Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1
Reactant: COC(=O)CBr
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(=O)OC)cc3)nc2Cc2ccc(Br)cc2)cc1

Procedure:
4-[2-(4-Bromo-benzyl)-1-(4-Nitro-phenyl)-1H-imidazol-4-yl]-benzoic acid methyl ester (9.8 g, 20 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give 4-{2-(4-Bromo-benzyl)-1-[4-(methoxycarbonylmethyl-amino)-phenyl]-1H-imidazol-4-yl}-benzoic acid methyl ester.
Reaction SMILES: [O:1]1[CH:10]2[CH:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][N:6]1[CH2:7][CH2:8][CH2:9][CH:10]2[O:1][CH2:2][CH2:3][CH2:4][CH:5]12
Reactant: ClCCCBr
Reactant: C1COC2CCCNC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CCCC2OCCCC21
Temperature: 25 °C
Yield: 30 %

Procedure:
A mixture of octahydro-2H-pyrano[3,2-b]pyridine (0.50 g), 1-bromo-3-chloropropane (0.90 mL) and K2CO3 (0.70 g) in acetone was heated to reflux for 10 h, then cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 25:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (0.23 g, 30.00%), HPLC: 80.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 218.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([O:17][CH3:18])[N:4]=1.[NH2:19][CH2:20][CH2:21][OH:22].C(O)(=O)C>CCO>[CH3:1][O:2][C:3]1[C:8](/[C:9](/[NH:19][CH2:20][CH2:21][OH:22])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([O:17][CH3:18])[N:4]=1
Reactant: NCCO
Reactant: CCOC(=O)CC(=O)c1ccc(OC)nc1OC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NCCO)c1ccc(OC)nc1OC
Temperature: 90 °C
Yield: 98.2 %

Procedure:
To a solution of ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-oxopropanoate (500 mg, 1.97 mmol) in EtOH (4 mL) was added 2-aminoethanol (0.60 mL, 9.9 mmol) followed by acetic acid (0.63 mL, 9.9 mmol). The reaction mixture was heated to 90° C. for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was concentrated in vacuo and the crude material was purified by chromatography on silica eluting with 20-80% EtOAc/heptane to provide the title compound (573 mg, 98%) as a clear gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CS(C)=O>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:24][CH2:25][CH2:26][Cl:27])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: ClCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Temperature: 0 °C

Procedure:
First 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (131.5 g, 0.6 mol) is suspended in dimethylsulfoxide (900 ml) and mixed with potassium tert.butoxide (80.8 g, 0.72 mol) with stirring. After 10 minutes the solution obtained is added dropwise to 1-bromo-3-chloropropane (77 ml, 0.72 mol) in dimethylsulfoxide (300 ml), while cooling with ice water. After an hour the mixture is poured onto ice water. After a short time the greasy precipitate begins to crystallize. The precipitate is suction filtered, dissolved in acetone, precipitated again water water, suction filtered and dried.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1.Cl[CH2:15][C:16]1[C:17]([CH3:25])=[C:18]([CH3:24])[CH:19]=[C:20]([CH3:23])[C:21]=1[CH3:22]>CCO.O>[CH3:22][C:21]1[C:20]([CH3:23])=[CH:19][C:18]([CH3:24])=[C:17]([CH3:25])[C:16]=1[CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:8][CH:9]=1
Reactant: Cc1cc(C)c(C)c(CCl)c1C
Reactant: CCC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=O)c1ccc(OCc2c(C)c(C)cc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
NaOH (1.6 g, 40 mmol) is added to the solution of 1-(4-hydroxy-phenyl)-propan-1-one (3.0 g, 20 mmol) in EtOH (50 mL) and water (30 mL), followed by the addition of 3-Chloromethyl-1,2,4,5-tetramethyl-benzene (5.5 g, 30 mol). The resulting mixture is heated to turn into clear solution and stirred at room temperature overnight. The reaction is quenched by 1N HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water, brine, dried (MgSO4), concentrated and chromatographed to afford the titled compound as a white solid (4.0 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:9]([CH2:14][NH:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:29]=1[CH2:36]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:29]=1[CH2:36][N:15]([CH2:14][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1CNCc1ncccc1NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1NC(=O)OC(C)(C)C
Yield: 90.2 %

Procedure:
Using General Procedure A: A solution (2-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl ester (0.220 g, 0.65 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.245 g, 0.97 mmol), and DIPEA (0.23 mL, 1.32 mmol) in CH3CN (7 mL) was stirred at room temperature for 21 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.294 g (88%) of 2-{[(3-tert-Butoxycarbonylamino-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.58 (s, 9H), 2.20 (s, 3H), 3.76 (s, 2H), 3.86 (s, 3H), 4.05 (s, 2H), 4.09 (s, 2H), 7.09-7.16 (m, 2H), 7.44 (d, 1H, J=7.8 Hz), 7.55 (dd, 1H, J=8.1, 1.5 Hz), 7.89 (d, 1H, J=8.1 Hz), 8.04 (d, 1H, J=1.5 Hz), 8.09 (dd, 1H, J=1.5, 4.8 Hz), 8.51 (d, 1H, J=7.8 Hz), 8.63 (d, 1H, J=4.8 Hz).
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH:20]([CH:24]=O)[C:21]([O-])=[O:22])[CH:15]=[N:16][C:17]=1[CH3:18]>CO>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]2[C:21](=[O:22])[NH:6][C:5]([NH:4][N+:1]([O-:3])=[O:2])=[N:7][CH:24]=2)[CH:15]=[N:16][C:17]=1[CH3:18]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: Cc1cc(CC(C=O)C(=O)[O-])cnc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C

Procedure:
Nitroguanidine (6.05 g) was added to a solution of sodium methoxide (prepared from 1.45 g sodium) in dry methanol (65 ml) and the mixture was boiled under reflux for 0.75 hours. 3-(5,6-Dimethyl-3-pyridyl)-2-formylpropionate (14.3 g) was added and the mixture was boiled under reflux for 40 hours and evaporated to dryness. Water (40 ml) was added to the residue and the mixture was extracted with chloroform (discarded). The aqueous phase was adjusted to pH 6 with hydrochloric acid and the solid which separated out was filtered off and recrystallised from dimethylformamide-ethanol to give 5-(5,6-dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone m.p. 212°-213°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13](OS(C(F)(F)F)(=O)=O)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:29][CH2:30][C:31]1[O:35][C:34](=[O:36])[NH:33][N:32]=1.C(NC(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([NH:29][CH2:30][C:31]3[O:35][C:34](=[O:36])[NH:33][N:32]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc1OC
Reactant: NCc1n[nH]c(=O)o1
Solvent: CC(=O)N(C)C
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2cc3ncccc3c(NCc3n[nH]c(=O)o3)n2)cc1OC
Temperature: 70 °C

Procedure:
97 mg Trifluoromethanesulfonic acid 7-(3,4-dimethoxy-phenyl)-[1,6]-naphthyridine-5-yl ester (6.2), 30 mg 5-aminomethyl-3H-[1,3,4]oxadiazole-2-one (2.33) and 0.132 mL N,N-diisopropylamine were placed in dimethylacetamide at ambient temperature. The reaction was heated to 70° C. overnight. After this time the reaction was cooled to ambient temperature and additional 0.132 mL N,N-diisopropylamine were added. The reaction was heated to 90° C. for 6 h. After this time, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with additional ethyl acetate (×3) and the combined organic fractions were dried over sodium sulfate, filtered and the solvent was concentrated from the filtrate under reduced pressure. Purification by and then by silica gel chromatography (ethyl acetate/methanol: 100:0 to 95:5) provided the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][NH:23]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[H-].[Na+].C([O:32][C:33](=[O:37])/[CH:34]=[CH:35]/[CH3:36])C>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][N:23]4[CH:35]([CH3:36])[CH2:34][C:33]([OH:37])=[O:32])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: C/C=C/C(=O)OCC
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cc[nH]c3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(C(C)CC(=O)O)c3c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.6 %

Procedure:
To 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37 mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 ml), sodium hydride (8 mg of 60% dispersion, 0.2 mmol, 2 eq.) and (E)-but-2-enoic acid ethyl ester (0.025 ml, 0.2 mmol, 2 eq.). The reaction was stirred at room temperature for 18 hr and heated at 50° C. for 2 hr. To the reaction was added more (E)-but-2-enoic acid ethyl ester (0.050 ml, 0.4 mmol, 4 eq.) and the reaction heated at 80° C. for 22 hr. The reaction was partitioned between ethyl acetate (10 mL) and aqueous citric acid (10 mL), the organic layer separated and washed with brine (saturated NaCl), dried over magnesium sulfate, filtered, evaporated under reduced pressure. The crude material was dissolved in dimethylsulfoxide and purified by HPLC with a 50-100% acetonitrile in water gradient to yield 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-butyric acid as white solid (3 mg, 6%). LC-MS (ES) calculated for C26H23F2NO4, 451.2; found m/z 452 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[O:34][C:33]([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:32][CH:31]=1)CCC.CN(C)C=O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([C:30]3[O:34][C:33]([Si:35]([CH:39]([CH3:41])[CH3:40])([CH:42]([CH3:44])[CH3:43])[CH:36]([CH3:37])[CH3:38])=[N:32][CH:31]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](c1ncc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)o1)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
150 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole (synthesized according to the method described in WO2007/17096), and 25 mg of tetrakis(triphenylphosphine)palladium were added in turn to 5 ml of degassed dimethylformamide, and then the mixture was stirred at 100° C. for 2.5 hours under argon atmosphere. 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole was added thereto, and the mixture was further stirred for four hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 153 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine as pale orange oil.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[C:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]CC)=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:24](=[O:26])[CH2:23][N:20]1[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:22][CH2:21]1
Reactant: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
N-Methoxy-N-methylamine hydrochloride (4.3 g, 44.1 mmol) was dissolved in methylene chloride (25 mL). The solution was cooled to −78° C., and a solution of trimethylaluminum (44.1 mL, 44.1 mmol, 1 M in heptane) was slowly added. The mixture was stirred at 0° C. for 30 min and was allowed to warm to room temperature and stirred for 30 min. The mixture was then cooled to 0° C., and a solution of ethyl 4-Boc-piperazin-1-ylacetate (10 g, 36.8 mmol) was added dropwise. After 15 min, the cold bath was removed and stirring continued overnight. The mixture was diluted with ethyl acetate and water. The layers were separated, and the water layer extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated to provide N-methoxy-N-methyl-4-Boc-piperazin-1-ylacetamide as a light yellow oil (6.02 g, 57%) that solidified upon standing. The product was used without further purification.
Reaction SMILES: PP.C(O)C.[C:6]([NH:9][C:10](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[CH3:7].[H][H]>C(N(CC)CC)C>[C:6]([NH:9][C@H:10]([C:11]([OH:13])=[O:12])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[CH3:7]
Reactant: [H][H]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Agent: PP
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 82 %

Procedure:
3.1 mg of the complex of the formula [RhCl-1,5-cyclooctadiene]2, 57 mg of the diphosphine of Example 1 and 400 cm3 of ethyl alcohol are introduced under an argon atmosphere into a reactor. The mixture is stirred for 1 hour. 66.62 g of α-acetamidocinnamic acid and 25 microliters of triethylamine are then added and hydrogen is introduced under a pressure of 1 bar at 25°C. After 4 hours 30 minutes the hydrogenation is complete. After treatment to remove the catalyst similar to that of Example 5, N-acetylphenylalanine is obtained, after extraction, in 97% chemical yield and with an optical rotation [α]D22 of 42.5° (optical yield 82%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)=[O:11]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1

Procedure:
A reaction mixture of 50 g. of m-trifluoromethylacetophenone and 50 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours under anhydrous conditions and then evaporated in vacuo to a thick orange-red oil. Hexane is added, the mixture is chilled and the desired product is collected by filtration as yellow crystals, m.p. 60.5°-62° C.
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35](Br)[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1.[C:40]([O:44][C:45]([N:47]1[CH2:51][C@@H:50]([CH2:52][O:53][CH3:54])[CH2:49][C@H:48]1[C:55]([OH:57])=[O:56])=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35]([O:57][C:55]([C@@H:48]6[CH2:49][C@H:50]([CH2:52][O:53][CH3:54])[CH2:51][N:47]6[C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])=[O:56])[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(C(=O)COC(=O)[C@@H]3CC[C@H](C)N3C(=O)OC(C)(C)C)ccc2-4)N(C(=O)OC(C)(C)C)C1
Temperature: 40 °C
Yield: 65.3 %

Procedure:
(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (800 mg, 1.34 mmol) was treated with a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (485 mg, 1.87 mmol) in acetone (6 mL) and Cs2CO3 (306 mg, 0.94 mmol). The stirred reaction mixture was heated to 40° C. for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,5S)-2-(2-(9-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (680 mg, 65%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[CH2:18]C(O)=O.C(OCC)(=O)C>C(#N)C.[Cu-]=O>[C:9]1([O:8][C:7]2[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][CH:4]=[C:3]([CH3:18])[C:2]=2[F:1])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Agent: O=[Cu-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Temperature: 90 °C
Yield: 67 %

Procedure:
Copper(I) oxide (0.077 g, 0.536 mmol) was added to a solution of [2-fluoro-4-nitro-3-(phenyloxy)phenyl]acetic acid (1.560 g, 5.36 mmol) in acetonitrile (20 mL). The mixture was heated in a 90° C. oil bath for 1 h. The reaction mixture was cooled to RT and the solvent was evaporated. The residue was taken up in dichloromethane and filtered through Celite. Flash chromatography (ethyl acetate:hexanes) gave 2-fluoro-3-methyl-6-nitrophenyl phenyl ether (0.888 g, 63.7% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74 (dd, 1H), 7.27-7.36 (m, 2H), 7.18 (t, 1H), 7.09 (t, 1H), 6.92 (d, 2H), 2.38 (s, 3H). ES MS: m/z 246 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]1[NH:14][NH:13][C:12](=[O:15])[C:11]=1[C:16]([O:18]CC)=O.C(O)C>CN(C)C=O>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[C:10]3[NH:14][NH:13][C:12](=[O:15])[C:11]=3[C:16]([OH:18])=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)c1c(-c2cc(Cl)c(Cl)cc2N)[nH][nH]c1=O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=c1[nH][nH]c2c1c(O)nc1cc(Cl)c(Cl)cc12

Procedure:
0.63 g (0.002 mol) of ethyl 5-(2-amino-4,5-dichlorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate was dissolved in 10 ml of dimethylformamide and boiled under reflux for 1/2 hr. The mixture was cooled, the suspension was treated with 50 ml of ethanol, suction filtered and dried in a vacuum. Yield: 0.18 g (33%) of 7,8-dichloro-4-hydroxy-2,3-dihydro-1H-pyrazolo[4,3-c]quinolin-3-one as beige crystals; m.p. >350° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:43])[CH:34]=[C:35]([S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:43][C:33]2[CH:34]=[C:35]([S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCCS(=O)(=O)c1cc(O)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCS(=O)(=O)c1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)c1
Yield: 96.8 %

Procedure:
A similar procedure as described in Example 40, step 6 was used, starting from 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.14 g, 4.53 mmol), 3-bromo-5-(propane-1-sulfonyl)-phenol (1.15 g, 4.12 mmol), and potassium carbonate (1.14 g, 8.24 mmol) to afford 4-[3-{6-[3-bromo-5-(propane-1-sulfonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.67 g, 97%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C32H45BrO8S (M+Na)+ 691.1911, found 691.1905.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[CH:16]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:18])[CH3:17].C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:18][CH:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:8]2[NH:9][C:10]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[CH:7]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:17]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-nitroindole-2 -carboxylic acid (0.86 g), 1-[3-(N-isopropyl)amino-2-pyridinyl]piperazine (0.43 g), 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.45 g) and THF (4 ml), the title compound is obtained, mp 153°-154°.