Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:47]([O-:49])=O.[NH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][C:47](=[O:49])[NH:50][CH2:51][CH2:52][N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1CCOCC1
Reactant: O=C([O-])Cl
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CC(COC(=O)NCCN2CCOCC2)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 150(a), from tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 148(h)] there was synthesized the corresponding chloroformate, reaction of which with 4-(2-aminoethyl)-morpholine gave tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(2-morpholin-4-yl-ethylcarbamoyloxymethyl)-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 768 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:20][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OC1CCCC1
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to example 2.2(b) from 2-chloro-5-methanesulfonyl-benzoic acid and cyclopentanol.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]4([CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20][CH2:19]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:26]([CH2:30][CH3:31])[N:27]=[C:28](C)[C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8]2[C:9]3[CH:28]=[N:27][N:26]([CH2:30][CH3:31])[C:10]=3[N:11]=[CH:12][C:13]=2[C:14]2[CH2:18][C:17]3([CH2:23][CH2:22][CH:21]([C:24]4[NH:34][N:33]=[N:32][N:25]=4)[CH2:20][CH2:19]3)[O:16][N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(C#N)CC4)C3)cnc21
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(c5nnn[nH]5)CC4)C3)cnc21

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile (0.00098 mole) (example 40), sodium azide (0.00147 mole) and triethyl amine hydrochloride (0.00147 mol) is taken in toluene. The reaction mixture is refluxed overnight. Toluene is removed and water is added. The extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1Br.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[NH4+]>CCOCC>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
n-Butyllithium (1.6M in hexane, 330 ml) was added dropwise with stirring to a solution of 2,6-dichloro-4-trifluoromethylbromobenzene (163.3 g) in ether while maintaining the temperature below -70° C. The mixture was stirred for 1 hour at -78° C. then ethyl chloroformate (61.7 g) was added while maintaining the temperature below -70° C. The mixture was stirred at room temperature overnight. It was cooled to 0° C. and a saturated aqueous solution of ammonium chloride was added. The layers were separated and the organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give ethyl 2,6-dichloro4-trifluoromethylbenzoate (123.9 g) as a colourless liquid bp 90°-96° C. at 5 mmHg.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[OH:16].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(F)c(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 28.9 %

Procedure:
Add triethylamine (28.6 mL, 205 mmol) dropwise to a mixture of 2-fluoro-5-methylphenol (5.18 g, 41.1 mmol), copper(II) acetate (7.46 g, 41.1 mmol), phenylboronic acid (10.0 g, 82.1 mmol), powdered 4 Å sieves (7 g), and methylene chloride (400 mL). Stir at ambient temperature. After 22 h, filter and concentrate the filtrate. Pirify the residue by silica gel chromatography (50% methylene chloride/hexanes), concentrate and purify again by silica gel chromatography (100% hexanes) to give 2.4 g (29%) of the title compound: MS (m/e): 202 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@:11]2([OH:28])[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C@@H:17]([CH2:18][C@@H:19]([OH:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3.C=O.[BH3-][C:33]#N.[Na+]>C(#N)C.Cl>[CH3:33][N:6]([CH2:7][C@H:8]1[CH2:13][CH2:12][C@:11]2([OH:28])[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C@@H:17]([CH2:18][C@@H:19]([OH:27])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)[O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:29]
Reactant: [BH3-]C#N
Reactant: CN(C)CCONC[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CCON(C)C[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 28 h

Procedure:
To a stirred solution of 0.41 g of 17β-(2-dimethylaminoethoxyamino)methyl-5β-androstane-3β,14β-diol (I-am) and 1.0 ml of 37% aqueous formaldehyde in 10 ml of acetonitrile 0.20 g of NaBH3CN was added. The reaction was stirred for 28 hr and then diluted with 0.1N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was basified to pH 9.5 with 2.5N NaOH and extracted with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using chloroform/methanol/26% aqueous ammonium hydroxide 90/9/1 as the eluant; the fractions containing the title compound were collected and evaporated to dryness under reduced pressure. The residue was dissolved with ethyl acetate and the stoichiometric amount of oxalic acid was added to give 0.33 g of the title compound (I-ap), as a white solid, oxalate.
Reaction SMILES: [C:1]([O:5]/[N:6]=[CH:7]\[C:8]1[C:9]([C:14](=[O:23])[C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=2[OH:22])=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)C>CC(C)=O>[C:1]([O:5]/[N:6]=[C:7](\[OH:26])/[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[OH:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O/N=C\c1cccnc1C(=O)c1cc(Br)ccc1O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)(C)O/N=C(\O)c1cccnc1C(=O)c1cc(Br)ccc1O

Procedure:
To a solution of (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-formylpyridine O-t-butyloxime (500 mg) in acetone (4 ml) was added, at room temperature, Jones reagent (1 ml), and the mixture was stirred for 30 minutes. To the reaction mixture was added diethyl ether. Insolubles then formed were filtered off. To the filtrate was added a small volume of isopropyl alcohol, and the mixture was concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: diethyl ether) to give (Z)-2-(5-bromo-2-hydroxybenzoyl)nicotinic acid O-t-butyloxime (240 mg (Compound 138).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: BrCCCCCCCCCc1ccccc1
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Reaction time: 6 h
Yield: 32.1 %

Procedure:
To a stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (4.7 g, 0.02 mol), 1 bromo-9-phenylnonane (4.2 g, 0.015 mol) and HMPA (10 ml), at 125°-130° C., was added dropwise, during 0.5 h, a mixture of propylene oxide (6 ml) and Et3N (1 ml). The reaction was continued for 6 h, allowed to cool and extracted successively with pet ether, Et2O and Me2CO leaving 1.9 g of insoluble starting material, 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline. The combined pet ether and Et2O extracts were washed (H2O, dil NaOH, H2O) dried (Na2SO4) and concentrated. The residual oil was dissolved in CHCl3, placed on a silica gel column (100 g) and eluted with CHCl3. The eluates were concentrated, triturated with pet ether and crystallized from Et2O (Darco) to give 2.1 g of 6-methoxy-4-methyl-8-nitro- 5-(9-phenylnonoxy) quinoline as yellow crystals, mp 56°-56.5° C. This material was used without further purification.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.[Cl:29][C:30]1[CH:31]=[C:32]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:33][N:34](C(OC(C)(C)C)=O)[CH2:35][CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:51])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:51])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:36][CH2:35][NH:34][CH2:33][C:32]2[CH:45]=[CH:46][C:47]([Cl:48])=[C:30]([Cl:29])[CH:31]=2)[CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N(CC=O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: N[C@@]1(C(=O)O)CN(CCNCc2ccc(Cl)c(Cl)c2)C[C@@H]1CCCB(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N-(3,4-dichlorobenzyl)-N-BOC-glycinaldehyde (0.240 g, 0.75 mmol) in anhydrous 1,2-dichloroethane (5 mL) was stirred at room temperature for 30 min, then cooled by ice bath and treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred for 3 h at room temperature. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and brine (20 mL each), dried (MgSO4), and concentrated in vacuo. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(2-(3,4-dichlorobenzylamino)ethyl)pyrrolidine-3-carboxylic acid (111 mg, 42%) as a white solid. NMR (D2O) δ 7.50-7.60 (m, 2 H), 7.28 (dd, J1=8.5 Hz, J2=2 Hz, 1 H), 4.20 (s, 2 H), 3.94 (d, J=12 Hz, 1 H), 3.84 (dd, J1=11.5 Hz, J2=8 Hz, 1 H), 3.60-3.75 (m, 3 H), 3.30-3.45 (m, 3 H), 2.50-2.65 (m, 1 H), 1.50-1.65 (m, 1 H), 1.10-1.35 (m, 3 H), 0.62-0.72 (m, 2 H). MS (m+1): 417.9; MS (m−H2O+1): 400.3.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>O1CCCC1CO.[OH-].[Pd+2].[OH-]>[NH3:8].[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([C:18]2[C:17]([C:15]([NH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:16])=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:28][CH:27]=1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: N
Product: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 24 h
Yield: 176.4 %

Procedure:
To a solution of the 1-benzyl-4-(4′-trifluoromethylbiphenyl-2-carbonylamino)piperidine (1.47 g) obtained in Example 8a) in tetrahydrofuran-methanol (1:1; 50 mL) was added palladium hydroxide (300 mg) in a stream of argon under ice-cooling. The mixture was stirred for one day at normal pressure under hydrogen atmosphere, and further stirred for one day at normal pressure under hydrogen atmosphere after further addition of palladium hydroxide (300 mg). The reaction mixture was filtered through a Celite pad and washed with methanol. The filtrate and the washings were combined, concentrated in vacuo and purified by column chromatography on silica gel with chloroform:methanol:aqueous ammonia=100:10:1 to give the title compound (1.03 g).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2(CC(O)=O)[NH:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[NH:8]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34].[O:39]1CC[CH2:41][CH2:40]1>>[Br:1][C:2]1[O:6][C:5]([C:7]2[N:15]([CH2:41][C:40]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:39])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CCCNCCC
Reactant: O=C(O)CC1(c2ccc(Br)o2)Nc2cccnc2N1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32 %

Procedure:
A suspension of 2-(5-bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine acetic acid (5.0 g, 0.0155 mole), 1,1'-carbonyldiimidazole (2.52 g, 0.0155 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2.5 hours with a stream of nitrogen bubbling through it. A solution of dipropylamine 4.71 g, 0.046 mole) in tetrahydrofuran (6 ml) was added and the reaction mixture was refluxed for 15 hours, then stirred at room temperature. The solvents were removed under reduced pressure, and the resulting oil was partitioned between ethyl acetate (100 ml) and water (100 ml). The layers were separated, and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with water, twice with a 5% potassium hydroxide solution and twice again with water, dried with magnesium sulfate, charcoaled, and filtered. The solvent was removed under reduced pressure to give an oil which crystallized upon trituration with isopropyl ether. The solid was collected by filtration and dried under high vacuum to give 2.0 g (32%) of title compound, mp 102°-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][N:14]3[C:19](=[O:28])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:30][CH2:31][C:32](Cl)=[O:33]>CCN(C(C)C)C(C)C>[O:21]([CH2:20][C:19]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]1[C:10]1[NH:11][N:12]=[C:8]([C:4]2[CH:3]=[C:2]([N:1]3[CH2:30][CH2:31][C:32]3=[O:33])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)CCBr
Reactant: Nc1cccc(-c2n[nH]c(C3CCCCN3C(=O)COc3ccccc3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN1c1cccc(-c2n[nH]c([C@H]3CCCCN3C(=O)COc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
75 mg of 1-{2-[5-(3-Amino-phenyl)-2H-[1,2,4]triazol-3-yl]-piperidin-1-yl}-2-phenoxy-ethanone were dissolved in MDF and 40 ul DIPEA added. 34 mg of 3-Bromo-propionyl chloride were added at 0° C. and the reaction warmed up to rt and stirred for another 30 min. The reaction mixture was heated to 120° C. using microwave heating and the product was isolated via preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[F:17][C:18]([F:30])([F:29])[C:19]1[N:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=[O:22].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([NH:24][NH:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[N:28][C:19]=1[C:18]([F:17])([F:29])[F:30])=[O:8]
Reactant: NNC(=O)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NNC(=O)c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A mixture of 3,4-dimethoxy-5-nitrobenzoic acid (0.53 g, 2.34 mmol) and 1,1-carbonyldiimidazole (0.42 g, 2.59 mmol) was heated in tetrahydrofuran (10 mL) at reflux for three hours and then cooled to room temperature. 2-Trifluoromethyl-nicotinic acid hydrazide (0.53 g, 2.57 mmol) was added in one portion and the yellowish mixture was stirred at reflux overnight and then allowed to cool to room temperature. The mixture was poured onto cold water (100 mL) and the copious precipitate was filtered off, washed with water and dried to give 2-trifluoromethyl-nicotinic acid N′-(3,4-dimethoxy-5-nitro-benzoyl)-hydrazide (0.71 g, 73%).
Reaction SMILES: [C:1]1(=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17]C(C)(C)C)=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[C:1]1(=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCC2)c2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCC2)c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-water cooled solution of 1,1-dimethylethyl (2E)-3-{4-[cyclopentylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (4) (0.28 g, 0.74 mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid (5 mL) with stirring under a nitrogen atmosphere. After 1 h, the reaction mixture was concentrated in vacuo to give a solid. The solid was dissolved in dichloromethane and the solution was concentrated in vacuo to give a pale tan solid. The solid was triturated with diethyl ether and filtered to give the acrylic acid as an off-white solid. The solid was dried overnight under vacuum at 70° C., however, 1H NMR indicated that solvent remained in the sample. The solid was dissolved in methanol and the solution was concentrated in vacuo to give an oil. The oil was dissolved in methanol and the solution was concentrated in vacuo under high vacuum at 60° C. to give an oil. Dichloromethane was added to the oil and crystallization was induced with the aid of a spatula. The suspension was filtered and the solid was dried in a vacuum oven overnight at 70° C. to give 0.072 g (30%) of compound 5 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.60 (m, 4H), 2.30 (m, 4H), 6.44 (d, J=15.9 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 9.32 (s, 1H). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C27H36Si2O3: 464.2203 (M+.). Found: 464.2210.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN1C(=O)CCC1>[C:32]([O:31][C:30](=[O:36])[NH:29][C@@H:27]([CH3:28])[CH2:26][NH:25][C:9]1[N:8]=[C:7]([C:6]2[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:3][C:2]=2[Br:1])[CH:12]=[CH:11][N:10]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: C[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1nccc(-c2c(Br)nc(C3CC3)n2COCC[Si](C)(C)C)n1)NC(=O)OC(C)(C)C
Temperature: 110 °C

Procedure:
A mixture of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (5.50 g, 12.8 mmol), (S)-tert-butyl 1-aminopropan-2-ylcarbamate (SM-1, 2.68 g, 15.4 mmol), diisopropylethylamine (2.68 mL, 15.4 mmol) and sodium carbonate (2.71 g, 25.6 mmol) in NMP (8 mL) was heated with 110° C. oil bath for 3.5 hours and LCMS analysis of an aliquot indicated reaction completion with desired product. The reaction was allowed to cool to ambient temperature, then partitioned between EtOAc (20 mL) and water (60 mL). The EtOAc layer was washed with water (60 mL), dried (Na2SO4), and concentrated to a light yellow foam (6.89 g, 12.1 mmol). A small portion of material was further purified by flash chromatography (SiO2, EtOAc in heptane): LCMS (m/z) 567.3 (MH+), tR=1.03 minutes; 1H NMR (CDCl3, 300 MHz) δ −0.09 (s, 9H), 0.80 (t, J=8.2 Hz, 2H), 0.98-1.07 (m, 2H), 1.10-1.18 (m, 2H), 1.21 (t, J=6.5 Hz, 3H), 1.40 (s, 9H), 1.91-2.08 (m, 1H), 3.41 (t, J=8.2 Hz, 2H), 3.44-3.59 (m, 2H), 3.82-4.01 (m, 1H), 4.65-4.87 (m, 1H), 5.41-5.61 (m, 1H), 5.78-5.99 (m, 2H), 7.10 (d, J=5.0 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:21])C=1.ClC1C=C(C=CC=1)C(O)=O>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:12])=[O:21])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C(=O)CBr)cc1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(C(=O)CBr)cc1
Yield: 33.2 %

Procedure:
A solution of 2-bromo-1-(4-methylsulphanylphenyl)-1-ethanone (3.7 g, 15 mmol) in CHCl3 (50 ml) is maintained at a temperature of −5° C. A solution of m-chloroperbenzoic acid (70%, 3.7 g, 15 mmol) in CHCl3 (30 ml) cooled to 0° C. is added dropwise while maintaining an IT of −5° C. to 0° C. After stirring for ½ hour in the cold, the deposited m-chlorobenzoic acid is filtered off. The filtrate is first washed with NaHCO3 solution (8% strength, 50 ml) until acid-free and then rewashed with water (50 ml). The CHCl3 phase dried over Na2SO4 sicc. is concentrated in vacuo. A yellowish residue (1.3 g) results.