Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([F:22])=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([O:19]C)=O)[O:14][C:13]3=[O:21])=[CH:11][C:6]=2[O:5][C:4]1=[O:23])[CH3:2].[NH3:24]>CO>[CH2:1]([N:3]1[C:7]2[C:8]([F:22])=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:24])=[O:19])[O:14][C:13]3=[O:21])=[CH:11][C:6]=2[O:5][C:4]1=[O:23])[CH3:2]
Reactant: N
Reactant: CCn1c(=O)oc2cc(N3C[C@H](C(=O)OC)OC3=O)cc(F)c21
Solvent: CO
Product: CCn1c(=O)oc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21

Procedure:
Prepared from methyl(5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 4, 0.250 g, 0.771 mmol) and ammonia in methanol (5 ml) according to the method of EXAMPLE 86, Step 10 (0.15 g, 63%); MS for C13H12FN3O5 m/z 310 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 7.87 (br s, 1H), 7.63 (br s, 1H), 7.52 (d, 1H), 7.44 (dd, 1H), 5.03 (dd, 1H), 4.26 (t, 1H), 4.02 (dd, 1H), 3.86 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([N:5]([CH2:20][P:21]([O:25]Cl)([O:23]Cl)=[O:22])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])=[O:4].[CH3:29][C:30]1[CH:31]=[C:32]([SH:36])[CH:33]=[CH:34][CH:35]=1.C(N([CH2:42][CH3:43])CC)C>CCOCC>[F:1][C:2]([F:28])([F:27])[C:3]([N:5]([CH2:20][P:21]([O:25][S:36][C:32]1[CH:31]=[CH:30][CH:29]=[C:42]([CH3:43])[CH:33]=1)([O:23][S:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=1)=[O:22])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8])=[O:4]
Reactant: CCCCCCCCCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: CCN(CC)CC
Reactant: Cc1cccc(S)c1
Solvent: CCOCC
Product: CCCCCCCCCCOC(=O)CN(CP(=O)(OSc1cccc(C)c1)OSc1cccc(C)c1)C(=O)C(F)(F)F
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of n-decyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (4.42 g, 0.01 mole) in 200 ml. of ether was added a solution of m-methylthiophenol (2.48 g, 0.02 mole) and triethylamine (2.02 g, 0.02 mole) in 50 ml. of ether. The resulting mixture was stirred for 16 hours at 20° C., then filtered. The filtrate was concentrated in vacuo to yield an oil which was chromatographed on silica gel (eluted with methylene chloride) to yield n-decyl N-trifluoroacetyl-N-(bis(m-methylphenylthio)phosphonomethyl)glycinate as an oil, nD27 =1.5267.
Reaction SMILES: [CH3:1]SCCC(Cl)=O.[CH3:8][S:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24]N=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[F:39].C1(C)C=CC=CC=1>C(O)C>[CH3:8][S:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:1]=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][S:9][CH3:8])=[S:16])=[CH:34][C:33]=1[F:39]
Reactant: CSCCC(=O)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CSCCC(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCSC)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
3-(Methylsulfanyl)propanoyl isothiocyanate was prepared using commercially available 3-(methylsulfanyl)propanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-(Methylsulfanyl)propanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]([C:12]2[O:23][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]=2)[C@@H:24]([OH:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 29 %

Procedure:
The crude material of N′-((2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 12b) (509 mg, 1.36 mmol) was added to THF (100 mL) stirred at room temperature. PS-BEMP (1.86 g, 4.09 mmol base) was added to the solution followed by slow addition of p-TSCl (286 mg, 1.50 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to provide the title compound (140 mg). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.93 (d, J=9 Hz, 2H), 7.54 (m, 1H), 7.46 (m, 3H), 6.83 (s, 1H), 6.65 (d, J=9 Hz, 1H), 5.35 (d, J=9 Hz, 1H), 4.70 (d, J=9 Hz, 1H), 4.62 (m, 1H), 3.30 (d, J=5 Hz, 1H), 1.42 (d, J=6 Hz, 3H).
Reaction SMILES: CCCCCC.[Li][CH2:8][CH2:9][CH2:10][CH3:11].O=C1CC[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:11]=[C:10]1[CH2:9][CH2:8][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: C=C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.9 %

Procedure:
A 2.5 M hexane solution of n-BuLi (4.86 mL, 12.15 mmol) was added to a suspension of methyltriphenylphosphonium bromide (4.34 g, 12.15 mmol) in Et2O (100 mL) at 0° C. The mixture was stirred at room temperature for 10 min. A solution of tert-butyl 3-oxopiperidine-1-carboxylate (2.2 g, 11.04 mmol) in ether (10 mL) was added dropwise. The resultant mixture was stirred at room temperature for 1 h, at reflux for 30 min, and cooled to room temperature. After the addition of water (30 mL), the two phases were separated. The aqueous phase was extracted with ether (3×60 mL). The combined ether extracts were washed with brine (20 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0 to 15% ethyl acetate in hexane, gave a colorless liquid (1.0 g, 46%). 1H NMR (400 MHz, chloroform-d) δ ppm 4.61-4.96 (2H, m), 3.87 (2H, s), 3.25-3.55 (2H, m), 2.09-2.39 (2H, m), 1.54-1.73 (2H, m), 1.46 (9H, s).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Br[C:26]1[C:27]2[O:36][CH:35]=[CH:34][C:28]=2[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=1.Br[C:38]1C2C(=CC=C(C(F)(F)F)C=2)C(=O)N(C)C=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:38])(=[O:13])=[O:14])=[CH:8][C:7]=2[C:26]2[C:27]3[O:36][CH:35]=[CH:34][C:28]=3[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Reactant: Cn1cc(Br)c2occc2c1=O
Reactant: Cn1cc(Br)c2cc(C(F)(F)F)ccc2c1=O
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3ccoc23)c1

Procedure:
The title compound was prepared in a manner similar to Example 197, by substituting 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 7-bromo-5-methylfuro[3,2-c]pyridin-4-one for 4-bromo-2-methyl-6-(trifluoromethyl)isoquinolin-1-one. 1H NMR (DMSO-d6, 400 MHz) δ 7.88 (m, 4H), 7.33 (d, J=9.4 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 4.02 (d, J=6.8 Hz, 2H), 3.58 (s, 3H), 3.28 (m, 2H), 1.12 (t, J=7.4 Hz, 3H), 1.08 (m, 1H), 0.45 (m, 2H), 0.24 (m, 2H). LCMS: 388.1 (M+H)+
Reaction SMILES: C(Cl)(Cl)Cl.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([O:25][C@@H:26]([C:35]([F:38])([F:37])[F:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])=[O:24])[CH2:17][CH2:16]2)C1C=CC=CC=1.I[Si](C)(C)C>CO>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([O:25][C@@H:26]([C:35]([F:36])([F:37])[F:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH3:34])=[O:24])[CH2:17][CH2:16]2
Reactant: CCOCCCCC[C@@H](OC(=O)C1=Cc2ccc(OCc3ccccc3)cc2CC1)C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOCCCCC[C@@H](OC(=O)C1=Cc2ccc(O)cc2CC1)C(F)(F)F
Yield: 414.1 %

Procedure:
To 10 ml of a chloroform solution of 0.19 g (0.4 mmol) of the (R)1-trifluoromethyl-6-ethoxyhexyl 6-benzyloxy-3,4-dihydro-2-naphthalenecarboxylate obtained in the first step was added 0.1 ml (0.4 mmol) of iodotrimethylsilane in a nitrogen atmosphere with stirring, and the mixture was reacted at room temperature for two and a half hours with stirring. Then, 8 ml of methanol was added, and the mixture was rapidly concentrated at room temperature under reduced pressure. The concentrate was separated by column chromatography, to obtain 0.64 g of (R)1-trifluoromethyl-6-ethoxyhexyl 6-hydroxy-3,4-dihydro-2-naphthalenecarboxylate as a crude product. The 1H-NMR data of this compound are described below. 1H-NMR (CDCl3), δ (ppm)
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:35]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH:44]2[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]2)[CH2:40][CH2:39]1)[CH2:36][CH3:37]>C1COCC1>[CH2:35]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH:44]2[CH2:49][CH2:48][C:47](=[CH:9][CH2:8][CH:3]3[O:2][CH2:7][CH2:6][CH2:5][O:4]3)[CH2:46][CH2:45]2)[CH2:40][CH2:39]1)[CH2:36][CH3:37]
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C2CCC(=CCC3OCCCO3)CC2)CC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A mixture of 531 g (1170 mmol) of 2-(1,3-dioxane-2-yl)ethyltriphenylphosphonium bromide and 4.0 l of THF was cooled to −30° C. under a nitrogen gas stream with a refrigeration medium. To this mixture, 121 g (1080 mmol) of t-BuOK was added, followed by stirring for 1 hour. Furthermore, 1 l of a THF solution containing 200 g (899 mmol) of 4-(trans-4-propylcyclohexyl)cyclohexanone was added dropwise to the mixture, while the temperature was maintained at −30° C. or less. After the dropping, the reaction temperature was slowly raised to room temperature, and the solution was further stirred for 5 hours. Next, the reaction solution was filtered through Celite, and the solvent was then distilled off under reduced pressure. The resulting residue was purified through silica gel column chromatography (a developing solvent: a mixed solvent of toluene/ethyl acetate=9/1 (v/v)) to obtain 277 g of crude 2-(2-(4-(trans-4-propylcyclohexyl)cyclohexylidene)ethyl)-1,3-dioxane.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH2:48][CH2:49][CH3:50])=[C:37]([OH:51])[C:36]3=[O:52])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH2:48][CH2:49][CH3:50])=[C:37]([O:51][CH3:3])[C:36]3=[O:52])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CCCC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: CCOCC
Product: CCCC1=C(OC)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/3 v/v, 40 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-hydroxy-4-propyl-1H-pyrrol-2(5H)-one (1.0 g, 2.71 mmol, 1 eq) and MeOH (10 ml), the product was further purified by preparative HPLC; yield: 0.120 g (11.6%); MS m/z: 384.1 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 0.96 (t, 3H), 1.6-1.4 (m, 6H), 1.94-1.87 (m, 1H), 2.47-2.39 (m, 1H), 4.08 (s, 3H), 5.90 (bs, 1H), 6.92 (bs, 1H), 7.03-6.94 (m, 2H), 7.54 (bs, 1H), 7.83 (s, 1H), 7.94 (s, 1H); HPLC (METHOD [A]): rt 14.38 min (100%)
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[Br-].[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:19][CH2:20]2)=[CH:16][CH:15]=1.[CH3:42][O:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=O>CCCCCC>[CH3:42][O:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:18]1[C:17]2[C:21](=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH2:20][CH:19]=1
Reactant: COc1ccc2c(c1)CCC2[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCCCC=O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(=O)CCCCCCC1=CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 9.625 g. of potassium t-butoxide in 60 ml. of dimethylsulfoxide is added dropwise a solution of 40 g. of the phosphonium salt of Example 1 in 300 ml. of dimethylsulfoxide. After six minutes an equimolar amount (12.93 g.) of methyl-6-formylhexanoate is added dropwise just discharging the red color of the reaction mixture. The mixture is stirred for 1 hour at room temperature, and then poured into 1 liter of ice-water and 350 ml. of hexane. It is shaken, the white triphenylphosphine oxide is filtered off and the aqueous layer is extracted with ten 75 ml. portions of hexane. The combined hexane extracts are successively washed with four 250 ml. portions of (1:1) dimethylsulfoxide-water, four portions of water and one 300 ml. portion of saturated salt solution. After drying over magnesium sulfate the hexane mixture is concentrated to a yellow oil containing 6-methoxy-Δ3,ω -indanheptanoic acid methyl ester (Compound 3). The yellow oil is dissolved in chloroform (200 ml.) and to this is added 5 drops of trifluoroacetic acid. The mixture is allowed to stand at room temperature for 4.5 hours and then concentrated to dryness in vacuo. Upon trituration with hexane (15 ml.) 6-methoxy-3-indeneheptanoic acid methyl ester (Compound 4) separates in crystalline form, m.p. 30°-31.5°C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](=[C:15]3[S:19][C:18](=[N:20][C:21]4[CH:22]=[C:23]([NH:30][C:31](=[O:36])[CH2:32][N:33]([CH3:35])[CH3:34])[CH:24]=[CH:25][C:26]=4[NH:27][CH2:28][CH3:29])[N:17]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:16]3=[O:44])[N:12]([CH3:45])[C:11]=2[CH:46]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](=[C:15]3[S:19][C:18](=[N:20][C:21]4[CH:22]=[C:23]([NH:30][C:31](=[O:36])[CH2:32][N:33]([CH3:35])[CH3:34])[CH:24]=[CH:25][C:26]=4[NH:27][CH2:28][CH3:29])[N:17]([CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:16]3=[O:44])[N:12]([CH3:45])[C:11]=2[CH:46]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCN=[N+]=[N-])cc3N2C)C(=O)N1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCN)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
To a solution of the above N-(3-{5-[5-(2-azidoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-phenyl)-2-dimethylaminoacetamide (0.34 mmol) in THF (13 mL) was added triphenylphosphine (100 mg, 380 mmol) and H2O (20 mL). The solution was stirred 48 h at room temperature. The solvent was removed under reduced pressure, and the crude material was chromatographed (silica gel, 0–5% MeOH/DCM) to afford the title compound (157 mg, 72% overall).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[N:52]1([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C>CN(C)C=O>[N:52]1([CH:56]2[CH2:61][CH2:60][N:59]([C:8]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][C:27]=4[F:48])[CH:22]=[CH:21][N:20]=3)=[O:7])[CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC(N2CCC2)CC1
Reaction time: 24 h
Yield: 59 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(azetidin-1-yl)piperidine dihydrochloride (85 mg) and triethylamine (0.112 ml) at room temperature, followed by stirring for 24 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (34.6 mg, 59%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18](O)=[O:19])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[NH:71]1[CH2:74][CH:73]([OH:75])[CH2:72]1>CN(C)C=O.O>[F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:71]4[CH2:74][CH:73]([OH:75])[CH2:72]4)=[O:19])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCN(CC(=O)O)CC3)cc12
Reactant: OC1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCN(CC(=O)N4CC(O)C4)CC3)cc12
Temperature: 70 °C

Procedure:
A mixture of Example 294A (0.100 g, 0.229 mmol), (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.143 g, 0.275 mmol), triethylamine (0.160 mL, 1.147 mmol), and azetidin-3-ol.hydrochloride (0.030 g, 0.275 mmol) in N,N-dimethylformamide (2.5 mL) was stirred for 3 hours and was treated slowly with water. The solid was filtered, washed with water, dried in a vacuum oven, heated in 6 mL ethyl acetate/heptanes (1:1) at 70° C. for 2 hours, filtered, washed with ethyl acetate/heptanes (1:1), and vacuum oven-dried to give the title compound. 1H NMR (500 MHz, Methanol-d4) δ 2.54-2.60 (m, 2H), 2.78 (t, J=5.7 Hz, 2H), 3.21 (d, J=2.9 Hz, 2H), 3.29 (d, J=3 Hz, 1H), 3.76 (s, 4H), 4.02-4.08 (m, 1H), 4.22 (dd, J=10.7, 6.8 Hz, 1H), 4.44-4.52 (m, 1H), 4.52-4.62 (m, 2H), 6.16 (s, 1H), 6.34-6.39 (m, 1H), 7.08-7.24 (m, 3H), 8.07 (d, J=2.8 Hz, 1H). MS (ESI+) m/z 455.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH:22][CH2:23][C:24]([CH:27]1[O:32][CH2:31][C:30]2([CH2:37][O:36][CH:35]([C:38]([CH3:42])([CH3:41])CO)[O:34][CH2:33]2)[CH2:29][O:28]1)([CH3:26])[CH3:25].[CH3:43][O-:44].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:38]([CH:35]2[O:34][CH2:33][C:30]3([CH2:29][O:28][CH:27]([C:24]([CH3:26])([CH3:25])[CH2:23][O:22][C:18](=[O:19])[CH2:17][CH2:16][C:7]4[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:43]([OH:44])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=4)[O:32][CH2:31]3)[CH2:37][O:36]2)([CH3:42])[CH3:41])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CO)C1OCC2(CO1)COC(C(C)(C)CO)OC2
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[O-]
Agent: [Na+]
Product: CC(C)(C)c1cc(CCC(=O)OCC(C)(C)C2OCC3(CO2)COC(C(C)(C)COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC3)cc(C(C)(C)C)c1O

Procedure:
A mixture of 35.3 g (0.121 mole) of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, 15.3 g (0.0503 mole of 3,9-bis(2-hydroxy-1,1-dimethylethyl)-2,4,8,10-tetraoxaspiro[5.5]undecane and 0.82 g (0.015 mole) of sodium methoxide was reacted, after-treated and purified in the same manner as in Production example 1 to obtain 21 g of a 99%-purity white crystal, 3,9-bis[2-{3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyloxy}-1,1-dimethylethyl]-2,4,8,10-tetraoxaspiro[5.5]undecane (Compound AO-1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:12](OCC)(OCC)OCC>>[Cl:8][C:6]1[CH:5]=[N:4][C:3]2[C:9](=[O:10])[N:11]=[CH:12][NH:1][C:2]=2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1ncc(Cl)cc1N
Product: O=c1nc[nH]c2cc(Cl)cnc12
Temperature: 155 °C
Reaction time: 22 h
Yield: 88.5 %

Procedure:
A suspension of 3-amino-5-chloropicolinamide (1.1 g, 6.41 mmol) in triethyl orthoformate (15.99 mL, 96 mmol) was stirred at 155° C. for 22 hours. After cooling to RT, the yellow precipitate was collected by vacuum filtration and washed with hexanes to yield the title intermediate (1.03 g, 5.67 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (s, 1H) 8.27 (d, J=2.35 Hz, 1H) 8.80 (d, J=2.25 Hz, 1H) 12.68 (br. s., 1H). LC/MS (ESI m/z=182 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[S:18][C:6]2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:19]([O:21][CH3:22])=[O:20].C[S:24][C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>COCCOCCOC>[CH3:12][N:9]1[C:10](=[O:11])[C:5]2[C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:3]([CH2:2][N:29]3[C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26][C:25]3=[S:24])[S:18][C:6]=2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]1=[O:13]
Reactant: CSc1nc2ccccc2s1
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Solvent: COCCOCCOC
Product: COC(=O)c1c(Cn2c(=S)sc3ccccc32)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
A solution of the product of example 3 step b) (300 mg) and 2-methylthiobenzothiazole (300 mg) in diglyme (3 ml) was heated by microwave irradiation (600 W) to 160° C. After 30 min the solvent was removed by vacuum distillation and the residue purified by gradient chromatography eluting with a gradient of dichloromethane to 5% methanol in dichloromethane to give the sub-title compound as a white solid (150 mg). δ 1HCDCl3 0.93 (6H,d), 2.22 (1H,non), 3.38 (3H,s), 3.71 (2H,d), 4.00 (3H,s), 4.80 (2H,s), 7.33 (1H,dt), 7.45 (1H,dt), 7.77 (1H,dd), 7.92 (1H,d).