Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3]Br.[Mg].Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.BrC1C=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1>C(OCC)C>[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[CH2:3]
Reactant: Cc1ccc(Br)cc1
Reactant: C=Cc1ccc(Br)cc1
Reactant: BrCCBr
Agent: [Mg]
Solvent: CCOCC
Product: C=Cc1ccc(-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Under a stream of an inert gas with agitation, a drop of 1,2-dibromoethane was added to a diethyl ether (100 ml) solution of 1.70 g (0.07 mole) of granular metallic magnesium and the Grignard reagent reaction was started by heating. The liquid temperature was increased up to refluxing and then a diethyl ether (70 ml) solution of 8.61 ml (0.07 mole) of p-bromotoluene was gradually added dropwise taking 30 minutes. After completion of the dropwise addition, it was kept standing under reflux for 1 hour. The reaction solution was cooled to room temperature and it was added dropwise, at room temperature, to a diethyl ether (100 ml) solution of 6.54 ml (0.05 mole) of p-bromo-styrene and 0.32 g (0.6 mmole) of a nickel chloride-(1,3-diphenyl phosphino propane) complex. After completion of the dropwise addition, refluxing was continued for 4 hours. The reaction solution was poured into 500 ml of ice water and the pH was adjusted to be weakly acidic. Extraction was made with hexane and, through purification by washing, drying, removal of the solvent by distillation and silica gel column chromatography, 7.28 g (yield 75%) of 4-vinyl-4'-methyl biphenyl were obtained.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][N:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)CCN1CCCC(C(=O)OCC)C1
Temperature: 80 °C

Procedure:
A 25 mL round-bottom flask was charged with ethyl nipecotate (8.0 mL, 51.5 mmol, Aldrich) and ethyl acrylate (6.0 mL, 55.4 mmol, Aldrich). The flask was purged with nitrogen and the mixture was heated to 80° C. for 20 hours. The excess ethyl acrylate was removed under reduced pressure. The remaining residue was purified by distillation (0.9 Ton, 122° C.) to provide the title compound: 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.27 (m, 6H), 1.41-1.59 (m, 2H), 1.69-1.74 (m, 1H), 1.90-1.94 (m, 1H), 2.05 (td, J=10.9, 2.9 Hz, 1H), 2.05 (t, J=10.7 Hz, 1H), 2.46-2.56 (m, 3H), 2.69-2.76 (m, 3H), 2.95-2.98 (m, 1H), 4.10-4.16 (m, 4H); 13C NMR (100 MHz, CDCl3) δ ppm 14.14, 14.15, 24.51, 26.78, 32.61, 41.80, 53.37, 53.79, 55.12, 60.28, 60.23, 172.50, 174.03; MS (DCI/NH3) m/z 258 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([F:21])[C:17]=2[C:19]#[CH:20])[C:12](=[O:23])[C:11]([C:24]([O:26]CC)=[O:25])=[CH:10]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([F:21])[C:17]=2[C:19]#[CH:20])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]1
Reactant: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(-c3ccc(F)cc3F)c12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)cc3F)c12
Yield: 90.3 %

Procedure:
1.17 g of ethyl 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are refluxed for 1 hour in a mixture of 9 ml of glacial acetic acid, 0.75 ml of water and 0.2 ml of concentrated sulphuric acid. The solid which has crystallised out at room temperature is filtered off with suction and dried. 0.98 g of 1-(2,4-difluorophenyl)-8-ethinyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is obtained (90% of theory).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9]N1C(=O)CCC1=O>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ncnc(Cl)c1I

Procedure:
To a solution of 6-chloropyrimidin-4-amine (1 g, 7.8 mmol) in 5 mL N,N-dimethylformamide was added N-iodosuccinimide (2.6 g, 11.6 mmol) and the mixture subjected to microwave irradiation (Biotage Initiator) at 100° C. for 30 minutes. The mixture was diluted with water and ethyl acetate and the ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 25% ethyl acetate in hexane) afforded the title compound. LCMS: 255.91 (M+1)+.
Reaction SMILES: [N:1]1([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:5][CH2:4][CH:3]([C:6]([O:8]C(C)(C)C)=[O:7])[N:2]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>ClCCl>[CH2:23]([O:22][C:20]([N:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH:2]1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)N1CCC(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)N1CCC(C(=O)O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
2,3-Bis(1,1-dimethylethyl) 1-(2-propen-1-yl) 1,2,3-pyrazolidinetricarboxylate (1.2 g, 3.37 mmol) was dissolved in dichloromethane (DCM) (6.63 ml) under N2 at ambient temperature. TFA (15.56 ml, 202 mmol) and water (1.820 ml, 101 mmol) were added in one portion. The reaction was stirred at ambient temperature for 3 days. The solvent was removed under reduced pressure to give crude 1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (0.674 g, 3.37 mmol, 100% crude yield). MS (ES+) m/z 201.0 (MH+).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18][N:19]([CH3:26])[C:20](=[O:25])[O:21][CH:22](Cl)[CH3:23])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27]([OH:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([O:35][CH:22]([O:21][C:20]([N:19]([CH2:18][CH2:17][CH2:16][N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH3:26])=[O:25])[CH3:23])=[O:34])[CH:29]=1
Reactant: CC(Cl)OC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Reactant: O=C(O)c1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(OC(=O)c1cccnc1)OC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Yield: 38.9 %

Procedure:
Following the general procedure of Example 52, but using 1.05 g (0.0028 mol) of the product of Example 51, 0.45 g (0.036 mol) of nicotinic acid and 0.36 g of triethylamine in 10 mL dimethylformamide and carrying out the reaction at 25°-30° C. for 48 hours, gave 0.5 g of the title compound as a yellow oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N+]([O-])=O.P(Cl)(Cl)[Cl:16]>>[Cl:16][C:3]1[CH:2]=[CH:11][C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:4]=1
Reactant: ClP(Cl)Cl
Reactant: O=[N+]([O-])c1ncc2ccccc2c1O
Product: Clc1ccc2ccccc2n1
Yield: 42.5 %

Procedure:
To 13.25 g (69.7 mmol) of 4-hydroxy-3-nitroisoquinoline was added 120 mL of phosphorous trichloride. After the mixture had been refluxed for 3 hours, 80 mL of POCl3 was distilled out. The remaining solution was poured onto approximately 150 g of crushed ice. The resulting solid was filtered and recrystallized from ethanol to give 6.2 g (42.5%) of the chioroquinoline as yellow needles: mp 103-104° C. (lit mp 108-109° C.); 1H-NMR (DMSO-d6, 200 MHz) δ 9.20 (s, 1H), 8.5 (d, 1H) 8.30 (d, 1H), 7.8 (m, 2H); IR (KBr) 1530 (s, NO2), 1344 (s, NO2) cm−1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a solution of p-hydroxybenzoic acid (3 g) and triethylamine (2.4 g) in dichloromethane (30 ml) were added undecanoyl chloride (4.5 g) and dimethylaminopyridine (0.2 g). The mixture was stirred at room temperature for about 20 hours. After dilute aqueous hydrochloric acid solution was added, an organic layer was separated by a funnel. After the solution was distilled to remove the solvent, the residue was washed with n-hexane and dried to obtain the titled compound (about 5 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([CH2:16][NH:23][C:24]([N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=3)[CH2:8]2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)N1CC(Oc2cccc(C(F)(F)F)c2)C1

Procedure:
To a stirred and chilled (10°-20° C.) solution of 0.04 mole of 3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of methylene chloride was added dropwise 6.12 g (0.046 mole) of benzyl isocyanate. The reaction mixture was stirred at room temperature for 2 hr and was filtered. The filter cake was washed with petroleum ether (2×50 ml), dilute aqueous sodium bicarbonate (2×50 ml), and water (2×50 ml), yielding 12 g (86%). Recrystallization twice from ethyl acetate gave 9.0 g of clear white flakes, m.p. 173.5°-175° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[OH:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[CH:24]=1>CC#N>[Br:20][C:27]1[CH:26]=[C:25]2[C:30]([CH:31]=[CH:32][C:23]([OH:22])=[CH:24]2)=[CH:29][CH:28]=1
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Oc1ccc2ccc(Br)cc2c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Triphenyl phosphine (89.7 g, 0.342 mol) and acetonitrile (350 mL) were combined in a 1-L flask under N2 atmosphere. The mixture was cooled to 10° C. Bromine (17.6 mL, 0.342 mol) was added dropwise over 10 minutes. The cooling bath was removed and 2,7-dihydroxynaphthalene (50.0 g, 0.312 mol) was added along with 350 mL of CH3CN rinse. The resulting yellow tan mixture was heated at reflux for 3 hours. Acetonitrile was distilled off using a water aspirator over 2 hours resulting in a grayish white solid. The solid was heated to 280° C. over 30 minutes giving a black liquid. The liquid was heated to 310° C. over 20 minutes and the temperature was maintained at 310° C. for an additional 15 minutes until gas evolution ceased. The black mixture was cooled to room temperature. Chromatography yielded 34.5 g of the intermediate title compound as an off-white solid which was 87% pure by HPLC (43% yield).
Reaction SMILES: [Na+].[CH3:2][S:3]([O-:5])=[O:4].Br[C:7]1[CH:8]=[C:9]([CH:13]=[C:14](I)[CH:15]=1)[C:10]([OH:12])=[O:11].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[C@:26]3([C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:35])[CH2:25]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]2[C@@:26]3([C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([C:7]4[CH:8]=[C:9]([CH:13]=[C:14]([S:3]([CH3:2])(=[O:5])=[O:4])[CH:15]=4)[C:10]([OH:12])=[O:11])[C:27]3=[O:35])[CH2:25]2)=[CH:22][CH:23]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@H]2c1ccc(Cl)cc1
Reactant: CS(=O)[O-]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: [Na+]
Product: CS(=O)(=O)c1cc(C(=O)O)cc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 92 starting from methanesulfinic acid sodium salt, 3-bromo-5-iodo-benzoic acid (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H18ClNO55: 467, observed (M+H)+: 468.1 1H NMR (400 MHz, MeOD-d4) δppm 2.27-2.36 (m, 2 H) 3.28 (s, 3 H) 3.38 (t, J=8.59 Hz, 1 H) 6.18 (d, J=7.58 Hz, 1 H) 6.85 (t, J=7.20 Hz, 1 H) 7.00 (d, J=7.83 Hz, 1 H) 7.14-7.23 (m, 1 H) 7.28-7.40 (m, 4 H) 8.38 (t, J=1.89 Hz, 1 H) 8.49 (s, 1 H) 8.62 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:5][C:6]1[NH:11][C:10](=[O:12])[NH:9][C:8](=[O:13])[C:7]=1[CH:14]([CH3:16])[CH3:15].[I-].[Li+].CS([CH2:27][C:28]#[CH:29])(=O)=O.[CH3:30]N(C=O)C>CCOCC>[CH2:27]([N:11]1[C:6]([O:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:19]=[C:18]([CH3:20])[CH:17]=2)=[C:7]([CH:14]([CH3:16])[CH3:15])[C:8](=[O:13])[NH:9][C:10]1=[O:12])[C:28]#[C:29][CH3:30]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CN(C)C=O
Reactant: C#CCS(C)(=O)=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOCC
Product: CC#CCn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 17 h
Yield: 84 %

Procedure:
To a stirred solution of 6-(3,5-dimethyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione (114) (548 mg, 2 mmol) anhydrous powdered K2CO3 (276 mg, 2 mmol), and lithium iodide (268 mg, 2 mmol) in DMF (10 mL), was added 1-methanesulfonyl-2-propyne (247 μL, 2.1 mmol). After stirring for 17 hrs., the reaction mixture was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 546 mg (84%) of a white solid. m.p. 158-160° C.; 1H-NMR (200 MHz, CDCl3) δ1.15 (6H, d, J=7.0 Hz), 1.69 (3H, t, J=2.2 Hz), 2.32 (6H, s), 2.80 (1H, m), 4.43 (2H, q, J=2.2 Hz), 6.60 (2H, s), 6.78 (1H, s), 8.55 (1H, s); m/z (EI) 326(M+).
Reaction SMILES: C([O:4][C:5](=[O:83])[CH2:6][C@H:7]([OH:82])[C@H:8]([NH:16][C:17](=[O:81])[C@H:18]([NH:40][C:41](=[O:80])[C@H:42]([NH:50][C:51](=[O:79])[CH2:52][C@H:53]([OH:78])/[CH:54]=[CH:55]/[CH2:56][CH2:57][S:58][C:59]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C=C.N1CCOCC1>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:82][C@H:7]([C@H:8]([NH:16][C:17](=[O:81])[C@H:18]([NH:40][C:41](=[O:80])[C@H:42]([NH:50][C:51](=[O:79])[CH2:52][C@H:53]([OH:78])/[CH:54]=[CH:55]/[CH2:56][CH2:57][S:58][C:59]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:19][S:20][C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:5]([OH:83])=[O:4]
Reactant: C=CCOC(=O)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a solution of 4E (210 mg, 0.184 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) in dry methanol/CH2Cl2 (5:1, 6 mL) under argon was added morpholine (32 μL, 0.37 mmol) which was allowed to stir for 3 h. The reaction mixture was concentrated in vacuo, CH2Cl2 (20 mL) was then added before washing with 1M HCl (15 mL), sat. sodium hydrogen carbonate (15 mL), sat. brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification was then carried out by column chromatography on silica gel (6-10% MeOH/CH2Cl2) to give 5E (140 mg, 0.13 mmol, 69%).
Reaction SMILES: O.O.O.[Ru:4](Cl)(Cl)[Cl:5].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Cl-:20].[Li+].CC(C)=O>CN(C)C=O>[Cl-:5].[Cl-:20].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Ru+2:4]
Reactant: Cl[Ru](Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: [Ru+2]
Temperature: 15 °C
Reaction time: 24 h

Procedure:
A mixture of ruthenium trichloride trihydrate (2.5 g), 2,2' bipyridyl (3.0 g) and lithium chloride (5.0 g) was placed in 50 ml of DMF under nitrogen. This mixtrue was stirred and refluxed for 7 hours. The resulting purple/black solution was allowed to cool slowly to about 15° C. with continued stirring. 250 ml of acetone was then added and the flask stoppered under nigrogen. This solution was left at 0° C. for 24 hours. A black microcrystalline solid was recovered by filtration which was washed with water three times and diethyl ether three times.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH2:27][C:28]#[N:29])[N:26]=1>>[C:28]([CH2:27][C:25]1[N:26]=[C:22]([NH:21][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:23][CH:24]=1)#[N:29]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: N#CCc1csc(N)n1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2nc(CC#N)cs2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using (2-Amino-thiazol-4-yl)-acetonitrile instead of 3-chloroaniline to yield the final compound as a off-white solid, MS (ISP): m/e=371.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][CH2:6][CH2:7][CH:8]([O:29][CH3:30])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[CH3:30][O:29][CH:8]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][CH2:6][S:5]([CH2:4][CH2:3][CH2:2][OH:1])=[O:39]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCCCCCCCCCCCOCC(CCSCCCO)OC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(CCS(=O)CCCO)OC
Yield: 92.7 %

Procedure:
In 20 ml of dichloromethane is dissolved 1.52 g of 3-methoxy-4-octadecyloxybutyl 3-hydroxypropyl sulfide, to which a solution of 0.61 g of m-chloroperbenzoic acid in 8 ml of dichloromethane is added dropwise with stirring under ice cooling. Thereafter, the mixture is stirred at room temperature for 30 minutes to complete the reaction. The reaction mixture is then washed with an aqueous sodium bisulfite solution, an aqueous sodium bicarbonate solution and then water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography to obtain 1.46 g of the captioned compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[CH3:16]SC#N.[Cl-].[Al+3].[Cl-].[Cl-].B(Cl)(Cl)Cl>C(Cl)CCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]2[S:4][CH2:3][C@H:2]([C:5]([OH:7])=[O:6])[N:1]=2)[CH:10]=1
Reactant: CSC#N
Reactant: N[C@H](CS)C(=O)O
Reactant: Oc1ccc(F)cc1
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)[C@H]1CSC(c2cc(F)ccc2O)=N1

Procedure:
(S)-4,5-Dihydro-2-(5-fluoro-2-hydroxyphenyl)-4-thiazolecarboxylic acid (5′-fluorodesazadesmethylDFT, 29a) is prepared from the cyclization of D-cysteine onto 5-fluoro-2-hydroxybenzonitrile in slightly acidic buffer. The aromatic precursor could be made by direct cyanation of p-fluorophenol using methyl thiocyanate, aluminum chloride, and boron trichloride in ethylene dichloride followed by heating in aqueous base (Adachi et al., Syn. Commun. 20:71-84 (1990)).
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[C@H:8]([NH:12][C:13]1[N:18]=[C:17]2[CH2:19][NH:20][CH2:21][CH2:22][C:16]2=[N:15][C:14]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1)([CH2:10][CH3:11])[CH3:9].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C@H:8]([NH:12][C:13]1[N:18]=[C:17]2[CH2:19][N:20]([C:2](=[O:1])[CH3:4])[CH2:21][CH2:22][C:16]2=[N:15][C:14]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1)([CH2:10][CH3:11])[CH3:9]
Reactant: CC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(C)=O)C2
Reaction time: 1 h

Procedure:
A solution of (R)—N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (136.4 mg) in DCM (2.57 mL) at 0° C. was treated with pyridine (0.062 mL, 0.770 mmol), followed by acetic anhydride (0.048 mL, 0.513 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in MeOH, filtered through a Millipore® 0.45 μm syringe filter, and purified by HPLC Method A to give title compound, as a TFA salt, as a yellow solid (52.0 mg, 32.2% over two steps). 1H NMR (500 MHz, methanol-d4) δ ppm 0.98 (m, 3H), 1.26 (m, 3H), 1.67 (m, 2H), 1.96 (m, 2H), 2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.73 (td, J=5.9, 1.5 Hz, 0.7H), 2.84 (td, J=5.9, 1.5 Hz, 1.3H), 3.08 (m, 2H), 3.43 (m, 2H), 3.82 (t, J=5.9 Hz, 1.3H), 3.86 (m, 0.7H), 3.97 (m, 1H), 4.49 (m, 1H), 4.59 (m, 0.7H), 4.63 (s, 1.3H), 6.87 (m, 1H), 6.98 (ddd, J=11.3, 8.4, 3.2 Hz, 1H), 7.17 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 460.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1)[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(#N)C.C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC#N
Product: CCc1ccc(Cc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of (4-ethylphenyl)(4-methoxyphenyl)methanone (1) (6.0 g, 25 mmol) in acetonitrile (50 mL) and DCM (50 mL) at 0° C., was added triethylsilane (6.7 g, 57.5 mmol), followed by addition of boron trifluoride etherate (5.3 g, 37.5 mmol). The reaction mixture was stirred at 0° C. for 2 h, then at 50° C. for 3 h. After cooling to rt, the reaction mixture was diluted with DCM (500 mL) and washed with 2N aqueous NaOH (200 mL×2), brine (200 mL×3), dried over MgSO4 and evaporated to give product as a colorless oil, 5.3 g, yield 93.7% 1H NMR (300 MHz, CDCl3) δ 7.06-7.09 (m, 6H), 6.79 (d, J=8.7 Hz, 2H), 3.87 (s, 2H), 3.76 (s, 3H), 2.60 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H).