Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][CH:6]1[CH2:11][C:10](=[O:12])[O:9][C:7]1=[O:8].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:19][C:13]1[CH:18]=[CH:17][C:16]([C:10]([CH2:11][CH:6]([CH3:5])[C:7]([OH:9])=[O:8])=[O:12])=[CH:15][CH:14]=1
Reactant: Cc1ccccc1
Reactant: CC1CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(C(=O)CC(C)C(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
Aluminium trichloride (50.7 g, 0.38 mol) is added, portionwise, over 15 min, to a solution of methylsuccinic anhydride (20 g, 0.175 mol), toluene (32.3 g, 0.35 mol) and nitrobenzene (100 ml). The reaction mixture is stirred for 3 hours and then warmed to 80° C. for half an hour. On cooling, it is quenched with water (75 ml) and then conc HCl (30 ml). The solid ppt. is filtered, dissolved in Na2CO3 solution, washed with CH2Cl2, re-acidified and the product filtered to yield 23.4 g of 3-(4-methylbenzoyl)-2-methyl-propionic acid as a white solid, m.p. 168°-170°.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:41][C:42]([OH:44])=[O:43])[CH2:6][CH2:7][N:8]([CH2:30][CH2:31][N:32]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][C:34]([OH:36])=[O:35])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[C:13]([Br:26])[CH:12]=1)([OH:3])=[O:2].[I:45]I>>[C:1]([CH2:4][N:5]([CH2:41][C:42]([OH:44])=[O:43])[CH2:6][CH2:7][N:8]([CH2:30][CH2:31][N:32]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][C:34]([OH:36])=[O:35])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([I:45])[CH:20]=2)=[C:13]([Br:26])[CH:12]=1)([OH:3])=[O:2]
Reactant: II
Reactant: O=C(O)CN(CCN(CCN(CC(=O)O)CC(=O)O)[C@@H](Cc1cc(Br)c(Oc2ccc(O)cc2)c(Br)c1)C(=O)O)CC(=O)O
Product: O=C(O)CN(CCN(CCN(CC(=O)O)CC(=O)O)[C@@H](Cc1cc(Br)c(Oc2cccc(I)c2)c(Br)c1)C(=O)O)CC(=O)O
Yield: 61 %

Procedure:
N,N-Bis[2-[bis(carboxymethyl)amino]ethyl]-3,5-dibromo-O-(4-hydroxyphenyl)-L-tyrosine, prepared according to Example 13 Step A, was monoiodinated in the outer ring with I2/KI at room temperature. The solution was concentrated, then acidified to pH 1 with 37% HCl and purified by preparative HPLC. Yield 61%.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:26][CH2:25][CH2:27][NH:28][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCO)ccc21
Yield: 8.9 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (9 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (90 mg), ethanolamine (17 mg), HBTU (114 mg), and DIEA (66 uL). LC/MS: m/z 402.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.35 (bs, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 7.45 (d, 1H), 7.37 (dd, 1H), 4.72 (t, 1H), 3.63 (bs, 3H), 3.52 (q, 2H), 3.34 (q, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9])=[O:4].[CH2:18]([O:22][CH2:23][CH2:24][CH:25]([CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH3:26])[CH2:19][CH2:20][CH3:21].Cl(O)(=O)(=O)=O>C(Cl)Cl>[CH2:18]([O:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH2:27][CH2:28][CH2:29][C:30]([C:15]1[CH:16]=[C:11]([C:8]([CH3:10])([CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH3:9])[CH:12]=[CH:13][C:14]=1[OH:17])([CH3:32])[CH3:31])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOCCC(C)CCC=C(C)C
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCCCOCCC(C)CCCC(C)(C)c1cc(C(C)(C)CCCC(=O)OC)ccc1O

Procedure:
10.3 Parts of 4-(5-methoxycarbonyl-2-methyl-pent-2-yl)-phenol, 4.2 parts of citronellyl n-butyl ether, and 0.5 parts of 70% perchloric acid in 25 parts of methylene chloride were stored at room temperature for 4 days. The work-up followed Example 61 and gave on distillation 2-(8-n-butyloxy-2,6-dimethyl-oct-2-yl)-4-(5-methoxycarbonyl-2-methyl-pent-2-yl)-phenol with b0.8, 228°-36° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([O-])=[O:26])[S:24][C:17]=12.[Li+]>>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([C:25]([C:23]1[S:24][C:17]3[C:18](=[N:19][CH:20]=[CH:21][C:16]=3[Cl:15])[CH:22]=1)=[O:26])[CH2:12]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CC(C)(C)OC(=O)NC1C2CNCC21
Agent: [Li+]
Product: CC(C)(C)OC(=O)NC1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC21

Procedure:
The title compound was prepared from (3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 394/396 (MH+); HPLC Rf: 5.30 min.; HPLC purity: 72%.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1][CH:2]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1=CCc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2=CCc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
5 g (0.031 mol) of 1H-indene-3-ethanol are dissolved in 50 ml of dry pyridine. The mixture is stirred and cooled using an ice bath, 5.9 g (0.031 mol) of 4-methylbenzenesulphonyl chloride are added in portions, and stirring is continued under cold conditions for 1 h and then at room temperature for 4 h. The solution obtained is poured into a mixture of 100 ml of 10N hydrochloric acid and 200 g of ice. The mixture is extracted twice with diethyl ether, and the organic phase is separated, washed with water, dried over magnesium sulphate and filtered. The filtrate is evaporated under reduced pressure. 7 g of an oily product are obtained which is used as it is in the following step.
Reaction SMILES: [NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[C:24]1([CH2:30][C:31](O)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[NH:8][C:31](=[O:32])[CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(O)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)Cc1ccccc1)C(=O)NCc1ccc(O)cc1
Yield: 61 %

Procedure:
Prepared analogously to Example 5f) from (R)-N5 -[amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl)-ornithinamide, phenylacetic acid and TBTU in a yield of 61% of theory. It was further processed without purification.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([O:23][CH3:24])=[CH:14][C:15]([NH2:22])=[C:16]([CH:21]=2)[C:17]([O:19]C)=O)[CH2:4][CH2:3]1.O.N.[C:27](#[N:29])[CH3:28]>>[O:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:16]3[C:15](=[CH:14][C:13]=2[O:23][CH3:24])[N:22]=[C:27]([CH3:28])[NH:29][C:17]3=[O:19])[CH2:6][CH2:7]1
Reactant: COC(=O)c1cc(OCCCN2CCOCC2)c(OC)cc1N
Reactant: CC#N
Agent: Cl
Agent: N
Solvent: O
Product: COc1cc2nc(C)[nH]c(=O)c2cc1OCCCN1CCOCC1
Yield: 98 %

Procedure:
Dry HCl gas was passed (until the clear solution observed) to a solution of methyl 5-(3-morpholinopropoxy)-2-amino-4-methoxy-benzoate (1.0 g, 3.0 mmol) in acetonitrile (16 mL) for 30 min at rt. The reaction mixture was refluxed for 3 h and attained to rt. The solution was poured into ice cooled water and basified with ammonia solution. The solution was extracted with EtOAc (3×100 mL) and the combined EtOAc layer was washed water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as an off-white color solid (1.0 g, 98%), mp 236-238° C. 1H NMR (400 MHz, CDCl3): δ 11.60 (1H, br s), 7.59 (1H, s), 7.08 (1H, s), 4.23 (2H, t, J=6.6 Hz), 3.97 (3H, s), 3.73 (4H, t, J=4.6 Hz), 2.56 (2H, t, J=7.0 Hz), 2.56 (3H, s), 2.48 (4H, t, J=4.4 Hz), 2.09 (2H, pentet, J=6.8 Hz); LC-MS (positive ion mode): m/z 334 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)([C:12]#[N:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N.O>CO.[Ni]>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:12][NH2:13])([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(C#N)(CC2CCOCC2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)N1CCC(CN)(CC2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a heavy wall flask was placed 1-(ethylsulfonyl)-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidine-4-carbonitrile (10) (1.25 g, 4.17 mmol) and 2N ammonia in methanol (50 ml). To this was added Raney nickel slurry in water (1.073 g, 12.52 mmol) and the reaction agitated under hydrogen atmosphere (45 psi) at room temp for 12 hours. The catalyst was filtered off using celite and washed with MeOH (200 ml) and the organics were concentrated in vacuo to give 1-[1-(ethylsulfonyl)-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidin-4-yl]methanamine (11) as a clear semi-solid. MS 304 (M+1)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]([NH2:26])=[S:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[S:25][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=3)[N:26]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: NC(=S)Nc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Product: CS(=O)(=O)c1ccc(-c2csc(Nc3ccc(Cl)c(Cl)c3)n2)cc1
Yield: 78 %

Procedure:
(3,4-Dichloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amine was prepared in 78% yield using the procedure described in example 31 from 2-Bromo-1-(4-methanesulfonyl-phenyl)-ethanone and (3,4-Dichloro-phenyl)-thiourea. 1H NMR (300 MHz, DMSO-d6) δ 8.16-7.56 (m, 8H), 3.24 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([OH:9])[N:4]=1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N12CCN(CC1)CC2.O>CN(C)C=O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:18]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:19])[N:4]=1
Reactant: Oc1nccc(C(F)(F)F)n1
Reactant: O=C(Cl)N1CCOCC1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1nccc(C(F)(F)F)n1)N1CCOCC1
Yield: 79.4 %

Procedure:
A solution of 4-(trifluoromethyl)-2-pyrimidol (0.49 g, 3.00 mmol), 4-morpholinecarbonyl chloride (0.45 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.51 g, 3.00 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo, The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70→50:50)) yielding the title compound (0.66 g, 80% yield) as a white solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:5]=2[N:6]=1.[C:23]1([CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30]I)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:30][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:5]=3[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ICC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCOc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)CCOc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 29 %

Procedure:
Using ethyl 3-[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]propionate and 2,2-diphenylethyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 29%.
Reaction SMILES: N[C:2]1[C:7]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([CH3:18])=[CH:4][C:3]=1[CH2:19][C:20]([NH2:22])=[O:21].Cl>C(O)C.O>[CH3:18][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([C:8](=[O:17])[C:9]3[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=3)[CH:6]=1)[NH:22][C:20](=[O:21])[CH2:19]2
Reactant: CSc1ccc(C(=O)c2cc(C)cc(CC(N)=O)c2N)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CSc1ccc(C(=O)c2cc(C)cc3c2NC(=O)C3)cc1
Yield: 61.7 %

Procedure:
A solution of 18.8 g (0.06 mole) of 2-amino-5-methyl-3-[4-(methylthio)benzoyl]phenylacetamide in 1700 ml of absolute ethanol with 16.6 ml (0.2 mol) of concentrated hydrochloric acid was heated at reflux for 45 min. The mixture was diluted with 50 ml of water and cooled. The precipitate was collected and recrystallized from 60% aqueous ethanol to give 11.0 g (62%) of the titled compound as tan crystals, m.p. 176.0°-177.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[N:21]([O-])=[O:22].[Na+]>Cl>[CH2:6]([C@H:2]([NH2:1])[C:3]([OH:5])=[O:4])[CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][S:13][N:21]=[O:22])=[O:9]
Reactant: O=N[O-]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Product: N[C@@H](CCC(=O)N[C@@H](CSN=O)C(=O)NCC(=O)O)C(=O)O
Temperature: 0 °C
Yield: 80 %

Procedure:
Briefly, to a stirred ice-cold solution of glutathione (GSH) (154 mg, 0.5 mmol) in 5 ml of 0.2 N HCl was added a portion of NaNO2 (35 mg, 0.5 mmol). This reaction gives GSNO in a high yield of more than 80%. The final red solution was protected from light with aluminum foil and stable in the dark, which allow it to be used directly after synthesis without purification.
Reaction SMILES: [C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:17][O-:18].[Na+]>CO>[C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[O:18][CH2:17]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC=Cc1ccc(OC(C)=O)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC=Cc1ccc(OCC2CO2)cc1
Temperature: 50 °C

Procedure:
13.0 g (0.05 mol) of p-(2-acetylaminovinyl)-acetoxy-benzene are suspended in 100 ml of absolute methanol, a solution of 2.8 g (0.05 mol) of sodium methoxide in 20 ml of absolute methanol is added and thereafter the mixture is warmed to 50°C for 15 minutes. It is then evaporated to dryness in vacuo. The resulting crude phenolate of p-(2-acetylaminovinyl)-phenol is heated with 65 ml of epichlorohydrin to the boil for 18 hours, under a reflux condenser and whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and ethyl acetate and the organic phase is siphoned off, dried over sodium sulphate and evaporated. After crystallisation of the crude product, thus obtained, from acetone-ether, 1-[p-(2-acetylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 135°-137°C is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.CN(C)C=O>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccc(Cl)cc2)cn1)c1ccccc1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A solution of 4-chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide (0.50 g, 2.01 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.01 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.22 g, 0.34 mmol) in dimethylformamide (10 mmol) was stirred at room temperature for 2 hours. Water (100 mL) was added and a thick oil was being formed. The water was decanted and the residue dissolved in dichloromethane, dried over sodium sulphate, filtered and evaporated in vacuo. Ethyl acetate was added and the solution was heated briefly (some of the compound does not dissolve). The solvent was decanted and heptane was added to it. After standing overnight, the crystals were isolated by suction, washed with heptane and dried in a vacuum oven at 45° C. Further purification by flash column chromatography (SiO2, ethyl acetate:heptane 50:50), yielded the title compound (0.41 g, 53% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:17]([CH3:19])[CH3:18])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C[N:27](C)C=O.[OH-].[NH4+]>ClCCl>[NH2:27][C:14]([C:11]1([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)C1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-isopropylpiperidine-4-carboxylic acid (500 mg, 1.843 mmol) in dichloromethane (5 ml) were added oxalyl chloride (2.76 ml, 5.53 mmol) and a drop (ca. 10 μl) of dimethylformamide. After stirring 1 h at room temperature, the mixture was concentrated and then dissolved in tetrahydrofuran (5 ml). Concentrated ammonium hydroxide (5 ml, 36.0 mmol) was added and the mixture was stirred overnight at room temperature, and then concentrated to a small volume, poured into 50 ml of 1 M NaOH, and diluted with 50 ml of ethyl acetate. The phases were separated, the aqueous was extracted with 2×25 ml of ethyl acetate, and then the combined organics were washed with 25 ml of brine, dried (Na2SO4), and concentrated to provide the title compound (411 mg, 1.520 mmol, 82% yield). Mass spectrum (ESI) 174.0 (M-Boc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
(4-Methoxyphenyl)magnesium bromide (0.5 M in THF, 90 mL, 45.0 mmol) was added slowly (˜25 minutes) via cannula to a cold (0° C.) solution of 1-benzylpiperidin-4-one (5.4 mL, 30.2 mmol) in THF (60 mL). The reaction was stirred at 0° C. under nitrogen for 2 hours. The reaction was quenched with saturated aqueous NH4Cl then diluted with ether. The organic fraction was washed with saturated aqueous NH4Cl (2×) brine (1×) and concentrated. Purification using flash chromatography (5-100% EtOAc/hexane) provided 4.02 g (44%) of the titled compound. MS (DCI) m/z 298 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[C:23](=O)[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:27]([NH2:29])[CH3:28].C([BH3-])#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH:23]([NH:29][CH2:27][CH3:28])[CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C(C)=O)c1
Reactant: CCN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(C)c1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Temperature: 60 °C

Procedure:
(2′-Acetyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.222 g, 0.61 mmol), ethylamine (2M in THF; 0.46 mL, 0.91 mmol), sodium cyanoborohydride (0.058 g, 0.91 mmol), and acetic acid (0.05 mL, 0.91 mmol) were combined in MeOH (2.2 mL) and heated to 60° C. overnight. Analytical LCMS showed starting material remained, so the reaction was stirred at 60° C. over the weekend. Once minimal starting material was seen by analytical LCMS, the mixture was cooled to room temperature and neutralized with saturated aqueous NaHCO3. The solution was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[C:15]([NH2:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH3:13][CH:12]([CH3:14])[CH2:11][CH:5]([C:3]1[N:23]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:22][CH:2]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)C(CC(C)C)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)c1csc(-c2ccccc2)n1

Procedure:
A solution comprised of ethyl 2-bromoacetyl-4-methylpentanoate (0.264 gm, 1 mmol) in ethanol (5 mL) was treated with thiobenzamide (0.15 gm, 1.1 mmol). The mixture was heated at refluxed for 1 hour and concentrated to provide ethyl 4-methyl-2-(2-phenylthiazol-4-yl)pentanoate as a crude product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([C@@H:12]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[N:4][C:5]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[N:6][CH:7]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(-n2cncn2)ncc1Br
Temperature: 120 °C

Procedure:
In a microwave tube were charged with compound 23B (100 mg, 0.2 mmol), 1H-1,2,4-triazole (42 mg, 0.6 mmol), triethylamine (84 μL, 0.6 mmol) and DMF (0.6 mL, The mixture was heated up to 120° C. for 15 min in a Microwave Synthesizer. After cooled down, it was partitioned between ethyl acetate and 5% of LiCl aqueous solution. The organic layer was separated and concentrated. The residue was purified on silica gel chromatography eluting with ethyl acetate and hexanes to afford the title compound. MS (m/z) 481.21 [M+H]+.