Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[B:17]1[O:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[O:21]1
Reactant: CC1(C)OB(c2ccccc2CBr)OC1(C)C
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NCc1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 1.60 g (15 mmol) of 2-methylaniline, 3.00 g (10 mmol) of 2-[2-(bromomethyl)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 1.52 g (11 mmol) of K2CO3 in 75 ml of DMF was stirred for 12 h at 80° C. The resulting mixture was poured into 300 ml of water. The product was extracted with 3×50 ml of ethyl acetate. The combined extract was dried over Na2SO4 and then evaporated to dryness. An excess of 2-methylaniline was distilled off using Kugelrohr apparatus. The residue was re-crystallized from 20 ml of n-hexane. Yield 1.82 g (56%) of red crystalline powder. Anal. calc. for C20H26BNO2: C, 74.32; H, 8.11; N, 4.33. Found: C, 73.99; H, 8.02; N, 4.45. 1H NMR (CDCl3): δ 7.82 (m, 1H, 5-H in 2-MeC6H4), 7.36-7.41 (m, 2H, 3, 5-H in C6H4CH2), 7.26 (m, 1H, 4-H in C6H4CH2), 7.08 (m, 1H, 5-H in 2-MeC6H4), 7.02 (m, 1H, 3-H in 2-MeC6H4), 6.71 (m, 1H, 6-H in 2-MeC6H4), 6.61 (m, 1H, 4-H in 2-MeC6H4), 4.55 (br.s, 2H, CH2NH), 4.31 (br.s, 1H, NH), 2.13 (s, 3H, Me in 2-MeC6H4), 1.31 (s, 12H, Bpin).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12](B4OC(C)(C)C(C)(C)O4)=[CH:13][C:8]=3[N:7]([CH3:23])[S:6]2(=[O:25])=[O:24])[CH2:3][CH2:2]1.Br[C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>CO.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd].O>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:27]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=4[C:29]#[N:30])=[CH:13][C:8]=3[N:7]([CH3:23])[S:6]2(=[O:24])=[O:25])[CH2:2][CH2:3]1
Reactant: CN1c2cc(B3OC(C)(C)C(C)(C)O3)ccc2N(CC2CC2)S1(=O)=O
Reactant: N#Cc1c(F)cccc1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CN1c2cc(-c3cccc(F)c3C#N)ccc2N(CC2CC2)S1(=O)=O
Temperature: 100 °C

Procedure:
To a microwave vial was added 1-(cyclopropylmethyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (2-1) (0.043 g, 0.12 mmol), 2-bromo-6-fluorobenzonitrile (0.035 g, 0.18 mmol), cesium carbonate (0.077 g, 0.24 mmol), palladium bis(tri-tert-butylphosphine) (0.012 g, 0.024 mmol), dioxane (1 mL), and water (0.2 mL). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, then filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 2-[1-(cyclopropylmethyl)-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl]-6-fluorobenzonitrile (2-2) as a white solid. HRMS (M+H)+: observed=358.1015, calculated=358.1020
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH2:17].[OH-].[Na+].Cl>CO>[NH2:17][C:5]1[CH:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:18])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1C(=O)O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 490 mg (1.85 mmol) of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester in 5 ml methanol, 4.7 ml (9.27 mmol) of 2 M sodium hydroxide solution is added. The yellow solution is stirred at 60° C. for 12 hours. Subsequently hydrochloric acid (1M) is added to adjust to pH=2. The solvent volume is reduced by evaporation and is extracted with ethyl acetate. The organic layers are combined, dried and the solvent is evaporated to yield 2-amino-5-nitro-4-trifluoromethyl-benzoic acid. 1H-NMR; DMSO-d6 (400 MHz, ppm): 8.58 (s, 1H, aromatic); 8.10 (s(broad), 2H, NH2); 7.35 (s, 1H, aromatic).; LC-MS: 249 [M-H]- ; Agilent LC/MSD 1100 Series; LC-MS method: Column: SunFireCl8, 4.6*50 mm, 3.5 μm; negative MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]([CH:26]=O)[CH:23]=[C:22]3[C:18]=2[CH:19]=[N:20][N:21]3COCC[Si](C)(C)C)=[CH:13][CH:12]=1.N1CCCC1>C(O)C>[N:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]([CH:26]=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])[CH:23]=[C:22]3[C:18]=2[CH:19]=[N:20][NH:21]3)=[CH:15][CH:16]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1ncc2c(-c3ccncc3)cc(C=O)cc21
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1cc(-c2ccncc2)c2cn[nH]c2c1
Temperature: 70 °C

Procedure:
To a solution of oxindole (12 mg, 0.08 mmol) and 4-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (31 mg, 0.087 mmol) in ethanol (2 mL) was added pyrrolidine (20 μL). The mixture was heated to 70° C. for 3 h. The solution was concentrated to dryness and treated with 4M HCl (1 mL) in ethanol (3 mL) at 70° C. for 4 h. The solution was cooled to rt and extracted with ethyl acetate (50 mL), dried over MgSO4 and concentrated to give the title compound as a mixture of E/Z isomers which were separated by preparatory HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:24]([O-])=O)[C:21]([F:23])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([NH2:24])[C:21]([F:23])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3cc(F)c([N+](=O)[O-])cc3O2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3cc(F)c(N)cc3O2)cc1

Procedure:
To a mixture of 3.52 g (9.17 mmole) of [(2S)-7-nitro-6-fluoro-2,3-dihydro-1,4-benzodioxin-2y]methyl 4-methylbenzenesulfonate and 2.5 mL of 4 N isopropanolic HCl in 200 mL of ethyl acetate was added 0.50 g of 10% palladium on carbon and the mixture treated with 50 psi of hydrogen on a Parr apparatus for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to give 3.04 g of the (R)-enantiomer of the title compound as beige solid hydrochloride salt. 1H-NMR (DSMO-d6): doublet 7.8 δ (2 H); doublet 7.5 δ (2 H); doublet 6.8 δ (1 H); doublet 6.55 δ (1 H); multiplet 4.4 δ (1 H); doublet of doublets 4.3 δ (1 H); multiplet 4.2 δ (2 H); multiplet 3.85 δ (1 H); singlet 2.4 δ (3 H).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[C:14]([O:21][CH3:22])(=[O:20])/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19].CC(C)([O-])C.[K+]>>[CH2:17]([C:16]1[C:15]([C:14]([O:21][CH3:22])=[O:20])=[CH:10][NH:11][CH:12]=1)[CH2:18][CH3:19]
Reactant: CCC/C=C/C(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1c[nH]cc1C(=O)OC
Yield: 38 %

Procedure:
Using p-toluenesulfonylmethyl isocyanide (8.6 g), methyl (2E)-hex-2-enoate (5.67 g) and potassium tert-butoxide (5.9 g), a procedure as in Reference Example 39 was performed to give the title compound as colorless crystals (yield 2.8 g, 38%).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([O:10][CH:11]([F:13])[F:12])=[CH:8][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[OH:23]O>CO>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([OH:23])=[CH:8][C:9]=2[O:10][CH:11]([F:13])[F:12])[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2cnc(C3CC3)c(OC(F)F)c2)OC1(C)C
Reactant: OO
Solvent: CO
Product: Oc1cnc(C2CC2)c(OC(F)F)c1
Temperature: 0 °C
Yield: 58 %

Procedure:
Methanol (5 mL) was added to the crude 2-cyclopropyl-3-difluoromethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 103, 450 mg, 1.5 mmol) and the resulting solution cooled to 0° C. with stirring. Hydrogen peroxide solution (35% in water, 0.70 mL) was added over 20 minutes. The reaction mixture was then allowed to warm to room temperature and stirred for 5 hours. The reaction was quenched by addition of 1M aqueous sodium thiosulfate solution (10 mL), and rapidly stirred for 15 minutes at room temperature. The mixture were evaporated in vacuo, and brine (50 mL) was added. The residue was extracted into ethyl acetate (3×50 mL) and the combined extracts were dried over magnesium sulfate, filtered and the solvent removed to leave a brown oil. The oil was purified by flash silica gel column chromatography eluting with EtOAc:heptane 1:1 to provide the title compound as a white solid (168 mg, 58% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:5]2[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=2[N:7]=1.[F:19][C:20]1[C:25]([F:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38]>>[F:19][C:20]1[C:25]([F:26])=[C:24]([C:2]2[N:3]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[C:5]3[CH2:10][N:9]([CH3:11])[CH2:8][C:6]=3[N:7]=2)[CH:23]=[CH:22][C:21]=1[NH:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1F
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)c(F)c1F
Yield: 4.2 %

Procedure:
Method as example 47 using (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 12) and 1-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-ethylurea as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The crude material was purified first by Flash Chromatography using a gradient of 0-40% DCM/MeOH, then prep. HPLC at low pH yielding the title compound (8.7 mg, 0.01 mmol, 4.2%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][C:6]([Cl:10])=[CH:7][C:8]#[N:9])#[N:2].C([O-])(=O)C.[Na+].[Br:16]Br>ClC(Cl)C>[C:1]([CH2:3][CH2:4][S:5][C:6]([Cl:10])=[C:7]([Br:16])[C:8]#[N:9])#[N:2]
Reactant: BrBr
Reactant: N#CC=C(Cl)SCCC#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: N#CCCSC(Cl)=C(Br)C#N
Yield: 40.5 %

Procedure:
17.3 g of 1-chloro-2-cyano-vinyl 2-cyano-ethyl sulphide were dissolved in 100 ml of dichloroethane, and 9.8 g of sodium acetate were added. 16 g of bromine were then added dropwise at 20° C. The organic phase was washed with water, concentrated and chromatographed. 10.2 g of 2-bromo-1-chloro-2-cyano-vinyl 2-cyano-ethyl sulphide were obtained as an oil, 1H-NMR: δ=2.6-2.9 (2H) and 3.1-3.5 (2H).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][S:5][C@H:4]2[CH2:20][CH2:21][C@@H:22](C(F)(F)F)[CH2:23][N:3]12.NC([C:35]([F:38])([F:37])[F:36])CCCCO.N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O>>[NH2:9][C@H:8]1[CH2:7][CH2:6][S:5][C@H:4]2[CH2:20][CH2:21][CH2:22][C@@H:23]([C:35]([F:38])([F:37])[F:36])[N:3]2[C:2]1=[O:1]
Reactant: O=C(N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O)OCc1ccccc1
Reactant: NC(CCCCO)C(F)(F)F
Agent: N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O
Product: N[C@H]1CCS[C@H]2CCC[C@@H](C(F)(F)F)N2C1=O

Procedure:
(4S,7S,10aS)-4-Amino-7-(trifluoromethyl)hexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one (53 mg, 0.20 mmol) was synthesized as described for the preparation of Intermediate 59 using 5-amino-6,6,6-trifluorohexan-1-ol in step A followed by the preparation of Intermediate 61. Anal. Calcd. for C10H15F3N2OS m/z 268.3. found: 269.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 5.42-5.27 (m, 1H), 5.21 (t, J=7.0 Hz, 1H), 3.99 (dd, J=10.3, 2.7 Hz, 1H), 3.15 (ddd, J=13.9, 10.9, 2.6 Hz, 1H), 2.81 (ddd, J=14.4, 6.3, 2.9 Hz, 1H), 2.23 (ddt, J=14.2, 6.0, 2.9 Hz, 1H), 2.19-2.07 (m, 1H), 2.06-1.79 (m, 7H), 1.54-1.39 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:17][C:18]3[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CO.C[O-].[Na+:32]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([S:17][C:18]3[N:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[N:23]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+:32]
Reactant: COc1cc(OC)nc(Sc2nccc(-c3ccc(Cl)cc3)c2C(=O)O)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1cc(OC)nc(Sc2nccc(-c3ccc(Cl)cc3)c2C(=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of 0.50 g (0.0012 mol) of 4-(4-chlorophenyl)-2-(4,6-dimethoxylpyrimidin-2ylthio)nicotinic acid in 7 ml of ethanol was added 0.30 g (0.0016 mol) of methanol solution of 28% sodium methylate at room temperature. After addition, the mixture was further stirred at room temperature for 20 minutes. The crystal thus precipitated was filtrated, and washed with ethanol and dried to obtain 0.46 g of a white powder of the aimed product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:40][O:41][C:42]1[C:43]([CH3:70])=[C:44]([C:61]([O:68][CH3:69])=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[CH2:45][C:46]1[CH:47]=[CH:48][C:49](O)=[C:50]([CH:59]=1)[C:51]([N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:52].[OH-].[Na+]>C1C=CC=CC=1>[CH3:40][O:41][C:42]1[C:43]([CH3:70])=[C:44]([C:61]([O:68][CH3:69])=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[CH2:45][C:46]1[CH:47]=[CH:48][C:49]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:50]([CH:59]=1)[C:51]([N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:52]
Reactant: OCc1cccnc1
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1c(C)c(Cc2ccc(OCc3cccnc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
3-Pyridinemethanol (0.102 g, 0.932 mmol), triphenylphosphine (0.293 g, 1.12 mmol) and diethylazodicarboxylate (0.195 g, 1.12 mmol) were added to a benzene solution (30 ml) of N-[5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]piperidine (0.320 g, 0.746 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into an aqueous 2N sodium hydroxide solution (15 ml) and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=1.5:8.5) to obtain the titled compound (0.350 g, 0.673 mmol, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[C:6]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:13][CH2:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH2:5]2.C(O)(=O)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([F:24])=[C:4]2[C:8]([C:7]3[C:6]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:5]2)[CH2:13][CH2:14][C:15](=[O:19])[C:16]=3[CH2:17][CH3:18])=[CH:9][C:10]=1[F:11]
Reactant: CCCCC1(CCC(=O)CCC)Cc2c(cc(F)c(N)c2F)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C(CC)=C1c1cc(F)c(N)c(F)c1C2
Temperature: 100 °C
Yield: 47.7 %

Procedure:
The crude diketone from step 1 (about 1.05 mmol) was treated with acetic acid (5 mL) and 6N HCl (5 mL). The resulting solution was stirred and heated in an oil bath at 100° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into a slurry of solid Na2CO3 in CH2Cl2, dried over MgSO4, then filtered through a pad of silica gel and the product washed off with EtOAc. The filtrate and washings were concentrated under vacuum. The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 30% EtOAc in hexanes, to afford 7-amino-9a-butyl-4-ethyl-6,8-difluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.16 g, 48%) as a yellow solid.
Reaction SMILES: OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.BrBr.Br[C:21]1[C:22](C(C2C=CC(O)=CC=2)(C)C)=[C:23]([Br:29])[C:24]([Br:28])=[C:25]([CH:27]=1)[OH:26].BrC1C(O)=C(Br)C(Br)=C(C(C2C=CC(O)=CC=2)(C)C)C=1Br>O.CO>[Br:29][C:23]1[C:24]([Br:28])=[C:25]([OH:26])[CH:27]=[CH:21][CH:22]=1
Reactant: CC(C)(c1ccc(O)cc1)c1c(Br)cc(O)c(Br)c1Br
Agent: BrBr
Agent: CC(C)(c1ccc(O)cc1)c1c(Br)c(Br)c(O)c(Br)c1Br
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CO
Solvent: O
Product: Oc1cccc(Br)c1Br
Temperature: 30 °C
Reaction time: 1 h
Yield: 0.03 %

Procedure:
To a 2-liter 4-neck flask equipped with a -10° C. Friedrichs condenser, thermometer, mechanical stirrer, and 0.16 centimeter in diameter dip tube are added 180 grams (0.79 moles) of bisphenol-A and 880 mL of methanol containing 4 wt. % water. Bromine (513 grams, 3.2 moles) was fed with a peristaltic pump to a 1.8 meter, 0.63 centimeter outside diameter teflon tube held in hot water which was maintained at a temperature of >80° C. Bromine vapor thus generated was fed to the reaction flask over a 52 minute period and the temperature was maintained during the ({reaction at 28-32° C. by use of an ice bath. When all of the bromine had been added, additional methanol (175 mL) containing 4 wt. % water was added to the reaction flask and the mixture was stirred at 30° C. The overall methanol to bisphenol-A ratio was 32 moles of methanol per mole of bisphenol-A. A first sample of the homogenous mixture was taken 60 minutes after the bromine was added. The first sample was analyzed and indicated the presence of 0.03% yield of dibromophenol, 0.03% hydrolyzable impurities, 2.79% tribromobisphenol-A, and 97.18% tetrabromobisphenol-A. After an additional 30 minutes, a sample of liquid portion of the heterogenous mixture was analyzed and contained 2.17% tribromobisphenol-A. Water (700 mL) addition was begun immediately after taking the second sample and was complete in 20 minutes. The resulting orange mixture was filtered and the tetrabromobisphenol-A product was washed with 500 mL of deionized water. The product, thus isolated, was placed in a crystallizing dish and 1 mL of 56 wt % HBr was added. The product was then oven dried at 130° C for four hours. The dried product was analyzed as in Example 2 and indicated 99.24 wt. % tetrabromobisphenol-A, an acetone color of 10 APHA, a TOHTO color of 20 APHA, an ionic bromide content of 0 ppm, and a hydrolyzable bromide content of 21 ppm.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=3[O:19][CH3:20])[CH2:12][CH2:11][CH2:10]2)[CH:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][O:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[C:18]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH:9]2[NH:8][C:6]1[CH:7]=[C:2]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:3]=[CH:4][C:5]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C1CNCCN1
Reactant: COc1ccc(OC)c2c1CCCC2Nc1cc(F)ccc1S(C)(=O)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OC)c2c1CCCC2Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O
Yield: 71.6 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalen-1-amine (1.234 g, 3.26 mmol), piperazine (5.63 g, 65.1 mmol) and N,N-diisopropylethylamine (5.7 mL, 32.6 mmol) in acetonitrile (20 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 1.04 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 610 mg (42%) of 1,2,3,4-tetrahydro-5,8-dimethoxy-N-(2-(methylsulfonyl)-5-(piperazin-1-yl)phenyl)naphthalen-1-amine: 1H NMR (400 MHz, CD3OD): δ 7.49 (d, 1H), 6.81 (d, 1H), 6.76 (d, 1H), 6.38-6.36 (m, 2H), 5.98 (d, 1H), 4.80 (br s, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 3.37-3.32 (m, 4H), 2.98-2.92 (m, 1H), 2.88-2.82 (m, 7H), 2.44-2.36 (m, 1H), 2.20 (br d, 1H0, 1.86-1.58 (m, 3H). MS (ESI) m/z: Calculated: 445.20; Observed: 446.2 (M++1).
Reaction SMILES: Br[CH2:2][C:3]1([N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[C-:15]#[N:16].[K+].[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[C:15]([CH2:2][C:3]1([N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1)#[N:16]
Reactant: CN(C(=O)OC(C)(C)C)C1(CBr)CC1
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)C1(CC#N)CC1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A mixture containing 26.4 g of the product of Step 1, 26 g of potassium cyanide and 2.6 g of potassium iodide in 264 ml of dimethyl sulphoxide is stirred at 70° C. for 20 hours. The mixture is cooled and 400 ml of 10% sodium carbonate in water are added. After extraction with ether and customary treatment, evaporation of the residue under reduced pressure allows the expected product to be isolated.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=3[C:11](=[O:16])[C:12]=2[N+:13]([O-])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[NH2:13][C:12]1[C:11](=[O:16])[C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=2[O:8][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1c([N+](=O)[O-])c(N2CCOCC2)oc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1c(N2CCOCC2)oc2ccccc2c1=O
Reaction time: 4 h
Yield: 94 %

Procedure:
Part B: 2-(4-Morpholinyl)-3-nitro-4H-1-benzopyran-4-one(500 mg) is dissolved in EtOAc (30 mL). Palladium on carbon (10%, 100 mg) is added under a nitrogen atmosphere. The mixture is fixed to a Parr hydrogenator at 30 psi for 4 hr, then filtered (Celite, 1 cm) and solvent removed in vacuo. The product is purified by flash chromatography (EtOAc) to give 3-Amino-2-(morpholinyl)-4H-1-benzopyran-4-one (419 mg, 94%). Mp 140°-1° C.; IR (mull) 2954, 2925, 2856, 1621, 1607, 1551, 1466, 1423, 1382, 1277, 1271, 1240, 1115, 952, 762 cm-1 ; 1H NMR (CDCl3, δ) 8.24 (dd, J=7.8, 2.0 Hz, 1H), 7.60 (ddd, J=6.8, 6.7, 1.8 Hz, 1 H) , 7.38 (br.d, J=7.8 Hz, 2 H), 3.91-3.76 (m, 4 H), 3.52-3.47 (m, 4 H), 3.43 (br.s, 2 H); UV (EtOH) λ max (ε) 212 (19,150), 233 (15,180), 255sh (9,900), 300 (3,000), 356 (12,100); Mass spectrum:ions at m/e (relative intensity) 262 (21), 246 (100), 201 (21), 188 (18), 187 (40), 148 (88), 121 (52), 114 (21), 70 (36), 42 (17); Anal. calc'd. for C13H14N2O3 : C, 63.40, H, 5.73, N, 11.38; found: C, 63.48; H, 5.84; N, 11.46.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC1CCCC1
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCCC(C)(C)C#N)c1
Product: CCc1cc(OCCCCCC(C)(C)C#N)c(OCc2ccccc2)c(OC2CCCC2)c1
Yield: 92 %

Procedure:
1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl-6-cyclopentyloxy benzene was prepared in 92% yield as a white solid from 1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and bromo-cyclopentane.