Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[CH3:15][O:16]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[CH:8][C:7]([O:13][CH3:14])=[C:6]2[CH:15]=[O:16])=[CH:11][CH:12]=1)#[N:2]
Reactant: COC(Cl)Cl
Reactant: COc1ccc2ccc(C#N)cc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ccc(C#N)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 3.7 g of 2-cyano-7-methoxynaphthalene was dissolved in 40 ml of dichloro-methane, and 6.6 ml of titanium tetrachloride and 4.6 ml of dichloromethyl methyl ether were added dropwise into the resulting solution at 0° C. in this order. The resulting mixture was stirred at room temperature for 30 minutes and cooled to 0° C. again. Water was added to the resulting mixture to cease the reaction, and the resulting mixture was extracted with dichloromethane (100 ml×2). The organic layers were combined, washed with water, a saturated aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the resulting crude crystal was washed with ether and dried to give 3.3 g of the title compound as colorless crystals.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO>ClCCl>[C:26]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([C:10]([OH:12])=[O:11])[NH2:3])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: N[C@@H](CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 43 %

Procedure:
Lysine 2HCL (1.012 g, 4.34 mmol) was suspended in 300 ml dichloromethane, and sonicated until suspension was homogeneous. Triethylamine (7.5 ml, 54.1 mmol, 2.5 eq.) was added and the mixture was left to stir for 20 minutes in Brine/Ice bath (−15° C). Triphenylmethylchloride (Trityl chloride) (6.00 g, 21.5 mmol, 1 eq.) was dissolved in 200 ml dichloromethane and then slowly added over a period of 1 hour via a dropping funnel to the reaction flask. The reaction was followed by TLC (Silica, 5% methanol/95% CH2Cl2) and was stopped 1 hour after disappearance of Trityl chloride. Volume was reduced by reduced pressure distillation. The reaction product was washed first with 5% sodium bicarbonate (2×, 20 ml each), brine (1×, 20 ml), dried over sodium sulfate, filtered, and the solvent removed at reduced pressure distillation. The product was purified by flash column chromatography (Silica Gel, 3% methanol/97% CH2Cl2) and isolated as a clear golden oil (0.753 g. Yield: 43%). 1H NMR (CDCl3, 300 MHz δ1.40 (m, 2H), 1.52 (m, 2H), 1.67 (m, 2H), 2.11 (t,2H), 3.41 (t, 1H), 3.69 (s,3H), 7.14-7.51 (m, 15H); 13C NMR (CDCl3, 75 MHz) δ23.6, 30.7, 35.0, 43.5, 51.9, 54.5, 71.0, 126.2, 127.8, 128.7, 146.4, 176.6; ESI-MS calculated for C27H30N2O2 402.53; found 403.6 [M++1].
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[Cl:26])(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[Cl:26][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:17]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Reactant: Oc1ccc2nc(Cl)ccc2c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc3c(F)c(O)ccc3n2)c(Cl)c1
Temperature: 95 °C
Yield: 15.7 %

Procedure:
2-Chloro-5-fluoroquinolin-6-ol (Intermediate 16, 1.0 mmol) and 4-borono-3-chlorobenzoic acid (1.1 mmol) were mixed with 5% (Ph3P)4Pd and 4.0 mmol of NaHCO3 in 20 ml 50% dioxane/water. The mixture was degassed three times by evacuation and argon filling and heated at 95° C. overnight. The reaction was diluted with 20 ml of water and filtered. The filtrate was acidified with 1N HCl to pH=4. The precipitate was filtered and washed with water, dried. The crude was purified by column using AcOH/MeOH/EtOAC (1/5/94) as solvent B and hexanes as solvent A with gradient 2 to 100%. The fractions with compound were pooled and evaporated to obtain white solid. The solid was triturated with diisopropyl ether. 50 mg of final product was obtained. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 10.55 (b, 1H), 8.47 (d, 1H), 8.01-8.03 (m, 2H), 7.79 (m, 3H), 7.56 (t, 1H). MS (ESI): m/z=316.3 [M−1]−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].CN(C=O)C.[H-].[Na+].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[N:20]=1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([NH:25][C:21]2[N:20]=[CH:19][N:24]=[C:23]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]=3[OH:10])[N:22]=2)[CH:27]=[C:28]([O:36][CH3:37])[C:29]=1[O:34][CH3:35]
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncnc(-c3c(O)[nH]c4ccccc34)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxindole (176 mg, 1.32 mmol) was dissolved in a 1:1 mixture of THF:DMF (4 mL), under N2, at RT. NaH (53 mg of a 60% suspension in mineral oil, 1.32 mmol) was added, which produced a vigorous gas evolution. This mixture was stirred for 30 min at RT, then (4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (156 mg, 0.53 mmol) was added and the reaction was heated to 80° C. for 2 h. The reaction was cooled to RT, partially concentrated under reduced pressure, diluted with EtOAc, then extracted with water. The water extract was back extracted two times with fresh EtOAc. All of the EtOAc extracts were washed with brine, combined, dried over NaSO4, filtered and concentrated. The recovered material was purified by preparative HPLC (5 to 100% CH3CN:H2O (0.1% TFA buffer) over 10 min at 20 mL/min) Crystals formed in the recovered eluant, which were recovered by vacuum filtration, washed with water, and dried under high vacuum giving 3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-indol-2-ol as a yellow solid: MS m/z=394 [M+H]+. Calc'd for C20H19N5O4: 393.14.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17]C)=[O:16].O1CCCC1.[OH-].[Na+]>CO>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cccc(OCc2nc3c(s2)CCCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(OCc2nc3c(s2)CCCC3)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
A mixture of methyl 3-(4,5,6,7-tetrahydrobenzothiazol-2-ylmethoxy)benzoate (361 mg, 1.2 mmol), tetrahydrofuran (2 ml), methanol (2 ml) and 1 N sodium hydroxide (2 ml) was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The resulting residue was dissolved in water and the solution was adjusted to pH 3 by adding 10% citric acid aqueous solution. Thereafter, the solid substance formed was collected by filtration, washed with water, and then dried under reduced pressure to give 3-(4,5,6,7-tetrahydrobenzothiazol-2-ylmethoxy)benzoic acid (257 mg, 0.89 mmol, 75%).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:47])[C@@H:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[CH:34]=[C:33]([C:35](=[O:45])[NH:36][O:37]C(OCC(C)C)C)[S:32][C:31]=4[CH:46]=3)=[CH:20][CH:19]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:47])[C@@H:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[CH:34]=[C:33]([C:35](=[O:45])[NH:36][OH:37])[S:32][C:31]=4[CH:46]=3)=[CH:20][CH:19]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NO)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3)cc2s1
Reaction time: 1 h
Yield: 59 %

Procedure:
(S)-2-[4-({[2-(1-Isobutoxy-ethoxycarbamoyl)-benzo[b]thiophen-6-ylmethyl]-amino}-methyl)-benzylamino]-3-phenyl-propionic acid cyclopentyl ester was dissolved in DCM (2 mL) and MeOH (2 mL) and treated with TFA (1 mL). The mixture was stirred for 1 h at r.t then concentrated to dryness and DCM (5 mL) and heptane (5 mL) added. The mixture was evaporated to dryness. This process was repeated three times to yield compound (104) (20 mg, 59%) as a oil. LCMS purity 95%, m/z 558 [M++H]+, 1H NMR (300 MHz, MeOD), δ: 1.25-1.91 (8H, m, 4×CH2), 3.12-3.47 (2H, m, CH2), 4.26 (1H, m, CH), 4.33 (2H, d, J=5.5 Hz, CH2), 4.36 (2H, s, CH2), 4.43 (1H, s, CH2), 5.16 (1H, s, CH), 5.13 (1H, m, CH), 7.25-7.37 (6H, m, ArH), 7.54-7.63 (4H, m, ArH), 7.94 (2H, m, ArH), 8.09 (1H, s, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:20])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:20]=[C:9]2[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])([CH3:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C(=N)Nc1ccc(Br)cc1)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(Br)cc2)c(C(C)(C)c2ccccc2F)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a 250 mL round bottom flask attached with condenser was added N-(4-bromophenyl)-2-(2-fluorophenyl)-2-methylpropanimidamide (5.0 g, 15 mmol), anhydrous THF (80 mL), NaHCO3 (2.52 g, 30 mmol), and 90% ethyl bromopyruvate (1.90 mL, 15.1 mmol). The reaction mixture was stirred at 70° C. for 2 hr prior to analysis by LCMS. The cooled reaction mixture was decanted and concentrated in vacuo. The residue was taken into toluene (65 mL) and acetic acid (1.8 mL). The solution was stirred at reflux for 1 hr. The cooled solution was washed with H2O (150 mL×3), dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a SiO2 column using a 100% Hx to 70% EtOAc gradient to afford purified title compound (4.3 g, 67% yield). LCMS (ES): m/z=431.3, 433.3 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18]3=[N:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])[C:21]=4[N:17]3[CH2:16][CH2:15][CH2:14]2)=[C:9]([CH3:36])[N:8]=1)(=O)=O.[CH3:39][N:40](C)C=O>O.[C-]#N.[Zn+2].[C-]#N.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>[Cl:26][C:25]1[C:20]2[N:19]=[C:18]3[N:13]([C:10]4[CH:11]=[CH:12][C:7]([C:39]#[N:40])=[N:8][C:9]=4[CH3:36])[CH2:14][CH2:15][CH2:16][N:17]3[C:21]=2[C:22]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:30])([F:29])[F:31])=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(OS(=O)(=O)C(F)(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1nc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Yield: 82 %

Procedure:
Under nitrogen atmosphere, to a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-yl trifluoromethanesulfonate (209.5 mg, 0.352 mmol), zinc cyanide (62.0 mg, 0.528 mmol), tetrakis(triphenylphosphine)palladium(0) (40.7 mg, 0.0352 mmol) and N,N-dimethylformamide (1.5 mL) was stirred at 100° C. for 2 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give a title compound as a colorless powder (136.1 mg, 0.288 mmol, 82%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([CH3:31])[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH3:20][CH:21]([CH3:31])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)Cc1ccc(C=O)cc1
Product: CC(C)Cc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(2-methylpropyl)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(2-methylpropyl)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17](N(CC)CC)[C:18]#N)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30](CCl)=[CH:29][CH:28]=1.CN(C=[O:39])C>CCCCCC>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:39])[CH2:18][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCN(CC)C(C#N)c1ccc(OCc2ccccc2)cc1
Reactant: CN(C)C=O
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (17 g, 0.42 mol) was washed with hexane and suspended in 200 mL DMF. 2-(4-benzyloxyphenyl)-2-(N,N-diethylamino)acetonitrile (94 g, 0.32 mol) in 350 mL DMF was added dropwise over 1 h at rt to the NaH suspension and stirred an additional 1 h. A 300 mL DMF solution of 4-methoxybenzylchloride (50 g, 0.32 mol) was added dropwise over 45 min to the reaction mixture causing a mild exotherm to 45° C. The reaction mixture was stirred for 16 h at rt, cooled in an ice bath, quenched with 100 mL MeOH, and reduced in vacuo to a smaller volume. The brown suspension was cooled in an ice bath and stirred while 2 L of 5N HCl was added at a rate to keep the temperature below 25° C. The suspension was stirred 18 h at rt, then extracted several times with CH2 Cl2. The CH2Cl2 extracts were combined, washed with brine, dried (Na2SO4), and concentrated to give an oily brown solid. The product was triturated with Et2O, filtered, and dried in vacuo to give 90 g (85%) of an off-white solid: mp 147°-148° C.; 1H NMR (CDCl3) d 3.80 (s, 3H, OCH3), 4.18 (s, 2H, O=CCH2), 5.13 (s, 2H, OCH2Ar), 7.00-7.03 (d, 2H, J=9 Hz, ArH), 7.18-7.21 (d, 2H, J=9 Hz, ArH), 7.41-7.44 (m, 5H, ArH), 7.99-8.02 (d, 2H, J=9 Hz, ArH); MS(FD) 332(M+). Anal. Calcd for C22H20 O3 : C, 79.49; H, 6.06. Found: C, 79.23; H, 6.08.
Reaction SMILES: [Cl:1][C:2]1[C:3](/[CH:16]=[CH:17]/[C@H:18]2[O:23][C:22](=[O:24])[CH2:21][C@@H:20]([OH:25])[CH2:19]2)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>CCOCC>[Cl:1][C:2]1[C:3](/[CH:16]=[CH:17]/[C@@H:18]2[O:23][C:22](=[O:24])[CH2:21][C@@H:20]([OH:25])[CH2:19]2)=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1C[C@@H](O)C[C@@H](/C=C/c2c(Cl)cc(Cl)cc2-c2ccc(F)cc2)O1
Solvent: CCOCC
Product: O=C1C[C@@H](O)C[C@H](/C=C/c2c(Cl)cc(Cl)cc2-c2ccc(F)cc2)O1
Yield: 91.8 %

Procedure:
A mixture of cis-(E)-6-[2-(3,5-dichloro-4'-fluoro-2-[1,1'-biphenyl]yl)ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (7.6 g, 20 mmole) and mercuric chloride (6 g, 22 mmole) was stirred at gentle reflux in H2O--acetonitrile (1:5; V:V; 120 ml) under N2 for 68 hours. The cooled reaction mixture was then diluted with Et2O (1 liter), washed with H2O (3×500 ml), and brine, dried (MgSO4), filtered and evaporated in vacuo to provide the crude title compound (7 g) as a pale amber gum (56% cis and 44% trans by HPLC).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+].C1COCC1>O>[NH:15]1[C:11]([CH:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[N:12][N:13]=[N:14]1
Reactant: COC(=O)C1CCC(c2nnn[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCC(c2nnn[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A mixture of 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid methyl ester (304 mg, 2.74 mmol), lithium hydroxide (121 mg 2.89), THF and water were stirred at RT overnight. The reaction was concentrated and diluted with water acidified with concentrated HCl to pH 1 and extracted with ethyl acetate to give 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid (173 mg, 61%) as an off white solid. LCMS calcd C8H12N4O2 (m/e) 196, obsd 197 (M+H).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28]>>[CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1
Reactant: CC(C)(C)COC(=O)Cl
Product: CC(C)(C)COC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1

Procedure:
From 0.45 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5 a) and neopentyl chloroformate, according to the general working procedure followed by extraction with EA and purification by flash chromatography 156 mg of 2′-(2,2-dimethylpropoxycarbonylaminomethyl)biphenyl-2-carboxylic acid phenethylamide were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)c1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
To a solution of 3-(4-hydroxy phenyl)2-[(pyridine-3-carbonyl)amino]propionic acid methyl ester (0.53 g, 1.76 mmol) in DMF (1 mL) was added N,N′-Di isopropyl ethyl amine (0.47 mL, 2.00 mmol) then reaction mixture cooled to (0° C.), t-butyl-dimethyl-silylchloride (0.26 g, 1.76 mmol), was added to reaction mass at (0° C.). The mixture was allowed to stir at room temperature (25° C.) over 5 h. The reaction mixture was quenched with ice, diluted with ethyl acetate (100 mL)), washed with water (3×50 mL) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain product as pale brown liquid (0.6 g, 82%).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.[F:27][C:28]1([F:39])[C:32](F)=[C:31](F)[C:30]([F:36])([F:35])[C:29]1([F:38])[F:37]>C1COCC1.CCOCC>[F:27][C:28]1([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:11][CH:12]=3)[S:4][C:3]=2[C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:21][CH:22]=2)=[C:32]1[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=1
Reactant: CC(C)(C)c1ccc(-c2cc(Br)c(-c3ccc(C(C)(C)C)cc3)s2)cc1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cc(C3=C(c4cc(-c5ccc(C(C)(C)C)cc5)sc4-c4ccc(C(C)(C)C)cc4)C(F)(F)C(F)(F)C3(F)F)c(-c3ccc(C(C)(C)C)cc3)s2)cc1
Reaction time: 0.25 h

Procedure:
A solution of (30) in anhydrous THF/ether cooled to −45° C. and treated with nBu—Li-(2.5 M in hexanes, 35 mL, 87 mmol) dropwise under a n argon atmosphere. The reaction mixture was stirred for a further 15 minutes followed by addition of octafluorocyclopentene (5.6 mL, 41.5 mmol) using a cooled gas tight syringe. The reaction was allowed to stir until the temperature reached −10° C., quenched by the addition of 10% HCl (50 mL). The aqueous layer was separated and extracted with ether. The organic phases were separated and pooled, dried over MgSO4, filtered and solvent removed by rotary evaporation. The crude product was stirred in MeOH for 3 hours, and the resulting precipitate filtered, dried and purified using flash chromatography (hexanes), affording 2 fractions—F1 was pure S006 (TLC), F2 contained S006 along with a fluorescent byproduct by TLC. F1, 5.35 g, 14.8%) and F2, 10.4 g (˜75% pure, 22%) as light yellow, powdery solids. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.5 Hz, 4H), 7.30 (d, J=8.5 Hz, 4H), 7.05 (d, J=8.4 Hz, 4H), 6.92 (d, J=8.4 Hz, 4H), 6.13 (s, 2H), 1.34 (s, 18H), 0.91 (s, 18H).
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:30])[CH:11]=[C:12]([C:28]#[N:29])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)=[O:8])[CH3:5].[H][H]>[OH-].[OH-].[Pd+2].C1COCC1>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:30])[CH:11]=[C:12]([C:28]#[N:29])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:8])[CH3:5]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)cn1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)cn1C
Reaction time: 18 h

Procedure:
Add a 1:2 ethanol:THF mixture to 20% palladium hydroxide on carbon (catalytic, 29.4 g) followed by 3-(4-benzyloxy-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (97.93 g, 0.271 mol, prepared in examples E-6a or E-6b). Subject the reaction to 344.74 kPa (50 psi) of hydrogen gas. After 18 hours, filter and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 271.1 (M+1).