Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=O>O1CCCC1>[OH:8][CH2:9][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cccc(-c2ccc(O)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccc(O)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of lithium aluminium hydride (1 M in ether, 2.5 ml) was added to dry tetrahydrofuran (10 ml) and the solution cooled to 0° C. A solution of 3'-methoxycarbonylbiphenyl-4-ol in (0.57 g) in tetrahydrofuran (10 ml) was then added and the resulting solution stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of water (0.1 ml) followed by aqueous sodium hydroxide (50%, 0.1 ml) and then water (0.5 ml). The mixture was acidified with dilute aqueous hydrochloric acid (2 M) and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as a white solid (0.48 g).
Reaction SMILES: [C:1]([C:3]([OH:6])([CH3:5])[CH3:4])#[N:2].[Cl:7][CH2:8][C:9](Cl)=[O:10].Cl>O>[Cl:7][CH2:8][C:9]([O:6][C:3]([C:1]#[N:2])([CH3:5])[CH3:4])=[O:10]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(O)C#N
Agent: Cl
Solvent: O
Product: CC(C)(C#N)OC(=O)CCl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.85 g of 2-cyano-2-propanol and solution F were mixed and stirred for 15 minutes at 0° C. To the mixture was added 0.8 ml of chloroacetic chloride and the solution was stirred for 5 minutes at 0° C., additional 2 hours at room temperature and further 1 hour at 70° C. Then, to the reaction mixture was added 1N hydrochloric acid and water, and extracted with ethyl acetate. The organic layer was washed successively with water and aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 0.25 g of (1-cyano-1-methylethyl) chloroacetate.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[CH:7][CH:6]=1>C(Cl)Cl>[CH3:1][N:2]([C:12](=[O:13])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=1)[NH2:3]
Reactant: CNN
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: ClCCl
Product: CN(N)C(=O)Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a −78° C. stirred solution of methyl hydrazine (11 mL, 208.5 mmol) in CH2Cl2 (100 mL) is added dropwise a solution of commercially available 4-fluorophenyl-acetyl chloride (12 g, 69.5 mmol) in CH2Cl2 (200 mL). The reaction mixture is stirred for 2 hours at −78° C. and is then slowly warmed to room temperature. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to give a pale yellow oil. Purification over silica (EtOAc) affords 7.6 g (61% yield) of the desired product: 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 6.99-6.92 (m, 2H), 3.87 (s, 2H), 3.190 (s, 2H), 3.11 (s, 3H); ESI/MS: 183.1 (M+H).
Reaction SMILES: [B:1]([OH:10])([OH:9])[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:11]Br>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([B:1]([OH:10])[OH:9])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: Cc1ccc(B(O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: OB(O)c1ccc(CBr)cc1

Procedure:
Into a solution of p-tolylboronic acid (2.0 g, 1.47×10-2 mol) in 40 ml of carbon tetrachloride was added 5 ml of a bromine solution prepared by dissolving 2.4 g of bromine (1.5×10-2 mol) in 20 ml of CCl4. The reaction was initiated by illumination with a 150 watt light bulb. The bromine color faded in 5 minutes. The remaining bromine solution was added after 15 minutes. The precipitate that formed was isolated by filtration, and recrystallized from chloroform. M.P. 154°-156° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C=Nc1ccccc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)Nc1ccccc1
Yield: 32 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with phenyl isocyanate (660 mg, 5.51 mmol). Recrystallization from acetonitrile provided 670 mg of N-(3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-phenylurea as light orange needles, m.p. ˜40° C. Analysis: Calculated for C23H26N6O2. 1.0 C2H3N: %C, 65.34; %H, 6.36; %N, 21.34; Found: %C, 65.13; %H, 6.26; %N, 21.35.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:33])[C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[C:23]([F:33])[C:24]=1[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Reactant: OB(O)c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(-n2ncc3c(OCc4ccccc4)cccc32)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 4-[(phenylmethyl)oxy]-1H-indazole (D1) (280 mg, 1.25 mmol) in dichloromethane (20 mL) was added {3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid {DE patent application 4236105} (660 mg, 2.50 mmol), pyridine (0.202 mL, 2.50 mmol), copper acetate (340 mg, 1.88 mmol) and powdered 4A molecular sieves (500 mg). The reaction mixture was stirred at room temperature in the presence of air for 6 days. Celite was added to the mixture then the mixture was filtered through a pad of celite and then the filtrate was washed with water. After separation of the layers, the aqueous phase was re-extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 5-100% ethyl acetate in hexane to yield the title compound (D35 (257 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.Cl.[NH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[OH:31]>>[OH:31][C@H:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[NH:25][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Agent: Cl
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N[C@H]2CCC[C@@H]2O)nc1
Yield: 78 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using trans-2-aminocyclopentanol hydrochloride instead of isopropylamine, to the title compound (100 mg, 78%), which was obtained as a white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31](O)=[O:32])(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>>[C:1]([O:5][C:6](=[O:12])[CH2:7][N:8]([CH2:9][CH2:10][OH:11])[C:31](=[O:32])[CH2:30][C@H:29]([O:28][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNCCO
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Solvent: CI
Solvent: ClCCCl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N(CCO)CC(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
In the same manner as described in Example 2-(5), N-(2-hydroxyethyl)glycine t-butyl ester (0.25 g, 1.43 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (0.714 g, 1.57 mmol) in the presence of EDC-MeI (0.466 g, 1.57 mmol) to give 0.46 g (51%) of N-(2-hydroxyethyl)-N-[(R)-3-tetradecanoyloxytetradecanoyl]glycine t-butyl ester as an amorphous solid: 1H NMR (CDCl3) δ0.88 (t, 6 H, J=~6.5 Hz), 1.15-1.7 (m, 51 H), 2.26 (t, 2 H, J=7.5 Hz), 2.60 (dd, 1 H, J=6.5, 15 Hz), 2.86 (dd, 1 H, J=6.7, 15 Hz), 3.40-4.15 (m, 7 H), 5.25 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.Br[CH:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:33](=[O:34])[CH:32]([CH2:36][CH3:37])[C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(NCc1ccc(OC)cc1OC)C(=O)OCC
Reactant: CCC(Br)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)OCC)C(CC)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 6 h
Yield: 87 %

Procedure:
30 g (0.092 mole) of diethyl N-(2,4-dimethoxybenzyl)-amino-malonate prepared according to paragraph (b) of Example 1 are dissolved in a mixture of 90 ml of benzene and 15.6 ml (11.2 g, 0.111 mole) of triethyl amine and thereafter 20.5 g (0.111 mole) of 2-bromo butyric acid chloride are added dropwise under external ice-cooling. The reaction mixture is stirred under cooling for half an hour and thereafter at room temperature for half an hour. The precipitated crystalline substance is filtered off and washed twice with 20 ml of benzene. To the combined benzene mother liquor 31.2 g (22.4 g, 0.222 mole) of triethyl amine are added and the mixture is boiled for 6 hours. The precipitated crystalline substance is cooled and filtered. The mother liquor is extracted successively with 100 ml of water, twice with 100 ml of diluted hydrochloric acid each (a mixture of 90 ml of water and 10 ml of hydrochloric acid) and twice with 100 ml of water each. The organic layer is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. The residual oil is made crystalline by rubbing with petrolether. Thus 31.5 g of diethyl 1-(2,4-dimethoxy-benzyl)-3-ethyl-4-oxo-2,2-azetidinedicarboxylate are obtained. M.p.: 69° C. (from a mixture of benzene and petrolether).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[C:12]2=[O:26])[C:3]=1[CH:4]=[O:5].[CH3:27][N:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([CH:56]4[CH2:59][O:58][CH2:57]4)[CH2:52][CH2:51]3)=[CH:46][N:45]=2)[C:29]1=[O:60].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[C:12](=[O:26])[N:11]([C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:32]3[CH:31]=[C:30]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([N:50]5[CH2:55][CH2:54][N:53]([CH:56]6[CH2:57][O:58][CH2:59]6)[CH2:52][CH2:51]5)=[CH:46][N:45]=4)[C:29](=[O:60])[N:28]([CH3:27])[CH:33]=3)[C:3]=1[CH:4]=[O:5])[N:20]=[CH:19]2)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cc(F)cc(Br)c3C=O)ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(F)cc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 70 °C
Yield: 59.9 %

Procedure:
A round-bottomed flask was charged with 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 102b (100 mg, 0.24 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (131 mg, 0.28 mmol), PdCl2(dppf) (25 mg, 0.03 mmol), K3PO4.3H2O(149 mg, 0.56 mmol), THF (10 mL), and H2O (5 mL). After three cycles of vacuum/argon flash, the mixture was heated at 70° C. for 6 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 102c as a yellow solid (98 mg, 60%). LCMS: [M+H]+ 682
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[CH3:14][C:15]1[C:19]([C:20]2[CH:21]=[C:22]([CH:39]=[O:40])[C:23]3[N:27]=[C:26]([O:28][CH2:29][CH3:30])[N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]=3[CH:38]=2)=[C:18]([CH3:41])[O:17][N:16]=1>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:39]([C:22]1[C:23]2[N:27]=[C:26]([O:28][CH2:29][CH3:30])[N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C:24]=2[CH:38]=[C:20]([C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[CH3:41])[CH:21]=1)=[O:40]
Reactant: Fc1cccc(F)c1
Reactant: CCOc1nc2c(C=O)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1nc2c(C(=O)c3c(F)cccc3F)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi (0.58 mL, 0.93 mmol) was added dropwise to a solution of 1,3-difluorobenzene (0.102 mL, 0.1 mmol) in THF (5 mL) cooled to −78° C. and allowed to stir for 1 hour. tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate (200 mg, 0.52 mmol) in THF was added and the reaction was allowed to stir for 5 mins at −78° C., quenched with ammonium chloride, extracted with EtOAc and concentrated. The crude was then taken up in DCM (2 mL), Des-Martin periodinane (290 mg, 0.78 mmol) was added and the reaction was allowed to stir for 15 mins. The reaction was quenched with sat. Na2S2O3, extracted with EtOAc, concentrated and purified by silica gel chromatography to give tert-butyl 4-(2,6-difluorobenzoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15](F)[C:14]=1[CH:20]=O>CN1C(=O)CCC1>[I:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[N:10]([C:3]3[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=3[F:1])[N:11]=[CH:20][C:14]=12
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1ccc(F)c(F)c1F
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3c(I)ccnc32)c(F)c1F
Temperature: 185 °C
Yield: 19.6 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added (2,3,4-trifluorophenyl)hydrazine (359 mg, 2.212 mmol), 4-iodo-2-fluoro-3-formylpyridine (555.1 mg, 2.212 mmol), and anhydrous NMP (5 mL). The reaction mixture was flushed with argon, securely capped, and heated at 185° C. for 3 h. The reaction mixture was worked up according to the procedure described in Intermediate 69A. The product was purified by Biotage Silica gel chromatography using a 25 g Thompson Single Step™ silica cartridge with a linear gradient from 100% hexanes to 100% CH2Cl2 over 12 column volumes gave 162.9 mg (20.4%) of the title compound as a yellow solid. LC/MS (Condition B): ret. T=4.0 min, (M+H)+ 375.93.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:15])[C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].[C:16]([CH:19]=[C:20]=[O:21])(=[O:18])[CH3:17]>CCOC(C)=O>[F:15][C:7]1[CH:6]=[C:4]([NH:5][C:20](=[O:21])[CH2:19][C:16](=[O:18])[CH3:17])[CH:3]=[C:2]([F:1])[C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1cc(F)c(N2CCOCC2)c(F)c1
Reactant: CC(=O)C=C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 83 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 3,5-difluoro-4-morpholinoaniline (3.42 g, 16.0 mmol) and acetyl ketene (1.61 g, 19.2 mmol) in EtOAc (20 mL) was stirred at 83° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (3.10 g, 65%).
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[C:7]=1[CH3:32])=[O:5])C.[CH3:33][S:34]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35].C[Al](C)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][CH2:12][CH2:11][C:9]1[N:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[C:28]([F:29])([F:31])[F:30])[C:7]([CH3:32])=[C:6]([C:4]([NH:41][C:40]2[CH:39]=[CH:38][C:37]([S:34]([CH3:33])(=[O:36])=[O:35])=[CH:43][CH:42]=2)=[O:5])[CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(CCOCc2ccccc2)n(-c2ccc(F)cc2C(F)(F)F)c1C
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CCOCc2ccccc2)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a suspension of 5-[2-(benzyloxy)ethyl]-1-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (332 mg, 0.74 mmol) and 4-(methylsulfonyl)aniline (133 mg, 0.78 mmol) in toluene (3 mL), Me3Al (0.41 mL, 0.74 mmol, 1.8 M solution in toluene) was added under N2 atmosphere at room temperature and stirred at 110° C. for 30 min. After the completion of the reaction, it was quenched with 1N HCl, and extracted with AcOEt. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated, and the residue was purified over silica gel (AcOEt/n-hexane, 2:3 v/v) to give the atropisomeric mixture of the title compound (220 mg, 52%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].O.[Cl-].[Na+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: O=[N+]([O-])O
Reactant: CN1Cc2cccc(O)c2C1=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN1Cc2ccc([N+](=O)[O-])c(O)c2C1=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
2.49 g (91.5 mmol) of 7-hydroxy-2-methyl-2,3-dihydroisoindol-1-one were dissolved at 0° C. in 6 ml of concentrated sulfuric acid. The reaction medium was cooled to −20° C. and 1.8 ml of a 4/5 mixture of concentrated sulfuric acid/nitric acid at 70% were added. After 10 minutes, the reaction medium was hydrolyzed with water. Sodium chloride was added and the medium was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a C18 column twice (40 g prepacked column, water/acetonitrile gradient). 350 mg of product were obtained in the form of a yellow solid. Yield=11%.
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:11][NH:12][C:13]1[N:14]=[N:15][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:17]([CH3:19])[N:18]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OC(C)C)(C)C>[C:3]([NH:11][NH:12][C:13]1[NH:14][N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]([CH3:19])[N:18]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nc(NNC(=O)c2ccccc2)nnc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: CC1N=C(NNC(=O)c2ccccc2)NN=C1c1ccccc1
Yield: 50.7 %

Procedure:
Sodium borohydride (1.98 g) and 3-(2-benzoylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (3.45 g) was reacted in a similar manner to that of Example 2-(2). The reaction mixture was diluted with diisopropyl ether and the resultant precipitates were collected, washed successively with water, methanol and diisopropyl ether, and recrystallized from a mixture of ethanol, chloroform and water to give colorless crystals of 3-(2-benzoylhydrazino)-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (1.76 g), m.p. 217.5°-218° C. (decomp.).
Reaction SMILES: [FH:1].[CH3:2][C:3]1([CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH3:11])[CH2:5]1)N.N([O-])=O.[Na+]>CS(C)=O>[F:1][C:9]1[C:3]([CH3:2])=[CH:5][C:6]([CH3:11])=[C:7]([F:10])[CH:8]=1
Reactant: F
Reactant: CC1=C(F)C=CC(C)(N)C1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(F)cc1F
Temperature: 25 °C

Procedure:
1.8 l of anhydrous hydrogen fluoride are initially introduced into a stirred vessel made of stainless steel and 625 g of 1,3-dimethyl-4-fluoro-aniline (see Am. Soc. 54, 2981) are introduced, whilst cooling. Subsequently, a diazotisation reaction is carried out, at 0° C, by adding 374 g of sodium nitrite in portions. The mixture is then slowly heated to room temperature. Since the splitting of the diazonium fluoride proceeds only slowly at this temperature, the temperature is raised up to the reflux temperature for hydrogen fluoride. Towards the end of the reaction 800 ml of dimethylsulphoxide are added and the temperature is further raised to 80° C and this temperature is maintained for 30 minutes. Subsequently, the reaction mixture is poured onto ice and extracted with methylene chloride and the organic phase is separated off, dried over sodium sulphate and then distilled. 428 g of 1,3-difluoro-4,6-dimethylbenzene with a boiling point of 143° C and a melting point of 30° to 31° C are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>>[Br:11][C:4]1[C:5]([OH:10])=[C:6]([CH:9]=[C:2]([CH3:1])[CH:3]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: O=C1CCC(=O)N1Br
Product: Cc1cc(Br)c(O)c(C=O)c1
Yield: 76.1 %

Procedure:
Proceeding as in Reference 9, but substituting 5-methyl salicylaldehyde (3 g, 22 mmol) and N-bromosuccinimide (4.7 g, 26.4 mmol), gave 3-bromo-2-hydroxy-5-methylbenzaldehyde (3.6 g).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].N([O-])=[O:11].[Na+]>C(O)(=O)C.O>[O:11]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 50 g portion of ethyl acetoacetate in 60 ml of acetic acid was stirred at 0° C. to 10° C., as a solution of 30 g of sodium nitrite in 50 ml of water was added dropwise. When addition was complete, the mixture was stirred at 0° to 10° C. for 30 minutes and then diluted with 300 ml of ice water. The mixture was stirred for 2 hours and then extracted with 500 ml of dichloromethane. The dichloromethane layer was separated, washed with two 500 ml portions of ice water, dried, filtered and evaporated in vacuo. The residual oil was stirred vigorously with 200 ml of hexane and the resulting solid collected, washed with hexane and air dried, giving 31.4 g of 2,3-dioxobutyric acid, ethyl ester, (Z)-2-oxime.