Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>S(=O)(=O)(O)O.O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCC3(CC2)OCCO3)ccn1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1CCN(c2ccncc2)CC1
Yield: 49.6 %

Procedure:
A solution of 8-(4-pyridyl)-1,4-dioxa-8-azaspiro[4,5]decane (10 g) in 2N sulphuric acid (140 ml) and tetrahydrofuran (70 ml) was stirred for 72 hr. The reaction was quenched with water (700 ml) and extracted with dichloromethane (400 ml). The organic extracts were dried (MgSO4) and evaporated to give a yellow solid which was purified by flash chromatography on silica, eluting with methanol/dichloromethane (10:90 v/v) to give 1-(4-pyridyl)-4-oxopiperidine as a solid (3.97 g); m.p. 101°-104° C.; NMR (d6-DMSO) δ 2.45 (4H, t), 3.75 (4H, t), 6.85 (2H, m), 8.20 (2H, m); m/e 177 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:31]>ClCCl.O1CCOCC1>[Cl:23][C:17]1[CH:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:20]=[CH:19][C:18]=1[C:21]#[N:22].[ClH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(Cl)c2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCNCC2)cc1Cl
Reaction time: 1 h

Procedure:
4-(3-Chloro-4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (290 mg; 0.87 mmol, prepared according to Example 103) is dissolved in dichloromethane (1.3 mL) and trifluoroacetic acid (0.7 mL) is added under stiffing. After 60 minutes, the reaction mixture is concentrated under reduced pressure and the residue obtained is co-evaporated with dichloromethane (2×5 mL). The product is then diluted in dioxane (1 mL) and a 4N solution of hydrochloric acid in dioxane (2 mL) is added. The precipitate formed is filtered and dried under high vacuum at 40° C. to afford the desired product as hydrochloride (210 mg; 0.77 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C@@H:19]([CH2:23][NH:24][C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[C:20](O)=[O:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:20]([C@@H:19]([CH:18]([CH3:34])[CH3:17])[CH2:23][NH:24][C:25](=[O:26])[O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CNC(=O)OCC[Si](C)(C)C)C(=O)O
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)[C@@H](CNC(=O)OCC[Si](C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a solution of (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (91 mg, 0.38 mmol), (S)-3-methyl-2-(((2-(trimethylsilyl)ethoxy)carbonylamino)methyl)butanoic acid (105 mg, 0.380 mmol), EDC (146 mg, 0.760 mmol) and HOBT (11.64 mg, 0.076 mmol) in CH2Cl2 (2 mL) was added Hunig's Base (0.199 mL, 1.140 mmol). Upon completion of addition, the reaction mixture was stirred at room temperature for 16 hrs. After this time, the reaction mixture was quenched with sat'd NaHCO3 and the crude product was extracted with EtOAc and the extract was washed with brine. The combined aqueous layers were back extracted with EtOAc. The EtOAc extracts were combined, dried over Na2SO4 and evaporated to give a solid residue. The solid residue was purified by Combiflash chromatography (40 g silica gel) eluting with 1:1 and 8:2 EtOAc-hexane to give 110.5 mg of the title compound as a white foamy solid. MS (ESI+)=497.15 (M+H)+.
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1([CH2:18]O)[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7].[I-:20].[Na+].[C:22]1(=O)[CH2:27]CCC[CH2:23]1>>[C:6]([C:10]1([CH2:18][I:20])[CH2:11][O:12][C:13]2([CH2:16][CH2:27][CH2:22][CH2:23][CH2:17]2)[O:14][CH2:15]1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CC1(C)OCC(CO)(C(C)(C)C)CO1
Reactant: [I-]
Reactant: O=C1CCCCC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Product: CC(C)(C)C1(CI)COC2(CCCCC2)OC1
Reaction time: 24 h

Procedure:
A mixture of cyclohexanone (150 ml.), 5-t-butyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane methanesulphonate (17.5 g.) (see synthesis of 2,2-dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane methanesulphonate and ref. 4) and sodium iodide (12 g.) was refluxed, with stirring, for 24 hours. The solvent was removed in vacuo and the resulting oil was poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with 5% aqueous sodium thiosulphate solution and then water. The ethereal extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with hexane. 3-t-Butyl-3-iodomethyl-(1,5-dioxaspiro[5,5]undecane) was obtained as a colourless oil (14 g.) Gas-liquid chromatography (g.l.c.): OV210 at 185° produced one peak.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NCCCCO
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.28 g (10.0 mmol) of 5-bromo-2,4-dichloro-pyrimidine and 1.7 ml (12.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed at 0° C. with 1.1 ml (12.0 mmol) of 4-amino-butanol. The reaction mixture is slowly heated to room temperature while being stirred by removal of the ice bath. After 16 hours, the precipitate that is formed is filtered off. The filtrate is completely concentrated by evaporation and digested with diisopropyl ether. 2.74 g (9.8 mmol, corresponding to 98% of theory) of the product is obtained.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[S:16])O)[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].O([CH2:27][P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])S(C(F)(F)F)(=O)=O>C1COCC1>[C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([CH2:27][P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])=[S:16])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Reactant: CC(C)(C)OC(=O)Nc1nc(C(O)=S)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=S)c1csc(NC(=O)OC(C)(C)C)n1)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of give 2-[N-Boc(amino)]-4-thiazolethiocarboxylic acid (1 mmole) in THF (5 mL) was cooled to −78° C. and treated with NaH (2 mmole) in small portions. After 10 min the reaction was treated with a solution of diethylphosphonomethyl triflate in THF (5 mL). The reaction was stirred at −78° C. for 1 h, and then quenched with H2O. Extraction and chromatography gave 2-[N-Boc(amino)]-4-diethylphosphonomethylthiocarbonylthiazole as a thick oil, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-4-phosphonomethylthiocarbonylthiazole (18.5) as a solid. Mp>230° C. (decomp). Anal. calcd. for C5H7N2O4PS2: C: 23.62; H: 2.78; N: 11.02. Found: C: 23.77; H: 2.61; N: 10.73.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH3:18])C(O)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[F:41][C:42]1[CH:55]=[CH:54][C:45]([CH2:46][N:47]2[CH2:52][CH2:51][NH:50][CH2:49][C:48]2=[O:53])=[CH:44][CH:43]=1.CN([CH:59]=[O:60])C>>[F:41][C:42]1[CH:55]=[CH:54][C:45]([CH2:46][N:47]2[CH2:52][CH2:51][N:50]([C:59](=[O:60])[CH2:18][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH2:12]3)[CH2:49][C:48]2=[O:53])=[CH:44][CH:43]=1
Reactant: CC(C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCN(Cc3ccc(F)cc3)C(=O)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-boc-piperidin-4-ylpropionic acid (1.20 g, 4.7 mmol, Astatech) in DMF (10 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.16 g, 6.1 mmol) and 1-hydroxy-7-azabenzotriazole (0.83 g, 6.1 mmol) were added and the solution was stirred at room temperature for 30 min. To the resultant solution, a solution of 1-(4-fluorobenzyl)piperazin-2-one (1.07 g, 5.1 mmol, see Example 31, Steps 5-8) in DMF (2 mL) was added and the mixture was stirred for two hours. The product mixture was concentrated under vacuum, and the residue partitioned between water and ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO column, 120 g silica gel) eluting with a 0-6% MeOH/CHCl3 gradient over 40 min. Collection and concentration of appropriate fractions provided the coupled product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[I:18][CH2:19][O:20][C:21]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[C:23]([CH2:29][CH3:30])[CH:22]=1>>[I-:18].[NH2:1][C:2]1[N:6]([CH2:19][O:20][C:21]2[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[C:23]([CH2:29][CH3:30])[CH:22]=2)[C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][C:4]=2[N+:3]=1[CH2:19][O:20][C:21]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[C:23]([CH2:29][CH3:30])[CH:22]=1
Reactant: CCc1cc(CC)cc(OCI)c1
Reactant: Nc1nc2ccc(Cc3ccccc3)cc2[nH]1
Product: CCc1cc(CC)cc(OCn2c(N)[n+](COc3cc(CC)cc(CC)c3)c3cc(Cc4ccccc4)ccc32)c1
Product: [I-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5-benzylbenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 3,5-diethylphenyl iodomethyl ether, the title compound is obtained.
Reaction SMILES: C(Cl)(=O)C.[C:5]([C:7]1[CH:8]=[C:9]([C:22]#[C:23][CH2:24][C@H:25]([NH:30]C(OC(C)(C)C)=O)[C:26]([O:28][CH3:29])=[O:27])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])#[N:6].CO>C(OCC)(=O)C>[NH2:30][C@@H:25]([CH2:24][C:23]#[C:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:7]([C:5]#[N:6])[CH:8]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)[C@H](CC#Cc1ccc(OCc2ccccc2F)c(C#N)c1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)[C@@H](N)CC#Cc1ccc(OCc2ccccc2F)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (225 ul, 248 mg, 3.16 mmol) was added dropwise to a solution of methyl (2S)-5-(3-cyano-4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D70, 286 mg, 0.631 mmol), prepared with analogous procedure to that described hereinabove, in dry ethyl acetate (10 ml) and dry methanol (2 ml). After stirring at room temperature overnight the solvent was evaporated, water (10 ml) and dioxin (10 ml) were added and the pH was adjusted to 10 using 28% NH3 in water. The mixture was extracted with DCM. The combined organic layer was dried (Na2SO4), filtered and evaporated. The crude product was used in the next step. MS: (ES/+) m/z: 353 [MH+], C20H17FN2O3 requires 352.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([CH:28]=C)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1.I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1)[CH:28]=[O:32]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1c(F)c(Cl)cc(C(C)Nc2ncnc3c2ncn3C2CCCCO2)c1OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
N-[1-(5-Chloro-4-fluoro-2-methoxy-3-vinylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (240 mg, 0.56 mmol) was dissolved in THF (10 mL) and 0.16 M osmium tetraoxide in water (700 μL) was added. Sodium metaperiodate (360 mg, 1.7 mmol) and water (1 mL, 60 mmol) were added. The reaction was stirred at 60° C. for 2 hours. Reagents were doubled. 0.16 M osmium tetraoxide in water (700 μL) was added. Sodium metaperiodate (360 mg, 1.7 mmol) and water (1 mL) were added and the mixture was warmed to 60° C. for another 2 hours. The mixture was evaporated and the solids were extracted with dichloromethane. The extracts were purified on silica gel using 0-60% EtOAc in hexanes to give the desired compound (50 mg, 20%). LCMS calculated for C20H22ClFN5O3 (M+H)+: m/z=434.1. found: 434.1.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:17][CH2:18][CH2:19][CH2:20][Cl:21]>CO>[Br-:17].[Cl:21][CH2:20][CH2:19][CH2:18][N+:11]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: ClCCCBr
Reactant: CCCCCCCCCCN1CCCCC1
Solvent: CO
Product: CCCCCCCCCC[N+]1(CCCCl)CCCCC1
Product: [Br-]
Temperature: 65 °C
Reaction time: 6 h
Yield: 800.7 %

Procedure:
N-decylpiperidine was synthesized by reacting 45.7 g piperidine with 118.7 g 1-bromodecane in 237 mL acetone in the presence of 74 g potassium carbonate. After refluxing this reaction mixture at 55° C. for 24 hr, it was filtered and acetone was removed from the filtrate to yield 61 g N-decylpiperidine. 5 g N-decylpiperidine and 42 g 1-bromo-3-chloropropane were dissolved in 50 mL methanol and the reaction mixture was heated at 65° C. for 18 hr. After cooling to room temperature, methanol was removed under reduced pressure. The residue was poured into 2 L tert.butylmethyl ether with stirring and then the mixture was allowed to stand for 6 hr. The white precipitate thus formed was filtered and was dried at 40° C. under vacuum for 24 hr yielding 68 g (3-chloropropyl)decylpiperidinium bromide as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: COCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 19.7 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (22 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-methoxy-ethylamine (18 mg), DPPA (53 uL), and DIEA (43 uL). LC/MS: m/z 466.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.36 (bs, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.53-3.38 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=2[CH2:24][CH3:25])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH2:32])=[O:31].O.[C:37]([OH:41])(=[O:40])[CH:38]=O>>[C:30]([C:29]1[CH:28]=[C:27]([NH:26][CH:38]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][O:12][C:10](=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[C:16]([CH2:24][CH3:25])[CH:17]=2)[C:37]([OH:41])=[O:40])[CH:35]=[CH:34][CH:33]=1)(=[O:31])[NH2:32]
Reactant: O=CC(=O)O
Reactant: NC(=O)c1cccc(N)c1
Reactant: CCc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Solvent: O
Product: CCc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Yield: 72 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 56B (175 mg, 0.52 mmol) was reacted with 3-aminobenzamide and glyoxylic acid monohydrate to afford 56C (175 mg, 72%) as an oil. MS (ESI) m/z 487.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[O:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[Cl:9][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([Cl:1])[C:7]=1[N:22]1[CH2:23][CH2:24][CH:19]([N:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)[CH2:20][CH2:21]1)[NH2:10]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Product: Nc1cc(Cl)c(N2CCC(N3CCOCC3)CC2)c(Cl)c1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 3,4,5-trichloronitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 144–146° C.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:12]([O:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])[CH3:13]>ClCCl>[C:12]([O:15][CH2:16][C:17]([N:1]1[CH2:4][CH2:3][CH2:2]1)=[O:18])(=[O:14])[CH3:13]
Reactant: C1CNC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Azetidine (546 mg, 9.56 mmol) was dissolved in dichloromethane (20 mL) in a 50 mL round bottom flask and treated with triethylamine (1.47 mL, 10.5 mmol) stirring at ambient temperature for 30 minutes. 2-chloro-2-oxoethyl acetate (1.03 mL, 9.56 mmol) was added to the mixture dropwise. The mixture was stirred at ambient temperature for 16 hours. The precipitated salt was removed by filtration and the filtrate was washed with water. The solution was concentrated under vacuum to give 2-(azetidin-1-yl)-2-oxoethyl acetate as a brown oil. Lithium aluminum hydride (10.0 mL, 10.0 mmol, 1 M in THF) in a 100 mL round bottom flask was cooled in an ice-water bath. 2-(Azetidin-1-yl)-2-oxoethyl acetate as a 0.6 M solution in THF was added dropwise to the lithium aluminum hydride solution. The ice bath was removed and the mixture was stirred at ambient temperature for 2 hours. A mixture of 1:1 Celite®/sodium sulfate decahydrate was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was filtered and the filter cake was washed with THF. The filtrated was concentrated under vacuum to give 2-(azetidin-1-yl)ethanol as a viscous, colorless oil (504 mg).
Reaction SMILES: N1C=CC=CC=1NC(N)=S.CI.COC1C=CC=CC=1CN.[C:23]([O-:26])(=[O:25])[CH3:24].[CH3:27][O:28][C:29]1[CH:45]=[CH:44][CH:43]=[CH:42][C:30]=1[CH2:31][NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[NH:34]>CO>[C:23]([OH:26])(=[O:25])[CH3:24].[CH3:27][O:28][C:29]1[CH:45]=[CH:44][CH:43]=[CH:42][C:30]=1[CH2:31][NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[NH:34]
Reactant: CC(=O)[O-]
Agent: COc1ccccc1CN
Agent: COc1ccccc1CNC(=N)Nc1ccccn1
Agent: NC(=S)Nc1ccccn1
Solvent: CO
Solvent: CI
Product: CC(=O)O
Temperature: 70 °C

Procedure:
0.800 g (5.117 mmol) N-pyridin-2-yl-thiourea was dissolved in 10 mL methanol, 0.45 mL (7.164 mmol) methyl iodide in 5 mL methanol was added dropwise, and the mixture was heated for 1 hr at 70° C. (oil bath temperature) and subsequently stirred at room temperature. The solvent was removed under vacuum and the intermediate product, methyl N-(pyridin-2-yl)imidothiocarbamate hydroiodide, was redissolved in 15 mL ethanol. 1.36 mL (10.235 mmol) 2-methoxybenzylamine was added dropwise, and the mixture was heated for 2.75 hr at 85° C. (oil bath temperature) and subsequently stirred at room temperature. The solvent was then evaporated under vacuum. The crude product was redissolved with dichloromethane and extracted with water (2×30 mL). After drying over magnesium sulfate and removal of the solvent, purification was carried out via preparative HPLC (Merck Chromolith RP-18 100×25 mm, eluent: water/acetonitrile/0.1 M acetic acid). For complete ion exchange with the ion exchanger (Fluka, acetate on 1.5 mmol CH3COO/g/resign polymer substrate), the purified N-(2-methoxybenzyl)-N′-pyridin-2-yl-guanidine was converted to the acetate salt in a yield of 0.357 g (1.128 mmol).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18]C[Cl:20])[C:5]=2[CH:4]=1.[CH2:23](N(CC)CC)C.[CH2:30]([C:37]1([O:43][CH2:44][CH2:45][OH:46])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(C(C)=O)C.[I-].[Na+]>[ClH:20].[F:21][C:2]([F:22])([F:1])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH:17]([CH2:23][N:40]3[CH2:41][CH2:42][C:37]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([O:43][CH2:44][CH2:45][OH:46])[CH2:38][CH2:39]3)[CH3:18])[C:5]=2[CH:4]=1
Reactant: CCCCCCCC1(OCCO)CCNCC1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: CCN(CC)CC
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCC1(OCCO)CCN(CC(C)N2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Product: Cl
Yield: 32.4 %

Procedure:
14.1 g of 2-trifluoromethyl-10-(3-chloropropyl)-phenothiazine were dissolved in 50 ml of methyl ethyl ketone and 6.14 g of sodium iodide, 4.15 g of triethylamine, then 10 g of 2-(4-heptyl-4-piperidyloxy)-ethanol dissolved in 50 ml of methyl ethyl ketone were successively added thereto. The mixture was refluxed with agitation for 40 hours and after cooling, the precipitate formed was removed by vacuum filtration. The organic solution was washed with an aqueous solution of sodium bicarbonate, then with water, dried and then concentrated. The said product was reacted with an ether solution of hydrogen chloride and the obtained precipitate was recovered by vacuum filtration and was crystallized from an ethanol ether mixture to obtain 7.8 g of 2-trifluoromethyl-10-[3-(4-heptyl-4-β-hydroxy-ethoxy-piperidino)-β-propyl]-phenothiazine hydrochloride as white crystals melting at 180° C and soluble in ethanol and insoluble in water and ether.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[I:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11](O)=[O:12]>C(Cl)(Cl)Cl>[I:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([Cl:2])=[O:12]
Reactant: COc1ccc(C(=O)O)cc1I
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1I
Yield: 85.3 %

Procedure:
To a suspension of PCl5 (33.0 g, 158 mmol) in 30 mL CHCl3 was added, with magnetic stirring, 3-iodo-p-anisic acid (40.0 g, 144 mmol) in small portions. The solution was heated at reflux for b 1 h under a gentle nitrogen sweep, during which time the solution became homogenous. The solvent was evaporated under reduced pressure, then the residue was distilled under high vacuum. The fraction distilling at 152-156° C. (5 mm Hg; lit.10 bp 183-185° C., 12-13 mm Hg) was collected, which rapidly solidified as a pink solid. Recrystallization from 200 mL hexane/CH2Cl2 afforded the desired product as white needles (36.4 g, 85.5%); mp 58° C.; 1H NMR (CDCl3) δ 3.99 (s, 3 H), 6.88 (d, 1 H, J=8.7 Hz), 8.13 (dd, 1 H, J=8.7, 2.4 Hz), 8.52 (d, 1 H, J=2.4 Hz); EI-MS m/z 296 (M+, 42), 261 (100).