Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([B:8]([C:20]2[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=2[F:30])[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34].[F:35][C:36]1[C:41]([Li:42])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]>>[F:26][C:25]1[C:20]([B-:8]([C:41]2[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=2[F:35])([C:7]2[C:2]([F:1])=[C:3]([F:34])[C:4]([F:33])=[C:5]([F:32])[C:6]=2[F:31])[C:9]2[C:10]([F:19])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=2[F:15])=[C:21]([F:30])[C:22]([F:29])=[C:23]([F:28])[C:24]=1[F:27].[Li+:42]
Reactant: [Li]c1c(F)c(F)c(F)c(F)c1F
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Product: Fc1c(F)c(F)c([B-](c2c(F)c(F)c(F)c(F)c2F)(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Product: [Li+]

Procedure:
The obtained tris(pentafluorophenyl)boron (41 mmol) was reacted with 41 mmol of pentafluorophenyllithium, to isolate lithium tetrakis(pentafluorophenyl)borate as a white solid product.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:12][C:13]([F:31])([F:30])[C:14]([N:16]([CH2:23][P:24]([O:28]Cl)([O:26]Cl)=[O:25])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15].[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CCOCC>[F:12][C:13]([F:31])([F:30])[C:14]([N:16]([CH:23]([O:4][CH:1]([CH3:3])[CH3:2])[P:24]([OH:28])([O:26][S:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:25])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: Sc1ccccc1
Reactant: CC(C)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(=O)C(F)(F)F)C(OC(C)C)P(=O)(O)OSc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
A solution of isopropanol (2.9 ml, 0.038 mole) and triethylamine (5.3 ml, 0.038 mole) in 50 ml. of ether was added to a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (13.2 g, 0.04 mole) in 150 ml. of ether at 0° C. After three hours, the solution was filtered and the cooled (0° C.) filtrate was treated with a solution of thiophenol (3.9 ml, 0.038 mole) and triethylamine (5.3 ml, 0.038 mole) in 50 ml. of ether. The resulting mixture was stirred at 25° C. for 16 hours, then filtered. The filtrate was washed with 3% hydrochloric acid, 3% ammonium hydroxide and saturated sodium chloride solution, then concentrated in vacuo. The residual oil was chromatographed on silica gel eluting with ethyl acetate/cyclohexane (6:4) to afford ethyl N-trifluoroacetyl-N-(isopropoxy(phenylthio)phosphonomethyl)glycinate (7.7 g) as a light yellow oil, ND25 =1.4951.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cu][C:11]#[N:12].O>CN(C=O)C>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:11]#[N:12])=[N:3][CH:4]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(Br)cnc1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1C#N
Temperature: 115 °C

Procedure:
A mixture of 2,5-dibromo-3-methylpyridine (20.17 g, 80.4 mmol) and copper(I) cyanide (7.24 g, 80.8 mmol) in 200 mL DMF was heated to 115° C. overnight. The reaction mixture was cooled to 25° C. and poured into 600 mL of H2O. The solid was filtered, washed with copious amounts of H2O. The filtrate was extracted with EtOAc (4×) and the combined organic layers were washed with H2O and dried over Na2SO4. The solution was filtered, evaporated onto silica gel and purified by flash chromatography eluting with EtOAc:hexane (0:1→1:9) to give the title compound as a white solid. MS m/z: 197.0 [M+1].
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44]O)=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:44][CH2:43][C:40]3[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: COc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCCc3ccc(OC)cc3)cc2)c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.04 g, 0.085 mmol), 2-(4-methoxyphenyl)ethanol (0.065 g, 0.427 mmol) and Ph3P (0.067 g, 0.256 mmol) in THF (5 mL) was added DEAD (0.041 ml, 0.256 mmol) at 0° C. After 1 h, the cold bath was removed and stirred for 16 h at rt. Then, the reaction mixture was concentrated and the residue purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-methoxyphenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0362 g, 0.060 mmol, 70.4% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.27-7.23 (m, 2H), 7.17-7.13 (m, 1H), 7.09-7.04 (m, 1H), 7.00-6.95 (m, 2H), 6.92-6.88 (m, 2H), 6.08 (s, 1H), 4.29-4.12 (m, 4H), 3.83 (s, 3H), 3.18 (br. s., 1H), 3.11 (t, J=7.1 Hz, 2H), 2.88 (br. s., 1H), 2.61 (s, 3H), 2.28 (br.s., 1H), 2.20 (s, 3H), 2.12-2.00 (m, 1H), 1.71-1.81 (m, 1H), 1.60-1.49 (m, 1H), 1.41-1.32 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.21 (s, 9H), 1.08-1.12 (m, 1H), 0.90 (br.s., 2H), 0.67 (br. s., 2H). LCMS (M+H)=603.5.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](O)(=O)[CH3:16].[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:19]([NH:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH2:15][CH3:16]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNc1cc(C(F)(F)F)ccc1C(=O)O
Reaction time: 8 h
Yield: 18 %

Procedure:
2-Amino-4-(trifluoromethyl)benzoic acid (714 mg, 3.48 mmol), propionylaldehyde (0.27 ml, 3.74 mmol), acetic acid (3.49 mmol) and sodium triacetoxyborohydride (1.12 g, 5.25 mmol) were added in THF (40 ml). The reaction mixture was stirred overnight. The reaction mixture was quenched by adding sat. NaHCO3 (50 ml). The aqueous mixture was extracted with CH2Cl2 (30 ml×3). A combined organic layer was dried over MgSO4, concentrated in vacuo, and purified with column chromatography to yield title compound (155 mg, 18%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:3][CH:4]=2)=[N:9]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(O)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of the corresponding inteimmediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.3 g, 0.9 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.33 g, 1.5 mmol), Na2CO3 (2 M, 2.7 mL), and Pd(PPh3)2Cl2 (8 mg, 0.075 mmol) in toluene/ethanol (1:1, 6 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give 4′-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pe ntalen-6-yl]-biphenyl-4-ol as brown solid in 52% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCO
Product: CCOC(=O)c1ccc(N)nc1

Procedure:
To a suspension of 1.3 g (9.4 mmol) 6-aminonicotinic acid in 100 mL of ethanol, was bubbled in dry hydrochloric acid at 0 C, then the solution was refluxed until all the solids dissolved. The solvents were removed under reduced pressure, the residue dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine and concentrated to afford 1.37 g of a white solid, m/e=166(M+H).
Reaction SMILES: [CH2:1]([Cl:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[CH2:17][CH3:18])[CH3:10]>C(O)(C)C>[Cl-:8].[CH2:1]([N+:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH3:18])=[C:11]([CH2:9][CH3:10])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccncc1CC
Reactant: ClCc1ccccc1
Solvent: CC(C)O
Product: CCc1cc[n+](Cc2ccccc2)cc1CC
Product: [Cl-]

Procedure:
Benzyl chloride (250 g.) was added dropwise to a solution of 3,4-diethylpyridine (262 g., Beilsteins Handbuch der Organischen Chemie, Vierte Auflage, Julius Springer, Berlin, 1935 p. 253) in isopropyl alcohol (700 ml.). The resulting solution was refluxed (for 2 hr.), then concentrated under water pump vacuum. Benzene (250 ml.) was added to the residue and the solution was concentrated again. The process was repeated with two further portions (250 ml. and 500 ml.) of benzene. The residue began to crystallize. Benzene (2250 ml.) was added, affording a thick slurry of 1-benzyl-3,4-diethylpyridinium chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Li]CCCC.[Br:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([Cl:22])[N:16]=1.CN([CH:26]=[O:27])C>C1COCC1>[Br:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([Cl:22])[N:16]=1.[Cl:1][C:2]1[N:3]=[C:4]([CH:26]=[O:27])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(Cl)nc1
Agent: Cc1ccc(Cl)nc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)nc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
2-Bromo-6-chloro-3-methyl-pyridine was prepared from 2-chloro-5-methylpyridine by by the method of Gros P. and Fort Y. (J. Org. Chem., 2005, 8220). A solution of n-BuLi (1.6M in hexanes) (2.0 ml, 3.30 mmol) in dry THF (6 ml) at −78° C. under argon was treated dropwise with a solution of 2-bromo-6-chloro-3-methyl-pyridine (642 mg, 3.10 mmol) in dry THF (4 ml) and stirred at this temperature for 30 minutes. A solution of DMF (385 μl, 4.70 mmol) in dry THF (1 ml) was added dropwise and stirred at −78° C. for a further 45 minutes before warming to ambient temperature. The reaction was quenched with MeOH (3 ml), treated with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2, eluting with 2% EtOH in DCM to afford 6-chloro-3-methyl-pyridine-2-carbaldehyde as a yellow solid (217 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.42 (d, J=7.7 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:6]([CH3:19])([OH:18])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:4][OH:5].N1C=CC=CC=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.O>ClC(Cl)C>[CH3:1][N:2]([CH:3]([C:6]([OH:18])([CH3:19])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:4][OH:5])[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1
Reactant: CNC(CO)C(C)(O)CCCC(C)CCCC(C)C
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)CCCC(C)CCCC(C)(O)C(CO)N(C)C(=O)c1cccnc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
In 100 ml of dichloroethane were dissolved 10 g of 2-(methylamino)-3,7,11-trimethyl-1,3-dodecanediol and 8.7 g of pyridine and the solution was cooled to -30° C. To this solution was added 7.2 g of nicotinoyl chloride hydrochloride gradually and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with dichloroethane. The organic layer was washed with aqueous sodium hydrogen carbonate and after drying over anhydrous magnesium sulfate, the solvent was distilled off. Finally, the residue was subjected to silica gel column chromatography (elution with ethanol) to give 12.0 g of N-methyl-N-(1,3-dihydroxy-3,7,11-trimethyldodecan-2-yl)nicotinamide [Compound (66)]. Yield 93%.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[NH:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]1.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([O:26][C:24]([C:22]1[CH:23]=[N:19][N:20]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:21]=1)=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 60 °C
Reaction time: 11 h
Yield: 68 %

Procedure:
tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate described in Production Example 13-1 (2.7 g, 9.67 mmol) and commercially available ethyl 4-pyrazole carboxylate (1.49 g, 10.6 mmol) were dissolved in N,N-dimethylformamide (30 mL), 50-72% oily sodium hydride (570 mg) was added at 0° C., and the mixture was heated and stirred at 60° C. for 11 hours. The reaction mixture was cooled to room temperature and water and ethyl acetate were added for partition. The organic layer was washed with water twice and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, the resultant residue was dissolved in dichloromethane, the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1-1:3-0:1), and the target fraction was concentrated under vacuum to obtain the title compound (2.11 g, 68%).
Reaction SMILES: Cl.[Si]([O:9][C@@H:10]([C@@H:12]1[C@@H:15]([C@@H:16]([CH3:35])[C:17]([C:19]2[S:23][C:22]3=[C:24]([C:27]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:28])[N:25]=[CH:26][N:21]3[CH:20]=2)=[O:18])[N:14]([C:36]([C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=2)=[O:57])=[P:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:13]1=[O:69])[CH3:11])(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+]>CO>[OH:9][C@@H:10]([C@@H:12]1[C@@H:15]([C@@H:16]([CH3:35])[C:17]([C:19]2[S:23][C:22]3=[C:24]([C:27]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:28])[N:25]=[CH:26][N:21]3[CH:20]=2)=[O:18])[N:14]([C:36]([C:56]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][C:63]([N+:66]([O-:68])=[O:67])=[CH:64][CH:65]=2)=[O:57])=[P:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:13]1=[O:69])[CH3:11]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A 5 N aqueous hydrochloric acid solution (1 ml) was added to a solution of 72.4 mg of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)-methyl]azetidin-2-one in 2 ml of methanol, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by thin layer chromatography (developed with 10% methanol/methylene chloride) to give 46.9 mg of (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenyl phosphoranylidene)methyl]azetidin-2-one.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([Cl:25])[CH:14]=2)[CH3:8])(=O)=O.[CH2:26]([NH2:28])[CH3:27]>O>[Cl:25][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:7]([CH3:8])[CH2:6][NH:28][CH2:26][CH3:27])[C:22]1[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=1[S:16]2
Reactant: CC(COS(C)(=O)=O)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reactant: CCN
Solvent: O
Product: CCNCC(C)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reaction time: 17 h

Procedure:
A mixture of 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile (55.1 g) and triethylamine (10.4 cc) in anhydrous pyridine (350 cc) is saturated by bubbling hydrogen sulphide in for 5 hours at 25° C. The clear solution obtained is kept stirred for 12 hours at 25° C., and the mixture is then outgassed by bubbling nitrogen through for 90 minutes. The reaction mixture is then diluted with ethyl acetate (1000 cc) and washed with distilled water (5×1000 cc). The organic phase is dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is purified by chromatography on a column of 0.02-0.6 mm silica gel (height: 31 cm; diameter: 7.5 cm), eluting with an 80:20 (by volume) mixture (30 liters) of cyclohexane and ethyl acetate and collecting 1000 cc-fractions. Fractions 22 to 38 are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) to give an oil containing the expected product. The oil obtained is purified by chromatography on a column of 0.04-0.06 mm silica gel with a slight excess pressure of nitrogen (40 kPa) (height: 30 cm; diameter: 4.5 cm), eluting with pure ethyl acetate (1.5 liters) and collecting 100-cc fractions. Fractions 8 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (1.7 g). An autoclave is charged with (2RS)-2-(7-chloro-2-cyano-10-phenothiazinyl)propyl methanesulphonate (36 g) and ethylamine (200 cc). The mixture is brought to 100° C. for 17 hours. After cooling, the reaction mixture is poured into water (1 liter). The solution is extracted with ethyl acetate (500 cc) and the organic phase is washed with distilled water (2×500 cc). After settling has taken place, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. to give a brown gum, which is purified by chromatography on a column (height: 50 cm; diameter: 6 cm) of silica (0.06-0.3 mm), eluting with pure ethyl acetate (8 liters) and then with a mixture of ethyl acetate and methanol (97:3 by volume mixture of ethyl acetate and triethylamine) (2 liters) and finally with a mixture (10:90 by volume) (2 liters) of diethylamine and methanol and collecting 500-cc fractions. The fractions 32 to 37 are combined and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-10-[ (2RS)-1-ethylamino-2-propyl]-2-phenothiazinecarbonitrile (20 g) in the form of a brown product of meringue-like consistency.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.CC(C)([O-])C.[K+].[CH3:19][C:20]1[C:21]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][C:22]=2[S:23][CH:24]=1.[C:36](=[O:38])=[O:37]>CCOCC>[CH3:19][C:20]1[C:21]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][C:22]=2[S:23][C:24]=1[C:36]([OH:38])=[O:37]
Reactant: Cc1csc2cc(Cc3cccnc3)ccc12
Reactant: O=C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: Cc1c(C(=O)O)sc2cc(Cc3cccnc3)ccc12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
n-Butyl lithium (0.65 ml. of 1.55M solution in hexane) was added dropwise to a stirred mixture of diisopropylamine (0.10 g.) and potassium t-butoxide (0.11 g.) in dry ether (10 ml.) at -78° C. under an atmosphere of dry nitrogen. The mixture was stirred at -78° C. for 45 minutes and then a solution of 3-methyl-6-(3-pyridylmethyl)benzo[b]thiophene (0.20 g.) in dry ether (5 ml.) was added. The solution was stirred at -78° C. for 45 minues and then an excess of crushed solid carbon dioxide was added. When all the carbon dioxide had evaporated, water (5 ml.) was added and the mixture was shaken. The aqueous layer was then separated and washed with ether. It was then acidified with acetic acid and the solid was filtered off and dissolved in 2N sodium hydroxide. The solution was decolorized by warming with charcoal and then filtered. Acidification of the filtrate with acetic acid gave a solid which was filtered off, washed with water and dried to give 3-methyl-6-(3-pyridylmethyl)benzo[b]thiophene-2-carboxylic acid (0.10 g.), m.p. 250°-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=O)[CH2:7]2.[C:13]1([N:19]2[C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:22](=[O:29])[NH:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:26]1[CH2:25][CH2:24][C:23]3([N:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][NH:21][C:22]3=[O:29])[CH2:28][CH2:27]1)[CH2:7]2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C1CCc2c(Cl)cccc2C1
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCc3c(Cl)cccc3C1)CC2

Procedure:
The title compound, m.p.>250° C. and MS: m/e=396.4, 398.4 (M+H+) was prepared in accordance with general method of example 1 from 5-chloro-2-tetralone and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([C:8](=[O:32])[C@@H:9]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2].[C:34]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([C:8](=[O:32])[C@@H:9]([NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:10][N:11]([CH3:34])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CN(C)C(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Compound B (8.0 g, 16.3 mmol) was dissolved in DMF (40 mL) and the reaction mixture was cooled to −10° C. To the reaction mixture was added K2CO3 (6.8 g, 49.1 mmol) followed by addition of MeI (5.1 mL, 81.9 mmol) drop wise and stirred at 0° C. for 1 h. The reaction mixture was filtered and washed with EtOAc. Solvents removed in vacuo and the residue was dissolved in EtOAc (250 mL) and poured into water (500 mL), extracted with EtOAc (2×250 mL), and washed with water (250 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and then concentrated in vacuo, to afford compound C (8.1 g, 98% yield) as a cream solid. LC-MS [M+H] 503.1 (C20H30N4O9S+H, calc: 503.5). Purity >95% (UV/254 nm). Compound C was used without further purification.