Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:24].[Cl:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:23]=[CH:22]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc2nc(N3CCNCC3)ccc2c1

Procedure:
Prepared in analogy to example 1.6 (d) from 4-(6-chloro-quinolin-2-yl)-piperazine-1-carboxylic acid tert.-butyl ester and dioxane saturated with gaseous hydrochloric acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.2 %

Procedure:
A solution of 4-fluoro-2-hydroxy-1-nitrobenzene (100 mg, 0.637 mmol) in N,N-dimethylformamide (3.2 mL) was added with potassium carbonate (132 mg, 0.955 mmol), then added with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at room temperature for 1 hour. The reaction solution was further added with potassium carbonate (132 mg, 0.955 mmol), then with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at 60° C. for 1 hour. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 4-fluoro-2-methoxy-1-nitro-benzene (118 mg, yield >100%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][CH:7]=1.[CH:14]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19])=O.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:14]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[N:13][C:4]=2[CH:3]=1
Reactant: N#Cc1ccccc1C=O
Reactant: CC(C)(C)Nc1ccc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(Br)ccc21
Reaction time: 2 h
Yield: 104.8 %

Procedure:
To a solution of 4-bromo-N1-tert-butyl-benzene-1,2-diamine (500 mg, 2.06 mmol) in DMF (20 mL) is added 2-formyl-benzonitrile (270 mg, 2.06 mmol) at room temperature. Oxone (758 mg, 1.23 mmol) is added and the solution is stirred at the same temperature for 2 hours. The reaction mixture is poured into 0.5 M K2CO3 solution (30 mL). The product is extracted into EtOAc (3×) and the combined organics are then dried (Na2SO4), filtered, and concentrated. Purification via flash chromatography (25 g silica gel, 0-4% MeOH/CH2Cl2) affords 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzonitrile (765 mg, 100%).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:28].[CH2:30]1CCN2C(=NCCC2)C[CH2:31]1.C(I)C.O>C(O)C.C(OCC)(=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[O:28][CH2:30][CH3:31]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Solvent: CCOC(C)=O
Solvent: CCI
Solvent: O
Product: CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC)co2)ccc1OC(F)F
Reaction time: 2 h

Procedure:
A 60 mg quantity of the compound obtained in Example 229 and 0.2 ml of DBU were dissolved in 4 ml of ethanol, 0.2 ml of ethyl iodide was then added to the obtained solution, and heating and refluxing were conducted for 2 hours. After cooling, water was added to the reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from ethanol, thereby yielding 36 mg of white powdery 3-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:14]([NH:15][NH:16][C:17]([NH:19][CH3:20])=S)=[CH:13][C:11](=[O:12])[N:10]([CH2:21][CH2:22][CH3:23])[C:8]2=[O:9])=[CH:4][CH:3]=1.CO>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:14]3[NH:15][N:16]=[C:17]([NH:19][CH3:20])[C:13]=3[C:11](=[O:12])[N:10]([CH2:21][CH2:22][CH3:23])[C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)cc(NNC(=S)NC)n(Cc2ccc(Cl)cc2)c1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(Cl)cc2)c1=O
Yield: 64 %

Procedure:
A solution of 1-(4-chlorobenzyl)-6-(4-methylthiosemicarbazido)-3-propyluracil (4.8 g, 12.6 mM) in DMF (50 ml) was stirred at 100° C. for 40 hours. To the solution was added 50% methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless crystals (2.8 g, 50%), m.p. 305°-307° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].C([O-])([O-])=O.[K+].[K+].[CH2:26](I)[CH3:27]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:26][CH3:27])=[O:18]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CC(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1cc(NC(=O)OC(C)(C)C)ccc1Cl
Yield: 97.6 %

Procedure:
To a solution of (2-chloro-5-(Boc-amino)phenyl)acetic acid (2.8 g; 9.8 mmol; from step (iv) above) in acetone (100 mL) was added K2CO3 (2.1 g, 15 mmol). EtI (70.6 g; 150 mmol) was then added whilst the reaction mixture was stirred and refluxed. The solution was concentrated, and the resultant mixture was partitioned between ether and water (1:1; 60 mL). The organic layer was separated, and the water layer was extracted once with ether (30 mL). The combined organic phase was washed with water, dried (Na2SO4), and concentrated to yield 3.0 g (98%) of the sub-title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[ClH:4].[Cl:5][CH2:6][CH2:7][CH:8]1[CH2:12][N:11]([CH2:13][CH3:14])[C:10](=[NH:15])[N:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[ClH:5].[ClH:4].[CH2:13]([N:11]1[CH2:12][CH:8]([CH2:7][CH2:6][N:2]([CH3:3])[CH3:1])[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[NH2:15])[CH3:14]
Reactant: CCN1CC(CCCl)N(c2ccccc2)C1=N
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCN1CC(CCN(C)C)N(c2ccccc2)C1N

Procedure:
To a 9.4 g (0.21 mole) of dimethylamine in 200 ml ethanol was added 20 g (0.0695 mole) of 4-(2-chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidine hydrochloride and the solution heated to 100° C. in a steel bomb for 18 hours. The contents were concentrated on the rotary evaporator and the resulting residue partitioned between chloroform and dilute NaOH. The chloroform solution was concentrated and the residue dissolved in isobutyl methyl ketone which was acidified with ethereal HCl. The resulting crystals were recrystallized from isopropanol-isobutyl methyl ketone. Yield 7.8 g (37.8%); m.p. 252°-254° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1[C:10](/[CH:22]=[CH:23]/[CH3:24])=[N:11][C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:13][C:14]=1[CH3:15])=[O:8]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:6][C:7]([C:9]2[C:10]([CH2:22][CH2:23][CH3:24])=[N:11][C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:13][C:14]=2[CH3:15])=[O:8])[CH:25]=[CH:26][CH:27]=1
Reactant: C/C=C/c1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: [Pd]
Solvent: CO
Product: CCCc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Reaction time: 3 h
Yield: 61.7 %

Procedure:
A solution of 300 mg (0.81 mmol) (E)-N-(3-fluorobenzyl)-4-methyl-6-morpholino-2-(prop-1-enyl)-pyridine-3-carboxylic acid amide (example 9) in MeOH (9 ml) was degassed with argon for 15 min. Then 0.065 g Pd/C (10% w/w) was added and the RM was stirred for 3 h under hydrogen atmosphere by use of an H2 balloon. Subsequently the mixture was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/acetone 17:3) provided 170 mg (0.5 mmol, 56%) N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-propyl-pyridine-3-carboxylic acid amide (example 10). [M+H]+ 372.2.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1>CCO>[Cl:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N:2][OH:3])=[CH:8][CH:7]=1
Reactant: NO
Reactant: O=Cc1ccc(CCl)cc1
Agent: Cl
Solvent: CCO
Product: ON=Cc1ccc(CCl)cc1
Temperature: 50 °C

Procedure:
Hydroxylamine hydrochloride (10.11 g, 145.5 mmol) was added to a solution of 4-(chloromethyl)benzaldehyde 4 (7.5 g, 48.51 mmol) in EtOH. The mixture was heated at 50° C. for 3 h then concentrated in vacuo. The residue was partitioned between DCM and water. The combined organic extract was dried (MgSO4) and concentrated in vacuo yielding a white solid that was used without further purification (8.1 g, 98%). 1H NMR (400 MHz, DMSO) d 4.77 (2H, s), 7.46 (2H, d, J=8.0 Hz), 7.60 (2H, d, J=8.0 Hz), 8.15 (1H, s), 11.32 (1H, s).
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.Cl[C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][N:13]([C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH2:12]2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCNC2)C(=O)O1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCN(c3nccc(C(F)(F)F)n3)C2)C(=O)O1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-pyrrolidin-3-yl)-1,3-oxazinan-2-one and 2-chloro-4-(trifluoromethyl)pyrimidine following a procedure analogous to that described in
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.O>CS(O)(=O)=O>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: CS(=O)(=O)O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
9α-Hydroxyandrostenedione (302 mg.) is added to a solution of water (2.5 ml.) in methanesulfonic acid (2.5 ml.) and heated to 100°. The mixture is slowly cooled over a period of 2 hours to 60°. Water (3 ml.) is added and the reaction mixture seeded. Work-up gives androsta-4,9(11)-diene-3,17-dione, 216 mg. (75.9% chemical yield - crude material), m.p. 170°-175°. Upon recrystallization a m.p. of 190°-194° is obtained.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][CH:10]=O.CCOC(C1CC(C(OCC)=O)=C(C)NC=1C)=O.N1C=CC=CC=1>CO.C(Cl)Cl>[CH2:9]([CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])[CH3:10]
Reactant: O=C1CCCC(=O)C1
Reactant: CC=O
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
1,3-Cyclohexanedione (10 g, 89.2 mmol), 40% aqueous CH3CHO (49.4 g, 445.9 mmol) were dissolved in methanol (40 mL) followed by addition of Hantzsch ester (22.7 g, 89.2 mmol) and pyridine (2.1 g, 18.74 mmol) under nitrogen. The resulting light yellow mixture was stirred at room temperature overnight, then concentrated to give crude product that was re-slurried in a mixture of CH2Cl2 (40 mL) and hexanes (60 mL) to furnish 2-ethyl-1,3-cyclohexanedione (8.6 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([O:27][CH3:28])=[O:26])[C:5]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[C:6]([N+:14]([O-])=O)[C:7]=1[C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C>CO.O.C(OCC)(=O)C.[Fe]>[NH2:14][C:6]1[C:7]([C:8]#[C:9][Si:10]([CH3:12])([CH3:11])[CH3:13])=[C:2]([Cl:1])[CH:3]=[C:4]([C:25]([O:27][CH3:28])=[O:26])[C:5]=1[C:17]1[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cc(F)cc(F)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c(N)c1-c1cc(F)cc(F)c1
Temperature: 60 °C
Yield: 98.8 %

Procedure:
A solution of methyl 4-chloro-3′,5′-difluoro-6-nitro-5-[(trimethylsilyl)ethynyl]biphenyl-2-carboxylate (4.6 g, 11 mmol) in methanol (46 mL), water (13 mL), and acetic acid (31 mL) was treated with iron (<10 micron) (3.0 g, 54 mmol) and heated at 60° C. for 2 hours. The reaction mixture was treated with additional iron (1.0 g, 18 mmol) and heated at 60° C. for 1 hour to drive the reaction to completion. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered over celite. The filtrate was concentrated to a crude residue. The crude residue was diluted with ethyl acetate and filtered through a short plug of silica gel. The filtrate was concentrated to give the desired product (4.28 g, quantitative). LCMS for C19H19ClF2NO2Si (M+H)+: m/z=394.1; Found: 393.9.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:60]=[CH:59][C:27]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:32][CH:31]=2)=[O:29])=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1COCC1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:28]([OH:29])[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[CH:32][CH:31]=2)=[CH:59][CH:60]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(O)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To 4,4′-didocosyloxy-benzophenone (28.3 g, 34.1 mmol) were added THF (300 mL) and methanol (15 mL), and the mixture was heated to 60° C. Sodium borohydride (6.10 g, 161 mmol) was slowly added, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was ice-cooled, and 1N hydrochloric acid (80 mL) was added dropwise. THF was evaporated, water (450 mL) was added, and 1N hydrochloric acid was added to adjust the pH to 5-7. The slurry was filtered, and the obtained crystals were washed with water and methanol to give the title compound (28.5 g, 34.1 mmol, 99%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([CH2:10][OH:11])[CH2:5]1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>CCCCCCC.C1COCC1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:11][CH2:10][C@@H:6]3[CH2:7][CH2:8][CH2:9][N:4]([CH3:3])[CH2:5]3)=[O:26])[CH2:23][CH2:24]2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(N2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: CN1CCC[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1ccc(N2CCN(C(=O)OC[C@@H]3CCCN(C)C3)CC2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
Sodium hydride (0.70 g, 60% dispersion in mineral oil, 17.5 mmol) was suspended in heptane (10 mL) under an argon atmosphere. The heptane was decanted off, and the flask was charged with THF (20 mL) and cooled to 0° C. A solution of (R)-(1-methylpiperidin-3-yl)methanol (0.75 g, 5.83 mmol) in THF (20 mL) was added drop-wise, followed by a solution of 4-nitrophenyl 4-(4-methylphenyl)piperazine-1-carboxylate (Intermediate 1; 2.19 g, 6.42 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then cooled to 0° C. and quenched with the drop-wise addition of sat aq NaHCO3 solution and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with sat aq NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with methanol in water, with 1% formic acid in each solvent, 0-25%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 min, filtered and concentrated in vacuo. The residue was further purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) to give [(3R)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate (619 mg, 32%) as a pale brown solid.
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=O)([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.[I:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25]>N1C=CC=CC=1>[I:21][C:22]1[CH:23]=[C:24]([NH:25][C:11](=[O:13])[CH2:10][N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(NC(=O)CN(CC(=O)O)CC(=O)O)cc1I
Temperature: 100 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
A slurry of 4.78 g of nitrilotriacetic acid in 40 ml of dry pyridine (dried over molecular sieves) is heated to 60° C. Acetic anhydride (2.55 g) is added slowly and the solution is heated to 100° C. After heating for 0.5 hour, the solution is cooled to 40° C. and a solution of 5.8 g of 3-iodo-4-methylaniline in 20 ml of dry pyridine is added over 25 minutes. The solution is heated at 100° C. for 1.0 hour. The reaction is cooled and rotary evaporated to a residue which is dissolved in 65 ml of 10% sodium hydroxide. This solution is extracted twice with 50 ml portions of methylene chloride diluted with 100 ml of distilled water, and neutralized with concentrated HCl to pH 3.2. The crude product is refrigerated for about 16 hours, filtered, washed twice with 50 ml portions of distilled water, and dried under vacuum at 40° C. The crude product (8.0 g) is recrystallized after Darco treatment to yield 5.7 g of product, melting point 213.5°-215.0° C. (dec).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:11][CH:10]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]#[C:15][C:12]1[CH:11]=[CH:10][C:9]([NH:7][CH3:6])=[CH:14][CH:13]=1
Reactant: CN(C)CCCC#Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(C#CCCCN(C)C)cc1
Temperature: 25 °C
Yield: 106 %

Procedure:
A solution of 1.45 g (4.58 mmol) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-carbamic acid tert-butyl ester in 25 ml CH2Cl2 was treated at 0° C. with 11.5 ml TFA (during 20 min) and warmed up to room temperature during 1 h. The solution was concentrated and the residual oil was extracted with aqueous sat. NaHCO3 (+Na2CO3)/EtOAc (3×). The organic phase was dried (Na2SO4) and evaporated to yield 1.05 g (quantitative) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-amine MS: 217 (MH+).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:24]([OH:26])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)N=C=NC(C)C.CN(C1C=CC=CN=1)C.CN1C=CN=C1.ClCCl.CN([CH:74]=[O:75])C>ClCCl>[CH3:74][O:75][C:21]1[CH:20]=[CH:19][C:18]([CH:5]2[NH:1][CH:2]([C:24]([OH:26])=[O:25])[CH2:3][S:4]2)=[CH:23][CH:22]=1
Reactant: CN(C)C=O
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(C2NC(C(=O)O)CS2)cc1
Reaction time: 9 h

Procedure:
Commercially available Fmoc-Cys(Trt) was attached to the linker based solid support 1 by DIC/DMAP procedure. The solid support (1.0 g) having substitution 0.4 meq/g was placed in reaction vessel and allowed to swell in dichloromethane (DCM) under nitrogen stirring. After 30 min. the resin was filtered and washed with DCM. To this resin a solution of Fmoc-Cys(Trt) (0.70 g, 1.2 mmol) dimethylaminopyridine (DMAP) or N-methyl imidazole (NMI) (0.4 mmol) in DCM:DMF (1:1) 20 ml and was added. This mixture was stirred for 8-10 hrs. The resin was washed three times with DCM and dried. An aliquot of this resin was tested to check the loading by the treatment with 20% piperidine and subsequently recording the absorbance in UV [Method A]. It came out to be 90% loading. The resin bearing Fmoc-Cys(Trt) was treated with 20% piperidine in DCM:DMF (1:1) 20 ml for 20 min to remove Fmoc group. The resin was washed three times with DCM and then treated with 10% trifluoric acid (TFA)/Bu3SiH in DCM for 30 min (three times) to remove the trityl group of Cys. After washing the resin with DCM 3 times, a solution of p-anisaldehyde (0.5 ml) in DCM:DMF (1:1) 15 ml was added under stirring and the stirring was continued for 8-10 hrs. The resin was washed three times with DCM and dried. It was treated with a mixture of dioxan-MeOH-4N. NaOH (30:9:1, 20 ml) for 30 min under stirring and the resin was filtered and washed with 2 ml of water. The combined filtrate was evaporated in vacuo. The residue was taken in water and extracted with ether. The aqueous layer acidified with 1N hydrochloric acid and extracted with EtOAc (3×70 ml). The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and evaporated in vacuo to yield 2-(4-methoxyphenyl) thiazolidine-4-carboxylic acid as white crystalline material. Yield: 0.061 g, 72%; m.p. 150-51° C.; FAB-MS [M+H]+ 239; 1H NMR (DMSO-d6) δ: 3.5 (m, 2H), 3.7 (s, 3H), 4.8 (bs, 1H), 5.9 (bs, 1H), 6.8-7.1 (Abq, 4H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[C:8]([OH:22])[CH:7]=1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:22][C:8]1[CH:7]=[C:6]([CH:4]=[O:5])[C:14]2[O:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[CH:11][C:10]=2[CH:9]=1
Reactant: CON(C)C(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a cooled (0° C) solution of 119 (0.18 g, 0.58 mmol) in THF (10 ml) was added LiAlH4 (1.5 ml of 1.0M in THF) dropwise. After stirring for 30 min, the reaction was quenched with 2N HCl and partitioned between 2N HCl and EtOAc. The EtOAc was separated, dried, and concentrated. The product was purified by column chromatography on silica gel (30% EtOAc/Hex) to give 120 as a yellow solid (0.075 g, 51%); Mp=261-263° C.; 1H NMR (DMSO-d6) δ 10.36 (s,1 H), 9.79 (s, 1 H), 9.77 (s, 1 H), 7.76 (d, 2 H, J=8.5 Hz), 7.25 (d, 1 H, J=2.0 Hz), 7.17 (s, 1 H), 7.12 (d, 1 H, J=2.1 Hz), 6.88 (d, 2 H, J=8.5 Hz); MS 255 (M+H)+