Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[Na].[CH2:13]([OH:18])[C:14]([F:17])([F:16])[F:15].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[O:18][CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: OCC(F)(F)F
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: Fc1nc(F)c(Cl)c(OCC(F)(F)F)c1F
Temperature: -78 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
3-Chloro-2,4,5,6-tetrafluoropyridine (18.0 g, 97.0 mmol) was dissolved in anhydrous THF (100 mL) under an N2 atmosphere and the resulting solution cooled to −78° C. To the cold solution was slowly added a solution of sodium 2,2,2-trifluoroehtoxide (97 mmol), prepared from trifluoroethanol (7.1 mL, 97.0 mmol) and NaH (3.88 g, 97.0 mmol, 60% dispersion in mineral oil), in anhydrous THF (100 mL). The resulting mixture was slowly warmed to ambient temperature. After 18 h at ambient temperature a GC analysis indicates all the starting material was consumed. The volatiles were evaporated and the residue dissolved in CH2Cl2 (200 mL). The organics were washed with H2O (3×100 mL), dried (MgSO4), filtered and concentrated to give the crude product as a yellow oil. The yellow oil was distilled at reduced pressure to afford 3-chloro-2,5,6-trifluoro-4-(2,2,2-trifluoroethoxy)pyridine as a clear oil (16.3 g, 63% yield): by 48° C. (ca 0.2 mm Hg); 1H NMR (CDCl3) δ 4.81-4.78 (dq, J=1.6, 7.7 Hz); GC-MS (EI, 70 eV) m/z (% relative intensity) 267 (33), 265 (100), 248 (5), 246 (16), 198 (22), 196 (60).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11]([Cl:18])[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[ClH:18].[NH2:14][C:9]([CH:25]1[CH2:26][CH2:27][N:23]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:21][CH2:22]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:24]1)([CH3:10])[CH3:8]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: C1CCNC1
Solvent: CC#N
Product: Cc1c(N2CCC(C(C)(C)N)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Product: Cl

Procedure:
A 150 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 1-amino-1-methylethyl)pyrrolidine (155 mg, 0.77 mmol, prepared by standard method from the free base described by Hayakawa et al., U.S. Pat. No. 5,098,912, issued Mar. 24, 1992), and carried forward as described in Example 253k-l to give the title product. MS (high resolution) found: 388.2047; calc: 388.2036 (M+H)+ ; 1H NMR (D6 -DMSO) ∂: 0.60 (m, 2H), 0.94 (m, 1H), 1.07 (m, 1H), 1.33 (s, 3H), 1.34 (s, 1H), 2.83 (m, 1H), 2.07 (m, 1H), 2.19 (m, 2H), 2.63 (s, 3H), 3.60 (b t, 1H), 3.68 (b t, 1H), 3.81 (m, 1H), 3.93 (m, 1H), 7.90 (s, 1H), 8.11 (b s, 1H), 9.08 (d, 1H), 13.83 ( b s, 1H). Anal. Calcd for C21H27N3O3FCl.1.5 H2O: C, 55.93; H, 6.71; N, 9.32; Found: C, 56.07; H, 6.71; N, 8.95.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([NH2:10])[CH:3]=1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccccc1)c1ccc(Br)cc1N
Temperature: 90 °C
Yield: 107.3 %

Procedure:
Dissolving 6.8 g (29 mmol) 4-bromo-N-methyl-2-nitroaniline obtained in the above step (1) into 20 milliliter of pyridine, further adding 5.0 g (35 mmol) benzoyl chloride, the resultant solution was refluxed with heating at the temperature of 90° C. under an atmosphere of argon gas for 7 hours. After completing the reaction, 200 milliliter of ethyl acetate was added and the resultant solution was washed with 10% HCL, with 10% K2CO3 and with a saturated solution of sodium chloride and then, dried with the use of magnesium sulfate. After filtration, the solvent was removed by distillation under reduced pressure and the residue was refined with silicagel column chromatography (hexane:ethyl acetate=10:1 at primary stage→2:1 from middle stage) resultantly obtaining 9.5 g of 4′-bromo-N-methyl-2′-amino-benzanilide as greenish white solids (yield: 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.Cl.[CH3:23][N:24]1[CH2:31][CH2:30][CH:29]=[C:26]([CH2:27]Cl)[CH2:25]1.C(=O)(O)[O-:33].[Na+]>O1CCCC1>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:27]([C:26]4[CH2:25][N:24]([CH3:23])[CH2:31][CH2:30][CH:29]=4)=[O:33])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CN1CCC=C(CCl)C1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC=C(C(=O)Nc2ccc3ncc(C#N)c(Nc4cccc(Br)c4)c3c2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1 g (2.95 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile and 1.9 g (14.7 mmol) of dissopropylethylamine was strirred in 19 ml of tetrahydrofuran and solid N-methyl-1,2,5,6-tetrahydronicotinyl chloride hydrochloride was added portionwise at 0° C. After stirring 1 hr at 0° C. and 2 hr at room temperature, the mixture was poured into saturated sodium bicarbonate and extracted with ethylacetate. The solution was dried over magnesium sulfate. Sovent was removed and the residue was recrystalized from methanol-ethylacetate giving 0.92 g of a yellow powder: mass spectrum (electrospray, m/e,): M+H 462.4, 464.4.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[OH:18].[CH:19]#[C:20][CH:21](O)[CH2:22][CH2:23][CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:20]([CH:21]([O:18][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:12])[C:2]=1[F:1])[O:9][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:6]2)[CH2:22][CH2:23][CH3:24])#[CH:19]
Reactant: CCCCCC1CCc2cc(O)c(F)c(F)c2O1
Reactant: C#CC(O)CCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C#CC(CCC)Oc1cc2c(c(F)c1F)OC(CCCCC)CC2
Reaction time: 18 h

Procedure:
10.0 g (39.0 mmol) of 7,8-difluoro-2-pentylchroman-6-ol are initially introduced in 140 ml of THF together with 4.0 g (41.0 mmol) of 1-hexyn-3-ol and 11.3 g (42.9 mmol) of triphenylphosphine, and 9.1 ml (46.8 mmol) of DIAD are added over the course of 20 min with ice-cooling. After 18 h at RT, water is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride soln., and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=2:1), giving 6-(1-ethynylbutoxy)-7,8-difluoro-2-pentylchroman as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:20]1[CH:21]=[C:22]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH:26]=1)[NH2:25]>C(OCC)(=O)C>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][C:22]1[C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH:26]=[C:20]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:21]=1)[NH2:25]
Reactant: COc1ccccc1Oc1cc(F)cc(N)c1[N+](=O)[O-]
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1cc(Oc2cccnc2)cc(N)c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1.24 g of 3-hydroxypyridine and 5.42 g of potassium carbonate were added to a dimethylformamide (30 ml) solution of 3.03 g of 5-fluoro-3-(2-methoxyphenoxy)-2-nitroaniline, and the reaction liquid was stirred overnight at 90° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and then dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/1 to 1/2) to obtain the entitled compound as an orange solid.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][C:6]1[CH:5]=[C:4]([F:3])[C:13]([OH:14])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: BrBr
Reactant: Oc1c(F)ccc2cccnc12
Solvent: CC(=O)O
Product: Oc1c(F)cc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.6 %

Procedure:
An rt solution of bromine (2.34 g, 14.7 mmol) in acetic acid (10 mL) was slowly added to a solution of 7-fluoro-8-quinolinol (2.0 g, 12.2 mmol) in acetic acid (30 mL). The brown reaction mixture was stirred at rt for 16 h, after which the mixture was quenched with saturated sodium bisulfite solution. The resulting mixture was extracted with methyl t-butyl ether 3 times. The combined organic phases were washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo to dryness to give 3.0 g (97.0%) 5-bromo-7-fluoro-8-quinolinol as a green solid.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](OCC)=O)=[CH:22][CH:21]=1.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:32])[F:33])=[CH:25][CH:24]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(C(F)(F)F)cc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 57.5 %

Procedure:
Sodium (622 mg) was dissolved in ethanol (45 mL) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.0 g, 13.5 mmol), followed by ethyl 4-trifluoromethylphenylacetate (6.27 g, 27 mmol) were added. The reaction mixture was refluxed overnight, cooled to room temperature, and the solvent was stripped. Water, followed by 2N HCl were added to the residue and the product was collected by filtration, recrystallized from ether and dried at 110° C. and 0.2 mm Hg to afford 3.03 g of 1-cyclopentyl-3-ethyl-6-(4-trifluoromethylphenylmethyl) pyrazolo[3,4-d]pyrimidin-4-one, m.p. 212°-213° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3](=O)[CH2:2]1.C(N(CC)CC)C.[C:14](#[N:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[S:1]1[C:2]2[C:3](=[N:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14]=2[NH2:22])[CH2:4][CH2:5]1
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCSC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c2c(nc3ccccc13)CCS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a stirred solution of tetrahydrothiophen-3-one (1.1 g, 11 mmole) in methylene chloride (10 ml) at -78° C., a 1M solution of titanium (IV) chloride in methylene chloride (11 ml) was added. A mixture of triethylamine (2.2 g, 22 mmole) and anthranilonitrile (1.2 gms, 10.0 mmole) in methylene chloride (30 ml) was then added to the reaction mixture over a period of 5 minutes. The reaction mixture was then slowly warmed to room temperature and stirred for 2 hours. Tetrahydrothiophen-3-one (1 ml) and titanium(IV) chloride (1.0 ml) was then added to the reaction mixture and the mixture was stirred at 25° C. for 16 hours. Thereafter, the reaction mixture was quenched with 12% aqueous NaOH (100 ml) and the reaction mixture was then stirred vigorously with additional methylene chloride (300 ml). The reaction mixture was then filtered through diatomaceous earth (Celite (trademark)) and the organic phase was separated. The organic solvents were removed under vacuum to afford a residue which was loaded on a flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine, afforded the title compound (1.3 gms, 64%) which was crystallized from chloroform (560 mg, 32%, m.p. 208°-210° C.). 1H-NMR (CDCl3, 300 MHz, δ): 4H, m, 3.4-3.56 ppm; 2H, bs, 4.51 ppm; 1H, dt, 7.37 ppm (J=7.0, 1.0 Hz); 1H, dt, 7.52 ppm (J=7.0, 1.10 ppm); 1H, dd, 7.61 ppm (J=7.0, 1.0 ppm); 1H, dd, 7.61 ppm (J=7.0, 1.0 ppm), 1H, dd, 7.86 ppm (J=7.0, 1.0 ppm). HRMS: Calculated--202.0575; Found--202.0545.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:14][O:15][CH3:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:18]>CCOC(C)=O.O1CCOCC1>[ClH:18].[CH3:16][O:15][CH2:14][C:8]1([NH2:7])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COCC1(NC(=O)OC(C)(C)C)CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCC1(N)CCOCC1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl[4-(methoxymethyl)tetrahydro-2H-pyran-4-yl]carbamate (0.45 g, 0.0018 mol) in EtOAc (0.2 mL) was added 4M of hydrogen chloride in 1,4-dioxane (3 mL) and stirred for 2 h. The volatiles were removed under reduced pressure to give the desired compound which was directly used in next step without further purification. LCMS: (M+H)=146.2.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1.C(N(CC)CC)C.[C:20]([OH:24])([CH3:23])([CH3:22])[CH3:21]>C(Cl)(Cl)Cl>[C:20]([O:24][C:1](=[O:2])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(N)n1
Reactant: CC(C)(C)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1.4 h
Yield: 94 %

Procedure:
295.7 g (199 mL) of chloroform were added to a reaction system and cooled to 0° C. followed by blowing in 43.08 g (0.436 moles) of phosgene over the course of 0.5 hours. A mixed solution containing 21.66 g (0.200 moles) of 2-amino-6-picoline, 20.26 g (0.200 moles) of triethylamine, 37.02 g (0.499 moles) of t-butanol and 89.6 g (60 mL) of chloroform were dropped into this phosgene solution over the course of 1.0 hours while holding the internal temperature at −3° C. to 2° C. Following completion of dropping, the solution was stirred for 1.4 hours. Next, 20.30 g (0.201 moles) of triethylamine and 59.4 g (40 mL) of chloroform were dropped in over the course of 0.8 hours while holding the internal temperature at 0° C. to 5° C. Following completion of dropping, the solution was stirred for 1.0 hours. Next, 122.5 g (82 mL) of chloroform were added. The reaction solution was subjected to quantitative analysis by HPLC. The target (6-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester was obtained at a yield of 94%. The yield of 1,3-bis-(6-methyl-pyridin-2-yl)-urea (urea compound) was 2%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][N:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[N:16]=[CH:17][C:18](/[CH:19]=[CH:28]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(N[C@@H]2CCCN(Cc3ccccc3)C2)nc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCN(Cc3ccccc3)C2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
To a solution of 6-{[(3R)-1-benzyl-3-piperidinyl]amino}nicotinaldehyde (110 mg, 0.37 mmol) in tetrahydrofuran (4 mL) was added (carbethoxymethylene)triphenylphosphorane (260 mg, 0.75 mmol) and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform-MeOH=15-1) to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-piperidinyl]amino}-3-pyridinyl)acrylate (77 mg, 57%) as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:15])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OCC(C)(C)C(=O)Cl

Procedure:
A benzene solution (25 ml) of crude 3-acetoxy-2,2-dimethyl propionic acid from Example 3(a) (7.4 g, 46.5 mmol), oxalyl chloride (6.45 g, 51 ml) and DMF (2 drops) was stirred at ambient temperature for 3 hours. The pale yellow solution was distilled to provide the title compound as a colorless liquid, b.p.15 85°-88° C. NMR (CDCl3) δ4.18 (2H, s), 2.08 (3H, s), 1.35 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.[CH2:38]([N:42]([CH2:45][CH2:46][CH2:47][CH3:48])[S:43]Cl)[CH2:39][CH2:40][CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:43][N:42]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:19])[CH2:6]2)=[O:4]
Reactant: CCCCN(CCCC)SCl
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(CCCC)SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Step B (Example 1) (0.4 g, 0.96 mmol) in 8 ml methylene chloride cooled to 0° C. was added triethylamine (0.15 g) and dibutylaminosulfenylchloride (0.2 g). The reaction mixture was warmed to room temperature and stirred for one hour. The mixture was subjected to silica gel column chromatography using hexane-ether (6:1) as the eluent. The title compound was obtained (0.24 g)in high purity.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([S:16](Cl)(=[O:18])=[O:17])[CH:11]=3)[C:6](=[O:20])[C:5]=2[CH:4]=[CH:3][C:2]=1[S:21](Cl)(=[O:23])=[O:22].[C:25]([CH:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].C([N:38]([CH2:41][CH3:42])CC)C>C(Cl)Cl>[C:25]([CH:29]1[CH2:30][CH2:31][CH:32]([NH:35][S:21]([C:2]2[CH:3]=[CH:4][C:5]3[C:6](=[O:20])[C:7]4[C:12](=[CH:11][C:10]([S:16]([NH:38][CH:41]5[CH2:42][CH2:34][CH:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:30][CH2:31]5)(=[O:18])=[O:17])=[CH:9][CH:8]=4)[C:13](=[O:15])[C:14]=3[CH:1]=2)(=[O:23])=[O:22])[CH2:33][CH2:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCN(CC)CC
Reactant: O=C1c2ccc(S(=O)(=O)Cl)cc2C(=O)c2cc(S(=O)(=O)Cl)ccc21
Reactant: CC(C)(C)C1CCC(N)CC1
Solvent: ClCCl
Product: CC(C)(C)C1CCC(NS(=O)(=O)c2ccc3c(c2)C(=O)c2cc(S(=O)(=O)NC4CCC(C(C)(C)C)CC4)ccc2C3=O)CC1
Temperature: -50 °C
Reaction time: 4 h
Yield: 333.3 %

Procedure:
Anthraquinone-2,7-disulfonylchloride (10 g, 24.7 mmol)) was dissolved in 200 mL DCM. The solution was cooled to −50° C. To this solution was added 4-tert-butylcyclohexanamine (8.43 g, 54 mmol), followed by triethyl amine (8.6 ml, 61:7 mmol). The reaction mixture was stirred at room temperature for 4 hrs. Solvent was evaporated and the residue was treated with MeOH, filtered off, and dried to obtain 15 g (95%) of the product (1-36) as yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[C:28]1([CH2:34][S:35](Cl)(=[O:37])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:35]([CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:37])=[O:36])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: Cc1ccc(Sc2ccc(OS(=O)(=O)Cc3ccccc3)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 5 (120 mg, 0.294 mmol) was reacted with phenyl-methanesulfonyl chloride (55 mg, 0.294 mmol) for 22 h following the procedure from Example 58 giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (15 mg, 9%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.31 (d, 1H) 7.73 (d, 1H) 7.11 (d, 1H) 6.85 (d, 1H) 6.74 (s, 2H) 6.64 (d, 2H) 6.53 (d, 2H) 5.75 (d, 1H) 2.81 (q, 2H) 2.42 (q, 2H) 1.78 (s, 3H) 0.76 (m, 6H); MS (ESI+) m/z 484 (M+H)+.
Reaction SMILES: C(OC(N[C@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)=O)(C)(C)C.Cl.BrC1SC2=NC(N)=CN2C=1.[C:37]([O:41][C:42](=[O:70])[NH:43][C@@H:44]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@@H:48]1[C:52](=[O:63])[NH:53][C:54]1[N:55]=[C:56]2[N:60]([CH:61]=1)[CH:59]=[C:58]([Br:62])[S:57]2)=[O:46])(C)(C)[CH3:38]>>[CH2:37]([O:41][C:42](=[O:70])[NH:43][C@@H:44]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@@H:48]1[C:52](=[O:63])[NH:53][C:54]1[N:55]=[C:56]2[N:60]([CH:61]=1)[CH:59]=[C:58]([Br:62])[S:57]2)=[O:46])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: Cl
Agent: Nc1cn2cc(Br)sc2n1
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1

Procedure:
Compound 44 was synthesized from compounds 43 (0.377 mmol) and 11 (0.565 mmol), following the procedure as described for compound 12a, at room temperature overnight, to give compound 44 as a yellow oil in 66% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.10 (t, 3H), 1.80 (m, 2H), 1.95 (m, 2H), 3.10 (m, 1H), 3.81 (m, 1H), 3.99 (m, 2H), 4.40 (m, 1H), 5.42 (m, 1H), 7.31 (m, 5H), 7.50 (d, 1H), 7.81 (s, 1H), 8.16 (s, 1H), 10.61 (s, 1H); MS (ESI, EI+) m/z=520-522 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[CH3:16])=[CH:4][CH:3]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:17]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[CH3:16])[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH2:28][CH3:29])=[O:26])=[CH:3][CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(O)ccc1C(=C1CCCCC1)c1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2C)cc1
Temperature: 140 °C
Yield: 60 %

Procedure:
To a solution of 4-[(4-bromophenyl)(cyclohexylidene)methyl]-3-methylphenol (29) (0.60 g, 1.68 mmol) in DMF (6 mL) was added ethyl acrylate (0.54 mL, 4.98 mmol), P(o-tolyl)3 (0.056 g, 0.184 mmol), Et3N (0.70 mL, 5.02 mmol), and Pd(OAc)2 (0.023 g, 0.10 mmol). The mixture was heated at 140° C. for 30 min in a microwave. Upon cooling, water (25 mL) was added, and the mixture was extracted with Et2O (3×20 mL). The organics were combined, dried (MgSO4), and concentrated. The crude material was purified by chromatography on silica gel (EtOAc:hexanes) to yield 0.13 g, (60%) of compound 30. 1H NMR (400 MHz, CDCl3): δ 1.32 (t, J=7.1 Hz, 3H), 1.52-1.61 (m, 6H), 1.98-2.01 (m, 2H), 2.06 (s, 3H), 2.32 (m, 2H), 4.24 (q, J=7.1 Hz, 2H), 4.78 (s, 1H), 6.36 (d, J=16.1 Hz, 1H), 6.62-6.63 (m, 2H), 6.96 (m, 1H), 7.13 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.63 (d, J=15.9 Hz, 1H).