Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]>C(O)C>[C:9]([C:8]1[CH:17]=[CH:18][C:5]([NH:2][NH2:3])=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 75 %

Procedure:
20 ml of hydrazine hydrate were added to the suspension of 52.33 g of 4-chloro-3-nitrobenzophenone in 200 ml of abs. ethanol under stirring. The reaction mixture was stirred at room temperature for 75 minutes, then slowly heated to the boiling point. After completion of the violent reaction, the mixture was refluxed for an additional 1 hour. After cooling down, the crystals were filtered by suction, thoroughly washed with water and dried at 80° C. Thus, 38.62 g (75%) of 4-benzoyl-2-nitrophenylhydrazine were obtained as orange-red crystals, m.p.: 163°-164° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1.CCOCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:24][CH2:25][CH3:26]
Reactant: C#Cc1ccccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](C#Cc1ccccn1)(CCCC)CCCC
Reaction time: 0.25 h

Procedure:
Dissolve 2-ethynylpyridine (7.14 g, 69.23 mmol) in THF (350 mL) and cool the solution to −10° C. (ice/methanol) under nitrogen. Add n-butyllithium (1.6 M in hexanes, 47.6 mL, 76.16 mmol) dropwise and stir the mixture. After 15 minutes, add tributyltin chloride (20.7 mL, 76.2 mL) dropwise. Warn the mixture to room temperature overnight. Quench the reaction with water, dilute with ether, and wash with saturated ammonium chloride, then brine. Dry over sodium sulfate, filter and concentrate. No further purification necessary to give the title compound: 1H NMR (CDCl3) δ 8.50-8.54 (m, 1H), 7.51-7.59 (m, 1H), 7.35-7.43 (m, 1H), 7.11-7.18 (m, 1H), 1.59-1.64 (m, 6H), 1.32-1.42 (m, 6H), 1.05-1.10 (m, 6H), 0.88-0.94 (m, 9H).
Reaction SMILES: [CH2:1](O)[CH3:2].Cl.[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:28])=[C:10]([CH2:12][CH2:13][NH:14][CH:15]2[CH2:24][CH2:23][CH2:22][C:21]3[N:20]=[C:19]([C:25]([OH:27])=[O:26])[CH:18]=[CH:17][C:16]2=3)[CH:11]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:28])=[C:10]([CH2:12][CH2:13][NH:14][CH:15]2[CH2:24][CH2:23][CH2:22][C:21]3[N:20]=[C:19]([C:25]([O:27][CH2:1][CH3:2])=[O:26])[CH:18]=[CH:17][C:16]2=3)[CH:11]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1O
Temperature: 25 °C

Procedure:
40 ml of anhydrous ethanol and 4 ml of a 4 N solution of hydrogen chloride in dioxane were added to 1.93 g (5.84 mmol) of rac-5-{[2-(5-fluoro-2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, and the mixture was stirred under reflux overnight. The reaction solution was then cooled to room temperature, and first ethyl acetate and then, slowly, saturated aqueous sodium bicarbonate solution were added. The organic phase was separated off, dried over magnesium sulphate, filtered and concentrated to dryness. This gave 1.67 g (4.66 mmol, 80% of theory) of the target compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH3:18])[C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([NH:9][CH:10]([CH3:18])[C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12])=[O:21])[CH3:24]
Reactant: CC(N)C(=O)c1cccs1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(C)C(=O)c1cccs1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A solution of triethylamine (5.455 g) in chloroform (5 ml) was added dropwise to a stirred solution of 2-amino-1-(2-thienyl)-1-propanone hydrochloride (2.585 g) in chloroform (26 ml) under ice cooling in 5 minutes. To the mixture was added dropwise a solution of ethyl chloroformate (2.929 g) in chloroform (7 ml), and the stirring was continued for 2 hours under the same conditions. The reaction mixture was evaporated, and the residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, washed successively with a saturated aqueous solution of sodium bicarbonate, water, 5% hydrochloric acid and water, dried over magnesium sulfate and evaporated to give an oil of 2-(2-ethoxycarbonylaminopropionyl)thiophene (2.752 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F-:13].[Cs+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [F-]
Reactant: COC(=O)c1cc(Br)cnc1Cl
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.6 %

Procedure:
To a solution of methyl 5-bromo-2-chloronicotinate (170 mg, 0.68 mmol) in 3 mL of DMSO was added CsF (152 mg, 1.0 mmol). The solution was stirred at room temperature for 2 d and then heated at 60° C. for 4 h. After cooling, the mixture was diluted with 30 mL of H2O. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by silica gel flash chromatography to give the desired product (90 mg, 57% yield). MS (ESI+) m/z 234.06, 236.09 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:52]1[S:53][CH:54]=[CH:55][N:56]=1)CCC>CN(C)C=O.C(Cl)(Cl)Cl.[Ag-]=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>[NH2:20][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[CH:17][CH:18]=1)[CH2:10][C@H:9]([O:31][Si:32]([C:35]([CH3:37])([CH3:38])[CH3:36])([CH3:34])[CH3:33])[C@@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:44])[CH3:45])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: O=[Ag-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](N)Cc1ccc(-c2nccs2)cc1)O[Si](C)(C)C(C)(C)C
Yield: 130.1 %

Procedure:
To a solution containing the product from Example 92D (0.050 g, 0.070 mmol) in N,N-dimethylformamide (1.8 mL) were added silver(I) oxide (0.016 g, 0.070 mmol), tetrakis(triphenylphosphine)palladium (0.004 g, 0.003 mmol), and 2-tributylstannylthiazole (0.126 g, 0.337 mmol), and the mixture was irradiated at 60 W in a microwave (internal temperature reached 100° C.) for 2 minutes. The mixture was then irradiated at 200 W in a microwave (internal temperature reached 100° C.) for 4 minutes The reaction was cooled, diluted with chloroform and washed with dilute NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 30% methanol in chloroform containing 0.2% ammonium hydroxide to give the title compound (0.053 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1(=[O:26])[N:11]([C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([OH:15])=[O:14])[C:10](=[O:21])[C:9]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:8]12.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:10]1(=[O:21])[N:11]([C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([O:15][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:14])[C:7](=[O:26])[C:8]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:9]12
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of cesium carbonate (3.819 g, 11.7 mmol.) and (S)-2-phthalimido-6-hydroxyhexanoic acid (6.00 g, 21.6 mmol.) in dimethylformamide (60 ml.) was treated with benzyl bromide (3.30 ml., 4.75 g., 27.7 mmol.). After stirring at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and water. The organic extract was washed with water (twice) and brine, then dried (sodium sulfate), filtered and stripped to give an oil. The oil was flash chromatographed (Merck silica gel, 6/4-ethyl acetate/hexane) to give essentially pure product as a solid. Recrystallization from ethyl acetate/hexane gave 7.173 g. (1st crop) and 394 (2nd crop) for a total of 7.567 g. of pure title product; m.p. 106°-108.5° C.; [α]D =-27.5° (c=1.5, methanol). TLC (75/25 ethyl acetate/hexanes) Rf =0.43.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:15]#[N:16])=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1.[CH2:17](I)[CH3:18]>CN(C=O)C>[CH2:17]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[CH:13]=2)[C:9]([C:15]#[N:16])=[C:10]1[CH3:14])[CH3:18]
Reactant: COc1ccc2c(C#N)c(C)[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) was added a solution of 6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.3 g, 7.0 mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 0° C. After stirring for 1 h, the mixture was poured into ice water and the extracted with CH2Cl2. The organic layer was washed with brine and dried with Na2SO4. The solvent was evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 92% of 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][CH3:13])#[N:2].[H-].[Na+].[C:18]([N:37]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=2)=[N:40][N:39]=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([C:3]1[N:7]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]3[N:37]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:38]=[N:39][N:40]=3)=[CH:55][CH:54]=2)[C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][CH3:13])#[N:2]
Reactant: CCCc1nc(C(C)(O)CC)c(C#N)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCc1nc(C(C)(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 77.4 %

Procedure:
Following a procedure similar to than described in Example 18(a), but using 380 mg of 5-cyano-4-(1-hydroxy-1-methylpropyl)-2-propylimidazole (prepared as described in Preparation 20), 88 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 1.07 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 0.97 g of the title compound were obtained as an amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:59]([C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][CH:63]=1)([O-:61])=[O:60].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:66](=[O:67])[C:65]2[CH:64]=[CH:63][C:62]([N+:59]([O-:61])=[O:60])=[CH:70][CH:69]=2)[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1-c1ccc(OC2CCCCC2)cc1
Yield: 77.5 %

Procedure:
To a stirred mixture of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Example 43, 1.18 mmol, 0.64 g), PPh3 (1.43 mmol, 0.375 g) and p-nitrobenzoic acid (1.5 mmol, 0.251 g) in anhydrous THF (15 mL) at −60° C. was added DIAD (1.43 mmol. 0.289 mL) over 10 min. The stirring was continued and let the reaction slowly attain room temperature over 3 h. The reaction mixture was diluted with ether (300 mL), washed with water (100 mL) followed by saturated sodium bicarbonate (100 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel flash column chromatography by eluting with 20% ethyl acetate in hexanes to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.63 g).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>>[Cl:33][C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C@@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: Clc1cnc(Cl)nc1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(Cl)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2,5-dichloro-pyrimidine following a procedure analogous to that described for Example 79. LC (method 7): tR=1.63 min; Mass spectrum (ESI+): m/z=476/478 (Cl) [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1([CH3:16])[O:9][C:8]2=[N:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][N:7]2[CH2:6]1.Cl[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>CN(C=O)C>[CH3:16][C:5]1([CH2:4][O:3][C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[O:9][C:8]2=[N:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][N:7]2[CH2:6]1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Clc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2nc3ccccc3o2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
Sodium hydride (77 mg, 1.9 mmol) was added to a solution of 2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 33 (0.32 g, 1.6 mmol) in DMF (3 ml) with cooling on ice-bath followed by stirring at 0° C. for 30 minutes. To the reaction mixture, 2-chlorobenzoxazole (0.30 g, 1.9 mmol) in DMF (3 ml) was added with cooling on ice-bath followed by stirring at room temperature for 44 hours. Ice-water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and recrystallized from acetonitrile-isopropanol to afford 2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)benzoxazole (0.20 g, 39%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:11]([CH:28]=[O:29])[CH:10]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:11]([CH:28]=[O:29])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C#CCCCCOC2CCCCO2)c(C=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(CCCCCCOC2CCCCO2)c(C=O)c1

Procedure:
A 1.2 g (2.88 mmol) sample of rac-4-[3-formyl-4-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexyn-1-yl]phenoxy]butanoic acid ethyl ester from example 49 was hydrogenated in ethyl acetate using 80 mg of 10% palladium on carbon, at room temperature, under 1 atmosphere of hydrogen. When the reduction was complete, the catalyst was filtered with suction and the filtrate concentrated under reduced pressure giving rac-4-[3-formyl-4-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]phenoxy]butanoic acid ethyl ester as a pale-yellow oil, in quantitative yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[CH3:18][O-:19].[Na+].CO>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([O:19][CH3:18])=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(Nc2nc(OC)ncc2I)cn1
Temperature: 140 °C
Yield: 90.6 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), sodium methoxide (0.5 M solution in methanol, 0.043 mL, 0.749 mmol) and methanol (1 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 15 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-2-methoxy-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (162 mg, 0.452 mmol, 91% yield). 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H); 8.26 (d, J=2.05 Hz, 1H); 7.83 (dd, J=8.84, 2.56 Hz, 1H); 6.87 (s, 1H); 6.78 (d, J=8.77 Hz, 1H); 3.94 (s, 3H); 3.89 (s, 3H). m/z (ESI, +ve ion) 359.0 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C@H:26]1[CH2:32][CH2:31][S:30][C@H:29]2[CH2:33][CH2:34][CH2:35][C@@H:36]([C:37]([O:39][CH3:40])=[O:38])[N:28]2[C:27]1=[O:41]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:15]([NH:25][C@H:26]1[CH2:32][CH2:31][S:30][C@H:29]2[CH2:33][CH2:34][CH2:35][C@@H:36]([C:37]([O:39][CH3:40])=[O:38])[N:28]2[C:27]1=[O:41])=[O:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)O)Cc1ccccc1
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21

Procedure:
(2R,5R)-2,5-Dibenzyl-6-((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)-6-oxohexanoic acid was synthesized as described in General Procedure G using (2R,5R)-2,5-dibenzylhexanedioic acid (200 mg, 0.613 mmol) and (4S,7S,10aS)-methyl 4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (249 mg, 0.643 mmol) to give a white solid (278 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.31-7.09 (10H, m), 6.88 (1H, d, J=6.6 Hz), 5.30 (1H, t, J=4.7 Hz), 5.17-5.11 (1H, m), 5.07-4.98 (1H, m), 3.68 (3H, s), 3.22-3.11 (1H, m), 3.02-2.92 (1H, m), 2.90-2.81 (1H, m), 2.80-2.63 (4H, m), 2.46-2.37 (2H, m), 2.06-1.96 (2H, m), 1.86-1.75 (2H, m), 1.72-1.47 (7H, m).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH2:19][Mg]Br.ClC1C=C(C=CC=1Cl)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>[Pd]>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH2:19][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COc1cccc(C[Mg]Br)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Pd]
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(Cl)c(Cl)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(OC)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (447 mg, 2.5 mmol) was reacted with 3-methoxybenzylmagnesium bromide (0.25 M in hexanes, (25 mL, 6.3 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3-methoxybenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 40% EtOAc to afford the title compound. 155 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.04-2.21 (m, 1H) 2.50-2.63 (m, 1H) 2.62-2.71 (m, 2H) 2.72-2.86 (m, 2H) 3.23-3.36 (m, 1H) 3.81 (s, 6H) 6.44 (d, J=1.56 Hz, 1H) 6.72-6.85 (m, 3H) 7.22 (t, J=7.78 Hz, 1H) 8.76 (br. s, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)=[CH:20][CH:19]=3)[CH3:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38]1([CH3:50])[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46](Cl)(=[O:48])=[O:47].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:50][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46]([N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:14][CH:13]=1)[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:22][CH:23]=1)[CH3:17])(=[O:47])=[O:48]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(Nc1ccc(OCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(c2ccc(OCCN3CCCC3)cc2)C(C)c2ccc(OC3CCCCO3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
To a solution of [4-(2-pyrrolid in-1-yl-ethoxy)-phenyl]-{1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethyl}-amine (0.050 g, 0.12 mmol) in 0.4 mL methylene chloride was added triethylamine (0.05 mL, 0.36 mmol) and 2-mesitylenesulfonyl chloride (0.066 g, 0.30 mmol). The reaction mixture was stirred at room temperature for 3 days. PS-isocyanate resin (0.050 g) and PS-trisamine resin (0.050 g) were added and the reaction mixture was stirred at room temperature for 45 minutes. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to afford 0.071 g of the crude title compound of Step A which was used without further purification. MS 593.2 (M+1)+