Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][N:11](C(OC(C)(C)C)=O)[CH:12]=2)=[C:6]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[N:27]([CH2:39][CH2:40][OH:41])[CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH3:38])[CH:32]=4)[N:30]=3)[CH2:22][CH2:21]2)[N:5]=[CH:4][N:3]=1.Cl>CO.O1CCOCC1>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[N:27]([CH2:39][CH2:40][OH:41])[CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH3:38])[CH:32]=4)[N:30]=3)[CH2:22][CH2:21]2)[C:7]=1[C:8]1[CH:12]=[N:11][NH:10][CH:9]=1
Reactant: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2cn(CCO)c(C3CCN(c4ncnc(N)c4-c4cn[nH]c4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-butyl 4-(4-amino-6-(4-(4-(4-fluoro-3-methylphenyl)-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-1-carboxylate (10.00 mg; 0.02 mmol) in 0.5 ml methanol was added 0.5 ml 4.0M HCl in dioxane, stirred at RT for 3 hrs, showed clean desired by LC-MS. Removed off solvent, got white solid as title compound. LC-MS: (M+1=463, obsd.=463).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1)=[O:4].C(N(C(C)C)CC)(C)C.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][CH2:37][CH2:38][NH2:39]>C1COCC1>[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][CH2:37][CH2:38][NH:39][CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)CC1CCN(C(=O)CBr)Cc2ccccc21
Reactant: NCCNc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(C(=O)CNCCNc2ccccn2)Cc2ccccc21
Reaction time: 18 h

Procedure:
To a stirring solution of methyl 2-(2-(2-bromoacetyl)-1H,3H,4H,5H-benzo[e]azepin-5-yl)acetate in THF (0.2 M), was added diisopropylethylamine (1.5 eq) and 2-(2-pyridylamino)-1-aminoethane (1.2 eq). The reaction was stirred for 18 hr, followed by concentration by rotary evaporation and the product was purified by flash chromatography (10% MeOH/CH2Cl2). EI-MS m/z 397 (M−H)−
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:4].C(N(CC)CC)C.Cl[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.C(Cl)(Cl)Cl>[F:15][C:2]([F:14])([F:1])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][N:11]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:12][CH2:13]1)=[O:4]
Reactant: CCOC(=O)CCl
Reactant: O=C(NCCN1CCNCC1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(CCNC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
1-(2-Trifluoroacetamidoethyl)piperazine (56 g, 0.25 mol), 37.5 ml of triethylamine, and 30.3 g (0.27 mol) of ethyl chloroacetate were combined in 200 ml of DMF. The temperature rose to 70° C. in 5 minutes. The reaction was allowed to stir overnight at room temperature, then filtered to remove triethylammonium hydrochloride. The solvent was removed, leaving an oily residue which was taken up in 250 ml of CHCl3 and washed with two 300 ml portions of H2O. The organic phase was separated, dried and evaporated to give 51 g of ethyl 4-(2-trifluoroacetamidoethyl)piperazine-1-acetate as a tan solid. This was not characterized. It was hydrolyzed by stirring for 6 hours in a solution of 20 g of KOH in 250 ml of 4:1 MeOH:H2O. The product was purified by chromatography on 1400 g of silica gel, eluting with 4:4:1 (v/v/v) CHCl3 :MeOH:conc. NH4OH. Recrystallization from MeOH gave 22.5 g of 4-(2-aminoethyl)piperazine-1-acetic acid as white crystals, m.p. 225° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=O)[CH:6]=[N:7][CH:8]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].N1CCCCC1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1>C(O)C>[NH2:14][C:13]1[O:29][C:25]2[C:26]([CH:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:12]=1[C:11]#[N:15])=[CH:27][CH:28]=[C:23]([NH2:22])[CH:24]=2
Reactant: Nc1cccc(O)c1
Reactant: COc1cncc(C=O)c1
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cncc(C2C(C#N)=C(N)Oc3cc(N)ccc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a mixture of 5-methoxypyridine-3-carboxaldehyde (69.2 mg, 0.5 mmol) and malononitrile (34 mg, 0.5 mmol) in ethanol (2.5 mL) was added piperidine (0.1 mL, 1 mmol) and 3-aminophenol (60 mg, 0.55 mmol). The mixture was stirred for 2 h under argon at room temperature. The solvent was evaporated and the residue was purified by chromatography on silica gel with hexane: EtOAc (4:1˜1:1) as eluant, yielding 44 mg of (31%) the title compound. 1H NMR (CD3OD): 8.02 (s, 1H), 7.88 (s, 1H), 6.93 (s, 1H), 6.75 (s, 1H), 6.51 (d, J=8.4 Hz, 1H), 6.18 (d, J=8.4 Hz, 1H), 6.09 (s, 1H), 5.15 (br, 1H), 4.49 (s, 1H), 3.66 (s, 3H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[C:19]2[C:18](=O)[O:17]C(=O)[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.CN.C1COCC1.C[N:30]([CH:32]=O)C>C(Cl)Cl.O>[NH2:15][C:14]1[C:19]([C:18]([NH:30][CH3:32])=[O:17])=[C:10]([F:9])[C:11]([Br:8])=[CH:12][CH:13]=1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)N1Br
Agent: CN
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(N)ccc(Br)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
NBS (9.42 g, 52.9 mmol) was added to a cold (0° C.) solution of 5-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 27E, 9.2 g, 50.8 mmol) in DCM and DMF (120 mL+60 mL) over the course of 40 min. The reaction mixture was stirred at 0° C. for 2 h then allowed to warm to RT. After 30 min, the DCM was removed in vacuo. The remaining reaction mixture was cooled −10° C., treated with a solution of 2M methyl amine in THF (50.8 mL, 101.6 mmol) and allowed to stir for overnight at room temperature. The reaction mixture was poured to water (240 mL) and the resulting suspension was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layer was washed with water (3×100 mL), dried (Na2SO4) and concentrated to give crude residue which was purified by column chromatography (20% ethyl acetate/hexanes) to afford 4 g of the title compound (32% over two steps). 1H NMR (CDCl3, 500 MHz) δ=2.98 (d, J=4.5 Hz, 3H), 5.90 (brs, 2H), 6.38 (d, J=9.0 Hz, 1H), 6.55 (brs, 1H), 7.24-7.27 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)#[CH:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC1(O)CCOCC1
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(C#CC3(O)CCOCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (80) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 4-ethynyltetrahydro-2H-pyran-4-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.76 (d, J=8 Hz, 7.68 (s, 1H), 7.57 (m, 3H), 7.42 (d, J=9 Hz, 1H), 7.30 (m, 2H), 5.16 (s, 1H), 3.85 (br m, 2H), 3.65 (br m, 2H), 2.60 (s, 3H), 1.92 (br m, 2H), 1.77 (br m, 2H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 3.5 min run): tR (min)=2.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C:13]([O:15][C:41]2[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=2[F:35])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCC(=O)O)cc1OC
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(SCC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1OC
Yield: 99.8 %

Procedure:
A solution of 2-(3,4-dimethoxyphenylmercapto)ethanoic acid (1.71 g, 7.5 mmol), N-methylmorpholine (0.99 ml, 9.0 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.87 g, 9.7 mmol) and pentafluorophenol (2.76 g, 15.0 mmol) in DCM (100 ml) was stirred at room temperature overnight. The solution was washed with 2M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, dried, filtered and concentrated to give crude pentafluorophenyl 2-(3,4-dimethoxyphenylmercapto)ethanoate (2.95 g, 99%) as pink oil which was used directly in the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12]([F:15])([F:13])[F:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Cl)cc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-acetamido-5-chlorobenzotrifluoride (890 mg, 3.74 mmol) in concentrated H2SO4 (4 mL) at 0° C. was added dropwise 70% HNO3 (0.5 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (15 g). The precipitate was collected by filtration, affording 700 mg of crude 2-acetamido-5-chloro-3-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to give 559 mg of pure 2-acetamido-5-chloro-3-nitrobenzotrifluoride as yellow needles. Mp 190°-2° C., 1H NMR (CDCl3): δ 2.210 (s, 3H), 7.357 (s, 1H), 7.896 (d, 1H, J=2.1 Hz), 8.105 (d, 1 H, J=2.1 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[F:20][C:21]([F:32])([F:31])C1C=CC=C2C=1NC=C2>>[F:20][C:21]([F:32])([F:31])[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: FC(F)(F)c1cccc2cc[nH]c12
Product: CC1(C)OB(c2cc3cccc(C(F)(F)F)c3[nH]2)OC1(C)C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-trifluoromethyl-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:11]=2)[CH:3]=1.[OH:28]OS([O-])=O.[K+].[OH2:34]>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:9])(=[O:28])=[O:34])[N:5]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:11]=2)[CH:3]=1
Reactant: O=S([O-])OO
Reactant: O
Reactant: CSc1nc(Cl)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)n1
Agent: [K+]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nc(Cl)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)n1
Yield: 87 %

Procedure:
A mixture of Example 42a (3.0 g, 7.20 mmol) and OXONE® (45 g, 48.8 mmol) in ethyl acetate (400 ml) and H2O (1 mL) was stirred at 80° C. for 16 hours. The reaction mixture was filtered and the solids were washed with ethyl acetate (about 600 mL). The filtrate was concentrated in vacuo to afford the title compound (2.8 g, 87% yield).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][C:3]=1[CH3:14].[F:15][C:16]1[CH:17]=[CH:18][C:19](B2OC(C)(C)C(C)(C)O2)=[C:20]2[C:24]=1[C@H:23]([O:25][C:26]1[CH:39]=[CH:38][C:29]3[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=1)[CH2:22][CH2:21]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:14][C:3]1[CH:4]=[C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:19]1[CH:18]=[CH:17][C:16]([F:15])=[C:24]2[C:20]=1[CH2:21][CH2:22][C@H:23]2[O:25][C:26]1[CH:39]=[CH:38][C:29]2[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1
Reactant: Cc1cc(-c2nnn[nH]2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nnn[nH]6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-bromo-3,5-dimethylphenyl)-1H-tetrazole and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.05 min; Mass spectrum (ESI+): m/z=515 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.[OH-].[Na+]>O1CCCC1.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>[CH:1]1[C:14]2[CH:13]=[C:12]([C:19]3[CH:20]=[C:21]([C:26]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:29]=[C:28]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[N:27]=4)[CH:22]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4cc5ccccc5c5ccccc45)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Yield: 66 %

Procedure:
In a stream of argon, 1.37 g (6.16 mmol) of 9-phenanthreneboronic acid, 1.20 g (2.57 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 72.1 mg (0.103 mmol) of dichlorobis(triphenylphosphine)palladium were suspended in 75 mL of tetrahydrofuran, and the temperature of the obtained suspension was elevated to 70° C. 4.81 mL (19.3 mmol) of an aqueous 4N NaOH solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 5 hours. The resultant reaction mixture was left to stand to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was recrystallized from o-xylene to give 1.13 g of the target 2-[3,5-di(9-phenanthryl)phenyl]-4,6-diphenyl-1,3,5-triazine as grayish white solid (yield: 66%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].N([O-])=[O:12].[Na+].FC(F)(F)C(O)=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:12])#[N:2]
Reactant: O=N[O-]
Reactant: N#Cc1cccc(CN)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(CO)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
m-Cyanobenzylamine (13.2 g), sodium nitrite (10.4 g), and dimethylformamide (100 ml) were mixed together, and the mixture was vigorously stirred at room temperature. Trifluoroacetic acid (22.8 g) was added dropwise to the mixture over one hour. After completion of addition, the mixture was further allowed to react at 100° C. for one hour. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.9 g of m-cyanobenzyl alcohol (bp. 128-130° C./400 Pa) (yield 52%). The purity of the product was 98%.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].F[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10](F)[C:9]=1[N+:16]([O-:18])=[O:17].[OH2:19]>C1(C)C=CC=CC=1>[F:14][C:12]1[CH:13]=[C:8]([O:19][CH2:3][C:2]([F:6])([F:5])[F:1])[C:9]([N+:16]([O-:18])=[O:17])=[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:11]=1
Reactant: OCC(F)(F)F
Reactant: O
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1c(OCC(F)(F)F)cc(F)cc1OCC(F)(F)F
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of 2,2,2-trifluoroethanol (28.2 g, 282.0 mmol) in toluene (120 mL) n-BuLi (1.6 M in hexane, 8.0 g, 80 mL, 125.0 mmol) was added at 0° C. and the reaction mixture warmed up to 25° C. A solution of 1,3,5-trifluoronitrobenzene (10.0 g, 56.5 mmol) in toluene (50 mL) was added dropwise. The reaction mixture was refluxed for 30 h and then poured into water (100 mL). The reaction mixture was extracted with EtOAc (3×100 mL). The organic layers were combined and dried over MgSO4. The solvent was evaporated under reduced pressure to give 5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene as a brown oil (18.0 g, 95%). The product was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 6.47 (d, J=9.4 Hz, 2H), 4.40 (q, J=8.0 Hz, 4H).
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([C:2]1[S:1][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:17]
Reactant: O=C(Cl)CCCCl
Reactant: O=C1NCCCc2ccsc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCCl)c1cc2c(s1)C(=O)NCCC2
Reaction time: 1.33 h
Yield: 36.9 %

Procedure:
To a solution of 2 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 2.5 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride under cooling. The mixture was stirred for 80 minutes, refluxed under heating and poured into water, and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was crystallized from ethyl acetate-isopropyl ether to give 1.2 g of 2-(4-chlorobutyryl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as white crystals, m.p. 163°14 165° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10].C[Si](C)(C)[N-:13][Si](C)(C)C.[K+].O.S(=O)(=O)(O)O.[C:27]1([CH3:33])[CH:32]=CC=C[CH:28]=1>C(OCC)(=O)C>[F:8][C:4]1[C:3]([O:9][CH3:10])=[C:2]([C:27]([CH3:33])([CH3:32])[C:28]#[N:13])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1c(F)cccc1F
Reactant: Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(F)cccc1C(C)(C)C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
10 g (69.39 mol) of 2,6-difluoroanisole is dissolved in 200 ml of toluene and mixed at room temperature with 5.75 g (83.27 mmol) of isobutyric acid nitrile. 166.5 ml of a 0.5 molar solution of potassium hexamethyldisilazide in toluene is added in drops within 35 minutes. In this case, a slight temperature rise to 27.5° C. takes place. After 16 hours of stirring at room temperature, the reaction mixture is mixed with 200 ml of water and 400 ml of ethyl acetate and acidified with 10% sulfuric acid to a pH of 4. The organic phase is separated, and the aqueous phase is shaken once with ethyl acetate (200 ml). The combined organic extracts are shaken with water and brine. After the solvent is dried, filtered and spun off, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 7.66 g (57.1%) of the desired compound is isolated.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CS(C)=O>[O:11]=[C:9]([CH3:10])[CH:8]([C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:12])[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CBr
Reactant: CC(=O)CC(=O)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CC(C(C)=O)C(=O)c1ccccn1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A solution of 3.38 g (20.7 mmol) of 1-(pyridin-2-yl)butane-1,3-dione dissolved in dimethyl sulfoxide was slowly added dropwise to 0.911 g (22.78 mmol) of sodium hydride in 25 ml of dimethyl sulfoxide such that the temperature did not exceed 30° C. The mixture was stirred at 20° C. for another 30 minutes. 3.486 g (22.78 mmol) of methyl bromoacetate in a little dimethyl sulfoxide were then slowly added dropwise at 0° C. The mixture was stirred at 20° C. for a further 4 hours. The reaction mixture was poured into ice-water and extracted with dichloromethane. The organic phase was repeatedly washed with water. Drying of the combined organic phases, removal of the solvent under reduced pressure and chromatography of the residue gave 3.48 g of product (71.4% of theory); NMR (CDCl3, 400 MHz): 2.4 (s, 3H); 2.9 (d, 1H); 3.05 (d, 1H); 3.69 (s, 3H); 5.49 (dd, 1H); 7.50 (m, 1H); 7.86 (m, 1H); 8.07 (m, 1H); 8.7 (m, 1H).
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].C(N(CC)CC)C.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>C1(C)C=CC=CC=1>[C:33]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:36])[CH2:34][CH3:35]
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Yield: 88.3 %

Procedure:
To a 300-ml four-necked flask equipped with a thermometer, stirring apparatus and condenser were added 34.51 g (0.10 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 50 g of toluene and 11.13 g (0.11 mole) of triethylamine. After replacing the air in the container with nitrogen, 10.20 g (0.11 mole) of propionyl chloride was added dropwise. After completion of the dropwise addition, after-treatment was carried out in the same manner as in Comparative example 1 to obtain 35.0 g of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monopropionate as a white crystal. Melting point, 108°-111° C. Yield, 88.4%.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:27]([C:23]1[S:22][CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1cccs1

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2-thiophenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give thiophene-2-sulfonic acid isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amide as a light yellow solid. MS: 487.0 ([M+NH4]+)