Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH:3]([C:7]1[S:8][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:10][N:11]=1)[CH2:4][C:5]#[N:6].CS(Cl)(=O)=O.[C-:34]#[N:35].[Na+]>C(Cl)Cl.O>[N:15]1[C:14]2[NH:18][CH:19]=[CH:20][C:13]=2[C:12]([C:9]2[S:8][C:7]([CH:3]([CH2:2][C:34]#[N:35])[CH2:4][C:5]#[N:6])=[N:11][CH:10]=2)=[N:17][CH:16]=1
Reactant: [C-]#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(C(CO)CC#N)s3)ncnc21
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CCC(CC#N)c1ncc(-c2ncnc3[nH]ccc23)s1
Reaction time: 0.5 h
Yield: 7 %

Procedure:
A solution of the above prepared 4-hydroxy-3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]butanenitrile in DCM (12 mL) at 0° C. was treated sequentially with TEA (130 μL, 0.94 mmol) and methanesulfonyl chloride (73 μL, 0.94 mmol). After 1 hour reaction time, the mixture was diluted with water and extracted with ethyl acetate three times. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then dissolved in DMSO (5 mL) and sodium cyanide (110 mg, 2.3 mmol) was added. After 30 minutes, the mixture was diluted with water, extracted with ether, washed with water, brine and dried over sodium sulfate. Concentration and purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (14 mg, 7%). MS(ES):425(M+1).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.Br[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:37]5[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccncc1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nccc(-n2cnc3cc(Nc4ccncc4)ccc32)n1)c1ccccc1
Temperature: 100 °C
Yield: 8.1 %

Procedure:
2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (49.8 mg) was dissolved in DMF (2 mL). Diisopropylethylamine (79 μL) and 4-bromopyridine hydrochloride (43.2 mg) were added, and the mixture left heating overnight at 100° C. After 17 h added more diisopropylethylamine (79 μL) and 4-bromopyridine hydrochloride (40.2 mg) and continued heating at 100° C. for another 24 h. The volatiles were removed in vacuo and the residue purified on silica gel (2-5%(2M NH3 in MeOH)/CH2Cl2) to yield 5.0 mg of impure product that was purified by HPLC (Zorbax Rx-SIL, 60:40 hexanes:ethanol) to yield 3.0 mg of the title compound. Mass spectrum (ESI) 408.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2.C([Li])CCC.CCCCCC.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:31]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:19])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCc2cc(-c3ccc(F)cc3F)ccc2N1Cc1ccccc1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (130 mg, 0.50 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. in a dry flask equipped with an inlet of dry nitrogen was added fresh 1.6 M n-butyl lithium in n-hexane (0.6 mL, 0.96 mmol) with stirring. The reaction mixture was stirred at 0° C. for 2 hours, followed by addition of a second portion of 1.6 M n-butyl lithium in n-hexane (0.6 mL, 0.96 mmol), and the mixture stirred for another 2 hours. To this mixture was added slowly a solution of benzyl bromide (855 mg, 5.00 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C., stirred overnight, and allowed to warm to room temperature. The reaction was followed by LCMS and stirring was continued until all of the starting material was consumed. The reaction mixture was quenched by slow addition of saturated aqueous ammonium chloride (10 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (20 mL) and dilute aqueous ammonium chloride (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase successively washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture, which was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford 1-benzyl-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (62 mg, 0.18 mmol, 35%). LCMS mz 350.0 (M+H), 372.0 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; CDCl3) δ7.10-7.40 (m, 8H); 6.80-7.00 (m, 3H); 5.22 (s, 2H); 3.05 (m, 2H); 2.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>>[C:11]12([C:21]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=4)[NH:8][CH:9]=3)=[O:22])[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]3)[CH2:12]1)[CH2:20]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Brc1cnc2[nH]ccc2n1
Product: O=C(c1c[nH]c2ncc(Br)nc12)C12CC3CC(CC(C3)C1)C2

Procedure:
Adamantan-1-yl-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone was prepared starting from 2-bromo-5H-pyrrolo[2,3-b]pyrazine and adamantane-1-carbonyl chloride following general procedures as described in these Examples. MP 279-280° C., M+H=360.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH3:17])[CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(Cl)=[S:19].C(N(CC)CC)C>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:18]2=[S:19])=[C:6]([CH3:17])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)c1NCCCNCC(C)C
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(Cl)c1N1CCCN(CC(C)C)C1=S
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
To a solution of the diamine of Step A (3.82 g) in dry chloroform (55 mL) was added dropwise at 0° C. under nitrogen triethylamine (4.18 mL) followed by thiophosgene (2.6 g). The mixture was stirred in the cold for 15 minutes and then at room temperature for 60 minutes. It was then diluted with water and after adjusting the pH to 8 with triethylamine, was extracted with dichloromethane. The combined extracts were washed with 20% aqueous sodium chloride, dried over anhydrous potassium carbonate and evaporated to dryness. The residue was flash chromatographed (on Merck-60 flash silica gel, 85:15 hexane-EtOAc) to provide 3.37 g of the title compound. Trituration and sonication with hexane and hexane-ether yielded an off-white solid (2.26 g, 51.1%), m.p. 119-121° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.[CH:21]([C:24]1[C:29]([N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[CH:28][C:27]([NH2:35])=[C:26]([F:36])[CH:25]=1)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.FC1C(NC2CC(C)(C)NC(C)(C)C2)=NC(OC(C)C)=NC=1>CC(O)C>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:6]2[C:5]([C:19]#[N:20])=[CH:4][N:3]=[C:2]([NH:35][C:27]3[CH:28]=[C:29]([N:30]4[CH:34]=[N:33][N:32]=[N:31]4)[C:24]([CH:21]([CH3:22])[CH3:23])=[CH:25][C:26]=3[F:36])[N:7]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC(C)c1cc(F)c(N)cc1-n1cnnn1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC(C)(C)N1
Agent: CC(C)Oc1ncc(F)c(NC2CC(C)(C)NC(C)(C)C2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(C)c1cc(F)c(Nc2ncc(C#N)c(NC3CC(C)(C)NC(C)(C)C3)n2)cc1-n1cnnn1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-5-cyano-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine (0.05 g, 0.17 mmol, 1 equiv), 4-isopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (0.045 g, 0.204 mmol, 1.2 equiv), and para-toluenesulfonic acid monohydrate (0.025 g, 0.136 mmol, 0.8 equiv) in IPA (5 mL) were heated to 80° C. overnight. LCMS indicated desired product plus approximately 10% of 5-fluoro-2-isopropoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine byproduct. After cooling to ambient temperature, the crude mixture was quenched with 2M NH3/MeOH followed by concentrating to dryness and repeating once. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH (100:0 to 95:5 using 1% 2M NH3/MeOH increments) to provide the desired product which was recrystallized with DCM/IPA to give the title compound (45 mg, 55%) as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH2:8][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1oc(=O)oc1CBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1oc(CBr)c(CBr)o1

Procedure:
To a stirred solution of 1.22 g of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole in 30 ml of carbon tetrachloride was added 1.125 g of N-bromosuccinimide. The resulting solution was heated under reflux and irradiated for 15 minutes. The reaction mixture was filtered hot, cooled, and then evaporated in vacuo to give the title product as a yellow oil.
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].CO[C:6](=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].[OH2:15].CO>CO>[C:6]([NH:2][NH:3][C:6](=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9])(=[O:15])[C:7]1[C:13](=[CH:12][CH:11]=[CH:10][CH:8]=1)[OH:1]
Reactant: NN
Reactant: O
Reactant: COC(=O)c1ccccc1O
Solvent: CO
Product: O=C(NNC(=O)c1ccccc1O)c1ccccc1O
Reaction time: 3 h

Procedure:
0.5 kg (10 mol) hydrazine hydrate was heated with 3.040 kg (20 mol) salicylic acid methyl ester and 2.714 kg vaseline in a protective gas such as nitrogen or argon in the apparatus according to the invention. The water-methanol mixture produced was continuously distilled-off from the reaction mixture. After about three hours, the reaction temperature had risen to 120° C. and approximately half of the quantity of methanol expected theoretically and the entire amount of water were distilled off (0.5 kg). The hydrazide was present in the vaseline as a crystal product in paste. The heating was continued after 30 g boron trioxide was added and the temperature was kept at 150° C. The remaining methanol (0.320 kg) was distilled off. After about three hours, the reaction was complete as determined by the amount of methanol distilled off.
Reaction SMILES: [CH3:1][C@:2]([C:11]([NH:13][CH2:14][C:15]([O:17]CC)=O)=[O:12])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3]>C(O)(CC)C.C1(C)C=CC=CC=1>[CH2:4]([C@@:2]1([CH3:1])[NH:3][C:15](=[O:17])[CH2:14][NH:13][C:11]1=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CNC(=O)[C@](C)(N)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCC(C)O
Product: C[C@]1(Cc2ccccc2)NC(=O)CNC1=O
Reaction time: 21 h
Yield: 97.4 %

Procedure:
A solution of (α-methyl-(R)-phenylalanyl)glycine, ethyl ester (0.63 g, 2.4 mmol) in sec-butanol (14 ml) and toluene (7 ml) was stirred at reflux. After 21 h, the solvent was removed in vacuo and the residue azeotroped with toluene (3×) to afford the product (0.51 g, 100% yield) as a white solid. MS (ESI) 219 (M+H). This was used in the next step without further purification.
Reaction SMILES: [H][H].[CH2:3]([N:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1)[CH3:4].[CH3:12][NH2:13]>[Pt](=O)=O.CO>[CH2:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:13][CH3:12])[CH2:6]1)[CH3:4]
Reactant: [H][H]
Reactant: CN
Reactant: CCN1CCCC(=O)C1
Agent: O=[Pt]=O
Solvent: CO
Product: CCN1CCCC(NC)C1

Procedure:
A suspension of 0.25 g. of platinum dioxide in 20 ml. of methanol was shaken under 30 p.s.i. of hydrogen for one hour. To this activated catalyst was added a solution of 7.9 g. (48 mmoles) of 1-ethyl-3-piperidone and 3.1 g. (100 mmoles) of methylamine in 40 ml. of methnol. This mixture was shaken under about 50 p.s.i. of hydrogen for 1.5 hours, then filtered. The solvent was distilled off the filtrate at atmospheric pressure. The residue was then distilled at reduced pressure to give 1-ethyl-3-methylaminopiperidine, b.p. 88°-90.5° C. at 28 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[N:4][C:3]=1[NH2:24].[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:27]=1[S:36]([NH:24][C:3]1[N:4]=[N:5][C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[CH3:1])(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Cc1cc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)nnc1N
Product: Cc1cc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)nnc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Cl

Procedure:
Can be prepared from 4-methyl-6-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridazin-3-ylamine and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride. 1H NMR (CDCl3) 8.30 (1H, d) 7.75 (2H, m) 7.70(1H, s) 7.6(3H, m) 7.05(1H, s) 3.0(4H, m)2.1 (3H, s) 1.6(4H, m) 1.40(2H, m) LCMS Polarity/Scan type: Negative Q1 Scan. M.wt. 605(-H), 607(-H). Retention time 7.39 minutes. HPLC MS8 Retention time 5.36 minutes.
Reaction SMILES: [C:1](N)(=O)C(C)=C.[Na].N(C(C#N)(C)CCC(O)=O)=NC(C#N)(C)CCC(O)=O.C(OCC)(=O)C=C.[C:35]([O:40][CH2:41][CH:42]1O[CH2:43]1)(=[O:39])[C:36]([CH3:38])=[CH2:37]>O>[C:35]([O:40][CH2:41][CH:42]([CH3:43])[CH3:1])(=[O:39])[C:36]([CH3:38])=[CH2:37]
Reactant: C=C(C)C(N)=O
Reactant: C=C(C)C(=O)OCC1CO1
Agent: C=CC(=O)OCC
Agent: CC(C#N)(CCC(=O)O)N=NC(C)(C#N)CCC(=O)O
Agent: [Na]
Solvent: O
Product: C=C(C)C(=O)OCC(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
is added within 3 hours at 80° C. Thereafter a solution of 10 g of methacrylamide and 0.6 g of the sodium salt of 4,4'-azobis-(4-cyanovaleric acid) in 300 ml of water and a monomer mixture consisting of 50 g of ethyl acrylate and 45 g of glycidyl methacrylate are added simultaneously. After stirring for 60 minutes at 80° C. one obtains a coagulate-free dispersion with a solid content of 20%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Yield: 57.3 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)phenylboronic acid (2.2 g, 8.5 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (1.79 g, 10.2 mmol), Pd(PPh3)2Cl2(179 mg, 0.26 mmol), K2CO3 (2.35 g, 17 mmol), and Cu2O (37 mg, 0.26 mmol) in THF (6 mL) and H2O (3 mL) in a tube sealed under N2 was heated at 80° C. for 4 h, cooled to rt and partitioned between EA and water, extracted with EA (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE to afford 1,3-bis(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.5 g, yield 55%) as oil.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:17]([N:24]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]1=[O:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O.C(Cl)Cl>[CH2:17]([N:24]1[C:28](=[O:29])[CH:27]2[CH:26]([C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)([OH:5])[C:3]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=3[CH2:1]2)[C:25]1=[O:30])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: Cc1ccc(C)c(C(=O)c2ccccc2)c1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)C(O)(c1ccccc1)C1C(=O)N(Cc3ccccc3)C(=O)C1C2
Yield: 52.9 %

Procedure:
A solution of 35 g of 2,5-dimethylbenzophenone and 31.5 g of N-benzylmaleimide in 500 cc of acetone or methylene chloride is irradiated with a mercury high pressure lamp through a pyrex filter, until all the material has reacted (20 to 130 hours), filtration and concentration by evaporation are then effected. After crystallization from ether, the residue yields 35 g of 2-benzyl-3a,4,9,9a-tetrahydro-6-methyl-4-phenyl-benz[f]isoindolin-4-ol-1,3-dione, having a M.P. of 162-164°, which are dissolved in 170 cc of trifluoroacetic acid. The solution is stirred at 25° for 3 hours and concentrated by evaporation. After crystallization from methylene chloride/methanol, the residue yields 30 g of (9aRS)-2-benzyl-9,9a-dihydro-6-methyl-4-phenyl-benz[f]isoindoline-1,3-dione, having a M.P. of 156°-158°.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.S(=O)(=O)(O)O.[CH3:22]O>C(OCC)C>[CH3:22][O:15][C:14]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[CH:4]=1)=[O:16]
Reactant: CO
Reactant: COc1ccc2cc(O)c(C(=O)O)cc2c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)c1cc2cc(OC)ccc2cc1O

Procedure:
To a solution of 3-hydroxy-7-methoxy-naphthalene-2-carboxylic acid (2.5 g, 11.45 mmol) in 50 mL methanol was added 0.3 mL of concentrated sulfuric acid. The resulting mixture was heated at reflux for 18 hours, then cooled and diluted with diethyl ether. The organic phase was washed with water and saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered and concentrated under reduced pressure to give 2.51 g of 3-hydroxy-7-methoxy-naphthalene-2-carboxylic acid methyl ester, MP=129-131° C.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=NC1C=CC=CC=1)C1C=CC=CC=1.S(=O)(=O)(O)[OH:31]>>[CH:1](=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C(=Nc1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: CC(=Nc1ccccc1)c1ccccc1
Product: Nc1ccccc1
Product: O=Cc1ccccc1

Procedure:
German Patent Specification No. 72173 discloses a method for producing an aromatic primary monoamine, such as p-nitroaniline, which comprises nitrating a benzalaniline (benzylideneaniline) which may be represented by the following formula ##STR5## wherein r represents a methyl or methoxy group and m is 0, 1 or 2, with nitric acid in sulfuric acid, and then hydrolyzing the resulting product. Example 1 of this patent document states that p-nitroaniline was obtained in a yield of 90% from benzalaniline. The German patent, however, does not at all refer to the use of an α-substituted compound of benzalaniline including the α-methylbenzalaniline represented by formula (III) given hereinabove. Furthermore, it is completely silent on the use of solvents other than sulfuric acid in the nitration reaction. The starting benzalaniline used in this patent can be obtained by condensation between benzaldehyde and aniline. Benzaldehyde, however, is not available at low cost because it is chemically unstable and its production requires a complex process and is costly. Hence, the starting benzalaniline is unsatisfactory for industrial production of p-nitroaniline at low cost.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29].CCOC(C)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([O:8][NH:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:28]([N:27]([CH3:31])[CH3:26])=[O:29])=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)ONCCc1ccc(O)cc1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc(CCNOC(=O)OC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
N-t-butoxycarbonyloxy 2-(4-hydroxyphenyl)ethylamine (2.53 g, 10.7 mmol), Et3N (2.96 mL, 2 eq.), a catalytic amount of DMAP (131 mg) and dimethylcarbamyl chloride (2.0 mL, 2 eq) are mixed in CH2Cl2 at 0° C. The resulting mixture is stirred overnight. EtOAc is added to dilute the reaction mixture and then is washed with 1N HCl, sat.Na2CO3 and brine. Solvent is removed under reduced pressure to give pure t-butoxycarbonyloxy 2-[4-(N,N-dimethylaminocarbonyloxy)phenyl]ethylamine as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:7]2[N:8]=[CH:9][C:10]([S:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:13])=[O:12])=[C:6]2[NH:5][CH:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>C1COCC1.O>[CH2:29]([N:5]1[CH:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][C:2]([CH3:28])([CH3:1])[N:7]2[N:8]=[CH:9][C:10]([S:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:12])=[O:13])=[C:6]12)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(CS(=O)(=O)c2cnn3c2NC(c2ccccc2)CC3(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CS(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of 0.34 g (0.86 mmol) of 5 in 10 mL of THF at 0° C. was added 0.128 mL (1.07 mmol) of benzyl bromide followed by 0.034 g (0.86 mmol) of sodium hydride (60% dispersion in mineral oil). The reaction was allowed to warm to room temperature after 30 min and stirred for an additional 30 min before being quenched with water. The quenched reaction was diluted with five volumes of water and extracted with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 70% hexanes/AcOEt to give 0.39 g (93%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.27 (s, 3H), 1.52 (s, 3H), 1.93-2.05 (m, 2H), 2.27 (s, 3H), 3.83 (d, J=15.8 Hz, 1H), 4.18-4.30 (m, 3H), 5.51 (d, J=15.8 Hz, 1H), 6.98-7.00 (m, 2H), 7.09 (dd, J=8.2, 12.1 Hz, 4H), 7.17 (d, J=6.8 Hz, 2H), 7.26-7.30 (m, 3H), 7.32-7.40 (m, 3H), 7.47 (s, 1H)
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15]C(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=O)C.[NH2:27][CH:28]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]1>>[C:13]([N:11]1[CH2:12][C:8](=[CH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[C:20]([NH:27][CH:28]1[CH2:29][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31]1)=[O:22])(=[O:15])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CC(=O)Cl
Product: CC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)NC1CN(C(=O)OC(C)(C)C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, acetyl chloride, and tert-butyl 3-amino-1-azetidinecarboxylate the title compound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=400.2.