Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[C:16](=S)=[S:17].II>C(O)C.O1CCOCC1>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[C:16]=[S:17]
Reactant: S=C=S
Reactant: Nc1ccc(C(=O)O)cc1
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A mixture comprising 4-aminobenzoic acid (0.20 g, 1.5 mmol), dioxane (5 mL), a saturated sodium hydrogencarbonate aqueous solution (5 mL) and carbon disulfide (0.37 mL, 6.1 mmol) was stirred in a nitrogen atmosphere at room temperature for 19 hours and then concentrated under reduced pressure to dryness. The obtained residue was dissolved in water (8.0 mL), and 1M sodium hydroxide aqueous solution (1.5 mL) was added. With stirring at room temperature, an ethanol (8.0 mL) solution of iodine (0.38 g, 1.5 mmol) was dropwise added thereto over a period of 8 minutes, followed by stirring at room temperature for further 12 minutes. Then, the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to remove ethanol and dioxane as far as possible. Then, 1M hydrochloric acid (4.5 mL) was added, and the precipitated solid was collected by filtration to obtain 4-isothiocyanatobenzoic acid as a ocher solid (0.20 g, yield: 78%). The HPLC purity was 62%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=O)[O:32][C:31]1=O.COC(OC)OC.[N+](O[La](O[N+]([O-])=O)O[N+]([O-])=O)([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[C:33](=[O:32])[C:34]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:30]=[CH:31]5)[C:3]=4[CH3:29])=[CH:9][N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=[N+]([O-])O[La](O[N+](=O)[O-])O[N+](=O)[O-]
Solvent: COC(OC)OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Temperature: 95 °C
Yield: 42.8 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (330 mg, 0.845 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (345 mg, 2.113 mmol), trimethoxymethane (0.926 mL, 8.45 mmol), and tris(nitrooxy)lanthanum, 6H2O (110 mg, 0.254 mmol) in tetrahydrofuran (Volume: 2 mL) was heated at 95° C. in a sealed vial for 20 hr. The mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL), 1 N NaOH solution (30 mL), and brine (30 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was subjected to prep. reverse phase HPLC purification. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (188 mg, 0.362 mmol, 42.8% yield) as a yellow solid. The product is mixture of two atropisomers at rt. LCMS (M+H)+=520.29. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.68 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.36 (s, 1H), 7.25 (d, J=8.9 Hz), 4.17 (m, 2H), 3.73 (m, 2H), 3.35 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]=[CH:10][C:11]([O:13]CC)=[O:12].C1COCC1>[OH-].[Na+]>[CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C=CCC1CC=C(C)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=CCC(CC=CC(=O)O)C1(C)C
Temperature: 83 °C
Yield: 90.4 %

Procedure:
Ethyl 4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enoate (2.0 g, 9.0 mmol) was added to THF (10 ml) in a 50 ml round bottom flask. Aqueous 1 N NaOH (10 ml) was then added to the flask and the reaction mixture was refluxed at 83° C. for 19 h. Upon completion of the reaction, the reaction mixture was diluted with 1 N NaOH (10 ml) and the aqueous layer was washed twice with MTBE (10 ml×2). The aqueous layer was treated with aqueous 1.0 N HCl until it reached a pH of about 3 (for example from 2 to 4), then extracted three times with AcOEt (10 ml×3). The combined AcOEt extracts were concentrated in vacuo and purified via flash column chromatography with MTBE/Hexanes (5-20% gradient) to give 4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enoic acid (1.58 g) as a viscous oil (1.58 g, 90%). The NMR data is indicated below.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([O:27]CC)=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[N:8]=[C:7]([C:25]([OH:27])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of ethyl 5-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]pyrazole-3-carboxylate (5.75 g) in methanol (100 ml) was added 2N-NaOH (15 ml) and the mixture was allowed to stand at room temperature for 2 hours. Water (10 ml) was added and methanol was evaporated under reduced pressure. The mixture was made acidic by addition of 2N-HCl, followed by extraction with ether. The organic layer was washed with water (20 ml×2), dried, and concentrated under reduced pressure, to give a colorless syrup. The syrup was recrystallized from chloroform to give colorless crystals (4.3 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[CH3:12][C:13]1[N:18]=[C:17]([C:19](O)=O)[CH:16]=[C:15]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:14]=1>>[CH3:19][C:17]1[N:18]=[C:13]([C:12]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=3)[N:7]=2)[CH:14]=[C:15]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH:16]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C(=O)O)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3ccc(N)nc3)no2)n1

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.113 g, 0.53 mmol) and 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example D.11) (0.10 g, 0.36 mmol) according to the general procedure V. Obtained as an off-white solid (0.045 g, 31%). MS (ISP) 398.1 [(M+H)+]; mp 163° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CC(C)([O-])C.[Na+].Br[C:14]1[CH:15]=[CH:16][C:17]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].Cl>O.CN(C=O)C>[F:26][C:25]([F:28])([F:27])[CH2:24][O:23][C:17]1[CH:16]=[CH:15][C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cc(Br)ccc1OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 100 °C
Reaction time: 10 h
Yield: 75.3 %

Procedure:
To a solution of 2,2,2-trifluoroethanol (14.7 g) and DMF (125 ml) was added sodium tert-butoxide (12.8 g) at 0° C. The solution was stirred at 20 to 25° C. for 1 hour at which point 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid (20 g) was added followed by cupric bromide (2.0 g). The mixture was stirred at 100° C. for 10 hours, cooled to 10° C., and water (30 ml) was added followed by 20% HCl solution (90 ml). The solution was extracted with dichloromethane (3×80 ml), and the combined organic layers were washed with water (3×60 ml). The solution was concentrated to one-third of the original volume and hexane (200 ml) was added. The resulting suspension was stirred at room temperature for 2 hours, filtered and the damp cake was rinsed with hexane (2×40 ml). The damp cake was dried in vacuo at 40° C. for 5 hours to give the product as a white solid (16.02 g, yield 75.3%).
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][CH2:11][N:12]1[C:17]2[CH2:18][CH2:19][S:20][CH2:21][C:16]=2[C:15](=[O:22])[NH:14][C:13]1=[O:23])C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27]>C(#N)C>[O:23]=[C:13]1[N:12]([CH2:11][CH2:10][CH2:9][N:8]([CH3:1])[C:26](=[O:27])[O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])[C:17]2[CH2:18][CH2:19][S:20][CH2:21][C:16]=2[C:15](=[O:22])[NH:14]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN(CCCn1c2c(c(=O)[nH]c1=O)CSCC2)Cc1ccccc1
Solvent: CC#N
Product: CN(CCCn1c2c(c(=O)[nH]c1=O)CSCC2)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of 11.5 g (33.29 mmol) of 1-{3-[benzyl(methyl)amino]propyl}-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidine-2,4-(3H)-dione in 200 ml of acetonitrile is treated with 7.92 g (36.63 mmol) of 2,2,2-trichloroethyl chloroformate, and the mixture is stirred at room temperature for 30 minutes. The solvent is then removed under reduced pressure and the residue is purified by column chromatography (silica gel, cyclohexane/ethyl acetate 1:1). This gives 9.4 g (63% yield) of a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Br:33][C:34]1[N:39]=[C:38]([NH2:40])[CH:37]=[CH:36][CH:35]=1>ClC(Cl)C.CN(C=O)C.N1C=CC=CC=1.CCOC(C)=O>[Br:33][C:34]1[N:39]=[C:38]([NH:40][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:21][CH:20]=2)=[O:19])[CH:37]=[CH:36][CH:35]=1
Reactant: Nc1cccc(Br)n1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 1.00 g, 2.654 mmol) in dichloroethane (2.6 ml) and DMF (1 drop) was added oxalyl chloride (0.2778 ml, 3.185 mmol), and the reaction was stirred at ambient temperature for 2 hours. The reaction was diluted with pyridine (10 ml), and 6-bromopyridin-2-amine (0.9183 g, 5.308 mmol) was added. The reaction was heated to 80° C. for 16 hours, then cooled to ambient temperature and diluted with EtOAc. The reaction was washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on silica gel eluting with a linear gradient of 5-70% EtOAc/hexanes to yield the desired compound (1.2 g, 2.257 mmol, 85.02% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][C:10]1[C:9]([C:21]([F:24])([F:23])[F:22])([O:16][Si](C)(C)C)[C:8]([F:26])([F:25])[CH2:7][CH2:6][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][C:10]1[C:9]([C:21]([F:22])([F:23])[F:24])([OH:16])[C:8]([F:25])([F:26])[CH2:7][CH2:6][C:5]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)c2[nH]c3c(Cl)cc(Cl)cc3c2CCC1(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)c2[nH]c3c(Cl)cc(Cl)cc3c2CCC1(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6,8-Dichloro-2,2-difluoro-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.12 g, 0.27 mmol) was dissolved in THF (5 mL) and KOH (0.055 g, 1.1 mmol) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 2 h, diluted with water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure to give the crude material which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to furnish the title compound. (0.012 g, 12%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.41 (br s, 1H), 7.44 (s, 1H), 7.3 (s, 1H), 3.35 (br s, 1H), 2.97 (t, J=12.0 Hz, 2H), 2.61-2.54 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[O:21][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:7]=1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9]2)=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1oc(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
o-benzoyl-p-chloro-phenylglyoxylic acid ethyl ester as a light-yellow thick oil after chromatography on silica gel with methylene chloride as the eluant.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:19]=3)[C:14]([OH:29])=[C:13]([C:30](OC)=[O:31])[C:12]2=[O:34])=[CH:7][CH:6]=1)=[O:4].[N:36]1([CH2:42][CH2:43][NH2:44])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CO>[CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:19]=3)[C:14]([OH:29])=[C:13]([C:30]([NH:44][CH2:43][CH2:42][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:31])[C:12]2=[O:34])=[CH:7][CH:6]=1)=[O:4]
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(C(=O)N(C)C)cc2)c1=O
Solvent: CO
Product: CN(C)C(=O)c1ccc(-n2c(=O)c(C(=O)NCCN3CCOCC3)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1
Yield: 83 %

Procedure:
In a similar manner to that described in example 196, from methyl 1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.0421 mmol), [2-(4-morpholinyl)ethyl]amine (0.05 mL), and methanol (2 mL), was prepared 1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (20 mg, 83% yield) as a tan solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.02 (br s, 1 H), 8.50 (s, 1 H), 7.64 (d, (J=8.4 Hz, 2 H), 7.26 (d, J=8.4 Hz, 2 H), 7.01-6.98 (m, 2 H), 6.94 (m, 2 H), 6.77 (s, 1 H), 3.93 (s, 2 H), 3.71-3.68 (m, 4 H), 3.58 (q, J=12.4, 6.4 Hz, 2 H), 3.15 (s, 3 H), 3.05 (s, 3 H), 2.63 (t, J=6.4 Hz, 2 H), 2.56-2.54 (m, 4 H); MS m/z 574 (M+1).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:29])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH:65]2[CH2:67][O:66]2)=[CH:59][CH:58]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:31]([NH:30][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:37]=[CH:38][C:7]([CH2:6][CH2:5][NH:4][CH2:67][C@H:65]([OH:66])[CH2:64][O:63][C:60]4[CH:61]=[CH:62][C:57]([OH:56])=[CH:58][CH:59]=4)=[CH:8][CH:9]=3)[CH2:17][CH2:16]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1)=[O:29])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 33.3 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N′-hexylurea formate (0.327 g 0.597 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.242 g, 0.598 mmol) according to Procedure G to give the title compound (0.180 g, 0.199 mmol).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5](Br)=[C:4]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])[C:3]=1Br.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.[Br-:39].[Br-:40].[Na+].Br([O-])(=O)=O.[Na+].Cl>C(Cl)Cl.O.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+]>[CH3:13][C:11]([C:14]1[CH:15]=[C:16]([Br:39])[C:17]([OH:20])=[C:18]([Br:40])[CH:19]=1)([C:4]1[CH:5]=[C:6]([Br:9])[C:7]([OH:8])=[C:2]([Br:1])[CH:3]=1)[CH3:12]
Reactant: [Br-]
Reactant: CC(C)(c1ccc(O)cc1)c1c(Br)c(Br)c(O)c(Br)c1Br
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(c1cc(Br)c(O)c(Br)c1)c1cc(Br)c(O)c(Br)c1
Temperature: 10 °C

Procedure:
Ramachandraiah, P. K. Ghosh, A. S. Mehta, R. P. Pandya, A. D. Jethva, S. S. Vaghela, S. N. Misra (pending U.S. pat. appln. Ser. No. 09/767,667 [2001]) have prepared tetrabromobisphenol-A from bisphenol-A using 2:1 molar ratio of bromide and bromate salts as brominating agent. To 0.50 kg (2.19 moles) of bisphenol-A in 1.50 liters of methylene chloride, a solution of 0.63 kg (6.14 moles) of sodium bromide, 0.44 kg (2.93 moles) of sodium bromate and 1 g of sodium lauryl sulfate in 2.5 liters of water was added. The flask was cooled to 10° C. by placing it in a cold water bath. To it, 0.90 liters (10.8 moles) of 12 N hydrochloric acid was added over 3 h under stirring. The contents were stirred for another 0.5 h and the separated solid product was filtered, washed twice with deionized water and dried in oven at 100° C. to give a yield of 0.85 kg of TBBPA. The organic layer was recycled in subsequent batches. The isolated yield of TBBPA (m.p. 178-180° C.) over three batches was 85.4%. Although the method has several advantages in that the brominating reagent is easy to handle, no catalyst is required, the bromine atom efficiency for the aromatic substitution reaction studied is as high as 95-100%, the main drawback of this method is that alkali bromide and bromate salts are individually much costlier than liquid bromine. Moreover the 4:2 stoichiometry of bromide:bromate is suitable for substitution reactions but not for addition of bromine across double bonds.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18]([O:22][CH3:23])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([O:30][CH:31]([F:33])[F:32])[C:26]([F:29])([F:28])[F:27])=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[CH3:55][N:56](C)C=O>C(=O)([O-])O.[Na+].[C-]#N.[Zn+2].[C-]#N.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]>[F:33][CH:31]([F:32])[O:30][CH:25]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[C:20]([CH3:21])=[N:19][C:18]([O:22][CH3:23])=[N:17][C:16]=4[CH3:24])[C:8]3=[N:9][C:10]=2[C:2]([C:55]#[N:56])=[CH:3][CH:4]=1)[C:26]([F:28])([F:27])[F:29]
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Br)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1nc(C)c(N2CCCn3c2nc2c(C#N)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 120 °C
Reaction time: 7 h
Yield: 52 %

Procedure:
A mixture of 9-bromo-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (254 mg, 0.474 mmol), zinc cyanide (557 mg, 4.74 mmol), 2-(di-tert-butylphosphino)biphenyl (14.1 mg, 0.0474 mmol), and tris(dibenzylideneacetone)dipalladium (43.4 mg, 0.0474 mmol) in N,N-dimethylformamide (2.4 ml) was stirred at 120° C. under nitrogen for 7 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 75-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as colorless crystals (118 mg, 0.245 mmol, 52%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[C@H:15]([CH2:17][CH3:18])C)=[O:12].[CH3:22]OC(=O)[C@H](CC(C)C)N>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:17]([CH3:18])[CH3:22])=[O:12]
Reactant: CC[C@H](C)[C@H](NC(=O)c1ccc2ccccc2c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Product: CC(C)C[C@H](NC(=O)c1ccc2ccccc2c1)C(=O)O
Yield: 98 %

Procedure:
The title compound is prepared analogously is prepared similar to N-(Naphthalene-2-carbonyl)-isoleucine (see above) in 98% yield, starting from leucine methylester.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:8])([CH3:3])[CH3:2]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Isopropoxy-N-(4-nitro-3-trifluromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:15][CH2:14][CH2:13][O:12]1.[C:16]12[CH2:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH:17]=2.N1CCCCC1.O>CN(C=O)C.C(O)=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:16]12[CH2:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH:17]2[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:15][CH2:14][CH2:13][O:12]1
Reactant: O=C1Nc2ccc(I)cc2C12OCCO2
Reactant: C1=C2CCC(C1)C2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C1Nc2ccc(C3CC4CCC3C4)cc2C12OCCO2
Temperature: 60 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
5'-Iodo-spiro[1,3-dioxolane-2,3'-[3H]indol]-2'(1'H)-one (3.5 g), bicyclo[2.2.1]heptene (1.15 g), piperidine (3.2 g) and bis(triphenylphosphine)palladium (II) acetate (0.35 g) in DMF (5 ml) and formic acid (1.1 ml) were heated and stirred under nitrogen at 60° C. for 1 hour. The mixture was cooled, water (50 ml) and ethyl acetate (50 ml) were added, and after 5 minutes the organic layer was separated, washed, dried and evaporated to dryness. The residue was purified by flash chromatography to yield the title compound (60%).