Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14](COCC)[C:13]([NH2:22])=[N:12][C:11]=2[N:10]([CH3:23])[C:8]1=[O:9].Cl>C(O)C>[OH:1][C@H:2]([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([NH2:22])=[N:12][C:11]=2[N:10]([CH3:23])[C:8]1=[O:9]
Reactant: CCOCn1c(N)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Agent: Cl
Solvent: CCO
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]c(N)nc2n(C)c1=O
Temperature: 80 °C

Procedure:
(R)-1-(5-Hydroxyhexyl)-7-ethoxymethyl-8-amino-3-methylxanthine libraries synthesized as described in Example 33 were treated with a solution composed of concentrated hydrochloric acid and ethanol (1:4, 0.8 ml per well) and the block was heated in an oven at 80° C. for 12 hours. Remaining reagents and byproducts were evaporated under reduced pressure providing (R)-1-(5-hydroxyhexyl)-8-amino-3-methylxanthine libraries.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Fc1cnc(Cl)nc1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ncc(F)cn1

Procedure:
The title compound, MS: m/e=314.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-5-fluoro-pyrimidine.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])([O-:8])=[O:7]>>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:1]([CH:2]([CH3:4])[CH3:3])[OH:5])([O-:8])=[O:7]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)C=O
Product: CC(C)C(O)Cc1ccccc1[N+](=O)[O-]
Yield: 2.2 %

Procedure:
JP-A-62-202091 describes the reaction of isobutyraldehyde with 2-nitrotoluene, which afforded only 2.2% 2-(2-nitrophenyl)-1-isopropylethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][S:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[C:30]([OH:40])=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:28][C:29]1[C:30]([OH:40])=[C:31]([S:36]([N:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][S:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=2)(=[O:38])=[O:37])[CH:32]=[C:33]([Cl:35])[CH:34]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: Fc1ccc(CCNCc2cccc(CSCCc3ccccc3)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(CCc1ccc(F)cc1)Cc1cccc(CSCCc2ccccc2)c1
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-N-(3-(phenethylthiomethyl)benzyl)ethanamine (70 mg, 0.184 mmol) in THF (3 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (63 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol). The resulting reaction mixture was stirred at it for 1.5 h. The reaction mixture was concentrated and the residue was dissolved in MeOH. The mixture was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated in vacuo and lyophilized to give the title compound (50 mg, 44%) as a white solid. 1H NMR (CDCl3) δ 9.15 (s, 1H), 7.55 (d, J=4.0 Hz, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.34-7.15 (m, 9H), 6.98-6.89 (m, 4H), 4.40 (s, 2H), 3.70 (s, 2H), 3.35 (t, J=8.0 Hz, 2H), 2.86 (t, J=4.0 Hz, 2H), 2.69-2.63 (m, 4H). MS (ESI): 602.0 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([NH:5][C@H:6]1[C@@H:16]2[N:10]([C:11]3[CH:24]=[C:23]([NH:25]CC4C=CC=CC=4)[CH:22]=[CH:21][C:12]=3[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)[CH2:9][CH2:8][CH2:7]1)=[O:4].Cl.O1CCOCC1>C(O)C.[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[C@@H:16]3[C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:33])([F:34])[F:1])[CH2:7][CH2:8][CH2:9][N:10]3[C:11]=2[CH:24]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(NCc4ccccc4)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1ccc2c(c1)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Reaction time: 6 h
Yield: 3.8 %

Procedure:
To a solution of trans-2,2,2-trifluoro-N-[2,3,4,14b-tetrahydro-7-[(phenylmethyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl]acetamide (944 mg, 2.0 mmol) in ethanol (16 mL) were added Pd/C 10% (111 mg) and a solution of 4M HCl in dioxane (778 μl, 3.11 mmol). The resulting reaction mixture was hydrogenated at 3 bar for 6 h. The reaction mixture was quenched with sat. NaHCO3 (aq) and diluted with ethanol. After filtration through dicalite and thorough washing with ethyl acetate, the volatiles were removed in vacuo. A part of the crude product was purified with HPLC to afford the title compound (29 mg, 53%). Data (m/z)=378 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:26][CH3:27])[C:7]([O:11][C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=2)=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[Br:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:9]2[N:8]=[C:7]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[C:6]([CH2:26][CH3:27])=[N:5][C:4]=2[C:1](=[O:3])[NH2:2])=[CH:31][CH:30]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1nc(C(N)=O)c(Oc2ccc(Br)cc2)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Yield: 88.9 %

Procedure:
A mixture of tert-butyl {3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]phenyl}carbamate (500 mg), 4-bromophenol (440 mg), potassium carbonate (440 mg), and N-methylpyrrolidone (5 mL) was reacted at 100° C. for 4 hours. The reaction mixture was left to be cooled, and then water-saturated brine (1:1) was added thereto, followed by extraction with ethyl acetate. Then, the organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-95:5, hexane:ethyl acetate=7:3-3:7) to obtain tert-butyl (3-{[6-(4-bromophenoxy)-5-carbamoyl-3-ethylpyrazin-2-yl]oxy}phenyl)carbamate (599 mg) as a colorless solid.
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].[N+:6]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[CH2:20][CH:21]=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:8])=[O:7].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:1][CH:20]([C:19]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7])[CH:21]=[O:22]
Reactant: CCOC(=O)c1ccc(CC=O)c([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(C)C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
Sodium bicarbonate (318 mg) was added to the mixture of ethyl 3-nitro-4-(2-oxoethyl)benzoate (401 mg) and MeI (426 mg) in DMF (5 ml), stirred for over night at r.t., diluted with ethyl acetate, washed with water and saturated saline water in that order, and dried with sodium sulfate. This was filtered, concentrated, and purified through silica gel column (hexane/ethyl acetate) to give title compound (227 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](Cl)[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[NH2:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([S:26]([NH:29][CH2:30][C:31]2[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=2)(=[O:28])=[O:27])=[CH:21][C:20]=1[Cl:37].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([S:26]([NH:29][CH2:30][C:31]4[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=4)(=[O:27])=[O:28])=[CH:21][C:20]=3[Cl:37])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Cn1ccnc1CNS(=O)(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: Clc1nc2ccc(Br)cc2c2c(Cl)nccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1ccnc1CNS(=O)(=O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(Cl)nccc23)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 9-bromo-1,5-dichlorobenzo[c]-2,6-naphthyridine (100 mg, 0.31 mmol) (Example 1, Step 5) and 4-amino-3,5-dichloro-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzenesulfonamide (123 mg, 0.37 mmol) in DMA (1.2 mL) was added NaHMDS (0.7 mL, 1 M in THF, 0.7 mmol). The reaction was stirred at room temperature for ten minutes and then heated in the microwave to 100° C. for 15 minutes. The reaction was then quenched by the addition of sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc and the organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-10% MeOH/DCM) afforded the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13](Cl)[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH:10]=[N:9][C:8]=2[CH:19]=1.[CH3:20]I.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl>C1(C)C=CC=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:20])[C:12]3[CH:15]=[CH:16][CH:17]=[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:11]=3[CH:10]=[N:9][C:8]=2[CH:19]=1
Reactant: C1CNCCN1
Reactant: CI
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1N2Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1c2ccc(Cl)cc2N=Cc2c(N3CCNCC3)cccc21
Reaction time: 1 h
Yield: 54.8 %

Procedure:
NaH (12 mg, 0.29 mmol, 60% in mineral oil) was added to a mixture of 8,5-dichloro-5H-dibenzo[b,e][1,4]diazepine (160FE64) (50 mg, 0.19 mmol) in toluene (1.5 mL) and DMF (0.5 mL). MeI (24 μL, 0.38 mmol) was then added. The resulting mixture was stirred for 1 h then quenched by addition of saturated aqueous NaHCO3-solution (2 mL). The mixture was extracted with diethyl ether, and the combined organic phases were dried (Na2SO4) and concentrated. The residue was taken up in toluene (2.0 mL), piperazine (98 mg, 1.1 mmol) was added, and the resulting mixture was stirred at 100° C. for 1 h. Aqueous HCl (1 mL, 2M) and EtOAc (2 mL) was then added to the mixture. The phases were separated and the aqueous phase was extracted with EtOAc (2 mL) and then aqueous NaOH (2 mL, 2 M) was added. The basic aqueous phase was extracted with EtOAc (3×2 mL) and the combined organic phases were dried (Na2SO4) and concentrated. The residue was dissolved in DMF and purified on HPLC to give 34 mg of the title compound (189JO25A). MS (ESI) 327 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C([Mg]Cl)(C)C.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]C(Cl)=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)O
Reactant: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of malonic acid monoethyl ester (16.9 g, 128 mmol) in dry THF (200 mL) was cooled to -78° C. under nitrogen, treated dropwise with 130 mL of isopropyl magnesium chloride (2.0 M in THF; 260 mmol), and stirred at -78° C. for 45 minutes. A solution of 3-(4-nitrophenyl)propanoyl chloride prepared in Example EE (13.5 g, 64 mmol) in dry THF (100 mL) was added dropwise. When addition was complete, the reaction mixture was stirred at -78° C. for 1 hour and then allowed to warm to room temperature, where the solution was stirred for 3 more hours. A mixture of ice (50 mL) and 3N HCl (100 mL) was added. The solution was extracted with EtOAc, and the combined extracts were washed with brine and dried (MgSO4). Concentration gave the title compound. 1H NMR (CDCl3) δ 1.21 (t, 3 H), 2.88-3.00 (m, 4 H), 3.40 (s, 2 H), 4.13 (q, 2 H), 7.32 (d, 2 H), 8.09 (d, 2 H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH2:34]([N:36]1[C:48]2[CH:47]=[CH:46][C:45]([NH2:49])=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]2[C:16]([NH:49][C:45]2[CH:46]=[CH:47][C:48]3[N:36]([CH2:34][CH3:35])[C:37]4[C:42]([C:43]=3[CH:44]=2)=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CC#N)CN3C(=O)c3ccc(-c4ccccc4)cc3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 32% purity by LC/MS. MS(ESI+): m/z=525.4.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[NH3:14]>C1C=CC=CC=1>[NH3:14].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:2]([CH3:5])([CH3:4])[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: OCCCCCCBr
Agent: N
Solvent: c1ccccc1
Product: C[Si](C)(C)OCCCCCCBr

Procedure:
13.8 G. of trimethylchlorosilane and 11.4 g. of 6-bromohexan-1-ol are mixed together in 100 ml. of dry benzene and are stirred in an ice-bath while anhydrous ammonia is passed therethrough until the odor of ammonia persists to obtain 6-bromohexyloxytrimethylsilane, which is worked up by filtration, followed by evaporation of the filtrate and distillation in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH2:39][CH2:40][F:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:39][CH2:40][F:41])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: FCCBr
Product: COc1ccc(CC2c3cc(OCCF)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 1-bromo-2-fluoro-ethane
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH2:6][CH3:7])=[O:4].O1CCCC1.[H-].[Na+].C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH2:6]([N:5]1[CH2:8][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:22][CH2:2][C:3]1=[O:4])[CH3:7]
Reactant: CCN(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)C(=O)CCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To a 250 mL round bottom flask containing tert-butyl 4-((2-chloro-N-ethylacetamido)methyl)-4-hydroxypiperidine-1-carboxylate (3.14 g) was added tetrahydrofuran (50 mL). The entire vessel was placed under nitrogen and stirred at room temperature. To this was portionwise added NaH (60% in mineral oil, 2 g, 50.0 mmol). After complete addition, the reaction mixture was stirred at room temperature. After 3 hours, saturated aq sodium bicarbonate (70 mL) was added to the flask (slowly dropwise via pipette at first, then the final 60 mL can be added directly). The solution was transferred to a reparatory funnel containing ethyl acetate (150 mL) and water (50 mL). The organic layer was washed with the aqueous solution, separated, and set aside. The aqueous layer was washed with ethyl acetate (1×50 mL). The combined organic extracts were washed with brine (2×50 mL), separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (50-100% ethyl acetate:hexanes) afforded the title compound (1.7 g, 61%). MS(ES)+ m/e 299.5 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N:8]1([C:14]2[C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3[S:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:5]([N:11]1[CH2:12][CH2:13][N:8]([C:14]2[C:15]3[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=3[S:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:10]1)(=[O:7])[CH3:6]
Reactant: c1ccc(-c2sc3ccccc3c2N2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2c(-c3ccccc3)sc3ccccc23)CC1
Reaction time: 2 h

Procedure:
6.15 g (60 mmole) of acetic anhydride are mixed with a solution of 11.8 g (40 mmole) of 3-piperazino-2-phenyl-benzo(b)thiophene in 50 milliliters of methylene chloride and left for 2 hours at ambient temperature. After washing with dilute ammonia the organic phase is dried over Na2SO4 and evaporated: 13.2 g (98% of theory) of colourless needles, mp 167°-169° (CCl4).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:47]1([CH2:53][CH2:54][CH:55]=[CH2:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N+:22]([C:11]1[CH:10]=[C:9]([CH:56]=[CH:55][CH2:54][CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=CCCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(C=CCCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
19 mg of palladium acetate (II) was added to 5 mL of toluene solution containing 0.50 g of tert-butyl 4-bromo-2-nitrobenzoate, 50 mg of tri(o-tolyl)phosphine, 0.50 mL of 4-phenyl-1-butene and 0.46 mL of triethylamine, and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours and 30 minutes. After the reaction mixture was cooled to room temperature, 20 mg of palladium acetate (II) was added and the resulting mixture was heated to reflux for 5 hours and 30 minutes. After cooled to room temperature, the reaction mixture was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=30:1] to obtain 0.35 g of tert-butyl 2-nitro-4-(4-phenyl-1-butenyl)benzoate.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].C([N:19]([CH2:22][CH3:23])CC)C.[CH3:24][C:25]([CH3:32])([C:29](Cl)=[O:30])[C:26](Cl)=[O:27].[Cl-].[NH4+]>ClCCl>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[C@H:2]([NH:1][C:26](=[O:27])[C:25]([CH3:32])([CH3:24])[C:29]([NH:19][C@@H:22]([C:23]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=1)[C:3]([CH3:2])([OH:5])[CH3:4])=[O:30])[C:3]([OH:5])([CH3:6])[CH3:4]
Reactant: CC(C)(O)[C@@H](N)c1ccc2ccccc2c1
Reactant: CCN(CC)CC
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C(=O)N[C@@H](c1ccc2ccccc2c1)C(C)(C)O)C(=O)N[C@@H](c1ccc2ccccc2c1)C(C)(C)O
Temperature: -10 °C
Reaction time: 0.05 h
Yield: 98.1 %

Procedure:
Under a nitrogen atmosphere, 1.5 g of (S)-1-amino-1-(2-naphthyl)-2-methyl-2-propanol, 0.84 g of triethylamine (dehydrated), and 13 mL of dichloromethane (dehydrated) were mixed and then cooled to an inner temperature of −10° C. 0.6 g of dimethylmalonic acid dichloride was added dropwise thereto over 3 minutes. The resulting mixture was warmed to room temperature. The mixture was stirred as such for 7 hours to effect reaction. After completion of the reaction, 20 mL of an aqueous saturated ammonium chloride solution was added thereto to separate into layers. The organic layer obtained was washed three times with 25 mL of water and concentrated. The concentrated residue was dried under reduced pressure at an inner temperature of 40° C. to obtain 1.8 g of N,N′-bis[(1S)-(2-naphthyl)-2-hydroxy-2-methylpropyl]-2,2-dimethylpropane-1,3-diamide (yield: 100%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C@@H:10]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[CH3:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C@H:11]1[CH2:12][CH2:13][CH2:14][NH2+:9][C@H:10]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(CO[C@H]2CCC[NH2+][C@H]2c2ccccc2)c1C
Reaction time: 2 h

Procedure:
Ethyl acetate (10 ml) was saturated with hydrogen chloride by passing HCl gas for 5 min and a solution of 0.254 g of (2S,3S)-1-t-butoxycarbonyl-3-((2,3-dimethylphenyl)methoxy)-2-phenylpiperidine (prepared according to Description 3d) in 7 ml of ethyl acetate was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo. The residual white solid was washed with ether, filtered and dried to obtain 0.23 g of (2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2-phenylpiperidinium hydrochloride. 1H NMR (DMSO-d6) δ1.6-1.9 (3H, m), 1.75 (3H, s), 2.15 (3H, s), 2.2 (1H, m), 3.05 (1H, m), 3.25 (1H, m), 3.84 (1H, s), 4.05 (1H, d, J=14 Hz), 4.45 (1H, d, J=14 Hz), 4.48 (1H, s), 6.95-7.5 (8H, m), 8.8 (1H, br s), 9.4 (1H, br s).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:31])=[C:8]([CH:30]=1)[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:11]=1)(O)=[O:2].[C:32]([C:36]1[CH:37]=[C:38]([S:45]([CH3:47])=[O:46])[C:39]([O:43][CH3:44])=[C:40]([CH:42]=1)[NH2:41])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>C(OCC)(=O)C.O1CCCC1>[C:32]([C:36]1[CH:37]=[C:38]([S:45]([CH3:47])=[O:46])[C:39]([O:43][CH3:44])=[C:40]([NH:41][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:31])=[C:8]([CH:30]=2)[O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]3)[CH:11]=2)=[O:2])[CH:42]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COc1c(N)cc(C(C)(C)C)cc1S(C)=O
Reactant: Cc1ccc(C(=O)O)cc1Oc1ccnc(CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2ccc(C)c(Oc3ccnc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)cc(C(C)(C)C)cc1S(C)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At ambient temperature 560 μl of a 50% solution of propanephosphoric acid cycloanhydride in ethyl acetate are added to a solution of 120 mg tert-butyl 4-[4-(5-carboxy-2-methyl-phenoxy)-pyridin-2-ylmethyl]-piperidine-1-carboxylate, mg 5-tert-butyl-3-methanesulphinyl-2-methoxy-aniline and 145 μl triethylamine in 4 ml of tetrahydrofuran. The solution is heated to 80° C. and stirred overnight at this temperature. Then the solution is evaporated to dryness and the residue is combined with saturated aqueous NaHCO3 solution and ethyl acetate. The organic phase is separated off and washed with water and saturated aqueous saline solution and dried (Na2SO4). The solvent is evaporated off, and the residue is chromatographed on silica gel with dichloromethane/10% methanolic ammonia solution (99:1→90:10) as eluant.