Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[C:50](OC(=O)C)(=[O:52])[CH3:51]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][N:13]([C:50](=[O:52])[CH3:51])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1CN(CC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mole) in anhydrous tetrahydrofuran (1.2 liters) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mole) and acetic anhydride (45.0 ml, 0.477 mole). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:22][CH2:23][CH2:24][CH2:25][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=CCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.60 mL (4.3 mmol) of triethylamine was added and dissolved in a suspension of 0.69 g (3.9 mmol) of ascorbic acid in acetonitrile (8 mL). The above crude product of (5,9,13-trimethyltetradec-4-enyl)tosylate was added thereto at room temperature, and the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([OH:20])=O)[NH:15][N:14]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C@@H:22]([CH3:38])[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([Cl:37])[CH:30]=2)=[N:25]1>>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([NH:21][C@@H:22]([CH3:38])[CH2:23][N:24]3[CH:28]=[CH:27][C:26]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([Cl:37])[CH:30]=4)=[N:25]3)=[O:20])[NH:15][N:14]=2)[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Yield: 44.9 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-(1-benzyl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid (0.268 g, 0.997 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified with flash chromatography. Yield 44.9%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 4.27 (dd, 1H), 4.41 (dd, 1H), 4.53-4.63 (m, 1H), 5.26 (s, 2H), 6.61 (d, 1H), 6.76 (s, 1H), 7.00-7.05 (m, 2H), 7.28-7.36 (m, 5H), 7.49 (d, 1H), 7.58-7.63 (m, 2H), 7.78 (dd, 1H), 8.03 (s, 1H), 11.75 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2scnc2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2scnc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5,7-dichlorothiazolo[4,5-d]pyrimidine 42, morpholine (8.11 mL, 2.2 eq.) and MeOH (150 mL) was stirred at room temperature for 1 h. The reaction mixture was then filtered, washed with water and MeOH, to yield 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:27].[OH-].[Na+]>C(O)CO.O1CCOCC1.[Cu-]=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:12][C:8]([C:6]2[N:7]=[C:2]([NH2:27])[CH:3]=[CH:4][CH:5]=2)=[N:9]1
Reactant: [NH4+]
Reactant: Fc1ccccc1Cn1nc(-c2cccc(Br)n2)nc1-c1nccs1
Agent: O=[Cu-]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: Nc1cccc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
To a suspension of 2-(3-(6-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole (I-19) and copper(I) oxide (0.2 eq) in ethylene glycol-dioxane (4:1) in a sealed tube was added ammonium hydroxide solution (˜29% in water, ˜30 eq). The resultant mixture was warmed to 100° C. and stirred at that temperature for 24 h. The reaction solution was cooled to rt, poured into 1N NaOH solution and then extracted with EtOAc. The organic phases were dried over Na2SO4, filtered and conc. The crude product was purified using SiO2 chromatography and an appropriate gradient (EtOAc/hexanes) to give 6-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-2-amine as a white solid (I-14, 69% yield).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].CC(C)([O-])C.[K+].[CH:38]([C:40]1[N:41]=[C:42]([NH:54][C:55](=[O:57])[CH3:56])[S:43][C:44]=1[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([S:52][CH3:53])=[CH:48][CH:47]=1)=O>CN(C=O)C>[C:55]([NH:54][C:42]1[S:43][C:44]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([S:52][CH3:53])=[CH:50][CH:51]=2)=[C:40](/[CH:38]=[CH:10]\[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)[N:41]=1)(=[O:57])[CH3:56]
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CSc1ccc(Cc2sc(NC(C)=O)nc2C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C\c2nc(NC(C)=O)sc2Cc2ccc(SC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
[4-(Methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (4.81 g) and DMF (60 ml) were combined under N2 atmosphere. Then potassium tert-butoxide (1.32 g) and N-{4-formyl-5-[4-(methylthio)benzyl]-1,3-thiazol-2-yl}acetamide (3 g) were added to the suspension at 0° C. The reaction mixture was stirred at r.t. for 18 hours, poured into ice-water, and extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CHCl3/AcOEt (2:1) as an eluent. The solid was suspended in AcOEt, and the suspension was filtered. The filtrate was concentrated in vacuo to give methyl 4-((Z)-2-(2-(acetylamino)-5-[4-(methylthio)benzyl]-1,3-thiazol-4-yl}vinyl)benzoate (4.16 g) as a yellow amorphous substance.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CC(=O)OCC>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: Fc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(2-fluorophenyl)piperazine (215 mg, 1.2 mmol), and D1 EA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.77 (m, 4H) 3.10 (m, 4H) 4.06 (s, 2H) 7.08 (m, 4H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 329 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([C:15]([CH3:16])=[N:18][N:19]=3)[N:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)NN
Reactant: Clc1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(Cl)c3)nn12

Procedure:
A mixture of 2.0 g. of 3-chloro-6-(m-chlorophenyl)pyridazine, 50 ml. of n-butanol and 1.32 g. of acetylhydrazine is refluxed for 18 hrs. The mixture is concentrated to dryness under vacuum and the residue dissolved in methylene chloride. The solution is passed through a short column of hydrous magnesium silicate. The eluent is refluxed while hexane is gradually added until crystals separated. Cooling and filtering gives 1.50 g. of crystals, m.p. 171°-172.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:12]1[C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:9](=[O:11])[CH3:10].C(N(CC)CC)C>CN(C=O)C.C([O-])(O)=O.[Na+].[Pd](Cl)Cl>[C:9]([N:8]1[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH:18]=[CH:19][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:20][C:6]=2[CH2:7]1)(=[O:11])[CH3:10]
Reactant: C=Cc1cccnc1N(Cc1cc(Br)ccc1I)C(C)=O
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Br)ccc2C=Cc2cccnc21
Temperature: 65 °C
Yield: 77 %

Procedure:
To a stirred mixture of N-(5-Bromo-2-iodo-benzyl)-N-(3-vinyl-pyridin-2-yl)-acetamide E (60.0 mg, 0.13 mmol) and triethyl amine (55.0 μL, 0.39 mmol) in anhydrous DMF (1.4 mL) under argon was added Palladium dichloride (4.60 mg, 26 μmol). This mixture was heated at 65° C. for 1 h, cooled and diluted with saturated NaHCO3 solution (20 mL). The mixture was extracted with EtOAc (4×30 mL). The combined EtOAc extracts were washed with water (3×10 mL), brine (1×10 mL), dried (MgSO4), filtered and concentrated in vacuo. This was purified by a ISCO auto CombiFlash with a RediSep 4 g column, eluted with CH2Cl2-EtOAc, detected at 254 nM to give 33 mg of 78F in 77% yield. HPLC Rt=3.04 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=329.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>O1CCOCC1.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[CH:6]=[N:5]2
Reactant: Clc1cnc2cc(Br)ccc2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: C=C(OCC)c1cnc2cc(Br)ccc2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Dichlorobis(triphenylphosphine)-palladium(II) (17.30 mg, 0.025 mmol) was added to a solution of 6-bromo-2-chloroquinoxaline (60 mg, 0.246 mmol) and tributyl(1-ethoxyvinyl)stannane (107 mg, 0.296 mmol) in dioxane (1.5 mL) and the mixture was stirred at 110° C. for 2 h. The reaction was diluted with MeOH, and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield 6-bromo-2-(1-ethoxyvinyl)quinoxaline (36 mg, 0.129 mmol, 52.3% yield) as white solid. LC-MS retention time 2.76 min; m/z 279 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH:20]([C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1)[C:21]#[N:22]>>[C:21]([CH:20]([C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1)[NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])#[N:22]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC1(C(N)C#N)COC1
Product: CC1(C(C#N)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c) and 2-amino-2-(3-methyloxetan-3-yl)acetonitrile (example 251b) as starting materials and isolated (105 mg, 85%); MS (ESI, m/z): 370.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O.CC(C)=O>[CH2:24]([O:17][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8]([O:7][C:6]=2[CH:5]=1)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2ccccc2oc2cc(O)cc(O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=c1c2ccccc2oc2cc(OCc3ccccc3)cc(O)c12
Temperature: 60 °C
Yield: 42.6 %

Procedure:
The compound (1.77 g, 7.75 mmol) synthesized in Step 1 of Example 2 and K2CO3 (2.76 g, 0.02 mol) were charged to a dry round-bottom flask, and anhydrous acetone (200 mL) was added thereto. To the reaction mixture was added benzyl bromide (1.38 mL, 11.63 mmol), followed by stirring under reflux at 60° C. for one day. After the reaction was completed, the reaction liquid was cooled to room temperature, and 200 mL of water was added thereto. The reaction liquid was acidified with 3M-HCl and extracted twice with ethyl acetate. The organic layer was combined, successively washed with water and brine, and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: CH2Cl2) to give the title compound (1.05 g, 42.6%) as a light yellow solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH3:14].[Si:24]([N:31]1[C@H:34]([CH2:35][CH:36]=[O:37])[C@@H:33]([C@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:39])[C:32]1=[O:48])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O1CCCC1>[Si:24]([N:31]1[C@H:34]([CH2:35][CH:36]([OH:37])[CH2:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@@H:33]([C@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[CH3:39])[C:32]1=[O:48])([C:27]([CH3:30])([CH3:28])[CH3:29])([CH3:26])[CH3:25]
Reactant: CC(=O)OCc1ccccc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(O)CC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.81 mmol) is added by syringe to a solution of diisopropylamine (1.81 mmol) in 9 ml of freshly distilled tetrahydrofuran at -78° C. The resulting solution is stirred for 15 min at -78° C. Benzyl acetate (1.81 mmol) is then added dropwise by syringe and the resulting solution is stirred at -78° C. for 20 min. A solution of (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one (1.64 mmol) in 3 ml of anhydrous tetrahydrofuran is added slowly by syringe. The reaction mixture is stirred at -78° C. an additional 15 min and then quenched by addition of saturated aqueous ammonium chloride solution. Ethyl acetate (50 ml) is added and the organic phase is separated, washed with water (2×10 ml) and brine and dried over magnesium sulfate. Removal of solvents in vacuo gives a white solid which is chromatographed on a short silica gel column (40 % ether in petroleum ether) to yield (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(3-benzyloxycarbonyl-2-hydroxypropyl)-azetidin-2-one. n.m.r. (CDCl3) δ7.32 (s,5), δ5.1 (s,2), δ4.0 (m,3), δ2.4-3.8 (m,4), δ2.0 (m,2), δ1.25 (overlapping d, 3), δ0.95 (s,9), δ0.9 (s,9), δ0.3 (s,6), δ0.18 (s,6).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:22][CH3:23])=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])[C:14]=2[CH:21]=1)(=O)=O.[C:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>C(O)C>[CH3:23][O:22][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:33]2[CH2:34][CH2:35][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:21][C:14]2[C:15]([CH3:20])=[CH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: COc1cc2oc(=O)cc(C)c2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: CCO
Product: COc1cc2oc(=O)cc(C)c2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 77 %

Procedure:
Method B (26 h at 50° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (example 74) and 4-phenylpiperidine; yield 77%; fusion point 141°-143° C. (from isopropanol and ethanol). Fumarate: method E; yield 89%; fusion point 221°-223° C. (from ethanol).
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3]1=O.[CH3:16][Li]>CCOCC>[CH3:1][N:2]1[CH:3]([CH3:16])[CH2:4][CH2:5][C@H:6]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1C(=O)CC[C@H]1COc1cccnc1
Reactant: [Li]C
Solvent: CCOCC
Product: CC1CC[C@@H](COc2cccnc2)N1C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A 1.24 g (6.0 mmol) sample of 3-(1-methyl-2-oxo-5-(S)-pyrrolidinylmethoxy)-pyridine, prepared as in Example 22b above, was dissolved in 50 mL of ether and cooled to -78° C. To this solution was added 4.71 mL (6.6 mmol) of methyl lithium, and the solution was warmed to room temperature and stirred for 2 hours. The solution was cooled to 0° C., 66 mL of a 1M solution of LAlH4 was added, and the reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched by addition of 1 mL of methanol, the solvents removed, and the residue purified by chromatography on silica gel, eluting with 200:1 to 100:1 chloroform:methanol. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 83.4-8.30 (m, 1H), 8.24-8.17 (m, 1H), 7.25-7.27 (m, 2H), 4.08-4.03 (m, 1H), 3.93-3.87 (m, 1H), 2.83-2.73 (m, 1H), 2.43 (s, 3H), 2.43-2.35 (m, 1H), 2.03-1.82 (m, 2H), 1.70-1.40 (m, 2H), 1.13 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([O:27][CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:43]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:14]([O:27][CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:13]=2)=[O:8])=[CH:35][CH:36]=1)(=[S:43])[NH2:2]
Reactant: S
Reactant: CC(C)(C)OCOc1cc(NC(=O)NC(=O)c2ccc(C#N)cc2)ccc1OCC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OCOc1cc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (2.2 g), pyridine (186 ml), triethylamine (26 ml) and H2S gas were reacted to give t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-2-(t-butoxymethoxy)phenoxyacetate (2.6 g) as a yellow solid: m.p. 198°-199° C.; NMR Spectrum (DMSO-d6) 1.43 (9H, s), 1.44 (9H, s), 4.61 (2H, s), 4.66 (2H, s), 6.89 (1H, d), 7.09 (1H, dd), 7.27 (1H, d), 7.98 (4H, m), 9.68 (1H, s), 10.02 (1H, s), 10.66 (1H, s), 11.07 (1H, s); Mass Spectrum m/Z 582 (M +Na)+.
Reaction SMILES: F[C:2]1C=CC(CCC2C(C(O)=O)=NC(OC(C3C=CC(F)=CC=3)CC3N(C)C=NC=3)=CC=2)=C[CH:3]=1.[F:35][C:36]1[CH:80]=[CH:79][C:39]([CH2:40][CH2:41][C:42]2[C:43]([C:64]([NH:66][C@@H:67]([CH2:75][CH2:76][S:77][CH3:78])[C:68]([O:70][C:71](C)([CH3:73])[CH3:72])=[O:69])=[O:65])=[N:44][C:45]([O:48][CH:49]([C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)[CH2:50][C:51]3[N:55]([CH3:56])[CH:54]=[N:53][CH:52]=3)=[CH:46][CH:47]=2)=[CH:38][CH:37]=1.C1(OC(=O)[C@H](CCSC)N)CCCC1.C(OC(=O)[C@H](CCSC)N)(C)(C)C>>[F:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:40][CH2:41][C:42]2[C:43]([C:64]([NH:66][C@@H:67]([CH2:75][CH2:76][S:77][CH3:78])[C:68]([O:70][CH:71]3[CH2:72][CH2:3][CH2:2][CH2:73]3)=[O:69])=[O:65])=[N:44][C:45]([O:48][CH:49]([C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)[CH2:50][C:51]3[N:55]([CH3:56])[CH:54]=[N:53][CH:52]=3)=[CH:46][CH:47]=2)=[CH:79][CH:80]=1
Reactant: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)n1)c1ccc(F)cc1
Reactant: CSCC[C@H](NC(=O)c1nc(OC(Cc2cncn2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: CSCC[C@H](N)C(=O)OC(C)(C)C
Agent: CSCC[C@H](N)C(=O)OC1CCCC1
Product: CSCC[C@H](NC(=O)c1nc(OC(Cc2cncn2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1)C(=O)OC1CCCC1

Procedure:
The title compound was prepared from 3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyridin-2-carboxylic acid by a similar route to that described for the preparation of tert-butyl (2S)-2-{3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyrid-2-oylamino}-4-methylsulfanylbutyrate but using L-methionine cyclopentyl ester rather than L-methionine-tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1F

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-fluoro-3-methoxy-phenylboronic acid (CAS RN 352303-67-4) and using preparative HPLC for the chromatographic purification. Off-white solid (42%). MS (ESI): m/z=472.8 [M+H]+.