Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[N:15]=[C:14]([NH2:21])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24](=O)[C:25]([O-:27])=[O:26].[CH2:29]1COC[CH2:30]1>C(O)C>[CH2:29]([O:27][C:25]([C:24]1[N:21]=[C:14]2[N:15]([C:16]3[CH2:20][CH2:19][CH2:18][C:17]=3[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:13]2)[CH:23]=1)=[O:26])[CH3:30]
Reactant: C1CCOC1
Reactant: O=C([O-])C(=O)CBr
Reactant: Nc1nc2c(c(OCCOCc3ccccc3)n1)CCC2
Solvent: CCO
Product: CCOC(=O)c1cn2c3c(c(OCCOCc4ccccc4)nc2n1)CCC3
Temperature: 23 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
6.0 gram (21 mmol) of 4-benzyloxyethoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 100 ml dry THF. Bromopyruvate (8 ml) was then added dropwise with in five minutes. The mixture was stirred at 23° C. for one hour. It was then filtered and washed with ether to give a solid. This solid was then dissolved in 50 ml ethanol and refluxed for two hours. The reaction mixture was cooled to room temperature and partitioned between 350 ml chloroform and 200 ml saturated sodium bicarbonate. The organic layer was separated and dried over magnesium sulfate. Filter off the drying agent and concentrate to give 5.36 gram of product (67% Yield). (M+H) 382.1
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Cl[CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].CCCCCC>CN(C)C=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NCCCl
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(O)cc1
Temperature: 25 °C

Procedure:
A mixture of hydroquinone (11.0 g, 100.0 mmol), ethyl 2-chloroethylcarbamate (7.6 g, 50.0 mmol) and potassium carbonate (13.8 g, 100.0 mmol) in 100 ml of dimethylformamide (DMF) is heated at 80° for 20 hours. After cooling to RT, the reaction mixture is poured into ice water and hexane, and the hexane layer is discarded to remove the bis ether by-product. The aqueous layer is then extracted with ether (3×) and the combined ether layers are washed with water, followed with brine, and dried over calcium sulfate. The solvent is removed and the residue is diluted with chloroform to precipitate out the excess hydroquinone. Following filtration, the filtrate is collected and rotoevaporated to give ethyl N-{2-(4-hydroxyphenoxy]ethyl}carbamate, a solid.
Reaction SMILES: [CH:1]1([C:7]([N:9]([CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH2:10]/[C:11](/[CH3:19])=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].C1(C)C=CC=CC=1>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH:1]1([C:7]([N:9]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:10]/[C:11](/[CH3:19])=[CH:12]/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C/C(=C\c1ccccc1)CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C/C(=C\c1ccccc1)CN(CC1CCNCC1)C(=O)C1CCCCC1
Yield: 99.8 %

Procedure:
To a solution of 4-(N-cyclohexylcarbonyl-N-(2-methyl-3-phenyl-2-(E)-propenyl)aminomethyl)-1-t-butoxycarbonylpiperidine (1.55 g, 3.4 mmol) in dichloromethane (15 mL) stirring at room temperature under argon, was added trifluoroacetic acid (3.7 g, 32 mmol). After 1 h toluene (15 mL) was added and the mixture was evaporated under vacuum. The residue was repeatedly dissolved in dichloromethane and evaporated under vacuum to obtain a colorless gum that solidified on standing. This gum contained 4-(N-cyclohexylcarbonyl-N-(2-methyl-3-phenyl-2-(E)-propenyl)aminomethyl)piperidine trifluoroacetic acid salt (1.59 g, quantitative yield) and trace residual trifluoroacetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[C:18]([C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:23][N:24]([CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:20]([C:18]1[N:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:15]=[CH:16][CH:17]=1)=[O:21]
Reactant: CNC1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[1-(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylic acid (247 mg) in dichloromethane (5 ml) are added, at room temperature, N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (130 mg), 4-dimethylaminopyridine (10 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (162 mg). The mixture is stirred at room temperature overnight, and then water is added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives tert-butyl 4-{6-[methyl(1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl]pyridin-2-yl}piperidine-1-carboxylate (219 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[C:15]([CH3:17])([CH3:16])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12]3)=[C:8]([C:22]([NH2:24])=[O:23])[CH:7]=[N:6][N:5]2[CH:25]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[CH3:16][C:15]1([CH3:17])[CH2:14][N:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:25]=[C:2]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:22]([NH2:24])=[O:23]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)CN(S(C)(=O)=O)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Product: Cn1cc(-c2cc3c(NC4CN(S(C)(=O)=O)CC4(C)C)c(C(N)=O)cnn3c2)cn1

Procedure:
The title compound was prepared according to the procedure described for Example 297 by Suzuki coupling with (+/−)-6-bromo-4-(4,4-dimethyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (from Step 1 of Example 297) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>C1C=CC=CC=1>[OH:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][OH:33])[C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: OCCNCCO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCC(=O)N(CCO)CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension is prepared containing 17.8 grams (0.1 mole)-β-benzoyl-propionic acid in 500 ml of anhydrous benzene; then are added in this order and at room temperature 10.5 grams triethylamine, 15 grams ethyl chlorocarbonate and 21 grams (0.2 moles) diethanolamine. The suspension is stirred for over two hours, always at room temperature, and it is then filtered to remove the triethylamine hydrochloride. The liquid is concentrated, at reduced pressure, to about half of the initial volume and it is left to rest about 12 hours at 5°-10° C. temperature. The crystallized solid is filtered, vacuum dried at reduced pressure, about 40° C., and is recrystallized from ethanol. 17.5 grams of N,N-bis(2- hydroxy-ethyl)-β-benzoyl-propionamide with m.p. 98° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>O.C(O)(C)C.[Pd]>[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:2]([C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:3])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1ccc(C=O)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(CN(N)C(=O)OC(C)(C)C)cc1
Temperature: 35 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a 10-gal stainless steel autoclave containing isopropanol (10 L) under nitrogen was charged t-butyl carbazate (1.25 kg, 9.46 mol)followed by isopropanol (2 L). The contents were stirred and heated at 35° C. for 30 min, then 4-methylbenzaldehyde (1.142 kg, 9.51 mol) was added, followed by isopropanol (0.3 L). The contents were heated to 45° C., and a slurry of 5% Pd/C (0.3 kg) in water (0.3 L) and isopropanol (4 L) was added, followed by rinses of isopropanol (2×1 L). The contents were hydrogenated at 40 psig and 45° C. for 4 h, then a second charge of 5% Pd/C (0.3 kg) in water (0.3 L) and isopropanol (4 L) was added, followed by rinses of isopropanol (2×1 L). Hydrogenation was continued at 40 psig and 45° C. for 14 h, at which the reaction was determined to be complete by HPLC. The contents were then cooled to 15° C. and filtered, and the filter cake rinsed with isopropanol (15 L). The filtrate was concentrated in vacuo to afford the title compound (1.97 kg, 88.2%) as a 33.8 wt-% solution in isopropanol.
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>CN(C)C=O>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([O:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2)=[O:23]
Reactant: O=c1[nH]cnc2nc[nH]c12
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCl)Oc1ncnc2nc[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of hypoxanthine (6.8 g, 50 mmoles) in dimethylformamide (200 ml) there is added triethylamine (5.05 g, 50 mmoles) and then at 15° to 20° C., 2-chloroethylisocyanate (5.8 g, 55 mmoles is dripped in. The reaction mixture is stirred at this temperature until dissolution of the solid (approx. for 2 hours), thereafter poured into an ice-water mixture (750 ml), the precipitate of the title product is separated by suction, washed with acetone and dried at room temperature. The yield is 8.2 g (67.8%) of compound Ib, m.p. 320°-240° C. (with decomposition), UV absorption spectrum (in dimethylsulfoxide), λ max 275 nm (log ⃝3.76).
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)=[O:11])(=O)OC.[CH3:19][O:20][C:21](=[O:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C@@H:29]1[CH:34]=O>COCCOC>[CH3:19][O:20][C:21](=[O:36])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C@@H:29]1/[CH:34]=[CH:9]/[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)=[O:11]
Reactant: COP(=O)(CC(=O)c1cccc(Br)c1)OC
Reactant: COC(=O)CCCCCCN1C(=O)CC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of NaH (0.14 g, 1 eq) in 30 mL of ethylene glycol dimethyl ether stirred at 0° C. under nitrogen was added [2-(3-bromo-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (1.82 g, 1.05 eq). After 1 hour at 0° C., 7-((R)-2-formyl-5-oxo-pyrrolidin-1-yl)-heptanoic acid methyl ester (1.44 g, 5.64 mmol) in 2 mL of DME was added slowly. The ice bath was removed and then the mixture was stirred for an additional 3 hours at room temperature. Saturated ammonium chloride solution was added and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by chromatography. EtOAc(1):Hexane(1)followed by EtOAc(5):Hexane(1) to yield 1.6 g of 7-{(R)-2-[(E)-3-(3-bromo-phenyl)-3-oxo-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid methyl ester.
Reaction SMILES: [C:1]1([B:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[B:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:23])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(O)C>[C:1]1([B:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[B:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:23][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[O:8][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccccn1
Reactant: OB(c1ccccc1)c1ccccc1Oc1ccccc1B(O)c1ccccc1
Solvent: CCO
Product: c1ccc(B(OCc2ccccn2)c2ccccc2Oc2ccccc2B(OCc2ccccn2)c2ccccc2)cc1

Procedure:
The entitled compound (38 mg) was obtained by allowing 42 mg of bis(4,4′-(phenylhydroxyboryl)phenyl) ether and 20 mg of 2-hydroxymethylpyridine to act in 0.25 mL of ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=NC2N(O)N=NC=2C=1>CCOC(C)=O.CN(C=O)C>[F:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][C:24]2[CH:25]=[C:26]([NH:27][C:14]([C:11]3([CH3:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:16])[CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1
Reactant: Nc1cccc(Oc2ccc(F)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CC1
Temperature: 80 °C

Procedure:
1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (243 mg, 1.0 mmol), 3-(4-fluorophenoxy)aniline (203 mg, 1.0 mmol), DCC (206 mg, 1.0 mmol), and HOAt (138 mg, 1.01 mmol) were combined in EtOAc (50 mL) and DMF (5 mL). The reaction mixture was heated at 80° C. for 20 hours. Most of the EtOAc was evaporated, resulting in precipitation of a solid, which was removed by filtration. The filtrate was diluted with EtOAc, washed with 1 N aq. HCl, water, and brine, dried, and concentrated under vacuum to give the title compound. MS (ES+) [M+H]+=429.
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[C:3](=[O:25])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH3:24].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[NH2:28][CH2:27][CH2:26][N:2]([CH3:1])[C:3](=[O:25])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH3:24]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCN
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethylcarbamate (1.71 g, 3.5 mmol)) in dichloromethane (50 mL) at 0° C. was slowly added TFA (17 mL). The mixture was stirred (0° C., 2 h) basified to pH 10 with saturated aqueous Na2CO3 and extracted with EA (3×150 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)-N-methyldocosa-4,7,10,13,16,19-hexaenamide (1.31 g, 97%) as a light yellow oil.
Reaction SMILES: Cl[CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N+:25]=[N-:26]
Reactant: CCCCCCCCCCCCC(Cl)c1coc([Si](C)(C)C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](C)(C)C)c1
Reaction time: 144 h

Procedure:
A mixture of 3(1-chlorotridecyl)-5-trimethylsilylfuran (468 mg, 1.31 mmol) and sodium azide (852 mg, 13.1 mmol) in dry dimethylformamide (2 ml) was stirred at 60 degrees for 6 days. Most of the solvent was evaporated under high vacuum and the residue dissolved in water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulfate) extracts gave an oil, which was flash chromatographed on silica using 5% ethyl ether/hexane. Fractions with Rf of about 0.73 on evaporation gave the title azide as a very pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:11].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC#N>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][PH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[Br-:11]
Reactant: COC(=O)CCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)CCCCCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 84.1 %

Procedure:
A solution of 8 (1.25 g, 5.23 mmol, 1.0 equiv.) in CH3CN (4.0 mL, 1.31M) was treated with triphenylphosphine (1.50 g, 5.75 mmol, 1.1 equiv.) and stirred at reflux for 10 h. Additional triphenylphosphine (0.685 g, 2.61 mmol 0.5 equiv.) was added to the reaction mixture and stirring was continued at reflux for 5 h. The reaction mixture was concentrated under reduced pressure and washed repeatedly with Et2O (5×10 mL washes). The remaining residue was then solubilized in the minimum volume of CH2Cl2 and concentrated under reduced pressure to afford 9 as a colorless foam (2.20 g, 2.61 g theoretical, 84.3%): 1H NMR (CDCl3, 250 MHz)δ7.82-7.51 (m, 15H, ArH), 3.70-3.46 (m, 5H, CH3OC(O)R and CH2PPh3), 2.13 (t, 2H, J=7.4 Hz, CH2C(O)OCH3), 1.62-1.43 (m, 6H, alkyl protons), 1.30-1.02 (m, 4H, alkyl protons); FABHRMS (NBA) m/e 419.2154 (C27H32BrO2P-Br- requires 419.2140).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[C:12](Cl)(=[O:14])[CH3:13].Cl>C(Cl)(Cl)(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([C:12](=[O:14])[CH3:13])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(Cl)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(OC)c(C(C)=O)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A mixture of 2 g of 1-chloro-2,4-dimethoxybenzene and 0.9 g of acetyl chloride in 20 ml of CCl4 is cooled to 0° C., and a solution of 1.3 ml of TiCl4 in 7 ml of CCl4 is added dropwise. The reaction mixture is left stirring for 2 hours while the temperature is allowed to rise to r.t. It is poured into a mixture of concentrated HCl and ice, the resulting mixture is extracted with DCM, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a DCM/heptane (70:30; v/v) mixture. 1.19 g of the expected product, m.p.=138° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[O:6][C:7](=[O:10])[NH:8][N:9]=2)[CH2:4][CH2:3]1.[C:11]1([Sn:17](Cl)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([C:5]2[O:6][C:7](=[O:10])[N:8]([Sn:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)[CH2:4][CH2:3]1
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(c2n[nH]c(=O)o2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2nn([Sn](c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)o2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 5 g (0.035 mole) 2-(1'-methylcyclopropyl)-5-oxo-1,3,4-oxadiazoline and 13.5 g (0.035 mole) triphenyl tin chloride in methylene chloride (about 100 ml), 3.5 g (0.035 mole) triethylamine in methylene chloride (about 50 ml) was added dropwise. The reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was refluxed (at about 40° C.) for about 3 hours, cooled and then allowed to stir at ambient temperature for about one hour. The reaction mixture was washed with water and then extracted with methylene chloride. The methylene chloride extract was dried and then stripped. The residue was washed with hexane to precipitate the above-identified product, melting point 165°-167° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:4]=2[S:3]1(=[O:14])=[O:13].[Br:15]N1C(=O)CCC1=O>CC(C)C#N>[Br:15][CH2:12][C:10]1[CH:9]=[CH:8][C:5]2[C:6](=[O:7])[N:2]([CH3:1])[S:3](=[O:13])(=[O:14])[C:4]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)S(=O)(=O)N(C)C2=O
Agent: CC(C)C#N
Product: CN1C(=O)c2ccc(CBr)cc2S1(=O)=O
Yield: 23.7 %

Procedure:
Using a procedure analogous to that described in Preparation 8, from 2,6-dimethyl-1,1-dioxo-benzo[d]isothiazole-3-one (2 g), N-bromosuccinimide (1.7 g) and 2,2'-azo-bis(2-methyl-propionitrile (10 mg) was obtained 650 mg of the title compound. m.p. 153°-154° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[N:10][N:9]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1CO.[CH3:28][OH:29]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([N:21]3[CH2:22][CH2:25][CH:26]([CH2:28][OH:29])[CH2:27]3)=[O:15])=[N:10][N:9]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COC(=O)c1nnc(-c2cnc(Cl)cc2NC(C)C)s1
Reactant: CO
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(C(=O)N2CCC(CO)C2)s1
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate (12) (60 mg, 0.1 mmol) in MeOH (2 mL), (S)-Prolinol (0.9 mmol, 5 equiv) was added and refluxed at 80° C. for 1 h. The reaction mixture was cooled and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH:DCM as eluent to isolate the desired product, (5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone (). LCMS: XBridge Phe 8, 4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.585 min; LCMS (ES-API), m/z 379.8 (M−H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C@H:8]([CH3:11])[CH2:9][OH:10].C(N(CC)C(C)C)(C)C.[S:21](Cl)(Cl)=[O:22]>ClCCl>[CH3:11][CH:8]1[CH2:9][O:10][S@@:21](=[O:22])[N:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: C[C@H](CO)Nc1ccccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CO[S@@](=O)N1c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 599.1 %

Procedure:
A solution of (R)-N-(2-pyridyl)-2-aminopropanol (20.0 g, 0.13 moles) and N,N-diisopropylethylamine (33.6 g, 0.13 moles) in dichloromethane (500 ml) was cooled to 5° C. Then thionyl chloride (15.5 g, 0.13 moles) in dichloromethane (100 ml) was added slowly whilst the temperature was kept below 10° C. The mixture was stirred for 0.5 h. and ice cold water (500 ml) was added. The organic phase was separated and washed with water (5×500 ml). The aqueous phase was back-extracted with dichloromethane (2×500 ml), the organic phases were combined, dried (MgSO4) and evaporated in vacuo to give a brown oil. This was purified on a silica column, eluting with diethyl ether to give (R)-4-methyl-3-(2-pyridyl)-[1,2,3] oxathiazolidine 2-oxide (154.4 g) as a clear oil.