Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[NH:13][N:14]=[C:15]3[C:20]=2[CH:19]=[CH:18][C:17]([F:21])=[CH:16]3)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=[C:15]3[C:20]=2[CH:19]=[CH:18][C:17]([F:21])=[CH:16]3)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCC(c2[nH]nc3cc(F)ccc23)CC1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2c3ccc(F)cc3nn2Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a stirred mixture of 15.8 parts of a sodium hydride dispersion 50% and 660 parts of dimethyl sulfoxide were added portionwise 78.4 parts of 1-acetyl-4-(6-fluoro-2H-indazol-3-yl)piperidine under nitrogen atmosphere. Upon complete addition, stirring was continued for 1 hour at room temperature. 42 Parts of chloromethylbenzene were added dropwise during 45 minutes. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into crushed ice and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of methylbenzene and methanol (90:10 by volume) as eluent. The first fraction was collected and the eluent was evaporated, yielding 91 parts (86.3%) of 1-acetyl-4-[6-fluoro-2-(phenylmethyl)-2H-indazol-3-yl]piperidine as a residue (int. 1).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.CN(C)C=O>O>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ncnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
4-{4-[4-(Tert-butyl)anilino]phenoxy}-6-methoxy-7-quinazolinol (starting compound 11) (100 mg), potassium carbonate (50 mg), and 4-(2-chloroethyl)morpholine hydrochloride (67 mg) were added to N,N-dimethylformamide (2 ml), and the mixture was stirred at 80° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and was dried over sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by thin-layer chromatography on silica gel using chloroform/methanol for development to give the title compound (120 mg, yield 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O-])=[O:22])[C:9]=2[S:24][CH3:25])=[CH:4][CH:3]=1.[Li+].[N:27]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:34][N:27]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])[C:9]=2[S:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CSc1c(C(=O)[O-])nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NN1CCCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1c(C(=O)NN2CCCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 52 %

Procedure:
Compound 3 was prepared analogously as described for compound 2 hereinabove from crude lithium 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate, azepan-1-ylamine, TBTU and Et3N in DMF in 52% yield.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([CH:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:13][NH:12][C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][N:4]=1.OO.[CH3:28]O.[S:30](S([O-])=O)([O-:32])=[O:31].[Na+].[Na+]>[O-][W]([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>[CH3:28][S:30]([C:3]1[N:8]=[C:7]([CH:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:13][NH:12][C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][N:4]=1)(=[O:32])=[O:31]
Reactant: CSc1nccc(C2CC(=O)NN=C2c2cccc(C(F)(F)F)c2)n1
Reactant: O=S([O-])S(=O)[O-]
Reactant: CO
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nccc(C2CC(=O)NN=C2c2cccc(C(F)(F)F)c2)n1

Procedure:
Compound 6 (17.8 mmol), sodium tungstate (587 mg, 1.78 mmol), 30% hydrogen peroxide (8.07 mL, 71.2 mmol), methanol (20 mL), and ethyl acetate (200 mL) were combined under argon, then heated to reflux for 4 h. The solution was cooled and aqueous sodium hydrosulfite was added. The methanol was removed in vacuo and saturated sodium bicarbonate was added. The resulting suspension was extracted several times with methylene chloride. The combined organic extracts were washed successively with water and brine. The organic layer was dried with anhydrous sodium sulfate then concentrated in vacuo to give Compound 7 as a foam: 5.0 g (13 mmol, 73% (two steps))
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16].O>CS(C)=O.C(OCC)(=O)C>[CH2:15]([O:17][C:18](=[O:25])[CH:19]([C:11]1[N:10]=[N:9][C:8]([Cl:7])=[CH:13][CH:12]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]
Reactant: Clc1ccc(Cl)nn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Cl)nn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Cesium carbonate (43.7 g) was added to a solution of 3,6-dichloropyridazine (10.0 g) and malonic acid diethyl ester (15.2 mL) in dimethyl sulfoxide (20 mL) at room temperature. The mixture was stirred at 110° C. for 1 h and then cooled to room temperature. Water and ethyl acetate were added and the resulting mixture was filtered over Celite. The aqueous phase of the filtrate was separated and extracted twice with ethyl acetate. The extracts and the organic phase of the filtrate were combined and washed with water and brine. Silica gel (50 g) and charcoal (5 g) were then added and the resulting mixture was stirred for 30 min at room temperature. The silica gel and charcoal were separated by filtration and the filtrate was concentrated to give the crude title compound that was used without further purification. Yield: 19.0 g (ca. 65% pure); LC (method 1): tR=1.25 min; Mass spectrum (ESI+): m/z=273/275 (Cl) [M+H]+.
Reaction SMILES: CC1C=CC(C)=CC=1.O.O.O.O.C([O-])(=[O:15])C.[Co+2:17].C([O-])(=[O:20])C.[Br-].[K+].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)(=O)C>[OH2:15].[OH2:20].[C:24]([O-:29])(=[O:28])[C:25]([O-:27])=[O:26].[Co+2:17]
Reactant: CC(=O)[O-]
Reactant: O=C(O)C(=O)O
Agent: [Co+2]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccc(C)cc1
Product: O=C([O-])C(=O)[O-]
Yield: 100.7 %

Procedure:
The experiment described in Example 8 was performed with the use of 200 g of p-xylene, 1000 g of acetic acid, 10 g of cobalt acetate tetrahydrate (corresponding to 2.37 g of cobalt) and 2.75 g of potassium bromide (corresponding to 1.86 g of bromine). After a reaction time of 252 minutes and an oxygen absorption of 147.2 liters, 294.5 g of terephthalic acid was obtained. After the addition of 4.7 g of oxalic acid, 7.4 g of cobalt oxalate dihydrate was isolated from the mother liquor.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=1)[CH:40]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:40][C:39]3[CH:42]=[C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:44]=[C:37]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:38]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc(OCc5ccccc5)cc(OCc5ccccc5)c4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3,5-bis-benzyloxy benzaldehyde. MS (ESI) m/z 681.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.5 %

Procedure:
A solution of 15 g (90.3 mmol) of methyl 4-hydroxyphenylacetate in 25 mL of dimethylformamide (DMF) was added 32.4 g (99.3 mmol) of cesium carbonate, followed by 13.4 mL (112.9 mmol) of benzyl bromide (BnBr), and the resulting heterogeneous mixture was stirred at rt for 72 h. The reaction mixture was filtered, the solids were washed with ethyl acetate, and the combined organic extracts were concentrated to give a residue which was chromatographed on silica gel (25% hexane in dichloromethane) to afford 19.1 g (83% yield) of desired (4-benzyloxy-phenyl)-acetic acid methyl ester as indicated by 1H NMR; LC-MS—calcd for C16H16O3 [M++H]+: 257.11, found: 257.2.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24](C(OCC(Cl)(Cl)[Cl:30])=O)[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[ClH:30].[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[NH:24][CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Agent: [Zn]
Solvent: CC(=O)O
Product: Cl
Product: c1ccc(Oc2ccc3c(c2)[C@@]24CCCC[C@H]2[C@@H](C3)NCC4)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.1 %

Procedure:
To a solution of 3.4 g (0.007 mol) of (-)-3-phenoxy-N-trichlorocarbethoxymorphinan in 40 ml of 90% acetic acid was added portionwise 2.0 g of zinc-dust. The mixture was stirred at room temperature for 16 hours and filtered. The filtrate was concentrated in vacuo and the residue was partitioned between ether and dilute ammonium hydroxide. The ether solution was extracted with 4 N hydrochloric acid. The acidic solution was extracted with chloroform. After removal of chloroform, the crude hydrochloride was crystallized from ethanol to afford 0.7 g (29%) of (-)-3-phenoxymorphinan hydrochloride, mp 322°-324°, [α]25D -33.88° (c 1.00, MeOH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][C:12]([I:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CO>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[C:12]([I:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(I)ccc1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Product: Cn1c(I)ccc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a solution of 3-(benzyloxy)-6-iodopyridin-2(1H)-one (20.48 g, 62.6 mmol) in methanol (626 mL) was added potassium carbonate (8.56 g, 62.6 mmol) and iodomethane (3.91 mL, 62.6 mmol), and the resulting mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure, and the resulting residue was partitioned between water and ethyl acetate. The aqueous layer was removed and discarded. The organic layer was collected, dried over anhydrous magnesium sulfate, and purified using silica gel chromatography to afford 3-(benzyloxy)-6-iodo-1-methylpyridin-2(1H)-one (15.4 g, 45.1 mmol, 72% yield). ES-MS (M+H)+=342.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[C:13]2[N:14]=[CH:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1.[C:17]([CH:21]([C:37]1[CH:42]=[CH:41][C:40]2[O:43][CH2:44][O:45][C:39]=2[CH:38]=1)[O:22][C:23]1[C:30]([CH2:31][CH2:32][CH3:33])=[CH:29][C:26]([CH2:27]Br)=[CH:25][C:24]=1[CH2:34][CH2:35][CH3:36])([O:19][CH3:20])=[O:18]>CN(C=O)C>[C:17]([CH:21]([C:37]1[CH:42]=[CH:41][C:40]2[O:43][CH2:44][O:45][C:39]=2[CH:38]=1)[O:22][C:23]1[C:30]([CH2:31][CH2:32][CH3:33])=[CH:29][C:26]([CH2:27][N:14]2[C:13]3[C:8]([Cl:7])=[N:9][CH:10]=[CH:11][C:12]=3[N:16]=[CH:15]2)=[CH:25][C:24]=1[CH2:34][CH2:35][CH3:36])([O:19][CH3:20])=[O:18]
Reactant: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reactant: Clc1nccc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2cnc3ccnc(Cl)c32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 25.9 %

Procedure:
Cesium carbonate (117.3 mg, 0.36 mmol) was added to 4-chloroimidazo[4,5-c]pyridine (25 mg, 0.18 mmol) in DMF (2 mL) at room temperature under nitrogen. After stirring for 15 min, a solution of 4-(1-carbomethoxy- 1-(3,4-methylenedioxyphenyl)methoxy)-3,5-dipropylbenzyl bromide (106.5 mg, 0.23 mmol) in DMF (2 mL) was added and the mixture stirred at room temperature for 12 h. The mixture was poured onto ice/water and the crude product that precipitated was collected by filtration. The crude material was pre-adsorbed on silica gel and chromatographed (0 to 50% hexane/ethyl acetate) to afford the title compound (25 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([CH3:20])[N:16]2[CH3:19])=[C:12]([C:21]2[CH:42]=[CH:41][C:24]([O:25][CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:22]=2)[N:11]=1)#[N:9].C(#N)C.C(Cl)[Cl:51]>>[ClH:51].[CH3:20][C:15]1[N:16]([CH3:19])[C:17]2[C:13]([N:14]=1)=[C:12]([C:21]1[CH:42]=[CH:41][C:24]([O:25][CH2:26][CH2:27][CH:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)=[C:23]([C:43]([F:45])([F:46])[F:44])[CH:22]=1)[N:11]=[C:10]([C:8]#[N:9])[N:18]=2
Reactant: ClCCl
Reactant: Cc1nc2c(-c3ccc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(C#N)nc2n1C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nc2c(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)nc(C#N)nc2n1C
Product: Cl
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-{2-[4-(2-cyano-8,9-dimethyl-9H-purin-6-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (100 mg) in CH2Cl2 (2 mL)-acetonitrile (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and CH2Cl2 (2 mL) was added to the residue. A 4 M solution of hydrogen chloride in EtOAc (0.2 mL) was added to the mixture at room temperature, and the precipitate was collected by filtration, whereby 8,9-dimethyl-6-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-9H-purine-2-carbonitrile monohydrochloride (59 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:6])[C:3]([OH:5])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:40][C:41]1[CH:42]=[C:43](O)[CH:44]=[C:45]([Cl:47])[CH:46]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:6][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:1])[C:3]([O:5][C:43]1[CH:42]=[C:41]([Cl:40])[CH:46]=[C:45]([Cl:47])[CH:44]=1)=[O:4]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Oc2cc(Cl)cc(Cl)c2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a suspension of 2-methyl-2-(6-methyl-5-phenyl-2,3-dihydro-4-oxo-4H-1,3-oxazin-3-yl)-propionic acid (1.1 g) in 14 ml of CCl4 --CH2Cl2 (1:1) was added triphenylphosphin (1.38 g), then the mixture was refluxed for 40 min. The reaction mixture was ice-cooled and 3,5-dichlorophenol (0.65 g) and triethylamine (0.4 g) were slowly added, then it was stirred at room temperature for 1 h. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The insolubles were filtered off and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column to get the captioned compound (0.7 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:7]([C:32](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:33])[C@H:8]([C:29]([OH:31])=[O:30])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[C:19]1[C:27](=[O:28])[CH2:26][C:23]([CH3:25])([CH3:24])[CH2:22][C:20]1=[O:21])[CH2:15][CH:16]([CH3:18])[CH3:17]>CN(C=O)C>[NH:1]([C:20]([CH3:19])=[O:21])[C@H:6]([C:32]([NH:7][C@H:8]([C:29]([OH:31])=[O:30])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[C:19]1[C:27](=[O:28])[CH2:26][C:23]([CH3:24])([CH3:25])[CH2:22][C:20]1=[O:21])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:33])[CH2:5][C:4]1[CH:29]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: C1CCNCC1
Reactant: CC(C)CC(NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(CC(C)C)=C1C(=O)CC(C)(C)CC1=O)C(=O)O
Reaction time: 0.02 h

Procedure:
In a separate control experiment, regular piperidine deprotection was used. To the Fmoc-Lys(ivDde)-resin (10 mg, ˜8 μmol) was added piperidine in DMF (20%, 2 mL). The mixture was shaken for 1 min and drained. Another 2 mL of 20% piperidine was added and the mixture was shaken for 15 min. The resin was then washed, coupled with Fmoc-Phe as described above to give Ac-Phe-Lys(ivDde)-resin.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=[N:19]O)CC)=[CH:15][C:10]=2[N:9]=[CH:8]1.[CH2:21]1COC[CH2:22]1>[Ni]>[CH2:21]([C:15]1[C:10]2[N:9]=[CH:8][N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[C:11]=2[CH:12]=[CH:13][C:14]=1[CH2:16][NH2:19])[CH3:22]
Reactant: CCC(=NO)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: C1CCOC1
Agent: [Ni]
Product: CCc1c(CN)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one oxime (30 mg, 0.11 mmol) in THF (3 mL), Raney-Ni (50 mg) was added. The mixture was stirred at RT overnight. Removal of solvent followed by reverse-phase chromatography gave (4-ethyl-1-tetrahydropyran-2-yl-benzimidazol-5-yl)methanamine (10 mg, 35% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=CN=C(NNC(OC(Cl)(Cl)Cl)=O)C=2C2C=CC=CC=2)=CC=1.Br[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:61][C:60]([F:62])([F:63])[C:57]1[CH:58]=[CH:59][C:54]([CH2:53][N:15]2[C:14](=[O:17])[N:11]3[CH:12]=[N:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[C:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:55][CH:56]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=c1[nH]nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Agent: O=C(NNc1ncnc(-c2ccc(Cl)cc2)c1-c1ccccc1)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 60 °C

Procedure:
To a stirred solution of 7-(4-chlorophenyl)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one and/or trichloromethyl 2-(6-(4-chlorophenyl)-5-phenylpyrimidin-4-yl)hydrazinecarboxylate (16.0 mg, 0.05 mmol) in acetone (5 mL) at room temperature under argon was added 1-(bromomethyl)-4-(trifluoromethyl)benzene (23.9 mg, 0.10 mmol), followed by K2CO3 (13.8 mg, 0.10 mmol). The resulting mixture was heated at 60° C. for 24 h. Insoluble material was filtered and rinsed with CH2Cl2. The filtrate was concentrated under reduced pressure and purified by reverse phase preparative HPLC (without TFA). Further purification was performed by silica gel column chromatography eluting with EtOAc-hexanes. Pure product was lyophilized from 1,4-dioxane to obtain the title compound (5.0 mg) as an off-white lyophilate. HPLC/MS: retention time=4.18 min. [M+H]30 =481. 1H NMR (CDCl3): δ 8.70 (s, 1H), 7.65 (d, J=7.3 Hz, 2H), 7.55 (d, J=7.3 Hz, 2H), 7.23-7.46 (m, 7H), 7.20 (d, J=7.2 Hz, 2H), 5.18 (s, 2H).
Reaction SMILES: CC(C)=O.[CH2:5]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O[C:19]([CH3:23])([CH3:22])[C:20]#[N:21]>CN(C)C(=O)C>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(O)C#N
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
4.5 ml of acetone, 20 g of dry MGSO4, 10 g of N,N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed together and heated at 45° C. for 48 hours with vigorous stirring. The reaction mixture is poured onto ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=2)[CH:9]=[CH:8][CH:7]=1.CCN(CC)CC.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>C(Cl)Cl>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:29](=[O:32])[CH2:30][CH3:31])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: CCC(=O)Cl
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCN)n2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A mixture of 3-(6-(2-aminoethoxyl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one hydrochloride 103a (250 mg, 0.66 mmol) and Et3N (0.23 mL, 6.0 mmol) in DCM (15 mL) was added propionyl chloride (70 uL, 0.79 mmol). The mixture was stirred at RT for 2 h. The mixture was washed with water (20 mL*2). The organic layer was dried and concentrated to give N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)propionamide 119a (140 mg, 54%) as a light yellow solid. ESI-LCMS: m/z=395.1.