Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:3].[Li+].CC([N-]C(C)C)C.COB(OC)OC.Cl[C:28]1[C:33]([O:34][CH3:35])=[CH:32][N:31]=[C:30]([S:36][CH3:37])[N:29]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:35][O:34][C:33]1[C:28]([C:8]2[S:7][C:6]([CH2:5][CH2:4][C:2]([CH3:1])([OH:11])[CH3:3])=[CH:10][CH:9]=2)=[N:29][C:30]([S:36][CH3:37])=[N:31][CH:32]=1
Reactant: COc1cnc(SC)nc1Cl
Reactant: CC(C)(O)CCc1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: COB(OC)OC
Solvent: C1CCOC1
Solvent: COCCOC
Product: COc1cnc(SC)nc1-c1ccc(CCC(C)(C)O)s1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution of 2-methyl-4-thiophen-2-yl-butan-2-ol (340 mg, 2 mmol)—synthesis see Step A of Example 1—in 20 ml of THF was treated with LDA (2M in THF/heptane/ethylbenzene, 5 ml, 10 mmol) at −78° C. under nitrogen and the mixture was stirred for 5 minutes. Then, trimethylborate (1.1 ml, 10 mmol) was added in one portion and the cooling bath was removed. After 15 minutes, the mixture was quenched with 50 ml of saturated ammonium chloride solution and extracted twice with ether. The aqueous layer was then acidified with 2N-HCl and extracted once more with ether. The combined organic extracts were washed with brine and evaporated. This crude boronic acid was redissolved in 10 ml of DME and added to a stirred suspension 4-chloro-5-methoxy-2-methylsulfanyl-pyrimidine (190 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), 20 ml of DME and 3 ml of a 10% solution of sodium bicarbonate. This mixture was then kept at reflux (100° C. heat bath) for 90 minutes. After cooling, most of the DME was evaporated and the crude was partitioned between water and ether. The organic layer was separated, washed with 0.2N-HCl, water and brine, dried over sodium sulfate and evaporated. The crude was purified by chromatography on silicagel (EtOAc/hexane:1/1) to give 4-[5-(5-methoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-methyl-butan-2-ol. Yield: 275 mg (85%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][NH:14][C@H:15]([CH:23]([CH3:25])[CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][NH:14][C@H:15]([CH:23]([CH3:25])[CH3:24])[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: CC(C)[C@@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)[C@@H](NCCN)C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
t-Butyl (R)-2-(2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylamino)-3-methylbutyrate (6.60 g; 19.05 mmol) was dissolved in ethanol (100 ml). Hydrazine hydrate (4.62 ml; 95.25 mmol) was added, and the reaction mixture was heated under reflux for 2 h. The solid was filtered off with suction through kieselguhr and washed with ethanol (100 ml). The solvent was removed and the residue was partitioned between saturated NaHCO3 solution (150 ml) and CH2Cl2 (150 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×; 100 ml). The combined organic phases were dried over MgSO4. Removal of the solvent under reduced pressure resulted in t-butyl (R)-2-(2-aminoethylamino)-3-methylbutyrate (4.60 g; 19.05 mmol). MS: 217.25 (M+H); Rt: 0.69 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.C(N(CC)C(C)C)(C)C.[NH:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>C(#N)C>[CH3:29][C:12]1[S:11]/[C:10](=[N:9]\[C:8]([N:40]2[CH2:44][CH2:43][CH2:42][CH:41]2[C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)=[O:30])/[N:14]([C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:25])([F:26])[C:21]([F:23])([F:24])[O:22][C:17]=3[CH:16]=2)[CH:13]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: c1cncc(C2CCCN2)c1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CCCC2c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide core (Example 81A, 0.88 mL of 0.16 M in acetonitrile, 80 mg, 0.1 mmol) was added to a 20 mL vial, followed by N,N-diisopropylethylamine (0.88 mL of 0.2 M in acetonitrile, 24 mg, 0.13 mmol). 3-(Pyrrolidin-2-yl)pyridine (0.79 mL of 0.2 M in acetonitrile, 0.11 mmol) was added last. The resulting mixture was shaken at room temperature overnight. It was then concentrated in vacuo, and the residue was taken up in 1:1 MeOH/DMSO and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method) to give the titled compound. 1H NMR (300 MHz, DMSO-d6/D2O) δ ppm 1.74-1.93 (3 H) 2.12-2.21 (3 H) 2.33-2.44 (1 H) 3.50-3.68 (2 H) 4.95-5.07 (1 H) 6.91-7.06 (1 H) 7.21-7.59 (3 H) 7.70-7.91 (1 H) 8.33-8.42 (1 H) 8.44-8.52 (1 H); MS (ESI+) m/z 495 (M+H).
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH2:20])=[NH:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:9])[F:8].CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=1)=O.[OH-].[Na+]>CC(O)C>[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:20]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=3)[CH:25]=[CH:24][N:19]=2)[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:8])[F:9]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: CCOc1cccc(C(=O)C=CN(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: CCOc1cccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)c1
Temperature: 25 °C

Procedure:
926.1 mg (3.69 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate are added to a solution of 801.1 mg (3.69 mmol) of 3-dimethylamino-1-(3-ethoxy-phenyl)-2-propen-1-one in 10 ml of 2-propanol. After the addition of 162.2 mg (4.05 mmol) of sodium hydroxide, the reaction mixture is boiled under reflux for 20 h. After cooling to RT, the reaction product is isolated by filtration and washed with 1-propanol, ethyl acetate and water. After chromatography (hexane:ethyl acetate=7:3), N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-ethoxy-phenyl)-2-pyrimidineamine is obtained; Rf =0.72 (methylene chloride:methanol=98:2), m.p. 88°-96°.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[CH:16][C:15]=3[S:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2N)cc1
Product: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (50 mg, 0.280 mmol) was reacted with the product from Example 35a (91 mg, 0.280 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (21.5 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.07 (s, 3H), 2.78 (s, 3H), 6.43 (d, J=6.99 Hz, 1H), 7.09-7.15 (m, 1H), 7.44 (d, J=8.46 Hz, 2H), 7.68 (d, J=8.46 Hz, 2H), 7.78 (dd, J=8.64, 1.65 Hz, 1H), 7.84 (d, J=8.82 Hz, 1H), 7.92 (d, J=1.84 Hz, 1H), 8.52 (d, J=7.35 Hz, 1H), 9.00 (d, J=8.46 Hz, 1H), 10.19 (s, 1H), 11.12 (s, 1H); MS (ESI+) m/z 469 (M+H−TFA)+, (ESI−) m/z 467 (M−H−TFA)−.
Reaction SMILES: C([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)C1C=CC=CC=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26]>C(#N)C1C=CC=CC=1>[C:25]([C:27]1[CH:28]=[C:29]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[N:9][OH:8])[C:18]23[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:30]=[CH:31][CH:32]=1)#[N:26]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Solvent: N#Cc1ccccc1
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=NO)N3)c1
Yield: 69.2 %

Procedure:
3-[Spiro[cyclohexane-1,3′-[3H]indol]-(1′H)-one-2′-(O-benzyloxime)]benzonitrile[3H]indol]-5-yl]benzonitrile. Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-cyanophenyl boronic acid (0.76 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography (eluant: 10:0.5 hexane:ethyl acetate) to give the desired product (0.75 g, 1.8 mmol, 71%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.41-1.81 (8H, m) 1.96-2.03 (2H, q) 5.01 (2H, s) 6.86 (1H, d) 7.28-7.33 (9H, m) 7.95-7.97 (1H, d) 8.12 (1H, s) 9.65 (1H, s); MS (ESI(−ve)) m/z 406 (M−H)−.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1.[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].N>>[CH2:14]([NH:13][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:7]=[C:2]([NH:30][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCN
Reactant: CCCCNc1nc(N)nc(NCCCC)n1
Agent: N
Product: CCCCCCCCCCCCNc1nc(NCCCC)nc(NCCCC)n1

Procedure:
The same procedures were repeated as in the N-substituted melamine (C1), except that n-dodecyl amine was employed in place of the aqueous ammonia to obtain 2,4-bis(monobutyl-amino)-6-(monododecylamino)-1,3,5-triazine which is in a solid-state.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]3[N:22]=[C:23]([NH:26][CH:27]4[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>O.CO>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]3[N:22]=[C:23]([NH:26][CH:27]4[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: NO
Reactant: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of hydroxylamine hydrochloride (15.3 mg, 0.22 mmol) and Na2CO3 (28 mg, 0.26 mmol) in water (0.7 mL) was added a solution of 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (50 mg, 0.147 mmol) in MeOH (0.5 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The mixture was poured into water and extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC and then by SFC to give EX. 8-92 (10 mg, 19%) as a white solid.
Reaction SMILES: C(OCC(COC(=O)C)CCN1C=NC2C1=NC(N)=NC=2)(=O)C.OCC(CO)CCN1C=NC2C(=O)NC(N)=NC1=2.[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([NH:47][CH:48]=[N:49]2)=[C:45]([Cl:52])[N:44]=1.Br[CH2:54][CH2:55][C:56]([C:67]([O:69]CC)=[O:68])([C:62]([O:64][CH2:65][CH3:66])=[O:63])[C:57]([O:59][CH2:60][CH3:61])=[O:58]>>[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([N:47]=[CH:48][N:49]2[CH2:54][CH2:55][C:56]([C:67]([OH:69])=[O:68])([C:57]([O:59][CH2:60][CH3:61])=[O:58])[C:62]([O:64][CH2:65][CH3:66])=[O:63])=[C:45]([Cl:52])[N:44]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOC(=O)C(CCBr)(C(=O)OCC)C(=O)OCC
Agent: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Agent: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Product: CCOC(=O)C(CCn1cnc2c(Cl)nc(N)nc21)(C(=O)O)C(=O)OCC

Procedure:
Nucleosides and Nucleotides, 15(5), 981-994 (1996) and WO 95/28402 disclose a process for the manufacture of the anti-viral agents 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (famciclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir). According to this process, the ‘bromoester’ route, 2-amino-6-chloropurine is reacted with triethyl 3-bromopropane-1,1,1-tricarboxylate in the presence of base to form diethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]-2-carboxymalonate. The crude isolate from this alkylation reaction is then treated with sodium methoxide in methanol to form dimethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl] malonate. This product is purified by crystallisation and then successively reduced using sodium borohydride and O-acetylated to give 9-(4-acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine. Famciclovir is produced directly from the latter compound by hydrogenation over a supported palladium catalyst; and penciclovir is produced from this compound by acid hydrolysis of the acetoxy groups.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([F:13])=[C:7](O)[N:6]=1.O=P(Cl)(Cl)[Cl:18]>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([F:13])=[C:7]([Cl:18])[N:6]=1
Reactant: COC(=O)Cc1nc(O)c(F)cc1C#N
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1nc(Cl)c(F)cc1C#N
Temperature: 95 °C
Reaction time: 7 h
Yield: 95.5 %

Procedure:
A mixture of (3-cyano-5-fluoro-6-hydroxy-pyridin-2-yl)-acetic acid methyl ester (9.10 g, 43.3 mmol), as prepared in the previous step, and POCl3 (40 mL, 433 mmol) was stirred at 95° C. for 7 h. The homogeneous brown solution was then concentrated under reduced pressure, and the residue was put on an ice bath, diluted with ether (200 mL), and then shaken with ice water (100 mL). The aqueous layer was extracted with ether (1×100 mL), and the organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure at 40° C. to afford the title compound as a clear dark amber oil (9.45 g, 96%). 1H-NMR (300 MHz, CDCl3) δ 7.75 (d, 1H), 4.06 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27]([N:2]([CH3:1])[C@H:3]2[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:5][CH2:4]2)=[O:28])=[CH:31][CH:32]=1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 245 mg (0.53 mmol) trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.trifluoroacetic acid salt and 143.5 mg (0.75 mmol) 4-chlorophenyl chloroformate in 4 ml dioxane, was added at RT 1.54 ml (3.12 mmol) Hünig's base. The mixture was stirred for 1 h, then extracted with EtOAc/1N HCl and water. The organic phases were concentrated under reduced pressure and purified by chromatography on silica gel with EtOAc/hexane 1:3 to yield 167 mg (73%, 2 steps) of pure trans-Methanesulfonic acid 5-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-pentyl ester, MS: 432 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([OH:21])([CH3:20])[CH3:19])[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([OH:21])([CH3:19])[CH3:20])[C:5]([OH:7])=[O:6]
Reactant: CC(C)(O)c1ccc(C(=O)OCc2ccccc2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)O)cc1F
Yield: 93.5 %

Procedure:
To a solution of 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (9.1 g, 45.7 mmol) in DMF (40 mL) was added cesium carbonate (22.3 g, 68.5 mmol) followed by benzyl bromide (11.7 g, 8.1 mL, 68.5 mmol) and reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed sequentially with H2O (3×10 mL), brine solution. The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with 10-20% EtOAc-hexanes to provide benzyl 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate (2.8 g, 21%) ESI-MS m/z calc. 288.2. Found 289.3 (M+1)+; Retention time: 1.79 min (3 min run). To a solution of benzyl 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate (2.8 g, 9.71 mmol) in MeOH (50 mL) was added palladium on carbon (100 mg, 0.09 mmol) and the reaction mixture was subjected to an atmosphere of hydrogen for 16 hours. The catalyst was removed via filtration over Celite® and the solvent removed in vacuo to provide 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (1.8 g, 96%) as a white solid. ESI-MS m/z calc. 198.2. Found 199.9 (M+1)+; Retention time: 0.91 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[C:14]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[C:11]=2[OH:32])=[C:4]([N+:33]([O-])=O)[CH:3]=1.[N+](C1C=CC=CC=1N=NC1C=C(C(CC(C)(C)C)(C)C)C=C(C(CC(C)(C)C)(C)C)C=1O)([O-])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][N:9]([C:10]3[CH:15]=[C:14]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[C:11]=3[OH:32])[N:33]=[C:4]2[CH:3]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)CC(C)(C)C)c1
Agent: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC(C)(C)C)c1
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)CC(C)(C)C)c1
Yield: 71.8 %

Procedure:
When, using the general procedure of Example 2, the amount of 4-chloro-2-nitro-2'-hydroxy-3',5'-di-tert-octylazobenzene was substituted for 2-nitro-2'-hydroxy-3',5'-di-tert-octylazobenzene, the abovenamed compound was prepared in a yield of 71.8% as pale yellow crystals melting at 121°-122° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCCC(CCCC(F)(F)C(F)(F)F)C(O)=O)[C:7]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:44][C:45]([F:71])([C:61]([F:70])([F:69])[C:62]([F:68])([F:67])[C:63]([F:66])([F:65])[F:64])[CH2:46][CH2:47][CH:48]([CH2:54][CH2:55][CH2:56]CCC=C)[C:49]([O:51]CC)=[O:50]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:56][CH2:55][CH2:54][CH:48]([CH2:47][CH2:46][C:45]([F:44])([F:71])[C:61]([F:70])([F:69])[C:62]([F:67])([F:68])[C:63]([F:64])([F:65])[F:66])[C:49]([OH:51])=[O:50])[C:7]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)([CH2:12][CH2:13][CH3:14])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: CCCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 29 and ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][N:9]([C:13]([C:15]34[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:18][C:17](=O)[CH2:16]4)=[O:14])[CH2:10][C:11]=2[CH:12]=1.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[C:26]1([CH:32]2[CH2:33][CH2:34][N:35]([CH:17]3[CH2:16][C:15]4([C:13]([N:9]5[CH2:8][CH2:7][C:6]6[N:5]=[CH:4][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:12][C:11]=6[CH2:10]5)=[O:14])[CH:19]([CH2:20][CH2:21][CH2:22]4)[CH2:18]3)[CH2:36][CH2:37]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1CC2CCCC2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)C12CCCC1CC(N1CCC(c3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)hexahydropentalen-2(1H)-one (0.175 g, 0.497 mmol) in DCE (4.3 mL) was added 4-phenylpiperidine (0.080 g, 0.50 mmol). The reaction mixture was stirred at ambient temperature for about 2 h then sodium triacetoxyborohydide (0.158 g, 0.745 mmol) and acetic acid (0.043 mL, 0.74 mmol) were added. The reaction mixture was then stirred at ambient temperature for about 18 h. Saturated aqueous sodium bicarbonate was added to the reaction mixture and the product was extracted into DCM (3×10 mL). The solvent was removed under reduced pressure and the crude material was purified by RP-HPLC to provide [2-(4-phenyl-piperidin-1-yl)-hexahydro-pentalen-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone as a mixture of four diastereomers (0.075 g). RP-HPLC (Table A, Method c) Rt 2.05 min; m/z: (M+H)+ 498. In addition, the diastereomers were separated using a two-step chiral HPLC method (Step 1: Diastereomer separation: Isocratic using 85% heptane, 7.5% methanol, 7.5% ethanol with 0.2% diethylamine on a Daicel OD-H column (20×250 mm) at 35 deg C. and 12 mL/min flow rate (UV wavelength monitored=265 nm). Step 2: Enantiomer separation: 10-70% gradient over 19 min of isopropanol in heptane with 0.2% diethylamine on a Daicel AD-H column (20×250 mm) at 35 deg C. and 16 ml/min flow rate (UV wavelength monitored=265 nm)) to provide the four enantiomers—the absolute configuration of each compound was not determined. Isomer 1: RP-HPLC (Table A, Method d) Rt 12.66 min. Isomer 2: RP-HPLC (Table A, Method d) Rt 13.57 min. Isomer 3: RP-HPLC (Table A, Method d) Rt 8.46 min. Isomer 4: RP-HPLC (Table A, Method d) Rt 11.76 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1>C(O)CC.ClCCl>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCCO
Solvent: ClCCl
Product: Cc1ccc(-c2cn3cc([N+](=O)[O-])ccc3n2)cc1
Yield: 22.9 %

Procedure:
S1 g (0.38 mole) of 1-bromo-2-(4-methylphenyl)-2-ethanone and 53 g (0.3S mole) of 2-amino-5-nitropyridine are reacted in 900 ml of n-propanol. The solution is maintained under reflux, the reaction being followed by thin layer chromatography. When there is no further change, the mixture is evaporated to dryness. The residue is taken up with water and treated with ammonia solution 1 10 until the pH >8. The insoluble material is filtered off and dried, and then treated with dichloromethane. The insoluble portion is recrystallized in ethyl acetate, which yields a first crop. The mother liquors are then combined with the portion soluble in dichloromethane, the mixture is concentrated and a second crop of product is obtained. The two crops are purified separately by chromatography. 22 g (23%) of yellow solid are obtained overall.