Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[N:9])[N:5]([CH3:7])[CH:6]=1.[Si:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:3]=[C:4]([C:8]#[N:9])[N:5]([CH3:7])[CH:6]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: Cn1cc(Br)cc1C#N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1cc(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1C#N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Nitrogen is bubbled through a solution of 4-bromo-1-methyl-1H-pyrrole-2-carbonitrile (2.82 g, 15.2 mmol) and 4-[(tert-butyldimethylsilyl)oxy]aniline (4.08 g, 18.3 mmol) in toluene (55 mL) for 5 minutes. Sodium tert-butylate (2.92 g, 30.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (556 mg, 0.6 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (255 mg, 0.6 mmol) are then added to the reaction mixture. The mixture is stirred for 1 hour at 80° C. under nitrogen. The suspension is then cooled to ambient temperature and filtered over Celite. The Celite cake is then rinsed with ethyl acetate. The filtrate is washed with water and then with brine. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The product is purified twice by chromatography over silica gel using ethyl acetate and heptane as eluants, and then by trituration in heptane to obtain the expected product in the form of a solid.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:19]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C.Cl>[CH2:19]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1Cc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2Cc2ccccc2)CCCC1=O
Reaction time: 0.05 h
Yield: 36.5 %

Procedure:
40% Methanolic Triton B (0.95 mL, 2.1 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (510 mg, 2.1 mM) in 30 mL of DMF at −10° C. After 3 minutes, 2-benzylbenzyl bromide (548 mg, 2.1 mM) was added and the resultant mixture stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate and 1 N HCl, washed twice with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The reside was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 324 mg (36%) of the 9-[(2-benzylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ7.45-7.0 (m, 10H), 6.9 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 5.2 (s, 2H), 4.15 (s, 2H), 4.05 (s, 3H), 2.5 (m, 4H), and 2.1 (m, 2H). IR (KBr, cm−1) 1726, 1653, 1466, 1443, 1411, 1283, 1200, 1119, and 749. MS (ES) m/e 422, 424.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13]S(F)(=O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>C(#N)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[C:21]1([C:19](=[O:20])[CH:18]=[CH:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=S(=O)(F)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 152.9 %

Procedure:
A catalytic amount (about 500 mg) of dibenzo-18-crown-6-ether and 68 g of anhydrous powdered potassium carbonate were added to a solution of 18.4 g phenylmethane-sulphonyl fluoride and 10.0 g of phenacyl bromide in 100 ml of acetonitrile at room temperature, while stirring. The mixture was then stirred under reflux for 10 hours. The reaction mixture was allowed to cool down to room temperature and was then concentrated by stripping off the solvent under reduced pressure. The residue was chromatographed over a silica gel column using toluene as the eluent. The eluate was evaporated. In this manner, 16.0 g of 1,3-di-phenyl-prop-2-en-1-one were obtained in the form of a solid substance of melting point 56° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCOCC>[C:18]1([NH:17][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2ccc(Cl)nc12
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1cccc2ccc(Nc3ccccc3)nc12
Temperature: 50 °C
Yield: 35 %

Procedure:
NaH (60% w/w in mineral oil; 0.549 g, 13.73 mmol) was added to a mixture of 2-chloroquinoline-8-carboxylic acid (181a, 0.95 g, 4.58 mmol) and aniline (0.834 ml, 9.15 mmol) in THF (11 ml) at 0° C.; the reaction was heated to 50° C. for 2 h. The mixture was diluted with 75 ml of Et2O and washed with 1 N NaOH. The organic layer was separated, and the aq. layer was acidified to ˜pH 1 with 5 N HCl and extracted 4 times with 75 ml of EtOAc. All organic extracts were then combined dried over Na2SO4, and concentrated to give 2-(phenylamino)quinoline-8-carboxylic acid (35% yield) as a light-brown solid. MS (ESI, pos. ion) m/z: 265.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[I-].[Na+].[CH2:15](Br)[C:16]#[CH:17].C(N(C(C)C)C(C)C)C>CC(C)=O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:17][C:16]#[CH:15])=[CH:9][C:6]=1[CH:7]=[O:8])([O-:12])=[O:11]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: C#CCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C#CCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A mixture of 25 g (150 mmol) 5-hydroxy-2-nitro-benzaldehyde, 44.9 g (299 mmol) sodium iodide, 44.5 g propargyl bromide (80% in toluene), 42 ml N-ethyl-diisopropy-lamine and 400 ml acetone is stirred at rt for 6 d. The reaction mixture is filtered, concentrated, taken up in 1M aqueous hydrochloric acid and extracted with ethyl acetate to yield 2-nitro-5-propargyloxy-benzaldehyde.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1.Cl[CH2:32][C:33]1[O:34][C:35]([CH3:38])=[N:36][N:37]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][CH2:32][C:33]3[O:34][C:35]([CH3:38])=[N:36][N:37]=3)[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Reactant: Cc1nnc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc(COCc2cccc(Nc3sc(-c4ccc(C(C)(C)O)cc4F)cc3C(N)=O)n2)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (14 mg, 0.35 mmol) in DMF (1.75 mL) at 0° C. under argon was added 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 43) (70 mg, 0.17 mmol) and the mixture was allowed to stir for 10 minutes. 2-(Chloromethyl)-5-methyl-1,3,4-oxadiazole (35 mg, 0.26 mmol) was then added and the reaction was allowed to warm to room temperature overnight. The reaction was then quenched by the addition of water, extracted with ethyl acetate and concentrated in vacuo. The crude residue was reverse phase HPLC (acteonitrile/water with formic acid as a modifier) to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[OH:9]O.CCCCCC>C(O)(=O)C>[N+:1]1([O-:9])[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1
Reactant: Cc1ccncc1C
Reactant: OO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1cc[n+]([O-])cc1C
Temperature: 75 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
The general procedure of Boekelheide1 for the preparation of hydroxymethylpyridines was used. Thus, a solution of freshly distilled 3,4-lutidine (46.0 g, 0.43 mol) in 120 mL of glacial acetic acid was cooled at 0° C. and then 64 mL of 30% H2O2 was added dropwise. The resulting solution was heated at 75° C. (oil-bath temperature) for 3 h. Another 20 mL of 30% H2O2 was then added and heating was continued for 18 h. Finally, 20 mL of 30% H2O2 was again added and the reaction was kept at 75° C. for another 3 h. The solution was then concentrated to about 100 mL under water-aspirator pressure, 50 mL of H2O was added and the mixture was concentrated to about one half volume. The resulting mixture was cooled (0°-5° C.) and basified to about pH 10 using cold 40% aqeuous NaOH. The mixture was then extracted with CH2Cl2 (5×) and the extract was dried (Na2CO3 +Na2SO4) and concentrated on the roto-vap to give a yellow solution. Dilution of this solution with hexane afforded a solid which was collected by filtration and then dried in vacuo to give 3,4-lutidine-N-oxide (48.0 g, 83%) as an off-white solid.
Reaction SMILES: [OH:1]O.[CH3:3][S:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH2:9][C:8]1=[O:25].O.N>C(O)(=O)C>[CH3:3][S:4]([CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH2:9][C:8]1=[O:25])=[O:1]
Reactant: OO
Reactant: CSCCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)CCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 10 ml of 15% aqueous hydrogen peroxide is added with ice-cooling to a mixture of 1.5 g of 1-(β-methylthioethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 20 ml of acetic acid. The resultant mixture is stirred at 0° C for 30 minutes and then at room temperature for 1 hour. The reaction mixture is poured into ice water, basified with ammonia water and extracted with chloroform. The chloroform extracts are combined, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The residue is allowed to stand to form crystals. Recrystallization from ethylacetate gives 1-(β-methylsulfinylethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 166° - 167° C.
Reaction SMILES: ClCCl.[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(N(CC)CC)C>[CH3:22][S:23]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:25])=[O:24]
Reactant: OCCCCCCCCCCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCCCCCCc1ccccc1

Procedure:
To a mixture of 750 ml. of dichloromethane, 37.2 g. of 11-phenyl-1-undecanol (prepared as described in Example 6) and 32 ml. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 13.2 ml. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. of cold water, 300 ml. of cold 10% hydrochloric acid, 300 ml. of cold 5% sodium carbonate and with 200 ml. of cold, saturated, sodium chloride solution. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:14][C:15]1[C:19]([CH3:20])=[C:18]([NH:21][S:22]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[O:38][CH:39]=[CH:40][N:41]=4)=[CH:33][C:32]=3[CH2:42][NH:43][CH3:44])=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[O:17][N:16]=1.CN1CCOCC1.[F:52][C:53]([F:59])([F:58])[CH2:54][C:55](O)=[O:56].OC1C2N=NNC=2C=CC=1>CN(C=O)C>[CH3:14][C:15]1[C:19]([CH3:20])=[C:18]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[O:38][CH:39]=[CH:40][N:41]=3)=[CH:33][C:32]=2[CH2:42][N:43]([CH3:44])[C:55](=[O:56])[CH2:54][C:53]([F:59])([F:58])[F:52])(=[O:24])=[O:23])[O:17][N:16]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)CC(F)(F)F)c1C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
1-Ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC, 50 mg; 0.26 mmol) was added to a solution of N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (100 mg; 0.21 mmol, prepared as in Step (A) of Example 28), N-methylmorpholine (0.80 ml; 0.73 mmol), 3,3,3-trifluoropropionic acid (33 mg; 0.26 mmol), and hydroxybenzotriazole (HOBT, 40 mg; 0.26 mmol) in DMF at 0° C. After 18 hours at room temperature, the reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was washed with saturated KHSO4 (2×30 ml), water (30 ml), brine (30 ml), dried (MgSO4) and concentrated. The residue was chromatographed on a 2.5×12 cm silica gel column using 1000 ml EtOAc:Hex, 3:1 and 500 ml EtOAc as the mobile phase. The pure fractions were concentrated to afford 49 mg (43%) of the title compound of this Example as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:21])[C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:6]=2[N:7]=1.[CH2:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)[CH3:23]>>[CH2:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[N:35]=[CH:34][C:33]([NH:36][C:2]3[N:3]=[C:4]([NH2:21])[C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[N:13][C:14]6[C:19]([CH:20]=5)=[CH:18][CH:17]=[CH:16][CH:15]=6)[C:6]=4[N:7]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)[CH3:23]
Reactant: Nc1nc(Cl)nc2c(-c3cnc4ccccc4c3)csc12
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Product: CCN1CCN(c2ccc(Nc3nc(N)c4scc(-c5cnc6ccccc6c5)c4n3)cn2)CC1
Yield: 68 %

Procedure:
The target compound of Example 30 (21 mg, 68% yield) was prepared in the same manner as Step 9 of Example 1 using 2-chloro-7-(quinolin-3-yl)thieno[3,2-d]pyrimidin-4-amine (20 mg, 0.064 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (20 mg, 0.096 mmol).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:9]=3[C:8]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:24]1[CH2:25][CH2:26][C:9]2[C:8]3[CH:7]=[C:6]([F:5])[CH:14]=[CH:13][C:12]=3[N:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]=2[CH2:22][CH2:23]1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(-n2c3c(c4cc(F)ccc42)CCNCC3)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN1CCc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)CC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
3.1 ml allyl bromide are added dropwise to 9.0 g of 9-fluoro-6-p-fluorophenyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole and 9 g potassium carbonate in 90 ml dimethylformamide. The mixture is stirred for 2 hours at 110° C., cooled to room temperature, poured onto water, and extracted with ether. The ether extracts are concentrated to give the title compound as a residue. M.p. of the hydrochloride 228°-228° (decomp.).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[S:8](N)([NH2:11])(=[O:10])=[O:9]>O1CCOCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:7]1
Reactant: NS(N)(=O)=O
Reactant: C[C@H]1CNCCN1
Solvent: C1COCCO1
Product: C[C@H]1CN(S(N)(=O)=O)CCN1
Yield: 19.4 %

Procedure:
To a solution of (2S)-2-methylpiperazine (0.914 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 3 d. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected dried and reduced in vacuo to yield (3S)-3-methylpiperazine-1-sulfonamide as a white solid (0.27 g). A mixture of (3S)-3-methylpiperazine-1-sulfonamide (0.27 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.50 g) in dioxane (20 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.940 g
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:19])=[C:8]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=2[O:4][C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[K+]>O.CO>[CH3:1][C:2]1[C:6]2[C:7]([OH:19])=[C:8]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:9]=[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:5]=2[O:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1oc2c(C(C)(C)C)cc(C(C)(C)C)c(O)c2c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)oc2c(C(C)(C)C)cc(C(C)(C)C)c(O)c12

Procedure:
Ethyl 3-methyl-4-hydroxy-5,7-di-tert-butylbenzofuran-2-carboxylate (0.475 g, 1.43 mmol) was refluxed in a solution of KOH (0.241 g, 4.29 mmol) in water (10 mL) and methanol (2 mL) for two hours. Acidification of the cooled mixture led to precipitation of the product. 3-Methyl-4-hydroxy-5,7-di-tert-butylbenzofuran-2-carboxylic acid, compound 9, was collected by filtration and vacuum dried. This material was decarboxylated without further purification. mp 241°-243° C.; 1H NMR (DMSO-d6) d 1.40 (18H, s), 2.71 (3H, s), 7.18 (1H, s), 8.35 (1H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:7][C:6]2=[O:17].[C:18]([O-:21])(=[O:20])[CH3:19].[Na+]>CN(C=O)C>[C:18]([O:21][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:7][C:6]2=[O:17])(=[O:20])[CH3:19]
Reactant: CCCCc1nc(=O)c2cc(CBr)ccc2[nH]1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(=O)c2cc(COC(C)=O)ccc2[nH]1
Temperature: 60 °C
Yield: 68 %

Procedure:
To a solution of 2.1 g (7.0 mmol) of the quinazolinone prepared in Example 18 in 15 mL of dry DMF was added 1.74 g (20.0 mmol) of sodium acetate. The mixture was heated to 60° C. for 3 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in 100 mL of CH2Cl2. The solution was washed with water (3×20 mL), brine (1×20 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo. The residue was recrystallized from MeOH/H2O to give the titled compound as a colorless solid. 68% yield. 1H-NMR (CDCl3): 0.99 (t, 3H, J=7.32 Hz), 1.50 (m, 2H), 1.83 (m, 2H), 2.14 (t, 3H), 2.77 (3 line m, 2H, J=7.71 Hz), 5.23 (s, 2H), 7.69-7/78 (m, 2H), 8.25 (s, 1H), 10.90 (bs, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][CH2:25]2)=[C:20](/[CH:34]=[CH:35]\[CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:37]1[C:46]2[C:41](=[N:42][C:43]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])=[CH:44][CH:45]=2)[O:40][CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:49]3[C:48](=[O:53])[C:47]([C:43]4[N:42]=[C:41]5[O:40][CH2:39][CH2:38][O:37][C:46]5=[CH:45][CH:44]=4)([CH3:54])[NH:51][C:50]3=[O:52])[CH2:26][CH2:25]2)=[C:20]([CH:34]=[CH:35][CH3:36])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Reactant: CC1(c2ccc3c(n2)OCCO3)NC(=O)NC1=O
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(n3)OCCO4)C2=O)CC1

Procedure:
(Z)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone and 5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:3])[CH3:2].[CH2:14](O)[CH2:15][CH2:16]CCCC/C=C\CCC.C(OCCCCCCCC=C)(=O)C.C=CCCC>C1COCC1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH3:16])(=[O:3])[CH3:2]
Reactant: CCCCCCCC=COC(C)=O
Reactant: CCC/C=C\CCCCCCCO
Agent: C=CCCCCCCCOC(C)=O
Solvent: C1CCOC1
Solvent: C=CCCC
Product: CCC/C=C\CCCCCCCOC(C)=O
Yield: 65 %

Procedure:
By cross metathesis of nonenyl acetate: according to the procedure for compound 12, 8-nonenyl acetate (0.76 g, 4.1 mmol) and 1-pentene (4 mL) in THF (4 mL) were reacted with 1 (0.026 g, 1 mol %) to provide 13 (0.60 g, 65% yield, 85% Z as determined by 1H-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.36 (2H, m), 4.05 (2H, t, J=6.8 Hz), 2.05 (3H, s), 2.01 (4H, m), 1.62 (2H, m), 1.27-1.41 (10H, m), 0.90 (3H, t, J=7.4 Hz); 13C NMR (CDCl3): δ 171.2, 129.9, 129.8, 64.7, 29.7, 29.3, 29.2 (2C), 28.6, 27.2, 25.9, 22.9, 21.0, 13.8; HRMS (EI): 227.2021, [C14H26O+H]+ requires 227.2011.
Reaction SMILES: C(O)(C(F)(F)F)=O.S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCOC3C=CC(C4C(C#N)=CSC=4)=CC=3)=C(C(O)=O)N=1)CC2)=O.S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCI)=C(C(OCC)=O)N=1)CC2)=O.[S:91]1[C:95]2[CH:96]=[CH:97][CH:98]=[CH:99][C:94]=2[N:93]=[C:92]1[NH:100][C:101]([C:103]1[CH:104]=[CH:105][CH:106]=[C:107]2[C:112]=1[CH2:111][N:110]([C:113]1[N:118]=[C:117]([C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[C:116]([CH2:126][CH2:127][CH2:128]I)=[CH:115][CH:114]=1)[CH2:109][CH2:108]2)=[O:102].[Cl:130][C:131]1[CH:136]=[C:135]([OH:137])[CH:134]=[CH:133][N:132]=1>>[S:91]1[C:95]2[CH:96]=[CH:97][CH:98]=[CH:99][C:94]=2[N:93]=[C:92]1[NH:100][C:101]([C:103]1[CH:104]=[CH:105][CH:106]=[C:107]2[C:112]=1[CH2:111][N:110]([C:113]1[N:118]=[C:117]([C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[C:116]([CH2:126][CH2:127][CH2:128][O:137][C:135]3[CH:134]=[CH:133][N:132]=[C:131]([Cl:130])[CH:136]=3)=[CH:115][CH:114]=1)[CH2:109][CH2:108]2)=[O:102]
Reactant: Oc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCI
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Agent: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCOc1ccnc(Cl)c1

Procedure:
Compound 109A was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A and compound 2C with compound 96D and 2-chloropyridin-4-ol, respectively: APCI (+)/LC/MS: 657 (M+H)+.