Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]([CH3:14])[CH3:13])=O)=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([N:12]([CH3:14])[CH3:13])=[N:9][N:8]=2)[CH:7]=1
Reactant: CN(C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)c1nnc2ccc(F)cn12
Temperature: 60 °C
Reaction time: 9 h
Yield: 14.5 %

Procedure:
To a solution of Intermediate 59a (590 mg, 2.98 mmol), Ph3P (1.56 g, 5.96 mmol) and Et3N (1.20 g, 11.9 mmol) in THF (40 mL) was added hexachloroethane (1.41 g, 5.96 mmol) and the mixture stirred at 60° C. for 9 h. The mixture was diluted with EtOAc (100 mL), washed with water, brine, dried (MgSO4) and then concentrated in vacuo. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, then triturated with diethyl ether to give the title compound (78 mg, 14%). LCMS (Method 1): Rt 2.24 min, m/z 181 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Ir:12](Cl)(Cl)Cl.[C:16]1([C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:31](=[O:34])([O-:33])[O-:32].[Na+].[Na+]>C(OCCO)C>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:31]([O-:33])=[O:32])[CH:8]=[CH:7]2.[Ir+3:12].[C:16]1([C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[C:16]1([C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:31]([O-:32])=[O:34])[CH:8]=[CH:7]2.[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:31]([O-:33])=[O:32])[CH:8]=[CH:7]2
Reactant: Cl[Ir](Cl)Cl
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2cccnc12
Agent: [Na+]
Agent: c1ccc(-c2nc3ccccc3s2)cc1
Solvent: CCOCCO
Product: O=C([O-])c1ccc2cccc(O)c2n1
Product: [Ir+3]
Temperature: 25 °C
Yield: 57 %

Procedure:
4.7 mmol (0.68 g) of 8-hydroxyquinoline was added to a room-temperature solution of 0.14 mmol 2-phenylbenzothiazole Iridium chloride dimer (0.19 g) in 20 mL of 2-ethoxyethanol. Approximately 700 mg of sodium carbonate was added, and the mixture was heated to reflux under nitrogen in an oil bath overnight (23 hrs.). Reaction mixture was cooled to room temperature, and the red precipitate was filtered off via vacuum. The filtrate was concentrated and methanol was added to precipitate more product. Successive filtrations and precipitations afforded a 57% yield. The emission spectrum is in FIG. 43 and the proton NMR spectrum is in FIG. 44.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](N)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:22].[OH-].[K+]>C(O)C>[O:1]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:22])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(COc2ccccc2)cc1)C(N)=O
Reactant: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ccc(COc2ccccc2)cc1)C(=O)O

Procedure:
One gram of 2-(4-phenoxymethylphenoxy)-propionamide (obtainable from the nitrile with sulfuric acid at 25°) and 2 g. of KOH are refluxed in 40 ml. of ethanol for 3 hours; after evaporation, the mixture is worked up as usual, yielding 2-(4-phenoxymethylphenoxy)-propionic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:12][CH3:13])=[N:7][C:6]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]1)[CH3:2].[Cl:25][C:26]1[C:39]([N:40]=[C:41]=S)=[C:38]([Cl:43])[CH:37]=[CH:36][C:27]=1[CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].CC(C)N=C=NC(C)C>CC#N>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[N:11]=[C:41]([NH:40][C:39]3[C:38]([Cl:43])=[CH:37][CH:36]=[C:27]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]=3[Cl:25])[N:12]([CH3:13])[C:8]2=[N:7][C:6]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:21])[F:22])[CH2:16][CH2:15]1)=[O:24])[CH3:2]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CCOC(=O)c1cc(N)c(NC)nc1N1CCC(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)n(C)c2nc1N1CCC(C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
A mixture of 6-methylamino-5-amino-2-(4-trifluoromethyl-piperidinyl)-nicotinic acid ethylester (2.80 g, 7.92 mmol), N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (2.76 g, 8.72 mmol) and MeCN (60 mL) is stirred overnight, concentrated and triturated with MeCN and Et2O. The resulting solid is diluted with 60 mL MeCN and DIC (1.06 mL, 6.8 mmol) is added and it is stirred for 3 h at 60° C. The crude mixture is concentrated, diluted with EtOAc, washed with water, dried with Na2SO4, filtered, concentrated and purified by flash chromatography (silica; PE:EtOAc 3:1->1:1). Yield: 4.04 g. HPLC Rt=1.56 min (method D). MS m/z: 629 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH3:27].O>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O:3][CH2:26][CH3:27])=[O:2]
Reactant: O=C(O)c1ccc(-c2nc3ccccc3s2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc3ccccc3s2)cc1
Reaction time: 48 h
Yield: 81 %

Procedure:
To a slurry of 2-(4-carboxyphenyl)benzothiazole (4.5 g, 17 mmol.) in DMF (38 mL), potassium carbonate (5.39 g, 39 mmol) was added and the mixture was cooled in an ice bath. Bromoethane (7.2 mL, 102 mmol) was added in portions, and the mixture was allowed to come to room temperature. After 48 hours, the mixture was poured into water and the separated solids (4.51 g) were collected. A solution of the crude product was passed through a column of silica gel. The product residue (4.19 g), left after evaporation of the solvent, was recrystallized from ethanol; 3.96 g (81% yield), m.p. 132-133.6° C. Mass spec: m/z 283 (M+). Anal. Calcd for C16H13NO2S: C, 67.83; H, 4.62; N, 4.94; S, 11.31%. Found, C, 67.86; H, 4.62; N, 4.89; S, 11.45%. FT-IR (KBr; cm−1): 3100 (sp2C—H), 2989 (sp3C—H), 1710 (C═O), 1522 (asym NO2), 1341 (sym NO2), 1279 (C—O—C), 1108, 773, 753, 696. 1H NMR (CDCl3; δ in ppm): 1.45 (t, 3H, methyl), 4.45 (q, 2H, OCH2), 7.4-7.55 (m, 2 ArH), 7.9 (d, 1 ArH), 8.05-8.20 (m, 5 ArH). 13C NMR (CDCl3; δ in ppm): 14.76, 61.72 (sp3 C), 122.12, 123.99, 126.09, 126.99, 127.78, 130.61, 132.79, 135.67, 137.67, 137.74, 154.51, 166.32 (sp2C).
Reaction SMILES: [CH:1]1([C:4](=[O:7])[CH:5]=[CH2:6])[CH2:3][CH2:2]1.C(O[CH2:13][N:14]([CH2:23][Si](C)(C)C)[C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])CCC.FC(F)(F)C(O)=O>ClC(Cl)C>[C:17]1([C@H:15]([N:14]2[CH2:13][CH2:6][CH:5]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:7])[CH2:23]2)[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCCOCN(C[Si](C)(C)C)[C@H](C)c1ccccc1
Reactant: C=CC(=O)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: C[C@H](c1ccccc1)N1CCC(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.6 %

Procedure:
In dry dichloroethane (350 ml) was dissolved the product (8.01 g) containing 1-cyclopropyl-2-propen-1-one described in Reference Example 2-1 and N-(n-butoxymethyl)-N-[1-(R)-phenylethyl]trimethylsilylmethylamine (23.2 g, 79.9 mmol), followed by dropwise addition of trifluoroacetic acid (500 μl). After stirring at room temperature for 12 hours, the reaction solution was washed with saturated sodium bicarbonate (100 ml) and then saturated saline (100 ml). The solution was dried over anhydrous sodium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography to obtain the title compound (9.08 g, 49.6%) as a colorless oil from the fraction eluted with n-hexane/ethyl acetate=2/1. By the way, this product was obtained as a 1:1 diastereomer mixture.
Reaction SMILES: [C:1](=[N:14][NH:15][C:16](=[O:29])[CH2:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:19][OH:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl>[C:1](=[N:14][NH:15][C:16]([CH2:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])=[O:29])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(C(CO)CC(=O)NN=C(c2ccccc2)c2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(C(COS(C)(=O)=O)CC(=O)NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-hydroxy-3-(3-methoxy-phenyl)-butyric acid benzhydrylidene-hydrazide and (1.7 g, 4.38 mmol) and 4-dimethylaminopyridine (26 mg, 0.22 mmol) in pyridine (15 mL) is cooled to 0° C. treated with methanesulfonyl chloride (0.4 mL, 5.25 mmol) and stirred 18 h at room temperature. The mixture is diluted with dichloromethane (30 mL) and washed with 1 N hydrochloric acid (30 mL), a saturated solution of sodium bicarbonate and brine. The mixture is dried over magnesium sulfate, filtered, concentrated in vacuo and chromatographed on SiO2 (2% methanol/dichloromethane) to yield the title compound, 1.64 g (80%), as yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[C:13](O)(=O)[CH3:14]>CC(C)(C)C([O-])([O-])[O-]>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:13]([CH3:14])[O:8][N:7]=2)[CH:9]=[C:10]([CH3:12])[N:11]=1
Reactant: Cc1cc(C(=N)NO)cc(Cl)n1
Reactant: CC(=O)O
Agent: CC(C)(C)C([O-])([O-])[O-]
Product: Cc1cc(-c2noc(C)n2)cc(Cl)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Chloro-N-hydroxy-6-methyl-isonicotinamidine (120 mg) was suspended in trimethylorthoacetate (3 ml) under inert atmosphere and acetic acid (0.3 ml) was added. The mixture was heated to 100° C. and stirred for 2 h. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue partitioned between EtOAc and aqueous solution of NaHCO3. The organic layer was separated, washed with water and brine, dried under Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography (10 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 10/0 to 9/1) affording the title compound (107 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH:6][C:7]1[CH:8]=[C:9]([C:13](=O)[C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.Cl.[NH2:19][OH:20].Cl>O>[OH:20][N:19]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([OH:6])[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: NO
Reactant: O=C(O)C(=O)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=NO)c1cccc(O)c1
Temperature: 25 °C

Procedure:
To a solution of sodium bicarbonate (5.56 g.) in water (200 ml.) was added and dissolved with stirring 3-hydroxyphenylglyoxylic acid (11 g.) under cooling. On the other hand, hydroxylamine hydrochloride (4.60 g.) was added and dissolved into a solution of sodium bicarbonate (5.56 g.) in water (70 ml.) with stirring at room temperature. Thus obtained solution was added with stirring to the above obtained solution under cooling. The mixture was stirred for 20 hours at room temperature and was subjected for salting-out treatment. Then, the reaction solution was acidified with hydrochloric acid and was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried. After solvent was distilled off, the residue was crystallized from benzene. The crystals were collected by filtration to obtain 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][C:4]=1[O:12][CH3:13].C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(Cl)Cl.C(Cl)(Cl)Cl>[S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)([O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:12][CH3:13])[CH:5]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(CCO)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of 3,4-dimethoxyphenethanol (4.4 g) in methylene chloride (15 ml) containing triethylamine (2.7 g or 3.7 ml), was added gradually a solution of tosyl chloride (5.07 g) in methylene chloride (15 ml). The mixture was stirred at room temperature overnight. The mixture was diluted with chloroform and washed with water. The organic layer was separated, dried and evaporated to yield a crude product (11.7 g). The product was passed through a column of silica gel (250 g) and the eluates were evaporated to give 3,4-dimethoxyphenethyl tosylate (7.2 g): ir(CHCl3) 1600 and 1500 cm-1 ; and nmr(CDCl3) δ2.4 (s, 3H), 2.85 (m, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 4.15 (t, 2H), 6.6 (m, 2H), 7.23 (m, 3H) and 7.64 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[Cl:12].[CH3:13][O:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[C@H:16]1[CH2:27][C:28](=[O:31])[CH2:29]Br>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:29][C:28](=[O:31])[CH2:27][C@H:16]3[C@H:15]([O:14][CH3:13])[CH2:20][CH2:19][CH2:18][N:17]3[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[C:10](=[O:11])[C:5]=2[S:4][C:3]=1[Cl:12]
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2c(Br)c(Cl)sc12
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2c(Br)c(Cl)sc2c1=O

Procedure:
According to the method of Example 4, 0.662 g (0.0025 mole) of 7-bromo-6-chlorothieno[3,2-d]pyrimidin-4(3H)-one and 1.24 g (0.0037 mole) of allyl trans-3-methoxy-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate were combined to give the title compound: yield 0.90 g (69%); 1H-nmr (CDCl3) delta 1.3-2.1 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.7-3.1 (multiplet, 4H, COCH2CH and NCH2), 3.3 (broad singlet, 1H, CH2CHNCO), 3.4 (singlet, 3HOCH3), 4.0 (broad doublet, 1H, CHOCH3), 4.6 (broad doublet, 2H, CH2CH=CH2), 4.9-5.1 (multiple peaks, 2H, NCH2CO), 5.3 (triplet with fine splitting, 2H, CH2 =CH), 5.9 (octet, 1H, CH=CH2), 7.2 [singlet, 0.15H, thieno H (some of the 6-chloro analog, an impurity)], 8.0 [broad singlet, 0.15H, (N=CH--N from the 6-chloro analog)], 8.1 (broad singlet, 1H, N=CH--N).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:28]1[CH2:29][CH:30]=[C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH2:26][CH2:27]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: C1=C(c2ccccn2)CCNC1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CC=C(c2ccccn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 49.6 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (2.21 g, 8.8 mmol) and 1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (7.47 g, 46.6 mmol) were dissolved in acetonitrile (100 ml), and lithium perchlorate trihydrate (7.48 g, 46.6 mmol) was added thereto and refluxed for 48 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 1.90 g of the intended substance (yield 49.6%).
Reaction SMILES: [CH:1]12[CH2:10][CH:4]([CH:5](C(O)=O)[CH2:6]1)[CH:3]=[CH:2]2.S(Cl)([Cl:13])=O.C(N(CC)CC)C.CC([O:26][CH3:27])(C)C>>[C:1]12([C:27]([Cl:13])=[O:26])[CH2:10][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2
Reactant: O=S(Cl)Cl
Reactant: COC(C)(C)C
Reactant: O=C(O)C1CC2C=CC1C2
Solvent: CCN(CC)CC
Product: O=C(Cl)C12C=CC(CC1)C2
Temperature: 3 °C

Procedure:
A 500 mL sulfur flask was equipped with magnetic stirring, addition funnel, thermometer, reflux condenser with N2-inlet adapter, and outlet adapter connected to a trap immersed in a dry ice/acetone bath. 58.28 g of 2-norbornene-5-carboxylic acid (Aldrich) were charged to the reactor under a positive flow of nitrogen, then 31.4 mL of thionyl chloride (51.32 g). 450 mL of methyl-tert-butyl ether were added, an ice bath was applied, and the contents of the reactor were stirred to mix and cool to 3° C. 51.6 mL of triethylamine (37.45 g) and 20 mL of MTBE were charged to the addition funnel and added dropwise to keep temperature less than 10° C. On completion of the addition the ice bath was removed and the flask was stirred for one hour. The resulting suspension was filtered to remove triethylamine hydrochloride. The resulting clear yellow solution was reduced to an oil on a rotary evaporator and purified by fractional distillation at 8 mBar (fraction boiling at 62-75° C.). 72% recovery at 99.13% purity was attained. The product was stored in a desiccator at room temperature until use.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=NC=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[CH3:48][N:49](C)C(=O)C>O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:48][N:49]=3)[O:6][C:7]=2[CH3:8])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1oc(-c2ccc(F)nc2)cc1C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Cc1oc(-c2ccc(F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-2-fluoropyridine (0.37 g), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.35 g), sodium carbonate (0.2 g) and sodium iodide (0.2 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.1 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (245 mg, 42%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:18])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([O:18][CH2:23][CH:22]=[CH2:21])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Oc1ccc(O)cc1C(C)(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OC(=O)C(C)(C)C)c(C(C)(C)C)c1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Under a nitrogen stream, 4.48 g of 3-t-butyl-4-trimethylacetoxyphenol synthesized in Example 15-2) was dissolved in 20 ml of dimethylformamide and a suspension of 0.86 g of oily sodium hydride in 20 ml of dimethylformamide at 0° C. was added dropwise. After stirring for 30 minutes, 1.86 ml of allyl bromide was added dropwise and the solution was stirred for 3 hours and allowed to attain room temperature. After the reaction was quenched with a saturated aqueous ammonium chloride solution, the mixture was extracted with water and n-hexane. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 4.31 g of 3-t-butyl-4-trimethylacetoxy-1-(2-propenyloxy)benzene as a colorless oil (yield 83%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12](Cl)[O:11][CH2:10]2)[CH2:8][O:7][P:6]1Cl)[CH:2]([CH3:4])[CH3:3].[CH2:17]([SH:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(N([CH2:41][CH3:42])CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9]2([CH2:14][O:13][P:12]([S:35][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:11][CH2:10]2)[CH2:8][O:7][P:6]1[S:35][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:41][CH3:42])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1P(Cl)OCC12COP(Cl)OC2
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCSP1OCC2(CO1)COP(SCCCCCCCCCCCCCCCCCC)N2CC(C)C
Yield: 30.9 %

Procedure:
The procedure of Example 10 is repeated using 8.72 g (28.5 mmol) of 1-isobutyl-2,8-dichloro-3,7,9-trioxa-1-aza-2,8-diphosphaspiro[4.5]decane, 16.33 g (57 mmol) of n-octadecyl mercaptan and 8.74 mL (63 mmol) of triethylamine in 200 mL of toluene. A white solid (7.11 g) is isolated. The product is identified by mass spectroscopy: m/z=805.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)#[N:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:20][CH3:21]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)Cc1ccc(C#N)cc1
Temperature: -30 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
1.0 g (3.47 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 10 ml of ethanol, and 684 mg (5.21 mmol, 1.5 equivalents) of 4-cyanobenzaldehyde were charged in a 100 ml three-necked flask. The mixture was cooled to −30° C. After the addition of 1.47 g (6.95 mmol, 2.0 equivalents) of sodium triacetoxyborohydride, the mixture was stirred for six hours and further stirred at room temperature for 12 hours. After confirming the disappearance of the raw material, the reaction solution was added into 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted with 100 ml of chloroform. The chloroform layer was washed with 50 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 1.35 g of 4-[(4-dipropylaminobutyl)-4-cyanobenzylamino]methylbenzonitrile (12) as a colorless oily substance (yield: 97%, GC: 87%).