)pyrimidin-4-ol (40.5 g, 289 mmol) in methanol (300 ml) was added 40% aqueous chloroacetoaldehyde (51.6 ml, 318 mmol) and potassium carbonate (44.0 g, 318 mmol), and the mixture was refluxed for 1 hour. After cooling, the resulting crystals were collected by filtration and washed with water to give 19.4 g (41%) of the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=2[CH3:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH2:38])[CH2:33]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: Cc1cccc(C)c1-c1nc(C(=O)O)c(NC(=O)OC(C)(C)C)s1
Product: Cc1cccc(C)c1-c1nc(C(=O)Nc2cnccc2N2CCC[C@H](N)C2)c(N)s1
Yield: 13 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(2,6-dimethylphenyl)thiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (8 mg, 13%). 1H NMR (400 MHz, DMSO) δ 9.22 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.48 (s, 2H), 7.35-7.26 (m, 1H), 7.17 (d, J=7.7 Hz, 2H), 7.04 (d, J=5.3 Hz, 1H), 3.06 (t, J=14.4 Hz, 1H), 2.99 (d, J=11.7 Hz, 1H), 2.83-2.66 (m, 1H), 2.64-2.48 (m, 1H), 2.45-2.31 (m, 1H), 2.21 (s, 6H), 1.64 (dd, J=17.0, 6.8 Hz, 2H), 1.57-1.41 (m, 1H), 1.17-0.95 (m, 1H). ESIMS m/z=423.2 (M+1).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=[O:32].[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([F:27])[CH:29]=1)[OH:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: COc1ccc(C=O)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1F
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.54 M, 6.79 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.5 g, 9.50 mmol) in THF (30 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 3-fluoro-4-methoxybenzaldehyde (1.32 g, 8.56 mmol) in THF (8 mL) was added dropwise at −78° C. The mixture was stirred at the same temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.79 g, 96%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:20]=2[O:19][CH2:18][CH2:17]1.C[O:28][C:29](=[O:39])[CH:30](Br)[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:26][C:25]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:21]=4[CH:22]=[CH:23][CH:24]=3)[CH:6]=[N:5]2)[C:29]([OH:28])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Oc1cccc2c1OCCO2
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCCC1
Product: O=C(O)C(CC1CCCCC1)n1ncc(Oc2cccc3c2OCCO3)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,3-dihydro-benzo[1,4]dioxin-5-ol and alkylating with 2-bromo-3-cyclohexyl-propionic acid methyl ester (Intermediate 12) afforded 3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (30 mg, 89% for the final step) which was used in Example 133.
Reaction SMILES: [Na].Br[C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][NH2:12])[CH:6]=[C:5]([CH3:13])[CH:4]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][NH2:12])[CH:6]=[C:5]([CH3:13])[CH:4]=1
Reactant: CO
Reactant: Cc1cc(Br)nc(NCCN)c1
Agent: [Na]
Product: COc1cc(C)cc(NCCN)n1
Temperature: 140 °C

Procedure:
Sodium (45 mg, 1.96 mmol) was dissolved in methanol (1.5 ml), N-(6-bromo-4-methyl-2-pyridyl)ethane-1,2-diamine (69 mg, 0.3 mmol) was added and the resulting mixture was stirred under microwave heating at 140° C. for three hours. The mixture was concentrated under reduced pressure and the residue was washed several times with ethyl acetate and acetonitrile. The washing solutions were decanted from the solid, the combined washing solutions were evaporated to dryness under reduced pressure to yield 58 mg. MS(ESI) m/z=182.0 [M+1]+.
Reaction SMILES: [CH2:1]1[CH2:12][C:10](=[O:11])[C:4]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=2[CH2:2]1.[ClH:13].[CH3:14][NH:15][CH3:16].C=O.[CH2:19](O)C>CC(C)=O>[ClH:13].[F:9][C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][CH:6]=1)[C:10](=[O:11])[CH:12]([CH2:14][N:15]([CH3:19])[CH3:16])[CH2:1][CH2:2]2
Reactant: CCO
Reactant: O=C1CCCc2cc(F)ccc21
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(C)=O
Product: CN(C)CC1CCc2cc(F)ccc2C1=O

Procedure:
A mixture comprising 8.0 g 6-fluoro-α-tetralone, 5.3 g of dimethylamine hydrochloride, 2.0 g paraformaldehyde, and 10 ml 95% ethanol containing 0.1 ml concentrated hydrogen chloride is heated on a steam bath for 1.5 hours. The reaction mixture soon because homogeneous and the paraformaldehyde dissolves. The warm solution (bright yellow) is transferred to a widemouthed flask and is quickly diluted by the addition of acetone (100 ml). Cooling this solution in the freezer for 16 hours produced a crystalline mass of white plates that is collected and washed with additional acetone. After drying this material in vacuo, the crystalline title compound weighs 10.1 g (80%) melting point 152°-153° C.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:33]I>[Ag]=O.C(Cl)(Cl)Cl>[CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH:30]([O:32][CH3:33])[CH3:31])=[CH:23][CH:24]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Reactant: CI
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OC)cc2)nc1
Yield: 52 %

Procedure:
At room temperature, 4.0 g (9 mmol) of the (-)-5-undecyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine obtained in Example 14, 40 ml of methyl iodide and 6.3 g (27 mmol) of silver oxide were stirred for 40 hours. Then, the reaction mixture was washed with 1 N hydrochloric acid and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography gave 2.1 g (yield 52%) of (-)-5-undecyloxy-2-{4-(6-methoxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =-1.6 (c=1.0, CHCl3).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[OH:10][CH:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(#N)C>[OH:10][C:11]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCC1(O)CCCCCCCCCCC(=O)O1
Yield: 66 %

Procedure:
To a refluxing solution of 510 mg (2.0 mmol) of 2-chloro-1-methylpyridinium iodide in 50 ml of acetonitrile, there was added a solution of 150 mg (0.5 mmol) of 12-hydroxyoctadecanoic acid and 404 mg (4.0 mmol) of triethylamine in 40 ml of acetonitrile over a period of 8 hours at a continuous and uniform rate, and the reaction mixture was refluxed for an additional 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 12-hydroxyoctadecane-1,12-lactone was obtained in 66% yield.
Reaction SMILES: NC1CCN(CC2C=CC=CC=2)C1.C(OC(N[C@H](C(O)=O)CCC)=O)(C)(C)C.ON1C(=O)CCC1=O.Cl[C:38]1[CH:39]=[CH:40][N:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[C:43]([C:48]([O:50]CC)=[O:49])[C:42]2=[O:53].C([NH:61][C@H:62]([C:66]([NH:68][CH:69]1[CH2:73][CH2:72][NH:71][CH2:70]1)=[O:67])[CH2:63][CH2:64][CH3:65])(OC(C)(C)C)=O>>[NH2:61][C@H:62]([C:66]([NH:68][CH:69]1[CH2:73][CH2:72][N:71]([C:38]2[CH:39]=[CH:40][N:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[C:43]([C:48]([OH:50])=[O:49])[C:42]3=[O:53])[CH2:70]1)=[O:67])[CH2:63][CH2:64][CH3:65]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCNC1
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Agent: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: NC1CCN(Cc2ccccc2)C1
Agent: O=C1CCC(=O)N1O
Product: CCC[C@H](N)C(=O)NC1CCN(c2ccn3c(=O)c(C(=O)O)ccc3c2)C1

Procedure:
3-Amino-1-benzylpyrrolidine (I. Sumio and T. Matsuo, Japanese Kokai JP 5328161, published Mar. 16, 1978) is coupled to N-t-butoxycarbonyl norvaline (Boc-nVal) using conventional N-hydroxysuccinimide coupling procedures. The 1-benzyl group is removed by hydrogenolysis in methanol using palladium on carbon catalyst. The 3-(N-Boc-norvalyl)aminopyrrolidine is then reacted with ethyl 8-chloro-4H-quinolizin-4-one-3-carboxylate, the product of Step 3 of Example 58, as described in Step 4 of Example 58, replacing 3-(N-t-butoxycarbonylamino)pyrrolidine with 3-(N-Boc-norvalyl)aminopyrrolidine, to give 8-(3-(N-norvalyl)amino-pyrrolidinyl)-4H-quinolizin-4-one-3-carboxylic acid with the nitrogen of the amino acid protected with a Boc group. The Boc protecting group is removed by standard hydrolysis using trifluoroacetic acid and dilute aqueous hydrochloric acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]23[CH2:20][CH2:19][C:16](C4C=CC=C(OC5C=CC=CC=5)C=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.BrC1C=CC=C(OC2C=CC=CC=2)C=1.[CH3:48][C:49]1[S:50][CH:51]=[C:52]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:53]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:51]4[S:50][C:49]([CH3:48])=[N:53][C:52]=4[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccccc2)cs1
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4cccc(Oc5ccccc5)c4)(CC2)OC3)cc1
Agent: Brc1cccc(Oc2ccccc2)c1
Product: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1

Procedure:
(1-(2-Methyl-4-phenylthiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate was prepared using a procedure analogous to (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate except that 1-bromo-3-phenoxybenzene was replaced with 2-methyl-4-phenylthiazole. The title compound was obtained (0.125 g, 0.266 mmol, 62.1% yield) as a light yellowish oil. LCMS, [M+H]+=470.1. 1H NMR (500 MHz, CDCl3) δ 7.77-7.72 (m, 2H), 7.43-7.32 (m, 7H), 3.75 (s, 2H), 3.66 (s, 2H), 2.64 (s, 3H), 2.45 (s, 3H), 2.08-1.99 (m, 2H), 1.82 (ddd, J=13.3, 11.6, 4.3 Hz, 2H), 1.61 (qd, J=7.2, 3.0 Hz, 2H), 1.43 (td, J=12.4, 4.8 Hz, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]([F:17])([F:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4].N1C=CC=CC=1.[C:24](Cl)(Cl)=[O:25]>ClCCl.C1(C)C=CC=CC=1>[F:17][C:8]([F:16])([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C@H:2]([N:1]=[C:24]=[O:25])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@@H](N)CC(F)(F)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)N=C=O
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
817 mg of methyl (S)-2-amino-4,4-difluoro-5-phenylpentanoate (3.36 mmol) were dissolved in 20 ml of dichloromethane, admixed with 1.08 ml of pyridine (4 eq.) and cooled to approx. 5° C. (ice bath). After 10 min, 2.3 ml (1.3 eq.) of a 20% phosgene solution in toluene were added dropwise. The resulting suspension was stirred with ice bath cooling for 4 h and then concentrated under reduced pressure. The residue thus obtained was taken up in toluene and filtered. After the solvent had been removed under reduced pressure, methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate was obtained as an orange oil which was used without further purification in the subsequent reaction. Yield: 943 mg (quant.)
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]([F:37])([F:36])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH2:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:35][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]([F:15])([F:36])[F:37])=[CH:19][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NC(c1ccc(OC(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccc(OC(F)(F)F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-trifluoromethoxy-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine (example 4.8).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][OH:9])[C@@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1.CCN(C(C)C)C(C)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].P([O-])([O-])([O-])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:23]([O:9][CH2:8][C@:2]1([CH3:1])[C@@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1)([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC[C@H]1O[C@]1(C)CO
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H]1O[C@]1(C)CO[Si](C)(C)C(C)(C)C
Yield: 89.6 %

Procedure:
Alcohol 3 (51.1 mg, 0.3925 mmol) in 3 ml of CH2Cl2 was treated successively with DIPEA (102 μl, 0.5888 mmol, 1.5 eq), DMAP (1 crystal), and TBSCl (77 mg, 0.5103 mmol, 1.3 eq) and refluxed for 12 h. The solution was poured onto 20 ml of 0.2M pH 7 phosphate buffer and 30 ml of low boiling petroleum ether, shaken, and separated. The aqueous phase was extracted with petroleum ether (3×10 ml), washed with pH 7 buffer (1×10 ml), H2O (1×5 ml), brine (1×5 ml), dried over MgSO4, and concentrated to give 86.0 mg of 4 as a clear oil (89.6%). 1H NMR (CDCl3, 360.134 MHz) δ:3.57 (1H, d, J=11.15 Hz), 3.53 (1H, d, J=11.17 Hz), 2.82 (1H, t, J=5.70 Hz), 1.6-1.4 (4H, m), 1.25 (3H,s), 0.95 (3H, t, J=7.13 Hz), 0.87 (9H, s), 0.04 (3H, s), and (3H, s). 13C NMR (CDCl3, 90.55 MHz) δ:68.0, 61.0, 60.8, 30.2, 25.8, 19.7, 18.3, 14.1, 13.9, and -5.4. IR (thin film): 2959 (s), 2930 (s), 2859 (s), 1473 (m), 1464 (m), 1382 (w), 1362 (w), 1253 (m), 1103 (s), 838 (s), 778 (s), and 667 (w) cm-1. [δ]D=+4.9° (c=2.62, CH2Cl2).