Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1>ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 52.1 %

Procedure:
Following the general procedure for Example 12 (step 2), boron tribromide (1.0 M solution in dichloromethane, 9.66 mL, 9.66 mmol) was added to the product from step 1 (0.76 g, 3.22 mmol) in dichloromethane (15 mL) to afford the title compound (0.37 g, 52%) as a light-green solid.
Reaction SMILES: [F:1][C:2]([Si:6]([CH3:17])([CH3:16])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)=[C:3](F)[F:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1.CCOCC.Cl>[F:1][C:2]([Si:6]([CH3:16])([CH3:17])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)=[CH:3][F:4]
Reactant: CCOc1ccc([Si](C)(C)C(F)=C(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc([Si](C)(C)C(F)=CF)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
A solution of p-[(trifluorovinyl)dimethylsilyl]phenetole (12.0 g, 0.046 mol) in tetrahydrofuran is added dropwise to a stirred mixture of lithium aluminum hydride (1.75 g, 0.046 mol) in tetrahydrofuran at -5° C. The resultant reaction mixture is stirred at room temperature for 4 hours, cooled to 0° C., treated sequentially with ethyl acetate, water and dilute hydrochloric acid, and diluted with additional ether and dilute hydrochloric acid. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow liquid (10.76 g) which is identified by 1H NMR analysis as a 9:1 mixture of Z:E isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:38])[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=[C:23]4[C:34]([F:37])([F:36])[F:35])=[O:19])=[C:13]([Cl:39])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:40][C:41]([Si](C)(C)C)([F:43])[F:42].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:38])[C:18]([OH:19])([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=[C:23]4[C:34]([F:35])([F:37])[F:36])[C:41]([F:43])([F:42])[F:40])=[C:13]([Cl:39])[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)C(C)c3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)ccc2n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(C(O)(C(C)c3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)C(F)(F)F)ccc2n1

Procedure:
In analogy to Example 1, step 3, 2-chloro-4-{3-chloro-4-[2-(2-isopropoxy-4-trifluoromethyl-quinolin-6-yl)-1-methyl-2-oxo-ethyl]-phenoxy}-benzonitrile was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as an off-white gum. MS (m/e, ISP neg. ion)=641.1 [M−H+].
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH:12]2[O:18][C:19]1[CH:20]=[C:21]([CH:27](O)[CH:28]2[C:33](=[O:34])[N:32]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:31]3[CH:42]=[CH:43][CH:44]=[CH:45][C:30]=3[S:29]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl.ClCl.C(OCC)(=O)C>[CH:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH:12]2[O:18][C:19]1[CH:20]=[C:21]([CH:27]=[C:28]2[C:33](=[O:34])[N:32]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:31]3[CH:42]=[CH:43][CH:44]=[CH:45][C:30]=3[S:29]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C(O)C2Sc3ccccc3N(Cc3ccccc3)C2=O)cc1OC1CC2CCC1C2
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C=C2Sc3ccccc3N(Cc3ccccc3)C2=O)cc1OC1CC2CCC1C2
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
To a stirred solution of (87 μl, 1.24 mmol, 2.0 eq) dry dimethylsulfoxide in 3 ml of dry CH2Cl2 at -65° C. was added (0.46 ml, 0.927 mmol, 1.5 eq) of 2.0M oxalyl chloride in CH2 Cl2. The mixture was stirred at ca. -60° C. for 15 minutes, then a solution of (310 mg, 0.618 mmol, 1.0 eq) 2-[[3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]hydroxy-methyl]-4-(phenylmethyl)-2H-1,4-benzothiazin-3(4H)-one in 10 ml dry CH2Cl2 was added dropwise at -65° C. The mixture was allowed to warm to -30° C. over 1 hour, then cooled to -78° C. and (0.43 ml, 3.09 mmol, 5.0 eq) triethylamine was added to the mixture. The mixture was stirred at room temperature for 1 hour then diluted with 400 ml ethyl acetate, washed twice with H2O, once with brine, dried over MgSO4, and concentrated to give 0.3 g of an oil. Silica gel chromatography eluting with 10% ethyl acetate-hexane gave 120 mg of a yellow oil, which was recrystallized from ether-hexane to yield 55 mg, 18%, of a yellow solid. M.P.: 135°-137° C. Elemental Analysis Calc'd for C30H29NO3S: Calc'd: C, 74.51; H, 6.04; N, 2.90. Found: C, 74.53; H, 5.48; N, 2.88.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.O1CCCC1.[H-].[Na+:16].[C:17](=[S:19])=[S:18]>>[O:1]([CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:17]([S-:19])=[S:18].[Na+:16]
Reactant: OCCN1CCOCC1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: S=C([S-])OCCN1CCOCC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4.91 g. of N-(2-hydroxyethyl)morpholine in 250 ml. of anhydrous tetrahydrofuran at room temperature was added 1.79 g. of a 50% dispersion of sodium hydride in mineral oil. A precipitate formed. The mixture was stirred for 30 minutes, and then 2.75 ml. of carbon disulfide was added, causing the initial precipitate to dissolve. The reaction mixture was stirred for 30 minutes during which time a further precipitate formed. To the mixture was added 200 ml. of anhydrous ether, and the precipitate was recovered by filtration. The solid was washed with ether, and dried, to give 8.8 g. of the title compound.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[C:7]([O:13][CH2:14][CH2:15][O:16][C:17](ON1C(=O)CCC1=O)=[O:18])(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]>>[CH3:2][N:1]([C:17]([O:16][CH2:15][CH2:14][O:13][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCCC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: CNCC(=O)O
Product: CCCCC(=O)OCCOC(=O)N(C)CC(=O)O
Yield: 53.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.104 g, 1.1 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl pentanoate (0.268 g, 0.93 mmol) were reacted to provide 0.130 g (53.3% yield) of the title compound (43) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=6.79 (q, 1H), 4.12 (m, 2H), 3.0 (2s, 2H), 2.36 (m, 2H), 1.62 (q, 2H), 1.56 (2d, 3H), 1.39 (q, 2H), 0.97 (t, 3H). MS (ESI) m/z 284.09 (M+Na)+; 260.05 (M−H)−.
Reaction SMILES: [O:1]=[CH:2][CH2:3][N:4]([C:18]1[C:19]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:20]=2[N:21]=[CH:22][N:23]=1)[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[OH:37]O>CC#N.CCOC(C)=O>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:5]([N:4]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][C:2]([OH:37])=[O:1])[CH2:6]1)=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC=O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Reactant: OO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC(=O)O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of (R)-tert-butyl 3-((2-oxoethyl)(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.5 g, 0.97 mmol) in CH3CN (2 mL) at rt, was added an aq. solution of NaH2PO4 (3 mL, 0.21 g, 1.75 mmol), aq. NaO2Cl (2 mL, 0.16 g, 1.75 mmol) and 30% H2O2 (0.17 ml, 1.5 mmol) at 0° C. The reaction mixture was warmed to rt and stirred for overnight. The organic phase was concentrated in vacuo to afford a residue that was dissolved in EtOAc, filtered and dried over Na2SO4, concentrated in vacuo and purified by column chromatography (Silica gel, gradient MeOH: CH2Cl2) to afford the titled compound (0.105 g, 20.38%). LCMS [M+1]: 530.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH:8]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[CH2:11][CH2:10][N:9]2[CH3:17])=[CH:5][CH:4]=1.[CH:20]#[CH:21].N>CCOCC>[C:20]([C:12]1([OH:16])[CH2:11][CH2:10][N:9]([CH3:17])[CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[C:13]1([CH3:15])[CH3:14])#[CH:21]
Reactant: C#C
Reactant: COc1ccc(CC2N(C)CCC(=O)C2(C)C)cc1
Agent: N
Solvent: CCOCC
Product: C#CC1(O)CCN(C)C(Cc2ccc(OC)cc2)C1(C)C
Reaction time: 16 h

Procedure:
A stream of acetylene, after successively having been washed with water, cooled to -80° C and dried with CaCl2, is led into a mechanically stirred solution of 7 g of lithium in 750 ml of dry liquid ammonia which is cooled at about -50° C. After about 5 hours the blue colour disappears. To the solution of acetylene lithium so obtained there is added dropwise 60 g of 2-(p-methoxybenzyl)-1,3,3-trimethyl-4-piperidone dissolved in 250 ml of absolute ether. During the addition a slow stream of acetylene is maintained, but afterwards this is stopped and the reaction mixture is stirred for 16 hours, the ammonia being allowed to evaporate gradually. The resulting suspension is diluted by addition of 250 ml of absolute ether and stirred for another 2 hours at 30° C. After cooling 54 g of ammonium chloride and water are added. The reaction product is secured from the organic layer in the usual manner. It is recrystallized from a mixture of benzene and petroleum ether. Yield 88%. Melting point 103°-110° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15](O)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].[C:25]1([CH:33]=[C:31]([OH:32])[CH:30]=[C:28]([OH:29])[CH:27]=1)O>CS(O)(=O)=O>[OH:32][C:31]1[C:33]2[C:15](=[O:23])[C:16]3[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:18][C:25]=2[CH:27]=[C:28]([OH:29])[CH:30]=1
Reactant: O=C(O)c1ccccc1S
Reactant: Oc1cc(O)cc(O)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1c2ccccc2sc2cc(O)cc(O)c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of phosphorous pentoxide (3.71 g, 26.15 mmol) and methane sulfonic acid (27.05 mL, 0.42 mmol) was stirred at 90° C. for about one hour until a clear solution was obtained. To the reaction solution were added thiosalicylic acid (1.04 g, 6.76 mmol) and phloroglucinol (1.02 g, 8.11 mmol), followed by stirring at 70° C. for 10 minutes. After the reaction was completed, the reaction mixture was poured in 1 L of ice water. The resulting precipitate was allowed to stand at 4° C. overnight, combined, washed with water, and then dried under reduced pressure to give an orange solid compound. This compound was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1 (v/v)) to give a yellow solid compound (1.14 g, 51.1%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[CH:11][CH:12]([OH:14])[CH3:13])=[C:4]([CH3:15])[CH2:3]1>CC(C)=O.[O-2].[O-2].[Mn+4]>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[C:5]([CH:10]=[CH:11][C:12](=[O:14])[CH3:13])=[C:4]([CH3:15])[CH2:3]1
Reactant: CC1=C(C=CC(C)O)C(C)(C)CC(O)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(=O)C=CC1=C(C)CC(O)CC1(C)C
Temperature: 25 °C
Yield: 60.6 %

Procedure:
In 50 ml of anhydrous acetone was dissolved 2.5 g of 4-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)but-3-en-2-ol, and 10.4 g of activated manganese dioxide was added to the solution, followed by heating at 40° to 50° C. for 24 hours while vigorous stirring. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, and any insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.5 g (yield: 60%) of 4-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)but-3-en-2-one.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:50][C@H:51]([C:61]([O:63][CH3:64])=[O:62])[CH2:52][CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57].Cl>CN(C=O)C.C(Cl)CCl>[CH3:64][O:63][C:61](=[O:62])[C@@H:51]([NH:50][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)=[O:30])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=1)=[O:28])[CH2:52][CH2:53][C:54]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:60]
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
To a solution of 1.1 g 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 20 ml DMF were added 1 ml DIPEA, 0.41 g HOBt, 0.51 g EDC and 0.68 g H-Glu(OtBu)-OMe hydrochloride. After stirring for 24 h the solution was concentrated, taken up with dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product was purified by flash chromatography on silica using an ethyl acetate/heptane 50:50 to 100:0 gradient.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)=[C:20]([CH:23]=1)[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[C:16]([NH:15][C:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]=2[CH3:11])=[O:14])[CH:17]=[CH:18][C:19]=1[N:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1)#[N:22]
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)O
Product: Cc1[nH]c2ccc(F)cc2c1C(=O)Nc1ccc(N2CCC(O)CC2)c(C#N)c1
Yield: 32.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 5-fluoro-2-methyl-1H-indole-3-carboxylic acid (0.9 g) and 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (1.1 g), the title compound (0.6 g) was obtained. melting point: 169-171° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[O:10][CH3:11].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:4]([O:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)ccc1CBr
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Cl)ccc1Cc1ccncc1
Yield: 34.6 %

Procedure:
A mixture of 1-bromomethyl-4-chloro-2-methoxy-benzene (50 mg, 0.21 mmol), 4-pyridyl boronic acid (39 mg, 0.32 mmol), Pd(PPh3)4 (24 mg, 0.021 mmol) and 2M Na2CO3 were combined in DME (2 mL), purged with N2, and heated to reflux for 3 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 17 mg (33%) of the title compound. MS (ESI) m/e 234 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[OH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[OH:49][CH:50]1[CH2:55][CH2:54][N:53]([C:30]([C:29]2[CH:33]=[CH:34][C:26]([I:25])=[CH:27][C:28]=2[NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])=[O:31])[CH2:52][CH2:51]1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCC(O)CC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 4, Step D) and 4-hydroxypiperidine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19IN4O4S, 538.0; m/z found, 539 [M+H]+. HPLC (reverse phase): RT=7.77 min. 1H NMR (400 MHz, CDCl3, rotameric broadening): 9.07 (d, J=1.8 Hz, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.90 (br s, 1H), 8.50 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.89 (dd, J=8.4, 7.4 Hz, 1H), 7.39 (dd, J=8.0, 1.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 3.94-3.90 (m, 1H), 3.80-3.75 (m, 1H), 3.2-2.8 (m, 3H), 2.05-2.01 (m, 2H), 1.7-1.3 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]2=[O:13].[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(=O)OCC>[F:16][C:17]([F:21])([F:20])[CH2:18][N:19]1[C:6](=[O:13])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:15])[F:14])[CH:4]=2)[C:8]1=[O:12]
Reactant: NCC(F)(F)F
Reactant: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)N1CC(F)(F)F
Reaction time: 16 h
Yield: 80 %

Procedure:
5.0 g of 5-trifluoromethyl-isobenzofuran-1,3-dione were dissolved using 50 ml of toluene(anhydrous) and 4.6 g of 2,2,2-trifluoro-ethylamine added. The mixture was left at ambient temperature for 16 h. 50 mg of toluene-4-sulfonic acid were then added and the mixture was refluxed for 5 h. 200 ml of EA were added and the mixture was washed twice using 50 ml of a 10% aqueous Na2CO3-solution. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to yield 5.5 g of a viscous oil (Rf(DIP)=0.57; MS (EI): 298 (M+1)+).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18].[CH:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:21]([C:23]1[CH:28]=[C:27]([C:2]2[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COCOc1cc(CC(=O)OC)c(Br)c(OCOC)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COCOc1cc(CC(=O)OC)c(-c2cccc(C=O)c2)c(OCOC)c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
Methyl 2-bromo-3,5-bis(methoxymethoxy)phenylacetate (630 mg, 1.8 mmol)-obtained in the step 2 in Example 1 was dissolved in a mixed solvent of 1,2-dimethoxyethane (10 mL) and water (2 mL), and in an argon atmosphere, 3-formylphenylboronic acid (400 mg, 2.7 mmol), bis(tri-o-tolylphosphine)palladium(II) dichloride (140 mg, 0.17 mmol) and cesium carbonate (1.1 g, 7.2 mmol) were added thereto, and stirred under heat for 10 hours. The reaction mixture was cooled to room temperature, then filtered, and the filtrate was concentrated under reduced pressure. Water was added to the resulting residue, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/n-hexane=1/4 to 1/2) to obtain methyl 2-(3-formylphenyl)-3,5-bis(methoxymethoxy)phenylacetate (500 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:13])[CH:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.O.[C:15]([O:19][CH:20]1[CH:25]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:23][C@@H:22]([CH3:29])[CH2:21]1)(=[O:18])[CH:16]=[O:17].C(O)(=O)C.C(#N)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:13])[C:8]([C@H:16]([OH:17])[C:15]([O:19][C@@H:20]3[CH2:21][C@H:22]([CH3:29])[CH2:23][CH2:24][C@H:25]3[CH:26]([CH3:28])[CH3:27])=[O:18])=[C:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: CC(C)C1CC[C@@H](C)CC1OC(=O)C=O
Reactant: Cc1cc(O)c2cc(Br)ccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2ccc(Br)cc2c(O)c1[C@H](O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 7-bromo-3-methylnaphthalen-1-ol (11.8 g, 50.0 mmol) in dichloromethane (25 mL) at −40° C. was added a 1 M titanium(IV) chloride solution in dichloromethane (50.0 mL, 50.0 mmol) and stirred for 20 min. (1R)-(−)-Menthyl glyoxylate hydrate (12.1 g, 52.5 mmol) was added over 15 minutes in small portions as a solid and stirred for 1 hour at 40° C. Then acetic acid (20 mL) and acetonitrile (60 mL) were added while cold. Water (200 mL) was added and the resulting solution was stirred at room temperature for 30 min. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried, filtered, concentrated. The crude material, which was about 8:1 d.r., was taken on without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6].O.[NH2:19][NH2:20].O>O1CCOCC1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:7]1[C:4]([C:5]#[N:6])=[CH:3][C:2]([NH:19][NH2:20])=[N:9][CH:8]=1
Reactant: N#Cc1cc(Cl)ncc1-c1ccc(Cl)cc1Cl
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(NN)ncc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 116.4 %

Procedure:
A solution of 2-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (453 mg, 1.6 mmol) and hydrazine monohydrate (7.76 mL, 160 mmol) in dioxane (9 mL) was heated at 90° C. and stirred for 14 h. The reaction mixture was cooled to RT, poured into water (50 mL) and extracted with AcOEt (3×25 mL). The combined organic fractions were dried over Na2SO4, filtered, and evaporated to provide the crude title compound (520 mg, quant.) as a yellow solid, which was used without further purification. MS: 279 [M+1]+; HPLC: AtRet=1.44.