Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.O>C1C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:3][CH:2]=[CH2:1])=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccc(-c2ccc(O)cc2Cl)cc1
Reactant: C=CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: C=CCOC(=O)Cc1ccc(-c2ccc(O)cc2Cl)cc1

Procedure:
After allyl alcohol (7.0 ml, 103 mmol) and concentrated sulfuric acid (0.1 ml) were successively added to a solution of (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetic acid (1.93 g, 7.35 mmol) obtained in Example (13-1) in benzene (30 ml), the mixture was heated under reflux for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=90/10-65/35) to give allyl (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate as a white powder (1.97 g, yield: 899.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[N:8]=[C:7]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]2)[CH:6]=1)=O.[CH2:38]([NH2:43])[CH2:39][CH2:40][CH2:41][CH3:42].[C-]#N.[Na+]>>[CH2:13]([O:12][C:10]([N:9]1[C:5]([C:3](=[O:2])[NH:43][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:6][C:7]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:34])([F:36])[F:35])[CH2:22][CH2:21]2)=[N:8]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCN
Reactant: COC(=O)c1cc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1C(=O)OCc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Product: CCCCCNC(=O)c1cc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of above 3-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]-pyrazole-1,5-dicarboxylic acid 1-benzyl ester 5-methyl ester (0.800 g, ca. 1.5 mmol), amylamine (3.0 mL) and sodium cyanide (0.150 g, 3.0 mmol) was stirred at room temperature overnight and then purified by column chromatography to give the title compound (0.238 g, 10% in 2 steps). 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.5 Hz, 1H), 7.61-7.49 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 7.25-7.17 (m, 5H), 5.93-5.85 (m, 2H), 5.56 (s, 2H), 3.98-3.84 (m, 2H), 3.33-3.05 (m, 8H), 1.57-1.44 (m, 2H), 1.31-1.18 (m, 4H), 0.86 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 159.7, 157.0, 137.7, 136.3, 134.6, 132.2, 129.2, 128.3, 127.6, 127.4, 127.2, 127.1, 126.6, 126.2, 125.4, 92.2, 53.9, 48.1, 47.8, 46.4, 41.0, 39.5, 29.1, 28.9, 22.3, 13.9. MS (ES+) m/z 572.0 (M+1). m.p. 58-61° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 1.07 g (5.24 mmol) of 2,6-dichlorobenzothiazole in dry DMF (25 mL) was added 2.4 g of potassium carbonate (15.7 mmol) and 0.5 g of piperazine (5.8 mmol). The mixture was stirred at room temperature for 4 h. When the reaction was complete it was partitioned between EtOAc (150 mL) and water (50 mL) and separated. The aqueous layer was extracted with EtOAC (2×100 mL). The combined organic layers were then washed with water (2×25 mL), brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give 1.33 g (100%) of desired product as a white solid. MS (electrospray): exact mass calculated for C11H12ClN3S, 253.04; m/z found, 254.0 [M+H]+.
Reaction SMILES: [CH2:1](Br)[CH2:2][C@H:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].[Li+].[Cl-].[CH3:14][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[CH3:9][C:8](=[CH:7][CH2:6][CH2:5][C@H:3]([CH3:4])[CH2:2][CH2:1][CH3:14])[CH3:10]
Reactant: CC(C)=CCC[C@H](C)CCBr
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@@H](C)CCC=C(C)C
Temperature: 25 °C

Procedure:
To (S)-citronellyl bromide (50 g, 0.228 mol) in THF (800 mL) at 0° C. was added LiCl (4.3 g) followed by CuCl2 (6.8 g). After 30 minutes methylmagnesium chloride (152 mL of a 3 M solution in THF, Aldrich) was added and the solution warmed to room temperature. After 10 hours the solution was cooled to 0° C. and a saturated aqueous solution of ammonium chloride carefully added. The resultant two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4) and concentrated to give an oil. 32.6 g; 93%. Used without further purification. 13C NMR (100 MHz; CDCl3) 131.13, 125.28, 39.50, 37.35, 32.35, 25.92, 25.77, 20.31, 19.74, 17.81, 14.60.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@@H:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=2)[O:2]1.C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C(OCC)(=O)C>[O:28]([C:26]([NH:12][CH2:11][C@@H:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCC[C@@H](CN)c1cccc2c1OCO2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCC[C@@H](CNC(=O)Oc1ccccc1)c1cccc2c1OCO2
Yield: 98.9 %

Procedure:
To a mixture of 2.35 g of (R)-2-(2, 3-methylenedioxyphenyl) heptylamine, 1.20 g of triethylamine and 20 ml of ethyl acetate was dropwise added 1.72 g of phenyl chloroformate with ice cooling and stirring, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate and the solvent evaporated to give 3.51 g of N-phenoxycarbonyl-(R)-2-(2, 3-methylenedioxyphenyl) heptylamine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH:9]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[N:16][OH:17])[CH:9]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1C(=O)CCN1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1C(=NO)CCN1Cc1ccccc1
Yield: 63.7 %

Procedure:
To 80 ml of ethanol solution containing 16 g of 1-benzyl-2-methyl-3-pyrrolidone was added 80 ml of aqueous solution containing 13 g of hydroxylamine hydrochloride. After adding 18 g of sodium carbonate to the solution, the mixture was warmed to 35°-40° C. for 30 minutes. The reaction mixture was condensed under reduced pressure to half volume, and the product was extracted twice each time with 80 ml of ether. The extracts were combined and dried over anhydrous magnesium sulfate. The extracts were condensed under reduced pressure to provide 11 g of oily crude 1-benzyl-3-hydroxyimino-2-methylpyrrolidine.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][CH3:16])[C:6]([C:17]([OH:19])=[O:18])=[C:5]([C:20]([F:23])([F:22])[F:21])[N:4]=1.S(Cl)(Cl)=O.[CH2:30](O)[CH3:31]>>[F:25][C:2]([F:24])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:15][CH3:16])[C:6]([C:17]([O:19][CH2:30][CH3:31])=[O:18])=[C:5]([C:20]([F:22])([F:21])[F:23])[N:4]=1
Reactant: CCO
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)O)c1OCC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1OCC

Procedure:
This material was obtained from product of Example 14 and ethanol according to the following general procedure: 5.0 g portion of the acid product of Example 14 was refluxed with excess thionyl chloride until te reaction was completed. Excess thionyl chloride was removed in vacuo. The residual acid chloride was refluxed with an excess of appropriate alcohol (ethanol in this Example) for 2-4 hours and concentrated to give the desired product. The crude product was purified by a wash with 20% K2CO3 and isolated as a solid (20.3% yield), mp 28°-30° C.
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C@H:5]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][N:7]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:24]=2[Cl:25])[C:20]([O:22]C)=[O:21])(=[O:14])=[O:13])[CH2:6]1>CO>[CH3:4][C@H:5]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][N:7]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:24]=2[Cl:25])[C:20]([OH:22])=[O:21])(=[O:13])=[O:14])[CH2:6]1
Reactant: COC(=O)c1cccc(S(=O)(=O)N2C[C@H](C)C[C@H](C)C2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2cccc(C(=O)O)c2Cl)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
An aqueous solution of 4.2 g. (105 m moles) of sodium hydroxide in 130 ml. of water is added to 18 g. (52.5 m moles) of methyl 5-(cis-3,5-dimethylpiperidinosulfonyl)-6-chlorobenzoate in 130 ml. of methanol, and resulting reaction mixture allowed to stir at 40° C. for 1 hr. The solution is poured into ice water (1.5 l.) and extracted several times with benzene. The aqueous phase is separated, acidified with 12N hydrochloric acid, and the precipitated product filtered and air dried, 17.3 g. Recrystallization from ethyl acetatehexane gave the purified product, 16.4 g., m.p. 152.5°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:9](/[CH2:15][CH2:16][OH:17])\[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+:29]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[C:9](/[CH2:15][CH2:16][OH:17])\[C:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[Na+:29]
Reactant: CCOC(=O)/C(CCO)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C(\CCO)C(=O)[O-])c2ccc(Cl)cc2)cc1
Yield: 101.6 %

Procedure:
To a solution of 5 g (0.0122 mole) of ethyl (Z)-3-(4-chlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate, prepared in example 4, in 10 ml of ethanol are added 11 ml (0.011 mole) of 1 M sodium hydroxide. The mixture is heated for 2 hours under reflux, then evaporated to dryness in vacuo. The crystals obtained are washed with ethyl acetate and with diethyl ether and then dried to provide 4.5 g of sodium (Z)-3-(4-chlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate as crystals with melting point of 257-259° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4](C2CCCCO2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:6]=2.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][O:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:6]=2
Reactant: CCCCCNc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCCNc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 8-methoxy-N2-pentyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (520 mg) in dry MeOH (5.2 mL) was added TFA (0.52 mL) and the mixture was stirred at room temperature for 48 h. The reaction was concentrated in vacuo to give an orange residue which was triturated with Et2O and filtered to give the title compound as an off-white solid (223 mg).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Product: COc1ccc(CN2C(=O)C(CCO)Oc3ccccc32)cc1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 4-methoxybenzyl chloride, in 48% overall yield after flash chromatography eluting with EtOAc/hexane, mp 80°-82° C.; IR (KBr) 3496, 1660, 1515, 1501, 1412, 1250, 1057, 754 cm-1 ; 1H NMR (CDCl3) 8 2.00 (v br s, 1H), 2.16-2.37 (m, 2H), 3.77 (s, 3H), 3.91 (t, J=6.1 Hz, 2H), 4.82 (dd, J=7.5, 5.6 Hz, 1H), 5.09 (s, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.91-7.00 (m, 4H), 7.18 (d, J=8.7 Hz, 2H); MH+ at m/z=314; Anal. Calc'd for C18H19 NO4 : C, 68.99; H, 6.11; N, 4.47. Found: C, 69.22; H, 6.10; N, 4.35.
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[CH:9]=2)[N:4]=1.[CH3:30][NH:31][CH3:32]>C(O)C>[CH3:30][N:31]([CH3:32])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:21])[CH2:18][CH2:19]3)[CH:9]=2)[N:4]=1
Reactant: CNC
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(-c3noc(C(Cl)(Cl)Cl)n3)ccn2)CC1
Solvent: CCO
Product: CN(C)c1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,2-Dimethylpropyl 4-{4-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}-1-piperazinecarboxylate (133 mg) obtained in Example 32 was dissolved in ethanol (4 mL), and aqueous 50% dimethylamine solution (1 mL) was added thereto, and stirred at room temperature for 3 hours. Then, the solvent was evaporated away and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 49.1 mg of the entitled compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5][OH:6].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].S(=O)(=O)(O)O>N1C=CC=CC=1>[F:1][C:2]([F:11])([C:7]([F:8])([F:9])[F:10])[CH2:3][CH2:4][CH2:5][O:6][S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: OCCCC(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(F)(F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
A solution of 17.3 g of 4,4,5,5,5-pentafluoropentanol in 40 ml of pyridine is mixed at 0° C. with 21 g of tosyl chloride and stirred for 3 hours at 0° C. For working up, the reaction mixture is added to 2 n sulfuric acid, extracted with diethyl ether, washed neutral with water, dried on sodium sulfate and concentrated by evaporation in a vacuum. 32.7 g of crude toluene-4-sulfonic acid-4,4,5,5,5-pentafluoropentyl ester is obtained as oil. The latter is dissolved in 300 ml of acetone and refluxed with 23 g of potassium thioacetate for 18 hours at 100° C. bath temperature. Then, it is mixed with water, extracted with diethyl ether, washed with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and distilled. At 173°-177° C., 15 g of thioacetic acid-S-(4,4,5,5,5-pentafluoropentyl)-ester is obtained.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH2:27]>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:27][CH2:26][C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: NCc1cccs1
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Solvent: CCO
Product: O[C@H](CNCc1cccs1)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 2-thiophenemethylamine and ethanol essentially as described above in Example 94. Purity by LC/MS=99%, [M+H]+=396.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]1[N:24]3[O:25][CH2:26][CH2:27][CH2:28][C:23]3=[N:22][C:15]=1[CH:16]=[N:17]2>ClCCl>[N:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]1[N:24]3[O:25][CH2:26][CH2:27][CH2:28][C:23]3=[N:22][C:15]=1[CH:16]=[N+:17]2[O-:6]
Reactant: c1cnc2c(c1)ncc1nc3n(c12)OCCC3
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc2nc3n(c2c2ncccc21)OCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Solid 3-chloroperoxybenzoic acid (0.26 g of approximately 77% pure material, 1.1 mmol) was added to a solution of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine (0.13 g, 0.6 mmol) in dichloromethane (15 mL). The reaction was stirred at room temperature for 1 hour and then washed with saturated aqueous sodium carbonate (10 mL). The aqueous fraction was extracted 5 times with 25 mL portions of dichloromethane. The combined organic fractions were dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine 5-oxide (0.13 g).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[N:4]=[CH:3]1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:10]1[C:5]2[N:4]=[CH:3][NH:2][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:13]
Reactant: CNOC
Reactant: O=C(O)c1cccc2[nH]cnc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a stirred solution of 1H-benzoimidazole-4-carboxylic acid hydrochloride (2.0 g, 10.1 mmol), N,O-dimethylhydroxylamine hydrochloride (1.47 g, 15.1 mmol) and ethyldiisopropylamine (7.02 mL, 40.3 mmol) in DMF (10 mL) at room temperature was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (3.90 g, 10.3 mmol) in a single portion. The mixture was stirred at room temperature overnight then concentrated in vacuo. Purification by SiO2 chromatography followed by trituration with EtOAc provided 1H-benzoimidazole-4-carboxylic acid methoxy-methyl-amide (945 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12](/[CH:13]=[C:14](\[CH3:21])/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[C].[Pd]>[CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCC/C(C)=C/c1cncn1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCCC(C)Cc1cncn1Cc1ccccc1
Yield: 95 %

Procedure:
In 10 ml of ethanol was dissolved 0.6 g of 1-benzyl-5-[(E)-2,6-dimethyl-1,5-heptadienyl]imidazole obtained in Reference Example 1. To the solution was added 0.1 g of 10% palladium-carbon, and the mixture was subjected to ctalytic reduction under atmospheric pressure. After a theoretical amount of hydrogen was consumed, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane, giving the title compound in a yield of 95%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][NH2:12])=[CH:7][C:6]=2[CH:13]=1.[C:14]([NH:16][C:17](=[N:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[O:26][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:28][CH:29]=1)SC)#[N:15]>>[C:14]([NH:16][C:17]([NH:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[O:26][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:28][CH:29]=1)=[N:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=2[CH:7]=1)#[N:15]
Reactant: Cc1ccc2oc(CCN)cc2c1
Reactant: CSC(=NCCSCc1ccc(CN(C)C)o1)NC#N
Product: Cc1ccc2oc(CCN=C(NC#N)NCCSCc3ccc(CN(C)C)o3)cc2c1

Procedure:
It was obtained by reacting amine (a) with N-cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]-methyl]thio]ethyl]-S-methyl-isothiourea, as described in Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:27])([F:26])[F:25])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH2:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:28](N(CC)CC)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:26])([F:25])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH:17][CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCN(CC)CC
Reactant: Nc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Solvent: ClCCl
Solvent: CI
Product: CNc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)aniline (0.3 g, 0.7 mmol) in DCM (10 mL) was added triethylamine (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at RT for 18 h. The DCM layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).
Reaction SMILES: [CH3:1][N:2]([CH3:48])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:47])[C@H:18]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2C(OC(C)(C)C)=O)=[O:29])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:4].Cl>CCOC(C)=O>[CH2:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:39][C@@H:30]([C:28]([NH:27][C@H:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([N:2]([CH3:1])[CH3:48])=[O:4])[CH2:16][CH2:15]2)=[O:47])=[O:29])[NH:31]1
Reactant: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
[2-(4-{(2R)-2-[((3S)(3-1,2,3,4-Tetrahydro-isoquinolyl))carbonylamino]-3-(4-chlorophenyl)-propanoyl}piperazinyl)phenyl]-N,N-dimethylcarboxamide was prepared according to the procedure described in Preparation XVI by using tert-butyl 3-[N-((1R)-2-{4-[2-(N,N-dimethylcarbamoyl)-phenyl]piperazinyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate (Step 6) (156 mg, 0.23 mmol) and a satd soln of HCl in EtOAc (5 mL). The title compound was isolated by filtration as a white solid, and purified by preparative HPLC (TFA buffer) (125 mg). MS (ESI, pos.ion) m/z: 574 (M+H). Calc'd for C32H36ClN5O3: 573.25.